ISSN 1866-8836
Клеточная терапия и трансплантация
Изменить отображение страницы на: только анонсы
array(11) { [0]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(3) "168" ["~IBLOCK_SECTION_ID"]=> string(3) "168" ["ID"]=> string(4) "1936" ["~ID"]=> string(4) "1936" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["~NAME"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "03.02.2021 13:45:03" ["~TIMESTAMP_X"]=> string(19) "03.02.2021 13:45:03" ["DETAIL_PAGE_URL"]=> string(21) "/ru/archive/-9-4/-/-/" ["~DETAIL_PAGE_URL"]=> string(21) "/ru/archive/-9-4/-/-/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(10791) "

This paper is based on the lecture held at the R. Gorbacheva Memorial Meeting in Hematopoietic Stem Cell Transplantation and Gene Therapy (Sept 19, 2020, St. Petersburg, Russia)

Background

Table 1. Indications for haematopoietic cell transplants in the US 2018 (https://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/pages/index.aspx)

Gale-tab01.jpg

Table 2. Some new drugs for blood and bone marrow cancers

Gale-tab02.jpg

Gale-fig01.jpg

Figure 1. Results of a randomized trial of azacitidine with or without venetoclax in persons with newly diagnosed AML judged inappropriate to receive intensive chemotherapy [1]

Haematopoietic cell transplants are increasingly done to treat blood and bone marrow cancers, bone marrow failure and genetic disorders. In the US there were about 14,000 autotransplants and 9,000 allotransplants in 2018. Global autotransplants in 2019 were about 28,000 and allotransplants, about 17,000 with a total of about 45,000. These rates are expected to increase. In the US most autotransplants are for plasma cell myeloma (PCM) and non-Hodgkin lymphoma (NHL) whereas most allotransplants are for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Relatively few allotransplants were done for acute lymphoblastic leukaemia (ALL) or myelo-proliferative neoplasms (MPNs; Table 1). This distribution is important as most immune therapies are for cancers not currently treated with haematopoietic cell transplants as I discuss below.

Discussion

Recent interventions which might compete with haematopoietic cell transplants include new anti-cancer chemotherapy and targeted and immune therapies. Several new drugs used to treat blood and bone marrow cancers are listed in Table 2.

Although progress in developing new drugs is encouraging the magnitude of benefit with several of these drugs is modest. An example of the impact of azacitidine and venetoclax in newly diagnosed persons with AML judged inappropriate to receive intensive chemotherapy is shown in Figure 1. Although adding venetoclax to azacitidine significantly improved survival, 65% of subjects died by 2.5 years.

Table 3 shows the 5-year survivals of persons with AML and PCM treated in 1999-2003, and treated 2010-2016. These data indicate only a modest improvement with about 70 percent of persons with AML and 45 percent of those with PCM dying before 5 years.

Examples of targeted therapies for myeloid cancers, especially AML are shown in Table 4 along with the target gene.

An example of the impact of targeted FLT3 mutation therapy in AML is shown in Fig. 2 [2]. Although adding midostaurin to cytarabine and daunorubicin improves survival, 55 percent of subjects died by 5 years and many survivors also received an allotransplant in 1st remission. These data indicate a modest impact of targeted therapy in AML.

Fig. 3 displays the estimated impact of targeted therapies on survival of persons with acute myeloblastic leukemia (AML) [3]. It seems only about 10 percent of people will benefit.

Galefig-02-03-tab03-04.jpg

Table 5. Some examples of immune therapies in blood and bone marrow cancers

Gale-tab05.jpg


Immune therapy is another new therapy of blood and bone marrow cancers. Some examples are displayed in Table 5.

However, these therapies are effective only in B-cell cancers and are lineage- but not cancer-specific (Fig. 4). Other than gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody, there is no proved safe and effective therapy of myeloid cancers.

CAR-T-cells are an important advance in therapy of lymphoid cancers with high response rates. However, often responses are not sustained unless a subsequent allogeneic haematopoietic cell transplant is done. An example of event-free survival (EFS) in children and young adults with advanced ALL is shown in Figure 5 with a failure rate of 40 percent at 1.5 years in complete responders [4].

Gale-fig04-05.jpg

Similarly, there are high rates of therapy-failure after successful CAR-T-cell therapy of diffuse large B-cell (DLBCL; Figure 6), follicular (FL) and marginal zone lymphomas (MZL; Fig. 7). [5] (https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.8008).

Gale-fig06-07.jpg

The argument CAR-T-cell therapy serves predominately as a bridge to an allotransplant is unconvincing as there are no strong data survival of persons with ALL transplanted in 2nd remission are better than those transplanted in relapse when all subjects are accounted for. Consequently, the best approach to someone responding to CAR-T-cell therapy is controversial. It may be reasonable to consider an allotransplant in persons with ALL and in those with MZL after responding to CAR-T-cell therapy, but wait for therapy failure in those with DLBCL and FL (Fig. 8).

It is also important to recall much of the efficacy of allotransplants results from an allogeneic anti-cancer effect so far difficult to distinguish from graft-versus-host disease (GvHD) [6]. These data are displayed in Fig. 9. For example, whether there is a specific anti-leukaemia effect is controversial, as reviewed in [7].

Some data suggest the potential use of donor-derived CAR-T-cells in persons relapsing after an allotransplant for B-cell cancers [8].

Gale-fig08-09.jpg

Conclusion

Advances in treating ALL, AML, lymphomas and PCM are important and exciting but the magnitude of benefit is modest and few people are cured. Many persons with immune therapy successes go on to receive an allotransplant. Most cancers where immune therapy is effective are B-cell cancers whereas most allotransplants are done for myeloid cancers. Moreover, these immune therapies are lineage-, not cancer-specific and lack the allogeneic anti-cancer effect associated with allotransplants. In young persons with PCM, autotransplants are better than new drugs in randomized clinical trials. CAR-T-cell therapy of B-cell cancers is effective but mostly not a cure. Donor CAR-T-cells are a promising in persons relapsing after an allogeneic haematopoietic cell transplant. Transplants will remain an important therapy in the immediate future. Put in terms of food, although there is nouvelle cuisine Boef Stroganoff remains a classic and my 1st dinner choice at Chekhov restaurant in Petersburg.

Acknowledgement

Supported by the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. Prof. Elena Parovichnikova and Drs. Kristina Zakurdaeva and Saida Kadyrova provided expert advice on Boef Stroganoff and Dr. Ivan Moiseev and the late Prof. Boris Afanasyev introduced me to Chekhov restaurant. My preference is for Boef Stroganoff with kasha. Bon Appetit.

Conflict of interest

RPG is a consultant to BeiGene Ltd., Fusion Pharma LLC, LaJolla NanoMedical Inc., Mingsight Parmaceuticals Inc. and CStone Pharmaceuticals; advisor to Antegene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd.

References

  1. DiNarco CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383:617-629.
  2. Stone RM, Mandrekar SJ, Sanford BL, Lauman K, Geyer S, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with FLT3 mutation. N Engl J Med. 2017;377:454-464.
  3. Prasad V, Gale RP. Precision medicine in acute myeloid leukemia: Hope, hype or both? Leuk Res. 2016;48:73-77.
  4. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. N Enl J Med. 2018;378:439-448.
  5. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol 2019; 20: 31-42.
  6. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555-562.
  7. Gale RP, Fuchs EJ. Is there really a specific graft-versus-leukaemia effect? Bone Marrow Transplant. 2016;51:1413-1415.

  8. Zhang C, Wang XQ, Zhang RL, Liu F, Wang Y, Yan ZL, et al. Donor-derived CD19 CAR-T-cell therapy of relapse of CD 19-positive B-ALL posttransplant. Leukemia.2020; In Press.


" ["~DETAIL_TEXT"]=> string(10791) "

This paper is based on the lecture held at the R. Gorbacheva Memorial Meeting in Hematopoietic Stem Cell Transplantation and Gene Therapy (Sept 19, 2020, St. Petersburg, Russia)

Background

Table 1. Indications for haematopoietic cell transplants in the US 2018 (https://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/pages/index.aspx)

Gale-tab01.jpg

Table 2. Some new drugs for blood and bone marrow cancers

Gale-tab02.jpg

Gale-fig01.jpg

Figure 1. Results of a randomized trial of azacitidine with or without venetoclax in persons with newly diagnosed AML judged inappropriate to receive intensive chemotherapy [1]

Haematopoietic cell transplants are increasingly done to treat blood and bone marrow cancers, bone marrow failure and genetic disorders. In the US there were about 14,000 autotransplants and 9,000 allotransplants in 2018. Global autotransplants in 2019 were about 28,000 and allotransplants, about 17,000 with a total of about 45,000. These rates are expected to increase. In the US most autotransplants are for plasma cell myeloma (PCM) and non-Hodgkin lymphoma (NHL) whereas most allotransplants are for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Relatively few allotransplants were done for acute lymphoblastic leukaemia (ALL) or myelo-proliferative neoplasms (MPNs; Table 1). This distribution is important as most immune therapies are for cancers not currently treated with haematopoietic cell transplants as I discuss below.

Discussion

Recent interventions which might compete with haematopoietic cell transplants include new anti-cancer chemotherapy and targeted and immune therapies. Several new drugs used to treat blood and bone marrow cancers are listed in Table 2.

Although progress in developing new drugs is encouraging the magnitude of benefit with several of these drugs is modest. An example of the impact of azacitidine and venetoclax in newly diagnosed persons with AML judged inappropriate to receive intensive chemotherapy is shown in Figure 1. Although adding venetoclax to azacitidine significantly improved survival, 65% of subjects died by 2.5 years.

Table 3 shows the 5-year survivals of persons with AML and PCM treated in 1999-2003, and treated 2010-2016. These data indicate only a modest improvement with about 70 percent of persons with AML and 45 percent of those with PCM dying before 5 years.

Examples of targeted therapies for myeloid cancers, especially AML are shown in Table 4 along with the target gene.

An example of the impact of targeted FLT3 mutation therapy in AML is shown in Fig. 2 [2]. Although adding midostaurin to cytarabine and daunorubicin improves survival, 55 percent of subjects died by 5 years and many survivors also received an allotransplant in 1st remission. These data indicate a modest impact of targeted therapy in AML.

Fig. 3 displays the estimated impact of targeted therapies on survival of persons with acute myeloblastic leukemia (AML) [3]. It seems only about 10 percent of people will benefit.

Galefig-02-03-tab03-04.jpg

Table 5. Some examples of immune therapies in blood and bone marrow cancers

Gale-tab05.jpg


Immune therapy is another new therapy of blood and bone marrow cancers. Some examples are displayed in Table 5.

However, these therapies are effective only in B-cell cancers and are lineage- but not cancer-specific (Fig. 4). Other than gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody, there is no proved safe and effective therapy of myeloid cancers.

CAR-T-cells are an important advance in therapy of lymphoid cancers with high response rates. However, often responses are not sustained unless a subsequent allogeneic haematopoietic cell transplant is done. An example of event-free survival (EFS) in children and young adults with advanced ALL is shown in Figure 5 with a failure rate of 40 percent at 1.5 years in complete responders [4].

Gale-fig04-05.jpg

Similarly, there are high rates of therapy-failure after successful CAR-T-cell therapy of diffuse large B-cell (DLBCL; Figure 6), follicular (FL) and marginal zone lymphomas (MZL; Fig. 7). [5] (https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.8008).

Gale-fig06-07.jpg

The argument CAR-T-cell therapy serves predominately as a bridge to an allotransplant is unconvincing as there are no strong data survival of persons with ALL transplanted in 2nd remission are better than those transplanted in relapse when all subjects are accounted for. Consequently, the best approach to someone responding to CAR-T-cell therapy is controversial. It may be reasonable to consider an allotransplant in persons with ALL and in those with MZL after responding to CAR-T-cell therapy, but wait for therapy failure in those with DLBCL and FL (Fig. 8).

It is also important to recall much of the efficacy of allotransplants results from an allogeneic anti-cancer effect so far difficult to distinguish from graft-versus-host disease (GvHD) [6]. These data are displayed in Fig. 9. For example, whether there is a specific anti-leukaemia effect is controversial, as reviewed in [7].

Some data suggest the potential use of donor-derived CAR-T-cells in persons relapsing after an allotransplant for B-cell cancers [8].

Gale-fig08-09.jpg

Conclusion

Advances in treating ALL, AML, lymphomas and PCM are important and exciting but the magnitude of benefit is modest and few people are cured. Many persons with immune therapy successes go on to receive an allotransplant. Most cancers where immune therapy is effective are B-cell cancers whereas most allotransplants are done for myeloid cancers. Moreover, these immune therapies are lineage-, not cancer-specific and lack the allogeneic anti-cancer effect associated with allotransplants. In young persons with PCM, autotransplants are better than new drugs in randomized clinical trials. CAR-T-cell therapy of B-cell cancers is effective but mostly not a cure. Donor CAR-T-cells are a promising in persons relapsing after an allogeneic haematopoietic cell transplant. Transplants will remain an important therapy in the immediate future. Put in terms of food, although there is nouvelle cuisine Boef Stroganoff remains a classic and my 1st dinner choice at Chekhov restaurant in Petersburg.

Acknowledgement

Supported by the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme. Prof. Elena Parovichnikova and Drs. Kristina Zakurdaeva and Saida Kadyrova provided expert advice on Boef Stroganoff and Dr. Ivan Moiseev and the late Prof. Boris Afanasyev introduced me to Chekhov restaurant. My preference is for Boef Stroganoff with kasha. Bon Appetit.

Conflict of interest

RPG is a consultant to BeiGene Ltd., Fusion Pharma LLC, LaJolla NanoMedical Inc., Mingsight Parmaceuticals Inc. and CStone Pharmaceuticals; advisor to Antegene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd.

References

  1. DiNarco CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383:617-629.
  2. Stone RM, Mandrekar SJ, Sanford BL, Lauman K, Geyer S, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with FLT3 mutation. N Engl J Med. 2017;377:454-464.
  3. Prasad V, Gale RP. Precision medicine in acute myeloid leukemia: Hope, hype or both? Leuk Res. 2016;48:73-77.
  4. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-Cell lymphoblastic leukemia. N Enl J Med. 2018;378:439-448.
  5. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol 2019; 20: 31-42.
  6. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555-562.
  7. Gale RP, Fuchs EJ. Is there really a specific graft-versus-leukaemia effect? Bone Marrow Transplant. 2016;51:1413-1415.

  8. Zhang C, Wang XQ, Zhang RL, Liu F, Wang Y, Yan ZL, et al. Donor-derived CD19 CAR-T-cell therapy of relapse of CD 19-positive B-ALL posttransplant. Leukemia.2020; In Press.


" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(2) "10" ["~SORT"]=> string(2) "10" ["CODE"]=> string(1) "-" ["~CODE"]=> string(1) "-" ["EXTERNAL_ID"]=> string(4) "1936" ["~EXTERNAL_ID"]=> string(4) "1936" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(159) "Есть ли будущее у трансплантации гемопоэтических клеток?Is there a Future for Haematopoietic Cell Transplants?" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(3055) "<p style="text-align: justify;">Нынешние успехи противоопухолевой терапии, таргетной и иммунотерапии поднимают вопрос о том, есть ли будущее у трансплантации гемопоэтических клеток (ТГСК). Я обсуждаю важность этого, но, в итоге, масштаб этих усовершенствований пока скромен</p> <p style="text-align: justify;">Я подчеркиваю, что эффективность иммунной терапии ограничена, преимущественно, В-клеточными опухолями, и что у многих, если не большинства больных, успешно леченных посредством иммунотерапии, может выполняться аллогенная ТГСК, особенно при остром лимфобластном лейкозе (ОЛЛ). </p> <p style="text-align: justify;">Я также обсуждаю то, что большинство аллотрансплантаций проводятся по поводу злокачественных заболеваний, которые не лечатся существующей иммунотерапией.</p> <p style="text-align: justify;">Рандомизированные испытания показывают, что аутотрансплантация – лучше, чем новые препараты при лечении молодых пациентов с плазмаклеточной миеломой. Значительное число данных указывает на то, что эффективность аллотрансплантации обусловлена не опухольспецифическими аллогенными эффектами, которые, очевидно, не связаны с существующей иммунотерапией.</p> <p style="text-align: justify;">Наконец, я обсуждаю роль применения Т-клеток с донорским химерным антигенным рецептором (CAR-T) у лиц, рецидивирующих после алло-ТГСК при В-клеточных опухолях. В итоге можно предполагать и в последующем значительную роль трансплантации гемопоэтических клеток в различных клинических ситуациях. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Трансплантация гемопоэтических стволовых клеток, таргетные препараты, иммунная терапия, CAR-T клетки, эффективность.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["SECTION_META_TITLE"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["SECTION_META_KEYWORDS"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["SECTION_META_DESCRIPTION"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["SECTION_PICTURE_FILE_ALT"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["SECTION_PICTURE_FILE_TITLE"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["SECTION_PICTURE_FILE_NAME"]=> string(64) "est-li-budushchee-u-transplantatsii-gemopoeticheskikh-kletok-img" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(105) "Есть ли будущее у трансплантации гемопоэтических клеток?" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(64) "est-li-budushchee-u-transplantatsii-gemopoeticheskikh-kletok-img" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(64) "est-li-budushchee-u-transplantatsii-gemopoeticheskikh-kletok-img" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(64) "est-li-budushchee-u-transplantatsii-gemopoeticheskikh-kletok-img" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "168" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27299" ["VALUE"]=> string(10) "02.10.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "02.10.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27300" ["VALUE"]=> string(10) "23.10.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "23.10.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27301" ["VALUE"]=> array(2) { ["TEXT"]=> string(188) "<p>Роберт П. Гэйл                        </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(176) "

Роберт П. Гэйл                        

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27302" ["VALUE"]=> array(2) { ["TEXT"]=> string(199) "<p>Центр гематологии, Департамент иммунологии и воспаления, Имперский коледж Лондон, Великобритания</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(187) "

Центр гематологии, Департамент иммунологии и воспаления, Имперский коледж Лондон, Великобритания

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27303" ["VALUE"]=> array(2) { ["TEXT"]=> string(3055) "<p style="text-align: justify;">Нынешние успехи противоопухолевой терапии, таргетной и иммунотерапии поднимают вопрос о том, есть ли будущее у трансплантации гемопоэтических клеток (ТГСК). Я обсуждаю важность этого, но, в итоге, масштаб этих усовершенствований пока скромен</p> <p style="text-align: justify;">Я подчеркиваю, что эффективность иммунной терапии ограничена, преимущественно, В-клеточными опухолями, и что у многих, если не большинства больных, успешно леченных посредством иммунотерапии, может выполняться аллогенная ТГСК, особенно при остром лимфобластном лейкозе (ОЛЛ). </p> <p style="text-align: justify;">Я также обсуждаю то, что большинство аллотрансплантаций проводятся по поводу злокачественных заболеваний, которые не лечатся существующей иммунотерапией.</p> <p style="text-align: justify;">Рандомизированные испытания показывают, что аутотрансплантация – лучше, чем новые препараты при лечении молодых пациентов с плазмаклеточной миеломой. Значительное число данных указывает на то, что эффективность аллотрансплантации обусловлена не опухольспецифическими аллогенными эффектами, которые, очевидно, не связаны с существующей иммунотерапией.</p> <p style="text-align: justify;">Наконец, я обсуждаю роль применения Т-клеток с донорским химерным антигенным рецептором (CAR-T) у лиц, рецидивирующих после алло-ТГСК при В-клеточных опухолях. В итоге можно предполагать и в последующем значительную роль трансплантации гемопоэтических клеток в различных клинических ситуациях. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Трансплантация гемопоэтических стволовых клеток, таргетные препараты, иммунная терапия, CAR-T клетки, эффективность.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2911) "

Нынешние успехи противоопухолевой терапии, таргетной и иммунотерапии поднимают вопрос о том, есть ли будущее у трансплантации гемопоэтических клеток (ТГСК). Я обсуждаю важность этого, но, в итоге, масштаб этих усовершенствований пока скромен

Я подчеркиваю, что эффективность иммунной терапии ограничена, преимущественно, В-клеточными опухолями, и что у многих, если не большинства больных, успешно леченных посредством иммунотерапии, может выполняться аллогенная ТГСК, особенно при остром лимфобластном лейкозе (ОЛЛ).

Я также обсуждаю то, что большинство аллотрансплантаций проводятся по поводу злокачественных заболеваний, которые не лечатся существующей иммунотерапией.

Рандомизированные испытания показывают, что аутотрансплантация – лучше, чем новые препараты при лечении молодых пациентов с плазмаклеточной миеломой. Значительное число данных указывает на то, что эффективность аллотрансплантации обусловлена не опухольспецифическими аллогенными эффектами, которые, очевидно, не связаны с существующей иммунотерапией.

Наконец, я обсуждаю роль применения Т-клеток с донорским химерным антигенным рецептором (CAR-T) у лиц, рецидивирующих после алло-ТГСК при В-клеточных опухолях. В итоге можно предполагать и в последующем значительную роль трансплантации гемопоэтических клеток в различных клинических ситуациях.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, таргетные препараты, иммунная терапия, CAR-T клетки, эффективность.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27304" ["VALUE"]=> string(36) "10.18620/ctt-1866-8836-2020-9-4-6-10" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(36) "10.18620/ctt-1866-8836-2020-9-4-6-10" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27307" ["VALUE"]=> array(2) { ["TEXT"]=> string(105) "<p>Robert P. Gale            </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(93) "

Robert P. Gale            

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27308" ["VALUE"]=> array(2) { ["TEXT"]=> string(564) "<p style="text-align: justify;">Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK</p><br> <p><b>Correspondence</b><br> <p style="text-align: justify;"> Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM, Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK<br> Phone: +1-908-656-0484<br> Fax: +1-310-388-1320<br> E-mail: robertpetergale@alumni.ucla.edu</p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(472) "

Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK


Correspondence

Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM, Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK
Phone: +1-908-656-0484
Fax: +1-310-388-1320
E-mail: robertpetergale@alumni.ucla.edu

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27309" ["VALUE"]=> array(2) { ["TEXT"]=> string(1477) "<p style="text-align: justify;">Recent advances in anti-cancer chemotherapy and in targeted and immune therapies raise the question whether there is a future for haematopoietic cell transplants. I discuss their importance but in the end the magnitude of these improvements is modest. I point out the efficacy of immune therapy is predominately restricted to B-cell cancers and that many if not most successful immune therapy recipients eventually receive an allogeneic haematopoietic cell transplant, especially those with acute lymphoblastic leukaemia (ALL).</p> <p style="text-align: justify;">I also discuss most allotransplants are done for cancers not treated with current immune therapy. Randomized trials show an autotransplant is better than new drugs in young persons with plasma cell myeloma. Considerable data indicate much of the efficacy of allotransplants results from a non-cancer-specific allogeneic effect not expected to operate with current immune therapies. Lastly, I discuss a role for donor-derived chimeric antigen receptor (CAR)-T-cells in persons relapsing after an allotransplant for B-cell cancers. The sum of these considerations suggest an ongoing role for haematopoietic cell transplants in diverse settings.</p> <h2>Keywords</h2> <p style="text-align: justify;">Hematopoietic stem cell transplantation, targeted drugs, immune therapy, (CAR)-T cells, efficiency.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1399) "

Recent advances in anti-cancer chemotherapy and in targeted and immune therapies raise the question whether there is a future for haematopoietic cell transplants. I discuss their importance but in the end the magnitude of these improvements is modest. I point out the efficacy of immune therapy is predominately restricted to B-cell cancers and that many if not most successful immune therapy recipients eventually receive an allogeneic haematopoietic cell transplant, especially those with acute lymphoblastic leukaemia (ALL).

I also discuss most allotransplants are done for cancers not treated with current immune therapy. Randomized trials show an autotransplant is better than new drugs in young persons with plasma cell myeloma. Considerable data indicate much of the efficacy of allotransplants results from a non-cancer-specific allogeneic effect not expected to operate with current immune therapies. Lastly, I discuss a role for donor-derived chimeric antigen receptor (CAR)-T-cells in persons relapsing after an allotransplant for B-cell cancers. The sum of these considerations suggest an ongoing role for haematopoietic cell transplants in diverse settings.

Keywords

Hematopoietic stem cell transplantation, targeted drugs, immune therapy, (CAR)-T cells, efficiency.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27305" ["VALUE"]=> string(54) "Is there a Future for Haematopoietic Cell Transplants?" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(54) "Is there a Future for Haematopoietic Cell Transplants?" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["PDF_RU"]=> array(36) { ["ID"]=> string(2) "43" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF RUS" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_RU" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "43" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27306" ["VALUE"]=> string(4) "2285" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2285" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF RUS" ["~DEFAULT_VALUE"]=> string(0) "" } ["PDF_EN"]=> array(36) { ["ID"]=> string(2) "44" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF ENG" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "44" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27310" ["VALUE"]=> string(4) "2286" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2286" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF ENG" ["~DEFAULT_VALUE"]=> string(0) "" } ["NAME_LONG"]=> array(36) { ["ID"]=> string(2) "45" ["TIMESTAMP_X"]=> string(19) "2023-04-13 00:55:00" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(72) "Название (для очень длинных заголовков)" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "NAME_LONG" ["DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "45" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27307" ["VALUE"]=> array(2) { ["TEXT"]=> string(105) "<p>Robert P. Gale            </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(93) "

Robert P. Gale            

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(93) "

Robert P. Gale            

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27309" ["VALUE"]=> array(2) { ["TEXT"]=> string(1477) "<p style="text-align: justify;">Recent advances in anti-cancer chemotherapy and in targeted and immune therapies raise the question whether there is a future for haematopoietic cell transplants. I discuss their importance but in the end the magnitude of these improvements is modest. I point out the efficacy of immune therapy is predominately restricted to B-cell cancers and that many if not most successful immune therapy recipients eventually receive an allogeneic haematopoietic cell transplant, especially those with acute lymphoblastic leukaemia (ALL).</p> <p style="text-align: justify;">I also discuss most allotransplants are done for cancers not treated with current immune therapy. Randomized trials show an autotransplant is better than new drugs in young persons with plasma cell myeloma. Considerable data indicate much of the efficacy of allotransplants results from a non-cancer-specific allogeneic effect not expected to operate with current immune therapies. Lastly, I discuss a role for donor-derived chimeric antigen receptor (CAR)-T-cells in persons relapsing after an allotransplant for B-cell cancers. The sum of these considerations suggest an ongoing role for haematopoietic cell transplants in diverse settings.</p> <h2>Keywords</h2> <p style="text-align: justify;">Hematopoietic stem cell transplantation, targeted drugs, immune therapy, (CAR)-T cells, efficiency.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1399) "

Recent advances in anti-cancer chemotherapy and in targeted and immune therapies raise the question whether there is a future for haematopoietic cell transplants. I discuss their importance but in the end the magnitude of these improvements is modest. I point out the efficacy of immune therapy is predominately restricted to B-cell cancers and that many if not most successful immune therapy recipients eventually receive an allogeneic haematopoietic cell transplant, especially those with acute lymphoblastic leukaemia (ALL).

I also discuss most allotransplants are done for cancers not treated with current immune therapy. Randomized trials show an autotransplant is better than new drugs in young persons with plasma cell myeloma. Considerable data indicate much of the efficacy of allotransplants results from a non-cancer-specific allogeneic effect not expected to operate with current immune therapies. Lastly, I discuss a role for donor-derived chimeric antigen receptor (CAR)-T-cells in persons relapsing after an allotransplant for B-cell cancers. The sum of these considerations suggest an ongoing role for haematopoietic cell transplants in diverse settings.

Keywords

Hematopoietic stem cell transplantation, targeted drugs, immune therapy, (CAR)-T cells, efficiency.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1399) "

Recent advances in anti-cancer chemotherapy and in targeted and immune therapies raise the question whether there is a future for haematopoietic cell transplants. I discuss their importance but in the end the magnitude of these improvements is modest. I point out the efficacy of immune therapy is predominately restricted to B-cell cancers and that many if not most successful immune therapy recipients eventually receive an allogeneic haematopoietic cell transplant, especially those with acute lymphoblastic leukaemia (ALL).

I also discuss most allotransplants are done for cancers not treated with current immune therapy. Randomized trials show an autotransplant is better than new drugs in young persons with plasma cell myeloma. Considerable data indicate much of the efficacy of allotransplants results from a non-cancer-specific allogeneic effect not expected to operate with current immune therapies. Lastly, I discuss a role for donor-derived chimeric antigen receptor (CAR)-T-cells in persons relapsing after an allotransplant for B-cell cancers. The sum of these considerations suggest an ongoing role for haematopoietic cell transplants in diverse settings.

Keywords

Hematopoietic stem cell transplantation, targeted drugs, immune therapy, (CAR)-T cells, efficiency.

" } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27304" ["VALUE"]=> string(36) "10.18620/ctt-1866-8836-2020-9-4-6-10" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(36) "10.18620/ctt-1866-8836-2020-9-4-6-10" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(36) "10.18620/ctt-1866-8836-2020-9-4-6-10" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27305" ["VALUE"]=> string(54) "Is there a Future for Haematopoietic Cell Transplants?" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(54) "Is there a Future for Haematopoietic Cell Transplants?" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(54) "Is there a Future for Haematopoietic Cell Transplants?" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27308" ["VALUE"]=> array(2) { ["TEXT"]=> string(564) "<p style="text-align: justify;">Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK</p><br> <p><b>Correspondence</b><br> <p style="text-align: justify;"> Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM, Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK<br> Phone: +1-908-656-0484<br> Fax: +1-310-388-1320<br> E-mail: robertpetergale@alumni.ucla.edu</p> " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(472) "

Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK


Correspondence

Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM, Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK
Phone: +1-908-656-0484
Fax: +1-310-388-1320
E-mail: robertpetergale@alumni.ucla.edu

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(472) "

Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK


Correspondence

Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM, Haematology Research Centre, Department of Immunology and Inflammation Imperial College, London, UK
Phone: +1-908-656-0484
Fax: +1-310-388-1320
E-mail: robertpetergale@alumni.ucla.edu

" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27301" ["VALUE"]=> array(2) { ["TEXT"]=> string(188) "<p>Роберт П. Гэйл                        </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(176) "

Роберт П. Гэйл                        

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(176) "

Роберт П. Гэйл                        

" } ["SUBMITTED"]=> array(37) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27299" ["VALUE"]=> string(10) "02.10.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "02.10.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "02.10.2020" } ["ACCEPTED"]=> array(37) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27300" ["VALUE"]=> string(10) "23.10.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "23.10.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "23.10.2020" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27303" ["VALUE"]=> array(2) { ["TEXT"]=> string(3055) "<p style="text-align: justify;">Нынешние успехи противоопухолевой терапии, таргетной и иммунотерапии поднимают вопрос о том, есть ли будущее у трансплантации гемопоэтических клеток (ТГСК). Я обсуждаю важность этого, но, в итоге, масштаб этих усовершенствований пока скромен</p> <p style="text-align: justify;">Я подчеркиваю, что эффективность иммунной терапии ограничена, преимущественно, В-клеточными опухолями, и что у многих, если не большинства больных, успешно леченных посредством иммунотерапии, может выполняться аллогенная ТГСК, особенно при остром лимфобластном лейкозе (ОЛЛ). </p> <p style="text-align: justify;">Я также обсуждаю то, что большинство аллотрансплантаций проводятся по поводу злокачественных заболеваний, которые не лечатся существующей иммунотерапией.</p> <p style="text-align: justify;">Рандомизированные испытания показывают, что аутотрансплантация – лучше, чем новые препараты при лечении молодых пациентов с плазмаклеточной миеломой. Значительное число данных указывает на то, что эффективность аллотрансплантации обусловлена не опухольспецифическими аллогенными эффектами, которые, очевидно, не связаны с существующей иммунотерапией.</p> <p style="text-align: justify;">Наконец, я обсуждаю роль применения Т-клеток с донорским химерным антигенным рецептором (CAR-T) у лиц, рецидивирующих после алло-ТГСК при В-клеточных опухолях. В итоге можно предполагать и в последующем значительную роль трансплантации гемопоэтических клеток в различных клинических ситуациях. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Трансплантация гемопоэтических стволовых клеток, таргетные препараты, иммунная терапия, CAR-T клетки, эффективность.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2911) "

Нынешние успехи противоопухолевой терапии, таргетной и иммунотерапии поднимают вопрос о том, есть ли будущее у трансплантации гемопоэтических клеток (ТГСК). Я обсуждаю важность этого, но, в итоге, масштаб этих усовершенствований пока скромен

Я подчеркиваю, что эффективность иммунной терапии ограничена, преимущественно, В-клеточными опухолями, и что у многих, если не большинства больных, успешно леченных посредством иммунотерапии, может выполняться аллогенная ТГСК, особенно при остром лимфобластном лейкозе (ОЛЛ).

Я также обсуждаю то, что большинство аллотрансплантаций проводятся по поводу злокачественных заболеваний, которые не лечатся существующей иммунотерапией.

Рандомизированные испытания показывают, что аутотрансплантация – лучше, чем новые препараты при лечении молодых пациентов с плазмаклеточной миеломой. Значительное число данных указывает на то, что эффективность аллотрансплантации обусловлена не опухольспецифическими аллогенными эффектами, которые, очевидно, не связаны с существующей иммунотерапией.

Наконец, я обсуждаю роль применения Т-клеток с донорским химерным антигенным рецептором (CAR-T) у лиц, рецидивирующих после алло-ТГСК при В-клеточных опухолях. В итоге можно предполагать и в последующем значительную роль трансплантации гемопоэтических клеток в различных клинических ситуациях.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, таргетные препараты, иммунная терапия, CAR-T клетки, эффективность.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2911) "

Нынешние успехи противоопухолевой терапии, таргетной и иммунотерапии поднимают вопрос о том, есть ли будущее у трансплантации гемопоэтических клеток (ТГСК). Я обсуждаю важность этого, но, в итоге, масштаб этих усовершенствований пока скромен

Я подчеркиваю, что эффективность иммунной терапии ограничена, преимущественно, В-клеточными опухолями, и что у многих, если не большинства больных, успешно леченных посредством иммунотерапии, может выполняться аллогенная ТГСК, особенно при остром лимфобластном лейкозе (ОЛЛ).

Я также обсуждаю то, что большинство аллотрансплантаций проводятся по поводу злокачественных заболеваний, которые не лечатся существующей иммунотерапией.

Рандомизированные испытания показывают, что аутотрансплантация – лучше, чем новые препараты при лечении молодых пациентов с плазмаклеточной миеломой. Значительное число данных указывает на то, что эффективность аллотрансплантации обусловлена не опухольспецифическими аллогенными эффектами, которые, очевидно, не связаны с существующей иммунотерапией.

Наконец, я обсуждаю роль применения Т-клеток с донорским химерным антигенным рецептором (CAR-T) у лиц, рецидивирующих после алло-ТГСК при В-клеточных опухолях. В итоге можно предполагать и в последующем значительную роль трансплантации гемопоэтических клеток в различных клинических ситуациях.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, таргетные препараты, иммунная терапия, CAR-T клетки, эффективность.

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27302" ["VALUE"]=> array(2) { ["TEXT"]=> string(199) "<p>Центр гематологии, Департамент иммунологии и воспаления, Имперский коледж Лондон, Великобритания</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(187) "

Центр гематологии, Департамент иммунологии и воспаления, Имперский коледж Лондон, Великобритания

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(187) "

Центр гематологии, Департамент иммунологии и воспаления, Имперский коледж Лондон, Великобритания

" } } } [1]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(3) "169" ["~IBLOCK_SECTION_ID"]=> string(3) "169" ["ID"]=> string(4) "1937" ["~ID"]=> string(4) "1937" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["~NAME"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "03.02.2021 16:48:07" ["~TIMESTAMP_X"]=> string(19) "03.02.2021 16:48:07" ["DETAIL_PAGE_URL"]=> string(25) "/ru/archive/-9-4/-/-eln-/" ["~DETAIL_PAGE_URL"]=> string(25) "/ru/archive/-9-4/-/-eln-/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(29015) "

Introduction

Since the first attempts at treating CML with arsenic in 1865, treatment has been mostly palliative. Some modest prolongation of survival was reported with hydroxyurea and interferon alpha, for review see Hehlmann (2020) [1]. The only curative approach was allogeneic transplantation which, however, was available only to those few patients who had a donor and could tolerate the procedure. The advent of tyrosine kinase inhibitors has profoundly changed CML management as normal survival has been achieved for most patients as seen from Table 1 [2-11]. The new goal for treating CML is now survival at good quality of life without life-long treatment: treatment discontinuation in sustained deep molecular remission (DMR) and treatment-free remission (TFR). The European LeukemiaNet (ELN) has accounted for this development with an update of its recommendations [12]. This review summarizes the most important new developments and recommendations for treating CML including early transplantation of patients with high-risk additional chromosomal abnormalities (ACA) in early CML end-phase [13].

Table 1. Survival of CML patients in clinical trials: update 2020

Hehlmann-tab01.jpg

Note: IM = imatinib, Nilo = nilotinib, Dasa = dasatinib, BOS = bosutinib, NA = not assessed

Diagnosis

At diagnosis, ELN recommends a complete blood count with microscopic differential and a physical examination with special reference to spleen and liver size. Marrow cytology, cytogenetics for securing the Philadelphia (Ph) chromosome and a qualitative polymerase chain reaction (PCR) for BCR-ABL1 transcripts detection and typing are also recommended as well as an EKG, standard clinical chemistry and a hepatitis serology [12].

Risk score

The preferred risk score is the new EUTOS score for long-term survival (ELTS), since it predicts death by CML better than all other scores [14, 15]. ELTS uses the same variables as the Sokal score, but with different weights. Age is much less important in the TKI era, since TKI treatment is virtually equally successful in older patients. The variables of the ELTS score and the calculation of relative risk are shown in Table 2.

Table 2. Risk assessment by ELTS14

Hehlmann-tab02.jpg

To calculate the ELTS scores go to: http://www.leukemia-net.org/content/leukemia/cml/elts score/index_eng.html

Molecular monitoring, response milestones and deep molecular response

Molecular monitoring has replaced cytogenetics in clinical routine and is considered mainstay of treatment monitoring. Cytogenetics is still needed in the case of atypical translocations or atypical transcripts that cannot be measured by standard PCR, and in the case of failure/resistance or progression for detecting additional chromosomal abnormalities (ACA).

Quantitative real-time PCR (RT-PCR) should be performed on blood cells by standard methodology and reported as % BCR-ABL1 transcripts on the international scale (IS) [16,17]. BCR-ABL1 in %IS underlies the response milestones guiding treatment (Table 3).

Table 3. Response milestones expressed as % BCR-ABL1IS

Hehlmann-tab03.jpg

*Loss of MMR indicates failure after treatment-free remission (TFR)

Hehlmann-fig01.jpg

Figure 1. Benchmark times for molecular responses with imatinib (updated from Kalmanti et al.) [19]

Deep molecular responses (DMR; MR4 or deeper) indicate a state of disease with a very low probability of progress [18]. They are observed in the majority of TKI treated patients.

Benchmark times for what can be expected have been determined in imatinib treated patients and are depicted in Fig. 1. Most molecular responses are stable. After 10 years, 92% of patients in MMR reached MR4.5, 88% in MR4 reached MR5. Only one of 1326 patients in MR4 progressed during a median of 3.8 years, and none of 1302 patients in MR4.5 during a median of 3 years [18].

Failure or intolerance (not for not-reaching MMR) in imatinib treated patients with treatment change to 2G-TKI were observed in 26.5% over 9.5 years after a median of 34 months [2]. Changing treatment identified patients who did worse than the rest of the cohort, thus representing a poorer risk group. Most imatinib-treated patients, however, are candidates for treatment discontinuation.

First-line treatment

At present, 4 drugs are approved for 1st line therapy in CML by EMA and FDA:
• imatinib;
• dasatinib;
• nilotinib;
• bosutinib.

Approved in Korea only:
• radotinib.

Generic imatinib, now available worldwide, is the cost-effective initial therapy in chronic phase (CP) CML. Dosing of generics should be the same as brand dosing. Patients should continue the same generic brand in order to avoid potential side-effects due to changes in drug structure, bioavailability and drug preparation [12].

Second- and higher-line treatment

Second and higher lines of treatment after intolerance or resistance to the first-line TKI usually also consist of a TKI, but may include allogeneic transplantation of hematopoietic cells (allo-HCT), see below.

Table 4. TKI drugs recommended in case of BCR-ABL1 resistance mutations

Hehlmann-tab04.jpg

In the instance of treatment failure/resistance or progression to accelerated phase or blast crisis a mutational analysis should be initiated (Table 4) and the treatment changed. If available, next-generation sequencing (NGS) should be used for mutational analysis [12, 20]. Imatinib resistance mutations are relatively rare in CP2, but are more frequent in advanced phases.

If 2G-TKI are applied, the following comorbidities and contraindications have to be considered:

• Dasatinib:
- Previous pleuro-pulmonary diseases are strong contraindications (cave pleural effusion).
- Uncontrolled hypertension, pulmonary arterial hypertension (PAH) and bleeding due to impaired platelet function (cave anticoagulation) are relative contraindications.

• Nilotinib:
- Coronary heart disease, cerebrovascular accidents and peripheral arterial occlusive disease represent strong contraindications.
- Also, hypertension, diabetes mellitus, hypercholesterolemia and a history of pancreatitis may represent contraindications.

• Bosutinib:
- No relevant comorbidities have been determined yet. Frequent and annoying, but mostly self-limited diarrhea occurs. Loperamide may be indicated.

• Ponatinib:
- Ponatinib is a third generation (3G-)TKI and the only TKI with activity against the T315I mutation.
- Because of its cardiotoxicity dosing is critical. An initial dose of 45 mg/day should be reduced to a lower dose (15 mg/day) as soon as a response has been achieved [21].

Allogeneic transplantation

Although drug therapy is clearly superior to transplantation in CP [22], transplantation still plays an important role in CML treatment. Indications have moved from CP to more advanced phases, accelerated phase (AP) and blast crisis (BC), but transplantation in CP has to be considered in high-risk patients. Transplantation in CP is still indicated in:
• TKI resistant disease
• Rare patients who are intolerant to all currently available TKI
• Resistance to initial 2G-TKI
• Resistance to 3G-TKI indicating high risk of progression
• End-phase CML with high-risk ACA.

Hehlmann-fig02.jpg

Figure 2. Clinical strategies in evolving acceleration phase and blast crisis of CML

Fig. 2 illustrates the management of progression and emerging AP and BC1. Outcome of transplantation in AP and BC is worse than in CP, but transplantation provides probably the best outcome in BC. In an analysis of 786 BC patients managed by the German CML Study Group, 29 of the 40 long-term survivors (72.5%) had received a transplant [23].

Since earlier transplantations have better outcomes [23], the strategy is to recognize emerging progression to BC earlier. High-risk ACA indicate emerging progression. High-risk ACA are observed with increasing frequency in the later course of CML and have a negative impact on survival (Fig. 3). High-risk ACA are as follows [13, 24-26]:
• +8
• +Ph
• i(17q)
• +19
• +21
• +17
• -7/7q-
• 3q26.2
• 11q23
• complex karyotypes (3 or more aberrations).

Hehlmann-fig03.jpg

High-risk ACA are used to define CML end-phase. CML end-phase comprises early progression with emerging high-risk ACA and late progression with failing hematopoiesis and blast proliferation (Fig. 4).

Hehlmann-fig04.jpg

Figure 4. High-risk ACA and progression to blast crisis [13, 27, 28]

Hehlmann-fig05.jpg

Figure 5. Early versus late transplantation in CML patients with high-risk ACA [13]

Table 5. Benchmark times for DMR (MR4, MR4.5)

Hehlmann-tab05.jpg

Notes: *imatinib (n=1442), **nilotinib 300 mg twice daily (n=282), imatinib 400 mg daily (n=283), ***dasatinib 100 mg once daily (n=259), imatinib 400 mg daily (n=260), ****bosutinib 400 mg once daily (n=268), imatinib 400 mg daily (n=268), NA = not available
DMR rates of these trials cannot be directly compared owing to different methods of trial evaluation.

A total of 42 patients with high-risk ACA were transplanted in CML Study IV. Transplantation in early CML end-phase with emerging high-risk ACA, but without progression to AP or BC has shown superior survival (Fig. 5), although the survival difference, due to the small numbers (n=13 without progression; n=26 with progression to AP or BC; n=3 phase unknown), has not reached statistical significance at p=0.09 [13].

High-risk ACA at low blast counts herald death by CML [13]. The hazard to die with high-risk ACA compared with no ACA is increased:
• Up to 3.9-fold at blood blast levels of 1-5%;
• Up to 6.5-fold at marrow blast levels of 1-15%.

The lower the blast count, the higher is the predictive power of high-risk ACA. Low-risk ACA are associated with lesser or non-increased hazard.

Treatment discontinuation and TFR

Achievement of TFR after treatment discontinuation in sustained DMR is a new goal in the management of CML[12]. The majority of imatinib-treated patients in CP have reached DMR (MR4 or deeper) after 3 years as seen from Fig. 1 [18, 19]. Benchmark times for DMR have been determined in long-term clinical trials for imatinib [2], dasatinib [7], nilotinib [6], and bosutinib [8] and are shown in Table 5.

After the first pioneering studies have been published by the French CML group [29,30] many more studies have followed. Table 6 shows a selection of 21 studies totaling close to 3000 patients. Rates of relapse-free remissions at 2 years range around 50% (33% to 72% at 0.5-10 years). The largest of the studies, the EURO-SKI study (n=755), reports a TFR rate of 49% at 2 years [31].

Duration of TFR and of TKI treatment appear to be the most important predictors of successful TFR [31]. Loss of MMR indicates failure after TFR [32]. After resumption of treatment, 95% of patients will regain pre-discontinuation response levels.

The ELN considers the following requirements mandatory for TKI discontinuation [12]:
• CML in first CP only (data are lacking outside this setting);
• motivated patient with structured communication;
• accessibility to high quality quantitative PCR using the International Scale (IS) with rapid turn-around of PCR test results;
• patient agreement to more frequent monitoring after stopping treatment meaning;
• monthly for the first 6 months, every 2 months for months 6-12, and every 3 months thereafter.

Table 6. Selected TKI-discontinuation studies, update 2020

Hehlmann-tab06-01.jpg Hehlmann-tab06-02.jpg

Notes: Updated from [1]. ND = not defined; UMRD = undetectable minimal residual disease; IM = Imatinib; Nilo = Nilotinib; Dasa = Dasatinib; MR = molecular response; RFS = relapse free survival.

Conclusion

By 2020, survival of patients with CML has approached that of the general population. ELTS score is the preferred risk score in the TKI era. Molecular monitoring of minimal residual disease has replaced cytogenetics in routine monitoring. The four TKIs available for first-line therapy show different adverse effects profiles, but no differences in survival. Generic imatinib is the cost-effective initial treatment in chronic phase CML. Usage of second and higher-line TKI therapy is specified by mutational analysis and comorbidities. Early allogeneic hematopoietic cell transplantation is indicated in high-risk patients, e.g. with high-risk ACA. The new treatment goal is TFR. TKI discontinuation is feasible and safe. The rate of successful TFR ranges around 50% at 2 years.

Conflict of interest

None declared.

References

  1. Hehlmann, R. Chronic Myeloid Leukemia in 2020. HemaSphere. 2020; 4(5): e468.
  2. Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017; 31(11):2398-2406.
  3. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. New Engl J Med. 2017; 376:917-927.
  4. Sasaki K, Strom SS, O’Brien S, Jabbour E, Ravandi F, Konopleva M et al. Relative survival in patients with chronic-phase chronic myeloid leukemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015; 2:e186-e193.
  5. ESH Update 2019 to: Preudhomme C, Guilhot J, Nicolini F et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010; 363:2511-2521.
  6. Hughes TP, Saglio G, Larson RA, Kantarjian HM, Kim D‐W, Issaragrisil S, et al. Long-term outcomes in patients with chronic myeloid leukemia in chronic phase receiving frontline nilotinib versus imatinib: Enestnd 10-year analysis. Blood. 2019; 134:2924-2924.
  7. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patient trial. J Clin Oncol. 2016; 34:2333-2340.
  8. Brümmendorf TH, Cortes JE, Milojkovic D, Gambacorti-Passerini C, Clark RE, Le Coutre PD, et al. Bosutinib (BOS) versus imatinib (IM) for newly diagnosed chronic myeloid leukemia (CML): Final 5-year results from the BFORE trial. Blood. 2020; 136 (Supplement 1): 41-42.
  9. Thielen N, Visser O, Ossenkoppele G, Janssen J. Chronic myeloid leukemia in the Netherlands: a population-based study on incidence, treatment, and survival in 3585 patients from 1989 to 2012. Eur J Haematol. 2016; 97(2): 145-154.
  10. Bower H, Bjorkholm M, Dickman PW, Höglund M, Lambert PC, Andersson TM. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016; 34(24): 2851-2857.
  11. Welch HG, Kramer BS, Black WC. Epidemiologic signatures in cancer. N Engl J Med. 2019; 381(14): 1378-1386.
  12. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley J F, Cervantes F et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020; 34(4):966-984.
  13. Hehlmann R, Voskanyan A, Lauseker M, Pfirrmann M, Kalmanti L, Rinaldetti S et al. High-risk additional chromosomal abnormalities at low blast counts herald death by CML. Leukemia. 2020; 34: 2074-2086.
  14. Pfirrmann M, Baccarani M, Saußele S, Guilhot J, Cervantes F, Ossenkoppele G, et al. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia. 2016; 30(1), 48-56.
  15. Pfirrmann M, Clark RE, Prejzner W, Lauseker M, Baccarani M, Saussele S, et al. The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia. Leukemia. 2020; 34(8), 2138-2149.
  16. Cross NCP, White HE, Müller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. 2012; 26:2172-2175.
  17. Cross NCP, White HE, Colomer D, Ehrencrona H, Foroni L, Gottardi E, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015; 29:999-1003.
  18. Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol. 2014; 32:415-423.
  19. Kalmanti L, Saußele S, Lauseker M, Müller MC, Dietz CT, Heinrich L et al. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015; 29:1123-1132.
  20. Soverini S, Bavaro L, De Benedittis C, Martelli M, Iurlo A, Orofino N, et al. Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study. Blood. 2020; 135:534-541.
  21. Cortes J, Lomaia E, Turkina A, Moiraghi B, Undurraga Sutton M, et al. Interim analysis from the OPTIC trial – a dose-ranging study of 3 starting doses of ponatinib. Clin Lymph Myel & Leuk. 2020; 20: S234-S234.
  22. Hehlmann R, Berger U, Pfirrmann M, Heimpel H, Hochhaus A, Hasford J, et al. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood. 2007; 109(11): 4686-4692.
  23. Gratwohl A, Pfirrmann M, Zander A, Kröger N, Beelen D, Novotny J, et al. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment. Leukemia. 2016; 30(3): 562-569.
  24. Fabarius A, Kalmanti L, Dietz CT, Lauseker M, Rinaldetti S, Haferlach C, et al. SAKK and the German CML Study Group. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML. Ann Hematol. 2015;94(12):2015-2024.
  25. Wang W, Cortes JE, Tang G. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016; 127(22):2742-2750.
  26. Gong Z, Medeiros LJ, Cortes JE, et al. Cytogenetics-based risk prediction of blastic transformation of chronic myeloid leukemia in the era of TKI therapy. Blood Adv. 2017; 1:2541-2552.
  27. Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood. 2006; 108(1): 319-327.
  28. Ko TK, Javed A, Lee KL, Pathiraja TN, Liu X, Malik S, et al. An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood. 2020;135(26):2337-2353.
  29. Rousselot P, Huguet F, Rea D, Legros L, Cayuela JM, Maarek O, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007; 109(1): 58-60.
  30. Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular remission for at least 2 years: the prospective, multicenter Stop Imatinib (STIM) trial. Lancet Oncol. 2010; 11(11), 1029-1035.
  31. Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (EURO-SKI): a prespecified interim analysis of a prospective, multicenter, non-randomized, trial. Lancet Oncol. 2018;19(6): 747-757.
  32. Rousselot P, Charbonnier A, Cony-Makhoul et al. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014;32(5): 424-430.
  33. Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Charbonnier A et al. Long-term follow-up of the French Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol. 2017; 35(3): 298-305.
  34. Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT et al (2013). Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013; 122(4): 515-522.
  35. Lee SE, Choi SY, Song HY, Kim SH, Choi MY, Park JS et al. Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study. Haematologica. 2016; 101(6): 717-723.
  36. Zang DY, Lee WS, Mun YC, et al. Long-term follow-up after treatment discontinuation in patients with chronic myeloid leukemia: the Korean Imatinib Discontinuation (KID) study. Blood. 2018; 132(Supplement 1): 4252-4252.
  37. Nicolini FE, Dulucq S, Guilhot J, Etienne G, Mahon FX. The evaluation of residual disease by digital PCR and TKI duration are critical predictive factors for molecular recurrence after stopping imatinib first-line in chronic phase CML patients: Results of the STIM2 Study. Blood. 2018; 132; ASH abstract 462.
  38. Mori S, Vagge E, Le Coutre P et al. Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study. Am J Hematol. 2015; 90(10): 910-914.
  39. Mori S, le Coutre P, Abruzzese E, et al. Imatinib Suspension and Validation (ISAV) study: final results at 79 months. Blood. 2018; 132(Supplement 1): 461-461.
  40. Rea D, Nicolini FE, Tulliez M et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2017; 29(7): 846-854.
  41. Imagawa J, Tanaka H, Okada M et al. Discontinuation of dasatinib in patients with chronic myeloid leukemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicenter phase 2 trial. Lancet Haematol. 2015; 2(12): e528-e535.
  42. Kadowaki N, Kawaguchi T, Kuroda J et al. Discontinuation of nilotinib in patients with chronic myeloid leukemia who have maintained deep molecular responses for at least 2 years: a multicenter phase 2 stop nilotinib (Nilst) trial. Blood 2016; 128 (ASH Abstracts): 790-790.
  43. Kim DDH, Bence-Bruckler I, Forrest DL et al. Treatment-free remission accomplished by dasatinib (TRAD): Preliminary results of the Pan-Canadian tyrosine kinase inhibitor discontinuation trial. Blood. 2016; 128 (ASH Abstracts): 1922-1922.
  44. Shah N, García-Gutiérrez JV, Jiménez-Velasco A et al. Dasfree 2-year update: dasatinib discontinuation in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) and deep molecular response (DMR): PF408. HemaSphere. 2019; 3: 156.
  45. Hughes TP, Boquimpani CM, Takahashi N et al. Treatment-free remission in patients with chronic myeloid leukemia in chronic phase according to reasons for switching from imatinib to nilotinib: subgroup analysis from ENESTop. Blood. 2016; 128 (ASH Abstracts): 792-792.
  46. Takahashi N, Nishiwaki K, Nakaseko C et al. Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan. Haematologica. 2018; 103(11): 1835-1842.
  47. Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gómez Casares MT et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7): 1525-1531.
  48. Kumagai T, Nakaseko C, Nishiwaki K et al. Discontinuation of dasatinib after deep molecular response for over 2 years in patients with chronic myelogenous leukemia and the unique profiles of lymphocyte subsets for successful discontinuation: a prospective, multicenter Japanese trial (D-STOP Trial). Blood. 2016; 128 (ASH Abstracts): 791-791.
  49. Hernández-Boluda JC, Pereira A, Pastor-Galán I, Alvarez-Larran A, Savchuk A, Puerta Puerta JM et al. Feasibility of treatment discontinuation in chronic myeloid leukemia in clinical practice: results from a nationwide series of 236 patients. Blood Cancer Journal. 2018; 8(10):1-8.
  50. Clark RE, Polydoros F, Apperley J F, Milojkovic D, Rothwell K, Pocock C. Initial reduction of therapy prior to complete treatment discontinuation in chronic myeloid leukaemia: final results of the British DESTINY Study. Lancet Haematol. 2019;6:e375-e383.
  51. Rousselot P, Loiseau C, Delord M, Cayuela JM, Spentchian M. Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission. Blood Adv. 2020; 4(13): 3034-3040.
  52. Legros L, Nicolini FE, Etienne G, Rousselot P, Rea D, Giraudier S et al. Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia. Cancer. 2017; 123(22), 4403-4410.

" ["~DETAIL_TEXT"]=> string(29015) "

Introduction

Since the first attempts at treating CML with arsenic in 1865, treatment has been mostly palliative. Some modest prolongation of survival was reported with hydroxyurea and interferon alpha, for review see Hehlmann (2020) [1]. The only curative approach was allogeneic transplantation which, however, was available only to those few patients who had a donor and could tolerate the procedure. The advent of tyrosine kinase inhibitors has profoundly changed CML management as normal survival has been achieved for most patients as seen from Table 1 [2-11]. The new goal for treating CML is now survival at good quality of life without life-long treatment: treatment discontinuation in sustained deep molecular remission (DMR) and treatment-free remission (TFR). The European LeukemiaNet (ELN) has accounted for this development with an update of its recommendations [12]. This review summarizes the most important new developments and recommendations for treating CML including early transplantation of patients with high-risk additional chromosomal abnormalities (ACA) in early CML end-phase [13].

Table 1. Survival of CML patients in clinical trials: update 2020

Hehlmann-tab01.jpg

Note: IM = imatinib, Nilo = nilotinib, Dasa = dasatinib, BOS = bosutinib, NA = not assessed

Diagnosis

At diagnosis, ELN recommends a complete blood count with microscopic differential and a physical examination with special reference to spleen and liver size. Marrow cytology, cytogenetics for securing the Philadelphia (Ph) chromosome and a qualitative polymerase chain reaction (PCR) for BCR-ABL1 transcripts detection and typing are also recommended as well as an EKG, standard clinical chemistry and a hepatitis serology [12].

