ISSN 1866-8836
Клеточная терапия и трансплантация
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Introduction

Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) is considered an integral component of most treatment protocols aimed for therapy of hematological malignancies and solid tumors as well as some genetic diseases in children and adolescents. It is a method of choice for the patients with non-malignant clinical conditions intended for correction of inherited deficiency typical to the given syndrome, repopulation of the immune system by normal cells, or replenishment of a deficient enzyme, e.g., in storage diseases [1, 2]. Choosing an optimally compatible donor is a key factor determining favorable outcome in HSCT [3]. An HLA-compatible unrelated donor is not available for ca. 15-20% of the patients, because of extreme allelic variability of HLA system. Lower HLA compatibility is associated with additional risks of severe posttransplant immune complications, e.g., graft-versus-host disease. Pharmacological prevention of acute GVHD is based on combined usage of different medications, i.e., calcineurin inhibitors, cytostatic drugs (metothrexate, micophenolate mophetyl), m-TOR inhibitors, antithymocyte immunoglobulins. Cyclophosphamide at early terms post-transplant (days +3+4) is considered as a novel approach to aGvHD prophylaxis after HSCT (PTCy). The mean purpose of this therapy is to abrogate effects of activated alloreactive T lymphocytes, thus allowing to decrease acute GVHD risk by 30%. However, most published data describes treatment of adult patients with hematological malignancies [5, 6], several studies in pediatric HSCT are also based on this category of patients. Hence, the aim of the present study was to assess efficiency of PTCy therapy in pediatric patients with non-malignant diseases.

Patients and Methods

Over the time period of 2005 to March 2018, we observed ninety-seven patients with various non-malignant diseases subjected to allo-HSCT at the clinic of R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation. A total of 118 allo-HSCT were performed including 21 cases (18%) of repeated transplants, due to initial graft failure, or secondary rejection. The primary non-malignant conditions were represented by the following disorders: hemoglobinopathies, 8 patients (8%); bone marrow insufficiency (both inborn and acquired), 44 cases (46%); metabolic diseases, 35 cases (36%), primary immune deficiencies, 10 patients (10%).
Acute GVHD (aGVHD) prophylaxis in majority of HSCT cases was based on calcineurin inhibitors (n=89, 75%). Posttransplant cyclophosphamide (PtCy) was administered in 29 cases (25%), at the dose of 50 mg/kg weight (days +3 and +4 after HSCT). This schedule of GVHD prophylaxis was most often in type 1 mucopolysaccharidosis (Hurler syndrome) (n=9), beta-thalassemia (n=9). In 11 cases (38%), HSCT was performed from haploidentical donors, or as a repeated transplant (n=9, 31%). Myeloablative and reduced-intensity conditioning regimens were applied at similar rates (respectively, for 15 and 14 cases).

Results

The two-year survival rates in total group did not substantially differ between standard GVHD prophylaxis schedule, and the PtCy protocol (62% versus 64%) (Fig. 1А). A number of factors did sufficiently improve this parameter: patient’s age (under 5 years old) by the moment of HSCT (77% vs 50%, р=0.004, see Fig. 1B); shorter time period (under 2 years) from diagnosis to allo-HSCT (74% vs 47%, р=0.003,see Fig. 1C), transplant engraftment (72% vs 44%, р=0.001, see Fig. 1D).
Successful engraftment was documented in 91 cases. Cumulative engraftment rates did not differ between the groups with standard protocol and PtCy prophylaxis (70% vs 84%, see Fig. 2А). Likewise, we have not revealed any significant differences for the groups treated according to MAC and RIC schedules (87.5% vs 77%, р=0.31, see Fig. 2B). However, the patients subjected to non-myeloablative conditioning followed by Cy treatment showed a definitely lower engraftment rate (86 vs 50%, р=0.004, see Fig. 2C).
Stem cell engraftment in our patients was dependent on the donor type. I.e., the patients who underwent HSCT from HLA-compatible donor (either related or unrelated) showed higher engraftment frequency than the patients who have got stem cells from haploidentical donor (92% vs 84% vs 58%, р=0.05, see Fig. 3).
The primary disease for which allo-HSCT was performed was also of importance. E.g., the patients with primary immune deficiencies demonstrated engraftment in all cases. The lowest engraftment rate was observed in patients with hemoglobinopathies. Functioning graft among the patients who received second HSCT due to failure of the first transplant, was achieved in only 46% of cases.
Cumulative incidence (CI) of aGVHD rate in post-HSCT patients was 32% of total. The patients with PtCy had lower CI aGVHD if compared to the group with standard prophylaxis (26% vs 47%, р=0.05, Fig. 4А). CI of aGVHD with skin affection was also significantly lower in the PtCy group (23% vs 45%, р=0.046) as seen from the Fig. 4B. Intestinal and hepatic aGVHD occurred in the both groups at comparable rates. The inter-group distribution for severity grade was also similar.
Clinical results of PtCy treatment were specially evaluated for the most homogenous group of the patients with Hurler syndrome (type 1 MPS). This cohort was represented by 22 allo-HSCT, with PtCy prophylaxis in six cases. Overall survival was similar for the patients subjected to different aGVHD prophylaxis (82% at standard aGVHD prophylaxis versus 100% in PtCy group, see Fig. 5А). Clinical engraftment was achieved in all cases, whereas CI of aGVHD was 63% in the standard prophylaxis group against 34% for the PtCy group (Fig. 5B). Frequency of life-threatening GVHD (stage III to IV) did not differ significantly (20% versus 18%, Fig. 5C).

28-35 figure 1-2.png

28-35 figure 1-2 (1).png

Table 1. Primary clinical conditions in the patients with non-malignant disorders.png

Table 2. Demographic and clinical characteristics of the patients subjected to acute GVHD prophylaxis based.png

Table 3. aGVHD frequency and distribution by severity for the groups with standard (calcineurin inhibitor-based).png

Figure 3. Cumulative engraftment rate (ordinate) in the.png

Figure 4. (A) Total CI of aGVHD (ordinate); (B) CI of skin aGVHD among the patients subjected to standard GVHD.png

Figure 5. (А) Overall survival among patients with.png

Discussion

Search for a fully HLA-matched donor for HSCT is critical to the patients with non-malignant diseases. Due to ethnic background of the patients with thalassemia, autosomal recessive osteopetrosis etc., they are unlikely to find a compatible donor. Time is also an important factor, especially for the patients with primary immune deficiencies or storage metabolic diseases which extends the prospective for recruitment of alternative stem cell donors [7]. Allo-HSCT from a nonrelated donor or partially compatible haploidentical donor exhibit comparable survival parameters for the patients with non-malignant disorders. Under these conditions, the PtCy-based GHD prophylaxis provides good control of evolving aGVHD [8]. A higher risk of non-engraftment in cases of haploidentical donorship could be decreased due to myeloablative conditioning regimens. The recruitment of haploidentical donors for HSCT in children with primary immune deficiencies and sickle-cell anemia have been described in present studies [9, 10, 11]. PtCy prophylaxis was applied in all these cases showing its clinical efficiency. This approach has additional benefits when applying peripheral blood stem cells as a source of transplant [8, 12].

Conclusion

aGVHD prevention based on cyclophosphamide prophylaxis is an effective treatment which may decrease risk of aGVHD specially in skin affection when compared to standard treatment methods based on calcineurin inhibitors. However, higher non-engraftment rate can be a potential hazard of HSCT performed in patients with non-malignant  disorders when using non-myeloablative conditioning regimens and PtCy-based GVHD prophylaxis.

Conflict of interest

No conflicts of interest are reported.

References

1. Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P , Duarte RF, Dufour C, Falkenburg JH, Farge-Bancel D, Gennery A, Kröger N, Lanza F, Nagler A, Sureda A, Mohty M; European Society for Blood and Marrow Transplantation (EBMT). Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplant 2015;50(4):476–482.

2. Afanasyev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: current issues and prospectives. Russian J Pediatric Hematol Oncol. 2015; 2(2): 28-42 (In Russian).

3. Afanasyev BV, Zubarovskaya LS, Alyansky AL. Paina OV, Borovkova AS, Kuzmich EV, Bykova TA, Deev RV, Isaev AA. Donor selection in allogeneic hematopoietic stem cell transplantation. Russian J Pediatric Hematol Oncol. 2016; 3(3): 30-36 (In Russian).

4. Owens AH, Santos GW. The effect of cytotoxic drugs on graft-versus-host disease in mice. Transplantation. 1971. 4(11): 378–382.

5. Moiseev IS, Pirogova OV, Babenko EV, Gindina TL, Darskaya EI, Morozova EV, Bondarenko SN, Afanasyev BV. Single-agent post-transplantation cyclophosphamide versus calcineurin-based graft-versus-host disease prophylaxis in matched related bone marrow transplantation. Cell Ther Transplant. 2017; 6(4): 52-59.

6. Moiseev IS, Pirogova OV, Alyanski AL, Babenko EV, Gindina TL, Darskaya EI, Slesarchuk OA, Bondarenko SN, Afanasyev BV. Graft-versus-host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Biol Blood Marrow Transplant. 2016; 22(6):1037-1042.

7. Booth C, Silva J, Veys P. Stem cell transplantation for the treatment of immunodeficiency in children: current status and hopes for the future. Expert Rev Clin Immunol. 2016;12(7):713-723.

8. Jaiswal SR, Chakrabarti A, Chatterjee S, Ray K, Chakrabarti S. Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: The need to look beyond post-transplantation cyclophosphamide in younger children. Pediatr Transplant. 2016;20(5):675-82.

9. Rastogi N, Katewa S,Thakkar D, Kohli S, Nivargi S,Yadav SP. Reduced-toxicity alternate-donor stem cell transplantation with posttransplant cyclophosphamide for primary immunodeficiency disorders. Pediat Blood Cancer. 2018;65(1). doi: 10.1002/pbc.26783.

10. Thakkar D, Katewa S, Rastogi N, Kohli S, Nivargi S, Yadav SP. Successful reduced intensity conditioning alternate donor stem cell transplant for Wiskott-Aldrich syndrome. J Pediat Hematol Oncol. 2017;39(8):e493-e496.

11. Wiebking V, Hütker S, Schmid I, Immler S, Feuchtinger T, Albert MH. Reduced toxicity, myeloablative HLA-haploidentical hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for sickle cell disease. Ann Hematol. 2017;96(8):1373-1377.

12. Jaiswal SR, Chakrabarti A, Chatterjee S, Ray K, Chakrabarti S. Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: The need to look beyond post-transplantation cyclophosphamide in younger children. Pediatr Transplant.2016;20(5):675-682.

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Introduction

Allogeneic transplantation of hematopoietic stem cells (allo-HSCT) is considered an integral component of most treatment protocols aimed for therapy of hematological malignancies and solid tumors as well as some genetic diseases in children and adolescents. It is a method of choice for the patients with non-malignant clinical conditions intended for correction of inherited deficiency typical to the given syndrome, repopulation of the immune system by normal cells, or replenishment of a deficient enzyme, e.g., in storage diseases [1, 2]. Choosing an optimally compatible donor is a key factor determining favorable outcome in HSCT [3]. An HLA-compatible unrelated donor is not available for ca. 15-20% of the patients, because of extreme allelic variability of HLA system. Lower HLA compatibility is associated with additional risks of severe posttransplant immune complications, e.g., graft-versus-host disease. Pharmacological prevention of acute GVHD is based on combined usage of different medications, i.e., calcineurin inhibitors, cytostatic drugs (metothrexate, micophenolate mophetyl), m-TOR inhibitors, antithymocyte immunoglobulins. Cyclophosphamide at early terms post-transplant (days +3+4) is considered as a novel approach to aGvHD prophylaxis after HSCT (PTCy). The mean purpose of this therapy is to abrogate effects of activated alloreactive T lymphocytes, thus allowing to decrease acute GVHD risk by 30%. However, most published data describes treatment of adult patients with hematological malignancies [5, 6], several studies in pediatric HSCT are also based on this category of patients. Hence, the aim of the present study was to assess efficiency of PTCy therapy in pediatric patients with non-malignant diseases.

Patients and Methods

Over the time period of 2005 to March 2018, we observed ninety-seven patients with various non-malignant diseases subjected to allo-HSCT at the clinic of R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation. A total of 118 allo-HSCT were performed including 21 cases (18%) of repeated transplants, due to initial graft failure, or secondary rejection. The primary non-malignant conditions were represented by the following disorders: hemoglobinopathies, 8 patients (8%); bone marrow insufficiency (both inborn and acquired), 44 cases (46%); metabolic diseases, 35 cases (36%), primary immune deficiencies, 10 patients (10%).
Acute GVHD (aGVHD) prophylaxis in majority of HSCT cases was based on calcineurin inhibitors (n=89, 75%). Posttransplant cyclophosphamide (PtCy) was administered in 29 cases (25%), at the dose of 50 mg/kg weight (days +3 and +4 after HSCT). This schedule of GVHD prophylaxis was most often in type 1 mucopolysaccharidosis (Hurler syndrome) (n=9), beta-thalassemia (n=9). In 11 cases (38%), HSCT was performed from haploidentical donors, or as a repeated transplant (n=9, 31%). Myeloablative and reduced-intensity conditioning regimens were applied at similar rates (respectively, for 15 and 14 cases).

Results

The two-year survival rates in total group did not substantially differ between standard GVHD prophylaxis schedule, and the PtCy protocol (62% versus 64%) (Fig. 1А). A number of factors did sufficiently improve this parameter: patient’s age (under 5 years old) by the moment of HSCT (77% vs 50%, р=0.004, see Fig. 1B); shorter time period (under 2 years) from diagnosis to allo-HSCT (74% vs 47%, р=0.003,see Fig. 1C), transplant engraftment (72% vs 44%, р=0.001, see Fig. 1D).
Successful engraftment was documented in 91 cases. Cumulative engraftment rates did not differ between the groups with standard protocol and PtCy prophylaxis (70% vs 84%, see Fig. 2А). Likewise, we have not revealed any significant differences for the groups treated according to MAC and RIC schedules (87.5% vs 77%, р=0.31, see Fig. 2B). However, the patients subjected to non-myeloablative conditioning followed by Cy treatment showed a definitely lower engraftment rate (86 vs 50%, р=0.004, see Fig. 2C).
Stem cell engraftment in our patients was dependent on the donor type. I.e., the patients who underwent HSCT from HLA-compatible donor (either related or unrelated) showed higher engraftment frequency than the patients who have got stem cells from haploidentical donor (92% vs 84% vs 58%, р=0.05, see Fig. 3).
The primary disease for which allo-HSCT was performed was also of importance. E.g., the patients with primary immune deficiencies demonstrated engraftment in all cases. The lowest engraftment rate was observed in patients with hemoglobinopathies. Functioning graft among the patients who received second HSCT due to failure of the first transplant, was achieved in only 46% of cases.
Cumulative incidence (CI) of aGVHD rate in post-HSCT patients was 32% of total. The patients with PtCy had lower CI aGVHD if compared to the group with standard prophylaxis (26% vs 47%, р=0.05, Fig. 4А). CI of aGVHD with skin affection was also significantly lower in the PtCy group (23% vs 45%, р=0.046) as seen from the Fig. 4B. Intestinal and hepatic aGVHD occurred in the both groups at comparable rates. The inter-group distribution for severity grade was also similar.
Clinical results of PtCy treatment were specially evaluated for the most homogenous group of the patients with Hurler syndrome (type 1 MPS). This cohort was represented by 22 allo-HSCT, with PtCy prophylaxis in six cases. Overall survival was similar for the patients subjected to different aGVHD prophylaxis (82% at standard aGVHD prophylaxis versus 100% in PtCy group, see Fig. 5А). Clinical engraftment was achieved in all cases, whereas CI of aGVHD was 63% in the standard prophylaxis group against 34% for the PtCy group (Fig. 5B). Frequency of life-threatening GVHD (stage III to IV) did not differ significantly (20% versus 18%, Fig. 5C).

28-35 figure 1-2.png

28-35 figure 1-2 (1).png

Table 1. Primary clinical conditions in the patients with non-malignant disorders.png

Table 2. Demographic and clinical characteristics of the patients subjected to acute GVHD prophylaxis based.png

Table 3. aGVHD frequency and distribution by severity for the groups with standard (calcineurin inhibitor-based).png

Figure 3. Cumulative engraftment rate (ordinate) in the.png

Figure 4. (A) Total CI of aGVHD (ordinate); (B) CI of skin aGVHD among the patients subjected to standard GVHD.png

Figure 5. (А) Overall survival among patients with.png

Discussion

Search for a fully HLA-matched donor for HSCT is critical to the patients with non-malignant diseases. Due to ethnic background of the patients with thalassemia, autosomal recessive osteopetrosis etc., they are unlikely to find a compatible donor. Time is also an important factor, especially for the patients with primary immune deficiencies or storage metabolic diseases which extends the prospective for recruitment of alternative stem cell donors [7]. Allo-HSCT from a nonrelated donor or partially compatible haploidentical donor exhibit comparable survival parameters for the patients with non-malignant disorders. Under these conditions, the PtCy-based GHD prophylaxis provides good control of evolving aGVHD [8]. A higher risk of non-engraftment in cases of haploidentical donorship could be decreased due to myeloablative conditioning regimens. The recruitment of haploidentical donors for HSCT in children with primary immune deficiencies and sickle-cell anemia have been described in present studies [9, 10, 11]. PtCy prophylaxis was applied in all these cases showing its clinical efficiency. This approach has additional benefits when applying peripheral blood stem cells as a source of transplant [8, 12].

Conclusion

aGVHD prevention based on cyclophosphamide prophylaxis is an effective treatment which may decrease risk of aGVHD specially in skin affection when compared to standard treatment methods based on calcineurin inhibitors. However, higher non-engraftment rate can be a potential hazard of HSCT performed in patients with non-malignant  disorders when using non-myeloablative conditioning regimens and PtCy-based GVHD prophylaxis.

Conflict of interest

No conflicts of interest are reported.

References

1. Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P , Duarte RF, Dufour C, Falkenburg JH, Farge-Bancel D, Gennery A, Kröger N, Lanza F, Nagler A, Sureda A, Mohty M; European Society for Blood and Marrow Transplantation (EBMT). Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplant 2015;50(4):476–482.

2. Afanasyev BV, Zubarovskaya LS, Moiseev IS. Allogeneic hematopoietic stem cell transplantation in children: current issues and prospectives. Russian J Pediatric Hematol Oncol. 2015; 2(2): 28-42 (In Russian).

3. Afanasyev BV, Zubarovskaya LS, Alyansky AL. Paina OV, Borovkova AS, Kuzmich EV, Bykova TA, Deev RV, Isaev AA. Donor selection in allogeneic hematopoietic stem cell transplantation. Russian J Pediatric Hematol Oncol. 2016; 3(3): 30-36 (In Russian).

4. Owens AH, Santos GW. The effect of cytotoxic drugs on graft-versus-host disease in mice. Transplantation. 1971. 4(11): 378–382.

5. Moiseev IS, Pirogova OV, Babenko EV, Gindina TL, Darskaya EI, Morozova EV, Bondarenko SN, Afanasyev BV. Single-agent post-transplantation cyclophosphamide versus calcineurin-based graft-versus-host disease prophylaxis in matched related bone marrow transplantation. Cell Ther Transplant. 2017; 6(4): 52-59.

6. Moiseev IS, Pirogova OV, Alyanski AL, Babenko EV, Gindina TL, Darskaya EI, Slesarchuk OA, Bondarenko SN, Afanasyev BV. Graft-versus-host disease prophylaxis in unrelated peripheral blood stem cell transplantation with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Biol Blood Marrow Transplant. 2016; 22(6):1037-1042.

7. Booth C, Silva J, Veys P. Stem cell transplantation for the treatment of immunodeficiency in children: current status and hopes for the future. Expert Rev Clin Immunol. 2016;12(7):713-723.

8. Jaiswal SR, Chakrabarti A, Chatterjee S, Ray K, Chakrabarti S. Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: The need to look beyond post-transplantation cyclophosphamide in younger children. Pediatr Transplant. 2016;20(5):675-82.

9. Rastogi N, Katewa S,Thakkar D, Kohli S, Nivargi S,Yadav SP. Reduced-toxicity alternate-donor stem cell transplantation with posttransplant cyclophosphamide for primary immunodeficiency disorders. Pediat Blood Cancer. 2018;65(1). doi: 10.1002/pbc.26783.

10. Thakkar D, Katewa S, Rastogi N, Kohli S, Nivargi S, Yadav SP. Successful reduced intensity conditioning alternate donor stem cell transplant for Wiskott-Aldrich syndrome. J Pediat Hematol Oncol. 2017;39(8):e493-e496.

11. Wiebking V, Hütker S, Schmid I, Immler S, Feuchtinger T, Albert MH. Reduced toxicity, myeloablative HLA-haploidentical hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for sickle cell disease. Ann Hematol. 2017;96(8):1373-1377.

12. Jaiswal SR, Chakrabarti A, Chatterjee S, Ray K, Chakrabarti S. Haploidentical transplantation in children with unmanipulated peripheral blood stem cell graft: The need to look beyond post-transplantation cyclophosphamide in younger children. Pediatr Transplant.2016;20(5):675-682.

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Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития. </p> <h3 style="text-align: justify;">Цель работы</h3> <p style="text-align: justify;"> Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами. </p> <h3 style="text-align: justify;">Пациенты и методы</h3> <p style="text-align: justify;"> В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4. </p> <h3 style="text-align: justify;">Результаты</h3> <p style="text-align: justify;"> Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004). </p> <h3 style="text-align: justify;">Заключение</h3> <p style="text-align: justify;"> Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. Однако, у пациентов с незлокачественными заболеваниями необходимо учитывать факт возможного увеличения частоты неприживления трансплантата при использовании немиелоаблативных режимов кондиционирования и профилактики на основе ПТЦ. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических стволовых клеток, неопухолевые заболевания, острая реакция «трансплантат против хозяина», профилактика циклофосфамидом. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(341) "Профилактика острой реакции «трасплантат против хозяина» с применением циклофосфамида после трансплантации гемопоэтических стволовых клеток пациентам с неопухолевыми заболеваниями" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(341) "Профилактика острой реакции «трасплантат против хозяина» с применением циклофосфамида после трансплантации гемопоэтических стволовых клеток пациентам с неопухолевыми заболеваниями" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> 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Быкова, Анастасия С. Боровкова, Анна А. Осипова, Варвара Н. Овечкина, Олеся В. Паина, Полина В. Кожокарь, Александр Л. Алянский, Александр Д. Кулагин, Елена В. Семенова, *Борис И. Смирнов, Людмила С. Зубаровская, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(429) "Татьяна А. Быкова, Анастасия С. Боровкова, Анна А. Осипова, Варвара Н. Овечкина, Олеся В. Паина, Полина В. Кожокарь, Александр Л. Алянский, Александр Д. Кулагин, Елена В. Семенова, *Борис И. Смирнов, Людмила С. Зубаровская, Борис В. Афанасьев
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*Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», 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) "20112" ["VALUE"]=> array(2) { ["TEXT"]=> string(4727) "<p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических стволовых клеток – эффективный метод терапии незлокачественных заболеваний системы кроветворения и наследственных синдромов. Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития. </p> <h3 style="text-align: justify;">Цель работы</h3> <p style="text-align: justify;"> Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами. </p> <h3 style="text-align: justify;">Пациенты и методы</h3> <p style="text-align: justify;"> В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4. </p> <h3 style="text-align: justify;">Результаты</h3> <p style="text-align: justify;"> Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004). </p> <h3 style="text-align: justify;">Заключение</h3> <p style="text-align: justify;"> Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. Однако, у пациентов с незлокачественными заболеваниями необходимо учитывать факт возможного увеличения частоты неприживления трансплантата при использовании немиелоаблативных режимов кондиционирования и профилактики на основе ПТЦ. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических стволовых клеток, неопухолевые заболевания, острая реакция «трансплантат против хозяина», профилактика циклофосфамидом. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4485) "

Аллогенная трансплантация гемопоэтических стволовых клеток – эффективный метод терапии незлокачественных заболеваний системы кроветворения и наследственных синдромов. Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития.

Цель работы

Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами.

Пациенты и методы

В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4.

Результаты

Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004).

Заключение

Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. Однако, у пациентов с незлокачественными заболеваниями необходимо учитывать факт возможного увеличения частоты неприживления трансплантата при использовании немиелоаблативных режимов кондиционирования и профилактики на основе ПТЦ.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, неопухолевые заболевания, острая реакция «трансплантат против хозяина», профилактика циклофосфамидом.

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" ["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) "20115" ["VALUE"]=> array(2) { ["TEXT"]=> string(327) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology; Department of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia *The St. Petersburg State Electrotechnical University (LETI), St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(327) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology; Department of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia *The St. Petersburg State Electrotechnical University (LETI), St. Petersburg, Russia" ["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) "20116" ["VALUE"]=> array(2) { ["TEXT"]=> string(2521) "<p style="text-align: justify;"> Transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is an effective treatment method for non-malignant diseases and inherited disorders. Development of acute graft-versus-host-disease (aGVHD) is a negative factor with adverse effects upon clinical outcomes. Usage of “novel” schedules for drug prophylaxis of this complication using posttransplant cyclophosphamide (PtCy) seems to decrease the GVHD risk. The aim of this study was to assess efficiency of PtCy as a tool for aGVHD prevention in the patients with non-malignant diseases of hematopoiesis and inherited syndromes. </p> <h3 style="text-align: justify;">Patients and Methods</h3> <p style="text-align: justify;"> 97 patients with non-malignant blood disorders and metabolic diseases underwent allo-HSCT at the R. Gorbacheva Memorial Institute of Children Oncology and Transplantation over a period of 2005 to 2018. A total of 118 HSCTs were carried out. The aGVHD prophylaxis in 89 cases was performed by a standard schedule (with calcineurin inhibitors). 29 patients were treated according to PtCy regimen, at a dose of 50 mg/kg at days +3 and +4. </p> <h3 style="text-align: justify;">Results</h3> <p style="text-align: justify;"> Cumulative frequency of acute GVHD comprised 32%. Patients treated with PtCy exhibited lower rates of this condition compared to the group with standard prophylaxis schedule (26% vs 47%, р=0.05). Frequency of skin aGVHD was also less common in the PtCy group (23% vs 45%, р=0.046); gastrointestinal aGVHD was observed at equal rates in the both groups. Stem cell engraftment after nonmyeloablative conditioning in HSCT patients with subsequent PtCy administration proved to be sufficiently weaker compared to other patients (86 vs 50%, р=0.004). In conclusion, posttransplant GVHD prevention based on cyclophosphamide prophylaxis is an efficient method which may decrease aGVHD risk. However, one should take into account a higher non-engraftment rate as a potential hazard of HSCT when using non-myeloablative conditioning regimens and Pt-Cy-based GVHD prophylaxis. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2367) "

Transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is an effective treatment method for non-malignant diseases and inherited disorders. Development of acute graft-versus-host-disease (aGVHD) is a negative factor with adverse effects upon clinical outcomes. Usage of “novel” schedules for drug prophylaxis of this complication using posttransplant cyclophosphamide (PtCy) seems to decrease the GVHD risk. The aim of this study was to assess efficiency of PtCy as a tool for aGVHD prevention in the patients with non-malignant diseases of hematopoiesis and inherited syndromes.

Patients and Methods

97 patients with non-malignant blood disorders and metabolic diseases underwent allo-HSCT at the R. Gorbacheva Memorial Institute of Children Oncology and Transplantation over a period of 2005 to 2018. A total of 118 HSCTs were carried out. The aGVHD prophylaxis in 89 cases was performed by a standard schedule (with calcineurin inhibitors). 29 patients were treated according to PtCy regimen, at a dose of 50 mg/kg at days +3 and +4.

Results

Cumulative frequency of acute GVHD comprised 32%. Patients treated with PtCy exhibited lower rates of this condition compared to the group with standard prophylaxis schedule (26% vs 47%, р=0.05). Frequency of skin aGVHD was also less common in the PtCy group (23% vs 45%, р=0.046); gastrointestinal aGVHD was observed at equal rates in the both groups. Stem cell engraftment after nonmyeloablative conditioning in HSCT patients with subsequent PtCy administration proved to be sufficiently weaker compared to other patients (86 vs 50%, р=0.004). In conclusion, posttransplant GVHD prevention based on cyclophosphamide prophylaxis is an efficient method which may decrease aGVHD risk. However, one should take into account a higher non-engraftment rate as a potential hazard of HSCT when using non-myeloablative conditioning regimens and Pt-Cy-based GVHD prophylaxis.

Keywords

Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis.

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Bykova, Anastasia S. Borovkova, Anna A. Osipova, Varvara N. Ovechkina, Olesya V. Paina, Polina V. Kozhokar, Alexander L. Alyanskyi, Alexander D. Kulagin, Elena V. Semenova, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Boris V. Afanasyev<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(250) "Tatiana A. Bykova, Anastasia S. Borovkova, Anna A. Osipova, Varvara N. Ovechkina, Olesya V. Paina, Polina V. Kozhokar, Alexander L. Alyanskyi, Alexander D. Kulagin, Elena V. Semenova, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Boris V. Afanasyev
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" } ["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) "20116" ["VALUE"]=> array(2) { ["TEXT"]=> string(2521) "<p style="text-align: justify;"> Transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is an effective treatment method for non-malignant diseases and inherited disorders. Development of acute graft-versus-host-disease (aGVHD) is a negative factor with adverse effects upon clinical outcomes. Usage of “novel” schedules for drug prophylaxis of this complication using posttransplant cyclophosphamide (PtCy) seems to decrease the GVHD risk. The aim of this study was to assess efficiency of PtCy as a tool for aGVHD prevention in the patients with non-malignant diseases of hematopoiesis and inherited syndromes. </p> <h3 style="text-align: justify;">Patients and Methods</h3> <p style="text-align: justify;"> 97 patients with non-malignant blood disorders and metabolic diseases underwent allo-HSCT at the R. Gorbacheva Memorial Institute of Children Oncology and Transplantation over a period of 2005 to 2018. A total of 118 HSCTs were carried out. The aGVHD prophylaxis in 89 cases was performed by a standard schedule (with calcineurin inhibitors). 29 patients were treated according to PtCy regimen, at a dose of 50 mg/kg at days +3 and +4. </p> <h3 style="text-align: justify;">Results</h3> <p style="text-align: justify;"> Cumulative frequency of acute GVHD comprised 32%. Patients treated with PtCy exhibited lower rates of this condition compared to the group with standard prophylaxis schedule (26% vs 47%, р=0.05). Frequency of skin aGVHD was also less common in the PtCy group (23% vs 45%, р=0.046); gastrointestinal aGVHD was observed at equal rates in the both groups. Stem cell engraftment after nonmyeloablative conditioning in HSCT patients with subsequent PtCy administration proved to be sufficiently weaker compared to other patients (86 vs 50%, р=0.004). In conclusion, posttransplant GVHD prevention based on cyclophosphamide prophylaxis is an efficient method which may decrease aGVHD risk. However, one should take into account a higher non-engraftment rate as a potential hazard of HSCT when using non-myeloablative conditioning regimens and Pt-Cy-based GVHD prophylaxis. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2367) "

Transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is an effective treatment method for non-malignant diseases and inherited disorders. Development of acute graft-versus-host-disease (aGVHD) is a negative factor with adverse effects upon clinical outcomes. Usage of “novel” schedules for drug prophylaxis of this complication using posttransplant cyclophosphamide (PtCy) seems to decrease the GVHD risk. The aim of this study was to assess efficiency of PtCy as a tool for aGVHD prevention in the patients with non-malignant diseases of hematopoiesis and inherited syndromes.

Patients and Methods

97 patients with non-malignant blood disorders and metabolic diseases underwent allo-HSCT at the R. Gorbacheva Memorial Institute of Children Oncology and Transplantation over a period of 2005 to 2018. A total of 118 HSCTs were carried out. The aGVHD prophylaxis in 89 cases was performed by a standard schedule (with calcineurin inhibitors). 29 patients were treated according to PtCy regimen, at a dose of 50 mg/kg at days +3 and +4.

Results

Cumulative frequency of acute GVHD comprised 32%. Patients treated with PtCy exhibited lower rates of this condition compared to the group with standard prophylaxis schedule (26% vs 47%, р=0.05). Frequency of skin aGVHD was also less common in the PtCy group (23% vs 45%, р=0.046); gastrointestinal aGVHD was observed at equal rates in the both groups. Stem cell engraftment after nonmyeloablative conditioning in HSCT patients with subsequent PtCy administration proved to be sufficiently weaker compared to other patients (86 vs 50%, р=0.004). In conclusion, posttransplant GVHD prevention based on cyclophosphamide prophylaxis is an efficient method which may decrease aGVHD risk. However, one should take into account a higher non-engraftment rate as a potential hazard of HSCT when using non-myeloablative conditioning regimens and Pt-Cy-based GVHD prophylaxis.

Keywords

Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis.

" ["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(2367) "

Transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is an effective treatment method for non-malignant diseases and inherited disorders. Development of acute graft-versus-host-disease (aGVHD) is a negative factor with adverse effects upon clinical outcomes. Usage of “novel” schedules for drug prophylaxis of this complication using posttransplant cyclophosphamide (PtCy) seems to decrease the GVHD risk. The aim of this study was to assess efficiency of PtCy as a tool for aGVHD prevention in the patients with non-malignant diseases of hematopoiesis and inherited syndromes.

Patients and Methods

97 patients with non-malignant blood disorders and metabolic diseases underwent allo-HSCT at the R. Gorbacheva Memorial Institute of Children Oncology and Transplantation over a period of 2005 to 2018. A total of 118 HSCTs were carried out. The aGVHD prophylaxis in 89 cases was performed by a standard schedule (with calcineurin inhibitors). 29 patients were treated according to PtCy regimen, at a dose of 50 mg/kg at days +3 and +4.