Risk score

The preferred risk score is the new EUTOS score for long-term survival (ELTS), since it predicts death by CML better than all other scores [14, 15]. ELTS uses the same variables as the Sokal score, but with different weights. Age is much less important in the TKI era, since TKI treatment is virtually equally successful in older patients. The variables of the ELTS score and the calculation of relative risk are shown in Table 2.

Table 2. Risk assessment by ELTS14

Hehlmann-tab02.jpg

To calculate the ELTS scores go to: http://www.leukemia-net.org/content/leukemia/cml/elts score/index_eng.html

Molecular monitoring, response milestones and deep molecular response

Molecular monitoring has replaced cytogenetics in clinical routine and is considered mainstay of treatment monitoring. Cytogenetics is still needed in the case of atypical translocations or atypical transcripts that cannot be measured by standard PCR, and in the case of failure/resistance or progression for detecting additional chromosomal abnormalities (ACA).

Quantitative real-time PCR (RT-PCR) should be performed on blood cells by standard methodology and reported as % BCR-ABL1 transcripts on the international scale (IS) [16,17]. BCR-ABL1 in %IS underlies the response milestones guiding treatment (Table 3).

Table 3. Response milestones expressed as % BCR-ABL1IS

Hehlmann-tab03.jpg

*Loss of MMR indicates failure after treatment-free remission (TFR)

Hehlmann-fig01.jpg

Figure 1. Benchmark times for molecular responses with imatinib (updated from Kalmanti et al.) [19]

Deep molecular responses (DMR; MR4 or deeper) indicate a state of disease with a very low probability of progress [18]. They are observed in the majority of TKI treated patients.

Benchmark times for what can be expected have been determined in imatinib treated patients and are depicted in Fig. 1. Most molecular responses are stable. After 10 years, 92% of patients in MMR reached MR4.5, 88% in MR4 reached MR5. Only one of 1326 patients in MR4 progressed during a median of 3.8 years, and none of 1302 patients in MR4.5 during a median of 3 years [18].

Failure or intolerance (not for not-reaching MMR) in imatinib treated patients with treatment change to 2G-TKI were observed in 26.5% over 9.5 years after a median of 34 months [2]. Changing treatment identified patients who did worse than the rest of the cohort, thus representing a poorer risk group. Most imatinib-treated patients, however, are candidates for treatment discontinuation.

First-line treatment

At present, 4 drugs are approved for 1st line therapy in CML by EMA and FDA:
• imatinib;
• dasatinib;
• nilotinib;
• bosutinib.

Approved in Korea only:
• radotinib.

Generic imatinib, now available worldwide, is the cost-effective initial therapy in chronic phase (CP) CML. Dosing of generics should be the same as brand dosing. Patients should continue the same generic brand in order to avoid potential side-effects due to changes in drug structure, bioavailability and drug preparation [12].

Second- and higher-line treatment

Second and higher lines of treatment after intolerance or resistance to the first-line TKI usually also consist of a TKI, but may include allogeneic transplantation of hematopoietic cells (allo-HCT), see below.

Table 4. TKI drugs recommended in case of BCR-ABL1 resistance mutations

Hehlmann-tab04.jpg

In the instance of treatment failure/resistance or progression to accelerated phase or blast crisis a mutational analysis should be initiated (Table 4) and the treatment changed. If available, next-generation sequencing (NGS) should be used for mutational analysis [12, 20]. Imatinib resistance mutations are relatively rare in CP2, but are more frequent in advanced phases.

If 2G-TKI are applied, the following comorbidities and contraindications have to be considered:

• Dasatinib:
- Previous pleuro-pulmonary diseases are strong contraindications (cave pleural effusion).
- Uncontrolled hypertension, pulmonary arterial hypertension (PAH) and bleeding due to impaired platelet function (cave anticoagulation) are relative contraindications.

• Nilotinib:
- Coronary heart disease, cerebrovascular accidents and peripheral arterial occlusive disease represent strong contraindications.
- Also, hypertension, diabetes mellitus, hypercholesterolemia and a history of pancreatitis may represent contraindications.

• Bosutinib:
- No relevant comorbidities have been determined yet. Frequent and annoying, but mostly self-limited diarrhea occurs. Loperamide may be indicated.

• Ponatinib:
- Ponatinib is a third generation (3G-)TKI and the only TKI with activity against the T315I mutation.
- Because of its cardiotoxicity dosing is critical. An initial dose of 45 mg/day should be reduced to a lower dose (15 mg/day) as soon as a response has been achieved [21].

Allogeneic transplantation

Although drug therapy is clearly superior to transplantation in CP [22], transplantation still plays an important role in CML treatment. Indications have moved from CP to more advanced phases, accelerated phase (AP) and blast crisis (BC), but transplantation in CP has to be considered in high-risk patients. Transplantation in CP is still indicated in:
• TKI resistant disease
• Rare patients who are intolerant to all currently available TKI
• Resistance to initial 2G-TKI
• Resistance to 3G-TKI indicating high risk of progression
• End-phase CML with high-risk ACA.

Hehlmann-fig02.jpg

Figure 2. Clinical strategies in evolving acceleration phase and blast crisis of CML

Fig. 2 illustrates the management of progression and emerging AP and BC1. Outcome of transplantation in AP and BC is worse than in CP, but transplantation provides probably the best outcome in BC. In an analysis of 786 BC patients managed by the German CML Study Group, 29 of the 40 long-term survivors (72.5%) had received a transplant [23].

Since earlier transplantations have better outcomes [23], the strategy is to recognize emerging progression to BC earlier. High-risk ACA indicate emerging progression. High-risk ACA are observed with increasing frequency in the later course of CML and have a negative impact on survival (Fig. 3). High-risk ACA are as follows [13, 24-26]:
• +8
• +Ph
• i(17q)
• +19
• +21
• +17
• -7/7q-
• 3q26.2
• 11q23
• complex karyotypes (3 or more aberrations).

Hehlmann-fig03.jpg

High-risk ACA are used to define CML end-phase. CML end-phase comprises early progression with emerging high-risk ACA and late progression with failing hematopoiesis and blast proliferation (Fig. 4).

Hehlmann-fig04.jpg

Figure 4. High-risk ACA and progression to blast crisis [13, 27, 28]

Hehlmann-fig05.jpg

Figure 5. Early versus late transplantation in CML patients with high-risk ACA [13]

Table 5. Benchmark times for DMR (MR4, MR4.5)

Hehlmann-tab05.jpg

Notes: *imatinib (n=1442), **nilotinib 300 mg twice daily (n=282), imatinib 400 mg daily (n=283), ***dasatinib 100 mg once daily (n=259), imatinib 400 mg daily (n=260), ****bosutinib 400 mg once daily (n=268), imatinib 400 mg daily (n=268), NA = not available
DMR rates of these trials cannot be directly compared owing to different methods of trial evaluation.

A total of 42 patients with high-risk ACA were transplanted in CML Study IV. Transplantation in early CML end-phase with emerging high-risk ACA, but without progression to AP or BC has shown superior survival (Fig. 5), although the survival difference, due to the small numbers (n=13 without progression; n=26 with progression to AP or BC; n=3 phase unknown), has not reached statistical significance at p=0.09 [13].

High-risk ACA at low blast counts herald death by CML [13]. The hazard to die with high-risk ACA compared with no ACA is increased:
• Up to 3.9-fold at blood blast levels of 1-5%;
• Up to 6.5-fold at marrow blast levels of 1-15%.

The lower the blast count, the higher is the predictive power of high-risk ACA. Low-risk ACA are associated with lesser or non-increased hazard.

Treatment discontinuation and TFR

Achievement of TFR after treatment discontinuation in sustained DMR is a new goal in the management of CML[12]. The majority of imatinib-treated patients in CP have reached DMR (MR4 or deeper) after 3 years as seen from Fig. 1 [18, 19]. Benchmark times for DMR have been determined in long-term clinical trials for imatinib [2], dasatinib [7], nilotinib [6], and bosutinib [8] and are shown in Table 5.

After the first pioneering studies have been published by the French CML group [29,30] many more studies have followed. Table 6 shows a selection of 21 studies totaling close to 3000 patients. Rates of relapse-free remissions at 2 years range around 50% (33% to 72% at 0.5-10 years). The largest of the studies, the EURO-SKI study (n=755), reports a TFR rate of 49% at 2 years [31].

Duration of TFR and of TKI treatment appear to be the most important predictors of successful TFR [31]. Loss of MMR indicates failure after TFR [32]. After resumption of treatment, 95% of patients will regain pre-discontinuation response levels.

The ELN considers the following requirements mandatory for TKI discontinuation [12]:
• CML in first CP only (data are lacking outside this setting);
• motivated patient with structured communication;
• accessibility to high quality quantitative PCR using the International Scale (IS) with rapid turn-around of PCR test results;
• patient agreement to more frequent monitoring after stopping treatment meaning;
• monthly for the first 6 months, every 2 months for months 6-12, and every 3 months thereafter.

Table 6. Selected TKI-discontinuation studies, update 2020

Hehlmann-tab06-01.jpg Hehlmann-tab06-02.jpg

Notes: Updated from [1]. ND = not defined; UMRD = undetectable minimal residual disease; IM = Imatinib; Nilo = Nilotinib; Dasa = Dasatinib; MR = molecular response; RFS = relapse free survival.

Conclusion

By 2020, survival of patients with CML has approached that of the general population. ELTS score is the preferred risk score in the TKI era. Molecular monitoring of minimal residual disease has replaced cytogenetics in routine monitoring. The four TKIs available for first-line therapy show different adverse effects profiles, but no differences in survival. Generic imatinib is the cost-effective initial treatment in chronic phase CML. Usage of second and higher-line TKI therapy is specified by mutational analysis and comorbidities. Early allogeneic hematopoietic cell transplantation is indicated in high-risk patients, e.g. with high-risk ACA. The new treatment goal is TFR. TKI discontinuation is feasible and safe. The rate of successful TFR ranges around 50% at 2 years.

Conflict of interest

None declared.

References

  1. Hehlmann, R. Chronic Myeloid Leukemia in 2020. HemaSphere. 2020; 4(5): e468.
  2. Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia. 2017; 31(11):2398-2406.
  3. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. New Engl J Med. 2017; 376:917-927.
  4. Sasaki K, Strom SS, O’Brien S, Jabbour E, Ravandi F, Konopleva M et al. Relative survival in patients with chronic-phase chronic myeloid leukemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015; 2:e186-e193.
  5. ESH Update 2019 to: Preudhomme C, Guilhot J, Nicolini F et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010; 363:2511-2521.
  6. Hughes TP, Saglio G, Larson RA, Kantarjian HM, Kim D‐W, Issaragrisil S, et al. Long-term outcomes in patients with chronic myeloid leukemia in chronic phase receiving frontline nilotinib versus imatinib: Enestnd 10-year analysis. Blood. 2019; 134:2924-2924.
  7. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patient trial. J Clin Oncol. 2016; 34:2333-2340.
  8. Brümmendorf TH, Cortes JE, Milojkovic D, Gambacorti-Passerini C, Clark RE, Le Coutre PD, et al. Bosutinib (BOS) versus imatinib (IM) for newly diagnosed chronic myeloid leukemia (CML): Final 5-year results from the BFORE trial. Blood. 2020; 136 (Supplement 1): 41-42.
  9. Thielen N, Visser O, Ossenkoppele G, Janssen J. Chronic myeloid leukemia in the Netherlands: a population-based study on incidence, treatment, and survival in 3585 patients from 1989 to 2012. Eur J Haematol. 2016; 97(2): 145-154.
  10. Bower H, Bjorkholm M, Dickman PW, Höglund M, Lambert PC, Andersson TM. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016; 34(24): 2851-2857.
  11. Welch HG, Kramer BS, Black WC. Epidemiologic signatures in cancer. N Engl J Med. 2019; 381(14): 1378-1386.
  12. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley J F, Cervantes F et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020; 34(4):966-984.
  13. Hehlmann R, Voskanyan A, Lauseker M, Pfirrmann M, Kalmanti L, Rinaldetti S et al. High-risk additional chromosomal abnormalities at low blast counts herald death by CML. Leukemia. 2020; 34: 2074-2086.
  14. Pfirrmann M, Baccarani M, Saußele S, Guilhot J, Cervantes F, Ossenkoppele G, et al. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia. 2016; 30(1), 48-56.
  15. Pfirrmann M, Clark RE, Prejzner W, Lauseker M, Baccarani M, Saussele S, et al. The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia. Leukemia. 2020; 34(8), 2138-2149.
  16. Cross NCP, White HE, Müller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. 2012; 26:2172-2175.
  17. Cross NCP, White HE, Colomer D, Ehrencrona H, Foroni L, Gottardi E, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015; 29:999-1003.
  18. Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol. 2014; 32:415-423.
  19. Kalmanti L, Saußele S, Lauseker M, Müller MC, Dietz CT, Heinrich L et al. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia. 2015; 29:1123-1132.
  20. Soverini S, Bavaro L, De Benedittis C, Martelli M, Iurlo A, Orofino N, et al. Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study. Blood. 2020; 135:534-541.
  21. Cortes J, Lomaia E, Turkina A, Moiraghi B, Undurraga Sutton M, et al. Interim analysis from the OPTIC trial – a dose-ranging study of 3 starting doses of ponatinib. Clin Lymph Myel & Leuk. 2020; 20: S234-S234.
  22. Hehlmann R, Berger U, Pfirrmann M, Heimpel H, Hochhaus A, Hasford J, et al. Drug treatment is superior to allografting as first-line therapy in chronic myeloid leukemia. Blood. 2007; 109(11): 4686-4692.
  23. Gratwohl A, Pfirrmann M, Zander A, Kröger N, Beelen D, Novotny J, et al. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment. Leukemia. 2016; 30(3): 562-569.
  24. Fabarius A, Kalmanti L, Dietz CT, Lauseker M, Rinaldetti S, Haferlach C, et al. SAKK and the German CML Study Group. Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML. Ann Hematol. 2015;94(12):2015-2024.
  25. Wang W, Cortes JE, Tang G. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016; 127(22):2742-2750.
  26. Gong Z, Medeiros LJ, Cortes JE, et al. Cytogenetics-based risk prediction of blastic transformation of chronic myeloid leukemia in the era of TKI therapy. Blood Adv. 2017; 1:2541-2552.
  27. Koptyra M, Falinski R, Nowicki MO, Stoklosa T, Majsterek I et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood. 2006; 108(1): 319-327.
  28. Ko TK, Javed A, Lee KL, Pathiraja TN, Liu X, Malik S, et al. An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia. Blood. 2020;135(26):2337-2353.
  29. Rousselot P, Huguet F, Rea D, Legros L, Cayuela JM, Maarek O, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007; 109(1): 58-60.
  30. Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular remission for at least 2 years: the prospective, multicenter Stop Imatinib (STIM) trial. Lancet Oncol. 2010; 11(11), 1029-1035.
  31. Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (EURO-SKI): a prespecified interim analysis of a prospective, multicenter, non-randomized, trial. Lancet Oncol. 2018;19(6): 747-757.
  32. Rousselot P, Charbonnier A, Cony-Makhoul et al. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014;32(5): 424-430.
  33. Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Charbonnier A et al. Long-term follow-up of the French Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol. 2017; 35(3): 298-305.
  34. Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT et al (2013). Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013; 122(4): 515-522.
  35. Lee SE, Choi SY, Song HY, Kim SH, Choi MY, Park JS et al. Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study. Haematologica. 2016; 101(6): 717-723.
  36. Zang DY, Lee WS, Mun YC, et al. Long-term follow-up after treatment discontinuation in patients with chronic myeloid leukemia: the Korean Imatinib Discontinuation (KID) study. Blood. 2018; 132(Supplement 1): 4252-4252.
  37. Nicolini FE, Dulucq S, Guilhot J, Etienne G, Mahon FX. The evaluation of residual disease by digital PCR and TKI duration are critical predictive factors for molecular recurrence after stopping imatinib first-line in chronic phase CML patients: Results of the STIM2 Study. Blood. 2018; 132; ASH abstract 462.
  38. Mori S, Vagge E, Le Coutre P et al. Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study. Am J Hematol. 2015; 90(10): 910-914.
  39. Mori S, le Coutre P, Abruzzese E, et al. Imatinib Suspension and Validation (ISAV) study: final results at 79 months. Blood. 2018; 132(Supplement 1): 461-461.
  40. Rea D, Nicolini FE, Tulliez M et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2017; 29(7): 846-854.
  41. Imagawa J, Tanaka H, Okada M et al. Discontinuation of dasatinib in patients with chronic myeloid leukemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicenter phase 2 trial. Lancet Haematol. 2015; 2(12): e528-e535.
  42. Kadowaki N, Kawaguchi T, Kuroda J et al. Discontinuation of nilotinib in patients with chronic myeloid leukemia who have maintained deep molecular responses for at least 2 years: a multicenter phase 2 stop nilotinib (Nilst) trial. Blood 2016; 128 (ASH Abstracts): 790-790.
  43. Kim DDH, Bence-Bruckler I, Forrest DL et al. Treatment-free remission accomplished by dasatinib (TRAD): Preliminary results of the Pan-Canadian tyrosine kinase inhibitor discontinuation trial. Blood. 2016; 128 (ASH Abstracts): 1922-1922.
  44. Shah N, García-Gutiérrez JV, Jiménez-Velasco A et al. Dasfree 2-year update: dasatinib discontinuation in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) and deep molecular response (DMR): PF408. HemaSphere. 2019; 3: 156.
  45. Hughes TP, Boquimpani CM, Takahashi N et al. Treatment-free remission in patients with chronic myeloid leukemia in chronic phase according to reasons for switching from imatinib to nilotinib: subgroup analysis from ENESTop. Blood. 2016; 128 (ASH Abstracts): 792-792.
  46. Takahashi N, Nishiwaki K, Nakaseko C et al. Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan. Haematologica. 2018; 103(11): 1835-1842.
  47. Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gómez Casares MT et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7): 1525-1531.
  48. Kumagai T, Nakaseko C, Nishiwaki K et al. Discontinuation of dasatinib after deep molecular response for over 2 years in patients with chronic myelogenous leukemia and the unique profiles of lymphocyte subsets for successful discontinuation: a prospective, multicenter Japanese trial (D-STOP Trial). Blood. 2016; 128 (ASH Abstracts): 791-791.
  49. Hernández-Boluda JC, Pereira A, Pastor-Galán I, Alvarez-Larran A, Savchuk A, Puerta Puerta JM et al. Feasibility of treatment discontinuation in chronic myeloid leukemia in clinical practice: results from a nationwide series of 236 patients. Blood Cancer Journal. 2018; 8(10):1-8.
  50. Clark RE, Polydoros F, Apperley J F, Milojkovic D, Rothwell K, Pocock C. Initial reduction of therapy prior to complete treatment discontinuation in chronic myeloid leukaemia: final results of the British DESTINY Study. Lancet Haematol. 2019;6:e375-e383.
  51. Rousselot P, Loiseau C, Delord M, Cayuela JM, Spentchian M. Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission. Blood Adv. 2020; 4(13): 3034-3040.
  52. Legros L, Nicolini FE, Etienne G, Rousselot P, Rea D, Giraudier S et al. Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia. Cancer. 2017; 123(22), 4403-4410.

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(2) "10" ["~SORT"]=> string(2) "10" ["CODE"]=> string(5) "-eln-" ["~CODE"]=> string(5) "-eln-" ["EXTERNAL_ID"]=> string(4) "1937" ["~EXTERNAL_ID"]=> string(4) "1937" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(395) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого рискаThe new ELN Recommendations for treating CML. Early transplantation in patients with high-risk ACA" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(1785) "<p style="text-align: justify;">Через 150 лет после, главным образом, паллиативной терапии хронического миелоидного лейкоза (ХМЛ), успехи лечения ингибиторами тирозинкиназы BCR-ABL1 (ИТК) привели к нормальным показателям выживаемости большинства пациентов с ХМЛ. Новой целью лечения является достижение ремиссии без лечения (РБЛ) с хорошим качеством жизни без пожизненной терапии. Европейская организация LeukemiaNet (ELN) учитывает эти разработки в своих свежих рекомендациях. Трансплантация гемопоэтических клеток (ТГСК) сохраняет важную роль в лечении пациентов с резистентностью или непереносимостью ИТК или прогрессированием заболевания в более агрессивную фазу. Данный обзор сосредоточен на рекомендациях ELN-2020 по лечению ХМЛ и ранней ТГСК у пациентов высокого риска.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Хронический миелоидный лейкоз, группы высокого риска, ингибиторы тирозинкиназы, трансплантация гемопоэтических стволовых клеток, рекомендации ELN.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["SECTION_META_TITLE"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["SECTION_META_KEYWORDS"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["SECTION_META_DESCRIPTION"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["SECTION_PICTURE_FILE_ALT"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["SECTION_PICTURE_FILE_TITLE"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "novye-rekomendatsii-eln-po-lecheniyu-khronicheskogo-mieloidnogo-leykoza-rannyaya-transplantatsiya-u-" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(297) "Новые рекомендации ELN по лечению хронического миелоидного лейкоза. Ранняя трансплантация у пациентов с дополнительными хромосомными аберрациями высокого риска" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "novye-rekomendatsii-eln-po-lecheniyu-khronicheskogo-mieloidnogo-leykoza-rannyaya-transplantatsiya-u-" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "novye-rekomendatsii-eln-po-lecheniyu-khronicheskogo-mieloidnogo-leykoza-rannyaya-transplantatsiya-u-" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "novye-rekomendatsii-eln-po-lecheniyu-khronicheskogo-mieloidnogo-leykoza-rannyaya-transplantatsiya-u-" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "169" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27311" ["VALUE"]=> string(10) "28.09.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "28.09.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27312" ["VALUE"]=> string(10) "13.11.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "13.11.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27313" ["VALUE"]=> array(2) { ["TEXT"]=> string(194) "<p>Рюдигер Хельманн                        </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(182) "

Рюдигер Хельманн                        

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27314" ["VALUE"]=> array(2) { ["TEXT"]=> string(184) "<p>Медицинский факультет Маннгейма, Гейдельбергский университет; Фонд ELN, Вайнхайм, Германия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(172) "

Медицинский факультет Маннгейма, Гейдельбергский университет; Фонд ELN, Вайнхайм, Германия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27315" ["VALUE"]=> array(2) { ["TEXT"]=> string(1785) "<p style="text-align: justify;">Через 150 лет после, главным образом, паллиативной терапии хронического миелоидного лейкоза (ХМЛ), успехи лечения ингибиторами тирозинкиназы BCR-ABL1 (ИТК) привели к нормальным показателям выживаемости большинства пациентов с ХМЛ. Новой целью лечения является достижение ремиссии без лечения (РБЛ) с хорошим качеством жизни без пожизненной терапии. Европейская организация LeukemiaNet (ELN) учитывает эти разработки в своих свежих рекомендациях. Трансплантация гемопоэтических клеток (ТГСК) сохраняет важную роль в лечении пациентов с резистентностью или непереносимостью ИТК или прогрессированием заболевания в более агрессивную фазу. Данный обзор сосредоточен на рекомендациях ELN-2020 по лечению ХМЛ и ранней ТГСК у пациентов высокого риска.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Хронический миелоидный лейкоз, группы высокого риска, ингибиторы тирозинкиназы, трансплантация гемопоэтических стволовых клеток, рекомендации ELN.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1729) "

Через 150 лет после, главным образом, паллиативной терапии хронического миелоидного лейкоза (ХМЛ), успехи лечения ингибиторами тирозинкиназы BCR-ABL1 (ИТК) привели к нормальным показателям выживаемости большинства пациентов с ХМЛ. Новой целью лечения является достижение ремиссии без лечения (РБЛ) с хорошим качеством жизни без пожизненной терапии. Европейская организация LeukemiaNet (ELN) учитывает эти разработки в своих свежих рекомендациях. Трансплантация гемопоэтических клеток (ТГСК) сохраняет важную роль в лечении пациентов с резистентностью или непереносимостью ИТК или прогрессированием заболевания в более агрессивную фазу. Данный обзор сосредоточен на рекомендациях ELN-2020 по лечению ХМЛ и ранней ТГСК у пациентов высокого риска.

Ключевые слова

Хронический миелоидный лейкоз, группы высокого риска, ингибиторы тирозинкиназы, трансплантация гемопоэтических стволовых клеток, рекомендации ELN.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27316" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-11-19" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-11-19" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27319" ["VALUE"]=> array(2) { ["TEXT"]=> string(180) "<p>Rüdiger Hehlmann                        </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(168) "

Rüdiger Hehlmann                        

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27320" ["VALUE"]=> array(2) { ["TEXT"]=> string(328) "<p>Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany</p><br> <p><b>Correspondence</b><br> Prof. Dr. Rüdiger Hehlmann, Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany<br> E-mail: Hehlmann.eln@gmail.com</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(274) "

Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany


Correspondence
Prof. Dr. Rüdiger Hehlmann, Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany
E-mail: Hehlmann.eln@gmail.com

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27321" ["VALUE"]=> array(2) { ["TEXT"]=> string(972) "<p style="text-align: justify;">After 150 years of mostly palliative CML therapy, treatment advances with BCR-ABL1 tyrosine kinase inhibitors (TKI) have resulted in normal survival for most patients with CML. The new treatment goal is treatment-free remission (TFR) with survival at good quality of life without life-long treatment. The European LeukemiaNet (ELN) has accounted for this development with its most recent recommendations. Hematopoietic stem cell transplantation has retained an important role in patients who have become resistant or intolerant to all TKI or progress to advanced phases. This review focuses on the ELN 2020 recommendations for treating CML and on early transplantation in high-risk patients.</p> <h2>Keywords</h2> <p style="text-align: justify;">Chronic myeloid leukemia, high-risk group, tyrosine kinase inhibitors, hematopoietic stem cell transplantation, ELN recommendations.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(916) "

After 150 years of mostly palliative CML therapy, treatment advances with BCR-ABL1 tyrosine kinase inhibitors (TKI) have resulted in normal survival for most patients with CML. The new treatment goal is treatment-free remission (TFR) with survival at good quality of life without life-long treatment. The European LeukemiaNet (ELN) has accounted for this development with its most recent recommendations. Hematopoietic stem cell transplantation has retained an important role in patients who have become resistant or intolerant to all TKI or progress to advanced phases. This review focuses on the ELN 2020 recommendations for treating CML and on early transplantation in high-risk patients.

Keywords

Chronic myeloid leukemia, high-risk group, tyrosine kinase inhibitors, hematopoietic stem cell transplantation, ELN recommendations.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27317" ["VALUE"]=> string(98) "The new ELN Recommendations for treating CML. Early transplantation in patients with high-risk ACA" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(98) "The new ELN Recommendations for treating CML. Early transplantation in patients with high-risk ACA" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["PDF_RU"]=> array(36) { ["ID"]=> string(2) "43" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF RUS" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_RU" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "43" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27318" ["VALUE"]=> string(4) "2297" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2297" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF RUS" ["~DEFAULT_VALUE"]=> string(0) "" } ["PDF_EN"]=> array(36) { ["ID"]=> string(2) "44" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF ENG" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "44" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27322" ["VALUE"]=> string(4) "2298" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2298" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF ENG" ["~DEFAULT_VALUE"]=> string(0) "" } ["NAME_LONG"]=> array(36) { ["ID"]=> string(2) "45" ["TIMESTAMP_X"]=> string(19) "2023-04-13 00:55:00" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(72) "Название (для очень длинных заголовков)" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "NAME_LONG" ["DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "45" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27319" ["VALUE"]=> array(2) { ["TEXT"]=> string(180) "<p>Rüdiger Hehlmann                        </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(168) "

Rüdiger Hehlmann                        

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(168) "

Rüdiger Hehlmann                        

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27321" ["VALUE"]=> array(2) { ["TEXT"]=> string(972) "<p style="text-align: justify;">After 150 years of mostly palliative CML therapy, treatment advances with BCR-ABL1 tyrosine kinase inhibitors (TKI) have resulted in normal survival for most patients with CML. The new treatment goal is treatment-free remission (TFR) with survival at good quality of life without life-long treatment. The European LeukemiaNet (ELN) has accounted for this development with its most recent recommendations. Hematopoietic stem cell transplantation has retained an important role in patients who have become resistant or intolerant to all TKI or progress to advanced phases. This review focuses on the ELN 2020 recommendations for treating CML and on early transplantation in high-risk patients.</p> <h2>Keywords</h2> <p style="text-align: justify;">Chronic myeloid leukemia, high-risk group, tyrosine kinase inhibitors, hematopoietic stem cell transplantation, ELN recommendations.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(916) "

After 150 years of mostly palliative CML therapy, treatment advances with BCR-ABL1 tyrosine kinase inhibitors (TKI) have resulted in normal survival for most patients with CML. The new treatment goal is treatment-free remission (TFR) with survival at good quality of life without life-long treatment. The European LeukemiaNet (ELN) has accounted for this development with its most recent recommendations. Hematopoietic stem cell transplantation has retained an important role in patients who have become resistant or intolerant to all TKI or progress to advanced phases. This review focuses on the ELN 2020 recommendations for treating CML and on early transplantation in high-risk patients.

Keywords

Chronic myeloid leukemia, high-risk group, tyrosine kinase inhibitors, hematopoietic stem cell transplantation, ELN recommendations.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(916) "

After 150 years of mostly palliative CML therapy, treatment advances with BCR-ABL1 tyrosine kinase inhibitors (TKI) have resulted in normal survival for most patients with CML. The new treatment goal is treatment-free remission (TFR) with survival at good quality of life without life-long treatment. The European LeukemiaNet (ELN) has accounted for this development with its most recent recommendations. Hematopoietic stem cell transplantation has retained an important role in patients who have become resistant or intolerant to all TKI or progress to advanced phases. This review focuses on the ELN 2020 recommendations for treating CML and on early transplantation in high-risk patients.

Keywords

Chronic myeloid leukemia, high-risk group, tyrosine kinase inhibitors, hematopoietic stem cell transplantation, ELN recommendations.

" } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27316" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-11-19" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-11-19" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-11-19" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27317" ["VALUE"]=> string(98) "The new ELN Recommendations for treating CML. Early transplantation in patients with high-risk ACA" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(98) "The new ELN Recommendations for treating CML. Early transplantation in patients with high-risk ACA" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(98) "The new ELN Recommendations for treating CML. Early transplantation in patients with high-risk ACA" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27320" ["VALUE"]=> array(2) { ["TEXT"]=> string(328) "<p>Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany</p><br> <p><b>Correspondence</b><br> Prof. Dr. Rüdiger Hehlmann, Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany<br> E-mail: Hehlmann.eln@gmail.com</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(274) "

Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany


Correspondence
Prof. Dr. Rüdiger Hehlmann, Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany
E-mail: Hehlmann.eln@gmail.com

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(274) "

Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany


Correspondence
Prof. Dr. Rüdiger Hehlmann, Medical Faculty Mannheim, Heidelberg University; ELN Foundation Weinheim, Germany
E-mail: Hehlmann.eln@gmail.com

" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27313" ["VALUE"]=> array(2) { ["TEXT"]=> string(194) "<p>Рюдигер Хельманн                        </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(182) "

Рюдигер Хельманн                        

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(182) "

Рюдигер Хельманн                        

" } ["SUBMITTED"]=> array(37) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27311" ["VALUE"]=> string(10) "28.09.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "28.09.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "28.09.2020" } ["ACCEPTED"]=> array(37) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27312" ["VALUE"]=> string(10) "13.11.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "13.11.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "13.11.2020" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27315" ["VALUE"]=> array(2) { ["TEXT"]=> string(1785) "<p style="text-align: justify;">Через 150 лет после, главным образом, паллиативной терапии хронического миелоидного лейкоза (ХМЛ), успехи лечения ингибиторами тирозинкиназы BCR-ABL1 (ИТК) привели к нормальным показателям выживаемости большинства пациентов с ХМЛ. Новой целью лечения является достижение ремиссии без лечения (РБЛ) с хорошим качеством жизни без пожизненной терапии. Европейская организация LeukemiaNet (ELN) учитывает эти разработки в своих свежих рекомендациях. Трансплантация гемопоэтических клеток (ТГСК) сохраняет важную роль в лечении пациентов с резистентностью или непереносимостью ИТК или прогрессированием заболевания в более агрессивную фазу. Данный обзор сосредоточен на рекомендациях ELN-2020 по лечению ХМЛ и ранней ТГСК у пациентов высокого риска.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Хронический миелоидный лейкоз, группы высокого риска, ингибиторы тирозинкиназы, трансплантация гемопоэтических стволовых клеток, рекомендации ELN.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1729) "

Через 150 лет после, главным образом, паллиативной терапии хронического миелоидного лейкоза (ХМЛ), успехи лечения ингибиторами тирозинкиназы BCR-ABL1 (ИТК) привели к нормальным показателям выживаемости большинства пациентов с ХМЛ. Новой целью лечения является достижение ремиссии без лечения (РБЛ) с хорошим качеством жизни без пожизненной терапии. Европейская организация LeukemiaNet (ELN) учитывает эти разработки в своих свежих рекомендациях. Трансплантация гемопоэтических клеток (ТГСК) сохраняет важную роль в лечении пациентов с резистентностью или непереносимостью ИТК или прогрессированием заболевания в более агрессивную фазу. Данный обзор сосредоточен на рекомендациях ELN-2020 по лечению ХМЛ и ранней ТГСК у пациентов высокого риска.

Ключевые слова

Хронический миелоидный лейкоз, группы высокого риска, ингибиторы тирозинкиназы, трансплантация гемопоэтических стволовых клеток, рекомендации ELN.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1729) "

Через 150 лет после, главным образом, паллиативной терапии хронического миелоидного лейкоза (ХМЛ), успехи лечения ингибиторами тирозинкиназы BCR-ABL1 (ИТК) привели к нормальным показателям выживаемости большинства пациентов с ХМЛ. Новой целью лечения является достижение ремиссии без лечения (РБЛ) с хорошим качеством жизни без пожизненной терапии. Европейская организация LeukemiaNet (ELN) учитывает эти разработки в своих свежих рекомендациях. Трансплантация гемопоэтических клеток (ТГСК) сохраняет важную роль в лечении пациентов с резистентностью или непереносимостью ИТК или прогрессированием заболевания в более агрессивную фазу. Данный обзор сосредоточен на рекомендациях ELN-2020 по лечению ХМЛ и ранней ТГСК у пациентов высокого риска.

Ключевые слова

Хронический миелоидный лейкоз, группы высокого риска, ингибиторы тирозинкиназы, трансплантация гемопоэтических стволовых клеток, рекомендации ELN.

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27314" ["VALUE"]=> array(2) { ["TEXT"]=> string(184) "<p>Медицинский факультет Маннгейма, Гейдельбергский университет; Фонд ELN, Вайнхайм, Германия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(172) "

Медицинский факультет Маннгейма, Гейдельбергский университет; Фонд ELN, Вайнхайм, Германия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(172) "

Медицинский факультет Маннгейма, Гейдельбергский университет; Фонд ELN, Вайнхайм, Германия

" } } } [2]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(3) "170" ["~IBLOCK_SECTION_ID"]=> string(3) "170" ["ID"]=> string(4) "1939" ["~ID"]=> string(4) "1939" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["~NAME"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "05.02.2021 11:57:40" ["~TIMESTAMP_X"]=> string(19) "05.02.2021 11:57:40" ["DETAIL_PAGE_URL"]=> string(138) "/ru/archive/-9-4/klinicheskie-raboty/dolgosrochnye-tseli-terapii-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-posle-allogennoy-so/" ["~DETAIL_PAGE_URL"]=> string(138) "/ru/archive/-9-4/klinicheskie-raboty/dolgosrochnye-tseli-terapii-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-posle-allogennoy-so/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(25361) "

Introduction

Chronic graft-versus-host disease (cGvHD) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is associated both with long-term mortality and significant disability in long-term survivors. Its incidence varies from 10% to 80% according to the type of prophylaxis, type of the donor and several other risk factors [1-4]. Although cGvHD is associated with reduced risk of relapse and improved survival in the majority of malignant diseases [5], the persistence of clinical signs is associated with long-term mortality due to cardiovascular disease, infections and secondary malignancies [6]. Also cGvHD is the major cause of decline in the quality of life (QoL), social and professional disability. Gastrointestinal, joint and kidney problems are the main drivers of QoL decline [7-9].

The early studies of cGvHD treatment demonstrated a superiority of steroids over other agents in the treatment of cGvHD in terms of survival [10, 11]. However all subsequent attempts to improve response rate with augmented immunosuppression were not successful. Addition of thalidomide and mycofenolate mofetil resulted in higher frequency of adverse events and infection-related mortality [12, 13]. The only combination with some benefit in terms of steroid sparing was the combination of steroids and cyclosporine A (CsA), which demonstrated comparable response rate and duration of immunosuppression, however the cumulative dose of steroids was less in the combination arm, which resulted in the reduced frequency of femur aseptic necrosis [14]. The failure of these clinical trials to demonstrate improved response rate lead to the shift in the concept of cGvHD treatment. Currenly it is considered that immunosuppressive therapy (IST) does not induce tolerance, but rather alleviates target organ damage before the tolerance between donor and recipient cells occur. This understanding creates a dissonance between endpoints from the clinical studies and the real clinical practice where the formal response criteria, like decrease in the severity score or improved 2-minute walk test results, does not necessarily correlate with long-term prognosis.

While several studies focus on the clinical features of cGvHD that are associated with adverse prognosis [15, 16], few focus on the prognosis according to the response to treatment. Now we have novel effective treatments for steroid-refractory disease, which could be steroid-sparing and facilitate better clinical responses [17, 18]. Thus it is important to define the goals of therapy for cGvHD. In this single center study we did not evaluate the outcomes of certain treatment modalities for chronic GvHD but rather focused on IST discontinuation, complete response of cGvHD and survival. For this purpose we included only patients who have long-term follow up after onset of cGvHD. As the first line of therapy 62% of patients received prednisone 1 mg/kg daily in combination with calcineurin inhibitor (CNI), 22% received CNI as the monotherapy, 16% received monotherapy with a second line treatments.

Patients and methods

Table 1.

Moiseev-tab01.jpg

Patients and transplantation procedures

Two hundred and nine patients transplanted in 2006-2017 in Pavlov First Saint Petersburg State Medical University were included in the study. The inclusion criteria were moderate or severe disease according to National Institute of Health (NIH) 2015 criteria [19], administration of systemic treatment for cGvHD, transplantation from 9-10/10 HLA-matched related or unrelated donor. All patients signed informed consent for the use of their medical data in research purposes. Two thirds of patients had either acute myeloblastic leukemia or acute lymphoblastic leukemia, 49% had severe cGvHD, 51% – moderate. Median time from HSCT to cGvHD onset was 166 days. Twenty three percent received GvHD prophylaxis with post-ransplantation cyclophosphamide (PTCY) and the rest – conventional prophylaxis with calcineurin inhibitor and antimetabolite. Median follow up time after the onset of cGvHD was 52 months. More than 56% had three or more organ involvement (Table 1).

Clinical definitions

Time to disease relapse incidence (RI), complete response (CR), non-relapse mortality (NRM), overall survival (OS) and event-free survival (EFS), were defined as the time from cGvHD onset to the event. RI and NRM were considered a competing risk events. RI and CR were also considered competing risks. cGvHD severity was evaluated using NIH 2015 criteria [19], while response using 2006 NIH criteria [20]. Complete response was defined as absence of cGvHD clinical signs with IST discontinued. Partial response (PR) was defined as decrease in the total NIH score without increase in each individual organ score.

Statistical analysis

Non-parametric analysis included Chi-square test, Mann-Whitney test according to the type of data. The survival distributions for OS, EFS, were calculated using Kaplan-Meier methodology. The comparisons were made using the log-rank test. Cumulative incidence analysis with competing risks RI, NRM, CR was performed using Gray test. Relapse and NRM were accounted as competing risks as well as RI and CR. Fine and Grey regression was used for the multivariate analysis of cumulative incidences. Factors used for multivariate correction had at least p=0.10 significance in the univariate analysis.

Results

As the first line of therapy 62% of patients received prednisone 1 mg/kg daily in combination with calcineurin inhibitor (CNI), 22% received CNI as the monotherapy, 16% received monotherapy with a second line treatment (pharmacological or extracorporeal photopheresis without steroids. Beyond the first line 39.56% of patients required additional treatment. The most frequent options were ECP, IL-2, JAK inhibitors, BTK inhibitors, tyrosine-kinase inhibitors (TKI).

At five years, the cumulative incidence of CR was 16.9% (95% CI 10.5-24.7%). The proportion of patients with CR was 18.68%. However the cumulative incidence of IST discontinuation without GVHD flare was higher – 51.2% (95% CI 40.0-61.2%), and close to the proportion of patients with CR and mild chronic GvHD manifestations after treatment (44.5%). The competing risk of relapse was 25.4% (95% CI 18.6-32.8%) (Fig. 1).

Moiseev-fig01.jpg

Figure 1. (A) Initial severity of cGvHD before treatment and at last follow up. (B) Cumulative incidence of complete remission and immunosuppression (IST) discontinuation. Relapse was accounted as competing risk

In the multivariate analysis there was only one significant predictor of CR – severe form of chronic GvHD comparing to the moderate disease (HR 0.26, 95%CI 0.08-0.728, p=0.0194). The other factors significant in the univariate analysis like type of initial treatment (HR 0.84, 95%CI 0.44-1.46, p=0.5154), type of GvHD prophylaxis (HR 0.95, 95%CI 0.34-2.48, p=0.9122), previous acute GvHD grade 3-4 (HR 0.82, 95%CI 0.28-2.40, p=0.82) and number of organs involved (HR 0.77, 95%CI 0.52-1.08, p=0.1751) had no impact on CR cumulative incidence.

In the multivariate analysis of IST discontinuation, the statistical significance was observed for overall severity of cGvHD (HR 0.45, 95%CI 0.25-0.84, p=0.0049) and female donor for male recipient (HR 0.33, 95%CI 0.25-0.81, p= 0.0370). The other factors like type of the donor (HR 0.70, 95%CI 0.37-1.38, p=0.2909), previous severe acute GvHD (HR 0.96, 95%CI 0.49-1.82, p=0.9379), type of initial GvHD treatment (HR 0.93, 95%CI 0.63-1.33, p=0.7021), GI involvement (HR 0.76, 95%CI 0.53-1.04, p=0.1223), or lung involvement (HR 0.78, 95%CI 0.47-1.17, p=0.2288) were not statistically significant (Figure 2A). However it is worth mentioning that 55% of patients without GI cGvHD discontinued IST, while 28% achieved this goal with mild GI GvHD, 26% with moderate and 8% with severe. The same pattern was observed for lung GvHD: 47% discontinued systemic IST without lung involvement and 25% with mild bronchiolitis obliterans (BO), 29% with moderate and only 10% with severe. Absence of significance in the multivariate analysis may be partially explained by certain overlap of these variables with overall severity of cGvHD. Among patients with moderate disease 56% discontinued IST, but with severe disease – only 25%. At the end of the follow up patients with CR discontinued IST in 91% of cases, with mild cGvHD in 53% of cases, with moderate in 24% of cases and with severe in 2% of cases.

The analysis of NRM demonstrated that the major factors with impact on 5-year NRM were severe form of cGvHD (32% vs 13%, p=0.0050), discontinuation of systemic IST (2% vs 42%, p<0.0001) and surprisingly steroid-free first-line therapy (8% vs 32%, p=0.0006). Although administration of second-line regimens were not statistically significant in this data set (NRM 20% vs 27%, p= 0.7092) (Fig. 3), it was forced in the subsequent multivariate analysis due to significant literature data on increased mortality in steroid- refractory GvHD.

In the multivariate analysis it was demonstrated that the initial severity of cGvHD did not influenced the NRM (HR 1.70, 95%CI 0.80-3.97, p=0.1959), while early discontinuation of IST (HR 0.03, 95%CI 0.01-0.15, p=0.0005), steroid-free starting therapy (HR 0.25, 95%CI 0.08-0.58, p=0.0035) and use of second-line therapy (HR 0.49, 95%CI 0.25-0.96, p=0.0322) were protective against NRM (Fig. 2B). Since it was a non-randomized study patients with steroid-free starting therapy more often had moderate disease compared to patients in the steroids group (41% vs 66%, p= 0.0011). The same is true for additional cGvHD therapy: 54% received it in the severe group, while only 20% received it in the mode-rate cGvHD group.

Moiseev-fig02.jpg

Figure 2. (A) Multivariate analysis of predictors for successful IST discontinuation. (B) Multivariate analysis of predictors for non-relapse mortality

MUD=matched unrelated donor, MRD=matched related donor, GI=gastrointestinal. IST= immunosuppressive treatment. Factors with significance <0.1 in the univariate analysis were included.

Moiseev-fig03.jpg

Figure 3. Major predictors of non-relapse mortality

Discussion

This retrospective analysis of the large single center-cohort is not in line with several previous studies. The initial studies of cGvHD treatment identified prednisone as an optimal therapy among the existing at that time immunosuppressive agents [10, 11]. Many clinics even do not use CNIs in combination with steroids for the treatment, given the comparable response rate [14]. All the subsequent studies demonstrated that addition of thalidomide [13], or MMF [21], or ECP [22] in the first line of therapy did not improve response or survival. In our single-center study of patients with cGvHD many did not receive first line steroids. Partly, this was due to the single-agent PTCY prophylaxis protocol involving first line CsA for both acute and chronic GvHD, but also due national peculiarities of healthcare when a patient cannot easily travel to the transplant center and CNIs had to be introduced during distant consultations, while treatment with steroids were saved only for patients who could be admitted to the outpatient care. Secondly, there was an internal policy of faster steroid tapper after introduction of second line treatment than in the majority of centers [23]. Hence, if the patient did not show the signs of the flair he usually completely discontinued steroids within a month and continued only second line treatment, while the standard policy is to continue steroids until response. These differences in the internal policies led to several interesting discoveries.

First, patients initially treated without steroids had significantly reduced NRM. Although it is not well documented in the literature, but the majority of early deaths in chronic GvHD patients occur not due to cGvHD clinical manifestations, but due to recurrent infections [24]. Hence, the modality of immunosuppressive therapy should focus on minimal increase in the rate of infectious complications while providing at least minimal continuous GvHD improvement. This goes in line with recent single cell sequencing studies demonstrating that variation in cGvHD manifestation is due to the mixture of alloreactive graft-derived cells and de novo T-cells generated in thymus. Exhaustion of these clones is associated with cGvHD amelioration or resolution [25, 26]. Now there is not enough data to support that exhaustion and elimination of GvHD-related T-cells is a consequence of IST. This might be as well the result of restored process of negative T-cell cell selection in the thymus [27]. This study proposes the idea that minimally effective immunosuppression should be used.

At the time R. Storb et al. compared the efficacy of various IST with prednisone the choice of agents was limited to azathioprine, methotrexate and cyclophosphamide. Now we have several effective therapy options for cGVHD, including ECP [28], JAK inhibitors [18], BTK inhibitors [17]. All of them were used either as early therapeutic intervention in the first or second lines of therapy in this study in a small proportion of patients. None of these agents were previously randomized against steroids but rather randomized on top of steroids. Second line therapy with kinase inhibitors demonstrated excellent survival, so moving this agents in the first line might reduce infection-related NRM [17, 19, 29]. Despite this was not a randomized study and steroid-free first line therapy group had less patients with severe cGvHD, at least these results warrant randomized studies of novel therapies against steroids, but not with steroids.

Although it was demonstrated previously that patients with improvement in cGvHD manifestations have better survival compared to patients without improvement [30], this study demonstrated how long the IST should continue and when it should be stopped. The ideal situation is reaching CR or mild manifestations of cGvHD when systemic IST could be stopped and GvHD controlled by topical therapy. A quarter of patients with formal moderate disease can also stop systemic IST without a flare. Usually, these are lung GvHD patients who may never restore the lung capacity to normal, or patients with eye involvement in whom it will be controlled with topical therapy. Still there is a problem with patients who still have severe disease after several years of therapy. Despite they will have higher mortality than patients with GvHD resolution, in this study we demonstrated that they may benefit in terms of NRM from early intervention with second-line therapies or using them in the first line. Also prospective trials are required to confirm these observations. The long-term results of this approach is unknown, however we know that prolonged use of steroids is associated with dismal prognosis [6].

Financial Disclosure Statement

The authors have nothing to disclaim.

Acknowledgements

The authors declare no conflicts of interest.

References

  1. Storb R, Deeg HJ, Pepe M, Appelbaum F, Anasetti C, Beatty P, Bensinger W, Berenson R, Buckner CD, Clift R, et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood. 1989;73(6):1729-1734. PMID: 2653461.
  2. Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, Oneto R, Bruno B, Barbanti M, Sacchi N, Van Lint MT, Bosi A. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001;98(10):2942-2947.
  3. Maschan M, Shelikhova L, Ilushina M, Kurnikova E, Boyakova E, Balashov D, Persiantseva M, Skvortsova Y, Laberko A, Muzalevskii Y, et al. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant. 2016;51(5):668-674.
  4. Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, Wang SA, Konopleva M, Fernandez-Vina M, Montes N, et al. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18(12):1835-1844.
  5. Stern M, de Wreede LC, Brand R, van Biezen A, Dreger P, Mohty M, de Witte TM, Kröger N, Ruutu T. Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia. 2014;28(11):2235-2240.
  6. Ruutu T, Nihtinen A, Niittyvuopio R, Juvonen E, Volin L. A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis. Cancer. 2018;124(4):727-733.
  7. Inamoto Y, Pidala J, Chai X, Kurland BF, Weisdorf D, Flowers ME, Palmer J, Arai S, Jacobsohn D, Cutler C, Jagasia M, Goldberg JD, Martin PJ, Pavletic SZ, Vogelsang GB, Lee SJ, Carpenter PA; Chronic GVHD Consortium. Assessment of joint and fascia manifestations in chronic graft-versus-host disease. Arthritis Rheumatol. 2014;66(4):1044-1052.
  8. Glezerman IG, Jhaveri KD, Watson TH, Edwards AM, Papadopoulos EB, Young JW, Flombaum CD, Jakubowski AA. Chronic kidney disease, thrombotic microangiopathy, and hypertension following T cell-depleted hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2010;16(7):976-984.
  9. Worel N, Biener D, Kalhs P, Mitterbauer M, Keil F, Schulenburg A, Höcker P, Dieckmann K, Fischer G, Rosenmayr A, et al. Long-term outcome and quality of life of patients who are alive and in complete remission more than two years after allogeneic and syngeneic stem cell transplantation. Bone Marrow Transplant. 2002;30(9):619-626.
  10. Sullivan KM, Shulman HM, Storb R, Weiden PL, Witherspoon RP, McDonald GB, Schubert MM, Atkinson K, Thomas ED. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood. 1981;57(2):267-276. PMID: 7004534.
  11. Sullivan KM, Witherspoon RP, Storb R, Deeg HJ, Dahlberg S, Sanders JE, Appelbaum FR, Doney KC, Weiden P, Anasetti C, et al. Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease. Blood. 1988;72(2):555-561.
  12. Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, Wingard JR, Shaughnessy PJ, DeVetten MP, Jagasia M, et al. Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood. 2009;113(21):5074-5082.
  13. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, Sanders JE, Witherspoon RP, Appelbaum FR, Storb R, Martin PJ. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood. 2000;96(12):3995-3996.
  14. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, Sanders JE, Witherspoon RP, Storb R, Appelbaum FR, Martin PJ. Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood. 2002;100(1):48-51.
  15. Ayuk F, Veit R, Zabelina T, Bussmann L, Christopeit M, Alchalby H, Wolschke C, Lellek H, Bacher U, Zander AR, Kröger N. Prognostic factors for survival of patients with newly diagnosed chronic GvHD according to NIH criteria. Ann Hematol. 2015;94(10):1727-1732.
  16. Pavletic SZ, Smith LM, Bishop MR, Lynch JC, Tarantolo SR, Vose JM, Bierman PJ, Hadi A, Armitage JO, Kessinger A. Prognostic factors of chronic graft-versus-host disease after allogeneic blood stem-cell transplantation. Am J Hematol. 2005;78(4):265-274.
  17. Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, Flowers ME, Logan AC, Nakamura R, Blazar BR, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243-2250. doi: 10.1182/blood-2017-07-793786.
  18. Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, Spoerl S, Ditschkowski M, Ecsedi M, Sockel K, Ayuk F, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29(10):2062-2068.
  19. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, Cheng GS, et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015; 21(3):389-401.e1.
  20. Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant 2006; 12: 252-266.
  21. Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, Wingard JR, Shaughnessy PJ, DeVetten MP, Jagasia M, et al. Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood. 2009; 113(21):5074-5082.
  22. Jagasia M, Scheid C, Socié G, Ayuk FA, Tischer J, Donato ML, Bátai Á, Chen H, Chen SC, Chin T, et al. Randomized controlled study of ECP with methoxsalen as first-line treatment of patients with moderate to severe cGVHD. Blood Adv. 2019;3(14):2218-2229.
  23. Sarantopoulos S, Cardones AR, Sullivan KM. How I treat refractory chronic graft-versus-host disease. Blood. 2019;133(11):1191-1200.
  24. Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, Sorror ML, Horowitz MM, Bolwell B, Rizzo JD, Socié G. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011;29(16):2230-2239.
  25. Balakrishnan A, Gloude N, Sasik R, Ball ED, Morris GP. Proinflammatory dual receptor T cells in chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2017;23(11):1852-1860.
  26. Kosugi-Kanaya M, Ueha S, Abe J, et al. Long-lasting graft-derived donor T cells contribute to the pathogenesis of chronic graft-versus-host disease in mice. Front Immunol. 2017;8:1842. doi:10.3389/fimmu.2017.01842.
  27. Klein L, Robey EA, Hsieh CS. Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation. Nat Rev Immunol. 2019;19(1):7-18.
  28. Greinix HT, Worel N, Just U, Knobler R. Extracorporeal photopheresis in acute and chronic graft-versus-host disease. Transfus Apher Sci. 2014;50(3):349-357.
  29. Escamilla Gómez V, García-Gutiérrez V, López Corral L, García Cadenas I, Pérez Martínez A, Márquez Malaver FJ, Caballero-Velázquez T, González Sierra PA, Viguria Alegría MC, Parra Salinas IM, et al.; Grupo Español de Trasplante Hematopoyético (GETH). Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study. Bone Marrow Transplant. 2020;55(3):641-648.
  30. Murata M, Nakasone H, Kanda J, Nakane T, Furukawa T, Fukuda T, Mori T, Taniguchi S, Eto T, Ohashi K, et al. Clinical factors predicting the response of acute graft-versus-host disease to corticosteroid therapy: an analysis from the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2013;19(8):1183-1189.

" ["~DETAIL_TEXT"]=> string(25361) "

Introduction

Chronic graft-versus-host disease (cGvHD) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is associated both with long-term mortality and significant disability in long-term survivors. Its incidence varies from 10% to 80% according to the type of prophylaxis, type of the donor and several other risk factors [1-4]. Although cGvHD is associated with reduced risk of relapse and improved survival in the majority of malignant diseases [5], the persistence of clinical signs is associated with long-term mortality due to cardiovascular disease, infections and secondary malignancies [6]. Also cGvHD is the major cause of decline in the quality of life (QoL), social and professional disability. Gastrointestinal, joint and kidney problems are the main drivers of QoL decline [7-9].

The early studies of cGvHD treatment demonstrated a superiority of steroids over other agents in the treatment of cGvHD in terms of survival [10, 11]. However all subsequent attempts to improve response rate with augmented immunosuppression were not successful. Addition of thalidomide and mycofenolate mofetil resulted in higher frequency of adverse events and infection-related mortality [12, 13]. The only combination with some benefit in terms of steroid sparing was the combination of steroids and cyclosporine A (CsA), which demonstrated comparable response rate and duration of immunosuppression, however the cumulative dose of steroids was less in the combination arm, which resulted in the reduced frequency of femur aseptic necrosis [14]. The failure of these clinical trials to demonstrate improved response rate lead to the shift in the concept of cGvHD treatment. Currenly it is considered that immunosuppressive therapy (IST) does not induce tolerance, but rather alleviates target organ damage before the tolerance between donor and recipient cells occur. This understanding creates a dissonance between endpoints from the clinical studies and the real clinical practice where the formal response criteria, like decrease in the severity score or improved 2-minute walk test results, does not necessarily correlate with long-term prognosis.

While several studies focus on the clinical features of cGvHD that are associated with adverse prognosis [15, 16], few focus on the prognosis according to the response to treatment. Now we have novel effective treatments for steroid-refractory disease, which could be steroid-sparing and facilitate better clinical responses [17, 18]. Thus it is important to define the goals of therapy for cGvHD. In this single center study we did not evaluate the outcomes of certain treatment modalities for chronic GvHD but rather focused on IST discontinuation, complete response of cGvHD and survival. For this purpose we included only patients who have long-term follow up after onset of cGvHD. As the first line of therapy 62% of patients received prednisone 1 mg/kg daily in combination with calcineurin inhibitor (CNI), 22% received CNI as the monotherapy, 16% received monotherapy with a second line treatments.

Patients and methods

Table 1.

Moiseev-tab01.jpg

Patients and transplantation procedures

Two hundred and nine patients transplanted in 2006-2017 in Pavlov First Saint Petersburg State Medical University were included in the study. The inclusion criteria were moderate or severe disease according to National Institute of Health (NIH) 2015 criteria [19], administration of systemic treatment for cGvHD, transplantation from 9-10/10 HLA-matched related or unrelated donor. All patients signed informed consent for the use of their medical data in research purposes. Two thirds of patients had either acute myeloblastic leukemia or acute lymphoblastic leukemia, 49% had severe cGvHD, 51% – moderate. Median time from HSCT to cGvHD onset was 166 days. Twenty three percent received GvHD prophylaxis with post-ransplantation cyclophosphamide (PTCY) and the rest – conventional prophylaxis with calcineurin inhibitor and antimetabolite. Median follow up time after the onset of cGvHD was 52 months. More than 56% had three or more organ involvement (Table 1).

Clinical definitions

Time to disease relapse incidence (RI), complete response (CR), non-relapse mortality (NRM), overall survival (OS) and event-free survival (EFS), were defined as the time from cGvHD onset to the event. RI and NRM were considered a competing risk events. RI and CR were also considered competing risks. cGvHD severity was evaluated using NIH 2015 criteria [19], while response using 2006 NIH criteria [20]. Complete response was defined as absence of cGvHD clinical signs with IST discontinued. Partial response (PR) was defined as decrease in the total NIH score without increase in each individual organ score.

Statistical analysis

Non-parametric analysis included Chi-square test, Mann-Whitney test according to the type of data. The survival distributions for OS, EFS, were calculated using Kaplan-Meier methodology. The comparisons were made using the log-rank test. Cumulative incidence analysis with competing risks RI, NRM, CR was performed using Gray test. Relapse and NRM were accounted as competing risks as well as RI and CR. Fine and Grey regression was used for the multivariate analysis of cumulative incidences. Factors used for multivariate correction had at least p=0.10 significance in the univariate analysis.

Results

As the first line of therapy 62% of patients received prednisone 1 mg/kg daily in combination with calcineurin inhibitor (CNI), 22% received CNI as the monotherapy, 16% received monotherapy with a second line treatment (pharmacological or extracorporeal photopheresis without steroids. Beyond the first line 39.56% of patients required additional treatment. The most frequent options were ECP, IL-2, JAK inhibitors, BTK inhibitors, tyrosine-kinase inhibitors (TKI).

At five years, the cumulative incidence of CR was 16.9% (95% CI 10.5-24.7%). The proportion of patients with CR was 18.68%. However the cumulative incidence of IST discontinuation without GVHD flare was higher – 51.2% (95% CI 40.0-61.2%), and close to the proportion of patients with CR and mild chronic GvHD manifestations after treatment (44.5%). The competing risk of relapse was 25.4% (95% CI 18.6-32.8%) (Fig. 1).

Moiseev-fig01.jpg

Figure 1. (A) Initial severity of cGvHD before treatment and at last follow up. (B) Cumulative incidence of complete remission and immunosuppression (IST) discontinuation. Relapse was accounted as competing risk

In the multivariate analysis there was only one significant predictor of CR – severe form of chronic GvHD comparing to the moderate disease (HR 0.26, 95%CI 0.08-0.728, p=0.0194). The other factors significant in the univariate analysis like type of initial treatment (HR 0.84, 95%CI 0.44-1.46, p=0.5154), type of GvHD prophylaxis (HR 0.95, 95%CI 0.34-2.48, p=0.9122), previous acute GvHD grade 3-4 (HR 0.82, 95%CI 0.28-2.40, p=0.82) and number of organs involved (HR 0.77, 95%CI 0.52-1.08, p=0.1751) had no impact on CR cumulative incidence.

In the multivariate analysis of IST discontinuation, the statistical significance was observed for overall severity of cGvHD (HR 0.45, 95%CI 0.25-0.84, p=0.0049) and female donor for male recipient (HR 0.33, 95%CI 0.25-0.81, p= 0.0370). The other factors like type of the donor (HR 0.70, 95%CI 0.37-1.38, p=0.2909), previous severe acute GvHD (HR 0.96, 95%CI 0.49-1.82, p=0.9379), type of initial GvHD treatment (HR 0.93, 95%CI 0.63-1.33, p=0.7021), GI involvement (HR 0.76, 95%CI 0.53-1.04, p=0.1223), or lung involvement (HR 0.78, 95%CI 0.47-1.17, p=0.2288) were not statistically significant (Figure 2A). However it is worth mentioning that 55% of patients without GI cGvHD discontinued IST, while 28% achieved this goal with mild GI GvHD, 26% with moderate and 8% with severe. The same pattern was observed for lung GvHD: 47% discontinued systemic IST without lung involvement and 25% with mild bronchiolitis obliterans (BO), 29% with moderate and only 10% with severe. Absence of significance in the multivariate analysis may be partially explained by certain overlap of these variables with overall severity of cGvHD. Among patients with moderate disease 56% discontinued IST, but with severe disease – only 25%. At the end of the follow up patients with CR discontinued IST in 91% of cases, with mild cGvHD in 53% of cases, with moderate in 24% of cases and with severe in 2% of cases.

The analysis of NRM demonstrated that the major factors with impact on 5-year NRM were severe form of cGvHD (32% vs 13%, p=0.0050), discontinuation of systemic IST (2% vs 42%, p<0.0001) and surprisingly steroid-free first-line therapy (8% vs 32%, p=0.0006). Although administration of second-line regimens were not statistically significant in this data set (NRM 20% vs 27%, p= 0.7092) (Fig. 3), it was forced in the subsequent multivariate analysis due to significant literature data on increased mortality in steroid- refractory GvHD.

In the multivariate analysis it was demonstrated that the initial severity of cGvHD did not influenced the NRM (HR 1.70, 95%CI 0.80-3.97, p=0.1959), while early discontinuation of IST (HR 0.03, 95%CI 0.01-0.15, p=0.0005), steroid-free starting therapy (HR 0.25, 95%CI 0.08-0.58, p=0.0035) and use of second-line therapy (HR 0.49, 95%CI 0.25-0.96, p=0.0322) were protective against NRM (Fig. 2B). Since it was a non-randomized study patients with steroid-free starting therapy more often had moderate disease compared to patients in the steroids group (41% vs 66%, p= 0.0011). The same is true for additional cGvHD therapy: 54% received it in the severe group, while only 20% received it in the mode-rate cGvHD group.

Moiseev-fig02.jpg

Figure 2. (A) Multivariate analysis of predictors for successful IST discontinuation. (B) Multivariate analysis of predictors for non-relapse mortality

MUD=matched unrelated donor, MRD=matched related donor, GI=gastrointestinal. IST= immunosuppressive treatment. Factors with significance <0.1 in the univariate analysis were included.

Moiseev-fig03.jpg

Figure 3. Major predictors of non-relapse mortality

Discussion

This retrospective analysis of the large single center-cohort is not in line with several previous studies. The initial studies of cGvHD treatment identified prednisone as an optimal therapy among the existing at that time immunosuppressive agents [10, 11]. Many clinics even do not use CNIs in combination with steroids for the treatment, given the comparable response rate [14]. All the subsequent studies demonstrated that addition of thalidomide [13], or MMF [21], or ECP [22] in the first line of therapy did not improve response or survival. In our single-center study of patients with cGvHD many did not receive first line steroids. Partly, this was due to the single-agent PTCY prophylaxis protocol involving first line CsA for both acute and chronic GvHD, but also due national peculiarities of healthcare when a patient cannot easily travel to the transplant center and CNIs had to be introduced during distant consultations, while treatment with steroids were saved only for patients who could be admitted to the outpatient care. Secondly, there was an internal policy of faster steroid tapper after introduction of second line treatment than in the majority of centers [23]. Hence, if the patient did not show the signs of the flair he usually completely discontinued steroids within a month and continued only second line treatment, while the standard policy is to continue steroids until response. These differences in the internal policies led to several interesting discoveries.

First, patients initially treated without steroids had significantly reduced NRM. Although it is not well documented in the literature, but the majority of early deaths in chronic GvHD patients occur not due to cGvHD clinical manifestations, but due to recurrent infections [24]. Hence, the modality of immunosuppressive therapy should focus on minimal increase in the rate of infectious complications while providing at least minimal continuous GvHD improvement. This goes in line with recent single cell sequencing studies demonstrating that variation in cGvHD manifestation is due to the mixture of alloreactive graft-derived cells and de novo T-cells generated in thymus. Exhaustion of these clones is associated with cGvHD amelioration or resolution [25, 26]. Now there is not enough data to support that exhaustion and elimination of GvHD-related T-cells is a consequence of IST. This might be as well the result of restored process of negative T-cell cell selection in the thymus [27]. This study proposes the idea that minimally effective immunosuppression should be used.

At the time R. Storb et al. compared the efficacy of various IST with prednisone the choice of agents was limited to azathioprine, methotrexate and cyclophosphamide. Now we have several effective therapy options for cGVHD, including ECP [28], JAK inhibitors [18], BTK inhibitors [17]. All of them were used either as early therapeutic intervention in the first or second lines of therapy in this study in a small proportion of patients. None of these agents were previously randomized against steroids but rather randomized on top of steroids. Second line therapy with kinase inhibitors demonstrated excellent survival, so moving this agents in the first line might reduce infection-related NRM [17, 19, 29]. Despite this was not a randomized study and steroid-free first line therapy group had less patients with severe cGvHD, at least these results warrant randomized studies of novel therapies against steroids, but not with steroids.

Although it was demonstrated previously that patients with improvement in cGvHD manifestations have better survival compared to patients without improvement [30], this study demonstrated how long the IST should continue and when it should be stopped. The ideal situation is reaching CR or mild manifestations of cGvHD when systemic IST could be stopped and GvHD controlled by topical therapy. A quarter of patients with formal moderate disease can also stop systemic IST without a flare. Usually, these are lung GvHD patients who may never restore the lung capacity to normal, or patients with eye involvement in whom it will be controlled with topical therapy. Still there is a problem with patients who still have severe disease after several years of therapy. Despite they will have higher mortality than patients with GvHD resolution, in this study we demonstrated that they may benefit in terms of NRM from early intervention with second-line therapies or using them in the first line. Also prospective trials are required to confirm these observations. The long-term results of this approach is unknown, however we know that prolonged use of steroids is associated with dismal prognosis [6].

Financial Disclosure Statement

The authors have nothing to disclaim.

Acknowledgements

The authors declare no conflicts of interest.

References

  1. Storb R, Deeg HJ, Pepe M, Appelbaum F, Anasetti C, Beatty P, Bensinger W, Berenson R, Buckner CD, Clift R, et al. Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood. 1989;73(6):1729-1734. PMID: 2653461.
  2. Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P, Oneto R, Bruno B, Barbanti M, Sacchi N, Van Lint MT, Bosi A. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001;98(10):2942-2947.
  3. Maschan M, Shelikhova L, Ilushina M, Kurnikova E, Boyakova E, Balashov D, Persiantseva M, Skvortsova Y, Laberko A, Muzalevskii Y, et al. TCR-alpha/beta and CD19 depletion and treosulfan-based conditioning regimen in unrelated and haploidentical transplantation in children with acute myeloid leukemia. Bone Marrow Transplant. 2016;51(5):668-674.
  4. Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, Wang SA, Konopleva M, Fernandez-Vina M, Montes N, et al. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18(12):1835-1844.
  5. Stern M, de Wreede LC, Brand R, van Biezen A, Dreger P, Mohty M, de Witte TM, Kröger N, Ruutu T. Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia. 2014;28(11):2235-2240.
  6. Ruutu T, Nihtinen A, Niittyvuopio R, Juvonen E, Volin L. A randomized study of cyclosporine and methotrexate with or without methylprednisolone for the prevention of graft-versus-host disease: Improved long-term survival with triple prophylaxis. Cancer. 2018;124(4):727-733.
  7. Inamoto Y, Pidala J, Chai X, Kurland BF, Weisdorf D, Flowers ME, Palmer J, Arai S, Jacobsohn D, Cutler C, Jagasia M, Goldberg JD, Martin PJ, Pavletic SZ, Vogelsang GB, Lee SJ, Carpenter PA; Chronic GVHD Consortium. Assessment of joint and fascia manifestations in chronic graft-versus-host disease. Arthritis Rheumatol. 2014;66(4):1044-1052.
  8. Glezerman IG, Jhaveri KD, Watson TH, Edwards AM, Papadopoulos EB, Young JW, Flombaum CD, Jakubowski AA. Chronic kidney disease, thrombotic microangiopathy, and hypertension following T cell-depleted hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2010;16(7):976-984.
  9. Worel N, Biener D, Kalhs P, Mitterbauer M, Keil F, Schulenburg A, Höcker P, Dieckmann K, Fischer G, Rosenmayr A, et al. Long-term outcome and quality of life of patients who are alive and in complete remission more than two years after allogeneic and syngeneic stem cell transplantation. Bone Marrow Transplant. 2002;30(9):619-626.
  10. Sullivan KM, Shulman HM, Storb R, Weiden PL, Witherspoon RP, McDonald GB, Schubert MM, Atkinson K, Thomas ED. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood. 1981;57(2):267-276. PMID: 7004534.
  11. Sullivan KM, Witherspoon RP, Storb R, Deeg HJ, Dahlberg S, Sanders JE, Appelbaum FR, Doney KC, Weiden P, Anasetti C, et al. Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease. Blood. 1988;72(2):555-561.
  12. Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, Wingard JR, Shaughnessy PJ, DeVetten MP, Jagasia M, et al. Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood. 2009;113(21):5074-5082.
  13. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, Sanders JE, Witherspoon RP, Appelbaum FR, Storb R, Martin PJ. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood. 2000;96(12):3995-3996.
  14. Koc S, Leisenring W, Flowers ME, Anasetti C, Deeg HJ, Nash RA, Sanders JE, Witherspoon RP, Storb R, Appelbaum FR, Martin PJ. Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone. Blood. 2002;100(1):48-51.
  15. Ayuk F, Veit R, Zabelina T, Bussmann L, Christopeit M, Alchalby H, Wolschke C, Lellek H, Bacher U, Zander AR, Kröger N. Prognostic factors for survival of patients with newly diagnosed chronic GvHD according to NIH criteria. Ann Hematol. 2015;94(10):1727-1732.
  16. Pavletic SZ, Smith LM, Bishop MR, Lynch JC, Tarantolo SR, Vose JM, Bierman PJ, Hadi A, Armitage JO, Kessinger A. Prognostic factors of chronic graft-versus-host disease after allogeneic blood stem-cell transplantation. Am J Hematol. 2005;78(4):265-274.
  17. Miklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, Flowers ME, Logan AC, Nakamura R, Blazar BR, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243-2250. doi: 10.1182/blood-2017-07-793786.
  18. Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, Spoerl S, Ditschkowski M, Ecsedi M, Sockel K, Ayuk F, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29(10):2062-2068.
  19. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, Palmer J, Weisdorf D, Treister NS, Cheng GS, et al. National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015; 21(3):389-401.e1.
  20. Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on criteria for clinical trials in chronic graft-versus-host disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant 2006; 12: 252-266.
  21. Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, Wingard JR, Shaughnessy PJ, DeVetten MP, Jagasia M, et al. Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease. Blood. 2009; 113(21):5074-5082.
  22. Jagasia M, Scheid C, Socié G, Ayuk FA, Tischer J, Donato ML, Bátai Á, Chen H, Chen SC, Chin T, et al. Randomized controlled study of ECP with methoxsalen as first-line treatment of patients with moderate to severe cGVHD. Blood Adv. 2019;3(14):2218-2229.
  23. Sarantopoulos S, Cardones AR, Sullivan KM. How I treat refractory chronic graft-versus-host disease. Blood. 2019;133(11):1191-1200.
  24. Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, Sorror ML, Horowitz MM, Bolwell B, Rizzo JD, Socié G. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011;29(16):2230-2239.
  25. Balakrishnan A, Gloude N, Sasik R, Ball ED, Morris GP. Proinflammatory dual receptor T cells in chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2017;23(11):1852-1860.
  26. Kosugi-Kanaya M, Ueha S, Abe J, et al. Long-lasting graft-derived donor T cells contribute to the pathogenesis of chronic graft-versus-host disease in mice. Front Immunol. 2017;8:1842. doi:10.3389/fimmu.2017.01842.
  27. Klein L, Robey EA, Hsieh CS. Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation. Nat Rev Immunol. 2019;19(1):7-18.
  28. Greinix HT, Worel N, Just U, Knobler R. Extracorporeal photopheresis in acute and chronic graft-versus-host disease. Transfus Apher Sci. 2014;50(3):349-357.
  29. Escamilla Gómez V, García-Gutiérrez V, López Corral L, García Cadenas I, Pérez Martínez A, Márquez Malaver FJ, Caballero-Velázquez T, González Sierra PA, Viguria Alegría MC, Parra Salinas IM, et al.; Grupo Español de Trasplante Hematopoyético (GETH). Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study. Bone Marrow Transplant. 2020;55(3):641-648.
  30. Murata M, Nakasone H, Kanda J, Nakane T, Furukawa T, Fukuda T, Mori T, Taniguchi S, Eto T, Ohashi K, et al. Clinical factors predicting the response of acute graft-versus-host disease to corticosteroid therapy: an analysis from the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2013;19(8):1183-1189.

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(2) "20" ["~SORT"]=> string(2) "20" ["CODE"]=> string(100) "dolgosrochnye-tseli-terapii-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-posle-allogennoy-so" ["~CODE"]=> string(100) "dolgosrochnye-tseli-terapii-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-posle-allogennoy-so" ["EXTERNAL_ID"]=> string(4) "1939" ["~EXTERNAL_ID"]=> string(4) "1939" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(424) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клетокLong-term goals in the treatment of chronic graft-versus-host disease after matched allogeneic hematopoietic stem cell transplantation" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(5075) "<p style="text-align: justify;">Хроническая реакция «трансплантат против хозяина» (хрРТПХ) является частым осложнением аллогенной трансплантации гемопоэтических стволовых клеток. Частота развития этого осложнения колеблется от 10% до 80% в зависимости от типа профилактики, типа донора и других факторов риска. Хотя хрРТПХ ассоциируется со сниженным риском рецидива, персистенция клинических симптомов связана с долгосрочной летальностью, частыми госпитализациями и инвалидностью. Несмотря на то, что существуют четкие критерии эффективности для клинических испытаний новых препаратов, определение тактики в клинической практике должно включать и долгосрочные цели, как при всех аутоиммунных заболеваниях. Пока нет единого мнения в отношении этих целей терапии. Анализируя результаты терапии хрРТПХ в большой когорте пациентов в рамках одноцентрового исследования, мы попытались сосредоточиться на предикторах долгосрочного прогноза и их связи с терапией.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">В исследование были включены 182 пациента с средней тяжестью и тяжелой хрРТПХ. Большинству пациентов была проведена аллогенная трансплантация по поводу злокачественных заболеваний, у 49% была тяжелая форма хрРТПХ, у 51% – проявления средней степени тяжести. Среднее время наблюдения составило 52 месяца. Помимо первой линии, 39,56% пациентов требовали дополнительного лечения.</p> <h3>Результаты</h3> <p style="text-align: justify;">Через пять лет кумулятивная частота полных ремиссии составила 16,9% (95% ДИ 10,5-24,7%), а частота прекращения иммуносупрессивной терапии (ИСТ) без обострения РТПХ составила 51,2% (95% ДИ 40,0-61,2%). Основными предикторами отмены ИСТ были общая тяжесть хрРТПХ (HR 0,45, 95% ДИ 0,25-0,84, p=0,0049) и женщина донор для реципиента мужчины (HR 0,33, 95% CI 0,25-0,81, p=0,0370). Анализ частоты летальности без рецидива (ЛБР) показал, что прекращение ИСТ было основным предиктором ЛБР (2% против 42%, HR 0,03, 95% CI 0,01-0,15, p=0,0005). В конце периода наблюдения пациенты с полным ответом прекратили ИСТ в 91% случаев, с легкой формой РТПХ в 53% случаев, со средней тяжести в 24% случаев и с тяжелой в 2% случаев. Другими значимыми факторами для ЛБР были начало терапии без стероидов (HR 0,25, 95% ДИ 0,08-0,58, p=0,0035) и раннее использование терапии второй линии (HR 0,49, 95% CI 0,25-0,96, p=0,0322).</p> <h3>Выводы</h3> <p style="text-align: justify;">Исследование продемонстрировало, что прекращение системной терапии ИСТ без обострения хронической РТПХ должно быть основной целью терапии. Кроме того, исследование указывает на обоснованность рандомизированных исследований новых методов второй линии не с глюкокортикостероидами в первой линии, а против них.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Хроническая реакция трансплантат против хозяина, терапия, долгосрочные результаты, цели терапии.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["SECTION_META_TITLE"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["SECTION_META_KEYWORDS"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["SECTION_META_DESCRIPTION"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["SECTION_PICTURE_FILE_ALT"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["SECTION_PICTURE_FILE_TITLE"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "dolgosrochnye-tseli-terapii-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-posle-allogennoy-so" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(290) "Долгосрочные цели терапии хронической реакции «трансплантат против хозяина» после аллогенной совместимой трансплантации гемопоэтических стволовых клеток" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "dolgosrochnye-tseli-terapii-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-posle-allogennoy-so" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "dolgosrochnye-tseli-terapii-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-posle-allogennoy-so" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "dolgosrochnye-tseli-terapii-khronicheskoy-reaktsii-transplantat-protiv-khozyaina-posle-allogennoy-so" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "170" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27333" ["VALUE"]=> string(10) "22.10.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "22.10.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27334" ["VALUE"]=> string(10) "13.11.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "13.11.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27339" ["VALUE"]=> array(2) { ["TEXT"]=> string(339) "<p>Иван С. Моисеев, Анна А. Доценко, Анна Г. Смирнова, Юлия Ю. Власова, Елена В. Морозова, Сергей Н. Бондаренко, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Борис В. Афанасьев</span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(305) "

Иван С. Моисеев, Анна А. Доценко, Анна Г. Смирнова, Юлия Ю. Власова, Елена В. Морозова, Сергей Н. Бондаренко, Борис В. Афанасьев

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27340" ["VALUE"]=> array(2) { ["TEXT"]=> string(368) "<p>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(356) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27341" ["VALUE"]=> array(2) { ["TEXT"]=> string(5075) "<p style="text-align: justify;">Хроническая реакция «трансплантат против хозяина» (хрРТПХ) является частым осложнением аллогенной трансплантации гемопоэтических стволовых клеток. Частота развития этого осложнения колеблется от 10% до 80% в зависимости от типа профилактики, типа донора и других факторов риска. Хотя хрРТПХ ассоциируется со сниженным риском рецидива, персистенция клинических симптомов связана с долгосрочной летальностью, частыми госпитализациями и инвалидностью. Несмотря на то, что существуют четкие критерии эффективности для клинических испытаний новых препаратов, определение тактики в клинической практике должно включать и долгосрочные цели, как при всех аутоиммунных заболеваниях. Пока нет единого мнения в отношении этих целей терапии. Анализируя результаты терапии хрРТПХ в большой когорте пациентов в рамках одноцентрового исследования, мы попытались сосредоточиться на предикторах долгосрочного прогноза и их связи с терапией.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">В исследование были включены 182 пациента с средней тяжестью и тяжелой хрРТПХ. Большинству пациентов была проведена аллогенная трансплантация по поводу злокачественных заболеваний, у 49% была тяжелая форма хрРТПХ, у 51% – проявления средней степени тяжести. Среднее время наблюдения составило 52 месяца. Помимо первой линии, 39,56% пациентов требовали дополнительного лечения.</p> <h3>Результаты</h3> <p style="text-align: justify;">Через пять лет кумулятивная частота полных ремиссии составила 16,9% (95% ДИ 10,5-24,7%), а частота прекращения иммуносупрессивной терапии (ИСТ) без обострения РТПХ составила 51,2% (95% ДИ 40,0-61,2%). Основными предикторами отмены ИСТ были общая тяжесть хрРТПХ (HR 0,45, 95% ДИ 0,25-0,84, p=0,0049) и женщина донор для реципиента мужчины (HR 0,33, 95% CI 0,25-0,81, p=0,0370). Анализ частоты летальности без рецидива (ЛБР) показал, что прекращение ИСТ было основным предиктором ЛБР (2% против 42%, HR 0,03, 95% CI 0,01-0,15, p=0,0005). В конце периода наблюдения пациенты с полным ответом прекратили ИСТ в 91% случаев, с легкой формой РТПХ в 53% случаев, со средней тяжести в 24% случаев и с тяжелой в 2% случаев. Другими значимыми факторами для ЛБР были начало терапии без стероидов (HR 0,25, 95% ДИ 0,08-0,58, p=0,0035) и раннее использование терапии второй линии (HR 0,49, 95% CI 0,25-0,96, p=0,0322).</p> <h3>Выводы</h3> <p style="text-align: justify;">Исследование продемонстрировало, что прекращение системной терапии ИСТ без обострения хронической РТПХ должно быть основной целью терапии. Кроме того, исследование указывает на обоснованность рандомизированных исследований новых методов второй линии не с глюкокортикостероидами в первой линии, а против них.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Хроническая реакция трансплантат против хозяина, терапия, долгосрочные результаты, цели терапии.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4917) "

Хроническая реакция «трансплантат против хозяина» (хрРТПХ) является частым осложнением аллогенной трансплантации гемопоэтических стволовых клеток. Частота развития этого осложнения колеблется от 10% до 80% в зависимости от типа профилактики, типа донора и других факторов риска. Хотя хрРТПХ ассоциируется со сниженным риском рецидива, персистенция клинических симптомов связана с долгосрочной летальностью, частыми госпитализациями и инвалидностью. Несмотря на то, что существуют четкие критерии эффективности для клинических испытаний новых препаратов, определение тактики в клинической практике должно включать и долгосрочные цели, как при всех аутоиммунных заболеваниях. Пока нет единого мнения в отношении этих целей терапии. Анализируя результаты терапии хрРТПХ в большой когорте пациентов в рамках одноцентрового исследования, мы попытались сосредоточиться на предикторах долгосрочного прогноза и их связи с терапией.

Пациенты и методы

В исследование были включены 182 пациента с средней тяжестью и тяжелой хрРТПХ. Большинству пациентов была проведена аллогенная трансплантация по поводу злокачественных заболеваний, у 49% была тяжелая форма хрРТПХ, у 51% – проявления средней степени тяжести. Среднее время наблюдения составило 52 месяца. Помимо первой линии, 39,56% пациентов требовали дополнительного лечения.

Результаты

Через пять лет кумулятивная частота полных ремиссии составила 16,9% (95% ДИ 10,5-24,7%), а частота прекращения иммуносупрессивной терапии (ИСТ) без обострения РТПХ составила 51,2% (95% ДИ 40,0-61,2%). Основными предикторами отмены ИСТ были общая тяжесть хрРТПХ (HR 0,45, 95% ДИ 0,25-0,84, p=0,0049) и женщина донор для реципиента мужчины (HR 0,33, 95% CI 0,25-0,81, p=0,0370). Анализ частоты летальности без рецидива (ЛБР) показал, что прекращение ИСТ было основным предиктором ЛБР (2% против 42%, HR 0,03, 95% CI 0,01-0,15, p=0,0005). В конце периода наблюдения пациенты с полным ответом прекратили ИСТ в 91% случаев, с легкой формой РТПХ в 53% случаев, со средней тяжести в 24% случаев и с тяжелой в 2% случаев. Другими значимыми факторами для ЛБР были начало терапии без стероидов (HR 0,25, 95% ДИ 0,08-0,58, p=0,0035) и раннее использование терапии второй линии (HR 0,49, 95% CI 0,25-0,96, p=0,0322).

Выводы

Исследование продемонстрировало, что прекращение системной терапии ИСТ без обострения хронической РТПХ должно быть основной целью терапии. Кроме того, исследование указывает на обоснованность рандомизированных исследований новых методов второй линии не с глюкокортикостероидами в первой линии, а против них.

Ключевые слова

Хроническая реакция трансплантат против хозяина, терапия, долгосрочные результаты, цели терапии.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27335" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-29-36" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-29-36" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27343" ["VALUE"]=> array(2) { ["TEXT"]=> string(247) "<p>Ivan S. Moiseev, Anna A. Dotsenko, Anna G. Smirnova, Yulia Yu. Vlasova, Elena V. Morozova, Sergey N. Bondarenko, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev</span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(213) "

Ivan S. Moiseev, Anna A. Dotsenko, Anna G. Smirnova, Yulia Yu. Vlasova, Elena V. Morozova, Sergey N. Bondarenko, Boris V. Afanasyev

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27344" ["VALUE"]=> array(2) { ["TEXT"]=> string(527) "<p>RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia</p><br> <p><b>Correspondence</b><br> Ivan S. Moiseev, PhD, MD. RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia<br> Phone: +7(812) 338 6259, +7 (921) 796 1951<br> Fax: +7(812) 338 6263<br> E-mail: moisiv@mail.ru</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(461) "

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia


Correspondence
Ivan S. Moiseev, PhD, MD. RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7(812) 338 6259, +7 (921) 796 1951
Fax: +7(812) 338 6263
E-mail: moisiv@mail.ru

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27345" ["VALUE"]=> array(2) { ["TEXT"]=> string(2710) "<p style="text-align: justify;">Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic hematopoietic stem cell transplantation. Its incidence varies from 10% to 80% according to the type of prophylaxis, type of the donor and other risk factors. Although cGvHD is associated with reduced risk of relapse, the persistence of clinical signs is associated with long-term mortality, morbidity and disability. Despite there are clear endpoints for the clinical trials of novel agents, the choices in clinical practice should involve long-term goals like in all autoimmune disease. So far, there is no consensus on these goals. Analyzing the results of cGvHD therapy in the large single-center cohort of patients we tried to focus on predictors of long-term prognosis and their association with therapy.</p> <h3>Patients and methods</h3> <p style="text-align: justify;">The study included 182 patients with moderate and severe cGvHD. The majority of patients were allografted for malignant diseases and 49% had severe cGvHD, 51% – moderate disease. Median follow up time was 52 months. Beyond the first line 39.56% of patients required additional treatment.</p> <h3>Results</h3> <p style="text-align: justify;">At five years the cumulative incidence of complete responses was 16.9% (95% CI 10.5-24.7%) and immunosuppressive therapy (IST) discontinuation without GvHD flare was 51.2% (95% CI 40.0-61.2%). The major predictors of IST discontinuation were overall severity of cGvHD (HR 0.45, 95%CI 0.25-0.84, p=0.0049) and female donor for male recipient (HR 0.33, 95%CI 0.25-0.81, p= 0.0370). The analysis of non-relapse mortality (NRM) demonstrated that discontinuation of IST was the major predictor (2% <i>vs</i> 42%, HR 0.03, 95%CI 0.01-0.15, p=0.0005). At the end of the follow up patients with complete response discontinued IST in 91% of cases, with mild cGvHD in 53% of cases, with moderate in 24% of cases and with severe in 2% of cases. The other significant factors for NRM were steroid-free starting therapy (HR 0.25, 95%CI 0.08-0.58, p=0.0035) and early use of second-line therapy (HR 0.49, 95%CI 0.25-0.96, p=0.0322). In conclusion, the study demonstrated that discontinuation of systemic IST therapy without the flare of cGvHD should be the goal of therapy. Also the study creates a rationale for randomized studies of novel second-line options not with but against steroids in the first line. </p> <h2>Keywords</h2> <p style="text-align: justify;">Chronic graft-versus-host disease, therapy, long-term outcomes, goals of therapy.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2574) "

Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic hematopoietic stem cell transplantation. Its incidence varies from 10% to 80% according to the type of prophylaxis, type of the donor and other risk factors. Although cGvHD is associated with reduced risk of relapse, the persistence of clinical signs is associated with long-term mortality, morbidity and disability. Despite there are clear endpoints for the clinical trials of novel agents, the choices in clinical practice should involve long-term goals like in all autoimmune disease. So far, there is no consensus on these goals. Analyzing the results of cGvHD therapy in the large single-center cohort of patients we tried to focus on predictors of long-term prognosis and their association with therapy.

Patients and methods

The study included 182 patients with moderate and severe cGvHD. The majority of patients were allografted for malignant diseases and 49% had severe cGvHD, 51% – moderate disease. Median follow up time was 52 months. Beyond the first line 39.56% of patients required additional treatment.

Results

At five years the cumulative incidence of complete responses was 16.9% (95% CI 10.5-24.7%) and immunosuppressive therapy (IST) discontinuation without GvHD flare was 51.2% (95% CI 40.0-61.2%). The major predictors of IST discontinuation were overall severity of cGvHD (HR 0.45, 95%CI 0.25-0.84, p=0.0049) and female donor for male recipient (HR 0.33, 95%CI 0.25-0.81, p= 0.0370). The analysis of non-relapse mortality (NRM) demonstrated that discontinuation of IST was the major predictor (2% vs 42%, HR 0.03, 95%CI 0.01-0.15, p=0.0005). At the end of the follow up patients with complete response discontinued IST in 91% of cases, with mild cGvHD in 53% of cases, with moderate in 24% of cases and with severe in 2% of cases. The other significant factors for NRM were steroid-free starting therapy (HR 0.25, 95%CI 0.08-0.58, p=0.0035) and early use of second-line therapy (HR 0.49, 95%CI 0.25-0.96, p=0.0322). In conclusion, the study demonstrated that discontinuation of systemic IST therapy without the flare of cGvHD should be the goal of therapy. Also the study creates a rationale for randomized studies of novel second-line options not with but against steroids in the first line.

Keywords

Chronic graft-versus-host disease, therapy, long-term outcomes, goals of therapy.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27336" ["VALUE"]=> string(134) "Long-term goals in the treatment of chronic graft-versus-host disease after matched allogeneic hematopoietic stem cell transplantation" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(134) "Long-term goals in the treatment of chronic graft-versus-host disease after matched allogeneic hematopoietic stem cell transplantation" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["PDF_RU"]=> array(36) { ["ID"]=> string(2) "43" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF RUS" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_RU" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "43" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27342" ["VALUE"]=> string(4) "2320" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2320" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF RUS" ["~DEFAULT_VALUE"]=> string(0) "" } ["PDF_EN"]=> array(36) { ["ID"]=> string(2) "44" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF ENG" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "44" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27346" ["VALUE"]=> string(4) "2321" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2321" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF ENG" ["~DEFAULT_VALUE"]=> string(0) "" } ["NAME_LONG"]=> array(36) { ["ID"]=> string(2) "45" ["TIMESTAMP_X"]=> string(19) "2023-04-13 00:55:00" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(72) "Название (для очень длинных заголовков)" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "NAME_LONG" ["DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "45" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27343" ["VALUE"]=> array(2) { ["TEXT"]=> string(247) "<p>Ivan S. Moiseev, Anna A. Dotsenko, Anna G. Smirnova, Yulia Yu. Vlasova, Elena V. Morozova, Sergey N. Bondarenko, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev</span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(213) "

Ivan S. Moiseev, Anna A. Dotsenko, Anna G. Smirnova, Yulia Yu. Vlasova, Elena V. Morozova, Sergey N. Bondarenko, Boris V. Afanasyev

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(213) "

Ivan S. Moiseev, Anna A. Dotsenko, Anna G. Smirnova, Yulia Yu. Vlasova, Elena V. Morozova, Sergey N. Bondarenko, Boris V. Afanasyev

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27345" ["VALUE"]=> array(2) { ["TEXT"]=> string(2710) "<p style="text-align: justify;">Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic hematopoietic stem cell transplantation. Its incidence varies from 10% to 80% according to the type of prophylaxis, type of the donor and other risk factors. Although cGvHD is associated with reduced risk of relapse, the persistence of clinical signs is associated with long-term mortality, morbidity and disability. Despite there are clear endpoints for the clinical trials of novel agents, the choices in clinical practice should involve long-term goals like in all autoimmune disease. So far, there is no consensus on these goals. Analyzing the results of cGvHD therapy in the large single-center cohort of patients we tried to focus on predictors of long-term prognosis and their association with therapy.</p> <h3>Patients and methods</h3> <p style="text-align: justify;">The study included 182 patients with moderate and severe cGvHD. The majority of patients were allografted for malignant diseases and 49% had severe cGvHD, 51% – moderate disease. Median follow up time was 52 months. Beyond the first line 39.56% of patients required additional treatment.</p> <h3>Results</h3> <p style="text-align: justify;">At five years the cumulative incidence of complete responses was 16.9% (95% CI 10.5-24.7%) and immunosuppressive therapy (IST) discontinuation without GvHD flare was 51.2% (95% CI 40.0-61.2%). The major predictors of IST discontinuation were overall severity of cGvHD (HR 0.45, 95%CI 0.25-0.84, p=0.0049) and female donor for male recipient (HR 0.33, 95%CI 0.25-0.81, p= 0.0370). The analysis of non-relapse mortality (NRM) demonstrated that discontinuation of IST was the major predictor (2% <i>vs</i> 42%, HR 0.03, 95%CI 0.01-0.15, p=0.0005). At the end of the follow up patients with complete response discontinued IST in 91% of cases, with mild cGvHD in 53% of cases, with moderate in 24% of cases and with severe in 2% of cases. The other significant factors for NRM were steroid-free starting therapy (HR 0.25, 95%CI 0.08-0.58, p=0.0035) and early use of second-line therapy (HR 0.49, 95%CI 0.25-0.96, p=0.0322). In conclusion, the study demonstrated that discontinuation of systemic IST therapy without the flare of cGvHD should be the goal of therapy. Also the study creates a rationale for randomized studies of novel second-line options not with but against steroids in the first line. </p> <h2>Keywords</h2> <p style="text-align: justify;">Chronic graft-versus-host disease, therapy, long-term outcomes, goals of therapy.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2574) "

Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic hematopoietic stem cell transplantation. Its incidence varies from 10% to 80% according to the type of prophylaxis, type of the donor and other risk factors. Although cGvHD is associated with reduced risk of relapse, the persistence of clinical signs is associated with long-term mortality, morbidity and disability. Despite there are clear endpoints for the clinical trials of novel agents, the choices in clinical practice should involve long-term goals like in all autoimmune disease. So far, there is no consensus on these goals. Analyzing the results of cGvHD therapy in the large single-center cohort of patients we tried to focus on predictors of long-term prognosis and their association with therapy.

Patients and methods

The study included 182 patients with moderate and severe cGvHD. The majority of patients were allografted for malignant diseases and 49% had severe cGvHD, 51% – moderate disease. Median follow up time was 52 months. Beyond the first line 39.56% of patients required additional treatment.

Results

At five years the cumulative incidence of complete responses was 16.9% (95% CI 10.5-24.7%) and immunosuppressive therapy (IST) discontinuation without GvHD flare was 51.2% (95% CI 40.0-61.2%). The major predictors of IST discontinuation were overall severity of cGvHD (HR 0.45, 95%CI 0.25-0.84, p=0.0049) and female donor for male recipient (HR 0.33, 95%CI 0.25-0.81, p= 0.0370). The analysis of non-relapse mortality (NRM) demonstrated that discontinuation of IST was the major predictor (2% vs 42%, HR 0.03, 95%CI 0.01-0.15, p=0.0005). At the end of the follow up patients with complete response discontinued IST in 91% of cases, with mild cGvHD in 53% of cases, with moderate in 24% of cases and with severe in 2% of cases. The other significant factors for NRM were steroid-free starting therapy (HR 0.25, 95%CI 0.08-0.58, p=0.0035) and early use of second-line therapy (HR 0.49, 95%CI 0.25-0.96, p=0.0322). In conclusion, the study demonstrated that discontinuation of systemic IST therapy without the flare of cGvHD should be the goal of therapy. Also the study creates a rationale for randomized studies of novel second-line options not with but against steroids in the first line.

Keywords

Chronic graft-versus-host disease, therapy, long-term outcomes, goals of therapy.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2574) "

Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic hematopoietic stem cell transplantation. Its incidence varies from 10% to 80% according to the type of prophylaxis, type of the donor and other risk factors. Although cGvHD is associated with reduced risk of relapse, the persistence of clinical signs is associated with long-term mortality, morbidity and disability. Despite there are clear endpoints for the clinical trials of novel agents, the choices in clinical practice should involve long-term goals like in all autoimmune disease. So far, there is no consensus on these goals. Analyzing the results of cGvHD therapy in the large single-center cohort of patients we tried to focus on predictors of long-term prognosis and their association with therapy.

Patients and methods

The study included 182 patients with moderate and severe cGvHD. The majority of patients were allografted for malignant diseases and 49% had severe cGvHD, 51% – moderate disease. Median follow up time was 52 months. Beyond the first line 39.56% of patients required additional treatment.

Results

At five years the cumulative incidence of complete responses was 16.9% (95% CI 10.5-24.7%) and immunosuppressive therapy (IST) discontinuation without GvHD flare was 51.2% (95% CI 40.0-61.2%). The major predictors of IST discontinuation were overall severity of cGvHD (HR 0.45, 95%CI 0.25-0.84, p=0.0049) and female donor for male recipient (HR 0.33, 95%CI 0.25-0.81, p= 0.0370). The analysis of non-relapse mortality (NRM) demonstrated that discontinuation of IST was the major predictor (2% vs 42%, HR 0.03, 95%CI 0.01-0.15, p=0.0005). At the end of the follow up patients with complete response discontinued IST in 91% of cases, with mild cGvHD in 53% of cases, with moderate in 24% of cases and with severe in 2% of cases. The other significant factors for NRM were steroid-free starting therapy (HR 0.25, 95%CI 0.08-0.58, p=0.0035) and early use of second-line therapy (HR 0.49, 95%CI 0.25-0.96, p=0.0322). In conclusion, the study demonstrated that discontinuation of systemic IST therapy without the flare of cGvHD should be the goal of therapy. Also the study creates a rationale for randomized studies of novel second-line options not with but against steroids in the first line.

Keywords

Chronic graft-versus-host disease, therapy, long-term outcomes, goals of therapy.

" } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27335" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-29-36" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-29-36" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-29-36" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27336" ["VALUE"]=> string(134) "Long-term goals in the treatment of chronic graft-versus-host disease after matched allogeneic hematopoietic stem cell transplantation" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(134) "Long-term goals in the treatment of chronic graft-versus-host disease after matched allogeneic hematopoietic stem cell transplantation" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(134) "Long-term goals in the treatment of chronic graft-versus-host disease after matched allogeneic hematopoietic stem cell transplantation" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27344" ["VALUE"]=> array(2) { ["TEXT"]=> string(527) "<p>RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia</p><br> <p><b>Correspondence</b><br> Ivan S. Moiseev, PhD, MD. RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia<br> Phone: +7(812) 338 6259, +7 (921) 796 1951<br> Fax: +7(812) 338 6263<br> E-mail: moisiv@mail.ru</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(461) "

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia


Correspondence
Ivan S. Moiseev, PhD, MD. RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7(812) 338 6259, +7 (921) 796 1951
Fax: +7(812) 338 6263
E-mail: moisiv@mail.ru

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(461) "

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia


Correspondence
Ivan S. Moiseev, PhD, MD. RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7(812) 338 6259, +7 (921) 796 1951
Fax: +7(812) 338 6263
E-mail: moisiv@mail.ru

" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27339" ["VALUE"]=> array(2) { ["TEXT"]=> string(339) "<p>Иван С. Моисеев, Анна А. Доценко, Анна Г. Смирнова, Юлия Ю. Власова, Елена В. Морозова, Сергей Н. Бондаренко, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Борис В. Афанасьев</span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(305) "

Иван С. Моисеев, Анна А. Доценко, Анна Г. Смирнова, Юлия Ю. Власова, Елена В. Морозова, Сергей Н. Бондаренко, Борис В. Афанасьев

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(305) "

Иван С. Моисеев, Анна А. Доценко, Анна Г. Смирнова, Юлия Ю. Власова, Елена В. Морозова, Сергей Н. Бондаренко, Борис В. Афанасьев

" } ["SUBMITTED"]=> array(37) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27333" ["VALUE"]=> string(10) "22.10.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "22.10.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "22.10.2020" } ["ACCEPTED"]=> array(37) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27334" ["VALUE"]=> string(10) "13.11.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "13.11.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "13.11.2020" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27341" ["VALUE"]=> array(2) { ["TEXT"]=> string(5075) "<p style="text-align: justify;">Хроническая реакция «трансплантат против хозяина» (хрРТПХ) является частым осложнением аллогенной трансплантации гемопоэтических стволовых клеток. Частота развития этого осложнения колеблется от 10% до 80% в зависимости от типа профилактики, типа донора и других факторов риска. Хотя хрРТПХ ассоциируется со сниженным риском рецидива, персистенция клинических симптомов связана с долгосрочной летальностью, частыми госпитализациями и инвалидностью. Несмотря на то, что существуют четкие критерии эффективности для клинических испытаний новых препаратов, определение тактики в клинической практике должно включать и долгосрочные цели, как при всех аутоиммунных заболеваниях. Пока нет единого мнения в отношении этих целей терапии. Анализируя результаты терапии хрРТПХ в большой когорте пациентов в рамках одноцентрового исследования, мы попытались сосредоточиться на предикторах долгосрочного прогноза и их связи с терапией.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">В исследование были включены 182 пациента с средней тяжестью и тяжелой хрРТПХ. Большинству пациентов была проведена аллогенная трансплантация по поводу злокачественных заболеваний, у 49% была тяжелая форма хрРТПХ, у 51% – проявления средней степени тяжести. Среднее время наблюдения составило 52 месяца. Помимо первой линии, 39,56% пациентов требовали дополнительного лечения.</p> <h3>Результаты</h3> <p style="text-align: justify;">Через пять лет кумулятивная частота полных ремиссии составила 16,9% (95% ДИ 10,5-24,7%), а частота прекращения иммуносупрессивной терапии (ИСТ) без обострения РТПХ составила 51,2% (95% ДИ 40,0-61,2%). Основными предикторами отмены ИСТ были общая тяжесть хрРТПХ (HR 0,45, 95% ДИ 0,25-0,84, p=0,0049) и женщина донор для реципиента мужчины (HR 0,33, 95% CI 0,25-0,81, p=0,0370). Анализ частоты летальности без рецидива (ЛБР) показал, что прекращение ИСТ было основным предиктором ЛБР (2% против 42%, HR 0,03, 95% CI 0,01-0,15, p=0,0005). В конце периода наблюдения пациенты с полным ответом прекратили ИСТ в 91% случаев, с легкой формой РТПХ в 53% случаев, со средней тяжести в 24% случаев и с тяжелой в 2% случаев. Другими значимыми факторами для ЛБР были начало терапии без стероидов (HR 0,25, 95% ДИ 0,08-0,58, p=0,0035) и раннее использование терапии второй линии (HR 0,49, 95% CI 0,25-0,96, p=0,0322).</p> <h3>Выводы</h3> <p style="text-align: justify;">Исследование продемонстрировало, что прекращение системной терапии ИСТ без обострения хронической РТПХ должно быть основной целью терапии. Кроме того, исследование указывает на обоснованность рандомизированных исследований новых методов второй линии не с глюкокортикостероидами в первой линии, а против них.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Хроническая реакция трансплантат против хозяина, терапия, долгосрочные результаты, цели терапии.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4917) "

Хроническая реакция «трансплантат против хозяина» (хрРТПХ) является частым осложнением аллогенной трансплантации гемопоэтических стволовых клеток. Частота развития этого осложнения колеблется от 10% до 80% в зависимости от типа профилактики, типа донора и других факторов риска. Хотя хрРТПХ ассоциируется со сниженным риском рецидива, персистенция клинических симптомов связана с долгосрочной летальностью, частыми госпитализациями и инвалидностью. Несмотря на то, что существуют четкие критерии эффективности для клинических испытаний новых препаратов, определение тактики в клинической практике должно включать и долгосрочные цели, как при всех аутоиммунных заболеваниях. Пока нет единого мнения в отношении этих целей терапии. Анализируя результаты терапии хрРТПХ в большой когорте пациентов в рамках одноцентрового исследования, мы попытались сосредоточиться на предикторах долгосрочного прогноза и их связи с терапией.

Пациенты и методы

В исследование были включены 182 пациента с средней тяжестью и тяжелой хрРТПХ. Большинству пациентов была проведена аллогенная трансплантация по поводу злокачественных заболеваний, у 49% была тяжелая форма хрРТПХ, у 51% – проявления средней степени тяжести. Среднее время наблюдения составило 52 месяца. Помимо первой линии, 39,56% пациентов требовали дополнительного лечения.

Результаты

Через пять лет кумулятивная частота полных ремиссии составила 16,9% (95% ДИ 10,5-24,7%), а частота прекращения иммуносупрессивной терапии (ИСТ) без обострения РТПХ составила 51,2% (95% ДИ 40,0-61,2%). Основными предикторами отмены ИСТ были общая тяжесть хрРТПХ (HR 0,45, 95% ДИ 0,25-0,84, p=0,0049) и женщина донор для реципиента мужчины (HR 0,33, 95% CI 0,25-0,81, p=0,0370). Анализ частоты летальности без рецидива (ЛБР) показал, что прекращение ИСТ было основным предиктором ЛБР (2% против 42%, HR 0,03, 95% CI 0,01-0,15, p=0,0005). В конце периода наблюдения пациенты с полным ответом прекратили ИСТ в 91% случаев, с легкой формой РТПХ в 53% случаев, со средней тяжести в 24% случаев и с тяжелой в 2% случаев. Другими значимыми факторами для ЛБР были начало терапии без стероидов (HR 0,25, 95% ДИ 0,08-0,58, p=0,0035) и раннее использование терапии второй линии (HR 0,49, 95% CI 0,25-0,96, p=0,0322).

Выводы

Исследование продемонстрировало, что прекращение системной терапии ИСТ без обострения хронической РТПХ должно быть основной целью терапии. Кроме того, исследование указывает на обоснованность рандомизированных исследований новых методов второй линии не с глюкокортикостероидами в первой линии, а против них.

Ключевые слова

Хроническая реакция трансплантат против хозяина, терапия, долгосрочные результаты, цели терапии.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(4917) "

Хроническая реакция «трансплантат против хозяина» (хрРТПХ) является частым осложнением аллогенной трансплантации гемопоэтических стволовых клеток. Частота развития этого осложнения колеблется от 10% до 80% в зависимости от типа профилактики, типа донора и других факторов риска. Хотя хрРТПХ ассоциируется со сниженным риском рецидива, персистенция клинических симптомов связана с долгосрочной летальностью, частыми госпитализациями и инвалидностью. Несмотря на то, что существуют четкие критерии эффективности для клинических испытаний новых препаратов, определение тактики в клинической практике должно включать и долгосрочные цели, как при всех аутоиммунных заболеваниях. Пока нет единого мнения в отношении этих целей терапии. Анализируя результаты терапии хрРТПХ в большой когорте пациентов в рамках одноцентрового исследования, мы попытались сосредоточиться на предикторах долгосрочного прогноза и их связи с терапией.

Пациенты и методы

В исследование были включены 182 пациента с средней тяжестью и тяжелой хрРТПХ. Большинству пациентов была проведена аллогенная трансплантация по поводу злокачественных заболеваний, у 49% была тяжелая форма хрРТПХ, у 51% – проявления средней степени тяжести. Среднее время наблюдения составило 52 месяца. Помимо первой линии, 39,56% пациентов требовали дополнительного лечения.

Результаты

Через пять лет кумулятивная частота полных ремиссии составила 16,9% (95% ДИ 10,5-24,7%), а частота прекращения иммуносупрессивной терапии (ИСТ) без обострения РТПХ составила 51,2% (95% ДИ 40,0-61,2%). Основными предикторами отмены ИСТ были общая тяжесть хрРТПХ (HR 0,45, 95% ДИ 0,25-0,84, p=0,0049) и женщина донор для реципиента мужчины (HR 0,33, 95% CI 0,25-0,81, p=0,0370). Анализ частоты летальности без рецидива (ЛБР) показал, что прекращение ИСТ было основным предиктором ЛБР (2% против 42%, HR 0,03, 95% CI 0,01-0,15, p=0,0005). В конце периода наблюдения пациенты с полным ответом прекратили ИСТ в 91% случаев, с легкой формой РТПХ в 53% случаев, со средней тяжести в 24% случаев и с тяжелой в 2% случаев. Другими значимыми факторами для ЛБР были начало терапии без стероидов (HR 0,25, 95% ДИ 0,08-0,58, p=0,0035) и раннее использование терапии второй линии (HR 0,49, 95% CI 0,25-0,96, p=0,0322).

Выводы

Исследование продемонстрировало, что прекращение системной терапии ИСТ без обострения хронической РТПХ должно быть основной целью терапии. Кроме того, исследование указывает на обоснованность рандомизированных исследований новых методов второй линии не с глюкокортикостероидами в первой линии, а против них.

Ключевые слова

Хроническая реакция трансплантат против хозяина, терапия, долгосрочные результаты, цели терапии.

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27340" ["VALUE"]=> array(2) { ["TEXT"]=> string(368) "<p>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(356) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(356) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

" } } } [3]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(3) "170" ["~IBLOCK_SECTION_ID"]=> string(3) "170" ["ID"]=> string(4) "1941" ["~ID"]=> string(4) "1941" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["~NAME"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "05.02.2021 14:52:04" ["~TIMESTAMP_X"]=> string(19) "05.02.2021 14:52:04" ["DETAIL_PAGE_URL"]=> string(138) "/ru/archive/-9-4/klinicheskie-raboty/anemiya-fankoni-v-cheshskoy-respublike-rol-transplantatsii-gemopoeticheskikh-stvolovykh-kletok-i-dli/" ["~DETAIL_PAGE_URL"]=> string(138) "/ru/archive/-9-4/klinicheskie-raboty/anemiya-fankoni-v-cheshskoy-respublike-rol-transplantatsii-gemopoeticheskikh-stvolovykh-kletok-i-dli/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(13933) "

Introduction

Fanconi anemia (FA) is a rare inherited condition characterized by heterogeneity of clinical signs and underling genetic mutations, which significantly increase the risk of bone marrow failure or malignancy (leukemia, solid tumors) development. Fanconi anemia is characterized by the presence of congenital anomalies occurring in approximately 75-80% of affected individuals, which include one or more of the following features: small stature, abnormal skin pigmentation, upper or lower limb skeletal malformation, microcephaly, visual and urogenital anomalies [1, 2]. The cumulative risk of developing bone marrow failure is 50%. Progressive bone marrow failure typically occurs in the first decade of life often starting with thrombocytopenia or leukopenia. Leukemia and solid tumors may occur as early as in 16 years. The diagnosis of FA is based on increased chromosome fragility detection in a test with or without an agent for DNA cross-link sensitivity testing, diepoxybutane (DEB) or mitomycin C (MMC). If hematopoietic sell still possess an intact DNA repair mechanism due to mosaicism these tests may be negative in blood cells cultures. Although these situations are rare, they may complicate diagnosis and warrant for test performed in non-hematopoietic cells culture, usually fibroblasts [3]. The final diagnosis nowadays is often confirmed by detection of a mutation in one of Fanconi complex genes [4].

Gene mutations in Fanconi anemia

• Bialellic pathogenic variant of one of 19 genes causing autosomal recessive form of FA.
• Heterozygous pathogenic variant in gene RAD51 (de novo; FANCO) causing autosomal dominant form of FA.
• Hemizygous pathogenic variant in gene FANCB causing X-linked form of FA.

There is a distinct flowchart for stepwise post-diagnostic monitoring and decision making in therapy of the Fanconi anemia patients, as described, e.g., by Dufour [5].

FA epidemiology in Czech Republic

The Czech population in 2020 is 10.7 millions (11th among EU countries) including 2.0 million children of 0 to 17.99 years with a birth rate of 115,000 per year. A total of 35 probands with Fanconi anemia were born in 1985-2019 in the Czech Republic with diagnosis confirmed in 1986-2020, it correlates with probable incidence of ca.1 patient/year. Diagnosis of FA was confirmed at the median age of 6 (0-24.3) years, 34/35 of patients were children at the moment of diagnosis. In all cases the diagnostic procedure included spontaneous and induced chromosomal breakage evaluation, then the diagnosis was prospectively or retrospectively confirmed by specific mutation detection in 33/35 patients.

The initial symptoms registered in FA patients included congenital effects in 5, thrombocytopenia in 9, bicytopenia or pancytopenia in 13 cases, accordingly. Also, 8 patients had characteristic family history (BMF, malignancies).

The main physical abnormalities and laboratory signs incidence in our FA group (n=35) at the time of diagnoses are summarized in Table 1. Table 2 and Fig.1 contain the list and relative frequency of mutations revealed in available patients (33 of 35 cases).

Sedlacek-tab01-02_fig01.jpg

Bone marrow failure (BMF) and malignancies, outcome

During the follow-up 17/31 (55%) children developed BMF at the median age of 8 (4.0-17.1) years. Five patients (3 boys and 2 girls) had prior history of anabolics treatment with some effect in two girls [6]. Among these, 15 patients consequently underwent allogeneic HSCT (2004-2020) at the median age of 9.3 (4.6-24.3) years.

Also, 7/35 (20%) patients developed the following malignancies during follow-up with a median age of 9.8 (1.0 - 32.3) at cancer diagnosis:
- Spinocellular carcinoma of GI (32 years); the patient died due to cancer progression,
- Gastrointestinal adenocarcinoma (at 15 years), later a squamous cell carcinoma of tongue (at 18 years); this patient had a history of HSCT at 5 years, then multiple surgical interventions were performed in order to eradicate cancers, is currently alive,
- Acute myeloid leukemia (at 6 years); this child died due to rapid leukemia progression.

Children with FANCD1 mutation (homozygous BRCA2 mutations) do not have a risk of bone marrow failure, but still the malignancies incidence is very high [7]. Among our cohort all 4 children with this mutation developed cancer early in their life. The following malignancies were registered:
- Acute lymphoblastic leukemia (at 1 year); the child responded to chemotherapy, but then a secondary acute myeloid lekemia developed and death of disease progression followed,
- Meduloblastoma (at 4.6 years); the patients died of relapse,
- Nephroblastoma (at 3.7 years); the child is alive and in complete remission (these three patients are siblings),
- Medulloblastoma (1.4 years); the patient has recently finished treatment and is currently alive.

At last visit with a median follow-up of 12.6 (0.2-34.4) years 28/35 (80%) patients are alive, 4 died of malignancy, 2 died after HSCT and one due to severe congenital defects.