Results

Cumulative frequency of acute GVHD comprised 32%. Patients treated with PtCy exhibited lower rates of this condition compared to the group with standard prophylaxis schedule (26% vs 47%, р=0.05). Frequency of skin aGVHD was also less common in the PtCy group (23% vs 45%, р=0.046); gastrointestinal aGVHD was observed at equal rates in the both groups. Stem cell engraftment after nonmyeloablative conditioning in HSCT patients with subsequent PtCy administration proved to be sufficiently weaker compared to other patients (86 vs 50%, р=0.004). In conclusion, posttransplant GVHD prevention based on cyclophosphamide prophylaxis is an efficient method which may decrease aGVHD risk. However, one should take into account a higher non-engraftment rate as a potential hazard of HSCT when using non-myeloablative conditioning regimens and Pt-Cy-based GVHD prophylaxis.

Keywords

Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis.

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Быкова, Анастасия С. Боровкова, Анна А. Осипова, Варвара Н. Овечкина, Олеся В. Паина, Полина В. Кожокарь, Александр Л. Алянский, Александр Д. Кулагин, Елена В. Семенова, *Борис И. Смирнов, Людмила С. Зубаровская, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(429) "Татьяна А. Быкова, Анастасия С. Боровкова, Анна А. Осипова, Варвара Н. Овечкина, Олеся В. Паина, Полина В. Кожокарь, Александр Л. Алянский, Александр Д. Кулагин, Елена В. Семенова, *Борис И. Смирнов, 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" } ["DISPLAY_VALUE"]=> string(429) "Татьяна А. Быкова, Анастасия С. Боровкова, Анна А. Осипова, Варвара Н. Овечкина, Олеся В. Паина, Полина В. Кожокарь, Александр Л. Алянский, Александр Д. Кулагин, Елена В. Семенова, *Борис И. Смирнов, Людмила С. Зубаровская, Борис В. Афанасьев
" } ["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) "20112" ["VALUE"]=> array(2) { ["TEXT"]=> string(4727) "<p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических стволовых клеток – эффективный метод терапии незлокачественных заболеваний системы кроветворения и наследственных синдромов. Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития. </p> <h3 style="text-align: justify;">Цель работы</h3> <p style="text-align: justify;"> Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами. </p> <h3 style="text-align: justify;">Пациенты и методы</h3> <p style="text-align: justify;"> В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4. </p> <h3 style="text-align: justify;">Результаты</h3> <p style="text-align: justify;"> Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004). </p> <h3 style="text-align: justify;">Заключение</h3> <p style="text-align: justify;"> Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. Однако, у пациентов с незлокачественными заболеваниями необходимо учитывать факт возможного увеличения частоты неприживления трансплантата при использовании немиелоаблативных режимов кондиционирования и профилактики на основе ПТЦ. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Аллогенная трансплантация гемопоэтических стволовых клеток, неопухолевые заболевания, острая реакция «трансплантат против хозяина», профилактика циклофосфамидом. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4485) "

Аллогенная трансплантация гемопоэтических стволовых клеток – эффективный метод терапии незлокачественных заболеваний системы кроветворения и наследственных синдромов. Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития.

Цель работы

Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами.

Пациенты и методы

В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4.

Результаты

Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004).

Заключение

Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. Однако, у пациентов с незлокачественными заболеваниями необходимо учитывать факт возможного увеличения частоты неприживления трансплантата при использовании немиелоаблативных режимов кондиционирования и профилактики на основе ПТЦ.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, неопухолевые заболевания, острая реакция «трансплантат против хозяина», профилактика циклофосфамидом.

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Аллогенная трансплантация гемопоэтических стволовых клеток – эффективный метод терапии незлокачественных заболеваний системы кроветворения и наследственных синдромов. Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития.

Цель работы

Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами.

Пациенты и методы

В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4.

Результаты

Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004).

Заключение

Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. Однако, у пациентов с незлокачественными заболеваниями необходимо учитывать факт возможного увеличения частоты неприживления трансплантата при использовании немиелоаблативных режимов кондиционирования и профилактики на основе ПТЦ.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, неопухолевые заболевания, острая реакция «трансплантат против хозяина», профилактика циклофосфамидом.

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Introduction

Parvovirus B19 (PVB19) is a well known small DNA virus from Erythrovirus genus which is in scope of pediatricians for decades being associated with erythropoiesis disturbances, arthropathies, myocarditis and other disabling clinical conditions [1]. PVB19 shows an affinity for the group P antigen of red blood cells, with lesser amounts in blood plasma [2]. The major hematotoxic effect of the virus is believed to occur at the pronormoblast stage, thus causing arrest of erythroid differentiation. PVB19 was occasionally found in aplastic anemias and pure red cell aplasia [3]. In this respect, most studies concerned resistant anemia cases in the patients subjected to renal transplantation where the PVB19 was not a rare finding [4].
Over past years, many cases of severe myocarditis and hepatitis were shown to be associated with parvovirus infection, as based on positive PVB19 antigen or DNA findings in affected tissues. Meanwhile, a latent persistence of PVB19 was quite common in skin, synovial tissues, myocardium and bone marrow [5]. The viral DNA was detectable in peripheral blood from 5% of healthy donors [6]. The authors suggest only a small risk for the donor-recipient viral transmission upon hematopoietic stem cell transplantation (HSCT).
Following allogeneic HSCT, a regular activation of herpesviruses and other latent pathogens is observed, due to acute myelosuppression and cellular immune deficiency [7]. Clinical significance of the PVB19 in immunocompromised patients is not yet properly evaluated. E.g., a prolonged study of the PVB19 viral load has been performed in 53 patients after allo-HSCT using quantitative PCR [8]. Specific viral DNA was detectable in blood serum from 30% of the HSCT recipients, either before, or after HSCT, at maximal viral load observed 2 months post-transplant. However, the patients with detectable PVB19 did not show specific clinical symptoms that could be ascribed to parvovirus infection.
Hence, the aim of our work was to compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels, and rates of hematopoietic recovery within 60 days after allo-HSCT. Our preliminary data point to a prognostic significance of parvovirus DNA detection and increased antibody levels is possible predictors for delayed engraftment and febrile neutropenia.
36-43 Table 1. Clinical and demographic characteristics of the patients at allo-HSCT.png

Patients and Methods

A total of 54 pediatric and adolescent patients were involved into the study at the median age of 7.2 (0.6 to 19 years old), who had a malignant disease of hematopoiesis or  inherited disorders as initial diagnosis who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fifty-one patient of this group were observed for at least 2 months (60 days) after HSCT. Selection of the patients for allo-HSCT, choice of conditioning regimens, prophylaxis of acute graftversus-host disease was performed according to current EBMT recommendations. Most part of this group was represented by the patients with acute myeloblastic leukemia (AML, n=16; 30%), acute lymphoblastic leukemia (ALL, n=14; 26%); severe anemias (SAA) of different origin (13%; n=7). 33% of the patients were in first remission after previous treatment. Socio-demographic features their distribution for diagnosis and stage of the disease, main parameters of allo-HSCT, are shown in Tables 1 and 2.
Bone marrow was used as a source of hematopoietic stem cells in 83% of cases (45 of 54 patients), infusion of peripheral stem cells was applied in the rest of cases. Allo-HSCT from unrelated donors was performed in 45% of cases (24 of 54); grafting from matched related donors or haploidentical transplant was carried out in, resp., 20% (11/54) and 35%(19/54) patients. Reduced-intensity conditioning was used in nearly all cases (51 of 54 patients). Development of acute GvHD within early period after allo-HSCT was observed in 25 patients, of them, 9 exhibited grade 3-4 GvHD. Regular examination of the patients before and after HSCT was carried out according to a standard local clinical protocol. He study was approved by the Local Institutional Board at the St.Petersburg State I. Pavlov Medical University. The laboratory studies included routine blood counts and serum biochemistry, urinalysis etc. Quantitative determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) in blood plasma was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. DNA extraction from the samples and quantitative evaluation of PVB19 DNA in the samples were performed by means of PCR with specific fluorescent probes using “Ampliprime” amplification kits» and «Amplisens® Parvovirus В19-FL» (Moscow, Russia). Moreover, quantitative determination of IgМ and IgG antibodies to PV B19 was performed by means of ELISA at 0, +30 and +60 days post-transplant using «Anti-Parvovirus B19 ELISA IgМ» and «Anti-Parvovirus B19 ELISA IgG» kits (EUROIMMUN, Germany). The diagnostic kits were used according to instruction. Statistical evaluation of the data was performed with a Winstat software package.
Table 2. Main characteristics of allogeneic HSCT in the group under study.png

Results

Transplant-related changes of PVB19 DNA levels and anti-PVB19 antibodies

The pre-transplant contents of PVB19 DNA and IgG antibodies to the virus showed a broad-range scatter (Table 3). PVB19 was found in about 30% of this group. Meanwhile, 68% of the patients exhibited increased levels of IgG-anti- PVB19 antibodies (>10 IU/ml), thus reflecting high prevalence of adaptive immune response. Mean pre-transplant contents of PVB19 DNA did not correlate either with age of the patients, or with clinical disease status, physical state, or activation of other latent viruses.
The detectability and average levels of PVB19 DNA as well as concentrations of anti-PVB19 antibodies did not show any significant changes at 30 or 60 days after HSCT, as seen from Table 1. However, actual scatter of these data proved to be rather sufficient, thus suggesting some correlations between these laboratory indexes and clinical signs in the individual patients. In particular, positive (non-zero) viral loads have been registered in 28% before allo-HSCT, 29% and 30.4% on day+30 and day+60 after allo-HSCT, i.e., ca 70% of the patients showed negative results for PVB19 over the early period after allo-HSCT.

Association between the PVB19 presence and specific antibody response after allogeneic HSCT

Detection of PVB19 DNA, both before and after allo-HSCT was not accompanied by IgM antibody detection at any observation point, thus suggesting absence of acute infectious process caused by parvovirus infection.
Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p=8x10-6, 153 assays in 54 clinical cases). In particular, a significant correlation was shown between initial viral load and anti-PVB19 levels at all three terms of the study (Table 3) being, however, maximal at the day+60 after allo-HSCT.
Table 3. Mean and median values for serum IgG PVB19 antibodies and specific viral DNA before and at different terms.png
As seen from Fig. 1, a significant correlation exists between pre-transplant PVB19 load and expressed antibody response detected 60 days after allo-HSCT, i.e., the non-zero viral loads were associated with higher contents of specific antibodies, thus suggesting an association between the PVB19 persistence and production of virus-specific antibodies (Fig. 1).
A half-life time for endogenous IgG antibodies in humans is about 1 to 4 weeks [10]. These findings suggest an opportunity of specific antibody production at early terms after intensive cytostatic treatment, due to potential activity of surviving memory cells, e.g., plasmocytes which are able to function for months and even years after their maturation.

Parvovirus В19 activation and hematopoiesis recovery

In our clinical series, altered engraftment was, generally, more common at increased IgG PVB19 antibody levels when determined 60 days after HSCT (r=0.315; p=0.034; n=46).
Specifically, significant correlations were shown between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels (Fig. 2-4). This association may suggest a relation between continued parvovirus persistence and slower hematopoiesis recovery at 30 to 60 days post-transplant.
In general, altered engraftment was also registered in cases with higher IgG antibodies against parvovirus 60 days after HSCT (r=0.315; p=0.034; n=46).

Parvovirus detection and febrile neutropenia

Positivity for PVB19 DNA by the day +30 after allo-HSCT was, in all cases (14/14), associated with febrile neutropenia (FN), as compared to 68% in patients with nondetectable PVB19 (23/34; р=0.015, see Table 4). Hence, active parvovirus infection could be a sufficient factor of common febrile reactions observed in early posttransplant neutropenia, thus supporting pathogenic significance of this infection, at least, in a subgroup of immunocompromised patiens. Development of these febrile responses could be either virus-induced, or combined with secondary bacterial infections caused by slow recovery of cellular immunity.

Discussion

The issue of optimal PVB19 diagnostics in heavily treated hematological patients is not yet clear, since the results of serological tests (serum IgM and IgG antibodies) did not correlate with detection of viral DNA in blood serum or bone marrow from the HSCT recipients [9]. In our study, a pilot group of the HSCT patients was studied for PVB19 DNA and specific serum antibodies before and at 30-60 days following transplantation. Generally, PVB19 was found at, generally, in about 30% of this group. Remarkably, these figures were at rather low levels, both pre-transplant and after HSCT and did not sufficiently increase post-translant. Mean initial concentrations of PVB19 DNA did not correlate either with age of the patients, or with clinical disease status, physical state, or activation of other latent viruses. IgM antibodies to PVB19 were not detectable in HSCT patients, thus suggesting absence of de novo infection. However, class IgG antibodies(>10 IU/ml) were, found in ca 70% of cases thus presuming previous contacts with the virus. Hence, the background levels of parvovirus exist both pre- and posttransplant.
A search for associations between PVB19 positivity and specific antibody production have shown a significant correlation between pre-transplant PVB19 load and expressed IgG antibody response detected 60 days after allo-HSCT, i.e., the non-zero viral loads were associated with higher contents of specific antibodies, thus suggesting an association between the PVB19 persistence and production of virus-specific antibodies.

Conclusions

1. Presence of parvovirus B19 in peripheral blood of children before allogeneic hematopoietic stem cell transplantation is followed by increased PV-specific antibodies of IgG class in blood serum at all terms after allo-HSCT.
2. Increased IgG levels of antibodies in blood of the patients after allo-HSCT is associated with relative neutropenia and thrombocytopenia at first 2 months after allo-HSCT.
3. Detection of parvovirus DNA at initial terms (before HSCT) and and 30-60 days later may be followed by development of early febrile neutropenias and slower recovery oferythrocyte and platelet counts in peripheral blood.
Table 4. Differences in PVB19 levels for the patients with vs without febrile neutropenia (p=0.015).png
figure 1-2.png
figure3-4.png

Conflict of interest

The authors report no conflicts of interest.

References

1. Asano Y, Yoshikawa T. Human herpesvirus-6 and parvovirus B19 infections in children. Curr Opin Pediatr. 1993;5(1):14-20.
2. Lee TH, Kleinman SH, Wen L, Montalvo L, Todd DS, Wright DJ, Tobler LH, Busch MP; NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II). Distribution of parvovirus B19 DNA in blood compartments and persistence of virus in blood donors. Transfusion. 2011;51(9):1896-908.
3. Urban C, Lackner H, Müller E, Benesch M, Strenger V, Sovinz P, Schwinger W. Stem cell transplantation in 6 children with parvovirus B19- induced severe aplastic anaemia or myelodysplastic syndrome. Klin Pädiatr. 2011;223(6):332-334.
4. Egbuna O, Zand MS, Arbini A, Menegus M, Taylor J. A cluster of parvovirus B19 infections in renal transplant recipients: a prospective case series and review of the literature. Am J Transplant. 2006;6(1):225-231.
5. Corcioli F, Zakrzewska K, Rinieri A, Fanci R, Innocenti M, Civinini R, De Giorgi V, Di Lollo S, Azzi A. Tissue persistence of parvovirus B19 genotypes in asymptomatic persons. J Med Virol. 2008;80(11):2005-2011.
6. Gama BE, Emmel VE, Oliveira-Silva M, Gutiyama LM, Arcuri L, Colares M, de Cássia Tavares R, Bouzas LF, Abdelhay E, Hassan R. Parvovirus B19 in the Context of Hematopoietic Stem Cell Transplantation: Evaluating Cell Donors and Recipients. Transplant Direct. 2017;3(11):e217. doi:10.1097/TXD.0000000000000731.
7. Pankratova OS, Chukhlovin AB. Time course of immune recovery and viral rwactivation following hematopoietic stem cell transplantation. Cell.Ther Transplant. 2016; 5(4):32-43.
8. Rahiala J, Koskenvuo M, Norja P, Meriluoto M, Toppinen M, Lahtinen A, Väisänen E, Waris M, Vuorinen T, Saarinen-Pihkala U, Lappalainen M, Allander T, Ruuskanen O, Hedman K, Söderlund-Venermo M, Vettenranta K. Human parvoviruses B19, PARV4 and bocavirus in pediatric patients with allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48(10):1308-1312.
9. Lundqvist A, Tolfvenstam T, Brytting M, Stolt CM, Hedman K, Broliden K. Prevalence of parvovirus B19 DNA in bone marrow of patients with haematological disorders. Scand J Infect Dis. 1999;31(2):119-122.
10. Kontermann RE. Strategies to extend plasma half-lives of recombinant antibodies. Biodrugs. 2009; 23(2): 93-109.

" ["~DETAIL_TEXT"]=> string(16764) "

Introduction

Parvovirus B19 (PVB19) is a well known small DNA virus from Erythrovirus genus which is in scope of pediatricians for decades being associated with erythropoiesis disturbances, arthropathies, myocarditis and other disabling clinical conditions [1]. PVB19 shows an affinity for the group P antigen of red blood cells, with lesser amounts in blood plasma [2]. The major hematotoxic effect of the virus is believed to occur at the pronormoblast stage, thus causing arrest of erythroid differentiation. PVB19 was occasionally found in aplastic anemias and pure red cell aplasia [3]. In this respect, most studies concerned resistant anemia cases in the patients subjected to renal transplantation where the PVB19 was not a rare finding [4].
Over past years, many cases of severe myocarditis and hepatitis were shown to be associated with parvovirus infection, as based on positive PVB19 antigen or DNA findings in affected tissues. Meanwhile, a latent persistence of PVB19 was quite common in skin, synovial tissues, myocardium and bone marrow [5]. The viral DNA was detectable in peripheral blood from 5% of healthy donors [6]. The authors suggest only a small risk for the donor-recipient viral transmission upon hematopoietic stem cell transplantation (HSCT).
Following allogeneic HSCT, a regular activation of herpesviruses and other latent pathogens is observed, due to acute myelosuppression and cellular immune deficiency [7]. Clinical significance of the PVB19 in immunocompromised patients is not yet properly evaluated. E.g., a prolonged study of the PVB19 viral load has been performed in 53 patients after allo-HSCT using quantitative PCR [8]. Specific viral DNA was detectable in blood serum from 30% of the HSCT recipients, either before, or after HSCT, at maximal viral load observed 2 months post-transplant. However, the patients with detectable PVB19 did not show specific clinical symptoms that could be ascribed to parvovirus infection.
Hence, the aim of our work was to compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels, and rates of hematopoietic recovery within 60 days after allo-HSCT. Our preliminary data point to a prognostic significance of parvovirus DNA detection and increased antibody levels is possible predictors for delayed engraftment and febrile neutropenia.
36-43 Table 1. Clinical and demographic characteristics of the patients at allo-HSCT.png

Patients and Methods

A total of 54 pediatric and adolescent patients were involved into the study at the median age of 7.2 (0.6 to 19 years old), who had a malignant disease of hematopoiesis or  inherited disorders as initial diagnosis who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fifty-one patient of this group were observed for at least 2 months (60 days) after HSCT. Selection of the patients for allo-HSCT, choice of conditioning regimens, prophylaxis of acute graftversus-host disease was performed according to current EBMT recommendations. Most part of this group was represented by the patients with acute myeloblastic leukemia (AML, n=16; 30%), acute lymphoblastic leukemia (ALL, n=14; 26%); severe anemias (SAA) of different origin (13%; n=7). 33% of the patients were in first remission after previous treatment. Socio-demographic features their distribution for diagnosis and stage of the disease, main parameters of allo-HSCT, are shown in Tables 1 and 2.
Bone marrow was used as a source of hematopoietic stem cells in 83% of cases (45 of 54 patients), infusion of peripheral stem cells was applied in the rest of cases. Allo-HSCT from unrelated donors was performed in 45% of cases (24 of 54); grafting from matched related donors or haploidentical transplant was carried out in, resp., 20% (11/54) and 35%(19/54) patients. Reduced-intensity conditioning was used in nearly all cases (51 of 54 patients). Development of acute GvHD within early period after allo-HSCT was observed in 25 patients, of them, 9 exhibited grade 3-4 GvHD. Regular examination of the patients before and after HSCT was carried out according to a standard local clinical protocol. He study was approved by the Local Institutional Board at the St.Petersburg State I. Pavlov Medical University. The laboratory studies included routine blood counts and serum biochemistry, urinalysis etc. Quantitative determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) in blood plasma was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. DNA extraction from the samples and quantitative evaluation of PVB19 DNA in the samples were performed by means of PCR with specific fluorescent probes using “Ampliprime” amplification kits» and «Amplisens® Parvovirus В19-FL» (Moscow, Russia). Moreover, quantitative determination of IgМ and IgG antibodies to PV B19 was performed by means of ELISA at 0, +30 and +60 days post-transplant using «Anti-Parvovirus B19 ELISA IgМ» and «Anti-Parvovirus B19 ELISA IgG» kits (EUROIMMUN, Germany). The diagnostic kits were used according to instruction. Statistical evaluation of the data was performed with a Winstat software package.
Table 2. Main characteristics of allogeneic HSCT in the group under study.png

Results

Transplant-related changes of PVB19 DNA levels and anti-PVB19 antibodies

The pre-transplant contents of PVB19 DNA and IgG antibodies to the virus showed a broad-range scatter (Table 3). PVB19 was found in about 30% of this group. Meanwhile, 68% of the patients exhibited increased levels of IgG-anti- PVB19 antibodies (>10 IU/ml), thus reflecting high prevalence of adaptive immune response. Mean pre-transplant contents of PVB19 DNA did not correlate either with age of the patients, or with clinical disease status, physical state, or activation of other latent viruses.
The detectability and average levels of PVB19 DNA as well as concentrations of anti-PVB19 antibodies did not show any significant changes at 30 or 60 days after HSCT, as seen from Table 1. However, actual scatter of these data proved to be rather sufficient, thus suggesting some correlations between these laboratory indexes and clinical signs in the individual patients. In particular, positive (non-zero) viral loads have been registered in 28% before allo-HSCT, 29% and 30.4% on day+30 and day+60 after allo-HSCT, i.e., ca 70% of the patients showed negative results for PVB19 over the early period after allo-HSCT.

Association between the PVB19 presence and specific antibody response after allogeneic HSCT

Detection of PVB19 DNA, both before and after allo-HSCT was not accompanied by IgM antibody detection at any observation point, thus suggesting absence of acute infectious process caused by parvovirus infection.
Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p=8x10-6, 153 assays in 54 clinical cases). In particular, a significant correlation was shown between initial viral load and anti-PVB19 levels at all three terms of the study (Table 3) being, however, maximal at the day+60 after allo-HSCT.
Table 3. Mean and median values for serum IgG PVB19 antibodies and specific viral DNA before and at different terms.png
As seen from Fig. 1, a significant correlation exists between pre-transplant PVB19 load and expressed antibody response detected 60 days after allo-HSCT, i.e., the non-zero viral loads were associated with higher contents of specific antibodies, thus suggesting an association between the PVB19 persistence and production of virus-specific antibodies (Fig. 1).
A half-life time for endogenous IgG antibodies in humans is about 1 to 4 weeks [10]. These findings suggest an opportunity of specific antibody production at early terms after intensive cytostatic treatment, due to potential activity of surviving memory cells, e.g., plasmocytes which are able to function for months and even years after their maturation.

Parvovirus В19 activation and hematopoiesis recovery

In our clinical series, altered engraftment was, generally, more common at increased IgG PVB19 antibody levels when determined 60 days after HSCT (r=0.315; p=0.034; n=46).
Specifically, significant correlations were shown between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels (Fig. 2-4). This association may suggest a relation between continued parvovirus persistence and slower hematopoiesis recovery at 30 to 60 days post-transplant.
In general, altered engraftment was also registered in cases with higher IgG antibodies against parvovirus 60 days after HSCT (r=0.315; p=0.034; n=46).

Parvovirus detection and febrile neutropenia

Positivity for PVB19 DNA by the day +30 after allo-HSCT was, in all cases (14/14), associated with febrile neutropenia (FN), as compared to 68% in patients with nondetectable PVB19 (23/34; р=0.015, see Table 4). Hence, active parvovirus infection could be a sufficient factor of common febrile reactions observed in early posttransplant neutropenia, thus supporting pathogenic significance of this infection, at least, in a subgroup of immunocompromised patiens. Development of these febrile responses could be either virus-induced, or combined with secondary bacterial infections caused by slow recovery of cellular immunity.

Discussion

The issue of optimal PVB19 diagnostics in heavily treated hematological patients is not yet clear, since the results of serological tests (serum IgM and IgG antibodies) did not correlate with detection of viral DNA in blood serum or bone marrow from the HSCT recipients [9]. In our study, a pilot group of the HSCT patients was studied for PVB19 DNA and specific serum antibodies before and at 30-60 days following transplantation. Generally, PVB19 was found at, generally, in about 30% of this group. Remarkably, these figures were at rather low levels, both pre-transplant and after HSCT and did not sufficiently increase post-translant. Mean initial concentrations of PVB19 DNA did not correlate either with age of the patients, or with clinical disease status, physical state, or activation of other latent viruses. IgM antibodies to PVB19 were not detectable in HSCT patients, thus suggesting absence of de novo infection. However, class IgG antibodies(>10 IU/ml) were, found in ca 70% of cases thus presuming previous contacts with the virus. Hence, the background levels of parvovirus exist both pre- and posttransplant.
A search for associations between PVB19 positivity and specific antibody production have shown a significant correlation between pre-transplant PVB19 load and expressed IgG antibody response detected 60 days after allo-HSCT, i.e., the non-zero viral loads were associated with higher contents of specific antibodies, thus suggesting an association between the PVB19 persistence and production of virus-specific antibodies.

Conclusions

1. Presence of parvovirus B19 in peripheral blood of children before allogeneic hematopoietic stem cell transplantation is followed by increased PV-specific antibodies of IgG class in blood serum at all terms after allo-HSCT.
2. Increased IgG levels of antibodies in blood of the patients after allo-HSCT is associated with relative neutropenia and thrombocytopenia at first 2 months after allo-HSCT.
3. Detection of parvovirus DNA at initial terms (before HSCT) and and 30-60 days later may be followed by development of early febrile neutropenias and slower recovery oferythrocyte and platelet counts in peripheral blood.
Table 4. Differences in PVB19 levels for the patients with vs without febrile neutropenia (p=0.015).png
figure 1-2.png
figure3-4.png

Conflict of interest

The authors report no conflicts of interest.

References

1. Asano Y, Yoshikawa T. Human herpesvirus-6 and parvovirus B19 infections in children. Curr Opin Pediatr. 1993;5(1):14-20.
2. Lee TH, Kleinman SH, Wen L, Montalvo L, Todd DS, Wright DJ, Tobler LH, Busch MP; NHLBI Retrovirus Epidemiology Donor Study-II (REDS-II). Distribution of parvovirus B19 DNA in blood compartments and persistence of virus in blood donors. Transfusion. 2011;51(9):1896-908.
3. Urban C, Lackner H, Müller E, Benesch M, Strenger V, Sovinz P, Schwinger W. Stem cell transplantation in 6 children with parvovirus B19- induced severe aplastic anaemia or myelodysplastic syndrome. Klin Pädiatr. 2011;223(6):332-334.
4. Egbuna O, Zand MS, Arbini A, Menegus M, Taylor J. A cluster of parvovirus B19 infections in renal transplant recipients: a prospective case series and review of the literature. Am J Transplant. 2006;6(1):225-231.
5. Corcioli F, Zakrzewska K, Rinieri A, Fanci R, Innocenti M, Civinini R, De Giorgi V, Di Lollo S, Azzi A. Tissue persistence of parvovirus B19 genotypes in asymptomatic persons. J Med Virol. 2008;80(11):2005-2011.
6. Gama BE, Emmel VE, Oliveira-Silva M, Gutiyama LM, Arcuri L, Colares M, de Cássia Tavares R, Bouzas LF, Abdelhay E, Hassan R. Parvovirus B19 in the Context of Hematopoietic Stem Cell Transplantation: Evaluating Cell Donors and Recipients. Transplant Direct. 2017;3(11):e217. doi:10.1097/TXD.0000000000000731.
7. Pankratova OS, Chukhlovin AB. Time course of immune recovery and viral rwactivation following hematopoietic stem cell transplantation. Cell.Ther Transplant. 2016; 5(4):32-43.
8. Rahiala J, Koskenvuo M, Norja P, Meriluoto M, Toppinen M, Lahtinen A, Väisänen E, Waris M, Vuorinen T, Saarinen-Pihkala U, Lappalainen M, Allander T, Ruuskanen O, Hedman K, Söderlund-Venermo M, Vettenranta K. Human parvoviruses B19, PARV4 and bocavirus in pediatric patients with allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013;48(10):1308-1312.
9. Lundqvist A, Tolfvenstam T, Brytting M, Stolt CM, Hedman K, Broliden K. Prevalence of parvovirus B19 DNA in bone marrow of patients with haematological disorders. Scand J Infect Dis. 1999;31(2):119-122.
10. Kontermann RE. Strategies to extend plasma half-lives of recombinant antibodies. Biodrugs. 2009; 23(2): 93-109.

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Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА.<br> Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (&gt;10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК.<br> Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p&lt;0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций.<br> В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения. </p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(318) "Частота выявления парвовируса B19, специфического антительного ответа и задержка восстановления гемопоза после аллогенной трансплантации гемопоэтических стволовых клеток" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(318) "Частота выявления парвовируса B19, специфического антительного ответа и задержка восстановления гемопоза после аллогенной трансплантации гемопоэтических стволовых клеток" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(318) "Частота выявления парвовируса B19, специфического антительного ответа и задержка восстановления гемопоза после аллогенной 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Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. Зубаровская, Борис В.Афанасьев" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(221) "Ирина В. Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. 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Пастера, Санкт-Петербург, Россия; НИИ детской онкологии, гематологии и Трансплантологии им. Р. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(465) "НИИ эпидемиологии и микробиологии им. Пастера, Санкт-Петербург, Россия; НИИ детской онкологии, гематологии и Трансплантологии им. Р. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. 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) "20124" ["VALUE"]=> array(2) { ["TEXT"]=> string(5888) "<p style="text-align: justify;"> Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА.<br> Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (&gt;10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК.<br> Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p&lt;0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций.<br> В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5796) "

Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА.
Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (>10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК.
Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p<0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций.
В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения.

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Khamitova, Irina N. Lavrentyeva, Maria Yu. Averyanova, Alexey B. Chukhlovin, Ludmila S. Zubarovskaya, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(129) "Irina V. Khamitova, Irina N. Lavrentyeva, Maria Yu. Averyanova, Alexey B. Chukhlovin, 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) "20126" ["VALUE"]=> array(2) { ["TEXT"]=> string(266) "L. Pasteur Research Institute of Epidemiology and Microbiology, St.Petersburg, Russia; R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State Medical I. Pavlov University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(266) "L. Pasteur Research Institute of Epidemiology and Microbiology, St.Petersburg, Russia; R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State Medical I. Pavlov University, St. Petersburg, Russia" ["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) "20127" ["VALUE"]=> array(2) { ["TEXT"]=> string(3344) "<p style="text-align: justify;"> Parvovirus B19 (PVB19) is a well known DNA virus which seems to be associated, e.g., with erythropoiesis disturbances. Being a latent virus, the PVB19 may become active in immunocompromised patients. However, clinical significance of PVB19 after hematopoietic stem cell transplantation (HSCT) is yet not clear. Therefore, the aim of our study was compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels and possible effects upon hematopoietic recovery within 60 days after HSCT. Our study included 54 pediatric and adolescent patients of 0.6 to 19 years old with blood malignancies or inherited disorders who underwent allogeneic HSCT. Fifty-one patient of this group were observed for at least 60 days after HSCT. 33% of the patients were in first remission after previous treatment. Non-myeloablative conditioning treatment was used in 94% of cases. Antilymphocyte immune globulin and/or cyclophosphamide were applied as immunosuppressive therapy. Determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. Quantitative determination of the PV B19 DNA was performed by gene-specific real-time PCR using commercial kits. IgG and IgM antibodies to PVB19 were determined quantitatively by means of ELISA method. </p> <p style="text-align: justify;"> Results of the study were as follows: PVB19 DNA at low levels was found in blood plasma samples of 31.5% HSCT patients. However, 68% of the patients exhibited detectable levels of IgG-anti-PVB19 antibodies (&gt;10 IU/ ml), thus reflecting high prevalence of adaptive immune response. Generally, prevalence and mean levels of PVB19 DNA as well as concentrations of anti-PV B19 antibodies did not show any significant changes at 30 or 60 days after HSCT. </p> <p style="text-align: justify;"> Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p&lt;0.0001). Moreover, positivity for PVB19 DNA by the day +30 after allo-HSCT was in all cases (14/14), associated with febrile neutropenia in the patients, thus suggesting their potential role in posttransplant infections. </p> <p style="text-align: justify;"> Specifically, important correlations were observed between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels. This finding may suggest an association between parvovirus activation and slower hematopoiesis recovery after allogeneic HSCT. </p> <h2 style="text-align: justify;"> Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3204) "

Parvovirus B19 (PVB19) is a well known DNA virus which seems to be associated, e.g., with erythropoiesis disturbances. Being a latent virus, the PVB19 may become active in immunocompromised patients. However, clinical significance of PVB19 after hematopoietic stem cell transplantation (HSCT) is yet not clear. Therefore, the aim of our study was compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels and possible effects upon hematopoietic recovery within 60 days after HSCT. Our study included 54 pediatric and adolescent patients of 0.6 to 19 years old with blood malignancies or inherited disorders who underwent allogeneic HSCT. Fifty-one patient of this group were observed for at least 60 days after HSCT. 33% of the patients were in first remission after previous treatment. Non-myeloablative conditioning treatment was used in 94% of cases. Antilymphocyte immune globulin and/or cyclophosphamide were applied as immunosuppressive therapy. Determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. Quantitative determination of the PV B19 DNA was performed by gene-specific real-time PCR using commercial kits. IgG and IgM antibodies to PVB19 were determined quantitatively by means of ELISA method.