Results of HSCT

A total of 15 patients with bone marrow failure due to FA underwent allogeneic hematopoietic stem cell transplantation (HSCT) at a median age of 9.3 (4.6-24.3) years from a matched sibling donor (MSD, n=3) or matched unrelated donor (MUD, n=12). The bone marrow was used in as graft source in 6, peripheral blood stem cells (PBSC) in 7, and umbilical cord blood in 2 cases, accordingly. In al cases the pre-transplant conditioning regimen was irradiation-free. The following regimens were used: FluCy ATG in 10 cases, FluCy MbC in 1 patient, and FluCy/Bu MbC(3)/ATG(1) in 4 patients. The regimen toxicity was acceptable and no early mortality (till D+100) was observed. All transplanted patients achieved stable hematopoietic engraftment after HSCT. Late mortality (after D+100) was registered in 2/15 patients (13%), both suffered from chronic graft- versus-host disease (GvHD), with extensive form in one case. These patients developed fatal infections due to inadequate immune reconstitution, dying of CMV pneumonia and invasive aspergillosis 12 and 14 months after HSCT, accordingly. Also, three patients require long-term immunosuppressive therapy due to chronic GvHD (limited in two cases, and extensive in one case). The patient who consequently developed two different malignancies did not suffer from chronic GvHD.

The overall survival (OS) and event-free survival (EFS) in total FA group are shown in Fig. 2.

Overall and event-free survival among the Fanconi anemia patients subjected to HSCT are shown in Fig. 3.

Sedlacek-fig02-03.jpg

Long-term monitoring

A lifelong and careful multidisciplinary follow-up of patients with FA is essential for early detection of bone marrow failure or any malignant disease [8, 9, 10].

The outpatient care includes long-term follow-up by hematologist/oncologist or bone marrow transplant specialist.

The following surveillance program should be scheduled for all the FA patients, whether they underwent allogeneic HSCT or not:

Evaluation by oncologists in order to check for signs of head and neck tumors, oral cancer, and gynecologic cancers (including breast carcinoma) once in every 6 months.

Hematological evaluation (every 6 months) due to the risk of bone marrow failure, myelodysplastic syndrome or acute leukemia. One should remember that 1/3 of FA patients may maintain mild/moderate cytopenia, while 2/3 cases will later develop progression.

Examination by specialists in endocrinology. Endocrinopathies, including thyroid dysfunction, growth hormone deficiency, and glucose intolerance, are common in patients with FA, even in ones without history of HSCT.
- Examination by specialists in dermatology, hearing, cardiology, pulmonology (every 12 months).
- Recommendations: no smoking, no alcohol use, correct oral hygiene, limited radiation exposure, limited sun and ultraviolet exposure.
- Human papilloma virus vaccination should be initiated at nine years in order to reduce the risk of gynecologic cancer in females and possibly reduce the risk of oral cancer in all individuals.

Conclusion

While HSCT is a demanding medical procedure in patients with FA due to disease biology leading to higher transplant-associated risk, it allows achieving very good results when performed in centers with adequate expertise using appropriate conditioning regimens. It reverses bone marrow failure and prevents further development of hematological malignancies. However, the indications have to be considered very carefully. Clinically significant chemotherapy and radiation toxicity due to impaired DNA damage repair mechanisms have historically made allogeneic HSCT for patients with FA extremely challenging. Chronic graft-versus-host disease of mouth and/or genitourinary tract has been associated with higher baseline risk of spinocellular carcinoma. HSCT may also increase the risk of other secondary solid tumors and therapy-related MDS or leukemia as it does the non-FA population, but to greater extent. Renal failure is rare in patients with FA despite the fact that about one-quarter of them have structural abnormalities involving kidneys and urinary tract. Renal function may be compromised during and after HSCT by chemotherapy and calcineurin inhibitors toxicity. HSCT can restore long-term hematopoiesis and cure the hematologic complications of FA; however, when compared with age-matched controls, these patients do not achieve complete health or normal life expectancy. The risk of long-term disease- or transplantation-related complications remain and patients with FA are still at risk of conditions caused by congenital anomalies, endocrinopathy, and cancer. Still, HSCT significantly increases a life span if indications were chosen carefully. However, a lifelong multidisciplinary follow-up of all patients with FA is essential for early detection of bone marrow failure or any malignant disease. Preventive measures include minimizing radiation exposure and contact with harmful substances (including smoking). Vaccination against human papillomavirus is recommended to reduce the risk of gynecological cancer in women and oral cancer in all subjects.

Conflict of interest

None declared.

References

  1. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018; 103(1): 30-39.
  2. Fiesco-Roa MO, Giri N, McReynolds LJ, Best AF, Alter BP. Genotype-phenotype associations in Fanconi anemia: A literature review. Blood Rev. 2019; 37: 100589.
  3. Soulier J, Leblanc T, Larghero J, Dastot H, Shimamura A, Guardiola P, et al. Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway. Blood. 2005; 105(3): 1329-1336.
  4. Bogliolo M, Pujol R, Aza-Carmona M, Munoz-Subirana N, Rodriguez-Santiago B, Casado JA, et al. Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies. J Med Genet. 2020; 57(4): 258-268.
  5. Dufour C. How I manage patients with Fanconi anaemia. Br J Haematol. 2017;178(1):32-47
  6. Paustian L, Chao MM, Hanenberg H, Schindler D, Neitzel H, Kratz CP, et al. Androgen therapy in Fanconi anemia: A retrospective analysis of 30 years in Germany. Pediatr Hematol Oncol. 2016; 33(1): 5-12.
  7. Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007; 44(1): 1-9.
  8. Kutler DI, Auerbach AD, Satagopan J, Giampietro PF, Batish SD, Huvos AG, et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg. 2003; 129(1): 106-112.
  9. Kelaidi C, Makis A, Petrikkos L, Antoniadi K, Selenti N, Tzotzola V, et al. Bone marrow failure in Fanconi anemia: clinical and genetic spectrum in a cohort of 20 pediatric patients. J Pediatr Hematol Oncol. 2019; 41(8): 612-617.
  10. Dietz AC, Savage SA, Vlachos A, Mehta PA, Bresters D, Tolar J, et al. Late effects screening guidelines after hematopoietic cell transplantation for inherited bone marrow failure syndromes: consensus statement from the second Pediatric Blood and Marrow Transplant Consortium International Conference on late effects after pediatric HCT. Biol Blood Marrow Transplant. 2017; 23(9):1422-1428.

" ["~DETAIL_TEXT"]=> string(13933) "

Introduction

Fanconi anemia (FA) is a rare inherited condition characterized by heterogeneity of clinical signs and underling genetic mutations, which significantly increase the risk of bone marrow failure or malignancy (leukemia, solid tumors) development. Fanconi anemia is characterized by the presence of congenital anomalies occurring in approximately 75-80% of affected individuals, which include one or more of the following features: small stature, abnormal skin pigmentation, upper or lower limb skeletal malformation, microcephaly, visual and urogenital anomalies [1, 2]. The cumulative risk of developing bone marrow failure is 50%. Progressive bone marrow failure typically occurs in the first decade of life often starting with thrombocytopenia or leukopenia. Leukemia and solid tumors may occur as early as in 16 years. The diagnosis of FA is based on increased chromosome fragility detection in a test with or without an agent for DNA cross-link sensitivity testing, diepoxybutane (DEB) or mitomycin C (MMC). If hematopoietic sell still possess an intact DNA repair mechanism due to mosaicism these tests may be negative in blood cells cultures. Although these situations are rare, they may complicate diagnosis and warrant for test performed in non-hematopoietic cells culture, usually fibroblasts [3]. The final diagnosis nowadays is often confirmed by detection of a mutation in one of Fanconi complex genes [4].

Gene mutations in Fanconi anemia

• Bialellic pathogenic variant of one of 19 genes causing autosomal recessive form of FA.
• Heterozygous pathogenic variant in gene RAD51 (de novo; FANCO) causing autosomal dominant form of FA.
• Hemizygous pathogenic variant in gene FANCB causing X-linked form of FA.

There is a distinct flowchart for stepwise post-diagnostic monitoring and decision making in therapy of the Fanconi anemia patients, as described, e.g., by Dufour [5].

FA epidemiology in Czech Republic

The Czech population in 2020 is 10.7 millions (11th among EU countries) including 2.0 million children of 0 to 17.99 years with a birth rate of 115,000 per year. A total of 35 probands with Fanconi anemia were born in 1985-2019 in the Czech Republic with diagnosis confirmed in 1986-2020, it correlates with probable incidence of ca.1 patient/year. Diagnosis of FA was confirmed at the median age of 6 (0-24.3) years, 34/35 of patients were children at the moment of diagnosis. In all cases the diagnostic procedure included spontaneous and induced chromosomal breakage evaluation, then the diagnosis was prospectively or retrospectively confirmed by specific mutation detection in 33/35 patients.

The initial symptoms registered in FA patients included congenital effects in 5, thrombocytopenia in 9, bicytopenia or pancytopenia in 13 cases, accordingly. Also, 8 patients had characteristic family history (BMF, malignancies).

The main physical abnormalities and laboratory signs incidence in our FA group (n=35) at the time of diagnoses are summarized in Table 1. Table 2 and Fig.1 contain the list and relative frequency of mutations revealed in available patients (33 of 35 cases).

Sedlacek-tab01-02_fig01.jpg

Bone marrow failure (BMF) and malignancies, outcome

During the follow-up 17/31 (55%) children developed BMF at the median age of 8 (4.0-17.1) years. Five patients (3 boys and 2 girls) had prior history of anabolics treatment with some effect in two girls [6]. Among these, 15 patients consequently underwent allogeneic HSCT (2004-2020) at the median age of 9.3 (4.6-24.3) years.

Also, 7/35 (20%) patients developed the following malignancies during follow-up with a median age of 9.8 (1.0 - 32.3) at cancer diagnosis:
- Spinocellular carcinoma of GI (32 years); the patient died due to cancer progression,
- Gastrointestinal adenocarcinoma (at 15 years), later a squamous cell carcinoma of tongue (at 18 years); this patient had a history of HSCT at 5 years, then multiple surgical interventions were performed in order to eradicate cancers, is currently alive,
- Acute myeloid leukemia (at 6 years); this child died due to rapid leukemia progression.

Children with FANCD1 mutation (homozygous BRCA2 mutations) do not have a risk of bone marrow failure, but still the malignancies incidence is very high [7]. Among our cohort all 4 children with this mutation developed cancer early in their life. The following malignancies were registered:
- Acute lymphoblastic leukemia (at 1 year); the child responded to chemotherapy, but then a secondary acute myeloid lekemia developed and death of disease progression followed,
- Meduloblastoma (at 4.6 years); the patients died of relapse,
- Nephroblastoma (at 3.7 years); the child is alive and in complete remission (these three patients are siblings),
- Medulloblastoma (1.4 years); the patient has recently finished treatment and is currently alive.

At last visit with a median follow-up of 12.6 (0.2-34.4) years 28/35 (80%) patients are alive, 4 died of malignancy, 2 died after HSCT and one due to severe congenital defects.

Results of HSCT

A total of 15 patients with bone marrow failure due to FA underwent allogeneic hematopoietic stem cell transplantation (HSCT) at a median age of 9.3 (4.6-24.3) years from a matched sibling donor (MSD, n=3) or matched unrelated donor (MUD, n=12). The bone marrow was used in as graft source in 6, peripheral blood stem cells (PBSC) in 7, and umbilical cord blood in 2 cases, accordingly. In al cases the pre-transplant conditioning regimen was irradiation-free. The following regimens were used: FluCy ATG in 10 cases, FluCy MbC in 1 patient, and FluCy/Bu MbC(3)/ATG(1) in 4 patients. The regimen toxicity was acceptable and no early mortality (till D+100) was observed. All transplanted patients achieved stable hematopoietic engraftment after HSCT. Late mortality (after D+100) was registered in 2/15 patients (13%), both suffered from chronic graft- versus-host disease (GvHD), with extensive form in one case. These patients developed fatal infections due to inadequate immune reconstitution, dying of CMV pneumonia and invasive aspergillosis 12 and 14 months after HSCT, accordingly. Also, three patients require long-term immunosuppressive therapy due to chronic GvHD (limited in two cases, and extensive in one case). The patient who consequently developed two different malignancies did not suffer from chronic GvHD.

The overall survival (OS) and event-free survival (EFS) in total FA group are shown in Fig. 2.

Overall and event-free survival among the Fanconi anemia patients subjected to HSCT are shown in Fig. 3.

Sedlacek-fig02-03.jpg

Long-term monitoring

A lifelong and careful multidisciplinary follow-up of patients with FA is essential for early detection of bone marrow failure or any malignant disease [8, 9, 10].

The outpatient care includes long-term follow-up by hematologist/oncologist or bone marrow transplant specialist.

The following surveillance program should be scheduled for all the FA patients, whether they underwent allogeneic HSCT or not:

Evaluation by oncologists in order to check for signs of head and neck tumors, oral cancer, and gynecologic cancers (including breast carcinoma) once in every 6 months.

Hematological evaluation (every 6 months) due to the risk of bone marrow failure, myelodysplastic syndrome or acute leukemia. One should remember that 1/3 of FA patients may maintain mild/moderate cytopenia, while 2/3 cases will later develop progression.

Examination by specialists in endocrinology. Endocrinopathies, including thyroid dysfunction, growth hormone deficiency, and glucose intolerance, are common in patients with FA, even in ones without history of HSCT.
- Examination by specialists in dermatology, hearing, cardiology, pulmonology (every 12 months).
- Recommendations: no smoking, no alcohol use, correct oral hygiene, limited radiation exposure, limited sun and ultraviolet exposure.
- Human papilloma virus vaccination should be initiated at nine years in order to reduce the risk of gynecologic cancer in females and possibly reduce the risk of oral cancer in all individuals.

Conclusion

While HSCT is a demanding medical procedure in patients with FA due to disease biology leading to higher transplant-associated risk, it allows achieving very good results when performed in centers with adequate expertise using appropriate conditioning regimens. It reverses bone marrow failure and prevents further development of hematological malignancies. However, the indications have to be considered very carefully. Clinically significant chemotherapy and radiation toxicity due to impaired DNA damage repair mechanisms have historically made allogeneic HSCT for patients with FA extremely challenging. Chronic graft-versus-host disease of mouth and/or genitourinary tract has been associated with higher baseline risk of spinocellular carcinoma. HSCT may also increase the risk of other secondary solid tumors and therapy-related MDS or leukemia as it does the non-FA population, but to greater extent. Renal failure is rare in patients with FA despite the fact that about one-quarter of them have structural abnormalities involving kidneys and urinary tract. Renal function may be compromised during and after HSCT by chemotherapy and calcineurin inhibitors toxicity. HSCT can restore long-term hematopoiesis and cure the hematologic complications of FA; however, when compared with age-matched controls, these patients do not achieve complete health or normal life expectancy. The risk of long-term disease- or transplantation-related complications remain and patients with FA are still at risk of conditions caused by congenital anomalies, endocrinopathy, and cancer. Still, HSCT significantly increases a life span if indications were chosen carefully. However, a lifelong multidisciplinary follow-up of all patients with FA is essential for early detection of bone marrow failure or any malignant disease. Preventive measures include minimizing radiation exposure and contact with harmful substances (including smoking). Vaccination against human papillomavirus is recommended to reduce the risk of gynecological cancer in women and oral cancer in all subjects.

Conflict of interest

None declared.

References

  1. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018; 103(1): 30-39.
  2. Fiesco-Roa MO, Giri N, McReynolds LJ, Best AF, Alter BP. Genotype-phenotype associations in Fanconi anemia: A literature review. Blood Rev. 2019; 37: 100589.
  3. Soulier J, Leblanc T, Larghero J, Dastot H, Shimamura A, Guardiola P, et al. Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway. Blood. 2005; 105(3): 1329-1336.
  4. Bogliolo M, Pujol R, Aza-Carmona M, Munoz-Subirana N, Rodriguez-Santiago B, Casado JA, et al. Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies. J Med Genet. 2020; 57(4): 258-268.
  5. Dufour C. How I manage patients with Fanconi anaemia. Br J Haematol. 2017;178(1):32-47
  6. Paustian L, Chao MM, Hanenberg H, Schindler D, Neitzel H, Kratz CP, et al. Androgen therapy in Fanconi anemia: A retrospective analysis of 30 years in Germany. Pediatr Hematol Oncol. 2016; 33(1): 5-12.
  7. Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007; 44(1): 1-9.
  8. Kutler DI, Auerbach AD, Satagopan J, Giampietro PF, Batish SD, Huvos AG, et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg. 2003; 129(1): 106-112.
  9. Kelaidi C, Makis A, Petrikkos L, Antoniadi K, Selenti N, Tzotzola V, et al. Bone marrow failure in Fanconi anemia: clinical and genetic spectrum in a cohort of 20 pediatric patients. J Pediatr Hematol Oncol. 2019; 41(8): 612-617.
  10. Dietz AC, Savage SA, Vlachos A, Mehta PA, Bresters D, Tolar J, et al. Late effects screening guidelines after hematopoietic cell transplantation for inherited bone marrow failure syndromes: consensus statement from the second Pediatric Blood and Marrow Transplant Consortium International Conference on late effects after pediatric HCT. Biol Blood Marrow Transplant. 2017; 23(9):1422-1428.

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(2) "40" ["~SORT"]=> string(2) "40" ["CODE"]=> string(100) "anemiya-fankoni-v-cheshskoy-respublike-rol-transplantatsii-gemopoeticheskikh-stvolovykh-kletok-i-dli" ["~CODE"]=> string(100) "anemiya-fankoni-v-cheshskoy-respublike-rol-transplantatsii-gemopoeticheskikh-stvolovykh-kletok-i-dli" ["EXTERNAL_ID"]=> string(4) "1941" ["~EXTERNAL_ID"]=> string(4) "1941" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(289) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюденияFanconi Anemia in the Czech Republic: role of HSCT and long-term follow-up" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(4777) "<p style="text-align: justify;">Анемия Фанкони (АФ) – редкий синдром с гетерогенной картиной, сочетающийся с недостаточностью костного мозга и повышенным риском злокачественных новообразований. Хотя АФ часто характеризуется наличием пороков развития, у некоторых пациентов единственным признаком может быть цитопения. В нашей когорте больных диагностика основывалась на повышенной ломкости хромосом с последующим подтверждением генных мутаций.</p> <h3>Методы</h3> <p style="text-align: justify;">Наша когорта включает 35 пробандов в возрасте от 0 до 24,3 (медиана – 6) лет, у которых была диагностирована АФ в сроки с января 1986 до августа 2020 г. Врожденные аномалии на момент диагноза наблюдались у 5 и цитопения – у 22 пациентов; 8 больных имели семейный анамнез АФ. Генетическое тестирование подтвердило мутации гена FANCA в 24 случаях, FANCG – в 3, FANCD1 – у 4 пациентов и FANCB – у двух сиблингов.</p> <h3>Результаты</h3> <p style="text-align: justify;">По мере наблюдения, у 7 пациентов развились злокачественные новообразования (в том числе – у 4 больных с мутацией FANCD1). У 17 пациентов развилась костномозговая недостаточность, в связи с чем 15 больным была выполнена трансплантация гемопоэтических стволовых клеток (ТГСК) в возрасте от 4,6 до 24,3 лет (медиана – 9,3 года). У всех трансплантированных пациентов было достигнуто стабильное гемопоэтическое приживление. Однако у 2 больных, в связи с неадекватным восстановлением иммунитета, через 12 и 14 мес. после ТГСК развились, соответственно, цитомегаловирусная пневмония и инвазивный аспергиллез со смертельными исходами. В одном случае мы диагностировали аденокарциному кишечника через 10 лет и сквамозноклеточную карциному языка через 13 лет после ТГСК. Тринадцать пациентов живы при среднем сроке наблюдения после ТГСК 10,6 (0,3-15,1) лет. При сроках наблюдения с медианой 12,6 (0,2-34,4) лет, 28/35 пациентов (80%) живы, 4 погибли от злокачественных новообразований, двое умерли от осложнений ТГСК, и один больной – в связи с тяжелыми врожденными соматическими пороками. </p> <h3>Выводы</h3> <p style="text-align: justify;">ТГСК эффективна у пациентов с АФ и костномозговой недостаточностью и предотвращает дальнейшее развитие гематологических осложнений. Необходимо пожизненное и тщательное мультидисциплинарное наблюдение пациентов с АФ для раннего выявления костномозговой недостаточности или злокачественного заболевания.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Анемия Фанкони, соматические аномалии, генные мутации, костномозговая недостаточность, солидные опухоли, трансплантация гемопоэтических стволовых клеток, амбулаторное долгосрочное наблюдение.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["SECTION_META_TITLE"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["SECTION_META_KEYWORDS"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["SECTION_META_DESCRIPTION"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["SECTION_PICTURE_FILE_ALT"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["SECTION_PICTURE_FILE_TITLE"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "anemiya-fankoni-v-cheshskoy-respublike-rol-transplantatsii-gemopoeticheskikh-stvolovykh-kletok-i-dli" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(215) "Анемия Фанкони в Чешской республике: роль трансплантации гемопоэтических стволовых клеток и длительного наблюдения" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "anemiya-fankoni-v-cheshskoy-respublike-rol-transplantatsii-gemopoeticheskikh-stvolovykh-kletok-i-dli" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "anemiya-fankoni-v-cheshskoy-respublike-rol-transplantatsii-gemopoeticheskikh-stvolovykh-kletok-i-dli" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "anemiya-fankoni-v-cheshskoy-respublike-rol-transplantatsii-gemopoeticheskikh-stvolovykh-kletok-i-dli" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "170" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27359" ["VALUE"]=> string(10) "09.11.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "09.11.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27360" ["VALUE"]=> string(10) "04.12.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "04.12.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27361" ["VALUE"]=> array(2) { ["TEXT"]=> string(235) "<p>Петр Седлачек, Петра Кеслова, Петр Смишек, Мартина Сукова, Марцела Маликова, Спирос Тавандзис, Ярослав Чермак, Ян Стари</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(223) "

Петр Седлачек, Петра Кеслова, Петр Смишек, Мартина Сукова, Марцела Маликова, Спирос Тавандзис, Ярослав Чермак, Ян Стари

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27362" ["VALUE"]=> array(2) { ["TEXT"]=> string(292) "<p>Департамент детской гематологии и онкологии, 2-я медицинская школа Карлова Университета, университетский госпиталь Мотол, Прага, Чешская республика</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(280) "

Департамент детской гематологии и онкологии, 2-я медицинская школа Карлова Университета, университетский госпиталь Мотол, Прага, Чешская республика

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27363" ["VALUE"]=> array(2) { ["TEXT"]=> string(4777) "<p style="text-align: justify;">Анемия Фанкони (АФ) – редкий синдром с гетерогенной картиной, сочетающийся с недостаточностью костного мозга и повышенным риском злокачественных новообразований. Хотя АФ часто характеризуется наличием пороков развития, у некоторых пациентов единственным признаком может быть цитопения. В нашей когорте больных диагностика основывалась на повышенной ломкости хромосом с последующим подтверждением генных мутаций.</p> <h3>Методы</h3> <p style="text-align: justify;">Наша когорта включает 35 пробандов в возрасте от 0 до 24,3 (медиана – 6) лет, у которых была диагностирована АФ в сроки с января 1986 до августа 2020 г. Врожденные аномалии на момент диагноза наблюдались у 5 и цитопения – у 22 пациентов; 8 больных имели семейный анамнез АФ. Генетическое тестирование подтвердило мутации гена FANCA в 24 случаях, FANCG – в 3, FANCD1 – у 4 пациентов и FANCB – у двух сиблингов.</p> <h3>Результаты</h3> <p style="text-align: justify;">По мере наблюдения, у 7 пациентов развились злокачественные новообразования (в том числе – у 4 больных с мутацией FANCD1). У 17 пациентов развилась костномозговая недостаточность, в связи с чем 15 больным была выполнена трансплантация гемопоэтических стволовых клеток (ТГСК) в возрасте от 4,6 до 24,3 лет (медиана – 9,3 года). У всех трансплантированных пациентов было достигнуто стабильное гемопоэтическое приживление. Однако у 2 больных, в связи с неадекватным восстановлением иммунитета, через 12 и 14 мес. после ТГСК развились, соответственно, цитомегаловирусная пневмония и инвазивный аспергиллез со смертельными исходами. В одном случае мы диагностировали аденокарциному кишечника через 10 лет и сквамозноклеточную карциному языка через 13 лет после ТГСК. Тринадцать пациентов живы при среднем сроке наблюдения после ТГСК 10,6 (0,3-15,1) лет. При сроках наблюдения с медианой 12,6 (0,2-34,4) лет, 28/35 пациентов (80%) живы, 4 погибли от злокачественных новообразований, двое умерли от осложнений ТГСК, и один больной – в связи с тяжелыми врожденными соматическими пороками. </p> <h3>Выводы</h3> <p style="text-align: justify;">ТГСК эффективна у пациентов с АФ и костномозговой недостаточностью и предотвращает дальнейшее развитие гематологических осложнений. Необходимо пожизненное и тщательное мультидисциплинарное наблюдение пациентов с АФ для раннего выявления костномозговой недостаточности или злокачественного заболевания.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Анемия Фанкони, соматические аномалии, генные мутации, костномозговая недостаточность, солидные опухоли, трансплантация гемопоэтических стволовых клеток, амбулаторное долгосрочное наблюдение.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4619) "

Анемия Фанкони (АФ) – редкий синдром с гетерогенной картиной, сочетающийся с недостаточностью костного мозга и повышенным риском злокачественных новообразований. Хотя АФ часто характеризуется наличием пороков развития, у некоторых пациентов единственным признаком может быть цитопения. В нашей когорте больных диагностика основывалась на повышенной ломкости хромосом с последующим подтверждением генных мутаций.

Методы

Наша когорта включает 35 пробандов в возрасте от 0 до 24,3 (медиана – 6) лет, у которых была диагностирована АФ в сроки с января 1986 до августа 2020 г. Врожденные аномалии на момент диагноза наблюдались у 5 и цитопения – у 22 пациентов; 8 больных имели семейный анамнез АФ. Генетическое тестирование подтвердило мутации гена FANCA в 24 случаях, FANCG – в 3, FANCD1 – у 4 пациентов и FANCB – у двух сиблингов.

Результаты

По мере наблюдения, у 7 пациентов развились злокачественные новообразования (в том числе – у 4 больных с мутацией FANCD1). У 17 пациентов развилась костномозговая недостаточность, в связи с чем 15 больным была выполнена трансплантация гемопоэтических стволовых клеток (ТГСК) в возрасте от 4,6 до 24,3 лет (медиана – 9,3 года). У всех трансплантированных пациентов было достигнуто стабильное гемопоэтическое приживление. Однако у 2 больных, в связи с неадекватным восстановлением иммунитета, через 12 и 14 мес. после ТГСК развились, соответственно, цитомегаловирусная пневмония и инвазивный аспергиллез со смертельными исходами. В одном случае мы диагностировали аденокарциному кишечника через 10 лет и сквамозноклеточную карциному языка через 13 лет после ТГСК. Тринадцать пациентов живы при среднем сроке наблюдения после ТГСК 10,6 (0,3-15,1) лет. При сроках наблюдения с медианой 12,6 (0,2-34,4) лет, 28/35 пациентов (80%) живы, 4 погибли от злокачественных новообразований, двое умерли от осложнений ТГСК, и один больной – в связи с тяжелыми врожденными соматическими пороками.

Выводы

ТГСК эффективна у пациентов с АФ и костномозговой недостаточностью и предотвращает дальнейшее развитие гематологических осложнений. Необходимо пожизненное и тщательное мультидисциплинарное наблюдение пациентов с АФ для раннего выявления костномозговой недостаточности или злокачественного заболевания.

Ключевые слова

Анемия Фанкони, соматические аномалии, генные мутации, костномозговая недостаточность, солидные опухоли, трансплантация гемопоэтических стволовых клеток, амбулаторное долгосрочное наблюдение.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27364" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-48-52" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-48-52" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27367" ["VALUE"]=> array(2) { ["TEXT"]=> string(141) "<p>Petr Sedlacek, Petra Keslova, Petr Smisek, Martina Sukova, Marcela Malikova, Spiros Tavandzis, Jaroslav Cermak, Jan Stary </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(129) "

Petr Sedlacek, Petra Keslova, Petr Smisek, Martina Sukova, Marcela Malikova, Spiros Tavandzis, Jaroslav Cermak, Jan Stary

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27368" ["VALUE"]=> array(2) { ["TEXT"]=> string(557) "<p>Department of Pediatric Hematology and Oncology, 2<sup>nd</sup> Medical School at Charles University, University Hospital Motol, Prague, Czech Republic</p><br> <p><b>Correspondence</b><br> Prof. Dr. Petr Sedlacek, Department of Pediatric Hematology and Oncology, 2nd Medical School at Charles University, University Hospital Motol, V Uvalu 84, 150 06 Prague, Czech Republic<br> Phone: +420 22443 6552<br> Fax: +420 22443 6519<br> E-mail: petr.sedlacek@lfmotol.cuni.cz</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(479) "

Department of Pediatric Hematology and Oncology, 2nd Medical School at Charles University, University Hospital Motol, Prague, Czech Republic


Correspondence
Prof. Dr. Petr Sedlacek, Department of Pediatric Hematology and Oncology, 2nd Medical School at Charles University, University Hospital Motol, V Uvalu 84, 150 06 Prague, Czech Republic
Phone: +420 22443 6552
Fax: +420 22443 6519
E-mail: petr.sedlacek@lfmotol.cuni.cz

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27369" ["VALUE"]=> array(2) { ["TEXT"]=> string(2524) "<p style="text-align: justify;">Fanconi anemia (FA) is a rare and heterogeneous syndrome associated with bone marrow failure and increased risk of cancer. While FA is often characterized by the presence of congenital malformations, in some patients cytopenia may be the only sign. In our cohort diagnosis was based on evidence of increased chromosome fragility with subsequent confirmation by gene mutation detection. </p> <h3>Methods</h3> <p style="text-align: justify;">Our cohort includes 35 probands diagnosed with FA aged 0-24.3 (median 6) years between January 1986 and August 2020. Congenital anomalies at diagnosis were seen in 5 and cytopenia in 22 patients, 8 patients had family history of FA. Genetic test confirmed FANCA gene mutations in 24, FANCG in 3, FANCD1 in 4, and FANCB in 2 siblings.</p> <h3>Results</h3> <p style="text-align: justify;">During follow-up 7 patients developed malignancy (among them all 4 patients with FANCD1 mutation). Seventeen patients developed marrow failure, for which 15 patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the median age of 9.3 (4.6-24.3) years. All transplanted patients achieved stable hematopoietic engraftment. However, in 2 patients due to inadequate immune reconstitution developed fatal CMV pneumonia and invasive aspergillosis 12 and 14 months post HSCT, accordingly. In one patient we have diagnosed adenocarcinoma of the gut 10 years and squamous cell carcinoma of tongue 13 years after HSCT. Thirteen patients are alive with a median follow-up of 10.6 (0.3 – 15.1 years) years after HSCT. With a median follow-up till the last visit of 12.6 (0.2-34.4) years 28/35 (80%) patients are alive, 4 died of malignancy, 2 died due to HSCT-related complications, and one due to severe congenital somatic defects.</p> <h3>Conclusions</h3> <p style="text-align: justify;">HSCT is effective in FA patients with bone marrow failure and prevents further development of hematological malignancies. A lifelong and careful multidisciplinary follow-up of patients with FA is essential for early detection of bone marrow failure or any malignant disease. </p> <h2>Keywords</h2> <p style="text-align: justify;">Fanconi anemia, somatic anomalies, gene mutations, bone marrow failure, solid tumors, hematopoietic stem cell transplantation, long-term outpatient observation.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2366) "

Fanconi anemia (FA) is a rare and heterogeneous syndrome associated with bone marrow failure and increased risk of cancer. While FA is often characterized by the presence of congenital malformations, in some patients cytopenia may be the only sign. In our cohort diagnosis was based on evidence of increased chromosome fragility with subsequent confirmation by gene mutation detection.

Methods

Our cohort includes 35 probands diagnosed with FA aged 0-24.3 (median 6) years between January 1986 and August 2020. Congenital anomalies at diagnosis were seen in 5 and cytopenia in 22 patients, 8 patients had family history of FA. Genetic test confirmed FANCA gene mutations in 24, FANCG in 3, FANCD1 in 4, and FANCB in 2 siblings.

Results

During follow-up 7 patients developed malignancy (among them all 4 patients with FANCD1 mutation). Seventeen patients developed marrow failure, for which 15 patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the median age of 9.3 (4.6-24.3) years. All transplanted patients achieved stable hematopoietic engraftment. However, in 2 patients due to inadequate immune reconstitution developed fatal CMV pneumonia and invasive aspergillosis 12 and 14 months post HSCT, accordingly. In one patient we have diagnosed adenocarcinoma of the gut 10 years and squamous cell carcinoma of tongue 13 years after HSCT. Thirteen patients are alive with a median follow-up of 10.6 (0.3 – 15.1 years) years after HSCT. With a median follow-up till the last visit of 12.6 (0.2-34.4) years 28/35 (80%) patients are alive, 4 died of malignancy, 2 died due to HSCT-related complications, and one due to severe congenital somatic defects.

Conclusions

HSCT is effective in FA patients with bone marrow failure and prevents further development of hematological malignancies. A lifelong and careful multidisciplinary follow-up of patients with FA is essential for early detection of bone marrow failure or any malignant disease.

Keywords

Fanconi anemia, somatic anomalies, gene mutations, bone marrow failure, solid tumors, hematopoietic stem cell transplantation, long-term outpatient observation.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27365" ["VALUE"]=> string(74) "Fanconi Anemia in the Czech Republic: role of HSCT and long-term follow-up" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(74) "Fanconi Anemia in the Czech Republic: role of HSCT and long-term follow-up" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["PDF_RU"]=> array(36) { ["ID"]=> string(2) "43" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF RUS" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_RU" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "43" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27366" ["VALUE"]=> string(4) "2335" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2335" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF RUS" ["~DEFAULT_VALUE"]=> string(0) "" } ["PDF_EN"]=> array(36) { ["ID"]=> string(2) "44" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF ENG" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "44" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27370" ["VALUE"]=> string(4) "2336" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2336" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF ENG" ["~DEFAULT_VALUE"]=> string(0) "" } ["NAME_LONG"]=> array(36) { ["ID"]=> string(2) "45" ["TIMESTAMP_X"]=> string(19) "2023-04-13 00:55:00" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(72) "Название (для очень длинных заголовков)" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "NAME_LONG" ["DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "45" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27367" ["VALUE"]=> array(2) { ["TEXT"]=> string(141) "<p>Petr Sedlacek, Petra Keslova, Petr Smisek, Martina Sukova, Marcela Malikova, Spiros Tavandzis, Jaroslav Cermak, Jan Stary </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(129) "

Petr Sedlacek, Petra Keslova, Petr Smisek, Martina Sukova, Marcela Malikova, Spiros Tavandzis, Jaroslav Cermak, Jan Stary

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(129) "

Petr Sedlacek, Petra Keslova, Petr Smisek, Martina Sukova, Marcela Malikova, Spiros Tavandzis, Jaroslav Cermak, Jan Stary

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27369" ["VALUE"]=> array(2) { ["TEXT"]=> string(2524) "<p style="text-align: justify;">Fanconi anemia (FA) is a rare and heterogeneous syndrome associated with bone marrow failure and increased risk of cancer. While FA is often characterized by the presence of congenital malformations, in some patients cytopenia may be the only sign. In our cohort diagnosis was based on evidence of increased chromosome fragility with subsequent confirmation by gene mutation detection. </p> <h3>Methods</h3> <p style="text-align: justify;">Our cohort includes 35 probands diagnosed with FA aged 0-24.3 (median 6) years between January 1986 and August 2020. Congenital anomalies at diagnosis were seen in 5 and cytopenia in 22 patients, 8 patients had family history of FA. Genetic test confirmed FANCA gene mutations in 24, FANCG in 3, FANCD1 in 4, and FANCB in 2 siblings.</p> <h3>Results</h3> <p style="text-align: justify;">During follow-up 7 patients developed malignancy (among them all 4 patients with FANCD1 mutation). Seventeen patients developed marrow failure, for which 15 patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the median age of 9.3 (4.6-24.3) years. All transplanted patients achieved stable hematopoietic engraftment. However, in 2 patients due to inadequate immune reconstitution developed fatal CMV pneumonia and invasive aspergillosis 12 and 14 months post HSCT, accordingly. In one patient we have diagnosed adenocarcinoma of the gut 10 years and squamous cell carcinoma of tongue 13 years after HSCT. Thirteen patients are alive with a median follow-up of 10.6 (0.3 – 15.1 years) years after HSCT. With a median follow-up till the last visit of 12.6 (0.2-34.4) years 28/35 (80%) patients are alive, 4 died of malignancy, 2 died due to HSCT-related complications, and one due to severe congenital somatic defects.</p> <h3>Conclusions</h3> <p style="text-align: justify;">HSCT is effective in FA patients with bone marrow failure and prevents further development of hematological malignancies. A lifelong and careful multidisciplinary follow-up of patients with FA is essential for early detection of bone marrow failure or any malignant disease. </p> <h2>Keywords</h2> <p style="text-align: justify;">Fanconi anemia, somatic anomalies, gene mutations, bone marrow failure, solid tumors, hematopoietic stem cell transplantation, long-term outpatient observation.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2366) "

Fanconi anemia (FA) is a rare and heterogeneous syndrome associated with bone marrow failure and increased risk of cancer. While FA is often characterized by the presence of congenital malformations, in some patients cytopenia may be the only sign. In our cohort diagnosis was based on evidence of increased chromosome fragility with subsequent confirmation by gene mutation detection.

Methods

Our cohort includes 35 probands diagnosed with FA aged 0-24.3 (median 6) years between January 1986 and August 2020. Congenital anomalies at diagnosis were seen in 5 and cytopenia in 22 patients, 8 patients had family history of FA. Genetic test confirmed FANCA gene mutations in 24, FANCG in 3, FANCD1 in 4, and FANCB in 2 siblings.

Results

During follow-up 7 patients developed malignancy (among them all 4 patients with FANCD1 mutation). Seventeen patients developed marrow failure, for which 15 patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the median age of 9.3 (4.6-24.3) years. All transplanted patients achieved stable hematopoietic engraftment. However, in 2 patients due to inadequate immune reconstitution developed fatal CMV pneumonia and invasive aspergillosis 12 and 14 months post HSCT, accordingly. In one patient we have diagnosed adenocarcinoma of the gut 10 years and squamous cell carcinoma of tongue 13 years after HSCT. Thirteen patients are alive with a median follow-up of 10.6 (0.3 – 15.1 years) years after HSCT. With a median follow-up till the last visit of 12.6 (0.2-34.4) years 28/35 (80%) patients are alive, 4 died of malignancy, 2 died due to HSCT-related complications, and one due to severe congenital somatic defects.

Conclusions

HSCT is effective in FA patients with bone marrow failure and prevents further development of hematological malignancies. A lifelong and careful multidisciplinary follow-up of patients with FA is essential for early detection of bone marrow failure or any malignant disease.

Keywords

Fanconi anemia, somatic anomalies, gene mutations, bone marrow failure, solid tumors, hematopoietic stem cell transplantation, long-term outpatient observation.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2366) "

Fanconi anemia (FA) is a rare and heterogeneous syndrome associated with bone marrow failure and increased risk of cancer. While FA is often characterized by the presence of congenital malformations, in some patients cytopenia may be the only sign. In our cohort diagnosis was based on evidence of increased chromosome fragility with subsequent confirmation by gene mutation detection.

Methods

Our cohort includes 35 probands diagnosed with FA aged 0-24.3 (median 6) years between January 1986 and August 2020. Congenital anomalies at diagnosis were seen in 5 and cytopenia in 22 patients, 8 patients had family history of FA. Genetic test confirmed FANCA gene mutations in 24, FANCG in 3, FANCD1 in 4, and FANCB in 2 siblings.

Results

During follow-up 7 patients developed malignancy (among them all 4 patients with FANCD1 mutation). Seventeen patients developed marrow failure, for which 15 patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) at the median age of 9.3 (4.6-24.3) years. All transplanted patients achieved stable hematopoietic engraftment. However, in 2 patients due to inadequate immune reconstitution developed fatal CMV pneumonia and invasive aspergillosis 12 and 14 months post HSCT, accordingly. In one patient we have diagnosed adenocarcinoma of the gut 10 years and squamous cell carcinoma of tongue 13 years after HSCT. Thirteen patients are alive with a median follow-up of 10.6 (0.3 – 15.1 years) years after HSCT. With a median follow-up till the last visit of 12.6 (0.2-34.4) years 28/35 (80%) patients are alive, 4 died of malignancy, 2 died due to HSCT-related complications, and one due to severe congenital somatic defects.

Conclusions

HSCT is effective in FA patients with bone marrow failure and prevents further development of hematological malignancies. A lifelong and careful multidisciplinary follow-up of patients with FA is essential for early detection of bone marrow failure or any malignant disease.

Keywords

Fanconi anemia, somatic anomalies, gene mutations, bone marrow failure, solid tumors, hematopoietic stem cell transplantation, long-term outpatient observation.

" } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27364" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-48-52" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-48-52" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-48-52" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27365" ["VALUE"]=> string(74) "Fanconi Anemia in the Czech Republic: role of HSCT and long-term follow-up" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(74) "Fanconi Anemia in the Czech Republic: role of HSCT and long-term follow-up" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(74) "Fanconi Anemia in the Czech Republic: role of HSCT and long-term follow-up" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27368" ["VALUE"]=> array(2) { ["TEXT"]=> string(557) "<p>Department of Pediatric Hematology and Oncology, 2<sup>nd</sup> Medical School at Charles University, University Hospital Motol, Prague, Czech Republic</p><br> <p><b>Correspondence</b><br> Prof. Dr. Petr Sedlacek, Department of Pediatric Hematology and Oncology, 2nd Medical School at Charles University, University Hospital Motol, V Uvalu 84, 150 06 Prague, Czech Republic<br> Phone: +420 22443 6552<br> Fax: +420 22443 6519<br> E-mail: petr.sedlacek@lfmotol.cuni.cz</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(479) "

Department of Pediatric Hematology and Oncology, 2nd Medical School at Charles University, University Hospital Motol, Prague, Czech Republic


Correspondence
Prof. Dr. Petr Sedlacek, Department of Pediatric Hematology and Oncology, 2nd Medical School at Charles University, University Hospital Motol, V Uvalu 84, 150 06 Prague, Czech Republic
Phone: +420 22443 6552
Fax: +420 22443 6519
E-mail: petr.sedlacek@lfmotol.cuni.cz

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(479) "

Department of Pediatric Hematology and Oncology, 2nd Medical School at Charles University, University Hospital Motol, Prague, Czech Republic


Correspondence
Prof. Dr. Petr Sedlacek, Department of Pediatric Hematology and Oncology, 2nd Medical School at Charles University, University Hospital Motol, V Uvalu 84, 150 06 Prague, Czech Republic
Phone: +420 22443 6552
Fax: +420 22443 6519
E-mail: petr.sedlacek@lfmotol.cuni.cz

" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27361" ["VALUE"]=> array(2) { ["TEXT"]=> string(235) "<p>Петр Седлачек, Петра Кеслова, Петр Смишек, Мартина Сукова, Марцела Маликова, Спирос Тавандзис, Ярослав Чермак, Ян Стари</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(223) "

Петр Седлачек, Петра Кеслова, Петр Смишек, Мартина Сукова, Марцела Маликова, Спирос Тавандзис, Ярослав Чермак, Ян Стари

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(223) "

Петр Седлачек, Петра Кеслова, Петр Смишек, Мартина Сукова, Марцела Маликова, Спирос Тавандзис, Ярослав Чермак, Ян Стари

" } ["SUBMITTED"]=> array(37) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27359" ["VALUE"]=> string(10) "09.11.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "09.11.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "09.11.2020" } ["ACCEPTED"]=> array(37) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27360" ["VALUE"]=> string(10) "04.12.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "04.12.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "04.12.2020" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27363" ["VALUE"]=> array(2) { ["TEXT"]=> string(4777) "<p style="text-align: justify;">Анемия Фанкони (АФ) – редкий синдром с гетерогенной картиной, сочетающийся с недостаточностью костного мозга и повышенным риском злокачественных новообразований. Хотя АФ часто характеризуется наличием пороков развития, у некоторых пациентов единственным признаком может быть цитопения. В нашей когорте больных диагностика основывалась на повышенной ломкости хромосом с последующим подтверждением генных мутаций.</p> <h3>Методы</h3> <p style="text-align: justify;">Наша когорта включает 35 пробандов в возрасте от 0 до 24,3 (медиана – 6) лет, у которых была диагностирована АФ в сроки с января 1986 до августа 2020 г. Врожденные аномалии на момент диагноза наблюдались у 5 и цитопения – у 22 пациентов; 8 больных имели семейный анамнез АФ. Генетическое тестирование подтвердило мутации гена FANCA в 24 случаях, FANCG – в 3, FANCD1 – у 4 пациентов и FANCB – у двух сиблингов.</p> <h3>Результаты</h3> <p style="text-align: justify;">По мере наблюдения, у 7 пациентов развились злокачественные новообразования (в том числе – у 4 больных с мутацией FANCD1). У 17 пациентов развилась костномозговая недостаточность, в связи с чем 15 больным была выполнена трансплантация гемопоэтических стволовых клеток (ТГСК) в возрасте от 4,6 до 24,3 лет (медиана – 9,3 года). У всех трансплантированных пациентов было достигнуто стабильное гемопоэтическое приживление. Однако у 2 больных, в связи с неадекватным восстановлением иммунитета, через 12 и 14 мес. после ТГСК развились, соответственно, цитомегаловирусная пневмония и инвазивный аспергиллез со смертельными исходами. В одном случае мы диагностировали аденокарциному кишечника через 10 лет и сквамозноклеточную карциному языка через 13 лет после ТГСК. Тринадцать пациентов живы при среднем сроке наблюдения после ТГСК 10,6 (0,3-15,1) лет. При сроках наблюдения с медианой 12,6 (0,2-34,4) лет, 28/35 пациентов (80%) живы, 4 погибли от злокачественных новообразований, двое умерли от осложнений ТГСК, и один больной – в связи с тяжелыми врожденными соматическими пороками. </p> <h3>Выводы</h3> <p style="text-align: justify;">ТГСК эффективна у пациентов с АФ и костномозговой недостаточностью и предотвращает дальнейшее развитие гематологических осложнений. Необходимо пожизненное и тщательное мультидисциплинарное наблюдение пациентов с АФ для раннего выявления костномозговой недостаточности или злокачественного заболевания.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Анемия Фанкони, соматические аномалии, генные мутации, костномозговая недостаточность, солидные опухоли, трансплантация гемопоэтических стволовых клеток, амбулаторное долгосрочное наблюдение.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4619) "

Анемия Фанкони (АФ) – редкий синдром с гетерогенной картиной, сочетающийся с недостаточностью костного мозга и повышенным риском злокачественных новообразований. Хотя АФ часто характеризуется наличием пороков развития, у некоторых пациентов единственным признаком может быть цитопения. В нашей когорте больных диагностика основывалась на повышенной ломкости хромосом с последующим подтверждением генных мутаций.

Методы

Наша когорта включает 35 пробандов в возрасте от 0 до 24,3 (медиана – 6) лет, у которых была диагностирована АФ в сроки с января 1986 до августа 2020 г. Врожденные аномалии на момент диагноза наблюдались у 5 и цитопения – у 22 пациентов; 8 больных имели семейный анамнез АФ. Генетическое тестирование подтвердило мутации гена FANCA в 24 случаях, FANCG – в 3, FANCD1 – у 4 пациентов и FANCB – у двух сиблингов.

Результаты

По мере наблюдения, у 7 пациентов развились злокачественные новообразования (в том числе – у 4 больных с мутацией FANCD1). У 17 пациентов развилась костномозговая недостаточность, в связи с чем 15 больным была выполнена трансплантация гемопоэтических стволовых клеток (ТГСК) в возрасте от 4,6 до 24,3 лет (медиана – 9,3 года). У всех трансплантированных пациентов было достигнуто стабильное гемопоэтическое приживление. Однако у 2 больных, в связи с неадекватным восстановлением иммунитета, через 12 и 14 мес. после ТГСК развились, соответственно, цитомегаловирусная пневмония и инвазивный аспергиллез со смертельными исходами. В одном случае мы диагностировали аденокарциному кишечника через 10 лет и сквамозноклеточную карциному языка через 13 лет после ТГСК. Тринадцать пациентов живы при среднем сроке наблюдения после ТГСК 10,6 (0,3-15,1) лет. При сроках наблюдения с медианой 12,6 (0,2-34,4) лет, 28/35 пациентов (80%) живы, 4 погибли от злокачественных новообразований, двое умерли от осложнений ТГСК, и один больной – в связи с тяжелыми врожденными соматическими пороками.

Выводы

ТГСК эффективна у пациентов с АФ и костномозговой недостаточностью и предотвращает дальнейшее развитие гематологических осложнений. Необходимо пожизненное и тщательное мультидисциплинарное наблюдение пациентов с АФ для раннего выявления костномозговой недостаточности или злокачественного заболевания.

Ключевые слова

Анемия Фанкони, соматические аномалии, генные мутации, костномозговая недостаточность, солидные опухоли, трансплантация гемопоэтических стволовых клеток, амбулаторное долгосрочное наблюдение.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(4619) "

Анемия Фанкони (АФ) – редкий синдром с гетерогенной картиной, сочетающийся с недостаточностью костного мозга и повышенным риском злокачественных новообразований. Хотя АФ часто характеризуется наличием пороков развития, у некоторых пациентов единственным признаком может быть цитопения. В нашей когорте больных диагностика основывалась на повышенной ломкости хромосом с последующим подтверждением генных мутаций.

Методы

Наша когорта включает 35 пробандов в возрасте от 0 до 24,3 (медиана – 6) лет, у которых была диагностирована АФ в сроки с января 1986 до августа 2020 г. Врожденные аномалии на момент диагноза наблюдались у 5 и цитопения – у 22 пациентов; 8 больных имели семейный анамнез АФ. Генетическое тестирование подтвердило мутации гена FANCA в 24 случаях, FANCG – в 3, FANCD1 – у 4 пациентов и FANCB – у двух сиблингов.

Результаты

По мере наблюдения, у 7 пациентов развились злокачественные новообразования (в том числе – у 4 больных с мутацией FANCD1). У 17 пациентов развилась костномозговая недостаточность, в связи с чем 15 больным была выполнена трансплантация гемопоэтических стволовых клеток (ТГСК) в возрасте от 4,6 до 24,3 лет (медиана – 9,3 года). У всех трансплантированных пациентов было достигнуто стабильное гемопоэтическое приживление. Однако у 2 больных, в связи с неадекватным восстановлением иммунитета, через 12 и 14 мес. после ТГСК развились, соответственно, цитомегаловирусная пневмония и инвазивный аспергиллез со смертельными исходами. В одном случае мы диагностировали аденокарциному кишечника через 10 лет и сквамозноклеточную карциному языка через 13 лет после ТГСК. Тринадцать пациентов живы при среднем сроке наблюдения после ТГСК 10,6 (0,3-15,1) лет. При сроках наблюдения с медианой 12,6 (0,2-34,4) лет, 28/35 пациентов (80%) живы, 4 погибли от злокачественных новообразований, двое умерли от осложнений ТГСК, и один больной – в связи с тяжелыми врожденными соматическими пороками.

Выводы

ТГСК эффективна у пациентов с АФ и костномозговой недостаточностью и предотвращает дальнейшее развитие гематологических осложнений. Необходимо пожизненное и тщательное мультидисциплинарное наблюдение пациентов с АФ для раннего выявления костномозговой недостаточности или злокачественного заболевания.

Ключевые слова

Анемия Фанкони, соматические аномалии, генные мутации, костномозговая недостаточность, солидные опухоли, трансплантация гемопоэтических стволовых клеток, амбулаторное долгосрочное наблюдение.

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27362" ["VALUE"]=> array(2) { ["TEXT"]=> string(292) "<p>Департамент детской гематологии и онкологии, 2-я медицинская школа Карлова Университета, университетский госпиталь Мотол, Прага, Чешская республика</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(280) "

Департамент детской гематологии и онкологии, 2-я медицинская школа Карлова Университета, университетский госпиталь Мотол, Прага, Чешская республика

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(280) "

Департамент детской гематологии и онкологии, 2-я медицинская школа Карлова Университета, университетский госпиталь Мотол, Прага, Чешская республика

" } } } [4]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(3) "170" ["~IBLOCK_SECTION_ID"]=> string(3) "170" ["ID"]=> string(4) "1942" ["~ID"]=> string(4) "1942" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["~NAME"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "05.02.2021 15:36:20" ["~TIMESTAMP_X"]=> string(19) "05.02.2021 15:36:20" ["DETAIL_PAGE_URL"]=> string(138) "/ru/archive/-9-4/klinicheskie-raboty/vyyavlenie-donor-spetsificheskikh-anti-hla-antitel-metodom-individualnoy-perekrestnoy-proby-de-fakto/" ["~DETAIL_PAGE_URL"]=> string(138) "/ru/archive/-9-4/klinicheskie-raboty/vyyavlenie-donor-spetsificheskikh-anti-hla-antitel-metodom-individualnoy-perekrestnoy-proby-de-fakto/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(20509) "

Introduction

Hematopoietic stem cell transplantation (HSCT) from haploidentical donors (haplo-HSCT) increasingly becomes the method of choice in the treatment of patients with hemoblastoses and hematopoietic depressions. HLA-matched related donors are often not available, and there is no sufficient time for searching unrelated donors, or matched unrelated donors cannot be found neither in the domestic nor in foreign bone marrow registers. New conditioning regimens implementation, improvement of graft processing technologies, as well as the use of effective methods of graft-versus-host disease (GvHD) prevention significantly reduced the risk of severe complications and allowed to expand the indications for such a kind of transplantations [1, 2]. Thus, indication of cyclophosphamide following haplo-HSCT for the GvHD-prevention and selective αβ-depletion of T-cells from a graft significantly increased patient survival rates [2, 3, 4, 5].

HLA-haploidentical donor may be available for the most of patients: first- and second-line relatives who inherit the same HLA-haplotype as the patient may be related HLA-haplocompatible, or even HLA-haploidentical donors. According to Fuchs [6] the related HLA-haploidentical donor in pediatric practice can be found for more than 95% of patients, and the average number of haploidentical donors for one patient can be two or more. Such donors are usually available and motivated to donate. But haplocompatible/haploidentical donors are just partially compatible with the patient's HLA-antigens. If the patient develops antibodies against HLA-antigens of its donor's cells, i.e., the donor-specific antibodies (DSA), these DSA may potentially cause the immunomediated haplo-HSCT complications. Primary graft failure is the most dangerous hazard. Ciurea et al. have found DSA in 18% (22 out of 122) of patients before haplo-HSCT. In the group of patients with DSA, the frequency of primary graft failure was significantly higher (32%) than in patients without DSA (4%) (p<0.001) [7]. Chang et al. found DSA in 11.3% of patients (39 out of 345) for whom then haplo-HSCT has been performed [8]. With DSA levels of more than 2000 units, the incidence of primary graft failure was significantly higher (23.7%) than at their absence, and DSA levels of less than 2000 units (1.9%) (p=0.003). Due to primary graft failure, the survival rate is significantly lower in patients with DSA after haplo-HSCT [9].

The aim of the current study was to determine frequency of anti-HLA DSA detection in recipients before haplo-HSCT using the enzyme-linked immunosorbent assay (ELISA) and to prove an association between the DSA presence and risk of primary graft failure and (or) graft hypofunction in children after haplo-HSCT.

Materials and methods

Table 1. Demographic and clinical characteristics of the patients

Paina-tab01.jpg

Note: AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndrome; AA, aplastic anemia; JMML, juvenile myelomonocytic leukemia.

Current publication presents the results of a pilot retrospective single-center study. Forty pediatric patients who received haplo-HSCT with unmanipulated graft have been included into the study. The study proceeded in the clinic of R. M. Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation over the period from July 2019 to March 2020. HLA-typing of recipients and their donors was performed with molecular-genetic methods. If based on the results of HLA-typing (HLA-A, B, C, DRB1, DQB1) in the patient and first-line relatives at low-resolution level, it was possible to establish four family haplotypes, then the recipient and the donor, matched by one of these haplotypes were considered as haploidentical. If the family study did not allow to determine four haplotypes, then the high-resolution HLA-typing has been performed by Sanger sequencing. The recipient/donor concordance for, at least, 5 alleles out of 10 was considered haplo-compatible. However, in vast majority of patients (95%), haploidentity could not be determined, so we considered haplo-compatible all the performed HSCTs. Demographics and clinical characteristics of the patients are presented in Table 1.

The median age of patients at the time of HSCT was 8 (1-17) years. The cohort was dominated by patients with ALL (67.5%) and AML (20%). Medians of the number of transplanted nucleated and CD34+ cells were 8.5×108/kg (2.3-17.9×108/kg) and 7.6×106/kg (2.3-8.2×106/kg), respectively. Stimulated, unmanipulated bone marrow was a source of CD34+ cells in all cases. The donor's hematopoesis was stimulated by G-CSF at the dose of 5 mcg/kg/day during 3 days, and the bone marrow myeloexfusion has been performed on the 4th day. 26 recipients (65%) received myeloablative conditioning (MAC) based on busulfan at a total dose of 12 mg/kg and fludarabine (150 mg/m2). The reduced-intensity conditioning (RIC) has been received by 14 (35%) of patients, i.e.,: melphalan at the total dose of 140 mg/m2 and fludarabine (150 mg/m2). Post-transplant cyclophosphamide at the days +3 and +4 post-HSCT was administered at the dose of 50 mg/kg per day, calcineurin inhibitor tacrolimus (0.03 mg/kg/day with a target concentration of 3-5 ng/ml), and mTOR inhibitor – sirolimus (1 mg/m2/day, with a target concentration of 3-5 ng/ml) were used to prevent acute GvHD. The distribution of HLA-haploidentical donors was as follows: fathers, 24 cases; mothers, 14 cases; siblings, in 2 cases.

The primary graft failure criterion was considered as failure to reach the level of neutrophils of more than 0.5×109/l within three consequent days +35 to 42 posttransplant. The hypofunction of the transplant was diagnosed as two- or three-lineage cytopenia (Hb< 100 g/l, neutrophils <0.5×109/l, platelets <109/l), regardless of the time post-transplant, requirements for blood transfusion, and hypocellular bone marrow in presence of complete donor chimerism and absence of acute GvHD, or a disease relapse.

Paina-fig01.jpg

Figure 1. Enzyme Immunoassay in the presence of DSA to HLA-antigens of the donor

All the patients were examined for the presence of anti-HLA DSA before haplo-HSCT. The laboratory method selected for DSA detection was an enzyme immunoassay analysis (XMatch®, PROTRANS, Germany). From the donor blood samples lymphocytes were isolated and then lysed. The cell lysates containing donor HLA-molecules were then incubated with capture antibodies precipitated at the bottom of ELISA-wells separately for HLA class I and II (Fig. 1).

The donor's native HLA-antigens were bound to the capturing antibodies fixed to the bottom of the wells. Then the patient's blood serum samples were incubated at this carrier. In the case of DSA presence, these antibodies were attached to the donor's HLA-antigens. After series of washings from unbound antibodies, secondary antibodies labeled with horseradish peroxidase were added. These antibodies could only bind to DSA previously fixed to the donor's HLA-antigens. To visualize the results, a peroxidase-oxidized substrate was added to change the color of the solution. Optical density of the reaction products was measured by using an enzyme immunoassay analyzer (Immunochem-2100, High Technology Inc, USA) at wavelengths of 450 and 620 nm. The result was accepted as valid if the optical density in positive control was ≥0.350 OD and in negative control ≤0.150 OD. The result was considered positive, if the optical density was at least twice higher than negative control.

We have used ELISA-based crossmatch to detect DSA de facto opposite to virtual crossmatching based on the analysis of Luminex results. The idea was to prove the direct interaction between HLA-antigens of the certain donor with antibodies of the patient. ELISA was also the method of choice since it allowed to avoid false-positive results that occur in CDC or FC-XM due to therapiutic monoclonal antibodies received by the patients before haplo-HSCT. Thus, the chosen method could provide the direct interaction evidence, and could be used qualitatively.

The differences in the frequency of primary graft failure and graft hypofunction between the analyzed groups were evaluated by means of the two-tailed Fisher's exact test. For statistical data processing, STATISTICA 8 software was used (StatSoft Inc., USA).

Results

Among all the examined children, three patients (7.5%) were found to be DSA-positive, while the vast majority (n=37; 92.5%) had no DSA. It was also found that, in all cases, DSA were directed against HLA class II antigens.

Brief description of patients with DSA is as follows:
1) Patient K.P., 10 years old; acquired idiopathic aplastic anemia, severe form; duration of the disease before haplo-HSCT was 5 years; previous history of multiple hemotransfusions.
2) Patient I.V., 15 years old; acute myeloblastic leukemia with interstitial 7p and 9q deletions; high risk group; allogeneic unrelated bone marrow transplantation (28.04.2018); engraftment by the day +20; donor lymphocyte infusion (DLI, n=5); isolated bone marrow relapse (of 11.02.2019); transplant rejection (25.03.2019); a history of multiple hemotransfusions; duration of the disease prior to haplo-HSCT was 1.5 years.
3) Patient K.P., 14 years old; acute myeloblastic leukemia (FAB M4) with co-expression of CD7, CD79A; NUP98 gene rearrangement; therapy according to the AML-BFM 2004 Protocol; the first early isolated bone marrow relapse documented at 07.03.2019 with resistance to therapy; duration of the disease from diagnosis to haplo-HSCT was 9 months.

When analyzing efficiency of performed haplo-HSCTs, we have found that nine patients (22.5%) had either primary graft failure (n=6; 15%) or graft hypofunction (n=3; 7.5%).

Primary graft failure and allograft hypofunction, being a sign of poor engraftment in these patients, required then a repeated allo-HSCT from other donor. Of note, the improved analytic technologies for evaluating donor chimerism have shown that some patients can develop graft hypofunction even when the complete donor chimerism is observed.

Comparative analysis of the results shows that patients with DSA prior to haplo-HSCT are more likely to develop primary graft failure, or hypofunction compared to the group of recipients without DSA. All three patients with detected antibodies were diagnosed with either primary graft failure (n=1; 33%) or graft hypofunction (n=2; 67%). In the control group of patients without DSA, primary graft failure or graft hypofunction were observed in 5 (13.5 %) and 1 (2.7 %) cases respectively, with a total of 6 cases (16.2%) (Table 2).

Table 2. Frequency of primary graft failure and graft hypofunction depending on the presence of DSA (n=40)

Paina-tab02.jpg

Discussion

The role of DSA in hematopoietic cell transplantation remained unclear for a long time. For allogeneic HSCT, clinicians tried to search for either HLA-identical related, or HLA-matched unrelated donors, in these cases DSA to HLA-antigens would not develop in principle. Therefore, when studying graft failure mechanisms, the cellular immunity has drawn much attention. Nowadays, its generally accepted that, following organ and tissue transplantation, the immune system reacts to the HLA-antigens differing from recipient HLA-antigens by the mechanisms of both cellular and humoral immune response. At the same time, it would be noted that the exact mechanism by which DSA causes graft failure in haplo-HSCT, remains undetermined.

The impact of DSA to the outcome of organ transplantation became the point for some studies on their role in haplo-HSCT. The results of these works represented the basis of clinical recommendations aimed for identification and elimination of DSA in patients before haplo-HSCT, published by the European Society for Blood and Marrow Transplantation (EBMT) in 2018 [10]. In adult patients with hemoblastosis requiring allo-HSCT, the detection frequency of anti-HLA antibodies may reach 40%, [11, 12, 13]. However, not all of these anti-HLA antibodies are directed against donor HLA-antigens. Using highly sensitive methods of solid-phase analysis, it was detected that anti-HLA antibodies were donor-specific in 24% of haplo-HSCT recipients [14]. According to the most researchers, the prevalence of DSA varies from 10% to 21% [9]. In the present study, we were able to identify DSA only in 7.5% of examined patients. Probably, the lower rate in children is observed due to anti-HLA antibodies arising after hemotransfusions and, in some cases, following previous HSCT from a partially matched donor. Among adults, HLA-allosensitization is most often detected in women (up to 86%, against 5% in men), with pregnancy being the most common reason.

Our data on the high frequency of primary graft failure and/or graft hypofunction in the recipient group with the presence of DSA (100%), compared to the group, in which DSA is not detectable (16.22%) agreed with previous data [9] about the influence of DSA upon the outcome of haplo-HSCT. However, due to minority of patients with identified DSA, one should continue this study in order to confirm these results in a more representative sample.

It is recommended to determine DSAs in all patients 1 month before haplo-HSCT. When DSA are detected, a search for alternative haplo-compatible donor should be considered. If such donors are not available, it is necessary to use the treatment reducing the DSA-levels and to prevent the development of new anti-HLA DSA. Laboratory monitoring of DSA would be used as a way to assess effectiveness of treatment, and should be performed just before transplantation and every week after it [10].

Conclusion

The method we used to determine DSA is sufficiently informative, has a number of advantages over the serological method using a lymphocytotoxic test, flow cytometry, as well as multiplex analysis methods, and it does not require intact donor lymphocytes incubated immediately with DSA. The test does not give false positive results in the presence of any non-anti-HLA IgG’s in the patient's serum that can contact the membrane and activate the complement. HLA-molecules of a real donor as an antigen material are used for the test. Results are recorded automatically. It is necessary to perform a comparative study of the results of DSA testing using enzyme immunoassay with a multiplex analysis which is more common method in routine practice, using the Luminex platform. Implementation of DSA-testing for the routine practice in recipients prior to haplo-HSCT will optimize the choice of a donor, as well as to select a group of potential recipients who requires desensitization treatment over the pre-transplant period.

Conflict of interest

None declared.

References

  1. Afanasyev BV, Zubarovskaya LS, Alyanskiy AL, et al. The donor choice for allogeneic stem cell transplantation. Russian Journal of Children Hematology and Oncology. 2016; 3(3): 30-36 (In Russian).
  2. Maschan MA. Т-lymphocytes alpha/beta depletion – reliable platform for the development of stem cell transplantaion from haploidentical donors. Russian Journal of Children Hematology and Oncology. 2015; 2 (3):34-38. (In Russian).
  3. Paina OV, Stancheva NV, Semenova EV, et al. Haploidentical transplantation of hematopoetic stem cells in treatment of children and adolescents with resistant forms of acute leucosis. Russian Journal of Children Hematology and Oncology. 2015; 2(3):39-45 (In Russian).
  4. Paina OV, Kojokar' PV, Borovkova AS, et al. Results of alogeneic stem cell transplantation from haploidentical donor with unmanipulated bone marrowtransplant in children and adolescents with acute leucosis from high risk group: 10 years experience. Issues in Hematology/Oncology and Immunology in Pediatrics. 2018; 17(2): 21-27 (In Russian).
  5. Lee CJ, Savani BN, Mohty M, Labopin M, Ruggeri A et al. Haploidentical hematopoietic cell transplantation for adult acute myeloid leukemia: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2017; 102(11);1810-1822.
  6. Fuchs EJ. Haploidentical transplantation for hematologic malignancies: where do we stand? Hematol. Am.Soc.Hematol.Educ.Program. 2012; 2012: 230-236.
  7. Ciurea SO, Mulanovich V, Jiang Y, et al. Lymphocyte recovery predicts outcomes in cord blood and T cell-depleted haploidentical stem cell transplantation. Biol Blood Marrow Transplant. 2011;17:1169-1175.
  8. Chang YJ, Zhao XY, Xu LP, Zhang XH, Wang Y, Han W, et al. Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets. J Hematol Oncol. 2015; 8:84.
  9. Ciurea SO, Thall PF, Milton DR, Barnes TH, Kongtim P, Carmazzi Y, et al. Complement-binding donor-specific anti-HLA antibodies and risk of primary graft failure in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21:1392-1398.
  10. The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the detection and treatment of donor specific anti-HLA antibodies (DSA) in haploidentical hematopoietic cell transplantation. Bone Marrow Transplantation. 2018; 53: 521-534.
  11. Yoshihara S, Maruya E, Taniguchi K, Kaida K, Kato R, Inoue T, et al. Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT. Bone Marrow Transplant. 2012; 47:508-515.
  12. Chang YJ, Zhao XY, Xu LP, Zhang XH, Wang Y, Han W, et al. Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets. J Hematol Oncol. 2015; 8:84.
  13. Ruggeri A, Rocha V, Masson E, Labopin M, Cunha R, Absi L, et al. Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Societe Francophone d’Histocompatibilite et d’Immunogenetique (SFHI) and Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) analysis. Haematologica. 2013; 98:1154-1160.
  14. Gladstone DE, Zachary AA, Fuchs EJ, Luznik L, Kasamon YL, King KE, et al. Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies. Biol Blood Marrow Transplant. 2013;19:647-652.

" ["~DETAIL_TEXT"]=> string(20509) "

Introduction

Hematopoietic stem cell transplantation (HSCT) from haploidentical donors (haplo-HSCT) increasingly becomes the method of choice in the treatment of patients with hemoblastoses and hematopoietic depressions. HLA-matched related donors are often not available, and there is no sufficient time for searching unrelated donors, or matched unrelated donors cannot be found neither in the domestic nor in foreign bone marrow registers. New conditioning regimens implementation, improvement of graft processing technologies, as well as the use of effective methods of graft-versus-host disease (GvHD) prevention significantly reduced the risk of severe complications and allowed to expand the indications for such a kind of transplantations [1, 2]. Thus, indication of cyclophosphamide following haplo-HSCT for the GvHD-prevention and selective αβ-depletion of T-cells from a graft significantly increased patient survival rates [2, 3, 4, 5].

HLA-haploidentical donor may be available for the most of patients: first- and second-line relatives who inherit the same HLA-haplotype as the patient may be related HLA-haplocompatible, or even HLA-haploidentical donors. According to Fuchs [6] the related HLA-haploidentical donor in pediatric practice can be found for more than 95% of patients, and the average number of haploidentical donors for one patient can be two or more. Such donors are usually available and motivated to donate. But haplocompatible/haploidentical donors are just partially compatible with the patient's HLA-antigens. If the patient develops antibodies against HLA-antigens of its donor's cells, i.e., the donor-specific antibodies (DSA), these DSA may potentially cause the immunomediated haplo-HSCT complications. Primary graft failure is the most dangerous hazard. Ciurea et al. have found DSA in 18% (22 out of 122) of patients before haplo-HSCT. In the group of patients with DSA, the frequency of primary graft failure was significantly higher (32%) than in patients without DSA (4%) (p<0.001) [7]. Chang et al. found DSA in 11.3% of patients (39 out of 345) for whom then haplo-HSCT has been performed [8]. With DSA levels of more than 2000 units, the incidence of primary graft failure was significantly higher (23.7%) than at their absence, and DSA levels of less than 2000 units (1.9%) (p=0.003). Due to primary graft failure, the survival rate is significantly lower in patients with DSA after haplo-HSCT [9].

The aim of the current study was to determine frequency of anti-HLA DSA detection in recipients before haplo-HSCT using the enzyme-linked immunosorbent assay (ELISA) and to prove an association between the DSA presence and risk of primary graft failure and (or) graft hypofunction in children after haplo-HSCT.

Materials and methods

Table 1. Demographic and clinical characteristics of the patients

Paina-tab01.jpg

Note: AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndrome; AA, aplastic anemia; JMML, juvenile myelomonocytic leukemia.

Current publication presents the results of a pilot retrospective single-center study. Forty pediatric patients who received haplo-HSCT with unmanipulated graft have been included into the study. The study proceeded in the clinic of R. M. Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation over the period from July 2019 to March 2020. HLA-typing of recipients and their donors was performed with molecular-genetic methods. If based on the results of HLA-typing (HLA-A, B, C, DRB1, DQB1) in the patient and first-line relatives at low-resolution level, it was possible to establish four family haplotypes, then the recipient and the donor, matched by one of these haplotypes were considered as haploidentical. If the family study did not allow to determine four haplotypes, then the high-resolution HLA-typing has been performed by Sanger sequencing. The recipient/donor concordance for, at least, 5 alleles out of 10 was considered haplo-compatible. However, in vast majority of patients (95%), haploidentity could not be determined, so we considered haplo-compatible all the performed HSCTs. Demographics and clinical characteristics of the patients are presented in Table 1.

The median age of patients at the time of HSCT was 8 (1-17) years. The cohort was dominated by patients with ALL (67.5%) and AML (20%). Medians of the number of transplanted nucleated and CD34+ cells were 8.5×108/kg (2.3-17.9×108/kg) and 7.6×106/kg (2.3-8.2×106/kg), respectively. Stimulated, unmanipulated bone marrow was a source of CD34+ cells in all cases. The donor's hematopoesis was stimulated by G-CSF at the dose of 5 mcg/kg/day during 3 days, and the bone marrow myeloexfusion has been performed on the 4th day. 26 recipients (65%) received myeloablative conditioning (MAC) based on busulfan at a total dose of 12 mg/kg and fludarabine (150 mg/m2). The reduced-intensity conditioning (RIC) has been received by 14 (35%) of patients, i.e.,: melphalan at the total dose of 140 mg/m2 and fludarabine (150 mg/m2). Post-transplant cyclophosphamide at the days +3 and +4 post-HSCT was administered at the dose of 50 mg/kg per day, calcineurin inhibitor tacrolimus (0.03 mg/kg/day with a target concentration of 3-5 ng/ml), and mTOR inhibitor – sirolimus (1 mg/m2/day, with a target concentration of 3-5 ng/ml) were used to prevent acute GvHD. The distribution of HLA-haploidentical donors was as follows: fathers, 24 cases; mothers, 14 cases; siblings, in 2 cases.

The primary graft failure criterion was considered as failure to reach the level of neutrophils of more than 0.5×109/l within three consequent days +35 to 42 posttransplant. The hypofunction of the transplant was diagnosed as two- or three-lineage cytopenia (Hb< 100 g/l, neutrophils <0.5×109/l, platelets <109/l), regardless of the time post-transplant, requirements for blood transfusion, and hypocellular bone marrow in presence of complete donor chimerism and absence of acute GvHD, or a disease relapse.

Paina-fig01.jpg

Figure 1. Enzyme Immunoassay in the presence of DSA to HLA-antigens of the donor

All the patients were examined for the presence of anti-HLA DSA before haplo-HSCT. The laboratory method selected for DSA detection was an enzyme immunoassay analysis (XMatch®, PROTRANS, Germany). From the donor blood samples lymphocytes were isolated and then lysed. The cell lysates containing donor HLA-molecules were then incubated with capture antibodies precipitated at the bottom of ELISA-wells separately for HLA class I and II (Fig. 1).

The donor's native HLA-antigens were bound to the capturing antibodies fixed to the bottom of the wells. Then the patient's blood serum samples were incubated at this carrier. In the case of DSA presence, these antibodies were attached to the donor's HLA-antigens. After series of washings from unbound antibodies, secondary antibodies labeled with horseradish peroxidase were added. These antibodies could only bind to DSA previously fixed to the donor's HLA-antigens. To visualize the results, a peroxidase-oxidized substrate was added to change the color of the solution. Optical density of the reaction products was measured by using an enzyme immunoassay analyzer (Immunochem-2100, High Technology Inc, USA) at wavelengths of 450 and 620 nm. The result was accepted as valid if the optical density in positive control was ≥0.350 OD and in negative control ≤0.150 OD. The result was considered positive, if the optical density was at least twice higher than negative control.

We have used ELISA-based crossmatch to detect DSA de facto opposite to virtual crossmatching based on the analysis of Luminex results. The idea was to prove the direct interaction between HLA-antigens of the certain donor with antibodies of the patient. ELISA was also the method of choice since it allowed to avoid false-positive results that occur in CDC or FC-XM due to therapiutic monoclonal antibodies received by the patients before haplo-HSCT. Thus, the chosen method could provide the direct interaction evidence, and could be used qualitatively.

The differences in the frequency of primary graft failure and graft hypofunction between the analyzed groups were evaluated by means of the two-tailed Fisher's exact test. For statistical data processing, STATISTICA 8 software was used (StatSoft Inc., USA).

Results

Among all the examined children, three patients (7.5%) were found to be DSA-positive, while the vast majority (n=37; 92.5%) had no DSA. It was also found that, in all cases, DSA were directed against HLA class II antigens.

Brief description of patients with DSA is as follows:
1) Patient K.P., 10 years old; acquired idiopathic aplastic anemia, severe form; duration of the disease before haplo-HSCT was 5 years; previous history of multiple hemotransfusions.
2) Patient I.V., 15 years old; acute myeloblastic leukemia with interstitial 7p and 9q deletions; high risk group; allogeneic unrelated bone marrow transplantation (28.04.2018); engraftment by the day +20; donor lymphocyte infusion (DLI, n=5); isolated bone marrow relapse (of 11.02.2019); transplant rejection (25.03.2019); a history of multiple hemotransfusions; duration of the disease prior to haplo-HSCT was 1.5 years.
3) Patient K.P., 14 years old; acute myeloblastic leukemia (FAB M4) with co-expression of CD7, CD79A; NUP98 gene rearrangement; therapy according to the AML-BFM 2004 Protocol; the first early isolated bone marrow relapse documented at 07.03.2019 with resistance to therapy; duration of the disease from diagnosis to haplo-HSCT was 9 months.

When analyzing efficiency of performed haplo-HSCTs, we have found that nine patients (22.5%) had either primary graft failure (n=6; 15%) or graft hypofunction (n=3; 7.5%).

Primary graft failure and allograft hypofunction, being a sign of poor engraftment in these patients, required then a repeated allo-HSCT from other donor. Of note, the improved analytic technologies for evaluating donor chimerism have shown that some patients can develop graft hypofunction even when the complete donor chimerism is observed.

Comparative analysis of the results shows that patients with DSA prior to haplo-HSCT are more likely to develop primary graft failure, or hypofunction compared to the group of recipients without DSA. All three patients with detected antibodies were diagnosed with either primary graft failure (n=1; 33%) or graft hypofunction (n=2; 67%). In the control group of patients without DSA, primary graft failure or graft hypofunction were observed in 5 (13.5 %) and 1 (2.7 %) cases respectively, with a total of 6 cases (16.2%) (Table 2).

Table 2. Frequency of primary graft failure and graft hypofunction depending on the presence of DSA (n=40)

Paina-tab02.jpg

Discussion

The role of DSA in hematopoietic cell transplantation remained unclear for a long time. For allogeneic HSCT, clinicians tried to search for either HLA-identical related, or HLA-matched unrelated donors, in these cases DSA to HLA-antigens would not develop in principle. Therefore, when studying graft failure mechanisms, the cellular immunity has drawn much attention. Nowadays, its generally accepted that, following organ and tissue transplantation, the immune system reacts to the HLA-antigens differing from recipient HLA-antigens by the mechanisms of both cellular and humoral immune response. At the same time, it would be noted that the exact mechanism by which DSA causes graft failure in haplo-HSCT, remains undetermined.

The impact of DSA to the outcome of organ transplantation became the point for some studies on their role in haplo-HSCT. The results of these works represented the basis of clinical recommendations aimed for identification and elimination of DSA in patients before haplo-HSCT, published by the European Society for Blood and Marrow Transplantation (EBMT) in 2018 [10]. In adult patients with hemoblastosis requiring allo-HSCT, the detection frequency of anti-HLA antibodies may reach 40%, [11, 12, 13]. However, not all of these anti-HLA antibodies are directed against donor HLA-antigens. Using highly sensitive methods of solid-phase analysis, it was detected that anti-HLA antibodies were donor-specific in 24% of haplo-HSCT recipients [14]. According to the most researchers, the prevalence of DSA varies from 10% to 21% [9]. In the present study, we were able to identify DSA only in 7.5% of examined patients. Probably, the lower rate in children is observed due to anti-HLA antibodies arising after hemotransfusions and, in some cases, following previous HSCT from a partially matched donor. Among adults, HLA-allosensitization is most often detected in women (up to 86%, against 5% in men), with pregnancy being the most common reason.

Our data on the high frequency of primary graft failure and/or graft hypofunction in the recipient group with the presence of DSA (100%), compared to the group, in which DSA is not detectable (16.22%) agreed with previous data [9] about the influence of DSA upon the outcome of haplo-HSCT. However, due to minority of patients with identified DSA, one should continue this study in order to confirm these results in a more representative sample.

It is recommended to determine DSAs in all patients 1 month before haplo-HSCT. When DSA are detected, a search for alternative haplo-compatible donor should be considered. If such donors are not available, it is necessary to use the treatment reducing the DSA-levels and to prevent the development of new anti-HLA DSA. Laboratory monitoring of DSA would be used as a way to assess effectiveness of treatment, and should be performed just before transplantation and every week after it [10].

Conclusion

The method we used to determine DSA is sufficiently informative, has a number of advantages over the serological method using a lymphocytotoxic test, flow cytometry, as well as multiplex analysis methods, and it does not require intact donor lymphocytes incubated immediately with DSA. The test does not give false positive results in the presence of any non-anti-HLA IgG’s in the patient's serum that can contact the membrane and activate the complement. HLA-molecules of a real donor as an antigen material are used for the test. Results are recorded automatically. It is necessary to perform a comparative study of the results of DSA testing using enzyme immunoassay with a multiplex analysis which is more common method in routine practice, using the Luminex platform. Implementation of DSA-testing for the routine practice in recipients prior to haplo-HSCT will optimize the choice of a donor, as well as to select a group of potential recipients who requires desensitization treatment over the pre-transplant period.

Conflict of interest

None declared.

References

  1. Afanasyev BV, Zubarovskaya LS, Alyanskiy AL, et al. The donor choice for allogeneic stem cell transplantation. Russian Journal of Children Hematology and Oncology. 2016; 3(3): 30-36 (In Russian).
  2. Maschan MA. Т-lymphocytes alpha/beta depletion – reliable platform for the development of stem cell transplantaion from haploidentical donors. Russian Journal of Children Hematology and Oncology. 2015; 2 (3):34-38. (In Russian).
  3. Paina OV, Stancheva NV, Semenova EV, et al. Haploidentical transplantation of hematopoetic stem cells in treatment of children and adolescents with resistant forms of acute leucosis. Russian Journal of Children Hematology and Oncology. 2015; 2(3):39-45 (In Russian).
  4. Paina OV, Kojokar' PV, Borovkova AS, et al. Results of alogeneic stem cell transplantation from haploidentical donor with unmanipulated bone marrowtransplant in children and adolescents with acute leucosis from high risk group: 10 years experience. Issues in Hematology/Oncology and Immunology in Pediatrics. 2018; 17(2): 21-27 (In Russian).
  5. Lee CJ, Savani BN, Mohty M, Labopin M, Ruggeri A et al. Haploidentical hematopoietic cell transplantation for adult acute myeloid leukemia: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2017; 102(11);1810-1822.
  6. Fuchs EJ. Haploidentical transplantation for hematologic malignancies: where do we stand? Hematol. Am.Soc.Hematol.Educ.Program. 2012; 2012: 230-236.
  7. Ciurea SO, Mulanovich V, Jiang Y, et al. Lymphocyte recovery predicts outcomes in cord blood and T cell-depleted haploidentical stem cell transplantation. Biol Blood Marrow Transplant. 2011;17:1169-1175.
  8. Chang YJ, Zhao XY, Xu LP, Zhang XH, Wang Y, Han W, et al. Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets. J Hematol Oncol. 2015; 8:84.
  9. Ciurea SO, Thall PF, Milton DR, Barnes TH, Kongtim P, Carmazzi Y, et al. Complement-binding donor-specific anti-HLA antibodies and risk of primary graft failure in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21:1392-1398.
  10. The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the detection and treatment of donor specific anti-HLA antibodies (DSA) in haploidentical hematopoietic cell transplantation. Bone Marrow Transplantation. 2018; 53: 521-534.
  11. Yoshihara S, Maruya E, Taniguchi K, Kaida K, Kato R, Inoue T, et al. Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT. Bone Marrow Transplant. 2012; 47:508-515.
  12. Chang YJ, Zhao XY, Xu LP, Zhang XH, Wang Y, Han W, et al. Donor-specific anti-human leukocyte antigen antibodies were associated with primary graft failure after unmanipulated haploidentical blood and marrow transplantation: a prospective study with randomly assigned training and validation sets. J Hematol Oncol. 2015; 8:84.
  13. Ruggeri A, Rocha V, Masson E, Labopin M, Cunha R, Absi L, et al. Impact of donor-specific anti-HLA antibodies on graft failure and survival after reduced intensity conditioning-unrelated cord blood transplantation: a Eurocord, Societe Francophone d’Histocompatibilite et d’Immunogenetique (SFHI) and Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) analysis. Haematologica. 2013; 98:1154-1160.
  14. Gladstone DE, Zachary AA, Fuchs EJ, Luznik L, Kasamon YL, King KE, et al. Partially mismatched transplantation and human leukocyte antigen donor-specific antibodies. Biol Blood Marrow Transplant. 2013;19:647-652.

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(2) "50" ["~SORT"]=> string(2) "50" ["CODE"]=> string(100) "vyyavlenie-donor-spetsificheskikh-anti-hla-antitel-metodom-individualnoy-perekrestnoy-proby-de-fakto" ["~CODE"]=> string(100) "vyyavlenie-donor-spetsificheskikh-anti-hla-antitel-metodom-individualnoy-perekrestnoy-proby-de-fakto" ["EXTERNAL_ID"]=> string(4) "1942" ["~EXTERNAL_ID"]=> string(4) "1942" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(552) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донораDonor-specific anti-HLA antibodies detection by de facto crossmatch method in pediatric recipients before haploidentical hematopoetic stem cell transplantation" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(5034) "<p style="text-align: justify;">Донор-специфические анти-HLA антитела (ДСА) могут являться важным фактором риска недостаточного приживления HLA-гаплосовместимых донорских гемопоэтических клеток (ГСК). Цель настоящего исследования – определить частоту выявления донор-специфических анти-HLA антител у реципиентов перед проведением гаплосовместимой трансплантации ГСК (ТГСК) с помощью метода иммуноферментного анализа и установить взаимосвязь наличия ДСА с первичным неприживлением трансплантата и (или) гипофункцией трансплантата у детей, перенесших ГТГСК.</p> <p style="text-align: justify;">В работе представлены результаты пилотного ретроспективного одноцентрового исследования. Обследованы 40 пациентов детского возраста, медиана возраста составила 8,5 лет (1 год – 17 лет), которым были выполнены гаплосовместимые трансплантации неманипулированных ГСК в клинике НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой (22-M, 18-ж): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. Средний возраст пациентов составил 8,5 лет (1-17 лет). Медианы общего числа трансплантированных ядросодержащих и CD34+ клеток составляли 8,5×10<sup>8</sup>/кг (2,3-17,9×10<sup>8</sup>/кг) и 7,6×10<sup>6</sup>/кг (2,3-8,2×10<sup>6</sup>/кг) соответственно. Во всех случаях источником CD34+ клеток был стимулированный неманипулированный костный мозг. Определение ДСА в сыворотке крови реципиентов выполнено с использованием коммерческого набора (XMatch®, Protrans), который позволяет определять антитела против донорских антигенов HLA- класса I и класса II отдельно в перекрестном сопоставлении ELISA de facto. Среди всех обследованных детей у 3-х пациентов (7,5%) выявлены ДСА, в то время как у подавляющего большинства (n=37; 92,5%) ДСА не было, во всех случаях ДСА были направлены против антигенов HLA класса II. Сравнительный анализ результатов показывает, что у пациентов с наличием ДСА до гаплосовместимой ТГСК более вероятно развитие первичной недостаточности трансплантата или гипофункции по сравнению с группой реципиентов без DSA. У всех 3 пациентов (100%) с обнаруженными антителами была диагностирована либо первичная недостаточность трансплантата (n=1, 33%), либо гипофункция трансплантата (n=2, 67%). В группе пациентов без ДСА первичная недостаточность трансплантата или гипофункция трансплантата наблюдались в 5 (13,5%) и 1 (2,7%) случаях соответственно, всего в 6 случаях (16,2%). Внедрение DSA-тестирования в рутинную практику у реципиентов перед гапло-ТГСК оптимизирует выбор донора, а также выберет группу потенциальных реципиентов, которым необходимо пройти курс лечения в предтрансплантационный период для десенсибилизации.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Донор-специфические антитела, трансплантация гемопоэтических стволовых клеток, HLA-гаплосовместимые доноры, HLA-гаплоидентичные доноры.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["SECTION_META_TITLE"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["SECTION_META_KEYWORDS"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["SECTION_META_DESCRIPTION"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["SECTION_PICTURE_FILE_ALT"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["SECTION_PICTURE_FILE_TITLE"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "vyyavlenie-donor-spetsificheskikh-anti-hla-antitel-metodom-individualnoy-perekrestnoy-proby-de-fakto" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(393) "Выявление донор-специфических анти-HLA-антител методом индивидуальной перекрестной пробы де-факто у педиатрических реципиентов перед трансплантацией гемопоэтических стволовых клеток от гаплосовместимого донора" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "vyyavlenie-donor-spetsificheskikh-anti-hla-antitel-metodom-individualnoy-perekrestnoy-proby-de-fakto" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "vyyavlenie-donor-spetsificheskikh-anti-hla-antitel-metodom-individualnoy-perekrestnoy-proby-de-fakto" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "vyyavlenie-donor-spetsificheskikh-anti-hla-antitel-metodom-individualnoy-perekrestnoy-proby-de-fakto" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "170" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27371" ["VALUE"]=> string(10) "02.09.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "02.09.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27372" ["VALUE"]=> string(10) "04.12.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "04.12.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27373" ["VALUE"]=> array(2) { ["TEXT"]=> string(593) "<p>Олеся В. Паина<sup>1</sup>, Ирина Е. Павлова<sup>1,2</sup>, Наталья Е. Иванова<sup>1</sup>, Александр Л. Алянский<sup>1</sup>, Татьяна А. Быкова<sup>1</sup>, Людмила С. Зубаровская<sup>1</sup>, Александр Д. Кулагин<sup>1</sup>, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Борис В. Афанасьев<sup>1</sup></span> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(463) "

Олеся В. Паина1, Ирина Е. Павлова1,2, Наталья Е. Иванова1, Александр Л. Алянский1, Татьяна А. Быкова1, Людмила С. Зубаровская1, Александр Д. Кулагин1, Борис В. Афанасьев1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27374" ["VALUE"]=> array(2) { ["TEXT"]=> string(703) "<p><sup>1</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия <br> <sup>2</sup> Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(661) "

1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27375" ["VALUE"]=> array(2) { ["TEXT"]=> string(5034) "<p style="text-align: justify;">Донор-специфические анти-HLA антитела (ДСА) могут являться важным фактором риска недостаточного приживления HLA-гаплосовместимых донорских гемопоэтических клеток (ГСК). Цель настоящего исследования – определить частоту выявления донор-специфических анти-HLA антител у реципиентов перед проведением гаплосовместимой трансплантации ГСК (ТГСК) с помощью метода иммуноферментного анализа и установить взаимосвязь наличия ДСА с первичным неприживлением трансплантата и (или) гипофункцией трансплантата у детей, перенесших ГТГСК.</p> <p style="text-align: justify;">В работе представлены результаты пилотного ретроспективного одноцентрового исследования. Обследованы 40 пациентов детского возраста, медиана возраста составила 8,5 лет (1 год – 17 лет), которым были выполнены гаплосовместимые трансплантации неманипулированных ГСК в клинике НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой (22-M, 18-ж): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. Средний возраст пациентов составил 8,5 лет (1-17 лет). Медианы общего числа трансплантированных ядросодержащих и CD34+ клеток составляли 8,5×10<sup>8</sup>/кг (2,3-17,9×10<sup>8</sup>/кг) и 7,6×10<sup>6</sup>/кг (2,3-8,2×10<sup>6</sup>/кг) соответственно. Во всех случаях источником CD34+ клеток был стимулированный неманипулированный костный мозг. Определение ДСА в сыворотке крови реципиентов выполнено с использованием коммерческого набора (XMatch®, Protrans), который позволяет определять антитела против донорских антигенов HLA- класса I и класса II отдельно в перекрестном сопоставлении ELISA de facto. Среди всех обследованных детей у 3-х пациентов (7,5%) выявлены ДСА, в то время как у подавляющего большинства (n=37; 92,5%) ДСА не было, во всех случаях ДСА были направлены против антигенов HLA класса II. Сравнительный анализ результатов показывает, что у пациентов с наличием ДСА до гаплосовместимой ТГСК более вероятно развитие первичной недостаточности трансплантата или гипофункции по сравнению с группой реципиентов без DSA. У всех 3 пациентов (100%) с обнаруженными антителами была диагностирована либо первичная недостаточность трансплантата (n=1, 33%), либо гипофункция трансплантата (n=2, 67%). В группе пациентов без ДСА первичная недостаточность трансплантата или гипофункция трансплантата наблюдались в 5 (13,5%) и 1 (2,7%) случаях соответственно, всего в 6 случаях (16,2%). Внедрение DSA-тестирования в рутинную практику у реципиентов перед гапло-ТГСК оптимизирует выбор донора, а также выберет группу потенциальных реципиентов, которым необходимо пройти курс лечения в предтрансплантационный период для десенсибилизации.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Донор-специфические антитела, трансплантация гемопоэтических стволовых клеток, HLA-гаплосовместимые доноры, HLA-гаплоидентичные доноры.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4908) "

Донор-специфические анти-HLA антитела (ДСА) могут являться важным фактором риска недостаточного приживления HLA-гаплосовместимых донорских гемопоэтических клеток (ГСК). Цель настоящего исследования – определить частоту выявления донор-специфических анти-HLA антител у реципиентов перед проведением гаплосовместимой трансплантации ГСК (ТГСК) с помощью метода иммуноферментного анализа и установить взаимосвязь наличия ДСА с первичным неприживлением трансплантата и (или) гипофункцией трансплантата у детей, перенесших ГТГСК.

В работе представлены результаты пилотного ретроспективного одноцентрового исследования. Обследованы 40 пациентов детского возраста, медиана возраста составила 8,5 лет (1 год – 17 лет), которым были выполнены гаплосовместимые трансплантации неманипулированных ГСК в клинике НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой (22-M, 18-ж): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. Средний возраст пациентов составил 8,5 лет (1-17 лет). Медианы общего числа трансплантированных ядросодержащих и CD34+ клеток составляли 8,5×108/кг (2,3-17,9×108/кг) и 7,6×106/кг (2,3-8,2×106/кг) соответственно. Во всех случаях источником CD34+ клеток был стимулированный неманипулированный костный мозг. Определение ДСА в сыворотке крови реципиентов выполнено с использованием коммерческого набора (XMatch®, Protrans), который позволяет определять антитела против донорских антигенов HLA- класса I и класса II отдельно в перекрестном сопоставлении ELISA de facto. Среди всех обследованных детей у 3-х пациентов (7,5%) выявлены ДСА, в то время как у подавляющего большинства (n=37; 92,5%) ДСА не было, во всех случаях ДСА были направлены против антигенов HLA класса II. Сравнительный анализ результатов показывает, что у пациентов с наличием ДСА до гаплосовместимой ТГСК более вероятно развитие первичной недостаточности трансплантата или гипофункции по сравнению с группой реципиентов без DSA. У всех 3 пациентов (100%) с обнаруженными антителами была диагностирована либо первичная недостаточность трансплантата (n=1, 33%), либо гипофункция трансплантата (n=2, 67%). В группе пациентов без ДСА первичная недостаточность трансплантата или гипофункция трансплантата наблюдались в 5 (13,5%) и 1 (2,7%) случаях соответственно, всего в 6 случаях (16,2%). Внедрение DSA-тестирования в рутинную практику у реципиентов перед гапло-ТГСК оптимизирует выбор донора, а также выберет группу потенциальных реципиентов, которым необходимо пройти курс лечения в предтрансплантационный период для десенсибилизации.

Ключевые слова

Донор-специфические антитела, трансплантация гемопоэтических стволовых клеток, HLA-гаплосовместимые доноры, HLA-гаплоидентичные доноры.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27376" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-53-58" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-53-58" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27379" ["VALUE"]=> array(2) { ["TEXT"]=> string(475) "<p>Olesya V. Paina<sup>1</sup>, Irina E. Pavlova<sup>1,2</sup>, Natalia E. Ivanova<sup>1</sup>, Alexander L. Alyanskiy<sup>1</sup>, Tatiana A. Bykova<sup>1</sup>, Ludmila S. Zubarovskaya<sup>1</sup>, Alexander D. Kulagin<sup>1</sup>, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev<sup>1</sup></span> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(345) "

Olesya V. Paina1, Irina E. Pavlova1,2, Natalia E. Ivanova1, Alexander L. Alyanskiy1, Tatiana A. Bykova1, Ludmila S. Zubarovskaya1, Alexander D. Kulagin1, Boris V. Afanasyev1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27380" ["VALUE"]=> array(2) { ["TEXT"]=> string(607) "<p><sup>1</sup> RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia<br> <sup>2</sup> Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia</p><br> <p><b>Correspondence</b><br> Dr. Irina E. Pavlova, Russian Research Institute of Hematology and Transfusiology, 2<sup>nd</sup> Sovetskaya St 16, 191024, St. Petersburg, Russia<br> Phone: +7 (921) 983 6664<br> E-mail: dr_pavlova_irina@mail.ru</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(505) "

1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia
2 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia


Correspondence
Dr. Irina E. Pavlova, Russian Research Institute of Hematology and Transfusiology, 2nd Sovetskaya St 16, 191024, St. Petersburg, Russia
Phone: +7 (921) 983 6664
E-mail: dr_pavlova_irina@mail.ru

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27381" ["VALUE"]=> array(2) { ["TEXT"]=> string(2415) "<p style="text-align: justify;">Donor-specific antibodies (DSA) have been recently recognized as an important risk factor for the failing engraftment of HLA-haploidentical donor cells. In this study, we aimed to determine the frequency of anti-HLA DSA detection in recipients before haplo-HSCT using the enzyme-linked immunosorbent assay and establishing an association between the DSA presence and primary graft failure and/or graft hypofunction in children after haplo-HSCT. 40 patients have been tested (22-M, 18-F): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. The median age of the patients was 8.5 years (1-17 years). Medians of the number of transplanted nucleated and CD34+ cells were 8.5×10<sup>8</sup>/kg (2.3-17.9×10<sup>8</sup>/kg) and 7.6×10<sup>6</sup>/kg (2.3-8.2×10<sup>6</sup>/kg) respectively. The donor bone marrow was the source of stem cells in all cases. Detection of DSA has been performed by using the commercial kit (XMatch®, Protrans) that allows determining antibodies against donor's HLA class I and class II separately in the ELISA de facto crossmatching. Among all the examined children, 3 patients (7.5%) were found to be positive for DSA, while the vast majority (n=37; 92.5%) had no detectable DSA. It was also found that in all cases DSA were directed against HLA class II antigens.</p> <p style="text-align: justify;">Comparative analysis of the results shows that patients with DSA before haplo-HSCT are more likely to develop primary graft failure or hypofunction compared to the group of recipients without DSA. All 3 patients with detected antibodies were diagnosed with either primary graft failure (n=1, 33%) or graft hypofunction (n=2, 67%). In the control group of patients without DSA primary graft failure or graft hypofunction were observed in 5 (13.5%) and 1 (2.7%) cases respectively, with a total of 6 cases (16.2%). Implementation of DSA-testing into routine practice in recipients before haplo-HSCT will optimize the choice of a donor, as well as select a group of potential recipients who need to be treated in the pre-transplant period for desensitization.</p> <h2>Keywords</h2> <p style="text-align: justify;">Donor-specific antibodies, hematopoietic stem cell transplantation, HLA-haplocompatible donors, HLA-haploidentical donors.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2289) "

Donor-specific antibodies (DSA) have been recently recognized as an important risk factor for the failing engraftment of HLA-haploidentical donor cells. In this study, we aimed to determine the frequency of anti-HLA DSA detection in recipients before haplo-HSCT using the enzyme-linked immunosorbent assay and establishing an association between the DSA presence and primary graft failure and/or graft hypofunction in children after haplo-HSCT. 40 patients have been tested (22-M, 18-F): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. The median age of the patients was 8.5 years (1-17 years). Medians of the number of transplanted nucleated and CD34+ cells were 8.5×108/kg (2.3-17.9×108/kg) and 7.6×106/kg (2.3-8.2×106/kg) respectively. The donor bone marrow was the source of stem cells in all cases. Detection of DSA has been performed by using the commercial kit (XMatch®, Protrans) that allows determining antibodies against donor's HLA class I and class II separately in the ELISA de facto crossmatching. Among all the examined children, 3 patients (7.5%) were found to be positive for DSA, while the vast majority (n=37; 92.5%) had no detectable DSA. It was also found that in all cases DSA were directed against HLA class II antigens.

Comparative analysis of the results shows that patients with DSA before haplo-HSCT are more likely to develop primary graft failure or hypofunction compared to the group of recipients without DSA. All 3 patients with detected antibodies were diagnosed with either primary graft failure (n=1, 33%) or graft hypofunction (n=2, 67%). In the control group of patients without DSA primary graft failure or graft hypofunction were observed in 5 (13.5%) and 1 (2.7%) cases respectively, with a total of 6 cases (16.2%). Implementation of DSA-testing into routine practice in recipients before haplo-HSCT will optimize the choice of a donor, as well as select a group of potential recipients who need to be treated in the pre-transplant period for desensitization.

Keywords

Donor-specific antibodies, hematopoietic stem cell transplantation, HLA-haplocompatible donors, HLA-haploidentical donors.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27377" ["VALUE"]=> string(159) "Donor-specific anti-HLA antibodies detection by de facto crossmatch method in pediatric recipients before haploidentical hematopoetic stem cell transplantation" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(159) "Donor-specific anti-HLA antibodies detection by de facto crossmatch method in pediatric recipients before haploidentical hematopoetic stem cell transplantation" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> &array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["PDF_RU"]=> array(36) { ["ID"]=> string(2) "43" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF RUS" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_RU" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "43" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27378" ["VALUE"]=> string(4) "2339" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2339" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF RUS" ["~DEFAULT_VALUE"]=> string(0) "" } ["PDF_EN"]=> array(36) { ["ID"]=> string(2) "44" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF ENG" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "44" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27382" ["VALUE"]=> string(4) "2340" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2340" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF ENG" ["~DEFAULT_VALUE"]=> string(0) "" } ["NAME_LONG"]=> array(36) { ["ID"]=> string(2) "45" ["TIMESTAMP_X"]=> string(19) "2023-04-13 00:55:00" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(72) "Название (для очень длинных заголовков)" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "NAME_LONG" ["DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "45" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27379" ["VALUE"]=> array(2) { ["TEXT"]=> string(475) "<p>Olesya V. Paina<sup>1</sup>, Irina E. Pavlova<sup>1,2</sup>, Natalia E. Ivanova<sup>1</sup>, Alexander L. Alyanskiy<sup>1</sup>, Tatiana A. Bykova<sup>1</sup>, Ludmila S. Zubarovskaya<sup>1</sup>, Alexander D. Kulagin<sup>1</sup>, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev<sup>1</sup></span> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(345) "

Olesya V. Paina1, Irina E. Pavlova1,2, Natalia E. Ivanova1, Alexander L. Alyanskiy1, Tatiana A. Bykova1, Ludmila S. Zubarovskaya1, Alexander D. Kulagin1, Boris V. Afanasyev1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(345) "

Olesya V. Paina1, Irina E. Pavlova1,2, Natalia E. Ivanova1, Alexander L. Alyanskiy1, Tatiana A. Bykova1, Ludmila S. Zubarovskaya1, Alexander D. Kulagin1, Boris V. Afanasyev1

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27381" ["VALUE"]=> array(2) { ["TEXT"]=> string(2415) "<p style="text-align: justify;">Donor-specific antibodies (DSA) have been recently recognized as an important risk factor for the failing engraftment of HLA-haploidentical donor cells. In this study, we aimed to determine the frequency of anti-HLA DSA detection in recipients before haplo-HSCT using the enzyme-linked immunosorbent assay and establishing an association between the DSA presence and primary graft failure and/or graft hypofunction in children after haplo-HSCT. 40 patients have been tested (22-M, 18-F): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. The median age of the patients was 8.5 years (1-17 years). Medians of the number of transplanted nucleated and CD34+ cells were 8.5×10<sup>8</sup>/kg (2.3-17.9×10<sup>8</sup>/kg) and 7.6×10<sup>6</sup>/kg (2.3-8.2×10<sup>6</sup>/kg) respectively. The donor bone marrow was the source of stem cells in all cases. Detection of DSA has been performed by using the commercial kit (XMatch®, Protrans) that allows determining antibodies against donor's HLA class I and class II separately in the ELISA de facto crossmatching. Among all the examined children, 3 patients (7.5%) were found to be positive for DSA, while the vast majority (n=37; 92.5%) had no detectable DSA. It was also found that in all cases DSA were directed against HLA class II antigens.</p> <p style="text-align: justify;">Comparative analysis of the results shows that patients with DSA before haplo-HSCT are more likely to develop primary graft failure or hypofunction compared to the group of recipients without DSA. All 3 patients with detected antibodies were diagnosed with either primary graft failure (n=1, 33%) or graft hypofunction (n=2, 67%). In the control group of patients without DSA primary graft failure or graft hypofunction were observed in 5 (13.5%) and 1 (2.7%) cases respectively, with a total of 6 cases (16.2%). Implementation of DSA-testing into routine practice in recipients before haplo-HSCT will optimize the choice of a donor, as well as select a group of potential recipients who need to be treated in the pre-transplant period for desensitization.</p> <h2>Keywords</h2> <p style="text-align: justify;">Donor-specific antibodies, hematopoietic stem cell transplantation, HLA-haplocompatible donors, HLA-haploidentical donors.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2289) "

Donor-specific antibodies (DSA) have been recently recognized as an important risk factor for the failing engraftment of HLA-haploidentical donor cells. In this study, we aimed to determine the frequency of anti-HLA DSA detection in recipients before haplo-HSCT using the enzyme-linked immunosorbent assay and establishing an association between the DSA presence and primary graft failure and/or graft hypofunction in children after haplo-HSCT. 40 patients have been tested (22-M, 18-F): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. The median age of the patients was 8.5 years (1-17 years). Medians of the number of transplanted nucleated and CD34+ cells were 8.5×108/kg (2.3-17.9×108/kg) and 7.6×106/kg (2.3-8.2×106/kg) respectively. The donor bone marrow was the source of stem cells in all cases. Detection of DSA has been performed by using the commercial kit (XMatch®, Protrans) that allows determining antibodies against donor's HLA class I and class II separately in the ELISA de facto crossmatching. Among all the examined children, 3 patients (7.5%) were found to be positive for DSA, while the vast majority (n=37; 92.5%) had no detectable DSA. It was also found that in all cases DSA were directed against HLA class II antigens.

Comparative analysis of the results shows that patients with DSA before haplo-HSCT are more likely to develop primary graft failure or hypofunction compared to the group of recipients without DSA. All 3 patients with detected antibodies were diagnosed with either primary graft failure (n=1, 33%) or graft hypofunction (n=2, 67%). In the control group of patients without DSA primary graft failure or graft hypofunction were observed in 5 (13.5%) and 1 (2.7%) cases respectively, with a total of 6 cases (16.2%). Implementation of DSA-testing into routine practice in recipients before haplo-HSCT will optimize the choice of a donor, as well as select a group of potential recipients who need to be treated in the pre-transplant period for desensitization.

Keywords

Donor-specific antibodies, hematopoietic stem cell transplantation, HLA-haplocompatible donors, HLA-haploidentical donors.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2289) "

Donor-specific antibodies (DSA) have been recently recognized as an important risk factor for the failing engraftment of HLA-haploidentical donor cells. In this study, we aimed to determine the frequency of anti-HLA DSA detection in recipients before haplo-HSCT using the enzyme-linked immunosorbent assay and establishing an association between the DSA presence and primary graft failure and/or graft hypofunction in children after haplo-HSCT. 40 patients have been tested (22-M, 18-F): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. The median age of the patients was 8.5 years (1-17 years). Medians of the number of transplanted nucleated and CD34+ cells were 8.5×108/kg (2.3-17.9×108/kg) and 7.6×106/kg (2.3-8.2×106/kg) respectively. The donor bone marrow was the source of stem cells in all cases. Detection of DSA has been performed by using the commercial kit (XMatch®, Protrans) that allows determining antibodies against donor's HLA class I and class II separately in the ELISA de facto crossmatching. Among all the examined children, 3 patients (7.5%) were found to be positive for DSA, while the vast majority (n=37; 92.5%) had no detectable DSA. It was also found that in all cases DSA were directed against HLA class II antigens.

Comparative analysis of the results shows that patients with DSA before haplo-HSCT are more likely to develop primary graft failure or hypofunction compared to the group of recipients without DSA. All 3 patients with detected antibodies were diagnosed with either primary graft failure (n=1, 33%) or graft hypofunction (n=2, 67%). In the control group of patients without DSA primary graft failure or graft hypofunction were observed in 5 (13.5%) and 1 (2.7%) cases respectively, with a total of 6 cases (16.2%). Implementation of DSA-testing into routine practice in recipients before haplo-HSCT will optimize the choice of a donor, as well as select a group of potential recipients who need to be treated in the pre-transplant period for desensitization.

Keywords

Donor-specific antibodies, hematopoietic stem cell transplantation, HLA-haplocompatible donors, HLA-haploidentical donors.

" } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27376" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-53-58" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-53-58" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-53-58" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27377" ["VALUE"]=> string(159) "Donor-specific anti-HLA antibodies detection by de facto crossmatch method in pediatric recipients before haploidentical hematopoetic stem cell transplantation" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(159) "Donor-specific anti-HLA antibodies detection by de facto crossmatch method in pediatric recipients before haploidentical hematopoetic stem cell transplantation" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(159) "Donor-specific anti-HLA antibodies detection by de facto crossmatch method in pediatric recipients before haploidentical hematopoetic stem cell transplantation" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27380" ["VALUE"]=> array(2) { ["TEXT"]=> string(607) "<p><sup>1</sup> RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia<br> <sup>2</sup> Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia</p><br> <p><b>Correspondence</b><br> Dr. Irina E. Pavlova, Russian Research Institute of Hematology and Transfusiology, 2<sup>nd</sup> Sovetskaya St 16, 191024, St. Petersburg, Russia<br> Phone: +7 (921) 983 6664<br> E-mail: dr_pavlova_irina@mail.ru</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(505) "

1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia
2 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia


Correspondence
Dr. Irina E. Pavlova, Russian Research Institute of Hematology and Transfusiology, 2nd Sovetskaya St 16, 191024, St. Petersburg, Russia
Phone: +7 (921) 983 6664
E-mail: dr_pavlova_irina@mail.ru

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(505) "

1 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia
2 Russian Research Institute of Hematology and Transfusiology, St. Petersburg, Russia


Correspondence
Dr. Irina E. Pavlova, Russian Research Institute of Hematology and Transfusiology, 2nd Sovetskaya St 16, 191024, St. Petersburg, Russia
Phone: +7 (921) 983 6664
E-mail: dr_pavlova_irina@mail.ru

" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27373" ["VALUE"]=> array(2) { ["TEXT"]=> string(593) "<p>Олеся В. Паина<sup>1</sup>, Ирина Е. Павлова<sup>1,2</sup>, Наталья Е. Иванова<sup>1</sup>, Александр Л. Алянский<sup>1</sup>, Татьяна А. Быкова<sup>1</sup>, Людмила С. Зубаровская<sup>1</sup>, Александр Д. Кулагин<sup>1</sup>, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Борис В. Афанасьев<sup>1</sup></span> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(463) "

Олеся В. Паина1, Ирина Е. Павлова1,2, Наталья Е. Иванова1, Александр Л. Алянский1, Татьяна А. Быкова1, Людмила С. Зубаровская1, Александр Д. Кулагин1, Борис В. Афанасьев1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(463) "

Олеся В. Паина1, Ирина Е. Павлова1,2, Наталья Е. Иванова1, Александр Л. Алянский1, Татьяна А. Быкова1, Людмила С. Зубаровская1, Александр Д. Кулагин1, Борис В. Афанасьев1

" } ["SUBMITTED"]=> array(37) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27371" ["VALUE"]=> string(10) "02.09.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "02.09.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "02.09.2020" } ["ACCEPTED"]=> array(37) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27372" ["VALUE"]=> string(10) "04.12.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "04.12.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "04.12.2020" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27375" ["VALUE"]=> array(2) { ["TEXT"]=> string(5034) "<p style="text-align: justify;">Донор-специфические анти-HLA антитела (ДСА) могут являться важным фактором риска недостаточного приживления HLA-гаплосовместимых донорских гемопоэтических клеток (ГСК). Цель настоящего исследования – определить частоту выявления донор-специфических анти-HLA антител у реципиентов перед проведением гаплосовместимой трансплантации ГСК (ТГСК) с помощью метода иммуноферментного анализа и установить взаимосвязь наличия ДСА с первичным неприживлением трансплантата и (или) гипофункцией трансплантата у детей, перенесших ГТГСК.</p> <p style="text-align: justify;">В работе представлены результаты пилотного ретроспективного одноцентрового исследования. Обследованы 40 пациентов детского возраста, медиана возраста составила 8,5 лет (1 год – 17 лет), которым были выполнены гаплосовместимые трансплантации неманипулированных ГСК в клинике НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой (22-M, 18-ж): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. Средний возраст пациентов составил 8,5 лет (1-17 лет). Медианы общего числа трансплантированных ядросодержащих и CD34+ клеток составляли 8,5×10<sup>8</sup>/кг (2,3-17,9×10<sup>8</sup>/кг) и 7,6×10<sup>6</sup>/кг (2,3-8,2×10<sup>6</sup>/кг) соответственно. Во всех случаях источником CD34+ клеток был стимулированный неманипулированный костный мозг. Определение ДСА в сыворотке крови реципиентов выполнено с использованием коммерческого набора (XMatch®, Protrans), который позволяет определять антитела против донорских антигенов HLA- класса I и класса II отдельно в перекрестном сопоставлении ELISA de facto. Среди всех обследованных детей у 3-х пациентов (7,5%) выявлены ДСА, в то время как у подавляющего большинства (n=37; 92,5%) ДСА не было, во всех случаях ДСА были направлены против антигенов HLA класса II. Сравнительный анализ результатов показывает, что у пациентов с наличием ДСА до гаплосовместимой ТГСК более вероятно развитие первичной недостаточности трансплантата или гипофункции по сравнению с группой реципиентов без DSA. У всех 3 пациентов (100%) с обнаруженными антителами была диагностирована либо первичная недостаточность трансплантата (n=1, 33%), либо гипофункция трансплантата (n=2, 67%). В группе пациентов без ДСА первичная недостаточность трансплантата или гипофункция трансплантата наблюдались в 5 (13,5%) и 1 (2,7%) случаях соответственно, всего в 6 случаях (16,2%). Внедрение DSA-тестирования в рутинную практику у реципиентов перед гапло-ТГСК оптимизирует выбор донора, а также выберет группу потенциальных реципиентов, которым необходимо пройти курс лечения в предтрансплантационный период для десенсибилизации.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Донор-специфические антитела, трансплантация гемопоэтических стволовых клеток, HLA-гаплосовместимые доноры, HLA-гаплоидентичные доноры.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4908) "

Донор-специфические анти-HLA антитела (ДСА) могут являться важным фактором риска недостаточного приживления HLA-гаплосовместимых донорских гемопоэтических клеток (ГСК). Цель настоящего исследования – определить частоту выявления донор-специфических анти-HLA антител у реципиентов перед проведением гаплосовместимой трансплантации ГСК (ТГСК) с помощью метода иммуноферментного анализа и установить взаимосвязь наличия ДСА с первичным неприживлением трансплантата и (или) гипофункцией трансплантата у детей, перенесших ГТГСК.