Results of the study were as follows: PVB19 DNA at low levels was found in blood plasma samples of 31.5% HSCT patients. However, 68% of the patients exhibited detectable levels of IgG-anti-PVB19 antibodies (>10 IU/ ml), thus reflecting high prevalence of adaptive immune response. Generally, prevalence and mean levels of PVB19 DNA as well as concentrations of anti-PV B19 antibodies did not show any significant changes at 30 or 60 days after HSCT.

Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p<0.0001). Moreover, positivity for PVB19 DNA by the day +30 after allo-HSCT was in all cases (14/14), associated with febrile neutropenia in the patients, thus suggesting their potential role in posttransplant infections.

Specifically, important correlations were observed between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels. This finding may suggest an association between parvovirus activation and slower hematopoiesis recovery after allogeneic HSCT.

Keywords

Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia.

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Being a latent virus, the PVB19 may become active in immunocompromised patients. However, clinical significance of PVB19 after hematopoietic stem cell transplantation (HSCT) is yet not clear. Therefore, the aim of our study was compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels and possible effects upon hematopoietic recovery within 60 days after HSCT. Our study included 54 pediatric and adolescent patients of 0.6 to 19 years old with blood malignancies or inherited disorders who underwent allogeneic HSCT. Fifty-one patient of this group were observed for at least 60 days after HSCT. 33% of the patients were in first remission after previous treatment. Non-myeloablative conditioning treatment was used in 94% of cases. Antilymphocyte immune globulin and/or cyclophosphamide were applied as immunosuppressive therapy. Determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. Quantitative determination of the PV B19 DNA was performed by gene-specific real-time PCR using commercial kits. IgG and IgM antibodies to PVB19 were determined quantitatively by means of ELISA method. </p> <p style="text-align: justify;"> Results of the study were as follows: PVB19 DNA at low levels was found in blood plasma samples of 31.5% HSCT patients. However, 68% of the patients exhibited detectable levels of IgG-anti-PVB19 antibodies (&gt;10 IU/ ml), thus reflecting high prevalence of adaptive immune response. Generally, prevalence and mean levels of PVB19 DNA as well as concentrations of anti-PV B19 antibodies did not show any significant changes at 30 or 60 days after HSCT. </p> <p style="text-align: justify;"> Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p&lt;0.0001). Moreover, positivity for PVB19 DNA by the day +30 after allo-HSCT was in all cases (14/14), associated with febrile neutropenia in the patients, thus suggesting their potential role in posttransplant infections. </p> <p style="text-align: justify;"> Specifically, important correlations were observed between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels. This finding may suggest an association between parvovirus activation and slower hematopoiesis recovery after allogeneic HSCT. </p> <h2 style="text-align: justify;"> Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3204) "

Parvovirus B19 (PVB19) is a well known DNA virus which seems to be associated, e.g., with erythropoiesis disturbances. Being a latent virus, the PVB19 may become active in immunocompromised patients. However, clinical significance of PVB19 after hematopoietic stem cell transplantation (HSCT) is yet not clear. Therefore, the aim of our study was compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels and possible effects upon hematopoietic recovery within 60 days after HSCT. Our study included 54 pediatric and adolescent patients of 0.6 to 19 years old with blood malignancies or inherited disorders who underwent allogeneic HSCT. Fifty-one patient of this group were observed for at least 60 days after HSCT. 33% of the patients were in first remission after previous treatment. Non-myeloablative conditioning treatment was used in 94% of cases. Antilymphocyte immune globulin and/or cyclophosphamide were applied as immunosuppressive therapy. Determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. Quantitative determination of the PV B19 DNA was performed by gene-specific real-time PCR using commercial kits. IgG and IgM antibodies to PVB19 were determined quantitatively by means of ELISA method.

Results of the study were as follows: PVB19 DNA at low levels was found in blood plasma samples of 31.5% HSCT patients. However, 68% of the patients exhibited detectable levels of IgG-anti-PVB19 antibodies (>10 IU/ ml), thus reflecting high prevalence of adaptive immune response. Generally, prevalence and mean levels of PVB19 DNA as well as concentrations of anti-PV B19 antibodies did not show any significant changes at 30 or 60 days after HSCT.

Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p<0.0001). Moreover, positivity for PVB19 DNA by the day +30 after allo-HSCT was in all cases (14/14), associated with febrile neutropenia in the patients, thus suggesting their potential role in posttransplant infections.

Specifically, important correlations were observed between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels. This finding may suggest an association between parvovirus activation and slower hematopoiesis recovery after allogeneic HSCT.

Keywords

Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia.

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Parvovirus B19 (PVB19) is a well known DNA virus which seems to be associated, e.g., with erythropoiesis disturbances. Being a latent virus, the PVB19 may become active in immunocompromised patients. However, clinical significance of PVB19 after hematopoietic stem cell transplantation (HSCT) is yet not clear. Therefore, the aim of our study was compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels and possible effects upon hematopoietic recovery within 60 days after HSCT. Our study included 54 pediatric and adolescent patients of 0.6 to 19 years old with blood malignancies or inherited disorders who underwent allogeneic HSCT. Fifty-one patient of this group were observed for at least 60 days after HSCT. 33% of the patients were in first remission after previous treatment. Non-myeloablative conditioning treatment was used in 94% of cases. Antilymphocyte immune globulin and/or cyclophosphamide were applied as immunosuppressive therapy. Determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. Quantitative determination of the PV B19 DNA was performed by gene-specific real-time PCR using commercial kits. IgG and IgM antibodies to PVB19 were determined quantitatively by means of ELISA method.

Results of the study were as follows: PVB19 DNA at low levels was found in blood plasma samples of 31.5% HSCT patients. However, 68% of the patients exhibited detectable levels of IgG-anti-PVB19 antibodies (>10 IU/ ml), thus reflecting high prevalence of adaptive immune response. Generally, prevalence and mean levels of PVB19 DNA as well as concentrations of anti-PV B19 antibodies did not show any significant changes at 30 or 60 days after HSCT.

Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p<0.0001). Moreover, positivity for PVB19 DNA by the day +30 after allo-HSCT was in all cases (14/14), associated with febrile neutropenia in the patients, thus suggesting their potential role in posttransplant infections.

Specifically, important correlations were observed between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels. This finding may suggest an association between parvovirus activation and slower hematopoiesis recovery after allogeneic HSCT.

Keywords

Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia.

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Pasteur Research Institute of Epidemiology and Microbiology, St.Petersburg, Russia; R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State Medical I. Pavlov University, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(266) "L. Pasteur Research Institute of Epidemiology and Microbiology, St.Petersburg, Russia; R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State Medical I. Pavlov University, St. Petersburg, Russia" ["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(266) "L. 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Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. Зубаровская, Борис В.Афанасьев" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(221) "Ирина В. Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, 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" } ["DISPLAY_VALUE"]=> string(221) "Ирина В. Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. Зубаровская, Борис В.Афанасьев" } ["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) "20124" ["VALUE"]=> array(2) { ["TEXT"]=> string(5888) "<p style="text-align: justify;"> Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА.<br> Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (&gt;10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК.<br> Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p&lt;0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций.<br> В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5796) "

Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА.
Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (>10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК.
Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p<0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций.
В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения.

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Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА.
Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (>10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК.
Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p<0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций.
В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения.

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Introduction

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal diseases with abnormalities in hematopoietic stem cells, which is based on somatic mutations of various genes and/or alterations in epigenetic regulation induced by disturbance of the microenvironment, as well as disturbances in the immune system of antitumor surveillance. In many patients, the development of MDS is preceded by a period of non-clonal or clonal cytopenia of an unclear significance, which is induced by somatic mutations associated with age and an increased risk of leukemia. This results in increased proliferation, inefficiency of clonal hematopoiesis and suppression of normal hematopoiesis, and in advanced stages in an abrogation of differentiation, accumulation of blasts and the risk of transformation into acute leukemia.
The incidence of MDS increases markedly with age and the disease is most prevalent in individuals who are white and male. It is conservatively estimated that >10,000 new cases of MDS occur annually, and that ≥60,000 individuals with MDS currently reside in the United States [1].
Recent studies have provided consistent evidence of age-related hematopoietic clones (clonal hematopoiesis of indeterminate potential; CHIP) [2], driven by mutations of genes that are recurrently mutated in myeloid neoplasms and associated with increase in the risk of hematologic cancer. Although several issues remain to be clarified, targeted gene sequencing may be of potential value in the dissection between clonal myelodysplasia, nonclonal cytopenia, and clonal hematopoiesis arising upon aging or in the context of acquired marrow failure [3].
A distinctive feature of both MDS and a number of related diseases (MDS/myeloproliferative tumors, secondary acute myeloid leukemia) is an alteration in DNA methylation processes [4]. Currently, hypomethylating agents (HMA: 5-azacytidine and decitabine) are the only approved medications for the treatment of MDS [5, 6], but only 40-50% of patients respond to therapy [7]. Though there is relatively favorable cytogenetic subset of patients bearing 5q deletion with high initial response rate to lenalidomide, 35% of them will not respond to or do not tolerate the drug. Moreover, most of these patients will lose their response after a few years, requiring switching to HMA as one of further treatment options [8].
Existing prognostic factors regarding survival and the likelihood of response to therapy are based largely on the results of morphological and cytogenetic studies [9]. At the moment, their predictive power is insufficient to make a clinical decision regarding the rationale for therapy with HMA [10]. In connection with these problems, the search for biomarkers, which have prognostic significance with respect to survival and individual response to treatment, is ongoing. The use of modern tools of genome research allowed taking a fresh look at the pathogenesis of MDS and related diseases. Genes involved in both methylation and other metabolic pathways are often mutated with MDS [11]. At the moment, a number of works have been published that analyze the mutational status of the main genes involved in the pathogenesis of MDS and their predictive value in the context of response to therapy and overall survival.
The main goal of our study was to compare the data on the frequency of mutations in different populations of patients with MDS. We also conducted a meta-analysis combining data from available studies to systematically assess the impact of mutation status on response and survival.

Materials and methods

Data collection

The electronic literature search was conducted in the Pub-Med and Cochrane database. Studies were selected if they enrolled patients with various forms of MDS, as well as MDS/myeloproliferative tumors, which underwent first-line therapy with hypomethylating agents. An additional prerequisite was the fact that these studies performed full-genomic or full-exome sequencing in order to identify somatic mutations having prognostic significance with respect to overall survival and/or response to therapy. The search terms were “myelodysplastic syndrome” “sequencing” “patients” and “azacitidine”/”decitabine”. Only articles in English were included in the analysis (Fig. 1). According to these criteria, 12 original articles were selected (Table 1), from which primary data were extracted, which served as the basis for the combined database of this study. Mutation frequencies in the following genes were included in the combined database: ASXL1, DNMT3A, EZH2, U2AF1, TET2, RUNX1, TP53, SRSF2, RAS, SF3B1, CBL (Table 2).
44-51 Table 1.The list of studies used for data analysis.png
44-51 Table 2. Number of patients in whom the gene.png

Statistical analysis

The meta-analysis included the studies with available individual mutational status along with response to HMA and/ or survival data. Based on this information a surrogate table was re-created with nominal variables. The interstudy difference in the prevalence of mutations as well as the response to therapy was analyzed with chi-square test based on the created surrogate tables. The survival variable was treated as logical and non-time dependent due to absence of individual time data. Confidence intervals for the incidence of mutations were calculated based on individual incidences in the studies with random effect model. The confidence intervals for response and survival were produced based on mixed models. The heterogeneity between studies was assessed with Cochran’s Q test with n degrees of freedom. The studies with lees then ten patients per mutation were excluded from the heterogeneity analysis. The analysis was performed in SAS 9.3. The significance for all tests was set at 0.05.
44-51 Figure 1. The diagram of the search process.png

Results

Frequency of mutations in the studied population

We observed a statistically significant difference in the frequencies of all the mutations studied, depending on the study population (for specific studies see Fig. 1). Mean frequency and 95%CI for each mutation were as follows: ASXL1 22.5% (13.6-29.8%); DNMT3A 10.7% (7.3-12.9%); EZH2 5.3% (2.4-7.0%); U2AF1 9.5% (3.7-13.8%); TET2 21.3% (14.2-32.5%); RUNX1 9.1% (3.9-13.7%); TP53 9.4% (4.7-15.2%); SRSF2 13.6% (7.1-28.1%); RAS 4.9% (2.2-15.1%); SF3B1 12.0% (4.4-12.2%); CBL 3.2% (0.1-8.9%); None 18.2% (8.0-23.3%); р<0.0001.
44-51 Figure 2. The inter-study differences for the incidence.png

Response to HMA and overall survival associated with presence of specific mutations

The simulation of common incidence table across studies demonstrated a statistically significant effect on the frequency of response to therapy for mutations in ASXL1, DNMT3A, TET2, RUNX1, TP53, SRSF2, SF3B1 genes and for patients without corresponding mutations (Fig. 3A, 4A). Mean response rates and 95%CI for each mutation were: ASXL1 50.2% (48.8-51.6%); DNMT3A 50.4% (48.3-52.5%); EZH2 49.6% (47.3-51.9%); U2AF1 49.7% (48.2-51.2%); TET2 50.6% (49.3-51.9%); RUNX1 49.6% (47.8-51.4%); TP53 52.0% (48.7-55.2%); SRSF2 51.0% (48.5-53.6%); RAS 50.9% (36.9-64.7%); SF3B1 50.3% (48.5-52.1%); CBL 49.0% (44.9-53.1%); None, 50.3% (47.7-52.8%).
A statistically significant effect on the level of survival for mutations in the genes ASXL1, DNMT3A, EZH2, U2AF1, TET2, RUNX1, TP53, SF3B1, CBL was revealed (Fig. 3B, 4B). Mean overall survival and 95%CI for each mutation were: ASXL1 49.5% (47.2-51.8%); DNMT3A 48.7% (45.6-51.9%); EZH2 49.1% (42.9-55.5%); U2AF1 49.0% (43.0-55.1%); TET2 48.8% (46.7-51.0%); RUNX1 49.0% (45.9-52.1%); TP53 46.8% (44.0-49.7%); SRSF2 51.3% (43.5-59.0%); SF3B1 50.4% (47.0-53.8%); CBL 48.7% (45.5-51.8); None, 52.6% (10.0-91.7%).
However, the magnitude of difference both in response and in survival was relatively modest. For example, the mean OS for DMT3A and TET2 were 48.7% and 48.8%, respectively. Another example of close incidences of responses: 52.0% and 50.2% for patients with TP53 and TET2 mutations, respectively.
Mutations in CBL, EZH2, U2AF1, RAS genes didn’t produce any significant effect on response rate as well as there was no significant impact on survival observed for SRSF2 mutation and in patients without any corresponding mutations.
Fig. 4 contains the forest plot showing mean effects of different gene mutations upon drug response, overall survival, and appropriate confidence intervals.
44-51 Figure 3. Frequency of response to the HMA therapy.png

Discussion

The identification of MDS patients with a high probability of response to HMA therapy remains an important and unresolved clinical task. From the available data, it is known that the presence of a number of somatic mutations can affect the response rates to therapy and the level of overall survival [12]. Mutations in the TET2, DNMT3A, TP53 genes were reported to be associated with a high probability of response to HMA [13, 14, 15]. At the same time, mutations in the EZH2 and TP53 genes are associated with a lower level of overall survival [11, 13]. However these findings are not confirmed in the other studies [11, 15]. Thus it is crucial to understand the reasons behind the variability of results.
In this study we summarized the results of 12 studies with whole exome/genome sequencing in MDS [10, 11, 13-22]. The main difference in this meta-analysis is the availability of individual patient data, thus we have not merged the confidence intervals and response rates, but re-created the interstudy database with mutations, response to therapy and survival. This approach allowed calculating very precise incidence of the mutations and confidence intervals on more than one thousand patients. The obvious weakness of the study is the absence of clinical risk stratification, longitudinal follow-up as well as duration and depth of the response.
One of the first important conclusions of this study is the significant heterogeneity in the incidence of mutations across studies. On the one hand, this might be due to heterogeneity in the age, gender, risk of the disease and high percentage of chronic myelomonocytic leukemia in several studies [18, 21]. On the other hand, the 2012 World Health Organization survey, revealed substantial difference in the incidence of blood cancer across the globe [23]. Thus the observed difference might be not only due to different inclusion criteria, but also due to variable prevalent biology of MDS in different ethnicities.
The other surprising finding was that despite significant differences in response and survival due to substantial number of patients in the analysis, the magnitude of difference was very modest almost for all of the mutations. The first studies identified significant impact of TET2 mutations on survival or response to therapy [24, 25], however after the accumulation of data in the other meta-analysis it was demonstrated that it is not a significant factor for response and survival [26]. The only exception found is the p53 mutation that has better primary response to therapy [11, 20], however it adversely affects survival compared to the other mutations, where despite lower response rates the survival was better. The study confirms the extremely negative impact of mutated p53 on prognosis that might not even be corrected by stem cell transplantation [27, 28]. Another finding is improved survival in the SF3B1 mutation cohort, however as with other mutations the magnitude of the difference was modest compared to the previous studies [29].
Despite the trend towards a lower frequency of responses in the presence of RUNX1 mutation, these data require further detailed testing, and it should be emphasized that no mutation associated solely with the lack of response to HMA therapy is currently known, which would allow discussion of the inadvisability of this type of treatment when clinically indicated [11].
Figure 4. Forest plot of survival and response to HMA with 95% confidence intervals.png
The observed confidence intervals of response to hypomethylating agents were comparable to the literature data of 40-50% [30, 31], with little variance due to mutational status, which raises the question, whether the mutational status is a good prognostic factor. On the other hand the clinical risk scales have a very good predictive power in terms of survival [29]. And the drawback of this study, as well as in every meta- analysis, was the absence of individual clinical prognostic features, thus the correction for clinical co-variables could not be made. With these co-variables the results of the study could be significantly different. This demonstrates the need for international cooperation and joining both the sequencing and clinical data from different institutions. This type of activity could have provided further understanding of MDS and the approaches to treat it.
The interesting group in this study was patients without mutations determined with sequencing. Interestingly, though they had the response rate around median, the survival of these patients was much more heterogenic then in the known mutations groups. It demonstrates that this is also a heterogenic group with variable prognosis. The underlining mechanisms are still to be determined. The most promising approach is further elucidation of microenvironment disturbances and changes in miRNA signaling that lead to MDS [32].
In conclusion, the study demonstrated, though significant, but moderate impact of mutations in patients with MDS on response to HMA. Further cooperative studies with sharing the clinical and sequencing data are required to understand MDS pathophysiology and approaches to treatment.

Acknowledgements

This work was supported by Russian Science Foundation, grant № 17-75-20145. Authors confirm the absence of any conflicts of interests.

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21. Meldi K, Qin T, Buchi F, Droin N, Sotzen J, Micol JB, Selimoglu-Buet D, Masala E, Allione B, Gioia D, Poloni A, Lunghi M, Solary E, Abdel-Wahab O, Santini V, Figueroa ME. Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia. J Clin Invest. 2015;125(5):1857-1872.
22. Polgarova K, Vargova K, Kulvait V, Dusilkova N, Minarik L, Zemanova Z, Pesta M, Jonasova A, Stopka T. Somatic mutation dynamics in MDS patients treated with azacitidine indicate clonal selection in patients-responders. Oncotarget. 2017;8(67):111966-111978.
23. GLOBOCAN 2012, IARC - 14.3.2018 24. Kosmider O, Gelsi-Boyer V, Cheok M, Grabar S, Della-Valle V, Picard F, Viguié F, Quesnel B, Beyne-Rauzy O, Solary E, Vey N, Hunault-Berger M, Fenaux P, Mansat-De Mas V, Delabesse E, Guardiola P, Lacombe C, Vainchenker W, Preudhomme C, Dreyfus F, Bernard OA, Birnbaum D, Fontenay M, Groupe Francophone des Myélodysplasies. TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs). Blood. 2009; 114(15):3285-3291.
25. Smith AE, Mohamedali AM, Kulasekararaj A, Lim Z, Göken J, Lea NC, Przychodzen B, Mian SA, Nasser EE, Shooter C, Westwood NB, Strupp C, Gattermann N, Maciejewski JP, Germing U, Mufti GJ. Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value. Blood. 2010; 116(19):3923-3932.
26. Lin Y, Lin Z, Cheng K, Fang Z, Li Z, Luo Y, Xu B. Prognostic role of TET2 deficiency in myelodysplastic syndromes: A meta-analysis. Oncotarget. 2017; 8(26): 43295–43305.
27. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, Gundem G, Van Loo P, Martincorena I, Ganly P, Mudie L, McLaren S, O'Meara S, Raine K, Jones DR, Teague JW, Butler AP, Greaves MF, Ganser A, Döhner K, Schlenk RF, Döhner H, Campbell PJ. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016; 374(23):2209-2221.
28. Kröger N, Iacobelli S, Franke GN, Platzbecker U, Uddin R, Hübel K, Scheid C, Weber T, Robin M, Stelljes M, Afanasyev B, Heim D, Deliliers GL, Onida F, Dreger P, Pini M, Guidi S, Volin L, Günther A, Bethge W, Poiré X, Kobbe G, van Os M, Brand R, de Witte T. Dose-reduced versus standard conditioning followed by allogeneic stem-cell transplantation for patients with myelodysplastic syndrome: a prospective randomized Phase III Study of the EBMT (RICMAC Trial). J ClinOncol. 2017;35(19):2157-2164.
29. Greenberg PL1, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstöcker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-2465.
30. Sekeres MA. Epidemiology, natural history, and practice patterns of patients with myelodysplastic syndromes in 2010. J Natl Compr Canc Netw. 2011;9(1):57-63.
31. Zeidan AM. Risk stratification in therapy-related myelodysplastic syndromes. Oncotarget. 2017;8(46):80103-80104.
32. Sokol L, Estes M, Williams AH, Ozawa Y, Volinia S, Liu CG, Croce CM, List AF. Myelodysplastic syndromes (MDS) display a risk and senescence-dependent microRNA (miRNA) signature. Blood 2006 108:2630.

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Introduction

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal diseases with abnormalities in hematopoietic stem cells, which is based on somatic mutations of various genes and/or alterations in epigenetic regulation induced by disturbance of the microenvironment, as well as disturbances in the immune system of antitumor surveillance. In many patients, the development of MDS is preceded by a period of non-clonal or clonal cytopenia of an unclear significance, which is induced by somatic mutations associated with age and an increased risk of leukemia. This results in increased proliferation, inefficiency of clonal hematopoiesis and suppression of normal hematopoiesis, and in advanced stages in an abrogation of differentiation, accumulation of blasts and the risk of transformation into acute leukemia.
The incidence of MDS increases markedly with age and the disease is most prevalent in individuals who are white and male. It is conservatively estimated that >10,000 new cases of MDS occur annually, and that ≥60,000 individuals with MDS currently reside in the United States [1].
Recent studies have provided consistent evidence of age-related hematopoietic clones (clonal hematopoiesis of indeterminate potential; CHIP) [2], driven by mutations of genes that are recurrently mutated in myeloid neoplasms and associated with increase in the risk of hematologic cancer. Although several issues remain to be clarified, targeted gene sequencing may be of potential value in the dissection between clonal myelodysplasia, nonclonal cytopenia, and clonal hematopoiesis arising upon aging or in the context of acquired marrow failure [3].
A distinctive feature of both MDS and a number of related diseases (MDS/myeloproliferative tumors, secondary acute myeloid leukemia) is an alteration in DNA methylation processes [4]. Currently, hypomethylating agents (HMA: 5-azacytidine and decitabine) are the only approved medications for the treatment of MDS [5, 6], but only 40-50% of patients respond to therapy [7]. Though there is relatively favorable cytogenetic subset of patients bearing 5q deletion with high initial response rate to lenalidomide, 35% of them will not respond to or do not tolerate the drug. Moreover, most of these patients will lose their response after a few years, requiring switching to HMA as one of further treatment options [8].
Existing prognostic factors regarding survival and the likelihood of response to therapy are based largely on the results of morphological and cytogenetic studies [9]. At the moment, their predictive power is insufficient to make a clinical decision regarding the rationale for therapy with HMA [10]. In connection with these problems, the search for biomarkers, which have prognostic significance with respect to survival and individual response to treatment, is ongoing. The use of modern tools of genome research allowed taking a fresh look at the pathogenesis of MDS and related diseases. Genes involved in both methylation and other metabolic pathways are often mutated with MDS [11]. At the moment, a number of works have been published that analyze the mutational status of the main genes involved in the pathogenesis of MDS and their predictive value in the context of response to therapy and overall survival.
The main goal of our study was to compare the data on the frequency of mutations in different populations of patients with MDS. We also conducted a meta-analysis combining data from available studies to systematically assess the impact of mutation status on response and survival.

Materials and methods

Data collection

The electronic literature search was conducted in the Pub-Med and Cochrane database. Studies were selected if they enrolled patients with various forms of MDS, as well as MDS/myeloproliferative tumors, which underwent first-line therapy with hypomethylating agents. An additional prerequisite was the fact that these studies performed full-genomic or full-exome sequencing in order to identify somatic mutations having prognostic significance with respect to overall survival and/or response to therapy. The search terms were “myelodysplastic syndrome” “sequencing” “patients” and “azacitidine”/”decitabine”. Only articles in English were included in the analysis (Fig. 1). According to these criteria, 12 original articles were selected (Table 1), from which primary data were extracted, which served as the basis for the combined database of this study. Mutation frequencies in the following genes were included in the combined database: ASXL1, DNMT3A, EZH2, U2AF1, TET2, RUNX1, TP53, SRSF2, RAS, SF3B1, CBL (Table 2).
44-51 Table 1.The list of studies used for data analysis.png
44-51 Table 2. Number of patients in whom the gene.png

Statistical analysis

The meta-analysis included the studies with available individual mutational status along with response to HMA and/ or survival data. Based on this information a surrogate table was re-created with nominal variables. The interstudy difference in the prevalence of mutations as well as the response to therapy was analyzed with chi-square test based on the created surrogate tables. The survival variable was treated as logical and non-time dependent due to absence of individual time data. Confidence intervals for the incidence of mutations were calculated based on individual incidences in the studies with random effect model. The confidence intervals for response and survival were produced based on mixed models. The heterogeneity between studies was assessed with Cochran’s Q test with n degrees of freedom. The studies with lees then ten patients per mutation were excluded from the heterogeneity analysis. The analysis was performed in SAS 9.3. The significance for all tests was set at 0.05.
44-51 Figure 1. The diagram of the search process.png

Results

Frequency of mutations in the studied population

We observed a statistically significant difference in the frequencies of all the mutations studied, depending on the study population (for specific studies see Fig. 1). Mean frequency and 95%CI for each mutation were as follows: ASXL1 22.5% (13.6-29.8%); DNMT3A 10.7% (7.3-12.9%); EZH2 5.3% (2.4-7.0%); U2AF1 9.5% (3.7-13.8%); TET2 21.3% (14.2-32.5%); RUNX1 9.1% (3.9-13.7%); TP53 9.4% (4.7-15.2%); SRSF2 13.6% (7.1-28.1%); RAS 4.9% (2.2-15.1%); SF3B1 12.0% (4.4-12.2%); CBL 3.2% (0.1-8.9%); None 18.2% (8.0-23.3%); р<0.0001.
44-51 Figure 2. The inter-study differences for the incidence.png

Response to HMA and overall survival associated with presence of specific mutations

The simulation of common incidence table across studies demonstrated a statistically significant effect on the frequency of response to therapy for mutations in ASXL1, DNMT3A, TET2, RUNX1, TP53, SRSF2, SF3B1 genes and for patients without corresponding mutations (Fig. 3A, 4A). Mean response rates and 95%CI for each mutation were: ASXL1 50.2% (48.8-51.6%); DNMT3A 50.4% (48.3-52.5%); EZH2 49.6% (47.3-51.9%); U2AF1 49.7% (48.2-51.2%); TET2 50.6% (49.3-51.9%); RUNX1 49.6% (47.8-51.4%); TP53 52.0% (48.7-55.2%); SRSF2 51.0% (48.5-53.6%); RAS 50.9% (36.9-64.7%); SF3B1 50.3% (48.5-52.1%); CBL 49.0% (44.9-53.1%); None, 50.3% (47.7-52.8%).
A statistically significant effect on the level of survival for mutations in the genes ASXL1, DNMT3A, EZH2, U2AF1, TET2, RUNX1, TP53, SF3B1, CBL was revealed (Fig. 3B, 4B). Mean overall survival and 95%CI for each mutation were: ASXL1 49.5% (47.2-51.8%); DNMT3A 48.7% (45.6-51.9%); EZH2 49.1% (42.9-55.5%); U2AF1 49.0% (43.0-55.1%); TET2 48.8% (46.7-51.0%); RUNX1 49.0% (45.9-52.1%); TP53 46.8% (44.0-49.7%); SRSF2 51.3% (43.5-59.0%); SF3B1 50.4% (47.0-53.8%); CBL 48.7% (45.5-51.8); None, 52.6% (10.0-91.7%).
However, the magnitude of difference both in response and in survival was relatively modest. For example, the mean OS for DMT3A and TET2 were 48.7% and 48.8%, respectively. Another example of close incidences of responses: 52.0% and 50.2% for patients with TP53 and TET2 mutations, respectively.
Mutations in CBL, EZH2, U2AF1, RAS genes didn’t produce any significant effect on response rate as well as there was no significant impact on survival observed for SRSF2 mutation and in patients without any corresponding mutations.
Fig. 4 contains the forest plot showing mean effects of different gene mutations upon drug response, overall survival, and appropriate confidence intervals.
44-51 Figure 3. Frequency of response to the HMA therapy.png

Discussion

The identification of MDS patients with a high probability of response to HMA therapy remains an important and unresolved clinical task. From the available data, it is known that the presence of a number of somatic mutations can affect the response rates to therapy and the level of overall survival [12]. Mutations in the TET2, DNMT3A, TP53 genes were reported to be associated with a high probability of response to HMA [13, 14, 15]. At the same time, mutations in the EZH2 and TP53 genes are associated with a lower level of overall survival [11, 13]. However these findings are not confirmed in the other studies [11, 15]. Thus it is crucial to understand the reasons behind the variability of results.
In this study we summarized the results of 12 studies with whole exome/genome sequencing in MDS [10, 11, 13-22]. The main difference in this meta-analysis is the availability of individual patient data, thus we have not merged the confidence intervals and response rates, but re-created the interstudy database with mutations, response to therapy and survival. This approach allowed calculating very precise incidence of the mutations and confidence intervals on more than one thousand patients. The obvious weakness of the study is the absence of clinical risk stratification, longitudinal follow-up as well as duration and depth of the response.
One of the first important conclusions of this study is the significant heterogeneity in the incidence of mutations across studies. On the one hand, this might be due to heterogeneity in the age, gender, risk of the disease and high percentage of chronic myelomonocytic leukemia in several studies [18, 21]. On the other hand, the 2012 World Health Organization survey, revealed substantial difference in the incidence of blood cancer across the globe [23]. Thus the observed difference might be not only due to different inclusion criteria, but also due to variable prevalent biology of MDS in different ethnicities.
The other surprising finding was that despite significant differences in response and survival due to substantial number of patients in the analysis, the magnitude of difference was very modest almost for all of the mutations. The first studies identified significant impact of TET2 mutations on survival or response to therapy [24, 25], however after the accumulation of data in the other meta-analysis it was demonstrated that it is not a significant factor for response and survival [26]. The only exception found is the p53 mutation that has better primary response to therapy [11, 20], however it adversely affects survival compared to the other mutations, where despite lower response rates the survival was better. The study confirms the extremely negative impact of mutated p53 on prognosis that might not even be corrected by stem cell transplantation [27, 28]. Another finding is improved survival in the SF3B1 mutation cohort, however as with other mutations the magnitude of the difference was modest compared to the previous studies [29].
Despite the trend towards a lower frequency of responses in the presence of RUNX1 mutation, these data require further detailed testing, and it should be emphasized that no mutation associated solely with the lack of response to HMA therapy is currently known, which would allow discussion of the inadvisability of this type of treatment when clinically indicated [11].
Figure 4. Forest plot of survival and response to HMA with 95% confidence intervals.png
The observed confidence intervals of response to hypomethylating agents were comparable to the literature data of 40-50% [30, 31], with little variance due to mutational status, which raises the question, whether the mutational status is a good prognostic factor. On the other hand the clinical risk scales have a very good predictive power in terms of survival [29]. And the drawback of this study, as well as in every meta- analysis, was the absence of individual clinical prognostic features, thus the correction for clinical co-variables could not be made. With these co-variables the results of the study could be significantly different. This demonstrates the need for international cooperation and joining both the sequencing and clinical data from different institutions. This type of activity could have provided further understanding of MDS and the approaches to treat it.
The interesting group in this study was patients without mutations determined with sequencing. Interestingly, though they had the response rate around median, the survival of these patients was much more heterogenic then in the known mutations groups. It demonstrates that this is also a heterogenic group with variable prognosis. The underlining mechanisms are still to be determined. The most promising approach is further elucidation of microenvironment disturbances and changes in miRNA signaling that lead to MDS [32].
In conclusion, the study demonstrated, though significant, but moderate impact of mutations in patients with MDS on response to HMA. Further cooperative studies with sharing the clinical and sequencing data are required to understand MDS pathophysiology and approaches to treatment.

Acknowledgements

This work was supported by Russian Science Foundation, grant № 17-75-20145. Authors confirm the absence of any conflicts of interests.

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Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(208) "Николай Ю. Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, Борис В. Афанасьев
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" ["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) "20132" ["VALUE"]=> array(2) { ["TEXT"]=> string(3996) "<p style="text-align: justify;"> Миелодиспластический синдром (МДС) представляет собой гетерогенную группу клональных заболеваний с поражением гемопоэтической стволовой клетки крови, в основе которых лежат соматические мутации различных генов и/или эпигенетической регуляции, индуцированной нарушением микроокружения, а также нарушения в иммунной системе противоопухолевого надзора. У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р&lt;0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3926) "

Миелодиспластический синдром (МДС) представляет собой гетерогенную группу клональных заболеваний с поражением гемопоэтической стволовой клетки крови, в основе которых лежат соматические мутации различных генов и/или эпигенетической регуляции, индуцированной нарушением микроокружения, а также нарушения в иммунной системе противоопухолевого надзора. У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р<0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций.

Ключевые слова

Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты.

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Tcvetkov, Olga S. Epifanovskaya, Yulia V. Rudnitskaya, Elena V. Morozova, Ivan S. Moiseev, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(120) "Nikolay U. Tcvetkov, Olga S. Epifanovskaya, Yulia V. Rudnitskaya, Elena V. Morozova, Ivan S. Moiseev, 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) "20135" ["VALUE"]=> array(2) { ["TEXT"]=> string(166) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(166) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia" ["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) "20136" ["VALUE"]=> array(2) { ["TEXT"]=> string(2427) "<p style="text-align: justify;"> Myelodysplastic syndrome represents a heterogenous group of clonal diseases affecting the hematopoietic stem cells underlied by different somatic gene mutations and/or altered epigenetic regulation induced by the disturbed microenvironment, as well as changes in the immune surveillance system. In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р&lt;0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2357) "

Myelodysplastic syndrome represents a heterogenous group of clonal diseases affecting the hematopoietic stem cells underlied by different somatic gene mutations and/or altered epigenetic regulation induced by the disturbed microenvironment, as well as changes in the immune surveillance system. In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р<0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations.

Keywords

Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis.

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Tcvetkov, Olga S. Epifanovskaya, Yulia V. Rudnitskaya, Elena V. Morozova, Ivan S. Moiseev, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(120) "Nikolay U. Tcvetkov, Olga S. Epifanovskaya, Yulia V. Rudnitskaya, Elena V. Morozova, Ivan S. Moiseev, 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(120) "Nikolay U. Tcvetkov, Olga S. Epifanovskaya, Yulia V. Rudnitskaya, Elena V. Morozova, Ivan S. Moiseev, 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) "20136" ["VALUE"]=> array(2) { ["TEXT"]=> string(2427) "<p style="text-align: justify;"> Myelodysplastic syndrome represents a heterogenous group of clonal diseases affecting the hematopoietic stem cells underlied by different somatic gene mutations and/or altered epigenetic regulation induced by the disturbed microenvironment, as well as changes in the immune surveillance system. In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р&lt;0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2357) "

Myelodysplastic syndrome represents a heterogenous group of clonal diseases affecting the hematopoietic stem cells underlied by different somatic gene mutations and/or altered epigenetic regulation induced by the disturbed microenvironment, as well as changes in the immune surveillance system. In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р<0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations.

Keywords

Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis.

" ["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(2357) "

Myelodysplastic syndrome represents a heterogenous group of clonal diseases affecting the hematopoietic stem cells underlied by different somatic gene mutations and/or altered epigenetic regulation induced by the disturbed microenvironment, as well as changes in the immune surveillance system. In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р<0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations.

Keywords

Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis.

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Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, Борис В. Афанасьев<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(208) "Николай Ю. Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, Борис В. Афанасьев
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" } ["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) "20132" ["VALUE"]=> array(2) { ["TEXT"]=> string(3996) "<p style="text-align: justify;"> Миелодиспластический синдром (МДС) представляет собой гетерогенную группу клональных заболеваний с поражением гемопоэтической стволовой клетки крови, в основе которых лежат соматические мутации различных генов и/или эпигенетической регуляции, индуцированной нарушением микроокружения, а также нарушения в иммунной системе противоопухолевого надзора. У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р&lt;0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3926) "

Миелодиспластический синдром (МДС) представляет собой гетерогенную группу клональных заболеваний с поражением гемопоэтической стволовой клетки крови, в основе которых лежат соматические мутации различных генов и/или эпигенетической регуляции, индуцированной нарушением микроокружения, а также нарушения в иммунной системе противоопухолевого надзора. У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р<0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций.

Ключевые слова

Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты.

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Миелодиспластический синдром (МДС) представляет собой гетерогенную группу клональных заболеваний с поражением гемопоэтической стволовой клетки крови, в основе которых лежат соматические мутации различных генов и/или эпигенетической регуляции, индуцированной нарушением микроокружения, а также нарушения в иммунной системе противоопухолевого надзора. У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р<0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций.

Ключевые слова

Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты.

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" ["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(369) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Российская Федерация
" } } } }

Клинические исследования

Профилактика острой реакции «трасплантат против хозяина» с применением циклофосфамида после трансплантации гемопоэтических стволовых клеток пациентам с неопухолевыми заболеваниями
Татьяна А. Быкова, Анастасия С. Боровкова, Анна А. Осипова, Варвара Н. Овечкина, Олеся В. Паина, Полина В. Кожокарь, Александр Л. Алянский, Александр Д. Кулагин, Елена В. Семенова, *Борис И. Смирнов, Людмила С. Зубаровская, Борис В. Афанасьев
Частота выявления парвовируса B19, специфического антительного ответа и задержка восстановления гемопоза после аллогенной трансплантации гемопоэтических стволовых клеток
Ирина В. Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. Зубаровская, Борис В.Афанасьев
Мета-анализ исследований с помощью геномного секвенирования пациентов с миелодиспластическим синдромом, получающих терапию гипометилирующими агентами
Николай Ю. Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, Борис В. Афанасьев

Клинические исследования

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Аллогенная трансплантация гемопоэтических стволовых клеток – эффективный метод терапии незлокачественных заболеваний системы кроветворения и наследственных синдромов. Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития.

Цель работы

Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами.

Пациенты и методы

В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4.

Результаты

Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004).

Заключение

Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. Однако, у пациентов с незлокачественными заболеваниями необходимо учитывать факт возможного увеличения частоты неприживления трансплантата при использовании немиелоаблативных режимов кондиционирования и профилактики на основе ПТЦ.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, неопухолевые заболевания, острая реакция «трансплантат против хозяина», профилактика циклофосфамидом.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Описание/Резюме [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [DOI] => Array ( [ID] => 28 [TIMESTAMP_X] => 2016-04-06 14:11:12 [IBLOCK_ID] => 2 [NAME] => DOI [ACTIVE] => Y [SORT] => 500 [CODE] => DOI [DEFAULT_VALUE] => [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 80 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 28 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 20113 [VALUE] => 10.18620/ctt-1866-8836-2018-7-1-28-35 [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => 10.18620/ctt-1866-8836-2018-7-1-28-35 [~DESCRIPTION] => [~NAME] => DOI [~DEFAULT_VALUE] => ) [AUTHOR_EN] => Array ( [ID] => 37 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Author [ACTIVE] => Y [SORT] => 500 [CODE] => AUTHOR_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 37 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20114 [VALUE] => Array ( [TEXT] => Tatiana A. Bykova, Anastasia S. Borovkova, Anna A. Osipova, Varvara N. Ovechkina, Olesya V. Paina, Polina V. Kozhokar, Alexander L. Alyanskyi, Alexander D. Kulagin, Elena V. Semenova, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Boris V. Afanasyev<br> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => Tatiana A. Bykova, Anastasia S. Borovkova, Anna A. Osipova, Varvara N. Ovechkina, Olesya V. Paina, Polina V. Kozhokar, Alexander L. Alyanskyi, Alexander D. Kulagin, Elena V. Semenova, *Boris I. Smirnov, Ludmila S. Zubarovskaya, Boris V. Afanasyev
[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20115 [VALUE] => Array ( [TEXT] => R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology; Department of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia *The St. Petersburg State Electrotechnical University (LETI), St. Petersburg, Russia [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantology; Department of Hematology, Transfusiology and Transplantology, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia *The St. Petersburg State Electrotechnical University (LETI), St. Petersburg, Russia [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20116 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is an effective treatment method for non-malignant diseases and inherited disorders. Development of acute graft-versus-host-disease (aGVHD) is a negative factor with adverse effects upon clinical outcomes. Usage of “novel” schedules for drug prophylaxis of this complication using posttransplant cyclophosphamide (PtCy) seems to decrease the GVHD risk. The aim of this study was to assess efficiency of PtCy as a tool for aGVHD prevention in the patients with non-malignant diseases of hematopoiesis and inherited syndromes. </p> <h3 style="text-align: justify;">Patients and Methods</h3> <p style="text-align: justify;"> 97 patients with non-malignant blood disorders and metabolic diseases underwent allo-HSCT at the R. Gorbacheva Memorial Institute of Children Oncology and Transplantation over a period of 2005 to 2018. A total of 118 HSCTs were carried out. The aGVHD prophylaxis in 89 cases was performed by a standard schedule (with calcineurin inhibitors). 29 patients were treated according to PtCy regimen, at a dose of 50 mg/kg at days +3 and +4. </p> <h3 style="text-align: justify;">Results</h3> <p style="text-align: justify;"> Cumulative frequency of acute GVHD comprised 32%. Patients treated with PtCy exhibited lower rates of this condition compared to the group with standard prophylaxis schedule (26% vs 47%, р=0.05). Frequency of skin aGVHD was also less common in the PtCy group (23% vs 45%, р=0.046); gastrointestinal aGVHD was observed at equal rates in the both groups. Stem cell engraftment after nonmyeloablative conditioning in HSCT patients with subsequent PtCy administration proved to be sufficiently weaker compared to other patients (86 vs 50%, р=0.004). In conclusion, posttransplant GVHD prevention based on cyclophosphamide prophylaxis is an efficient method which may decrease aGVHD risk. However, one should take into account a higher non-engraftment rate as a potential hazard of HSCT when using non-myeloablative conditioning regimens and Pt-Cy-based GVHD prophylaxis. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Transplantation of allogeneic hematopoietic stem cells (allo-HSCT) is an effective treatment method for non-malignant diseases and inherited disorders. Development of acute graft-versus-host-disease (aGVHD) is a negative factor with adverse effects upon clinical outcomes. Usage of “novel” schedules for drug prophylaxis of this complication using posttransplant cyclophosphamide (PtCy) seems to decrease the GVHD risk. The aim of this study was to assess efficiency of PtCy as a tool for aGVHD prevention in the patients with non-malignant diseases of hematopoiesis and inherited syndromes.

Patients and Methods

97 patients with non-malignant blood disorders and metabolic diseases underwent allo-HSCT at the R. Gorbacheva Memorial Institute of Children Oncology and Transplantation over a period of 2005 to 2018. A total of 118 HSCTs were carried out. The aGVHD prophylaxis in 89 cases was performed by a standard schedule (with calcineurin inhibitors). 29 patients were treated according to PtCy regimen, at a dose of 50 mg/kg at days +3 and +4.

Results

Cumulative frequency of acute GVHD comprised 32%. Patients treated with PtCy exhibited lower rates of this condition compared to the group with standard prophylaxis schedule (26% vs 47%, р=0.05). Frequency of skin aGVHD was also less common in the PtCy group (23% vs 45%, р=0.046); gastrointestinal aGVHD was observed at equal rates in the both groups. Stem cell engraftment after nonmyeloablative conditioning in HSCT patients with subsequent PtCy administration proved to be sufficiently weaker compared to other patients (86 vs 50%, р=0.004). In conclusion, posttransplant GVHD prevention based on cyclophosphamide prophylaxis is an efficient method which may decrease aGVHD risk. However, one should take into account a higher non-engraftment rate as a potential hazard of HSCT when using non-myeloablative conditioning regimens and Pt-Cy-based GVHD prophylaxis.

Keywords

Allogeneic hematopoietic stem cell transplantation, non-malignant disorders, acute graft-versus-host disease, cyclophosphamide prophylaxis.

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Профилактика острой реакции «трасплантат против хозяина» с применением циклофосфамида после трансплантации гемопоэтических стволовых клеток пациентам с неопухолевыми заболеваниями

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Татьяна А. Быкова, Анастасия С. Боровкова, Анна А. Осипова, Варвара Н. Овечкина, Олеся В. Паина, Полина В. Кожокарь, Александр Л. Алянский, Александр Д. Кулагин, Елена В. Семенова, *Борис И. Смирнов, Людмила С. Зубаровская, Борис В. Афанасьев

Научно-исследовательский институт детской онкологии, гематологии и трансплантологии имени Р. М. Горбачевой и кафедра гематологии, трансфузиологии и трансплантологии, Федеральное государственное бюджетное образовательное учреждение высшего образования «Первый Санкт-Петербургский государственный медицинский университет имени академика И. П. Павлова» Министерства здравоохранения Российской Федерации
*Санкт-Петербургский государственный электротехнический университет «ЛЭТИ», Санкт-Петербург, Россия

Аллогенная трансплантация гемопоэтических стволовых клеток – эффективный метод терапии незлокачественных заболеваний системы кроветворения и наследственных синдромов. Фактором, значимо влияющим на ухудшение прогноза, является развитие острой реакции «трансплантат против хозяина» (оРТПХ). Использование «новых» схем фармакологической профилактики данного осложнения на основе посттрансплантационного циклофосфамида (ПТЦ) позволяет снизить вероятность его развития.

Цель работы

Оценить эффективность использования ПТЦ в качестве профилактики оРТПХ у пациентов с незлокачественными заболеваниями системы кроветворения и наследственными синдромами.

Пациенты и методы

В клинике НИИ ДОГиТ им. Р. М. Горбачевой наблюдается 97 пациентов с различными незлокачественными заболеваниями системы кроветворения и наследственными синдромами, которым в период с 2005 по март 2018 года выполнено 118 алло-ТГСК. В качестве профилактики оРТПХ у 89 пациентов использовались схемы на основе ингибиторов кальциневрина, в 29 случаях на основе ПТЦ в дозе 50 мг/кг на Д+3, Д+4.

Результаты

Кумулятивная частота развития оРТПХ составила 32%. Пациенты с использованием ПТЦ имели ниже уровень данного осложнения в сравнении с группой стандартной профилактики (26% vs 47%, р=0,05), также кумулятивная частота оРТПХ с поражением кожи была значимо ниже в группе с ПТЦ (23% vs 45%, р=0,046), частота развития оРТПХ с поражением желудочно-кишечного тракта, печени были сопоставимы в обеих группах. Показатель приживления трансплантата у пациентов, получивших немиелоаблативные режимы с последующим введением ПЦТ был значимо ниже в сравнении с остальной группой (86 vs 50%р=0,004).

Заключение

Профилактика оРТПХ на основе Посттрансплантационного циклофосфамида является эффективным методом, снижающим вероятность развития оРТПХ. Однако, у пациентов с незлокачественными заболеваниями необходимо учитывать факт возможного увеличения частоты неприживления трансплантата при использовании немиелоаблативных режимов кондиционирования и профилактики на основе ПТЦ.

Ключевые слова

Аллогенная трансплантация гемопоэтических стволовых клеток, неопухолевые заболевания, острая реакция «трансплантат против хозяина», профилактика циклофосфамидом.

Клинические исследования

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	 Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА.<br>
	 Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (&gt;10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК.<br>
	 Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p&lt;0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций.<br>
	 В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК.
</p>
<h2 style="text-align: justify;">Ключевые слова</h2>
<p style="text-align: justify;">
	 Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения.
</p>
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Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА.
Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (>10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК.
Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p<0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций.
В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения.

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Khamitova, Irina N. Lavrentyeva, Maria Yu. Averyanova, Alexey B. Chukhlovin, Ludmila S. Zubarovskaya, Boris V. Afanasyev [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => Irina V. Khamitova, Irina N. Lavrentyeva, Maria Yu. Averyanova, Alexey B. Chukhlovin, Ludmila S. Zubarovskaya, Boris V. Afanasyev [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20126 [VALUE] => Array ( [TEXT] => L. Pasteur Research Institute of Epidemiology and Microbiology, St.Petersburg, Russia; R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State Medical I. Pavlov University, St. Petersburg, Russia [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => L. Pasteur Research Institute of Epidemiology and Microbiology, St.Petersburg, Russia; R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State Medical I. Pavlov University, St. Petersburg, Russia [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20127 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Parvovirus B19 (PVB19) is a well known DNA virus which seems to be associated, e.g., with erythropoiesis disturbances. Being a latent virus, the PVB19 may become active in immunocompromised patients. However, clinical significance of PVB19 after hematopoietic stem cell transplantation (HSCT) is yet not clear. Therefore, the aim of our study was compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels and possible effects upon hematopoietic recovery within 60 days after HSCT. Our study included 54 pediatric and adolescent patients of 0.6 to 19 years old with blood malignancies or inherited disorders who underwent allogeneic HSCT. Fifty-one patient of this group were observed for at least 60 days after HSCT. 33% of the patients were in first remission after previous treatment. Non-myeloablative conditioning treatment was used in 94% of cases. Antilymphocyte immune globulin and/or cyclophosphamide were applied as immunosuppressive therapy. Determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. Quantitative determination of the PV B19 DNA was performed by gene-specific real-time PCR using commercial kits. IgG and IgM antibodies to PVB19 were determined quantitatively by means of ELISA method. </p> <p style="text-align: justify;"> Results of the study were as follows: PVB19 DNA at low levels was found in blood plasma samples of 31.5% HSCT patients. However, 68% of the patients exhibited detectable levels of IgG-anti-PVB19 antibodies (&gt;10 IU/ ml), thus reflecting high prevalence of adaptive immune response. Generally, prevalence and mean levels of PVB19 DNA as well as concentrations of anti-PV B19 antibodies did not show any significant changes at 30 or 60 days after HSCT. </p> <p style="text-align: justify;"> Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p&lt;0.0001). Moreover, positivity for PVB19 DNA by the day +30 after allo-HSCT was in all cases (14/14), associated with febrile neutropenia in the patients, thus suggesting their potential role in posttransplant infections. </p> <p style="text-align: justify;"> Specifically, important correlations were observed between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels. This finding may suggest an association between parvovirus activation and slower hematopoiesis recovery after allogeneic HSCT. </p> <h2 style="text-align: justify;"> Keywords</h2> <p style="text-align: justify;"> Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Parvovirus B19 (PVB19) is a well known DNA virus which seems to be associated, e.g., with erythropoiesis disturbances. Being a latent virus, the PVB19 may become active in immunocompromised patients. However, clinical significance of PVB19 after hematopoietic stem cell transplantation (HSCT) is yet not clear. Therefore, the aim of our study was compare the PVB19 DNA levels prior to allogeneic HSCT, and at 1-2 months post-transplant, as well as search for correlations with specific antibody levels and possible effects upon hematopoietic recovery within 60 days after HSCT. Our study included 54 pediatric and adolescent patients of 0.6 to 19 years old with blood malignancies or inherited disorders who underwent allogeneic HSCT. Fifty-one patient of this group were observed for at least 60 days after HSCT. 33% of the patients were in first remission after previous treatment. Non-myeloablative conditioning treatment was used in 94% of cases. Antilymphocyte immune globulin and/or cyclophosphamide were applied as immunosuppressive therapy. Determination of the PVB19 DNA as well as herpesviruses (CMV, EBV, HSV) and polyomaviruses (BK, JC) was performed before conditioning therapy which preceded allo-HSCT, as well as on day +30 (D+30) and day+60 (D+60) post-transplant. Quantitative determination of the PV B19 DNA was performed by gene-specific real-time PCR using commercial kits. IgG and IgM antibodies to PVB19 were determined quantitatively by means of ELISA method.

Results of the study were as follows: PVB19 DNA at low levels was found in blood plasma samples of 31.5% HSCT patients. However, 68% of the patients exhibited detectable levels of IgG-anti-PVB19 antibodies (>10 IU/ ml), thus reflecting high prevalence of adaptive immune response. Generally, prevalence and mean levels of PVB19 DNA as well as concentrations of anti-PV B19 antibodies did not show any significant changes at 30 or 60 days after HSCT.

Meanwhile, a significant positive correlation was revealed between the overall PVB19 viral load and serum levels of IgG antiviral antibodies (r=0.351; p<0.0001). Moreover, positivity for PVB19 DNA by the day +30 after allo-HSCT was in all cases (14/14), associated with febrile neutropenia in the patients, thus suggesting their potential role in posttransplant infections.

Specifically, important correlations were observed between initial parvovirus DNA detection, and delayed reconstitution of erythrocytes and platelets in peripheral blood (respectively, r=-0,281; p=0.02; r=-0,303, p=0.01). Moreover, a marked correlation was shown by the day +60 between decreased neutrophils and platelet counts, and increased anti-PVD19 antibody levels. This finding may suggest an association between parvovirus activation and slower hematopoiesis recovery after allogeneic HSCT.

Keywords

Hematopoietic stem cell transplantation, parvovirus B19, activation, antiviral antibodies, myelosuppression, febrile neutropenia.

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Частота выявления парвовируса B19, специфического антительного ответа и задержка восстановления гемопоза после аллогенной трансплантации гемопоэтических стволовых клеток

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Ирина В. Хамитова, Ирина Н. Лаврентьева, Мария Ю. Аверьянова, Алексей Б. Чухловин, Людмила С. Зубаровская, Борис В.Афанасьев

НИИ эпидемиологии и микробиологии им. Пастера, Санкт-Петербург, Россия; НИИ детской онкологии, гематологии и Трансплантологии им. Р. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

Парвовирус B19 (ПВ B19) является хорошо известным ДНК-вирусом, который, возможно, ассоциирован с нарушениями эритропоэза. Будучи латентным вирусом, ПВ В19 может активироваться у пациентов с ослабленным иммунитетом. Однако клиническое значение PV В19 после трансплантации гемопоэтических стволовых клеток (ТГСК) до сих пор не выяснено. Поэтому целью нашего исследования было сравнение уровней ПВ В19 до аллогенной ТГСК и через 1-2 месяца после трансплантации, а также поиск корреляций между наличием вируса и уровнями специфических антител, а также возможным влиянием вируса на восстановление гемопоэза впределах 60 сут. после ТГСК. Наше исследование включало 54 больных детского и подросткового возраста (0.6-19 лет) с онкогематологическими заболеваниями или наследственной патологией, которым проводили аллогенную ТГСК. Из этой группы, 51 пациента наблюдали в течение, по крайней мере, 60 дней после ТГСК. 33% больных этой группы находились в первой ремиссии после предыдущего лечения. Немиелоаблативное кондиционирование применяли в 94% случаев. Антилимфоцитарный иммуноглобулин и/или циклофосфамид применяли в качестве иммуносупрессивной терапии. Определение ДНК ПВ В19, а также герпесвирусов (CMV, EBV, HSV) и полиомавирусов (BK, JC) проводили до кондиционирующей терапии, предшествующей ТГСК, а также в дни +30 и +60 после трансплантации. Количественное определение ПВ В19 осуществляли с помощью геноспецифической ПЦР в реальном времени коммерческой тест-системой. Антитела классов IgG and IgM к ПВ В19 определяли в количественном формате методом ИФА.
Получены следующие результаты: невысокие уровни ДНК ПВ В19 были обнаружены в плазме крови у 31.5% пациентов данного контингента. Однако 68% этих больных имели значимые уровни антител класса IgG к парвовирусу В19 в плазме крови (>10 ME/мл), что отражает высокую частоту адаптивного иммунного ответа на данный вирус. В целом, встречаемость и средние уровни ДНК ПВ В19, а также концентрации антител к парвовирусу В19 не проявляют существенных изменений в течение 30-60 суток после ТГСК.
Между тем, показана существенная положительная корреляция между вирусной нагрузкой ПВ В19 по всему массиву данных и уровнями специфических антител класса IgG (r=0.351; p<0.0001). Кроме того, ПЦР-позитивность по ПВ В19 на день +30 после алло-ТГСК была во всех случаях (14/14) ассоциирована с диагностированной фебрильной нейтропенией у этих пациентов, что предполагает потенциальную роль парвовирусной инфекции в генезе посттрансплантационных инфекций.
В частности, важные корреляции показаны между исходным выявлением ДНК парвовируса и отложенным восстановлением числа эритроцитов итромбоцитов в периферической крови (соответственно, r=-0,281; p=0.02, и r=-0,303, p=0.01). Выявлена и достоверная корреляция между сниженными уровнями нейтрофилов и тромбоцитов через 60 сут., и повышенными титрами антител IgG к PV В19 в этот срок. Данные факты допускают ассоциацию между активацией парвовируса В19 и замедленным восстановлением гемопоэза после аллогенной ТГСК.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, парвовирус B19, активация, антивирусные антитела, миелосупрессия, фебрильная нейтропения.

Клинические исследования

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[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Организации [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_RU] => Array ( [ID] => 27 [TIMESTAMP_X] => 2015-09-02 18:01:20 [IBLOCK_ID] => 2 [NAME] => Описание/Резюме [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_RU [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 27 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20132 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Миелодиспластический синдром (МДС) представляет собой гетерогенную группу клональных заболеваний с поражением гемопоэтической стволовой клетки крови, в основе которых лежат соматические мутации различных генов и/или эпигенетической регуляции, индуцированной нарушением микроокружения, а также нарушения в иммунной системе противоопухолевого надзора. У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р&lt;0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций. </p> <h2 style="text-align: justify;">Ключевые слова</h2> <p style="text-align: justify;"> Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Миелодиспластический синдром (МДС) представляет собой гетерогенную группу клональных заболеваний с поражением гемопоэтической стволовой клетки крови, в основе которых лежат соматические мутации различных генов и/или эпигенетической регуляции, индуцированной нарушением микроокружения, а также нарушения в иммунной системе противоопухолевого надзора. У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р<0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций.

Ключевые слова

Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты.

[TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Описание/Резюме [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [DOI] => Array ( [ID] => 28 [TIMESTAMP_X] => 2016-04-06 14:11:12 [IBLOCK_ID] => 2 [NAME] => DOI [ACTIVE] => Y [SORT] => 500 [CODE] => DOI [DEFAULT_VALUE] => [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 80 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 28 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => [USER_TYPE_SETTINGS] => [HINT] => [PROPERTY_VALUE_ID] => 20133 [VALUE] => 10.18620/ctt-1866-8836-2018-7-1-44-51 [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => 10.18620/ctt-1866-8836-2018-7-1-44-51 [~DESCRIPTION] => [~NAME] => DOI [~DEFAULT_VALUE] => ) [AUTHOR_EN] => Array ( [ID] => 37 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Author [ACTIVE] => Y [SORT] => 500 [CODE] => AUTHOR_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 37 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20134 [VALUE] => Array ( [TEXT] => Nikolay U. Tcvetkov, Olga S. Epifanovskaya, Yulia V. Rudnitskaya, Elena V. Morozova, Ivan S. Moiseev, Boris V. Afanasyev [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => Nikolay U. Tcvetkov, Olga S. Epifanovskaya, Yulia V. Rudnitskaya, Elena V. Morozova, Ivan S. Moiseev, Boris V. Afanasyev [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Author [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [ORGANIZATION_EN] => Array ( [ID] => 38 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Organization [ACTIVE] => Y [SORT] => 500 [CODE] => ORGANIZATION_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 38 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20135 [VALUE] => Array ( [TEXT] => R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] => R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia [TYPE] => HTML ) [~DESCRIPTION] => [~NAME] => Organization [~DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) ) [SUMMARY_EN] => Array ( [ID] => 39 [TIMESTAMP_X] => 2015-09-02 18:02:59 [IBLOCK_ID] => 2 [NAME] => Description / Summary [ACTIVE] => Y [SORT] => 500 [CODE] => SUMMARY_EN [DEFAULT_VALUE] => Array ( [TEXT] => [TYPE] => HTML ) [PROPERTY_TYPE] => S [ROW_COUNT] => 1 [COL_COUNT] => 30 [LIST_TYPE] => L [MULTIPLE] => N [XML_ID] => 39 [FILE_TYPE] => [MULTIPLE_CNT] => 5 [TMP_ID] => [LINK_IBLOCK_ID] => 0 [WITH_DESCRIPTION] => N [SEARCHABLE] => N [FILTRABLE] => N [IS_REQUIRED] => N [VERSION] => 1 [USER_TYPE] => HTML [USER_TYPE_SETTINGS] => Array ( [height] => 200 ) [HINT] => [PROPERTY_VALUE_ID] => 20136 [VALUE] => Array ( [TEXT] => <p style="text-align: justify;"> Myelodysplastic syndrome represents a heterogenous group of clonal diseases affecting the hematopoietic stem cells underlied by different somatic gene mutations and/or altered epigenetic regulation induced by the disturbed microenvironment, as well as changes in the immune surveillance system. In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р&lt;0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations. </p> <h2 style="text-align: justify;">Keywords</h2> <p style="text-align: justify;"> Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis. </p> [TYPE] => HTML ) [DESCRIPTION] => [VALUE_ENUM] => [VALUE_XML_ID] => [VALUE_SORT] => [~VALUE] => Array ( [TEXT] =>

Myelodysplastic syndrome represents a heterogenous group of clonal diseases affecting the hematopoietic stem cells underlied by different somatic gene mutations and/or altered epigenetic regulation induced by the disturbed microenvironment, as well as changes in the immune surveillance system. In many patients, the MDS is preceded by a period of non-clonal or clonal cytopenias of a non-clear significance that are determined by age-associated somatic mutations and increased leukemia risks resulting into a higher cellular proliferation, inefficient clonal growth, suppression of normal hematopoiesis, and, finally, into altered differentiation, thus causing accumulation of blast forms and a risk of evolving into acute leukemia. Substantial data on prevalence and impact of mutations on the prognosis in myelodysplastic syndrome was accessed by multiple groups however the results of several published studies are controversial. Thus we have performed an unconventional meta-analysis by accessing resulting confidence intervals both by statistical means and by creating pulled database with available individual patient data. 12 studies with 1238 patients were analyzed. The observed prevalence of mutations was the subject to significant variability (95%CI: ASXL1 13.6-29.8%; DNMT3A 7.3-12.9%; EZH2 2.4-7.0%; U2AF1 3.7-13.8%; TET2 14.2-32.5%; RUNX1 3.9-13.7%; TP53 4.7-15.2%; SRSF2 7.1-28.1%; RAS 2.2-15,1%; SF3B1 4.4-12.2%; CBL 0.1-8.9%; None, 8.0-23.3%; р<0.0001). The analysis of response to hypomethylating agents revealed improved response in patients with TP53 (95% CI 49-55%, p=0.0003), TET2(95% CI 49-52%, p=0.0001) and SRSF2 (95% CI 48-54%, p=0.0005) mutations; however the survival was worse in TP53 mutated patients (95% CI 44-49%, p=0.002) and better in SF3B1 mutated disease (95% CI 47-54%, p=0.01). The magnitude of difference was less than previously reported. The study confirmed the previous reports on the impact of TP53, TET2 and SF3B1 mutations on prognosis. Further studies on the potential prognostic markers are required, especially in patients with absence of conventional mutations.

Keywords

Myelodysplastic syndrome, sequencing, mutations, treatment response, hypomethylating agents, metaanalysis.

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Мета-анализ исследований с помощью геномного секвенирования пациентов с миелодиспластическим синдромом, получающих терапию гипометилирующими агентами

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Николай Ю. Цветков, Ольга С. Епифановская, Юлия В. Рудницкая, Елена В. Морозова, Иван С. Моисеев, Борис В. Афанасьев

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

Миелодиспластический синдром (МДС) представляет собой гетерогенную группу клональных заболеваний с поражением гемопоэтической стволовой клетки крови, в основе которых лежат соматические мутации различных генов и/или эпигенетической регуляции, индуцированной нарушением микроокружения, а также нарушения в иммунной системе противоопухолевого надзора. У многих пациентов развитию МДС предшествует период неклональных или клональных цитопений неясного значения, что обусловлено появлением соматических мутаций, ассоциированных с возрастом и повышенной вероятностью развития лейкоза. Результатом этого является увеличение пролиферации, нарастанием неэффективности клонального и угнетением нормального гемопоэза и, на конечных этапах, нарушением дифференцировки, что приводит к накоплению бластов и риску трансформации в острый лейкоз. Значительные данные о распространенности и воздействии мутаций на прогноз при миелодиспластическом синдроме были получены различными группами, однако результаты во многих случаях противоречивы. В связи с этим мы провели метаанализ с объединением доступных данных. Было проанализировано 12 исследований с общим количеством пациентов – 1238. Наблюдалась значительная вариабельность в распространенности мутаций между исследованиями (95% ДИ: ASXL1 13,6-29,8%, DNMT3A 7,3-12,9%, EZH2 2,4-7,0%, U2AF1 3,7-13,8%, TET2 14,2-32,5%, RUNX1 3,9-13,7%, TP53 4,7-15,2%, SRSF2 7,1-28,1%, RAS 2,2-15,1%, SF3B1 4,4-12,2%, CBL 0,1-8,9%, нет 8,0-23,3%, р<0,0001). Анализ эффективности гипометилирующих препаратов показал более высокий ответ у пациентов с мутациями TP53 (95% CI 49-55%, p=0.0003), TET2 (95% CI 49-52%, p=0.0001) и SRSF2 (95% CI 48-54%, p=0.0005), однако выживаемость была хуже у пациентов cмутированным TP53 (95% CI 44-49%, p=0.002) и лучше в случае мутации SF3B1 (95% CI 47-54%, p=0.01). Величина различий была меньше, чем сообщалось ранее. Исследование подтвердило предыдущие сообщения о влиянии мутации p53, tet2 и sf3b1 на прогноз. Дальнейшие исследования потенциальных прогностических маркеров необходимы при вариантах МДС без общепризнанных мутаций.

Ключевые слова

Миелодиспластический синдром, секвенирование, мутации, ответ на терапию, мета-анализ, гипометилирующие препараты.