В работе представлены результаты пилотного ретроспективного одноцентрового исследования. Обследованы 40 пациентов детского возраста, медиана возраста составила 8,5 лет (1 год – 17 лет), которым были выполнены гаплосовместимые трансплантации неманипулированных ГСК в клинике НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой (22-M, 18-ж): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. Средний возраст пациентов составил 8,5 лет (1-17 лет). Медианы общего числа трансплантированных ядросодержащих и CD34+ клеток составляли 8,5×108/кг (2,3-17,9×108/кг) и 7,6×106/кг (2,3-8,2×106/кг) соответственно. Во всех случаях источником CD34+ клеток был стимулированный неманипулированный костный мозг. Определение ДСА в сыворотке крови реципиентов выполнено с использованием коммерческого набора (XMatch®, Protrans), который позволяет определять антитела против донорских антигенов HLA- класса I и класса II отдельно в перекрестном сопоставлении ELISA de facto. Среди всех обследованных детей у 3-х пациентов (7,5%) выявлены ДСА, в то время как у подавляющего большинства (n=37; 92,5%) ДСА не было, во всех случаях ДСА были направлены против антигенов HLA класса II. Сравнительный анализ результатов показывает, что у пациентов с наличием ДСА до гаплосовместимой ТГСК более вероятно развитие первичной недостаточности трансплантата или гипофункции по сравнению с группой реципиентов без DSA. У всех 3 пациентов (100%) с обнаруженными антителами была диагностирована либо первичная недостаточность трансплантата (n=1, 33%), либо гипофункция трансплантата (n=2, 67%). В группе пациентов без ДСА первичная недостаточность трансплантата или гипофункция трансплантата наблюдались в 5 (13,5%) и 1 (2,7%) случаях соответственно, всего в 6 случаях (16,2%). Внедрение DSA-тестирования в рутинную практику у реципиентов перед гапло-ТГСК оптимизирует выбор донора, а также выберет группу потенциальных реципиентов, которым необходимо пройти курс лечения в предтрансплантационный период для десенсибилизации.

Ключевые слова

Донор-специфические антитела, трансплантация гемопоэтических стволовых клеток, HLA-гаплосовместимые доноры, HLA-гаплоидентичные доноры.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(4908) "

Донор-специфические анти-HLA антитела (ДСА) могут являться важным фактором риска недостаточного приживления HLA-гаплосовместимых донорских гемопоэтических клеток (ГСК). Цель настоящего исследования – определить частоту выявления донор-специфических анти-HLA антител у реципиентов перед проведением гаплосовместимой трансплантации ГСК (ТГСК) с помощью метода иммуноферментного анализа и установить взаимосвязь наличия ДСА с первичным неприживлением трансплантата и (или) гипофункцией трансплантата у детей, перенесших ГТГСК.

В работе представлены результаты пилотного ретроспективного одноцентрового исследования. Обследованы 40 пациентов детского возраста, медиана возраста составила 8,5 лет (1 год – 17 лет), которым были выполнены гаплосовместимые трансплантации неманипулированных ГСК в клинике НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой (22-M, 18-ж): 27 ALL, 8 AML, 1 MDS, 1 AA, 3 JMML. Средний возраст пациентов составил 8,5 лет (1-17 лет). Медианы общего числа трансплантированных ядросодержащих и CD34+ клеток составляли 8,5×108/кг (2,3-17,9×108/кг) и 7,6×106/кг (2,3-8,2×106/кг) соответственно. Во всех случаях источником CD34+ клеток был стимулированный неманипулированный костный мозг. Определение ДСА в сыворотке крови реципиентов выполнено с использованием коммерческого набора (XMatch®, Protrans), который позволяет определять антитела против донорских антигенов HLA- класса I и класса II отдельно в перекрестном сопоставлении ELISA de facto. Среди всех обследованных детей у 3-х пациентов (7,5%) выявлены ДСА, в то время как у подавляющего большинства (n=37; 92,5%) ДСА не было, во всех случаях ДСА были направлены против антигенов HLA класса II. Сравнительный анализ результатов показывает, что у пациентов с наличием ДСА до гаплосовместимой ТГСК более вероятно развитие первичной недостаточности трансплантата или гипофункции по сравнению с группой реципиентов без DSA. У всех 3 пациентов (100%) с обнаруженными антителами была диагностирована либо первичная недостаточность трансплантата (n=1, 33%), либо гипофункция трансплантата (n=2, 67%). В группе пациентов без ДСА первичная недостаточность трансплантата или гипофункция трансплантата наблюдались в 5 (13,5%) и 1 (2,7%) случаях соответственно, всего в 6 случаях (16,2%). Внедрение DSA-тестирования в рутинную практику у реципиентов перед гапло-ТГСК оптимизирует выбор донора, а также выберет группу потенциальных реципиентов, которым необходимо пройти курс лечения в предтрансплантационный период для десенсибилизации.

Ключевые слова

Донор-специфические антитела, трансплантация гемопоэтических стволовых клеток, HLA-гаплосовместимые доноры, HLA-гаплоидентичные доноры.

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27374" ["VALUE"]=> array(2) { ["TEXT"]=> string(703) "<p><sup>1</sup> НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия <br> <sup>2</sup> Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(661) "

1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(661) "

1 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
2 Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства, Санкт-Петербург, Россия

" } } } [5]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(3) "170" ["~IBLOCK_SECTION_ID"]=> string(3) "170" ["ID"]=> string(4) "1940" ["~ID"]=> string(4) "1940" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["~NAME"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "05.02.2021 14:09:11" ["~TIMESTAMP_X"]=> string(19) "05.02.2021 14:09:11" ["DETAIL_PAGE_URL"]=> string(138) "/ru/archive/-9-4/klinicheskie-raboty/faktory-riska-nedostatochnosti-transplantata-pri-allogennoy-transplantatsii-gemopoeticheskikh-stvolo/" ["~DETAIL_PAGE_URL"]=> string(138) "/ru/archive/-9-4/klinicheskie-raboty/faktory-riska-nedostatochnosti-transplantata-pri-allogennoy-transplantatsii-gemopoeticheskikh-stvolo/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(32360) "

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for hematological diseases. Sustained engraftment of the donor stem cells is essential for transplant success and overall favourable outcomes. Graft failure (GF) is an uncommon (incidence 5-6%) complication post-allo-HCT and is associated with a poor prognosis, especially in allo-HCT for malignant disorders [1]. There are differences in the definition of primary and secondary graft failure [1-10]. Numerous risk factors have been previously associated with GF such as myelofibrosis (MF), aplastic anemia (AA), bone marrow as a graft source or donor HLA mismatch, while other factors such as ABO mismatch, graft-versus-host disease prophylaxis or infections, particularly viral reactivation, remain a matter of debate [11]. The incidence of GF may increase to 20-25% with the use of alternative modalities of HCT, including non-myeloablative conditioning, intensive T-cell depletion of the graft, human leukocyte antigen (HLA) disparity between donor and recipient or cord blood as the progenitor source [1, 11]. The use of filgrastim-mobilized peripheral blood (PB) stem cells instead of bone marrow (BM) decreases the risk of GF, especially in unrelated allo-HCT [8]. Many factors have been proposed to be involved in the etiology of GF, including defects in the BM microenvironment, immune-mediated rejection, drug toxicity or viral infections [12, 13].

The management of GF includes the administration of growth factor, additional hematopoietic progenitor boost or a second allo-HCT with conditioning therapy [11, 13]. Data available on patient outcomes after the development of GF are limited and heterogeneous. Strategies for reversing GF depend on the options available in each situation, and there is no clear recommendation for the best approach to this complication. Some reports have suggested that a second transplant could benefit patients who develop GF [14]. However, transplant-related mortality compromises the overall survival (OS) of these patients. In the present study, we assessed the incidence and the risk factors for GF in a single-center population and the impact on the patients’ outcome.

Patients and methods

Between January 1, 2015, and December 31, 2018, 557 patients underwent allo-HCT at the Princess Margaret Cancer Center. Data was collected retrospectively and updated in June 2019. Cases were included regardless of the underlying diagnosis, disease status prior to transplant, preparative regimen, or stem cell source. Acute (aGvHD) and chronic GvHD (cGvHD) were diagnosed and graded using the aGvHD consensus conference criteria and the NIH consensus criteria for cGvHD, respectively [15, 16]. Conditioning therapy was considered as nonmyeloablative when patients received busulfan < 9 mg/kg, and total body irradiation ≤500 cGy as a single fraction or ≤800 cGy if fractionated. All patients received granulocyte colony-stimulating factor from day +6 following transplant until neutrophil engraftment.

Primary graft failure was defined as the failure to achieve an absolute neutrophil count (ANC) of 0.5×109/L by 28 days after BM or PB [17]. Secondary graft failure was defined as sustained fall in ANC <0.5×109/L after initial engraftment, and one of the following: (a) donor chimerism of less than 5%, or (b) intervention such as use of DLI or second transplant for falling blood counts, or (c) patient death due to cytopenia, with falling donor chimerism, but level of donor chimerism >5% but <95% [1, 17]. Decrease in peripheral blood counts due to relapse of disease was excluded as a cause of GF. Outcomes examined included overall survival (OS), the cumulative incidence of GF and non-relapse mortality (NRM) as well as the cause of death.

Patients were managed clinically according to Princess Margaret Cancer Center guidelines. BM aspirates were monitored for disease status and donor chimerism was assessed in sex-mismatched donor–recipient pairs by metaphase karyotype analyses; restriction fragment length DNA polymorphisms were compared in sex-matched pairs; whole blood chimerism was assay for the duration of this study.

This study was approved by the institutional research ethics board of our center, and consent had been obtained from all the patients for transplant procedures and sharing data following local policies.

Overall survival (OS) was calculated using the Kaplan-Meier method and compared with the log-rank test. Survival time was calculated from the day of first transplantation until death or last follow-up. Incidences of graft failure (GF) were obtained using an estimator of cumulative incidence curves. Patients were censored at the time of death or last follow-up. Competing events for GF were death or relapse without GF. For SGF, PGF was also considered as a competing event.

Uni- and multivariate predictive analyses for GF were performed with the proportional sub-distribution hazard regression model of Fine and Gray [18]. Factors with a p-value <0.10 in the univariate analysis were included in the backwards elimination multivariate analysis.

Analyses were performed using the EZR freely available software and Statistica 13 (TIBCO, Palo Alto, CA, USA) software [19].

Results

Baseline characteristics are summarized in Table 1. Pretransplant therapies where indicated for hematological malignancies consisted of current North American induction protocols: for ALL, Dana Farber Cancer Institute regimen for ALL (1 patient received blinatumomab); for AML either daunorubicin and cytarabine (‘3+7’) or FLAG-Ida; for MDS/MPN supportive care, azacytidine, hydroxyurea or ‘3+7’; ruxolitinib for MF, ibrutinib for CLL, and standard salvage regimens (Bendamustine/rituximab or ‘ICE’) for non-Hodgkin lymphoma.

Table 1. Patients’ characteristics and main factors contributing to GF

Novitzky-Basso-tab01.jpg

Abbreviations: MDS, myelodysplasia; MF, myelofibrosis; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MUD, matched unrelated donor; MRD, matched related donor; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; PTCY, post-transplant cyclophosphamide; ATG, anti-thymocyte globulin; MMF, myecophenolate; CSA, cyclosporine; MTX, methotrexate; CMV, cytomegalovirus; BM, bone marrow; PBSC, peripheral blood stem cells; BSI, bloodstream infections; HCT-CI, hematopoietic stem cell transplant co-morbidity index; KPS, Karnofsky performance score

The cumulative incidence of relapse (CIR) for the entire cohort (n=557) was 7.9% (CI95%; 5.9-10.3) at 100 days and 24.3% (CI95%; 20.6-28.1) at 2 years. In particular, the CIR for patients transplanted for AML (n=284) was 7.7% (CI95%; 5.0-11.2) at 100 days and 21.4% (CI95%; 16.7-26.6) at 2 years, whereas it was 14.6% (CI95%; 5.8-27.2) at 100 days and 45.0% (CI95%; 27.9-60.6%) at 2 years in patients transplanted for ALL (n=41). For MF (n=47), CIR was 2.1% (CI95%; 0.2-9.9) at 100 days and 10.2% (CI95%; 2.9-22.8) at 2 years, CIR for MDS/MPN (n=102) was 11.8% (CI95%; 6.4-18.9) at 100 days and 30.4% CI95%; (21.5-39.8) 2 years. Finally, CIR of patients transplanted for Lymphoma (n=31) was 6.5% (CI95%; 1.1-18.9) at 100 days, and 36.6% (CI95%; 19.6-53.8) at 2 years.

Median survival following PGF was 41 days, while in SGF it was 144 days (Figure 1b). The one hundred days OS in PGF was 22%, whereas it was 64% for SGF. One-year and two-year OS for SGF were 33% and 28%, respectively, Figure 1b. Survival of GF patients was calculated from the date of GF.

Percentage donor chimerism (Figure 1c), was as follows: for primary graft failure, at day 30 post-transplant, n=9, median 19.9% (0.8-75.7%), at day 60 post-transplant, n=5, median 0% (0-27%), at day 90 post-transplant, n=3, median 1% (0-1%). For secondary graft failure, at day 30 post-transplant, n=33, median 96.85% (70.4-100%) (missing data for one patient), at day 60 post-transplant, n=32, median 87.65% (0-99.3%), at day 90 post-transplant, n=24, median 74.15% (3.2-98.2%).

Novitzky-Basso-fig01.jpg

Figure 1. A, cumulative incidence to primary and secondary graft failure (GF). Numbers represent median number of days to graft failure diagnosis with range. B, median survival from primary and secondary graft failure. C, percentage donor chimerism in patients with primary and secondary graft failure. Bars represent the inter-quartile range, and round circles, the median. The percentage donor chimerism at day 30 (D30), day 60 (D60) and day 90 (D90) post-transplant are represented. D, overall survival from allogeneic stem cell transplant for the whole cohort, and patients with GF. Survival of GF patients was calculated from date of GF.

Percentage donor chimerism (Figure 1c), was as follows: for primary graft failure, at day 30 post-transplant, n=9, median 19.9% (0.8-75.7%), at day 60 post-transplant, n=5, median 0% (0-27%), at day 90 post-transplant, n=3, median 1% (0-1%). For secondary graft failure, at day 30 post-transplant, n=33, median 96.85% (70.4-100%) (missing data for one patient), at day 60 post-transplant, n=32, median 87.65% (0-99.3%), at day 90 post-transplant, n=24, median 74.15% (3.2-98.2%).

Table 2. Results of univariate analysis

Novitzky-Basso-tab02-01.jpg Novitzky-Basso-tab02-02.jpg

Abbreviations: MAC, myeloablative conditioning; RIC, reduced intensity conditioning; PTCY, post-transplant cyclophosphamide; ATG, anti-thymocyteglobulin; BM, bone marrow; PBSC, peripheral blood stem cells; BSI, bloodstream infection; HCT-CI, hematopoietic stem cell transplant co-morbidity index; KPS, Karnofsky performance score; SCT, stem cell transplant; CR, complete remission

DLI was administered to nine patients with SGF. Five of these experienced grade I-II acute GvHD, and two, grade III-IV acute GvHD. Two subsequently experienced moderately severe GvHD. Of these nine patients, one experienced relapse and died, another demised with post-transplant lymphoproliferative disorder, two with GvHD, and ultimately 5 were alive at last follow-up.

Second allo-HCT was performed in 5 patients (56%) with PGF and 15 patients (44%) with SGF (see Table 4). Another 8 patients with SGF received donor lymphocyte infusions (DLI). The primary complication following second allo-HCT was infection. Median time from GF diagnosis to second allo-HCT was 35 days (20-172), whilst median time from GF diagnosis to DLI was 90 days (7-288). Six out of 15 patients who received a second transplant for SGF developed Grade 3/4 acute GvHD and 4 out of these patients developed moderately severe chronic GvHD.

Median survival (Figure 1d) post second transplant was 109 days (9-1014); survival was calculated from second HCT. Median survival post DLI was 293 days (22-868).

Overall, all the patients with PGF died because of GF or complications related to it. In SGF 22 of 43 patients (51%) died, the most common causes of death were infections (30%), GvHD (18%) and one patient died related to veno-occlusive disease. The median neutrophil count for the SGF patients that died in GF was 0 ×109/L (0-0.5×109/L) and median platelet count was 6 ×109/L (3-41×109/L).

Table 3. Results of multivariate analysis for factors associated with GF

Novitzky-Basso-tab03.jpg

Table 4. Characteristics of patients who underwent a second transplant for GF

Novitzky-Basso-tab04.jpg

Abbreviations: GF, graft failure; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; MF, myelofibrosis; MDS, myelodysplasia; MPN, myeloproliferative neoplasm; MUD, matched unrelated donor; GvHD, graft versus host disease

Factors associated with graft failure on univariate analysis are shown in Table 2. Diagnoses associated with GF were MDS (p=0.04), MF (p=0.005), lymphoma (p=0.002) and non-malignant conditions (aplastic anemia, adrenoleukodystrophy, mitochondrial neurogastrointestinal encephalopathy syndrome) (p<0.001). Other significant factors were incomplete remissions prior to allo-HCT (p=0.01), mismatched unrelated donors (p=0.002) or haploidentical donors (p=0.004), use of BM as graft source (p=0.008). CMV mismatch, CD34 stem cell dose, and freezing of the stem cell product were not significant factors.

Multivariate analysis was undertaken with the following variables: diagnosis, age, donor type, sex, disease stage at allo-HCT, donor age, stem cell source, CD34 dose, stem cells frozen or fresh, myeloablative or reduced-intensity conditioning, use of post-transplant cyclophosphamide, use of anti-thymocyte globulin as GvHD prophylaxis, presence of CMV serological mismatch, presence of bloodstream infection before D+20 post-allo-HCT, primary disease, disease risk index, Karnofsky performance score (KPS) at allo-HCT, HCT-CI (hematopoietic cell transplant co-morbidity index20) score, presence of donor and recipient of blood group mismatch, and time from diagnosis to transplant.

Multivariate analysis of all GF demonstrated that transplant indication (MDS, MF, lymphoma or non-malignant diseases) and donor type (HLA-mismatched unrelated or haploidentical) were the significant factors associated with increased GF (Table 3). For PGF significant factors were: non-malignant disease (HR 114.3 95% confidence interval [CI] [4.53-2881], p<0.004), MF (HR 27.6 [2.84-268], p=0.004), MDS (HR 18.2 [1.99-166], p=0.01) and graft from haploidentical donor (HR 12.5 [3-51.6], p<0.001), Figure 2c. For SGF significant factors were: non-malignant disease (HR 4.31 [1.06-17.5], p=0.04), and lymphoma (HR 4.19 [1.71-10.3], p=0.002), Figure 2d. Taken together, non-leukemia diagnosis and mismatched unrelated or haploidentical donors were significantly associated with graft failure (see Figure 2e).

The effect of more than one of the previously described risk factors (non-leukemia diagnosis and mismatched unrelated or haploidentical donors) on the occurrence of graft failure is shown in Figure 2e. For the absence of any of the risk factors (n=279), the incidence of GF was 3.6%. For the presence of one risk factor (n=229), the incidence of GF was 9.9%, while for 2 concurrent risk factors (n=49), the incidence of GF was 24.5%.

Novitzky-Basso-fig02.jpg

Figure 2. A, cumulative incidence of GF according to transplant indication/disease. B, cumulative incidence of GF according to donor type. C, cumulative incidence of primary GF according to the presence of risk factors from multivariable analysis. D, cumulative incidence of secondary GF according to the presence of risk factors from multivariable analysis. E, cumulative incidence of overall GF from multivariable analysis according to the presence of no risk factors (3.6%), 1 risk factor (9.9%) and 2 risk factors (24.5%).

Abbreviations: Haplo, haploidentical; MUD, matched unrelated donor; MMURD, mismatched unrelated donor; MRD, matched related donor; Other Mal, other malignancies; RF, risk factor

Discussion

GF remains a significant clinical problem post allo-HCT. It is important to identify patients who are at risk of GF to potentially limit the number of risk factors for prevention of this high-risk complication. Our study showed an increased risk for GF following the use of mismatched unrelated or haploidentical donors for diseases such as lymphoma, myelofibrosis, myelodysplastic syndrome and non-malignant diseases.

A number of factors found significant in other studies were not significant on multivariate analysis in the present study. Cryopreservation was a significant factor in a large retrospective study on PGF from CIBMTR data, but this was not significant in the present cohort (p=0.79) [6]. This may be due to the more rigorous standardization of cryopreservation and thawing techniques at our center, compared to the multicenter data in the CIBMTR study. Other stated significant factors from the CIBMTR study, including age, bone marrow source, ABO incompatibility and sex-mismatched transplants (male recipients of female grafts) were similarly not significant on multivariate analysis in the present study. This may be related to our limited numbers compared to the 23,272 transplants examined in the CIBMTR study. Both the present study and the CIBMTR study are in concordance that HLA-mismatch and non-leukemic myeloid malignancies are significant risk factors for GF. Possible explanations for the differences in other results include the use of myeloablative conditioning as an inclusion criterion in the CIBMTR study, the use of haploidentical donors at our center, and the exclusive examination of PGF in the CIBMTR study. In support of our findings, another report has similarly identified mismatched donors and non-malignant conditions as significantly associated with GF on multivariate analysis [1]. Other factors also identified in this single-center report which identified GF in 54 (5.6%) patients of 967 transplants undertaken from 1995 to 2010, were non-myeloablative conditioning, total nucleated cell dose <2.4×108/kg, HLA-mismatch and ex vivo T-cell depletion. We analyzed separately effects of CD34 dose above and below the median, as well as stem cell source, but there were no significant associations in all GF or in PGF-only patients.

Treatment strategies for GF vary, while second transplant remains a common option, particularly in our center, as CD34-selected stem cell boost is not available. Using data reported to the National Marrow Donor Program (NMDP) of 14,564 transplants, of which 981 experienced PGF, Schriber, et al. (2010) described 122 patients who received a subsequent second unrelated transplant [21]. One-year OS after the second HCT was 11%, with only 10 patients alive at the last follow-up. The cumulative probability of NRM was high at 39% and 75% at 30 and 100 days, respectively. In this study, engraftment data from 79 patients were included, and the cumulative incidence of neutrophil engraftment at 28 days was 66%. Survival was poor (10%) for patients who received a second allo-HCT; however, the mortality rate was 99% at 1 year in patients not undergoing a second HCT. Only 162 patients out of 981 reported with GF had received a second HCT, of which 122 were from unrelated donors. This could be because the first HCT was from an unrelated donor, making the attainment of a second donation more complicated than from a related donor. However, where donors were available for the second SCT, no differences were observed between patients who received grafts from the same (80%) or a different donor, or if the stem cells had been previously cryopreserved.

In contrast to our findings and that of the CIBMTR study, the MD Anderson group7 reported 68 patients out of 1726 who experienced GF, showing that a diagnosis of acute leukemia was found to be the only prognostic marker for survival on multivariate analysis [7]. A patient was considered to have GF if any of these 3 conditions were met: (1) PGF: failure to achieve ANC of <0.5×109/L by 28 days after BM or PB progenitor cell transplantation or 42 days after cord blood (CB) transplantation, (2) SGF: loss of neutrophil engraftment as determined by an ANC of <0.5×109/L for 3 consecutive days after having achieved neutrophil engraftment with documented donor cell chimerism and no evidence of disease progression in the marrow, or (3) PGF with autologous reconstitution defined as achievement of an ANC of at least 0.5×109/L but without evidence of at least 5% or more donor cell chimerism as defined by cytogenetics or molecular techniques [7]. They reported a 1-, 2- and 5-year OS of 31%, 24% and 15%, respectively. The most common causes of death were original malignancy (41%), infection (27%), and GF (18%). Twenty-nine patients had PGF, with a median survival of 2.9 months, and 7 were re-transplanted, with only 2 surviving over 5 months. 9 patients had GF with autologous reconstitution, and their median survival was 13.7 months. Thirty patients had SGF; 3 patients survived over 4 years. Five of the 30 received a second transplant, but none survived longer than a year. Overall, patients with autologous reconstitution survived longer, but long-term outcomes were similar.

Using different methodology, a Spanish group reported the outcome of 89 patients with GF, irrespective of donor chimerism [2]. This group used the standard criteria for PGF and SGF was defined as a recurrent ANC <0.5×109/L for at least 7 days. They did not state chimerism as a requirement for SGF. Of these, 80 patients received a second allo-HCT, with a 5-year survival probability of 31% (95% confidence interval [CI]: 18-44%), NRM 47% (95% CI 36-58%), and relapse 21% (95% CI 4-28%).

A review of various studies highlights the significant discordance in definitions of SGF: some authors include the presence of donor chimerism in the definition, whilst others do not [1, 2, 4, 6, 7, 8, 9, 10]. Including those cases with low blood counts which may be secondary to causes such as drugs, infection and GvHD may lead to over-diagnosis and possibly inappropriate treatment, given that a proportion of these will be transient and demonstrate recovery of blood counts. This lack of uniformity may hamper common definitions of what constitutes GF [3]. A definition of SGF which requires donor chimerism <5% will exclude patients who had falling chimerism (between 5% and 95%) but insufficient time for this to fall below 5%, or those who died due to cytopenia without documenting <5% donor chimerism. We, therefore, included patients with cytopenia, who had falling donor chimerism (Figure 1c) and died due to complications or received salvage DLI or second transplant. Importantly, we excluded those patients whose cytopenia was due to relapse. We were assiduous in ensuring that the presenting cytopenia were not due to relapse of the underlying disease. This serves to reduce ambiguity and focus resources on those patients in urgent need of salvage from GF. Often, relapsed myelodysplasia or acute leukemia may present with progressive single- or multi-lineage cytopenia, and it is crucial to make every attempt to exclude relapse, either by repeated bone marrow examination or the use of modern techniques for minimal or measurable residual disease by flow cytometry and/or quantitative polymerase chain reaction, as appropriate.

Interestingly, the significant factors for primary and SGF in our cohort were slightly different, which may represent that these types of GF represent different phenomena, with differing mechanisms. This is evidenced by the fact that PGF risks included myelofibrosis, myelodysplasia, myeloproliferative neoplasm, while these were absent from those factors found significant for SGF (lymphoma/non-malignant diagnosis, Figures 2c and 2d).

There are limitations to our analysis. Numbers of patients with primary or SGF are few and therefore the analysis was improved by evaluating all GF together. Nevertheless, analysis within primary and SGF cohorts gave broadly similar results. The inclusion of patients who died with cytopenia in the SGF may not be conventional, but this allowed study of relevant groups which would have otherwise have been excluded.

Conclusion

According to the results from the present study, the prognosis of GF remains poor even after successful treatment of GF, with a few long-term survivors. Those patients with mismatched donors and certain hematological conditions as previously mentioned, should be counselled carefully that the risk of GF may be near 25%, with a mortality rate of approximately 73-89% should it occur. Whereas risk factors such as primary diagnosis are unavoidable, it may be possible to reduce the other risk factors, including careful donor selection. However, most patients with MMUD or haploidentical donors will not have a readily available alternative donor. Measures that could be taken to reduce risk of GF include choice of haploidentical donor, utilizing a more immunosuppressive conditioning regimen or increasing the immunosuppressive component of the GvHD prophylaxis. If appropriate, a myeloablative regimen is more likely to ensure full donor engraftment. Furthermore, careful attention could be paid to the presence of donor-specific antibodies (DSA) and their titers when using MMURD and haploidentical donors. Post-transplant monitoring modification could be implemented, such as lineage-specific chimerism, which our center has recently introduced, and more frequent monitoring of chimerism, e.g. every 30 days with priority for rapid results. More careful use of myelo-suppressive medication such as valganciclovir and co-trimoxazole in these patients is another suggested strategy, with early adoption of alternative therapies in the event of cytopenias. These special precautions could be taken in those cases with 1 or more risk factors as identified in this study. Further studies are required to establish whether close monitoring and early intervention improve outcomes. The optimal treatment strategies for graft failure remain to be established.

Conflicts of interests

None declared.

References

  1. Olsson R, Remberger M, Schaffer M, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48(4):537-543.
  2. Ferra C, Sanz J, Diaz-Perez MA, et al. Outcome of graft failure after allogeneic stem cell transplant: study of 89 patients. Leuk Lymphoma. 2015;56(3):656-662.
  3. Gale RP. Early and late graft-failure after transplants. Bone Marrow Transplant. 2016;51(2):182-183.
  4. Satwani P, Jin Z, Duffy D, et al. Transplantation-related mortality, graft failure, and survival after reduced-toxicity conditioning and allogeneic hematopoietic stem cell transplantation in 100 consecutive pediatric recipients. Biol Blood Marrow Transplant. 2013;19(4):552-561.
  5. Ozdemir ZN, Civriz Bozdag S. Graft failure after allogeneic hematopoietic stem cell transplantation. Transfus Apher Sci. 2018;57(2):163-167.
  6. Olsson RF, Logan BR, Chaudhury S, et al. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia. 2015;29(8):1754-1762.
  7. Rondon G, Saliba RM, Khouri I, et al. Long-term follow-up of patients who experienced graft failure postallogeneic progenitor cell transplantation. Results of a single institution analysis. Biol Blood Marrow Transplant. 2008;14(8):859-866.
  8. Passweg JR, Zhang MJ, Rocha V, et al. Donor characteristics affecting graft failure, graft-versus-host disease, and survival after unrelated donor transplantation with reduced-intensity conditioning for hematologic malignancies. Biol Blood Marrow Transplant. 2011;17(12):1869-1873.
  9. Hutt D. Engraftment, Graft Failure, and Rejection. In: Kenyon M, Babic A, eds. The European Blood and Marrow Transplantation Textbook for Nurses: Under the Auspices of EBMT. Cham (CH)2018:259-270.
  10. Lund TC, Liegel J, Bejanyan N, et al. Second allogeneic hematopoietic cell transplantation for graft failure: poor outcomes for neutropenic graft failure. Am J Hematol. 2015;90(10):892-896.
  11. Mattsson J, Ringden O, Storb R. Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;14(1 Suppl 1):165-170.
  12. Masouridi-Levrat S, Simonetta F, Chalandon Y. Immunological Basis of Bone Marrow Failure after Allogeneic Hematopoietic Stem Cell Transplantation. Frontiers in immunology. 2016;7:362.
  13. Wolff SN. Second hematopoietic stem cell transplantation for the treatment of graft failure, graft rejection or relapse after allogeneic transplantation. Bone Marrow Transplant. 2002;29(7):545-552.
  14. Stucki A, Leisenring W, Sandmaier BM, Sanders J, Anasetti C, Storb R. Decreased Rejection and Improved Survival of First and Second Marrow Transplants for Severe Aplastic Anemia (A 26-Year Retrospective Analysis). Blood. 1998;92(8):2742-2749.
  15. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825-828.
  16. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21(3):389-401 e381.
  17. Ferrà C, Sanz J, Díaz-Pérez M-A, et al. Outcome of graft failure after allogeneic stem cell transplant: study of 89 patients. Leukemia & Lymphoma. 2015;56(3):656-662.
  18. Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. Journal of the American Statistical Association. 1999;94(446):496-509.
  19. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48(3):452-458.
  20. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific co-morbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912-2919.
  21. Schriber J, Agovi MA, Ho V, et al. Second unrelated donor hematopoietic cell transplantation for primary graft failure. Biol Blood Marrow Transplant. 2010;16(8):1099-1106.
  22. Armand P, Gibson CJ, Cutler C, et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood. 2012;120(4):905-913.

" ["~DETAIL_TEXT"]=> string(32360) "

Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for hematological diseases. Sustained engraftment of the donor stem cells is essential for transplant success and overall favourable outcomes. Graft failure (GF) is an uncommon (incidence 5-6%) complication post-allo-HCT and is associated with a poor prognosis, especially in allo-HCT for malignant disorders [1]. There are differences in the definition of primary and secondary graft failure [1-10]. Numerous risk factors have been previously associated with GF such as myelofibrosis (MF), aplastic anemia (AA), bone marrow as a graft source or donor HLA mismatch, while other factors such as ABO mismatch, graft-versus-host disease prophylaxis or infections, particularly viral reactivation, remain a matter of debate [11]. The incidence of GF may increase to 20-25% with the use of alternative modalities of HCT, including non-myeloablative conditioning, intensive T-cell depletion of the graft, human leukocyte antigen (HLA) disparity between donor and recipient or cord blood as the progenitor source [1, 11]. The use of filgrastim-mobilized peripheral blood (PB) stem cells instead of bone marrow (BM) decreases the risk of GF, especially in unrelated allo-HCT [8]. Many factors have been proposed to be involved in the etiology of GF, including defects in the BM microenvironment, immune-mediated rejection, drug toxicity or viral infections [12, 13].

The management of GF includes the administration of growth factor, additional hematopoietic progenitor boost or a second allo-HCT with conditioning therapy [11, 13]. Data available on patient outcomes after the development of GF are limited and heterogeneous. Strategies for reversing GF depend on the options available in each situation, and there is no clear recommendation for the best approach to this complication. Some reports have suggested that a second transplant could benefit patients who develop GF [14]. However, transplant-related mortality compromises the overall survival (OS) of these patients. In the present study, we assessed the incidence and the risk factors for GF in a single-center population and the impact on the patients’ outcome.

Patients and methods

Between January 1, 2015, and December 31, 2018, 557 patients underwent allo-HCT at the Princess Margaret Cancer Center. Data was collected retrospectively and updated in June 2019. Cases were included regardless of the underlying diagnosis, disease status prior to transplant, preparative regimen, or stem cell source. Acute (aGvHD) and chronic GvHD (cGvHD) were diagnosed and graded using the aGvHD consensus conference criteria and the NIH consensus criteria for cGvHD, respectively [15, 16]. Conditioning therapy was considered as nonmyeloablative when patients received busulfan < 9 mg/kg, and total body irradiation ≤500 cGy as a single fraction or ≤800 cGy if fractionated. All patients received granulocyte colony-stimulating factor from day +6 following transplant until neutrophil engraftment.

Primary graft failure was defined as the failure to achieve an absolute neutrophil count (ANC) of 0.5×109/L by 28 days after BM or PB [17]. Secondary graft failure was defined as sustained fall in ANC <0.5×109/L after initial engraftment, and one of the following: (a) donor chimerism of less than 5%, or (b) intervention such as use of DLI or second transplant for falling blood counts, or (c) patient death due to cytopenia, with falling donor chimerism, but level of donor chimerism >5% but <95% [1, 17]. Decrease in peripheral blood counts due to relapse of disease was excluded as a cause of GF. Outcomes examined included overall survival (OS), the cumulative incidence of GF and non-relapse mortality (NRM) as well as the cause of death.

Patients were managed clinically according to Princess Margaret Cancer Center guidelines. BM aspirates were monitored for disease status and donor chimerism was assessed in sex-mismatched donor–recipient pairs by metaphase karyotype analyses; restriction fragment length DNA polymorphisms were compared in sex-matched pairs; whole blood chimerism was assay for the duration of this study.

This study was approved by the institutional research ethics board of our center, and consent had been obtained from all the patients for transplant procedures and sharing data following local policies.

Overall survival (OS) was calculated using the Kaplan-Meier method and compared with the log-rank test. Survival time was calculated from the day of first transplantation until death or last follow-up. Incidences of graft failure (GF) were obtained using an estimator of cumulative incidence curves. Patients were censored at the time of death or last follow-up. Competing events for GF were death or relapse without GF. For SGF, PGF was also considered as a competing event.

Uni- and multivariate predictive analyses for GF were performed with the proportional sub-distribution hazard regression model of Fine and Gray [18]. Factors with a p-value <0.10 in the univariate analysis were included in the backwards elimination multivariate analysis.

Analyses were performed using the EZR freely available software and Statistica 13 (TIBCO, Palo Alto, CA, USA) software [19].

Results

Baseline characteristics are summarized in Table 1. Pretransplant therapies where indicated for hematological malignancies consisted of current North American induction protocols: for ALL, Dana Farber Cancer Institute regimen for ALL (1 patient received blinatumomab); for AML either daunorubicin and cytarabine (‘3+7’) or FLAG-Ida; for MDS/MPN supportive care, azacytidine, hydroxyurea or ‘3+7’; ruxolitinib for MF, ibrutinib for CLL, and standard salvage regimens (Bendamustine/rituximab or ‘ICE’) for non-Hodgkin lymphoma.

Table 1. Patients’ characteristics and main factors contributing to GF

Novitzky-Basso-tab01.jpg

Abbreviations: MDS, myelodysplasia; MF, myelofibrosis; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; MUD, matched unrelated donor; MRD, matched related donor; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; PTCY, post-transplant cyclophosphamide; ATG, anti-thymocyte globulin; MMF, myecophenolate; CSA, cyclosporine; MTX, methotrexate; CMV, cytomegalovirus; BM, bone marrow; PBSC, peripheral blood stem cells; BSI, bloodstream infections; HCT-CI, hematopoietic stem cell transplant co-morbidity index; KPS, Karnofsky performance score

The cumulative incidence of relapse (CIR) for the entire cohort (n=557) was 7.9% (CI95%; 5.9-10.3) at 100 days and 24.3% (CI95%; 20.6-28.1) at 2 years. In particular, the CIR for patients transplanted for AML (n=284) was 7.7% (CI95%; 5.0-11.2) at 100 days and 21.4% (CI95%; 16.7-26.6) at 2 years, whereas it was 14.6% (CI95%; 5.8-27.2) at 100 days and 45.0% (CI95%; 27.9-60.6%) at 2 years in patients transplanted for ALL (n=41). For MF (n=47), CIR was 2.1% (CI95%; 0.2-9.9) at 100 days and 10.2% (CI95%; 2.9-22.8) at 2 years, CIR for MDS/MPN (n=102) was 11.8% (CI95%; 6.4-18.9) at 100 days and 30.4% CI95%; (21.5-39.8) 2 years. Finally, CIR of patients transplanted for Lymphoma (n=31) was 6.5% (CI95%; 1.1-18.9) at 100 days, and 36.6% (CI95%; 19.6-53.8) at 2 years.

Median survival following PGF was 41 days, while in SGF it was 144 days (Figure 1b). The one hundred days OS in PGF was 22%, whereas it was 64% for SGF. One-year and two-year OS for SGF were 33% and 28%, respectively, Figure 1b. Survival of GF patients was calculated from the date of GF.

Percentage donor chimerism (Figure 1c), was as follows: for primary graft failure, at day 30 post-transplant, n=9, median 19.9% (0.8-75.7%), at day 60 post-transplant, n=5, median 0% (0-27%), at day 90 post-transplant, n=3, median 1% (0-1%). For secondary graft failure, at day 30 post-transplant, n=33, median 96.85% (70.4-100%) (missing data for one patient), at day 60 post-transplant, n=32, median 87.65% (0-99.3%), at day 90 post-transplant, n=24, median 74.15% (3.2-98.2%).

Novitzky-Basso-fig01.jpg

Figure 1. A, cumulative incidence to primary and secondary graft failure (GF). Numbers represent median number of days to graft failure diagnosis with range. B, median survival from primary and secondary graft failure. C, percentage donor chimerism in patients with primary and secondary graft failure. Bars represent the inter-quartile range, and round circles, the median. The percentage donor chimerism at day 30 (D30), day 60 (D60) and day 90 (D90) post-transplant are represented. D, overall survival from allogeneic stem cell transplant for the whole cohort, and patients with GF. Survival of GF patients was calculated from date of GF.

Percentage donor chimerism (Figure 1c), was as follows: for primary graft failure, at day 30 post-transplant, n=9, median 19.9% (0.8-75.7%), at day 60 post-transplant, n=5, median 0% (0-27%), at day 90 post-transplant, n=3, median 1% (0-1%). For secondary graft failure, at day 30 post-transplant, n=33, median 96.85% (70.4-100%) (missing data for one patient), at day 60 post-transplant, n=32, median 87.65% (0-99.3%), at day 90 post-transplant, n=24, median 74.15% (3.2-98.2%).

Table 2. Results of univariate analysis

Novitzky-Basso-tab02-01.jpg Novitzky-Basso-tab02-02.jpg

Abbreviations: MAC, myeloablative conditioning; RIC, reduced intensity conditioning; PTCY, post-transplant cyclophosphamide; ATG, anti-thymocyteglobulin; BM, bone marrow; PBSC, peripheral blood stem cells; BSI, bloodstream infection; HCT-CI, hematopoietic stem cell transplant co-morbidity index; KPS, Karnofsky performance score; SCT, stem cell transplant; CR, complete remission

DLI was administered to nine patients with SGF. Five of these experienced grade I-II acute GvHD, and two, grade III-IV acute GvHD. Two subsequently experienced moderately severe GvHD. Of these nine patients, one experienced relapse and died, another demised with post-transplant lymphoproliferative disorder, two with GvHD, and ultimately 5 were alive at last follow-up.

Second allo-HCT was performed in 5 patients (56%) with PGF and 15 patients (44%) with SGF (see Table 4). Another 8 patients with SGF received donor lymphocyte infusions (DLI). The primary complication following second allo-HCT was infection. Median time from GF diagnosis to second allo-HCT was 35 days (20-172), whilst median time from GF diagnosis to DLI was 90 days (7-288). Six out of 15 patients who received a second transplant for SGF developed Grade 3/4 acute GvHD and 4 out of these patients developed moderately severe chronic GvHD.

Median survival (Figure 1d) post second transplant was 109 days (9-1014); survival was calculated from second HCT. Median survival post DLI was 293 days (22-868).

Overall, all the patients with PGF died because of GF or complications related to it. In SGF 22 of 43 patients (51%) died, the most common causes of death were infections (30%), GvHD (18%) and one patient died related to veno-occlusive disease. The median neutrophil count for the SGF patients that died in GF was 0 ×109/L (0-0.5×109/L) and median platelet count was 6 ×109/L (3-41×109/L).

Table 3. Results of multivariate analysis for factors associated with GF

Novitzky-Basso-tab03.jpg

Table 4. Characteristics of patients who underwent a second transplant for GF

Novitzky-Basso-tab04.jpg

Abbreviations: GF, graft failure; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; MF, myelofibrosis; MDS, myelodysplasia; MPN, myeloproliferative neoplasm; MUD, matched unrelated donor; GvHD, graft versus host disease

Factors associated with graft failure on univariate analysis are shown in Table 2. Diagnoses associated with GF were MDS (p=0.04), MF (p=0.005), lymphoma (p=0.002) and non-malignant conditions (aplastic anemia, adrenoleukodystrophy, mitochondrial neurogastrointestinal encephalopathy syndrome) (p<0.001). Other significant factors were incomplete remissions prior to allo-HCT (p=0.01), mismatched unrelated donors (p=0.002) or haploidentical donors (p=0.004), use of BM as graft source (p=0.008). CMV mismatch, CD34 stem cell dose, and freezing of the stem cell product were not significant factors.

Multivariate analysis was undertaken with the following variables: diagnosis, age, donor type, sex, disease stage at allo-HCT, donor age, stem cell source, CD34 dose, stem cells frozen or fresh, myeloablative or reduced-intensity conditioning, use of post-transplant cyclophosphamide, use of anti-thymocyte globulin as GvHD prophylaxis, presence of CMV serological mismatch, presence of bloodstream infection before D+20 post-allo-HCT, primary disease, disease risk index, Karnofsky performance score (KPS) at allo-HCT, HCT-CI (hematopoietic cell transplant co-morbidity index20) score, presence of donor and recipient of blood group mismatch, and time from diagnosis to transplant.

Multivariate analysis of all GF demonstrated that transplant indication (MDS, MF, lymphoma or non-malignant diseases) and donor type (HLA-mismatched unrelated or haploidentical) were the significant factors associated with increased GF (Table 3). For PGF significant factors were: non-malignant disease (HR 114.3 95% confidence interval [CI] [4.53-2881], p<0.004), MF (HR 27.6 [2.84-268], p=0.004), MDS (HR 18.2 [1.99-166], p=0.01) and graft from haploidentical donor (HR 12.5 [3-51.6], p<0.001), Figure 2c. For SGF significant factors were: non-malignant disease (HR 4.31 [1.06-17.5], p=0.04), and lymphoma (HR 4.19 [1.71-10.3], p=0.002), Figure 2d. Taken together, non-leukemia diagnosis and mismatched unrelated or haploidentical donors were significantly associated with graft failure (see Figure 2e).

The effect of more than one of the previously described risk factors (non-leukemia diagnosis and mismatched unrelated or haploidentical donors) on the occurrence of graft failure is shown in Figure 2e. For the absence of any of the risk factors (n=279), the incidence of GF was 3.6%. For the presence of one risk factor (n=229), the incidence of GF was 9.9%, while for 2 concurrent risk factors (n=49), the incidence of GF was 24.5%.

Novitzky-Basso-fig02.jpg

Figure 2. A, cumulative incidence of GF according to transplant indication/disease. B, cumulative incidence of GF according to donor type. C, cumulative incidence of primary GF according to the presence of risk factors from multivariable analysis. D, cumulative incidence of secondary GF according to the presence of risk factors from multivariable analysis. E, cumulative incidence of overall GF from multivariable analysis according to the presence of no risk factors (3.6%), 1 risk factor (9.9%) and 2 risk factors (24.5%).

Abbreviations: Haplo, haploidentical; MUD, matched unrelated donor; MMURD, mismatched unrelated donor; MRD, matched related donor; Other Mal, other malignancies; RF, risk factor

Discussion

GF remains a significant clinical problem post allo-HCT. It is important to identify patients who are at risk of GF to potentially limit the number of risk factors for prevention of this high-risk complication. Our study showed an increased risk for GF following the use of mismatched unrelated or haploidentical donors for diseases such as lymphoma, myelofibrosis, myelodysplastic syndrome and non-malignant diseases.

A number of factors found significant in other studies were not significant on multivariate analysis in the present study. Cryopreservation was a significant factor in a large retrospective study on PGF from CIBMTR data, but this was not significant in the present cohort (p=0.79) [6]. This may be due to the more rigorous standardization of cryopreservation and thawing techniques at our center, compared to the multicenter data in the CIBMTR study. Other stated significant factors from the CIBMTR study, including age, bone marrow source, ABO incompatibility and sex-mismatched transplants (male recipients of female grafts) were similarly not significant on multivariate analysis in the present study. This may be related to our limited numbers compared to the 23,272 transplants examined in the CIBMTR study. Both the present study and the CIBMTR study are in concordance that HLA-mismatch and non-leukemic myeloid malignancies are significant risk factors for GF. Possible explanations for the differences in other results include the use of myeloablative conditioning as an inclusion criterion in the CIBMTR study, the use of haploidentical donors at our center, and the exclusive examination of PGF in the CIBMTR study. In support of our findings, another report has similarly identified mismatched donors and non-malignant conditions as significantly associated with GF on multivariate analysis [1]. Other factors also identified in this single-center report which identified GF in 54 (5.6%) patients of 967 transplants undertaken from 1995 to 2010, were non-myeloablative conditioning, total nucleated cell dose <2.4×108/kg, HLA-mismatch and ex vivo T-cell depletion. We analyzed separately effects of CD34 dose above and below the median, as well as stem cell source, but there were no significant associations in all GF or in PGF-only patients.

Treatment strategies for GF vary, while second transplant remains a common option, particularly in our center, as CD34-selected stem cell boost is not available. Using data reported to the National Marrow Donor Program (NMDP) of 14,564 transplants, of which 981 experienced PGF, Schriber, et al. (2010) described 122 patients who received a subsequent second unrelated transplant [21]. One-year OS after the second HCT was 11%, with only 10 patients alive at the last follow-up. The cumulative probability of NRM was high at 39% and 75% at 30 and 100 days, respectively. In this study, engraftment data from 79 patients were included, and the cumulative incidence of neutrophil engraftment at 28 days was 66%. Survival was poor (10%) for patients who received a second allo-HCT; however, the mortality rate was 99% at 1 year in patients not undergoing a second HCT. Only 162 patients out of 981 reported with GF had received a second HCT, of which 122 were from unrelated donors. This could be because the first HCT was from an unrelated donor, making the attainment of a second donation more complicated than from a related donor. However, where donors were available for the second SCT, no differences were observed between patients who received grafts from the same (80%) or a different donor, or if the stem cells had been previously cryopreserved.

In contrast to our findings and that of the CIBMTR study, the MD Anderson group7 reported 68 patients out of 1726 who experienced GF, showing that a diagnosis of acute leukemia was found to be the only prognostic marker for survival on multivariate analysis [7]. A patient was considered to have GF if any of these 3 conditions were met: (1) PGF: failure to achieve ANC of <0.5×109/L by 28 days after BM or PB progenitor cell transplantation or 42 days after cord blood (CB) transplantation, (2) SGF: loss of neutrophil engraftment as determined by an ANC of <0.5×109/L for 3 consecutive days after having achieved neutrophil engraftment with documented donor cell chimerism and no evidence of disease progression in the marrow, or (3) PGF with autologous reconstitution defined as achievement of an ANC of at least 0.5×109/L but without evidence of at least 5% or more donor cell chimerism as defined by cytogenetics or molecular techniques [7]. They reported a 1-, 2- and 5-year OS of 31%, 24% and 15%, respectively. The most common causes of death were original malignancy (41%), infection (27%), and GF (18%). Twenty-nine patients had PGF, with a median survival of 2.9 months, and 7 were re-transplanted, with only 2 surviving over 5 months. 9 patients had GF with autologous reconstitution, and their median survival was 13.7 months. Thirty patients had SGF; 3 patients survived over 4 years. Five of the 30 received a second transplant, but none survived longer than a year. Overall, patients with autologous reconstitution survived longer, but long-term outcomes were similar.

Using different methodology, a Spanish group reported the outcome of 89 patients with GF, irrespective of donor chimerism [2]. This group used the standard criteria for PGF and SGF was defined as a recurrent ANC <0.5×109/L for at least 7 days. They did not state chimerism as a requirement for SGF. Of these, 80 patients received a second allo-HCT, with a 5-year survival probability of 31% (95% confidence interval [CI]: 18-44%), NRM 47% (95% CI 36-58%), and relapse 21% (95% CI 4-28%).

A review of various studies highlights the significant discordance in definitions of SGF: some authors include the presence of donor chimerism in the definition, whilst others do not [1, 2, 4, 6, 7, 8, 9, 10]. Including those cases with low blood counts which may be secondary to causes such as drugs, infection and GvHD may lead to over-diagnosis and possibly inappropriate treatment, given that a proportion of these will be transient and demonstrate recovery of blood counts. This lack of uniformity may hamper common definitions of what constitutes GF [3]. A definition of SGF which requires donor chimerism <5% will exclude patients who had falling chimerism (between 5% and 95%) but insufficient time for this to fall below 5%, or those who died due to cytopenia without documenting <5% donor chimerism. We, therefore, included patients with cytopenia, who had falling donor chimerism (Figure 1c) and died due to complications or received salvage DLI or second transplant. Importantly, we excluded those patients whose cytopenia was due to relapse. We were assiduous in ensuring that the presenting cytopenia were not due to relapse of the underlying disease. This serves to reduce ambiguity and focus resources on those patients in urgent need of salvage from GF. Often, relapsed myelodysplasia or acute leukemia may present with progressive single- or multi-lineage cytopenia, and it is crucial to make every attempt to exclude relapse, either by repeated bone marrow examination or the use of modern techniques for minimal or measurable residual disease by flow cytometry and/or quantitative polymerase chain reaction, as appropriate.

Interestingly, the significant factors for primary and SGF in our cohort were slightly different, which may represent that these types of GF represent different phenomena, with differing mechanisms. This is evidenced by the fact that PGF risks included myelofibrosis, myelodysplasia, myeloproliferative neoplasm, while these were absent from those factors found significant for SGF (lymphoma/non-malignant diagnosis, Figures 2c and 2d).

There are limitations to our analysis. Numbers of patients with primary or SGF are few and therefore the analysis was improved by evaluating all GF together. Nevertheless, analysis within primary and SGF cohorts gave broadly similar results. The inclusion of patients who died with cytopenia in the SGF may not be conventional, but this allowed study of relevant groups which would have otherwise have been excluded.

Conclusion

According to the results from the present study, the prognosis of GF remains poor even after successful treatment of GF, with a few long-term survivors. Those patients with mismatched donors and certain hematological conditions as previously mentioned, should be counselled carefully that the risk of GF may be near 25%, with a mortality rate of approximately 73-89% should it occur. Whereas risk factors such as primary diagnosis are unavoidable, it may be possible to reduce the other risk factors, including careful donor selection. However, most patients with MMUD or haploidentical donors will not have a readily available alternative donor. Measures that could be taken to reduce risk of GF include choice of haploidentical donor, utilizing a more immunosuppressive conditioning regimen or increasing the immunosuppressive component of the GvHD prophylaxis. If appropriate, a myeloablative regimen is more likely to ensure full donor engraftment. Furthermore, careful attention could be paid to the presence of donor-specific antibodies (DSA) and their titers when using MMURD and haploidentical donors. Post-transplant monitoring modification could be implemented, such as lineage-specific chimerism, which our center has recently introduced, and more frequent monitoring of chimerism, e.g. every 30 days with priority for rapid results. More careful use of myelo-suppressive medication such as valganciclovir and co-trimoxazole in these patients is another suggested strategy, with early adoption of alternative therapies in the event of cytopenias. These special precautions could be taken in those cases with 1 or more risk factors as identified in this study. Further studies are required to establish whether close monitoring and early intervention improve outcomes. The optimal treatment strategies for graft failure remain to be established.

Conflicts of interests

None declared.

References

  1. Olsson R, Remberger M, Schaffer M, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48(4):537-543.
  2. Ferra C, Sanz J, Diaz-Perez MA, et al. Outcome of graft failure after allogeneic stem cell transplant: study of 89 patients. Leuk Lymphoma. 2015;56(3):656-662.
  3. Gale RP. Early and late graft-failure after transplants. Bone Marrow Transplant. 2016;51(2):182-183.
  4. Satwani P, Jin Z, Duffy D, et al. Transplantation-related mortality, graft failure, and survival after reduced-toxicity conditioning and allogeneic hematopoietic stem cell transplantation in 100 consecutive pediatric recipients. Biol Blood Marrow Transplant. 2013;19(4):552-561.
  5. Ozdemir ZN, Civriz Bozdag S. Graft failure after allogeneic hematopoietic stem cell transplantation. Transfus Apher Sci. 2018;57(2):163-167.
  6. Olsson RF, Logan BR, Chaudhury S, et al. Primary graft failure after myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies. Leukemia. 2015;29(8):1754-1762.
  7. Rondon G, Saliba RM, Khouri I, et al. Long-term follow-up of patients who experienced graft failure postallogeneic progenitor cell transplantation. Results of a single institution analysis. Biol Blood Marrow Transplant. 2008;14(8):859-866.
  8. Passweg JR, Zhang MJ, Rocha V, et al. Donor characteristics affecting graft failure, graft-versus-host disease, and survival after unrelated donor transplantation with reduced-intensity conditioning for hematologic malignancies. Biol Blood Marrow Transplant. 2011;17(12):1869-1873.
  9. Hutt D. Engraftment, Graft Failure, and Rejection. In: Kenyon M, Babic A, eds. The European Blood and Marrow Transplantation Textbook for Nurses: Under the Auspices of EBMT. Cham (CH)2018:259-270.
  10. Lund TC, Liegel J, Bejanyan N, et al. Second allogeneic hematopoietic cell transplantation for graft failure: poor outcomes for neutropenic graft failure. Am J Hematol. 2015;90(10):892-896.
  11. Mattsson J, Ringden O, Storb R. Graft failure after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;14(1 Suppl 1):165-170.
  12. Masouridi-Levrat S, Simonetta F, Chalandon Y. Immunological Basis of Bone Marrow Failure after Allogeneic Hematopoietic Stem Cell Transplantation. Frontiers in immunology. 2016;7:362.
  13. Wolff SN. Second hematopoietic stem cell transplantation for the treatment of graft failure, graft rejection or relapse after allogeneic transplantation. Bone Marrow Transplant. 2002;29(7):545-552.
  14. Stucki A, Leisenring W, Sandmaier BM, Sanders J, Anasetti C, Storb R. Decreased Rejection and Improved Survival of First and Second Marrow Transplants for Severe Aplastic Anemia (A 26-Year Retrospective Analysis). Blood. 1998;92(8):2742-2749.
  15. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825-828.
  16. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21(3):389-401 e381.
  17. Ferrà C, Sanz J, Díaz-Pérez M-A, et al. Outcome of graft failure after allogeneic stem cell transplant: study of 89 patients. Leukemia & Lymphoma. 2015;56(3):656-662.
  18. Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. Journal of the American Statistical Association. 1999;94(446):496-509.
  19. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48(3):452-458.
  20. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific co-morbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106(8):2912-2919.
  21. Schriber J, Agovi MA, Ho V, et al. Second unrelated donor hematopoietic cell transplantation for primary graft failure. Biol Blood Marrow Transplant. 2010;16(8):1099-1106.
  22. Armand P, Gibson CJ, Cutler C, et al. A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood. 2012;120(4):905-913.

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(2) "30" ["~SORT"]=> string(2) "30" ["CODE"]=> string(100) "faktory-riska-nedostatochnosti-transplantata-pri-allogennoy-transplantatsii-gemopoeticheskikh-stvolo" ["~CODE"]=> string(100) "faktory-riska-nedostatochnosti-transplantata-pri-allogennoy-transplantatsii-gemopoeticheskikh-stvolo" ["EXTERNAL_ID"]=> string(4) "1940" ["~EXTERNAL_ID"]=> string(4) "1940" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(363) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследованиеRisk factors for graft failure in allogeneic hematopoietic stem cell transplantation: a single-center study" ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(4106) "<h3>Цель работы</h3> <p style="text-align: justify;">Недостаточность трансплантата (НТ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК) имеет плохой прогноз. Целью данного исследования было установление частоты возникновения, факторов риска (Фри исходов НТ в контингенте из одного центра.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">В период с 2015 по 2018 гг., алло-ТГСК была выполнена у 557 больных. Первичную НТ (ПНТ) определяли как отсутствие роста абсолютного количества нейтрофилов (АКН) до >0.5×10<sup>9</sup>/л к 28 сут. после алло-ТГСК. Вторичную НТ (ВНТ) характеризовало снижение числа донорских клеток после начального приживления с возвратом КН к уровням <0.5×10<sup>9</sup>/л без рецидива или иных причин цитопении. Конечными результатами исследования была кумулятивная встречаемость НТ и общая выживаемость (ОВ); факторы риска НТ определяли путем многофакторного анализа.</p> <h3>Результаты</h3> <p style="text-align: justify;">В 9 случаях выявлена ПНТ, и у 34 больных была ВНТ. Кумулятивная встречаемость НТ была, соответственно, 1,6% ко дню +100 (CI95%; 0,8- 3,0%), и 6,5% – (CI95%; 4,5-8,8%) ко дню +800. Многофакторный анализ показал, что лиагноз (миелодиспластический синдром, миелофиброз, лимфома или неопухолевые заболевания), а также тип донора (HLA-несовместимый неродственный или гаплоидентичный) были достоверно ассоциированы с НТ. Частота НТ составила 3,6% при отсутствии указанных факторов риска, 9.9% при наличии одного ФР и 24.5% при двух ФР. Медиана выживаемости пациентов после ПНТ составила 41 сут., после ВНТ – 144 сут. Общая выживаемость на день +100 при ПНТ была 22%, при ВНТ – 64%. Двухлетняя общая выживаемость в случаях ВНТ была 28%.</p> <h3>Выводы</h3> <p style="text-align: justify;">Данное исследование показало наличие повышенного риска недостаточности трансплантата после алло-ТГСК от несовместимого/неродственного или гаплоидентичного донора, или при нелейкемическом диагнозе. Для таких случаев мы предлагаем тщательный мониторинг, ранние диагностические и терапевтические мероприятия и для улучшения клинических исходов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Аллогенная трансплантация гемопоэтических стволовых клеток, недостаточность трансплантата, встречаемость, факторы риска. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["SECTION_META_TITLE"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["SECTION_META_KEYWORDS"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["SECTION_META_DESCRIPTION"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["SECTION_PICTURE_FILE_ALT"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["SECTION_PICTURE_FILE_TITLE"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "faktory-riska-nedostatochnosti-transplantata-pri-allogennoy-transplantatsii-gemopoeticheskikh-stvolo" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(256) "Факторы риска недостаточности трансплантата при аллогенной трансплантации гемопоэтических стволовых клеток: одноцентровое исследование" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "faktory-riska-nedostatochnosti-transplantata-pri-allogennoy-transplantatsii-gemopoeticheskikh-stvolo" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "faktory-riska-nedostatochnosti-transplantata-pri-allogennoy-transplantatsii-gemopoeticheskikh-stvolo" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "faktory-riska-nedostatochnosti-transplantata-pri-allogennoy-transplantatsii-gemopoeticheskikh-stvolo" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "170" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27347" ["VALUE"]=> string(10) "22.09.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "22.09.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27348" ["VALUE"]=> string(10) "04.12.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "04.12.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27349" ["VALUE"]=> array(2) { ["TEXT"]=> string(803) "<p>Игорь Новицки-Бассо<sup>1</sup>, Эшрак Аль-Шайбани<sup>1</sup>, Мата Рембергер<sup>2</sup>, Кэрол Чен<sup>1</sup>, Уилсон Лэм<sup>1</sup>, Арджун Д. Лоу<sup>1</sup>, Айвэн Пазич<sup>1</sup>, Фотиос В. Микелис<sup>1</sup>, Ауро Висвабандья<sup>1</sup>, Деннис Д. Ким<sup>1</sup>, Джеффри Х. Липтон<sup>1</sup>, Армин Гербитц<sup>1</sup>, Ионас Маттсон<sup>1</sup>, Раджат Кумар<sup>1</sup>, Зейяд Аль-Шайбани<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(611) "

Игорь Новицки-Бассо1, Эшрак Аль-Шайбани1, Мата Рембергер2, Кэрол Чен1, Уилсон Лэм1, Арджун Д. Лоу1, Айвэн Пазич1, Фотиос В. Микелис1, Ауро Висвабандья1, Деннис Д. Ким1, Джеффри Х. Липтон1, Армин Гербитц1, Ионас Маттсон1, Раджат Кумар1, Зейяд Аль-Шайбани1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27350" ["VALUE"]=> array(2) { ["TEXT"]=> string(585) "<p><sup>1</sup> Программа аллогенных трансплантаций Ханса Месснера, Онкологический Центр принцессы Маргарет, университетская сеть здравоохранения, Университет Торонто, Торонто, Канада<br> <sup>2</sup> Департамент медицинских наук, университет Уппсала, университетский госпиталь Уппсала, Уппсала, Швеция</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(543) "

1 Программа аллогенных трансплантаций Ханса Месснера, Онкологический Центр принцессы Маргарет, университетская сеть здравоохранения, Университет Торонто, Торонто, Канада
2 Департамент медицинских наук, университет Уппсала, университетский госпиталь Уппсала, Уппсала, Швеция

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27351" ["VALUE"]=> array(2) { ["TEXT"]=> string(4106) "<h3>Цель работы</h3> <p style="text-align: justify;">Недостаточность трансплантата (НТ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК) имеет плохой прогноз. Целью данного исследования было установление частоты возникновения, факторов риска (Фри исходов НТ в контингенте из одного центра.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">В период с 2015 по 2018 гг., алло-ТГСК была выполнена у 557 больных. Первичную НТ (ПНТ) определяли как отсутствие роста абсолютного количества нейтрофилов (АКН) до >0.5×10<sup>9</sup>/л к 28 сут. после алло-ТГСК. Вторичную НТ (ВНТ) характеризовало снижение числа донорских клеток после начального приживления с возвратом КН к уровням <0.5×10<sup>9</sup>/л без рецидива или иных причин цитопении. Конечными результатами исследования была кумулятивная встречаемость НТ и общая выживаемость (ОВ); факторы риска НТ определяли путем многофакторного анализа.</p> <h3>Результаты</h3> <p style="text-align: justify;">В 9 случаях выявлена ПНТ, и у 34 больных была ВНТ. Кумулятивная встречаемость НТ была, соответственно, 1,6% ко дню +100 (CI95%; 0,8- 3,0%), и 6,5% – (CI95%; 4,5-8,8%) ко дню +800. Многофакторный анализ показал, что лиагноз (миелодиспластический синдром, миелофиброз, лимфома или неопухолевые заболевания), а также тип донора (HLA-несовместимый неродственный или гаплоидентичный) были достоверно ассоциированы с НТ. Частота НТ составила 3,6% при отсутствии указанных факторов риска, 9.9% при наличии одного ФР и 24.5% при двух ФР. Медиана выживаемости пациентов после ПНТ составила 41 сут., после ВНТ – 144 сут. Общая выживаемость на день +100 при ПНТ была 22%, при ВНТ – 64%. Двухлетняя общая выживаемость в случаях ВНТ была 28%.</p> <h3>Выводы</h3> <p style="text-align: justify;">Данное исследование показало наличие повышенного риска недостаточности трансплантата после алло-ТГСК от несовместимого/неродственного или гаплоидентичного донора, или при нелейкемическом диагнозе. Для таких случаев мы предлагаем тщательный мониторинг, ранние диагностические и терапевтические мероприятия и для улучшения клинических исходов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Аллогенная трансплантация гемопоэтических стволовых клеток, недостаточность трансплантата, встречаемость, факторы риска. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3906) "

Цель работы

Недостаточность трансплантата (НТ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК) имеет плохой прогноз. Целью данного исследования было установление частоты возникновения, факторов риска (Фри исходов НТ в контингенте из одного центра.

Пациенты и методы

В период с 2015 по 2018 гг., алло-ТГСК была выполнена у 557 больных. Первичную НТ (ПНТ) определяли как отсутствие роста абсолютного количества нейтрофилов (АКН) до >0.5×109/л к 28 сут. после алло-ТГСК. Вторичную НТ (ВНТ) характеризовало снижение числа донорских клеток после начального приживления с возвратом КН к уровням <0.5×109/л без рецидива или иных причин цитопении. Конечными результатами исследования была кумулятивная встречаемость НТ и общая выживаемость (ОВ); факторы риска НТ определяли путем многофакторного анализа.

Результаты

В 9 случаях выявлена ПНТ, и у 34 больных была ВНТ. Кумулятивная встречаемость НТ была, соответственно, 1,6% ко дню +100 (CI95%; 0,8- 3,0%), и 6,5% – (CI95%; 4,5-8,8%) ко дню +800. Многофакторный анализ показал, что лиагноз (миелодиспластический синдром, миелофиброз, лимфома или неопухолевые заболевания), а также тип донора (HLA-несовместимый неродственный или гаплоидентичный) были достоверно ассоциированы с НТ. Частота НТ составила 3,6% при отсутствии указанных факторов риска, 9.9% при наличии одного ФР и 24.5% при двух ФР. Медиана выживаемости пациентов после ПНТ составила 41 сут., после ВНТ – 144 сут. Общая выживаемость на день +100 при ПНТ была 22%, при ВНТ – 64%. Двухлетняя общая выживаемость в случаях ВНТ была 28%.

Выводы

Данное исследование показало наличие повышенного риска недостаточности трансплантата после алло-ТГСК от несовместимого/неродственного или гаплоидентичного донора, или при нелейкемическом диагнозе. Для таких случаев мы предлагаем тщательный мониторинг, ранние диагностические и терапевтические мероприятия и для улучшения клинических исходов.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, недостаточность трансплантата, встречаемость, факторы риска.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27352" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-37-47" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-37-47" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27355" ["VALUE"]=> array(2) { ["TEXT"]=> string(620) "<p>Igor Novitzky-Basso<sup>1</sup>, Eshrak Al-Shaibani<sup>1</sup>, Mats Remberger<sup>2</sup>, Carol Chen<sup>1</sup>, Wilson Lam<sup>1</sup>, Arjun D. Law<sup>1</sup>, Ivan Pasic<sup>1</sup>, Fotios V. Michelis<sup>1</sup>, Auro Viswabandya<sup>1</sup>, Dennis D. Kim<sup>1</sup>, Jeffrey H. Lipton<sup>1</sup>, Armin Gerbitz<sup>1</sup>, Jonas Mattsson<sup>1</sup>, Rajat Kumar<sup>1</sup>, Zeyad Al-Shaibani<sup>1</sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(428) "

Igor Novitzky-Basso1, Eshrak Al-Shaibani1, Mats Remberger2, Carol Chen1, Wilson Lam1, Arjun D. Law1, Ivan Pasic1, Fotios V. Michelis1, Auro Viswabandya1, Dennis D. Kim1, Jeffrey H. Lipton1, Armin Gerbitz1, Jonas Mattsson1, Rajat Kumar1, Zeyad Al-Shaibani1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27356" ["VALUE"]=> array(2) { ["TEXT"]=> string(721) "<p><sup>1</sup> Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada<br> <sup>2</sup> Department of Medical Sciences, Uppsala University and KFUE, Uppsala University Hospital, Uppsala, Sweden</p><br> <p><b>Correspondence</b><br> Igor Novitzky-Basso MD PhD, Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 610 University Avenue, Toronto, ON, M5G 2M9, Canada<br> Phone: +1 647 927 8700<br> Fax: +1 416 946 4407<br> E-mail: igor.novitzkybasso@uhn.ca</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(625) "

1 Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
2 Department of Medical Sciences, Uppsala University and KFUE, Uppsala University Hospital, Uppsala, Sweden


Correspondence
Igor Novitzky-Basso MD PhD, Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
Phone: +1 647 927 8700
Fax: +1 416 946 4407
E-mail: igor.novitzkybasso@uhn.ca

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27358" ["VALUE"]=> array(2) { ["TEXT"]=> string(2384) "<h3>Objectives</h3> <p style="text-align: justify;">Graft failure (GF) following allogeneic hematopoietic stem cell transplantation (allo-HCT) has a dismal prognosis. This study assessed incidence, risk factors (RF) and outcome of GF in a single-center population.</p> <h3>Patients and methods</h3> <p style="text-align: justify;">Between 2015-2018, 557 patients underwent allo-HCT. Primary GF (PGF) was defined as failure to achieve absolute neutrophil count (ANC) of >0.5×10<sup>9</sup>/L by 28 days after allo-HCT. Secondary GF (SGF) was characterized by loss of donor cells after initial engraftment with recurrence of ANC <0.5×10<sup>9</sup>/L without relapse or other causes of cytopenia. Endpoints of the study were cumulative incidence of GF and overall survival (OS). Risk factors for GF were assessed in multivariate analysis.</p> <h3>Results</h3> <p style="text-align: justify;">Nine patients had PGF, and 34 had SGF. The cumulative incidence of GF overall (primary and secondary) is 1.6% (CI95%; 0.8-3.0%) at day 100 and 6.5% (CI95%; 4.5-8.8%) at day 800 respectively. Multivariate analysis showed diagnosis (myelodysplastic syndrome [MDS], myelofibrosis [MF], lymphoma or non-malignant diseases) and donor type (HLA-mismatched-unrelated or haploidentical) were significantly associated with GF. For the absence of any of the risk factors (n=279), the incidence of GF was 3.6%. For the presence of one risk factor (n=229), the incidence of GF was 9.9%, while for 2 concurrent risk factors (n=49), the incidence of GF was 24.5% (p=0.002). Median OS of patients following PGF was 41 days, SGF – 144 days. The D100 OS in PGF was 22%, SGF – 64%; 2-year overall survival for SGF was 28%.</p> <h3>Conclusions</h3> <p style="text-align: justify;">This study showed increased risk of GF following mismatched-unrelated or haploidentical donor allo-HCT or for non-leukemia diagnosis, for which we suggest close monitoring for early diagnostic and therapeutic interventions, in order to improve clinical outcomes. </p> <h2>Keywords</h2> <p style="text-align: justify;">Allogeneic hematopoietic stem cell transplantation, graft failure, incidence, risk factors. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2184) "

Objectives

Graft failure (GF) following allogeneic hematopoietic stem cell transplantation (allo-HCT) has a dismal prognosis. This study assessed incidence, risk factors (RF) and outcome of GF in a single-center population.

Patients and methods

Between 2015-2018, 557 patients underwent allo-HCT. Primary GF (PGF) was defined as failure to achieve absolute neutrophil count (ANC) of >0.5×109/L by 28 days after allo-HCT. Secondary GF (SGF) was characterized by loss of donor cells after initial engraftment with recurrence of ANC <0.5×109/L without relapse or other causes of cytopenia. Endpoints of the study were cumulative incidence of GF and overall survival (OS). Risk factors for GF were assessed in multivariate analysis.

Results

Nine patients had PGF, and 34 had SGF. The cumulative incidence of GF overall (primary and secondary) is 1.6% (CI95%; 0.8-3.0%) at day 100 and 6.5% (CI95%; 4.5-8.8%) at day 800 respectively. Multivariate analysis showed diagnosis (myelodysplastic syndrome [MDS], myelofibrosis [MF], lymphoma or non-malignant diseases) and donor type (HLA-mismatched-unrelated or haploidentical) were significantly associated with GF. For the absence of any of the risk factors (n=279), the incidence of GF was 3.6%. For the presence of one risk factor (n=229), the incidence of GF was 9.9%, while for 2 concurrent risk factors (n=49), the incidence of GF was 24.5% (p=0.002). Median OS of patients following PGF was 41 days, SGF – 144 days. The D100 OS in PGF was 22%, SGF – 64%; 2-year overall survival for SGF was 28%.

Conclusions

This study showed increased risk of GF following mismatched-unrelated or haploidentical donor allo-HCT or for non-leukemia diagnosis, for which we suggest close monitoring for early diagnostic and therapeutic interventions, in order to improve clinical outcomes.

Keywords

Allogeneic hematopoietic stem cell transplantation, graft failure, incidence, risk factors.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27353" ["VALUE"]=> string(107) "Risk factors for graft failure in allogeneic hematopoietic stem cell transplantation: a single-center study" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(107) "Risk factors for graft failure in allogeneic hematopoietic stem cell transplantation: a single-center study" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["PDF_RU"]=> array(36) { ["ID"]=> string(2) "43" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF RUS" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_RU" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "43" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27354" ["VALUE"]=> string(4) "2326" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2326" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF RUS" ["~DEFAULT_VALUE"]=> string(0) "" } ["PDF_EN"]=> array(36) { ["ID"]=> string(2) "44" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF ENG" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "44" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27357" ["VALUE"]=> string(4) "2327" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2327" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF ENG" ["~DEFAULT_VALUE"]=> string(0) "" } ["NAME_LONG"]=> array(36) { ["ID"]=> string(2) "45" ["TIMESTAMP_X"]=> string(19) "2023-04-13 00:55:00" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(72) "Название (для очень длинных заголовков)" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "NAME_LONG" ["DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "45" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27355" ["VALUE"]=> array(2) { ["TEXT"]=> string(620) "<p>Igor Novitzky-Basso<sup>1</sup>, Eshrak Al-Shaibani<sup>1</sup>, Mats Remberger<sup>2</sup>, Carol Chen<sup>1</sup>, Wilson Lam<sup>1</sup>, Arjun D. Law<sup>1</sup>, Ivan Pasic<sup>1</sup>, Fotios V. Michelis<sup>1</sup>, Auro Viswabandya<sup>1</sup>, Dennis D. Kim<sup>1</sup>, Jeffrey H. Lipton<sup>1</sup>, Armin Gerbitz<sup>1</sup>, Jonas Mattsson<sup>1</sup>, Rajat Kumar<sup>1</sup>, Zeyad Al-Shaibani<sup>1</sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(428) "

Igor Novitzky-Basso1, Eshrak Al-Shaibani1, Mats Remberger2, Carol Chen1, Wilson Lam1, Arjun D. Law1, Ivan Pasic1, Fotios V. Michelis1, Auro Viswabandya1, Dennis D. Kim1, Jeffrey H. Lipton1, Armin Gerbitz1, Jonas Mattsson1, Rajat Kumar1, Zeyad Al-Shaibani1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(428) "

Igor Novitzky-Basso1, Eshrak Al-Shaibani1, Mats Remberger2, Carol Chen1, Wilson Lam1, Arjun D. Law1, Ivan Pasic1, Fotios V. Michelis1, Auro Viswabandya1, Dennis D. Kim1, Jeffrey H. Lipton1, Armin Gerbitz1, Jonas Mattsson1, Rajat Kumar1, Zeyad Al-Shaibani1

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27358" ["VALUE"]=> array(2) { ["TEXT"]=> string(2384) "<h3>Objectives</h3> <p style="text-align: justify;">Graft failure (GF) following allogeneic hematopoietic stem cell transplantation (allo-HCT) has a dismal prognosis. This study assessed incidence, risk factors (RF) and outcome of GF in a single-center population.</p> <h3>Patients and methods</h3> <p style="text-align: justify;">Between 2015-2018, 557 patients underwent allo-HCT. Primary GF (PGF) was defined as failure to achieve absolute neutrophil count (ANC) of >0.5×10<sup>9</sup>/L by 28 days after allo-HCT. Secondary GF (SGF) was characterized by loss of donor cells after initial engraftment with recurrence of ANC <0.5×10<sup>9</sup>/L without relapse or other causes of cytopenia. Endpoints of the study were cumulative incidence of GF and overall survival (OS). Risk factors for GF were assessed in multivariate analysis.</p> <h3>Results</h3> <p style="text-align: justify;">Nine patients had PGF, and 34 had SGF. The cumulative incidence of GF overall (primary and secondary) is 1.6% (CI95%; 0.8-3.0%) at day 100 and 6.5% (CI95%; 4.5-8.8%) at day 800 respectively. Multivariate analysis showed diagnosis (myelodysplastic syndrome [MDS], myelofibrosis [MF], lymphoma or non-malignant diseases) and donor type (HLA-mismatched-unrelated or haploidentical) were significantly associated with GF. For the absence of any of the risk factors (n=279), the incidence of GF was 3.6%. For the presence of one risk factor (n=229), the incidence of GF was 9.9%, while for 2 concurrent risk factors (n=49), the incidence of GF was 24.5% (p=0.002). Median OS of patients following PGF was 41 days, SGF – 144 days. The D100 OS in PGF was 22%, SGF – 64%; 2-year overall survival for SGF was 28%.</p> <h3>Conclusions</h3> <p style="text-align: justify;">This study showed increased risk of GF following mismatched-unrelated or haploidentical donor allo-HCT or for non-leukemia diagnosis, for which we suggest close monitoring for early diagnostic and therapeutic interventions, in order to improve clinical outcomes. </p> <h2>Keywords</h2> <p style="text-align: justify;">Allogeneic hematopoietic stem cell transplantation, graft failure, incidence, risk factors. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2184) "

Objectives

Graft failure (GF) following allogeneic hematopoietic stem cell transplantation (allo-HCT) has a dismal prognosis. This study assessed incidence, risk factors (RF) and outcome of GF in a single-center population.

Patients and methods

Between 2015-2018, 557 patients underwent allo-HCT. Primary GF (PGF) was defined as failure to achieve absolute neutrophil count (ANC) of >0.5×109/L by 28 days after allo-HCT. Secondary GF (SGF) was characterized by loss of donor cells after initial engraftment with recurrence of ANC <0.5×109/L without relapse or other causes of cytopenia. Endpoints of the study were cumulative incidence of GF and overall survival (OS). Risk factors for GF were assessed in multivariate analysis.

Results

Nine patients had PGF, and 34 had SGF. The cumulative incidence of GF overall (primary and secondary) is 1.6% (CI95%; 0.8-3.0%) at day 100 and 6.5% (CI95%; 4.5-8.8%) at day 800 respectively. Multivariate analysis showed diagnosis (myelodysplastic syndrome [MDS], myelofibrosis [MF], lymphoma or non-malignant diseases) and donor type (HLA-mismatched-unrelated or haploidentical) were significantly associated with GF. For the absence of any of the risk factors (n=279), the incidence of GF was 3.6%. For the presence of one risk factor (n=229), the incidence of GF was 9.9%, while for 2 concurrent risk factors (n=49), the incidence of GF was 24.5% (p=0.002). Median OS of patients following PGF was 41 days, SGF – 144 days. The D100 OS in PGF was 22%, SGF – 64%; 2-year overall survival for SGF was 28%.

Conclusions

This study showed increased risk of GF following mismatched-unrelated or haploidentical donor allo-HCT or for non-leukemia diagnosis, for which we suggest close monitoring for early diagnostic and therapeutic interventions, in order to improve clinical outcomes.

Keywords

Allogeneic hematopoietic stem cell transplantation, graft failure, incidence, risk factors.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2184) "

Objectives

Graft failure (GF) following allogeneic hematopoietic stem cell transplantation (allo-HCT) has a dismal prognosis. This study assessed incidence, risk factors (RF) and outcome of GF in a single-center population.

Patients and methods

Between 2015-2018, 557 patients underwent allo-HCT. Primary GF (PGF) was defined as failure to achieve absolute neutrophil count (ANC) of >0.5×109/L by 28 days after allo-HCT. Secondary GF (SGF) was characterized by loss of donor cells after initial engraftment with recurrence of ANC <0.5×109/L without relapse or other causes of cytopenia. Endpoints of the study were cumulative incidence of GF and overall survival (OS). Risk factors for GF were assessed in multivariate analysis.

Results

Nine patients had PGF, and 34 had SGF. The cumulative incidence of GF overall (primary and secondary) is 1.6% (CI95%; 0.8-3.0%) at day 100 and 6.5% (CI95%; 4.5-8.8%) at day 800 respectively. Multivariate analysis showed diagnosis (myelodysplastic syndrome [MDS], myelofibrosis [MF], lymphoma or non-malignant diseases) and donor type (HLA-mismatched-unrelated or haploidentical) were significantly associated with GF. For the absence of any of the risk factors (n=279), the incidence of GF was 3.6%. For the presence of one risk factor (n=229), the incidence of GF was 9.9%, while for 2 concurrent risk factors (n=49), the incidence of GF was 24.5% (p=0.002). Median OS of patients following PGF was 41 days, SGF – 144 days. The D100 OS in PGF was 22%, SGF – 64%; 2-year overall survival for SGF was 28%.

Conclusions

This study showed increased risk of GF following mismatched-unrelated or haploidentical donor allo-HCT or for non-leukemia diagnosis, for which we suggest close monitoring for early diagnostic and therapeutic interventions, in order to improve clinical outcomes.

Keywords

Allogeneic hematopoietic stem cell transplantation, graft failure, incidence, risk factors.

" } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27352" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-37-47" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-37-47" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-37-47" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27353" ["VALUE"]=> string(107) "Risk factors for graft failure in allogeneic hematopoietic stem cell transplantation: a single-center study" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(107) "Risk factors for graft failure in allogeneic hematopoietic stem cell transplantation: a single-center study" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(107) "Risk factors for graft failure in allogeneic hematopoietic stem cell transplantation: a single-center study" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27356" ["VALUE"]=> array(2) { ["TEXT"]=> string(721) "<p><sup>1</sup> Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada<br> <sup>2</sup> Department of Medical Sciences, Uppsala University and KFUE, Uppsala University Hospital, Uppsala, Sweden</p><br> <p><b>Correspondence</b><br> Igor Novitzky-Basso MD PhD, Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 610 University Avenue, Toronto, ON, M5G 2M9, Canada<br> Phone: +1 647 927 8700<br> Fax: +1 416 946 4407<br> E-mail: igor.novitzkybasso@uhn.ca</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(625) "

1 Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
2 Department of Medical Sciences, Uppsala University and KFUE, Uppsala University Hospital, Uppsala, Sweden


Correspondence
Igor Novitzky-Basso MD PhD, Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
Phone: +1 647 927 8700
Fax: +1 416 946 4407
E-mail: igor.novitzkybasso@uhn.ca

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(625) "

1 Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Canada
2 Department of Medical Sciences, Uppsala University and KFUE, Uppsala University Hospital, Uppsala, Sweden


Correspondence
Igor Novitzky-Basso MD PhD, Hans Messner Allogeneic Transplant Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, 610 University Avenue, Toronto, ON, M5G 2M9, Canada
Phone: +1 647 927 8700
Fax: +1 416 946 4407
E-mail: igor.novitzkybasso@uhn.ca

" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27349" ["VALUE"]=> array(2) { ["TEXT"]=> string(803) "<p>Игорь Новицки-Бассо<sup>1</sup>, Эшрак Аль-Шайбани<sup>1</sup>, Мата Рембергер<sup>2</sup>, Кэрол Чен<sup>1</sup>, Уилсон Лэм<sup>1</sup>, Арджун Д. Лоу<sup>1</sup>, Айвэн Пазич<sup>1</sup>, Фотиос В. Микелис<sup>1</sup>, Ауро Висвабандья<sup>1</sup>, Деннис Д. Ким<sup>1</sup>, Джеффри Х. Липтон<sup>1</sup>, Армин Гербитц<sup>1</sup>, Ионас Маттсон<sup>1</sup>, Раджат Кумар<sup>1</sup>, Зейяд Аль-Шайбани<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(611) "

Игорь Новицки-Бассо1, Эшрак Аль-Шайбани1, Мата Рембергер2, Кэрол Чен1, Уилсон Лэм1, Арджун Д. Лоу1, Айвэн Пазич1, Фотиос В. Микелис1, Ауро Висвабандья1, Деннис Д. Ким1, Джеффри Х. Липтон1, Армин Гербитц1, Ионас Маттсон1, Раджат Кумар1, Зейяд Аль-Шайбани1

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(611) "

Игорь Новицки-Бассо1, Эшрак Аль-Шайбани1, Мата Рембергер2, Кэрол Чен1, Уилсон Лэм1, Арджун Д. Лоу1, Айвэн Пазич1, Фотиос В. Микелис1, Ауро Висвабандья1, Деннис Д. Ким1, Джеффри Х. Липтон1, Армин Гербитц1, Ионас Маттсон1, Раджат Кумар1, Зейяд Аль-Шайбани1

" } ["SUBMITTED"]=> array(37) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27347" ["VALUE"]=> string(10) "22.09.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "22.09.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "22.09.2020" } ["ACCEPTED"]=> array(37) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27348" ["VALUE"]=> string(10) "04.12.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "04.12.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "04.12.2020" } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27351" ["VALUE"]=> array(2) { ["TEXT"]=> string(4106) "<h3>Цель работы</h3> <p style="text-align: justify;">Недостаточность трансплантата (НТ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК) имеет плохой прогноз. Целью данного исследования было установление частоты возникновения, факторов риска (Фри исходов НТ в контингенте из одного центра.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">В период с 2015 по 2018 гг., алло-ТГСК была выполнена у 557 больных. Первичную НТ (ПНТ) определяли как отсутствие роста абсолютного количества нейтрофилов (АКН) до >0.5×10<sup>9</sup>/л к 28 сут. после алло-ТГСК. Вторичную НТ (ВНТ) характеризовало снижение числа донорских клеток после начального приживления с возвратом КН к уровням <0.5×10<sup>9</sup>/л без рецидива или иных причин цитопении. Конечными результатами исследования была кумулятивная встречаемость НТ и общая выживаемость (ОВ); факторы риска НТ определяли путем многофакторного анализа.</p> <h3>Результаты</h3> <p style="text-align: justify;">В 9 случаях выявлена ПНТ, и у 34 больных была ВНТ. Кумулятивная встречаемость НТ была, соответственно, 1,6% ко дню +100 (CI95%; 0,8- 3,0%), и 6,5% – (CI95%; 4,5-8,8%) ко дню +800. Многофакторный анализ показал, что лиагноз (миелодиспластический синдром, миелофиброз, лимфома или неопухолевые заболевания), а также тип донора (HLA-несовместимый неродственный или гаплоидентичный) были достоверно ассоциированы с НТ. Частота НТ составила 3,6% при отсутствии указанных факторов риска, 9.9% при наличии одного ФР и 24.5% при двух ФР. Медиана выживаемости пациентов после ПНТ составила 41 сут., после ВНТ – 144 сут. Общая выживаемость на день +100 при ПНТ была 22%, при ВНТ – 64%. Двухлетняя общая выживаемость в случаях ВНТ была 28%.</p> <h3>Выводы</h3> <p style="text-align: justify;">Данное исследование показало наличие повышенного риска недостаточности трансплантата после алло-ТГСК от несовместимого/неродственного или гаплоидентичного донора, или при нелейкемическом диагнозе. Для таких случаев мы предлагаем тщательный мониторинг, ранние диагностические и терапевтические мероприятия и для улучшения клинических исходов. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Аллогенная трансплантация гемопоэтических стволовых клеток, недостаточность трансплантата, встречаемость, факторы риска. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3906) "

Цель работы

Недостаточность трансплантата (НТ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК) имеет плохой прогноз. Целью данного исследования было установление частоты возникновения, факторов риска (Фри исходов НТ в контингенте из одного центра.

Пациенты и методы

В период с 2015 по 2018 гг., алло-ТГСК была выполнена у 557 больных. Первичную НТ (ПНТ) определяли как отсутствие роста абсолютного количества нейтрофилов (АКН) до >0.5×109/л к 28 сут. после алло-ТГСК. Вторичную НТ (ВНТ) характеризовало снижение числа донорских клеток после начального приживления с возвратом КН к уровням <0.5×109/л без рецидива или иных причин цитопении. Конечными результатами исследования была кумулятивная встречаемость НТ и общая выживаемость (ОВ); факторы риска НТ определяли путем многофакторного анализа.

Результаты

В 9 случаях выявлена ПНТ, и у 34 больных была ВНТ. Кумулятивная встречаемость НТ была, соответственно, 1,6% ко дню +100 (CI95%; 0,8- 3,0%), и 6,5% – (CI95%; 4,5-8,8%) ко дню +800. Многофакторный анализ показал, что лиагноз (миелодиспластический синдром, миелофиброз, лимфома или неопухолевые заболевания), а также тип донора (HLA-несовместимый неродственный или гаплоидентичный) были достоверно ассоциированы с НТ. Частота НТ составила 3,6% при отсутствии указанных факторов риска, 9.9% при наличии одного ФР и 24.5% при двух ФР. Медиана выживаемости пациентов после ПНТ составила 41 сут., после ВНТ – 144 сут. Общая выживаемость на день +100 при ПНТ была 22%, при ВНТ – 64%. Двухлетняя общая выживаемость в случаях ВНТ была 28%.

Выводы

Данное исследование показало наличие повышенного риска недостаточности трансплантата после алло-ТГСК от несовместимого/неродственного или гаплоидентичного донора, или при нелейкемическом диагнозе. Для таких случаев мы предлагаем тщательный мониторинг, ранние диагностические и терапевтические мероприятия и для улучшения клинических исходов.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, недостаточность трансплантата, встречаемость, факторы риска.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3906) "

Цель работы

Недостаточность трансплантата (НТ) после аллогенной трансплантации гемопоэтических клеток (алло-ТГСК) имеет плохой прогноз. Целью данного исследования было установление частоты возникновения, факторов риска (Фри исходов НТ в контингенте из одного центра.

Пациенты и методы

В период с 2015 по 2018 гг., алло-ТГСК была выполнена у 557 больных. Первичную НТ (ПНТ) определяли как отсутствие роста абсолютного количества нейтрофилов (АКН) до >0.5×109/л к 28 сут. после алло-ТГСК. Вторичную НТ (ВНТ) характеризовало снижение числа донорских клеток после начального приживления с возвратом КН к уровням <0.5×109/л без рецидива или иных причин цитопении. Конечными результатами исследования была кумулятивная встречаемость НТ и общая выживаемость (ОВ); факторы риска НТ определяли путем многофакторного анализа.

Результаты

В 9 случаях выявлена ПНТ, и у 34 больных была ВНТ. Кумулятивная встречаемость НТ была, соответственно, 1,6% ко дню +100 (CI95%; 0,8- 3,0%), и 6,5% – (CI95%; 4,5-8,8%) ко дню +800. Многофакторный анализ показал, что лиагноз (миелодиспластический синдром, миелофиброз, лимфома или неопухолевые заболевания), а также тип донора (HLA-несовместимый неродственный или гаплоидентичный) были достоверно ассоциированы с НТ. Частота НТ составила 3,6% при отсутствии указанных факторов риска, 9.9% при наличии одного ФР и 24.5% при двух ФР. Медиана выживаемости пациентов после ПНТ составила 41 сут., после ВНТ – 144 сут. Общая выживаемость на день +100 при ПНТ была 22%, при ВНТ – 64%. Двухлетняя общая выживаемость в случаях ВНТ была 28%.

Выводы

Данное исследование показало наличие повышенного риска недостаточности трансплантата после алло-ТГСК от несовместимого/неродственного или гаплоидентичного донора, или при нелейкемическом диагнозе. Для таких случаев мы предлагаем тщательный мониторинг, ранние диагностические и терапевтические мероприятия и для улучшения клинических исходов.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, недостаточность трансплантата, встречаемость, факторы риска.

" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27350" ["VALUE"]=> array(2) { ["TEXT"]=> string(585) "<p><sup>1</sup> Программа аллогенных трансплантаций Ханса Месснера, Онкологический Центр принцессы Маргарет, университетская сеть здравоохранения, Университет Торонто, Торонто, Канада<br> <sup>2</sup> Департамент медицинских наук, университет Уппсала, университетский госпиталь Уппсала, Уппсала, Швеция</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(543) "

1 Программа аллогенных трансплантаций Ханса Месснера, Онкологический Центр принцессы Маргарет, университетская сеть здравоохранения, Университет Торонто, Торонто, Канада
2 Департамент медицинских наук, университет Уппсала, университетский госпиталь Уппсала, Уппсала, Швеция

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(543) "

1 Программа аллогенных трансплантаций Ханса Месснера, Онкологический Центр принцессы Маргарет, университетская сеть здравоохранения, Университет Торонто, Торонто, Канада
2 Департамент медицинских наук, университет Уппсала, университетский госпиталь Уппсала, Уппсала, Швеция

" } } } [6]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(3) "170" ["~IBLOCK_SECTION_ID"]=> string(3) "170" ["ID"]=> string(4) "1938" ["~ID"]=> string(4) "1938" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["~NAME"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "05.02.2021 11:16:38" ["~TIMESTAMP_X"]=> string(19) "05.02.2021 11:16:38" ["DETAIL_PAGE_URL"]=> string(138) "/ru/archive/-9-4/klinicheskie-raboty/klinicheskie-iskhody-u-patsientov-s-khronicheskim-mieloidnym-leykozom-prodvinutykh-stadiy-pri-alloge/" ["~DETAIL_PAGE_URL"]=> string(138) "/ru/archive/-9-4/klinicheskie-raboty/klinicheskie-iskhody-u-patsientov-s-khronicheskim-mieloidnym-leykozom-prodvinutykh-stadiy-pri-alloge/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(32457) "

Introduction

The cases of chronic myeloid leukemia (CML) in acceleration phase (AP) and blast crisis (BC) are still associated with very unfavorable prognosis. Introduction of low-molecular BCR/ABL1 inhibitors into clinical practice has caused a decrease in BC incidence from 1.5-3.7% to 0.3-2.2% per year [1].

The median overall survival (OS) in untreated patients with BC CML does not exceed 3-6 months. The results of conservative treatment approach with chemotherapy and tyrosine kinase inhibitors (TKIs) are also unsatisfactory. The median OS in patients with BC is about 12 months [2]. According to ELN and NCCN guidelines, the evolving AP or BCs upon TKIs therapy are indications for allogeneic hemopoietic stem cell transplantation (allo-HSCT). The latter represents the only curative option for some CML patients. Starting from 2004, the cohort of allo-HSCT recipients shifted significantly from the 1st chronic phase to TKIs non-responders and initially advanced-stage CML [3-5].

The CML evolution to BC is characterized by rather distinct biological features, which make it quite different from chronic phase [6]. These differences are evident not only in such characteristics as cellular proliferation, differentiation and apoptosis, but also in clinical course and therapy response rate which is associated with clonal evolution [6].

However, according to EBMT data, the long-term prognosis for patients transplanted in BC is still unfavorable [7]. The status at the time of allo-HSCT is still one of the most important prognostic factors along with donor HLA-compatibility, disease duration, and recipient’s age [7].

According to the data by Khoury et al. the 3-year event-free survival (EFS) for patients transplanted in BC and AP is 8-11% and 26-27%, accordingly [8]. Also, in 40% of cases patients died of disease progression.

The aim of our retrospective study was to compare two patient’s cohorts receiving allo-HSCT or conservative TKI therpy in order to evaluate the therapeutic approaches that provide a survival advantage.

Patients and methods

Clinical characteristics

A total of 162 patients with CML, who had AP or BC were included in this retrospective study. All the patients included into the study were under the age of 62 years without severe cardiac, pulmonary, renal, and other comorbidities. A cohort of 82 patients received TKIs and allo-HSCT (allo-HSCT+TKI) in RM Gorbacheva Research Institute, Pavlov University since 2002 to 2019. Moreover, eighty patients received only TKIs or their combination with chemotherapy according to acute leukemia protocol, as reported elsewhere [9]. TKIs were given according to ELN recommendations [9]. The patients in TKI group did not proceed to allo-HSCT due to lack of potential stem cell donor, due to refusal for personal reasons, or delay in referral to transplant center.

The CML diagnosis was based on clinical criteria and presence of Philadelphia (Ph) chromosome and/or chimeric BCR-ABL gene [15]. The disease stage was established according to the WHO criteria [9]. Hematological, cytogenetic and molecular responses were evaluated in compliance with ELN criteria [9]. Molecular response after allo-HSCT was evaluated according to the NCCN criteria. PCR monitoring of BCR/ABL was carried out according to NCCN recommendations once in 3 months for 2 years, then once in every 3 to 6 months. Cytogenetic investigation of bone marrow was performed according to a standard procedure with at least 20 metaphases analyzed per a sample (GTG method). The karyotype was evaluated according to International System for Human Cytogenetic Nomenclature (ISCN) [10]. In cases when the standard cytogenetic investigation was not available (insufficient material), the bone marrow was assessed by fluorescence in situ hybridization (FISH) probes aiming for detection of (9;22) variants (LSI BCR-ABL , Dual Color, Dual Fusion, "Vysis").

The relative BCR-ABL1 expression level was evaluated according to method described by Gabert et al [11]. The approach consists of the following stages: 1) total RNA extraction from peripheral blood of patients with CML, 2) reverse transcription with random hexameric primers, 3) real-time PCR with primers and probes specific to р210, р190 control ABL gene sequences. Assessment of relative expression levels is based on evaluation of BCR-ABL1/ABL1 ratios in the studied cDNA samples. The ABL1 gene was used for normalization of the results. In order to determine copy numbers of the BCR-ABL1 and ABL1 transcripts, and to assess the reaction effectiveness, standard dilution curves were plotted using a plasmid with inserts of known target gene sequences (Invitrogen, USA), at a standard concentration ranges of 102-106 copies/mcl, according to 2020 European LeukemiaNet (ELN) Recommendations [9] [12].

Treatment options

The conditioning regimen included fludarabine (180 mg/m2) and busulfan (8-12 mg/kg), or 140 mg/m2 of melphalan. Fifty-four patients (66%) received post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GvHD) prophylaxis. The PTCy was given at 50 mg/kg on D +3 and +4 after allo-HSCT 5 mg/kg of rabbit antithymocyte globulin (n=3) in combination with tacrolimus (target concentration of 5-10 ng/ml) from D+5 to D+120, and 30 mg/kg of mycophenolate mofetil (MMF) from D+5 to D+30, or 60 mg/kg of horse (n=12), or 5 mg/kg of rabbit antithymocyte globulin (n=3) in combination with tacrolimus (target concentration, 5-10 ng/ml) from D-1 to D+120, and 30 mg/kg of MMF from D-1 to D+30. If allo-HSCT was performed from matched related donor, the GvHD prophylaxis consisted of tacrolimus (target concentration of 5-10 ng/ml) from D-1 to D+120, 30 mg/kg of MMF rom D-1 to D+30, 15 mg/m2 of methotrexate on D+1, and 10 mg/m2 of methotrexate on D+3 and D+6.

The acute and chronic GvHD stage was assessed according to the common Glucksberg criteria [13], and NIH criteria [14]. The engraftment was confirmed in patients with WBC count >1 × 109/l, neutrophils of > 0.5 × 109/l without granulocyte colony stimulating factor support for 3 days, platelets count of > 20 × 109/l for 3 days. The primary non-engraftment was diagnosed, if no complete donor chimerism was observed on D+40. The comorbidity index was determined according to the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) [15]. The allo-HSCT associated risk was evaluated in accordance with the Group for Blood and Marrow Transplantation Scale [7]. The immunosuppression was ceased, If there was a disease relapse, followed by donor lymphocyte infusions and/or TKIs were given as described before [16].

The TKIs were given in the post-transplant period to prevent relapses, or in cases of persistent BCR-ABL transcription as shown by PCR. TKIs were given if the neutrophil counts exceeded 0.5×109/l, or at platelet counts of > 50×109/l on D+60. The TKI choice was based on resistance pattern or history of intolerability. In 86% of cases, the patients were given 2nd generation TKI dasatinib, since it proved to be more effective in BC, and is able to penetrate the blood-brain barrier [17]. All the patients signed an informed consent for processing of personal data; the trial was approved by the Pavlov University Local Ethical Committee.

Evaluation of results in TKI and TKI+ allo-HSCT groups

The overall survival (OS) was estimated as a period from treatment initiation of allo-HSCT until death by any cause, or till last contact date. The event-free survival (EFS) was estimated as a period from treatment initiation of allo-HSCT until death, last contact date, or any of the following events: failure to obtain hematological response within 3 months, loss of previously achieved complete molecular response (CMR), complete cytogenetic response (CCR), or complete hematological response (CHR), post-transplant molecular relapse. Post-transplant relapse was diagnosed in case of two consecutive positive PCR assays or at least 1-log persistent increase of BCR/ABL transcript level. If patient received a second allo-HSCT due to primary non-engraftment or a relapse, the survival terms were dated back from second allo-HSCT.

Statistical analysis

The standard SPSS, IBM Statistics and R 1.41 software was used for statistical evaluation. The quantitative attributes of groups were compared using Mann-Whitney U-test. The qualitative attributes were compared by Chi-square test, Fisher’s exact test. Survival charts were plotted using Kaplan-Meier method. The statistical significance of differences evaluated via Kaplan-Meier test was checked by Log-rank test, the differences at р <0.05 were considered statistically significant. The cumulative risk of non relapse-related mortality was evaluated as competing risk.

Results

A total of 162 patients with advanced CML were included into the study. In 82 cases, the allo-HSCT was performed. The remaining 80 patients received only TKIs or TKIs in combination with chemotherapy. The median follow-up was 44 (1 to 344) months. There were no significant differences in gender, age, somatic status, disease phase or presence of additional chromosomal aberrations (ACAs) between allo-HSCT and TKI groups (see Tab. 1). The number of patient with BC was higher in allo-HSCT group compared to TKI group, i.e., 28% versus 12%. At the same time, non-transplanted patients were more likely to receive 3rd line of TKIs than allo-HSCT group (37% versus 18%) as seen from Table 1.

Table 1. Characteristics of patient groups receiving allo-HSCT or TKIs

Morozova-tab01-01.jpg Morozova-tab01-02.jpg Morozova-tab01-03.jpg

Therapy and clinical response prior to allo-HSCT

A total of 82 patients received allo-HSCT. In 48% of cases, the disease was initially in CP, and it progressed later to more advanced stage (AC or BC). 52% of the cases had an advanced-stage disease at diagnosis. The median time span from diagnosis to allo-HSCT was 2.2 (0.3-21.4) years. Most patients received chemotherapy in combination with TKIs, 37% of patients was administered only TKIs. All but two patients, who received allo-HSCT in 2002, had previous history of TKI treatment. Most patients (61%) had 2 or 3 lines of TKIs, with imatinib, dasatinib or nilotinib used. Only seven patients received bosutinib and two patients received ponatinib.

Patients in CP at diagnosis

A total of 29 (74%) of patients who were initially in CP, later developed BC. In 17 cases, a 2nd CP was achieved prior to allo-HSCT. Six patients were subjected to allo-HSCT in AP, six patients did not respond to therapy and underwent allo-HSCT in BC. In ten patients, the AP developed, and it persisted until allo-HSCT.

Patients in AP at diagnosis

A total of 20 patients had AP at diagnosis, ten of them subsequently developed blast crisis (BC). In six cases, the CP was achieved after TKI + chemotherapy (n=4) or TKI treatment (n=2); two patients were in AP after TKI + chemotherapy, and two patients still had BC after TKI + chemotherapy (n=1) or TKI only (n=1) at the moment of allo-HSCT. The remaining 10 patients had no history of BC. Six of them subsequently achieved CP, four patients were still in AP at the moment of allo-HSCT.

Patients with BC at diagnosis

A total of 23 patients had BC at the time of diagnosis. In 20 cases, a subsequent chronic phase was achieved after TKI + chemotherapy (n=17) or TKI therapy (n=3), in one case, AP was documented after TKI therapy, and two patients were still in BC after TKI + chemotherapy (n=2) at the moment of allo-HSCT.

Morozova-fig01.jpg

Figure 1. Cumulative 2-year relapse rate and 1-year non-relapse mortality after allo-HSCT.

Abbreviations: NRM, non-relapse mortality

Engraftment, causes of death and non-relapse mortality

Post-transplant engraftment was achieved in 71 (86%) patients. The median time to WBC engraftment was 22 (8 to 39) days, median time to the neutrophil engraftment was 22 (8 to 35) days. Median time to the platelet engraftment was 19 (6 to 57) days. In 9 cases of primary non-engraftment, the 2nd allo-HSCT was performed. The median follow-up was 35 (1 to 161) months.

Thirty-two patients died after allo-HSCT. The most common causes of death were relapse (n=16, 50%); GvHD (n=8, 25%); infectious complications (n=5, 16%); heart failure (n=2, 6%); hepatic veno-occlusive disease (n=1, 3%). One-year NRM was 18% (95% CI 10-28%), 100-day NRM 10% (95% CI 5-18%), as shown in Fig. 1.

Also, 48 (58%) patients received TKIs after allo-HSCT, 45 (88%) of them as relapse prophylaxis. 28 patients did not develop subsequent relapses. Two patients received bosutinib, 36 dasatinib, 8 nilotinib, and 2 ponatinib.

In 31 cases (38%), a relapse was developed, 16 of patients who relapsed received TKI prophylaxis. The cumulative relapse incidence was 39% (95% CI 28-51%). In 11 patients (34%), molecular relapse was shown; in one case, cytogenetic (3%), and in 19 cases (63%), hematological relapses were documented. Six patients received donor lymphocyte infusions (DLIs) for relapse treatment, five subjects received only TKIs; TKIs, chemotherapy and DLI were used in four cases; TKIs and DLIs were applied in 15 patients, and a combination of DLI and chemotherapy was used in one case. In 29% of the cases (n=9), the patients had durable molecular response, in 61% (n=19), the disease progression. Evaluation of therapeutic response was impossible for 10% of the patients. DLI was performed in the remaining six 6 cases, due to primary non-engraftment or poor graft function post-transplant. In three cases, DLIs were carried out due to persisting BCR/ABL transcript.

The incidence of grade 2-4 acute GvHD was 29% (n=21), grade 3-4 acute GvHD was registered in 20% (n=14). Chronic GvHD (cGvHD) incidence was 27% (n=18), having been mild in 6 cases (9%). Moderate cGvHD was observed in 8 cases (12%), and four patients (6%) developed severe cGvHD.

Patients who received only TKIs

A cohort of 80 patients received only TKIs, or their combination with chemotherapy. The median follow-up was 93 (13-344) months. The data on outcomes was available for 71 patients. Among the patients with BC, 36 (59%) did not respond to therapy, in 22 cases (34%) CHR was documented, in one case (2%) complete cytogenetic response (CCR) was revealed, and a complete molecular response (CMR) was achieved in two cases (3%). Among 10 patients without history of BC, one patient did not respond, 5 achieved CHR; 2 patients developed CCR, and CMR was registered in 2 cases. Sixty-nine patients died, more than half of them deceased due to disease progression/relapse.

Morozova-fig02.jpg

Figure 2. Four-year OS for allo-HSCT+TKIs and TKIs groups (А), and four-year EFS for allo-HSCT+TKIs and TKIs groups (B)

Abbreviations: allo-HSCT, allogeneic hematopoietic stem cell transplantation; TKI, tyrosine kinase inhibitor

Morozova-fig03.jpg

Figure 3. Four-year OS for patients treated in BC who received allo-HSCT+TKIs in CP≥2/AP+TKI, TKIs, and allo- HSCT in BC

Abbreviations: allo-HSCT, allogeneic hematopoietic stem cell transplantation; CP≥2, chronic phase; AP, acceleration phase; TKI, therapy with tyrosine kinase inhibitors; allo-HSCT in BC +TKI, allogeneic hematopoietic stem cell transplantation in blast crisis

Comparisons between allo-HSCT+TKIs and TKIs groups

The CML patients who received allo-HSCT exhibited significantly better 4-year OS compared to the TKI-treated group, i.e., 58% (95% CI 44%-69%) versus 33% (95% CI 23-44%), accordingly (р=0.032), as shown in Fig. 2А). At the same time, no statistically significant differences were found between the 4-year EFS, which was 35% (95% CI 24%-47%) in allo-HSCT, and 17% (95% CI 10%-26%) in TKIs group (р=0.5) (Fig. 2B). Also, there was no statistically significant difference between the 4-year OS receiving allo-HSCT in BC CML. This value was 33% for TKIs group (95% CI 23%-44%), and 23% for allo-HSCT patients (95% CI 3-52%) (р=0.217). However, the 4-year OS reached 63% (95% CI 48%-74%) for the patients transplanted in AP or CP after TKIs therapy, which is significantly better compared to other groups (р=0.005) (Fig. 3).

Discussion

In our study, we compared therapy results for advanced-phase patients with CML who received TKIs with or without allo- HSCT. In allo-HSCT group, the 4-year OS was significantly longer if compared to patients, who were not transplanted (58% versus 33%, accordingly). The 4-year EFS was also longer in allo-HSCT group (35% versus 17%, accordingly), although without statistical significance in this case.

One should note that the relapse rate in allotransplanted patients is still as high as 39%. However, CML is one of the most immunotherapy-responsive malignancies. Kolb et al. have first shown clinical success of DLIs in allo-HSCT recipients with CML [18]. Moreover, development of acute or chronic GvHD was more important for CML patients as a factor able to decrease relapse rate compared to patients with AML, MDS or plasma cell disorders [19, 20].

This may be a reason for higher OS in allo-HSCT group, while EFS rates have not differed significantly. As many relapses were sensitive to immune therapy, they were not invariably fatal, and many patients responded to post-transplant therapy. In our study, 29% of the patients achieved durable CMR upon DLI-containing treatment. However, usage of this method may be limited due to the risk of GvHD, since grade 2-4 acute GVHD develops in 15%, and chronic GvHD occurs in 22% of patients [21]. Donor lymphocyte infusions should not be performed in patients with a history of chronic GvHD. Moreover, donor cells are not available in some cases.

Efficiency of donor lymphocyte infusions depends on many factors. The study by Basak et al. in patients with CML has shown that PBSCs as graft source worsen the long-term OS among DLI recipients. The authors note that there were more patients with advanced stages in PBSC group, and suppose a connection between worse DLI effect and immune response attenuation due to lower immunogenicity of malignant cells in advanced stage patients [22]. Early CML relapse is another potentially negative factor making DLIs less effective [22].

The response to DLI may depend on the type of relapse. In this study we performed DLI for 26 patients who usually presented with hematological relapses. In a study by Radujkovic et al., this method was more effective in treatment of patients with molecular or cytogenetic, but not hematologic relapses. Five-year relapse and GvHD-free survival in patients with cytogenetic and hematological relapses was 40% and 20%, accordingly [22]. In our study, more than a half of relapsed patients developed hematological relapse, which may be a reason for lower response rate observed.

Prophylactic use of TKIs may exert important influence on the allo-HSCT outcomes. The relapses developed only in 38% of HSCT recipients after TKI-based prophylaxis. However, the actual role of prophylactic interventions is yet not quite clear. The largest patient cohort described by DeFilipp et al. included 89 patients [23]. The authors have not found significant differences in OS, which was 61% in recipients with post-transplant TKI prophylaxis versus 57% in the patients without such prophylaxis, and EFS was 42% versus 44%, accordingly (all differences not statistically significant). Hence, the results of our retrospective study may suggest whether prophylactic TKIs improve allo-HSCT results.

Some studies have compared the results of allo-HSCT and TKIs with or without chemotherapy in advanced-stage CML patients. Worth of note, the 1st line therapy was performed in most of these reports. In our study, however, nearly half of patients in each group received 2nd line TKIs; 38% in TKIs and 20% in allo-HSCT+TKIs group received 3 or more lines of TKIs. Allo-HSCT was not performed, due to the lack of potential donor or failure to sign an informed consent. Therefore, the non-transplant group was more likely to receive 3rd line TKIs than the allo-HSCT group. In study by Jiang et al., the results of TKIs with or without allo-HSCT were evaluated in 83 patients with CML BC. The allo-HSCT proved to be advantageous in 4-year OS compared to other treatment modalities, with OS of 46.7% versus 9.7%, and EFS of 47.1% versus 6.7%, accordingly [24]. Jiang et al. analyzed imatinib therapy results compared with allo-HSCT in 132 AP CML cases and found survival advantage for allo-HSCT compared to TKI group [25], with 5-year OS of 100% versus 18% and EFS 67% versus 9%, accordingly. Jain et al. had analyzed survival rates from the moment of BC diagnosis in a group including 104 allo-HSCT recipients and demonstrated that allo-HSCT decreases risk of death [2].

Allo-HSCT in patients with BC lead to the same results as other treatment options, with 4-year OS of 33% and 23% in TKIs and allo-HSCT groups, respectively. It corresponds to the published data from some other studies [24, 26, 27, 28], which makes us to recommend preferential usage of this approach in the patients with therapy-resistant disease.

Of course, the retrospective nature of our study urges us to be cautious for interpretation of its results. Meanwhile, we compared here extensive groups without showing statistically significant differences for the main clinical characteristics that could influence the CML outcomes.

Conclusions

This study has shown allo-HSCT still to be a curative method in many patients with AP and BC of CML in the presence of new-generation TKIs. However, the relapses are probable even after allo-HSCT. Due to good response to immune therapy in CML patients, a long-term remission and even curation may be achieved even after relapse of malignancy following allo-HSCT.

Tyrosine kinase inhibitors may be used as additional method for relapse therapy and prophylaxis. Performing allo-HSCT in patients with BC without achievement of hematological response does not lead to significantly better outcome. The indications for allo-HSCT should be discussed individually for each patient.

Ackhowledgements

No conflicts of interest reported.

References

  1. Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia 2017;31:2398-2406.
  2. Jain P, Kantarjian HM, Ghorab A, Sasaki K, Jabbour EJ, Nogueras Gonzalez G, et al. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer 2017;123:4391-4402.
  3. Bacher U, Klyuchnikov E, Zabelina T, Ottinger H, Beelen DW, Schrezenmeier H, et al. The changing scene of allogeneic stem cell transplantation for chronic myeloid leukemia – A report from the German Registry covering the period from 1998 to 2004. Ann Hematol 2009;88:1237-1247.
  4. Morozova E, Barabanshchikova M, Mamaev N, Barkhatov I, Alyanskii A, Darskaya E, et al. Chronic myeloid leukemia: Role of allogeneic hematopoietic stem cell transplantation in the era of tyrosine kinase inhibitors. Clin Oncohematology 2020;13:193-198 In Russian).
  5. Saussele S, Lauseker M, Gratwohl A, Beelen DW, Bunjes D, Schwerdtfeger R, et al. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: Evaluation of its impact within a subgroup of the randomized German CML study IV. Blood 2010;115:1880-1885.
  6. Calabretta B, Perrotti D. Review in translational hematology The biology of CML blast crisis. Blood 2004;103:4010-4022.
  7. Gratwohl A. The EBMT risk score. Bone Marrow Transplant 2012;47:749-756.
  8. Khoury HJ, Kukreja M, Goldman JM, Wang T, Halter J, Arora M, et al. Prognostic factors for outcomes in allogeneic transplantation for CML in the imatinib era: A CIBMTR analysis. Bone Marrow Transplant 2012;47:810-816.
  9. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 2020;34:966-984.
  10. Simons A, Shaffer LG, Hastings RJ. Cytogenetic Nomenclature: Changes in the ISCN 2013 Compared to the 2009 Edition. Cytogenet Genome Res 2013;141:1-6.
  11. Gabert J, Beillard E, van der Velden VHJ, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of "real time" quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program. Leukemia 2003;17:2318-2357.
  12. Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: Recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011;118:1208-1215.
  13. Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Jean Henslee‐Downey P, et al. IBMTR Severity index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997;97:855-864.
  14. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.e1.
  15. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: A new tool for risk assessment before allogeneic HCT. Blood 2005;106:2912-2919.
  16. Radujkovic A, Guglielmi C, Bergantini S, Iacobelli S, van Biezen A, Milojkovic D, et al. Donor lymphocyte infusions for chronic myeloid leukemia relapsing after allogeneic stem cell transplantation: May we predict graft-versus-leukemia without graft-versus-host disease? Biol Blood Marrow Transplant 2015;21:1230-1236.
  17. Porkka K, Koskenvesa P, Lundán T, Rimpiläinen J, Mustjoki S, Smykla R, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia. Blood 2008;112:1005-1012.
  18. Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990;76:2462-2465.
  19. Stern M, de Wreede LC, Brand R, van Biezen A, Dreger P, Mohty M, et al. Impact of graft-versus-host disease on relapse after allogeneic hematopoietic stem cell transplantation, an EBMT Megafile Study. Blood 2012;120:469-469.
  20. Oyekunle AA, Kröger N, Zabelina T, Ayuk F, Schieder H, Renges H, et al. Allogeneic stem-cell transplantation in patients with refractory acute leukemia: A long-term follow-up. Bone Marrow Transplant 2006;37:45-50.
  21. Chalandon Y, Passweg JR, Guglielmi C, Iacobelli S, Apperley J, Schaap NPM, et al. Early administration of donor lymphocyte infusions upon molecular relapse after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia: A study by the chronic malignancies working party of the EBMT. Haematologica 2014;99:1492-1498.
  22. Basak GW, De Wreede LC, Van Biezen A, Wiktor-Jedrzejczak W, Halaburda K, Schmid C, et al. Donor lymphocyte infusions for the treatment of chronic myeloid leukemia relapse following peripheral blood or bone marrow stem cell transplantation. Bone Marrow Transplant 2013;48:837-842.
  23. DeFilipp Z, Ancheta R, Liu Y, Hu ZH, Gale RP, Snyder D, et al. Maintenance tyrosine kinase inhibitors following allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia: A center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant 2020;26:472-479.
  24. Jiang H, Xu LP, Liu DH, Liu KY, Chen SS, Jiang B, et al. Allogeneic hematopoietic SCT in combination with tyrosine kinase inhibitor treatment compared with TKI treatment alone in CML blast crisis. Bone Marrow Transplant 2014;49:1146-1154.
  25. Jiang Q, Xu LP, Liu DH, Liu KY, Chen SS, Jiang B, et al. Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. Blood 2011;117:3032-3040.
  26. Gratwohl A, Pfirrmann M, Zander A, Kröger N, Beelen D, Novotny J, et al. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: A randomized comparison of stem cell transplantation with drug treatment. Leukemia 2016;30:562-569.
  27. Radujkovic A, Dietrich S, Blok H-J, Nagler A, Ayuk F, Finke J, et al. Allogeneic stem cell transplantation for blast crisis chronic myeloid leukemia in the era of tyrosine kinase inhibitors: A retrospective study by the EBMT Chronic Malignancies Working Party. Biol Blood Marrow Transplant 2019;25:2008-2016.
  28. Hehlmann R. The new ELN Recommendations for treating CML. Early transplantation in patients with high-risk ACA. Cell Ther Transplant. 2020; 9(4): 11-19.

" ["~DETAIL_TEXT"]=> string(32457) "

Introduction

The cases of chronic myeloid leukemia (CML) in acceleration phase (AP) and blast crisis (BC) are still associated with very unfavorable prognosis. Introduction of low-molecular BCR/ABL1 inhibitors into clinical practice has caused a decrease in BC incidence from 1.5-3.7% to 0.3-2.2% per year [1].

The median overall survival (OS) in untreated patients with BC CML does not exceed 3-6 months. The results of conservative treatment approach with chemotherapy and tyrosine kinase inhibitors (TKIs) are also unsatisfactory. The median OS in patients with BC is about 12 months [2]. According to ELN and NCCN guidelines, the evolving AP or BCs upon TKIs therapy are indications for allogeneic hemopoietic stem cell transplantation (allo-HSCT). The latter represents the only curative option for some CML patients. Starting from 2004, the cohort of allo-HSCT recipients shifted significantly from the 1st chronic phase to TKIs non-responders and initially advanced-stage CML [3-5].

The CML evolution to BC is characterized by rather distinct biological features, which make it quite different from chronic phase [6]. These differences are evident not only in such characteristics as cellular proliferation, differentiation and apoptosis, but also in clinical course and therapy response rate which is associated with clonal evolution [6].

However, according to EBMT data, the long-term prognosis for patients transplanted in BC is still unfavorable [7]. The status at the time of allo-HSCT is still one of the most important prognostic factors along with donor HLA-compatibility, disease duration, and recipient’s age [7].

According to the data by Khoury et al. the 3-year event-free survival (EFS) for patients transplanted in BC and AP is 8-11% and 26-27%, accordingly [8]. Also, in 40% of cases patients died of disease progression.

The aim of our retrospective study was to compare two patient’s cohorts receiving allo-HSCT or conservative TKI therpy in order to evaluate the therapeutic approaches that provide a survival advantage.

Patients and methods

Clinical characteristics

A total of 162 patients with CML, who had AP or BC were included in this retrospective study. All the patients included into the study were under the age of 62 years without severe cardiac, pulmonary, renal, and other comorbidities. A cohort of 82 patients received TKIs and allo-HSCT (allo-HSCT+TKI) in RM Gorbacheva Research Institute, Pavlov University since 2002 to 2019. Moreover, eighty patients received only TKIs or their combination with chemotherapy according to acute leukemia protocol, as reported elsewhere [9]. TKIs were given according to ELN recommendations [9]. The patients in TKI group did not proceed to allo-HSCT due to lack of potential stem cell donor, due to refusal for personal reasons, or delay in referral to transplant center.

The CML diagnosis was based on clinical criteria and presence of Philadelphia (Ph) chromosome and/or chimeric BCR-ABL gene [15]. The disease stage was established according to the WHO criteria [9]. Hematological, cytogenetic and molecular responses were evaluated in compliance with ELN criteria [9]. Molecular response after allo-HSCT was evaluated according to the NCCN criteria. PCR monitoring of BCR/ABL was carried out according to NCCN recommendations once in 3 months for 2 years, then once in every 3 to 6 months. Cytogenetic investigation of bone marrow was performed according to a standard procedure with at least 20 metaphases analyzed per a sample (GTG method). The karyotype was evaluated according to International System for Human Cytogenetic Nomenclature (ISCN) [10]. In cases when the standard cytogenetic investigation was not available (insufficient material), the bone marrow was assessed by fluorescence in situ hybridization (FISH) probes aiming for detection of (9;22) variants (LSI BCR-ABL , Dual Color, Dual Fusion, "Vysis").

The relative BCR-ABL1 expression level was evaluated according to method described by Gabert et al [11]. The approach consists of the following stages: 1) total RNA extraction from peripheral blood of patients with CML, 2) reverse transcription with random hexameric primers, 3) real-time PCR with primers and probes specific to р210, р190 control ABL gene sequences. Assessment of relative expression levels is based on evaluation of BCR-ABL1/ABL1 ratios in the studied cDNA samples. The ABL1 gene was used for normalization of the results. In order to determine copy numbers of the BCR-ABL1 and ABL1 transcripts, and to assess the reaction effectiveness, standard dilution curves were plotted using a plasmid with inserts of known target gene sequences (Invitrogen, USA), at a standard concentration ranges of 102-106 copies/mcl, according to 2020 European LeukemiaNet (ELN) Recommendations [9] [12].

Treatment options

The conditioning regimen included fludarabine (180 mg/m2) and busulfan (8-12 mg/kg), or 140 mg/m2 of melphalan. Fifty-four patients (66%) received post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GvHD) prophylaxis. The PTCy was given at 50 mg/kg on D +3 and +4 after allo-HSCT 5 mg/kg of rabbit antithymocyte globulin (n=3) in combination with tacrolimus (target concentration of 5-10 ng/ml) from D+5 to D+120, and 30 mg/kg of mycophenolate mofetil (MMF) from D+5 to D+30, or 60 mg/kg of horse (n=12), or 5 mg/kg of rabbit antithymocyte globulin (n=3) in combination with tacrolimus (target concentration, 5-10 ng/ml) from D-1 to D+120, and 30 mg/kg of MMF from D-1 to D+30. If allo-HSCT was performed from matched related donor, the GvHD prophylaxis consisted of tacrolimus (target concentration of 5-10 ng/ml) from D-1 to D+120, 30 mg/kg of MMF rom D-1 to D+30, 15 mg/m2 of methotrexate on D+1, and 10 mg/m2 of methotrexate on D+3 and D+6.

The acute and chronic GvHD stage was assessed according to the common Glucksberg criteria [13], and NIH criteria [14]. The engraftment was confirmed in patients with WBC count >1 × 109/l, neutrophils of > 0.5 × 109/l without granulocyte colony stimulating factor support for 3 days, platelets count of > 20 × 109/l for 3 days. The primary non-engraftment was diagnosed, if no complete donor chimerism was observed on D+40. The comorbidity index was determined according to the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) [15]. The allo-HSCT associated risk was evaluated in accordance with the Group for Blood and Marrow Transplantation Scale [7]. The immunosuppression was ceased, If there was a disease relapse, followed by donor lymphocyte infusions and/or TKIs were given as described before [16].

The TKIs were given in the post-transplant period to prevent relapses, or in cases of persistent BCR-ABL transcription as shown by PCR. TKIs were given if the neutrophil counts exceeded 0.5×109/l, or at platelet counts of > 50×109/l on D+60. The TKI choice was based on resistance pattern or history of intolerability. In 86% of cases, the patients were given 2nd generation TKI dasatinib, since it proved to be more effective in BC, and is able to penetrate the blood-brain barrier [17]. All the patients signed an informed consent for processing of personal data; the trial was approved by the Pavlov University Local Ethical Committee.

Evaluation of results in TKI and TKI+ allo-HSCT groups

The overall survival (OS) was estimated as a period from treatment initiation of allo-HSCT until death by any cause, or till last contact date. The event-free survival (EFS) was estimated as a period from treatment initiation of allo-HSCT until death, last contact date, or any of the following events: failure to obtain hematological response within 3 months, loss of previously achieved complete molecular response (CMR), complete cytogenetic response (CCR), or complete hematological response (CHR), post-transplant molecular relapse. Post-transplant relapse was diagnosed in case of two consecutive positive PCR assays or at least 1-log persistent increase of BCR/ABL transcript level. If patient received a second allo-HSCT due to primary non-engraftment or a relapse, the survival terms were dated back from second allo-HSCT.

Statistical analysis

The standard SPSS, IBM Statistics and R 1.41 software was used for statistical evaluation. The quantitative attributes of groups were compared using Mann-Whitney U-test. The qualitative attributes were compared by Chi-square test, Fisher’s exact test. Survival charts were plotted using Kaplan-Meier method. The statistical significance of differences evaluated via Kaplan-Meier test was checked by Log-rank test, the differences at р <0.05 were considered statistically significant. The cumulative risk of non relapse-related mortality was evaluated as competing risk.

Results

A total of 162 patients with advanced CML were included into the study. In 82 cases, the allo-HSCT was performed. The remaining 80 patients received only TKIs or TKIs in combination with chemotherapy. The median follow-up was 44 (1 to 344) months. There were no significant differences in gender, age, somatic status, disease phase or presence of additional chromosomal aberrations (ACAs) between allo-HSCT and TKI groups (see Tab. 1). The number of patient with BC was higher in allo-HSCT group compared to TKI group, i.e., 28% versus 12%. At the same time, non-transplanted patients were more likely to receive 3rd line of TKIs than allo-HSCT group (37% versus 18%) as seen from Table 1.

Table 1. Characteristics of patient groups receiving allo-HSCT or TKIs

Morozova-tab01-01.jpg Morozova-tab01-02.jpg Morozova-tab01-03.jpg

Therapy and clinical response prior to allo-HSCT

A total of 82 patients received allo-HSCT. In 48% of cases, the disease was initially in CP, and it progressed later to more advanced stage (AC or BC). 52% of the cases had an advanced-stage disease at diagnosis. The median time span from diagnosis to allo-HSCT was 2.2 (0.3-21.4) years. Most patients received chemotherapy in combination with TKIs, 37% of patients was administered only TKIs. All but two patients, who received allo-HSCT in 2002, had previous history of TKI treatment. Most patients (61%) had 2 or 3 lines of TKIs, with imatinib, dasatinib or nilotinib used. Only seven patients received bosutinib and two patients received ponatinib.

Patients in CP at diagnosis

A total of 29 (74%) of patients who were initially in CP, later developed BC. In 17 cases, a 2nd CP was achieved prior to allo-HSCT. Six patients were subjected to allo-HSCT in AP, six patients did not respond to therapy and underwent allo-HSCT in BC. In ten patients, the AP developed, and it persisted until allo-HSCT.

Patients in AP at diagnosis

A total of 20 patients had AP at diagnosis, ten of them subsequently developed blast crisis (BC). In six cases, the CP was achieved after TKI + chemotherapy (n=4) or TKI treatment (n=2); two patients were in AP after TKI + chemotherapy, and two patients still had BC after TKI + chemotherapy (n=1) or TKI only (n=1) at the moment of allo-HSCT. The remaining 10 patients had no history of BC. Six of them subsequently achieved CP, four patients were still in AP at the moment of allo-HSCT.

Patients with BC at diagnosis

A total of 23 patients had BC at the time of diagnosis. In 20 cases, a subsequent chronic phase was achieved after TKI + chemotherapy (n=17) or TKI therapy (n=3), in one case, AP was documented after TKI therapy, and two patients were still in BC after TKI + chemotherapy (n=2) at the moment of allo-HSCT.

Morozova-fig01.jpg

Figure 1. Cumulative 2-year relapse rate and 1-year non-relapse mortality after allo-HSCT.

Abbreviations: NRM, non-relapse mortality

Engraftment, causes of death and non-relapse mortality

Post-transplant engraftment was achieved in 71 (86%) patients. The median time to WBC engraftment was 22 (8 to 39) days, median time to the neutrophil engraftment was 22 (8 to 35) days. Median time to the platelet engraftment was 19 (6 to 57) days. In 9 cases of primary non-engraftment, the 2nd allo-HSCT was performed. The median follow-up was 35 (1 to 161) months.

Thirty-two patients died after allo-HSCT. The most common causes of death were relapse (n=16, 50%); GvHD (n=8, 25%); infectious complications (n=5, 16%); heart failure (n=2, 6%); hepatic veno-occlusive disease (n=1, 3%). One-year NRM was 18% (95% CI 10-28%), 100-day NRM 10% (95% CI 5-18%), as shown in Fig. 1.

Also, 48 (58%) patients received TKIs after allo-HSCT, 45 (88%) of them as relapse prophylaxis. 28 patients did not develop subsequent relapses. Two patients received bosutinib, 36 dasatinib, 8 nilotinib, and 2 ponatinib.

In 31 cases (38%), a relapse was developed, 16 of patients who relapsed received TKI prophylaxis. The cumulative relapse incidence was 39% (95% CI 28-51%). In 11 patients (34%), molecular relapse was shown; in one case, cytogenetic (3%), and in 19 cases (63%), hematological relapses were documented. Six patients received donor lymphocyte infusions (DLIs) for relapse treatment, five subjects received only TKIs; TKIs, chemotherapy and DLI were used in four cases; TKIs and DLIs were applied in 15 patients, and a combination of DLI and chemotherapy was used in one case. In 29% of the cases (n=9), the patients had durable molecular response, in 61% (n=19), the disease progression. Evaluation of therapeutic response was impossible for 10% of the patients. DLI was performed in the remaining six 6 cases, due to primary non-engraftment or poor graft function post-transplant. In three cases, DLIs were carried out due to persisting BCR/ABL transcript.

The incidence of grade 2-4 acute GvHD was 29% (n=21), grade 3-4 acute GvHD was registered in 20% (n=14). Chronic GvHD (cGvHD) incidence was 27% (n=18), having been mild in 6 cases (9%). Moderate cGvHD was observed in 8 cases (12%), and four patients (6%) developed severe cGvHD.

Patients who received only TKIs

A cohort of 80 patients received only TKIs, or their combination with chemotherapy. The median follow-up was 93 (13-344) months. The data on outcomes was available for 71 patients. Among the patients with BC, 36 (59%) did not respond to therapy, in 22 cases (34%) CHR was documented, in one case (2%) complete cytogenetic response (CCR) was revealed, and a complete molecular response (CMR) was achieved in two cases (3%). Among 10 patients without history of BC, one patient did not respond, 5 achieved CHR; 2 patients developed CCR, and CMR was registered in 2 cases. Sixty-nine patients died, more than half of them deceased due to disease progression/relapse.

Morozova-fig02.jpg

Figure 2. Four-year OS for allo-HSCT+TKIs and TKIs groups (А), and four-year EFS for allo-HSCT+TKIs and TKIs groups (B)

Abbreviations: allo-HSCT, allogeneic hematopoietic stem cell transplantation; TKI, tyrosine kinase inhibitor

Morozova-fig03.jpg

Figure 3. Four-year OS for patients treated in BC who received allo-HSCT+TKIs in CP≥2/AP+TKI, TKIs, and allo- HSCT in BC

Abbreviations: allo-HSCT, allogeneic hematopoietic stem cell transplantation; CP≥2, chronic phase; AP, acceleration phase; TKI, therapy with tyrosine kinase inhibitors; allo-HSCT in BC +TKI, allogeneic hematopoietic stem cell transplantation in blast crisis

Comparisons between allo-HSCT+TKIs and TKIs groups

The CML patients who received allo-HSCT exhibited significantly better 4-year OS compared to the TKI-treated group, i.e., 58% (95% CI 44%-69%) versus 33% (95% CI 23-44%), accordingly (р=0.032), as shown in Fig. 2А). At the same time, no statistically significant differences were found between the 4-year EFS, which was 35% (95% CI 24%-47%) in allo-HSCT, and 17% (95% CI 10%-26%) in TKIs group (р=0.5) (Fig. 2B). Also, there was no statistically significant difference between the 4-year OS receiving allo-HSCT in BC CML. This value was 33% for TKIs group (95% CI 23%-44%), and 23% for allo-HSCT patients (95% CI 3-52%) (р=0.217). However, the 4-year OS reached 63% (95% CI 48%-74%) for the patients transplanted in AP or CP after TKIs therapy, which is significantly better compared to other groups (р=0.005) (Fig. 3).

Discussion

In our study, we compared therapy results for advanced-phase patients with CML who received TKIs with or without allo- HSCT. In allo-HSCT group, the 4-year OS was significantly longer if compared to patients, who were not transplanted (58% versus 33%, accordingly). The 4-year EFS was also longer in allo-HSCT group (35% versus 17%, accordingly), although without statistical significance in this case.

One should note that the relapse rate in allotransplanted patients is still as high as 39%. However, CML is one of the most immunotherapy-responsive malignancies. Kolb et al. have first shown clinical success of DLIs in allo-HSCT recipients with CML [18]. Moreover, development of acute or chronic GvHD was more important for CML patients as a factor able to decrease relapse rate compared to patients with AML, MDS or plasma cell disorders [19, 20].

This may be a reason for higher OS in allo-HSCT group, while EFS rates have not differed significantly. As many relapses were sensitive to immune therapy, they were not invariably fatal, and many patients responded to post-transplant therapy. In our study, 29% of the patients achieved durable CMR upon DLI-containing treatment. However, usage of this method may be limited due to the risk of GvHD, since grade 2-4 acute GVHD develops in 15%, and chronic GvHD occurs in 22% of patients [21]. Donor lymphocyte infusions should not be performed in patients with a history of chronic GvHD. Moreover, donor cells are not available in some cases.

Efficiency of donor lymphocyte infusions depends on many factors. The study by Basak et al. in patients with CML has shown that PBSCs as graft source worsen the long-term OS among DLI recipients. The authors note that there were more patients with advanced stages in PBSC group, and suppose a connection between worse DLI effect and immune response attenuation due to lower immunogenicity of malignant cells in advanced stage patients [22]. Early CML relapse is another potentially negative factor making DLIs less effective [22].

The response to DLI may depend on the type of relapse. In this study we performed DLI for 26 patients who usually presented with hematological relapses. In a study by Radujkovic et al., this method was more effective in treatment of patients with molecular or cytogenetic, but not hematologic relapses. Five-year relapse and GvHD-free survival in patients with cytogenetic and hematological relapses was 40% and 20%, accordingly [22]. In our study, more than a half of relapsed patients developed hematological relapse, which may be a reason for lower response rate observed.

Prophylactic use of TKIs may exert important influence on the allo-HSCT outcomes. The relapses developed only in 38% of HSCT recipients after TKI-based prophylaxis. However, the actual role of prophylactic interventions is yet not quite clear. The largest patient cohort described by DeFilipp et al. included 89 patients [23]. The authors have not found significant differences in OS, which was 61% in recipients with post-transplant TKI prophylaxis versus 57% in the patients without such prophylaxis, and EFS was 42% versus 44%, accordingly (all differences not statistically significant). Hence, the results of our retrospective study may suggest whether prophylactic TKIs improve allo-HSCT results.

Some studies have compared the results of allo-HSCT and TKIs with or without chemotherapy in advanced-stage CML patients. Worth of note, the 1st line therapy was performed in most of these reports. In our study, however, nearly half of patients in each group received 2nd line TKIs; 38% in TKIs and 20% in allo-HSCT+TKIs group received 3 or more lines of TKIs. Allo-HSCT was not performed, due to the lack of potential donor or failure to sign an informed consent. Therefore, the non-transplant group was more likely to receive 3rd line TKIs than the allo-HSCT group. In study by Jiang et al., the results of TKIs with or without allo-HSCT were evaluated in 83 patients with CML BC. The allo-HSCT proved to be advantageous in 4-year OS compared to other treatment modalities, with OS of 46.7% versus 9.7%, and EFS of 47.1% versus 6.7%, accordingly [24]. Jiang et al. analyzed imatinib therapy results compared with allo-HSCT in 132 AP CML cases and found survival advantage for allo-HSCT compared to TKI group [25], with 5-year OS of 100% versus 18% and EFS 67% versus 9%, accordingly. Jain et al. had analyzed survival rates from the moment of BC diagnosis in a group including 104 allo-HSCT recipients and demonstrated that allo-HSCT decreases risk of death [2].

Allo-HSCT in patients with BC lead to the same results as other treatment options, with 4-year OS of 33% and 23% in TKIs and allo-HSCT groups, respectively. It corresponds to the published data from some other studies [24, 26, 27, 28], which makes us to recommend preferential usage of this approach in the patients with therapy-resistant disease.

Of course, the retrospective nature of our study urges us to be cautious for interpretation of its results. Meanwhile, we compared here extensive groups without showing statistically significant differences for the main clinical characteristics that could influence the CML outcomes.

Conclusions

This study has shown allo-HSCT still to be a curative method in many patients with AP and BC of CML in the presence of new-generation TKIs. However, the relapses are probable even after allo-HSCT. Due to good response to immune therapy in CML patients, a long-term remission and even curation may be achieved even after relapse of malignancy following allo-HSCT.

Tyrosine kinase inhibitors may be used as additional method for relapse therapy and prophylaxis. Performing allo-HSCT in patients with BC without achievement of hematological response does not lead to significantly better outcome. The indications for allo-HSCT should be discussed individually for each patient.

Ackhowledgements

No conflicts of interest reported.

References

  1. Hehlmann R, Lauseker M, Saußele S, Pfirrmann M, Krause S, Kolb HJ, et al. Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants. Leukemia 2017;31:2398-2406.
  2. Jain P, Kantarjian HM, Ghorab A, Sasaki K, Jabbour EJ, Nogueras Gonzalez G, et al. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer 2017;123:4391-4402.
  3. Bacher U, Klyuchnikov E, Zabelina T, Ottinger H, Beelen DW, Schrezenmeier H, et al. The changing scene of allogeneic stem cell transplantation for chronic myeloid leukemia – A report from the German Registry covering the period from 1998 to 2004. Ann Hematol 2009;88:1237-1247.
  4. Morozova E, Barabanshchikova M, Mamaev N, Barkhatov I, Alyanskii A, Darskaya E, et al. Chronic myeloid leukemia: Role of allogeneic hematopoietic stem cell transplantation in the era of tyrosine kinase inhibitors. Clin Oncohematology 2020;13:193-198 In Russian).
  5. Saussele S, Lauseker M, Gratwohl A, Beelen DW, Bunjes D, Schwerdtfeger R, et al. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: Evaluation of its impact within a subgroup of the randomized German CML study IV. Blood 2010;115:1880-1885.
  6. Calabretta B, Perrotti D. Review in translational hematology The biology of CML blast crisis. Blood 2004;103:4010-4022.
  7. Gratwohl A. The EBMT risk score. Bone Marrow Transplant 2012;47:749-756.
  8. Khoury HJ, Kukreja M, Goldman JM, Wang T, Halter J, Arora M, et al. Prognostic factors for outcomes in allogeneic transplantation for CML in the imatinib era: A CIBMTR analysis. Bone Marrow Transplant 2012;47:810-816.
  9. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 2020;34:966-984.
  10. Simons A, Shaffer LG, Hastings RJ. Cytogenetic Nomenclature: Changes in the ISCN 2013 Compared to the 2009 Edition. Cytogenet Genome Res 2013;141:1-6.
  11. Gabert J, Beillard E, van der Velden VHJ, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of "real time" quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program. Leukemia 2003;17:2318-2357.
  12. Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: Recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011;118:1208-1215.
  13. Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Jean Henslee‐Downey P, et al. IBMTR Severity index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997;97:855-864.
  14. Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 2015;21:389-401.e1.
  15. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: A new tool for risk assessment before allogeneic HCT. Blood 2005;106:2912-2919.
  16. Radujkovic A, Guglielmi C, Bergantini S, Iacobelli S, van Biezen A, Milojkovic D, et al. Donor lymphocyte infusions for chronic myeloid leukemia relapsing after allogeneic stem cell transplantation: May we predict graft-versus-leukemia without graft-versus-host disease? Biol Blood Marrow Transplant 2015;21:1230-1236.
  17. Porkka K, Koskenvesa P, Lundán T, Rimpiläinen J, Mustjoki S, Smykla R, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia. Blood 2008;112:1005-1012.
  18. Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990;76:2462-2465.
  19. Stern M, de Wreede LC, Brand R, van Biezen A, Dreger P, Mohty M, et al. Impact of graft-versus-host disease on relapse after allogeneic hematopoietic stem cell transplantation, an EBMT Megafile Study. Blood 2012;120:469-469.
  20. Oyekunle AA, Kröger N, Zabelina T, Ayuk F, Schieder H, Renges H, et al. Allogeneic stem-cell transplantation in patients with refractory acute leukemia: A long-term follow-up. Bone Marrow Transplant 2006;37:45-50.
  21. Chalandon Y, Passweg JR, Guglielmi C, Iacobelli S, Apperley J, Schaap NPM, et al. Early administration of donor lymphocyte infusions upon molecular relapse after allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia: A study by the chronic malignancies working party of the EBMT. Haematologica 2014;99:1492-1498.
  22. Basak GW, De Wreede LC, Van Biezen A, Wiktor-Jedrzejczak W, Halaburda K, Schmid C, et al. Donor lymphocyte infusions for the treatment of chronic myeloid leukemia relapse following peripheral blood or bone marrow stem cell transplantation. Bone Marrow Transplant 2013;48:837-842.
  23. DeFilipp Z, Ancheta R, Liu Y, Hu ZH, Gale RP, Snyder D, et al. Maintenance tyrosine kinase inhibitors following allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia: A center for International Blood and Marrow Transplant Research Study. Biol Blood Marrow Transplant 2020;26:472-479.
  24. Jiang H, Xu LP, Liu DH, Liu KY, Chen SS, Jiang B, et al. Allogeneic hematopoietic SCT in combination with tyrosine kinase inhibitor treatment compared with TKI treatment alone in CML blast crisis. Bone Marrow Transplant 2014;49:1146-1154.
  25. Jiang Q, Xu LP, Liu DH, Liu KY, Chen SS, Jiang B, et al. Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. Blood 2011;117:3032-3040.
  26. Gratwohl A, Pfirrmann M, Zander A, Kröger N, Beelen D, Novotny J, et al. Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: A randomized comparison of stem cell transplantation with drug treatment. Leukemia 2016;30:562-569.
  27. Radujkovic A, Dietrich S, Blok H-J, Nagler A, Ayuk F, Finke J, et al. Allogeneic stem cell transplantation for blast crisis chronic myeloid leukemia in the era of tyrosine kinase inhibitors: A retrospective study by the EBMT Chronic Malignancies Working Party. Biol Blood Marrow Transplant 2019;25:2008-2016.
  28. Hehlmann R. The new ELN Recommendations for treating CML. Early transplantation in patients with high-risk ACA. Cell Ther Transplant. 2020; 9(4): 11-19.

" ["DETAIL_TEXT_TYPE"]=> string(4) "html" ["~DETAIL_TEXT_TYPE"]=> string(4) "html" ["PREVIEW_TEXT"]=> string(0) "" ["~PREVIEW_TEXT"]=> string(0) "" ["PREVIEW_TEXT_TYPE"]=> string(4) "text" ["~PREVIEW_TEXT_TYPE"]=> string(4) "text" ["PREVIEW_PICTURE"]=> NULL ["~PREVIEW_PICTURE"]=> NULL ["LANG_DIR"]=> string(4) "/ru/" ["~LANG_DIR"]=> string(4) "/ru/" ["SORT"]=> string(2) "10" ["~SORT"]=> string(2) "10" ["CODE"]=> string(100) "klinicheskie-iskhody-u-patsientov-s-khronicheskim-mieloidnym-leykozom-prodvinutykh-stadiy-pri-alloge" ["~CODE"]=> string(100) "klinicheskie-iskhody-u-patsientov-s-khronicheskim-mieloidnym-leykozom-prodvinutykh-stadiy-pri-alloge" ["EXTERNAL_ID"]=> string(4) "1938" ["~EXTERNAL_ID"]=> string(4) "1938" ["IBLOCK_TYPE_ID"]=> string(7) "journal" ["~IBLOCK_TYPE_ID"]=> string(7) "journal" ["IBLOCK_CODE"]=> string(7) "volumes" ["~IBLOCK_CODE"]=> string(7) "volumes" ["IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["~IBLOCK_EXTERNAL_ID"]=> string(1) "2" ["LID"]=> string(2) "s2" ["~LID"]=> string(2) "s2" ["EDIT_LINK"]=> NULL ["DELETE_LINK"]=> NULL ["DISPLAY_ACTIVE_FROM"]=> string(0) "" ["IPROPERTY_VALUES"]=> array(18) { ["ELEMENT_META_TITLE"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["ELEMENT_META_KEYWORDS"]=> string(0) "" ["ELEMENT_META_DESCRIPTION"]=> string(431) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нееThe outcome of patients with advanced phase chronic myeloid leukemia with and without allogeneic hematopoietic stem cell transplantation " ["ELEMENT_PREVIEW_PICTURE_FILE_ALT"]=> string(4447) "<p style="text-align: justify;">Клинический прогноз у пациентов с хроническим миелоидным лейкозом (ХМЛ) в развернутой стадии (фаза акселерации – ФА, или бластный криз – БК) все еще остается неблагоприятным в эру применения ингибиторов тирозинкиназ (ИТК). Данное исследование проводилось, чтобы оценить, насколько аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) улучшает их прогноз.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">Общая группа из 162 пациентов с ХМЛ в ФА/БК была разделена на две гомогенные когорты. Первая из них состояла из реципиентов, получавших кондиционирование со сниженной интенсивностью перед алло-ТГСК (n=82). Вторая группа (n=80) включала пациентов, получавших только терапию на базе ИТК (в 85% случаев – препараты 2-го и 3-го поколения), не направленных в центры трансплантации или отказавшихся от нее. Ответ на терапию определяли в соответствии с рекомендациями ELN и NCCN. </p> <h3>Результаты</h3> <p style="text-align: justify;">Медиана сроков наблюдения для всей когорты составляла 44 (1-344) мес. Среди пациентов с БК 36 больных (59%) не отвечали на лечение, в 22 случаях (34%) была установлена полная гематологическая ремиссия (CHR), в одном случае (2%) – полная цитогенетическая ремиссия, и полный молекулярный ответ (ПМО) был достигнут в 2 случаях (3%). Среди реципиентов алло-ТГСК, приживление отмечено в 86% случаев. Кумулятивная безрецидивная смертность на D+100 и через 1 год составила, соответственно, 10% и 18%. У 28 пациентов с посттрансплантационным рецидивом проведена дополнительная терапия, и достигнут ПМО в 9 случаях. Общая 4-летняя выживаемость и бессобытийная выживаемость (ОВ) были лучше после алло-ТГСК по сравнению с группой, леченой ИТК: 58% против 33% (p=0,032) и 35% против 17% (p=0,5), соответственно. Пациенты в БК на момент ТГСК имели значительно более низкие уровни 3-летней ОВ по сравнению с больными, ответившими на лечение: 23% против 63% (p=0,007), соответственно. </p> <h3>Заключение</h3> <p style="text-align: justify;">Хотя алло-ТГСК имеет преимущество у многих больных ХМЛ в развернутых стадиях, результаты ее применения при БК сравнимы с лечением ИТК. Поэтому данные пациенты должны направляться в центры трансплантации по мере достижения ими второй хронической фазы заболевания.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Хронический миелоидный лейкоз, BCR/ABL, аллогенная трансплантация гемопоэтических стволовых клеток, ингибиторы тирозинкиназы, бластный криз, исходы заболевания.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["SECTION_META_TITLE"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["SECTION_META_KEYWORDS"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["SECTION_META_DESCRIPTION"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["SECTION_PICTURE_FILE_ALT"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["SECTION_PICTURE_FILE_TITLE"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["SECTION_PICTURE_FILE_NAME"]=> string(100) "klinicheskie-iskhody-u-patsientov-s-khronicheskim-mieloidnym-leykozom-prodvinutykh-stadiy-pri-alloge" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(294) "Клинические исходы у пациентов с хроническим миелоидным лейкозом продвинутых стадий при аллогенной трансплантации гемопоэтических стволовых клеток и без нее" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(100) "klinicheskie-iskhody-u-patsientov-s-khronicheskim-mieloidnym-leykozom-prodvinutykh-stadiy-pri-alloge" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(100) "klinicheskie-iskhody-u-patsientov-s-khronicheskim-mieloidnym-leykozom-prodvinutykh-stadiy-pri-alloge" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(100) "klinicheskie-iskhody-u-patsientov-s-khronicheskim-mieloidnym-leykozom-prodvinutykh-stadiy-pri-alloge" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "170" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "KEYWORDS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "19" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "4" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "Y" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "Y" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(27) "Ключевые слова" ["~DEFAULT_VALUE"]=> string(0) "" } ["SUBMITTED"]=> array(36) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27337" ["VALUE"]=> string(10) "25.07.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "25.07.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27338" ["VALUE"]=> string(10) "23.10.2020" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "23.10.2020" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL } ["CONTACT"]=> array(36) { ["ID"]=> string(2) "23" ["TIMESTAMP_X"]=> string(19) "2015-09-03 14:43:05" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(14) "Контакт" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "CONTACT" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "23" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(14) "Контакт" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHORS"]=> array(36) { ["ID"]=> string(2) "24" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:45:07" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "AUTHORS" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "E" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "Y" ["XML_ID"]=> string(2) "24" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27323" ["VALUE"]=> array(2) { ["TEXT"]=> string(547) "<p>Елена В. Морозова, Юлия Ю. Власова, Мария В. Барабанщикова, Ксения С. Юровская, Татьяна В. Шнайдер, Татьяна Л. Гиндина, Ильдар М. Бархатов, Евгений А. Бакин, Иван С. Моисеев, Александр Д. Кулагин, Людмила С. Зубаровская, <br><span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Борис В. Афанасьев</span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(507) "

Елена В. Морозова, Юлия Ю. Власова, Мария В. Барабанщикова, Ксения С. Юровская, Татьяна В. Шнайдер, Татьяна Л. Гиндина, Ильдар М. Бархатов, Евгений А. Бакин, Иван С. Моисеев, Александр Д. Кулагин, Людмила С. Зубаровская,
Борис В. Афанасьев

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27324" ["VALUE"]=> array(2) { ["TEXT"]=> string(367) "<p>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(355) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27325" ["VALUE"]=> array(2) { ["TEXT"]=> string(4447) "<p style="text-align: justify;">Клинический прогноз у пациентов с хроническим миелоидным лейкозом (ХМЛ) в развернутой стадии (фаза акселерации – ФА, или бластный криз – БК) все еще остается неблагоприятным в эру применения ингибиторов тирозинкиназ (ИТК). Данное исследование проводилось, чтобы оценить, насколько аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) улучшает их прогноз.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;">Общая группа из 162 пациентов с ХМЛ в ФА/БК была разделена на две гомогенные когорты. Первая из них состояла из реципиентов, получавших кондиционирование со сниженной интенсивностью перед алло-ТГСК (n=82). Вторая группа (n=80) включала пациентов, получавших только терапию на базе ИТК (в 85% случаев – препараты 2-го и 3-го поколения), не направленных в центры трансплантации или отказавшихся от нее. Ответ на терапию определяли в соответствии с рекомендациями ELN и NCCN. </p> <h3>Результаты</h3> <p style="text-align: justify;">Медиана сроков наблюдения для всей когорты составляла 44 (1-344) мес. Среди пациентов с БК 36 больных (59%) не отвечали на лечение, в 22 случаях (34%) была установлена полная гематологическая ремиссия (CHR), в одном случае (2%) – полная цитогенетическая ремиссия, и полный молекулярный ответ (ПМО) был достигнут в 2 случаях (3%). Среди реципиентов алло-ТГСК, приживление отмечено в 86% случаев. Кумулятивная безрецидивная смертность на D+100 и через 1 год составила, соответственно, 10% и 18%. У 28 пациентов с посттрансплантационным рецидивом проведена дополнительная терапия, и достигнут ПМО в 9 случаях. Общая 4-летняя выживаемость и бессобытийная выживаемость (ОВ) были лучше после алло-ТГСК по сравнению с группой, леченой ИТК: 58% против 33% (p=0,032) и 35% против 17% (p=0,5), соответственно. Пациенты в БК на момент ТГСК имели значительно более низкие уровни 3-летней ОВ по сравнению с больными, ответившими на лечение: 23% против 63% (p=0,007), соответственно. </p> <h3>Заключение</h3> <p style="text-align: justify;">Хотя алло-ТГСК имеет преимущество у многих больных ХМЛ в развернутых стадиях, результаты ее применения при БК сравнимы с лечением ИТК. Поэтому данные пациенты должны направляться в центры трансплантации по мере достижения ими второй хронической фазы заболевания.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Хронический миелоидный лейкоз, BCR/ABL, аллогенная трансплантация гемопоэтических стволовых клеток, ингибиторы тирозинкиназы, бластный криз, исходы заболевания.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4289) "

Клинический прогноз у пациентов с хроническим миелоидным лейкозом (ХМЛ) в развернутой стадии (фаза акселерации – ФА, или бластный криз – БК) все еще остается неблагоприятным в эру применения ингибиторов тирозинкиназ (ИТК). Данное исследование проводилось, чтобы оценить, насколько аллогенная трансплантация гемопоэтических клеток (алло-ТГСК) улучшает их прогноз.

Пациенты и методы

Общая группа из 162 пациентов с ХМЛ в ФА/БК была разделена на две гомогенные когорты. Первая из них состояла из реципиентов, получавших кондиционирование со сниженной интенсивностью перед алло-ТГСК (n=82). Вторая группа (n=80) включала пациентов, получавших только терапию на базе ИТК (в 85% случаев – препараты 2-го и 3-го поколения), не направленных в центры трансплантации или отказавшихся от нее. Ответ на терапию определяли в соответствии с рекомендациями ELN и NCCN.

Результаты

Медиана сроков наблюдения для всей когорты составляла 44 (1-344) мес. Среди пациентов с БК 36 больных (59%) не отвечали на лечение, в 22 случаях (34%) была установлена полная гематологическая ремиссия (CHR), в одном случае (2%) – полная цитогенетическая ремиссия, и полный молекулярный ответ (ПМО) был достигнут в 2 случаях (3%). Среди реципиентов алло-ТГСК, приживление отмечено в 86% случаев. Кумулятивная безрецидивная смертность на D+100 и через 1 год составила, соответственно, 10% и 18%. У 28 пациентов с посттрансплантационным рецидивом проведена дополнительная терапия, и достигнут ПМО в 9 случаях. Общая 4-летняя выживаемость и бессобытийная выживаемость (ОВ) были лучше после алло-ТГСК по сравнению с группой, леченой ИТК: 58% против 33% (p=0,032) и 35% против 17% (p=0,5), соответственно. Пациенты в БК на момент ТГСК имели значительно более низкие уровни 3-летней ОВ по сравнению с больными, ответившими на лечение: 23% против 63% (p=0,007), соответственно.

Заключение

Хотя алло-ТГСК имеет преимущество у многих больных ХМЛ в развернутых стадиях, результаты ее применения при БК сравнимы с лечением ИТК. Поэтому данные пациенты должны направляться в центры трансплантации по мере достижения ими второй хронической фазы заболевания.

Ключевые слова

Хронический миелоидный лейкоз, BCR/ABL, аллогенная трансплантация гемопоэтических стволовых клеток, ингибиторы тирозинкиназы, бластный криз, исходы заболевания.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27326" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-20-28" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-20-28" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27329" ["VALUE"]=> array(2) { ["TEXT"]=> string(362) "<p>Elena V. Morozova, Yulia Yu. Vlasova, Maria V. Barabanshikova, Ksenia S. Jurovskaya, Tatyana V. Shneider, Tatyana L. Gindina, Ildar M. Barkhatov, Evgenij A. Bakin, Ivan S. Moiseev, Alexander D. Kulagin, Ludmila S. Zubarovskaya, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev</span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(328) "

Elena V. Morozova, Yulia Yu. Vlasova, Maria V. Barabanshikova, Ksenia S. Jurovskaya, Tatyana V. Shneider, Tatyana L. Gindina, Ildar M. Barkhatov, Evgenij A. Bakin, Ivan S. Moiseev, Alexander D. Kulagin, Ludmila S. Zubarovskaya, Boris V. Afanasyev

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_EN"]=> array(36) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27330" ["VALUE"]=> array(2) { ["TEXT"]=> string(479) "<p>RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia</p> <br> <p><b>Correspondence</b><br> Dr. Elena V. Morozova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia<br> Phone: +7(911) 927 8229<br> E-mail: dr_morozova@mail.ru</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(419) "

RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, St. Petersburg, Russia


Correspondence
Dr. Elena V. Morozova, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, L.Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7(911) 927 8229
E-mail: dr_morozova@mail.ru

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27331" ["VALUE"]=> array(2) { ["TEXT"]=> string(2185) "<p style="text-align: justify;">Prognosis of patients with advanced stage CML (accelerated phase, AP, or blast crisis, BC) is still dismal in the era of tyrosine kinase inhibitors (TKIs). This study is aimed to evaluate whether allogeneic hemopoietic stem cell transplantation (allo-HSCT) improves their prognosis. </p> <p style="text-align: justify;">A total of 162 patients with AP/BC CML were divided into two homogeneous cohorts. The first one consisted of reduced-intensity conditioning allo-HSTC (n=82) recipients. The second (n=80) consisted of patients receiving only TKI-based therapy (in 85% of cases 2nd and 3rd generation TKIs) while not being referred to transplant center or refusing allo-HSCT. The response to therapy was defined according to ELN and NCCN recommendations. </p> <p style="text-align: justify;">The median follow-up for entire cohort was 44 (1-344) months. Among the patients with BC, 36 (59%) did not respond to therapy, in 22 cases (34%) CHR was documented, in one case (2%) complete cytogenetic response (CCR) was revealed, and a complete molecular response (CMR) was achieved in two cases (3%). Among allo-HST recipients 86% engrafted, the D+100 and 1-year cumulative non-relapse mortality were 10% and 18%, respectively. Twenty eight patients with post-transplant relapse received additional therapy achieving CMR in 9 cases. The 4-year OS and EFS were better in allo-HSCT compared to TKIs group: 58% <i>vs</i> 33% (p=0.032) and 35% <i>vs</i> 17% (p=0.5), accordingly. Patients in BC at the moment of allo-HSCT had significantly worse 4-year OS compared to responders: 23% <i>vs</i> 63% (p=0.007), accordingly. While allo-HSCT has an advantage for many advanced-stage CML patients, in BC its results are comparable to TKIs treatment. Therefore, these patients should be referred to transplant center as soon as the second chronic phase is achieved.</p> <h2>Keywords</h2> <p style="text-align: justify;">Chronic myelogenous leukemia, BCR/ABL, allo-HSCT, tyrosine kinase inhibitors, blast crisis, outcomes.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2049) "

Prognosis of patients with advanced stage CML (accelerated phase, AP, or blast crisis, BC) is still dismal in the era of tyrosine kinase inhibitors (TKIs). This study is aimed to evaluate whether allogeneic hemopoietic stem cell transplantation (allo-HSCT) improves their prognosis.

A total of 162 patients with AP/BC CML were divided into two homogeneous cohorts. The first one consisted of reduced-intensity conditioning allo-HSTC (n=82) recipients. The second (n=80) consisted of patients receiving only TKI-based therapy (in 85% of cases 2nd and 3rd generation TKIs) while not being referred to transplant center or refusing allo-HSCT. The response to therapy was defined according to ELN and NCCN recommendations.

The median follow-up for entire cohort was 44 (1-344) months. Among the patients with BC, 36 (59%) did not respond to therapy, in 22 cases (34%) CHR was documented, in one case (2%) complete cytogenetic response (CCR) was revealed, and a complete molecular response (CMR) was achieved in two cases (3%). Among allo-HST recipients 86% engrafted, the D+100 and 1-year cumulative non-relapse mortality were 10% and 18%, respectively. Twenty eight patients with post-transplant relapse received additional therapy achieving CMR in 9 cases. The 4-year OS and EFS were better in allo-HSCT compared to TKIs group: 58% vs 33% (p=0.032) and 35% vs 17% (p=0.5), accordingly. Patients in BC at the moment of allo-HSCT had significantly worse 4-year OS compared to responders: 23% vs 63% (p=0.007), accordingly. While allo-HSCT has an advantage for many advanced-stage CML patients, in BC its results are comparable to TKIs treatment. Therefore, these patients should be referred to transplant center as soon as the second chronic phase is achieved.

Keywords

Chronic myelogenous leukemia, BCR/ABL, allo-HSCT, tyrosine kinase inhibitors, blast crisis, outcomes.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["NAME_EN"]=> array(36) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27327" ["VALUE"]=> string(137) "The outcome of patients with advanced phase chronic myeloid leukemia with and without allogeneic hematopoietic stem cell transplantation " ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(137) "The outcome of patients with advanced phase chronic myeloid leukemia with and without allogeneic hematopoietic stem cell transplantation " ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" } ["FULL_TEXT_RU"]=> array(36) { ["ID"]=> string(2) "42" ["TIMESTAMP_X"]=> string(19) "2015-09-07 20:29:18" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(23) "Полный текст" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(12) "FULL_TEXT_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "42" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(23) "Полный текст" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["PDF_RU"]=> array(36) { ["ID"]=> string(2) "43" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF RUS" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_RU" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "43" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27328" ["VALUE"]=> string(4) "2311" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2311" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF RUS" ["~DEFAULT_VALUE"]=> string(0) "" } ["PDF_EN"]=> array(36) { ["ID"]=> string(2) "44" ["TIMESTAMP_X"]=> string(19) "2015-09-09 16:05:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(7) "PDF ENG" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(6) "PDF_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "F" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "44" ["FILE_TYPE"]=> string(18) "doc, txt, rtf, pdf" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27332" ["VALUE"]=> string(4) "2312" ["DESCRIPTION"]=> NULL ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(4) "2312" ["~DESCRIPTION"]=> NULL ["~NAME"]=> string(7) "PDF ENG" ["~DEFAULT_VALUE"]=> string(0) "" } ["NAME_LONG"]=> array(36) { ["ID"]=> string(2) "45" ["TIMESTAMP_X"]=> string(19) "2023-04-13 00:55:00" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(72) "Название (для очень длинных заголовков)" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "NAME_LONG" ["DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "45" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(80) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> NULL ["VALUE"]=> string(0) "" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(0) "" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(72) "Название (для очень длинных заголовков)" ["~DEFAULT_VALUE"]=> array(2) { ["TYPE"]=> string(4) "HTML" ["TEXT"]=> string(0) "" } } } ["DISPLAY_PROPERTIES"]=> array(10) { ["AUTHOR_EN"]=> array(37) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27329" ["VALUE"]=> array(2) { ["TEXT"]=> string(362) "<p>Elena V. Morozova, Yulia Yu. Vlasova, Maria V. Barabanshikova, Ksenia S. Jurovskaya, Tatyana V. Shneider, Tatyana L. Gindina, Ildar M. Barkhatov, Evgenij A. Bakin, Ivan S. Moiseev, Alexander D. Kulagin, Ludmila S. Zubarovskaya, <span style="border: 1px solid black; margin: 0; padding: 2px 2px;">Boris V. Afanasyev</span></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(328) "

Elena V. Morozova, Yulia Yu. Vlasova, Maria V. Barabanshikova, Ksenia S. Jurovskaya, Tatyana V. Shneider, Tatyana L. Gindina, Ildar M. Barkhatov, Evgenij A. Bakin, Ivan S. Moiseev, Alexander D. Kulagin, Ludmila S. Zubarovskaya, Boris V. Afanasyev

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(328) "

Elena V. Morozova, Yulia Yu. Vlasova, Maria V. Barabanshikova, Ksenia S. Jurovskaya, Tatyana V. Shneider, Tatyana L. Gindina, Ildar M. Barkhatov, Evgenij A. Bakin, Ivan S. Moiseev, Alexander D. Kulagin, Ludmila S. Zubarovskaya, Boris V. Afanasyev

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27331" ["VALUE"]=> array(2) { ["TEXT"]=> string(2185) "<p style="text-align: justify;">Prognosis of patients with advanced stage CML (accelerated phase, AP, or blast crisis, BC) is still dismal in the era of tyrosine kinase inhibitors (TKIs). This study is aimed to evaluate whether allogeneic hemopoietic stem cell transplantation (allo-HSCT) improves their prognosis. </p> <p style="text-align: justify;">A total of 162 patients with AP/BC CML were divided into two homogeneous cohorts. The first one consisted of reduced-intensity conditioning allo-HSTC (n=82) recipients. The second (n=80) consisted of patients receiving only TKI-based therapy (in 85% of cases 2nd and 3rd generation TKIs) while not being referred to transplant center or refusing allo-HSCT. The response to therapy was defined according to ELN and NCCN recommendations. </p> <p style="text-align: justify;">The median follow-up for entire cohort was 44 (1-344) months. Among the patients with BC, 36 (59%) did not respond to therapy, in 22 cases (34%) CHR was documented, in one case (2%) complete cytogenetic response (CCR) was revealed, and a complete molecular response (CMR) was achieved in two cases (3%). Among allo-HST recipients 86% engrafted, the D+100 and 1-year cumulative non-relapse mortality were 10% and 18%, respectively. Twenty eight patients with post-transplant relapse received additional therapy achieving CMR in 9 cases. The 4-year OS and EFS were better in allo-HSCT compared to TKIs group: 58% <i>vs</i> 33% (p=0.032) and 35% <i>vs</i> 17% (p=0.5), accordingly. Patients in BC at the moment of allo-HSCT had significantly worse 4-year OS compared to responders: 23% <i>vs</i> 63% (p=0.007), accordingly. While allo-HSCT has an advantage for many advanced-stage CML patients, in BC its results are comparable to TKIs treatment. Therefore, these patients should be referred to transplant center as soon as the second chronic phase is achieved.</p> <h2>Keywords</h2> <p style="text-align: justify;">Chronic myelogenous leukemia, BCR/ABL, allo-HSCT, tyrosine kinase inhibitors, blast crisis, outcomes.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2049) "

Prognosis of patients with advanced stage CML (accelerated phase, AP, or blast crisis, BC) is still dismal in the era of tyrosine kinase inhibitors (TKIs). This study is aimed to evaluate whether allogeneic hemopoietic stem cell transplantation (allo-HSCT) improves their prognosis.

A total of 162 patients with AP/BC CML were divided into two homogeneous cohorts. The first one consisted of reduced-intensity conditioning allo-HSTC (n=82) recipients. The second (n=80) consisted of patients receiving only TKI-based therapy (in 85% of cases 2nd and 3rd generation TKIs) while not being referred to transplant center or refusing allo-HSCT. The response to therapy was defined according to ELN and NCCN recommendations.

The median follow-up for entire cohort was 44 (1-344) months. Among the patients with BC, 36 (59%) did not respond to therapy, in 22 cases (34%) CHR was documented, in one case (2%) complete cytogenetic response (CCR) was revealed, and a complete molecular response (CMR) was achieved in two cases (3%). Among allo-HST recipients 86% engrafted, the D+100 and 1-year cumulative non-relapse mortality were 10% and 18%, respectively. Twenty eight patients with post-transplant relapse received additional therapy achieving CMR in 9 cases. The 4-year OS and EFS were better in allo-HSCT compared to TKIs group: 58% vs 33% (p=0.032) and 35% vs 17% (p=0.5), accordingly. Patients in BC at the moment of allo-HSCT had significantly worse 4-year OS compared to responders: 23% vs 63% (p=0.007), accordingly. While allo-HSCT has an advantage for many advanced-stage CML patients, in BC its results are comparable to TKIs treatment. Therefore, these patients should be referred to transplant center as soon as the second chronic phase is achieved.

Keywords

Chronic myelogenous leukemia, BCR/ABL, allo-HSCT, tyrosine kinase inhibitors, blast crisis, outcomes.

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2049) "

Prognosis of patients with advanced stage CML (accelerated phase, AP, or blast crisis, BC) is still dismal in the era of tyrosine kinase inhibitors (TKIs). This study is aimed to evaluate whether allogeneic hemopoietic stem cell transplantation (allo-HSCT) improves their prognosis.

A total of 162 patients with AP/BC CML were divided into two homogeneous cohorts. The first one consisted of reduced-intensity conditioning allo-HSTC (n=82) recipients. The second (n=80) consisted of patients receiving only TKI-based therapy (in 85% of cases 2nd and 3rd generation TKIs) while not being referred to transplant center or refusing allo-HSCT. The response to therapy was defined according to ELN and NCCN recommendations.

The median follow-up for entire cohort was 44 (1-344) months. Among the patients with BC, 36 (59%) did not respond to therapy, in 22 cases (34%) CHR was documented, in one case (2%) complete cytogenetic response (CCR) was revealed, and a complete molecular response (CMR) was achieved in two cases (3%). Among allo-HST recipients 86% engrafted, the D+100 and 1-year cumulative non-relapse mortality were 10% and 18%, respectively. Twenty eight patients with post-transplant relapse received additional therapy achieving CMR in 9 cases. The 4-year OS and EFS were better in allo-HSCT compared to TKIs group: 58% vs 33% (p=0.032) and 35% vs 17% (p=0.5), accordingly. Patients in BC at the moment of allo-HSCT had significantly worse 4-year OS compared to responders: 23% vs 63% (p=0.007), accordingly. While allo-HSCT has an advantage for many advanced-stage CML patients, in BC its results are comparable to TKIs treatment. Therefore, these patients should be referred to transplant center as soon as the second chronic phase is achieved.

Keywords

Chronic myelogenous leukemia, BCR/ABL, allo-HSCT, tyrosine kinase inhibitors, blast crisis, outcomes.

" } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "27326" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-20-28" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-20-28" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2020-9-4-20-28" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE