ISSN 1866-8836
Клеточная терапия и трансплантация
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drmed-alexander-g-roumiantsev.jpg

This year we are celebrating the 70th Anniversary of Prof. Dr.Med. Alexander G. Roumiantsev, one of the most outstanding scientists, a hematologist-pediatrician of Russia, a person of the highest professional qualities and humanity. His achievements in the area are well known not only in Russia, but also worldwide. He is the President of National Association of Pediatric Oncologists and Hematologists, Chief Pediatrician of the Moscow Health Care Department, General Director of D.Rogacheva National Scientific and Practical Center of Pediatric Hematology and Oncology. A. G. Roumiantsev headed The Chair of Oncology, Hematology and Radiation Therapy at the Pediatric Faculty of N. Pirogov Russian National Research Medical University for many years.

Alexander Grigoryevich graduated with honors from the Pediatric Faculty at the 2nd N. I. Pirogov Moscow State Medical Institute in 1971, and, in subsequent times, he was within the walls of the 2nd MOLGMI (since 1991 – Russian State Medical University, since 2011 – N. I. Pirogov Russian National Research Medical University). Over these years, А. G. Roumiantsev approved himself a highly qualified specialist in pediatrics, hematology/immunology, a skilled scientist and university professor. A gifted teacher who authored and co-authored several basic educational programs in children diseases, polyclinic pediatrics, pediatric hematology/oncology, immunology/allergology, transfusion medicine, scientific editor of some basic textbooks and teaching media in pediatrics, pediatric hematology and immunology. In 1991, A. Roumiantsev was among founders of a tutorial course in pediatric Hematology/Oncology aimed for clinical teaching of pediatricians in this field of medicine. In the same year, he has organized a new Research Institute of Children Hematology.

Roumiantsev authored more than 650 scientific works, including 45 monographs and manuals. As a researcher, he is known for his studies in the field of pediatric hematology and immunology, medical ecology, intensive and outpatient pediatrics, adolescent medicine and arrangements in public health, clinical physiology and pathophysiology of blood, regulation of hematopoiesis and immune response, pathogenesis and treatment of hereditary and acquired blood diseases in children.

A. G. Roumiantsev is the author (co-author) of the original scientific concepts of the mechanism of adjuvant response in immunotherapy of leukemia, the biochemical limitation (tolerance) of the immune response in adjuvant immunotherapy of cancer patients. He carried out fundamental and applied research in the field of pathogenesis, diagnosis and treatment of anemia, hematopoietic depressions and leukemias. He organized a service of pediatric hematology/oncology in Russia, for the first time in the country cooperative groups were established to study the effectiveness of treatment of acute leukemia, malignant lymphomas in children,with arrangement of original protocols for the treatment of children with acute lymphoblastic leukemia, which received international admission. For the first time in Russia, molecular chips for the diagnosis of leukemia, a bank of umbilical precursor cells for unrelated transplants in pediatrics have been developed. Under the guidance of A. G. Roumiantsev for the first time in Russia, stem cell cord transplantation was performed for children with primary immunodeficiency, hematological and oncological diseases, and systemic studies of maternal and child microchimerism were organized.

A. G. Roumiantsev is the author of the guidelines on clinical pediatric transfusion and transplantation of hematopoietic cells in children, he and his co-workers have diagnosed and monitored cancer with the help of molecular probes of nucleic acids and their products in blood serum.

As to his most significant studies, one should mention the works concerning development of methods for diagnosing and treating blood diseases in children, functional methods for evaluating blood cells and bone marrow under normal and pathological conditions, immunotherapy of endotoxic shock, crush syndrome, clinical hematological and molecular genetic studies of environmental disasters. Under his direction, fundamental studies on the action of incorporated radionuclides upon the child’s organism were performed based on his efforts during liquidation of the Chernobyl nuclear power plant accident.

Since 2015, A. G. Roumiantsev is the president of National Society of Pediatric Hematology and Oncology. He is heading the scientific platform “Oncology” of Russia Healthcare Ministry, Editor-in-Chief, or Editorial Board Member at several leading journals in pediatrics,hematology and oncology, member of the Russian Pharmaceutical Committee. For his scientific and pedagogical activities he was awarded honorary medal at the University of Montpellier (France, 1990), a number of national prizes and honorary diploma. In 1994, he was awarded the Russian Order of People’s Friendship.

In December 1993 he was elected a corresponding member, in November 1995 – an academician of the Biomedicine Branch at the Russian Academy of Natural Sciences. In 2004, he was elected a corresponding member, in 2011 – Academician at the Russian Academy of Medical Sciences, in 2013 – Academician at the Russian Academy of Sciences. 

Despite his high academic positions, he is always the big-hearted person, optimistic, being of hopeful attitude toward friends and colleagues who wish him his usual creative activities in life and research, like as good health for long years.


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drmed-alexander-g-roumiantsev.jpg

This year we are celebrating the 70th Anniversary of Prof. Dr.Med. Alexander G. Roumiantsev, one of the most outstanding scientists, a hematologist-pediatrician of Russia, a person of the highest professional qualities and humanity. His achievements in the area are well known not only in Russia, but also worldwide. He is the President of National Association of Pediatric Oncologists and Hematologists, Chief Pediatrician of the Moscow Health Care Department, General Director of D.Rogacheva National Scientific and Practical Center of Pediatric Hematology and Oncology. A. G. Roumiantsev headed The Chair of Oncology, Hematology and Radiation Therapy at the Pediatric Faculty of N. Pirogov Russian National Research Medical University for many years.

Alexander Grigoryevich graduated with honors from the Pediatric Faculty at the 2nd N. I. Pirogov Moscow State Medical Institute in 1971, and, in subsequent times, he was within the walls of the 2nd MOLGMI (since 1991 – Russian State Medical University, since 2011 – N. I. Pirogov Russian National Research Medical University). Over these years, А. G. Roumiantsev approved himself a highly qualified specialist in pediatrics, hematology/immunology, a skilled scientist and university professor. A gifted teacher who authored and co-authored several basic educational programs in children diseases, polyclinic pediatrics, pediatric hematology/oncology, immunology/allergology, transfusion medicine, scientific editor of some basic textbooks and teaching media in pediatrics, pediatric hematology and immunology. In 1991, A. Roumiantsev was among founders of a tutorial course in pediatric Hematology/Oncology aimed for clinical teaching of pediatricians in this field of medicine. In the same year, he has organized a new Research Institute of Children Hematology.

Roumiantsev authored more than 650 scientific works, including 45 monographs and manuals. As a researcher, he is known for his studies in the field of pediatric hematology and immunology, medical ecology, intensive and outpatient pediatrics, adolescent medicine and arrangements in public health, clinical physiology and pathophysiology of blood, regulation of hematopoiesis and immune response, pathogenesis and treatment of hereditary and acquired blood diseases in children.

A. G. Roumiantsev is the author (co-author) of the original scientific concepts of the mechanism of adjuvant response in immunotherapy of leukemia, the biochemical limitation (tolerance) of the immune response in adjuvant immunotherapy of cancer patients. He carried out fundamental and applied research in the field of pathogenesis, diagnosis and treatment of anemia, hematopoietic depressions and leukemias. He organized a service of pediatric hematology/oncology in Russia, for the first time in the country cooperative groups were established to study the effectiveness of treatment of acute leukemia, malignant lymphomas in children,with arrangement of original protocols for the treatment of children with acute lymphoblastic leukemia, which received international admission. For the first time in Russia, molecular chips for the diagnosis of leukemia, a bank of umbilical precursor cells for unrelated transplants in pediatrics have been developed. Under the guidance of A. G. Roumiantsev for the first time in Russia, stem cell cord transplantation was performed for children with primary immunodeficiency, hematological and oncological diseases, and systemic studies of maternal and child microchimerism were organized.

A. G. Roumiantsev is the author of the guidelines on clinical pediatric transfusion and transplantation of hematopoietic cells in children, he and his co-workers have diagnosed and monitored cancer with the help of molecular probes of nucleic acids and their products in blood serum.

As to his most significant studies, one should mention the works concerning development of methods for diagnosing and treating blood diseases in children, functional methods for evaluating blood cells and bone marrow under normal and pathological conditions, immunotherapy of endotoxic shock, crush syndrome, clinical hematological and molecular genetic studies of environmental disasters. Under his direction, fundamental studies on the action of incorporated radionuclides upon the child’s organism were performed based on his efforts during liquidation of the Chernobyl nuclear power plant accident.

Since 2015, A. G. Roumiantsev is the president of National Society of Pediatric Hematology and Oncology. He is heading the scientific platform “Oncology” of Russia Healthcare Ministry, Editor-in-Chief, or Editorial Board Member at several leading journals in pediatrics,hematology and oncology, member of the Russian Pharmaceutical Committee. For his scientific and pedagogical activities he was awarded honorary medal at the University of Montpellier (France, 1990), a number of national prizes and honorary diploma. In 1994, he was awarded the Russian Order of People’s Friendship.

In December 1993 he was elected a corresponding member, in November 1995 – an academician of the Biomedicine Branch at the Russian Academy of Natural Sciences. In 2004, he was elected a corresponding member, in 2011 – Academician at the Russian Academy of Medical Sciences, in 2013 – Academician at the Russian Academy of Sciences. 

Despite his high academic positions, he is always the big-hearted person, optimistic, being of hopeful attitude toward friends and colleagues who wish him his usual creative activities in life and research, like as good health for long years.


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Он является президентом Национальной Ассоциации детских онкологов и гематологов, главным педиатром Московского департамента здравоохранения, генеральным директором Национального научно-практического центра детской гематологии и онкологии имени Димы Рогачева. В течение многих лет А. Г. Румянцев был главой кафедры онкологии, гематологии и радиационной терапии педиатрического факультета Российского национального исследовательского медицинского университета им. Н. И. Пирогова.

Александр Григорьевич в 1971 г. окончил с отличием педиатрический факультет Второго Московского ордена Ленина государственного медицинского института, и в последующие годы он работал в стенах этого ВУЗа (2-го МОЛГМИ, с 1991 г. – Российского государственного медицинского университета, с 2011 г. – Российского национального исследовательского медицинского университета им. Н. И. Пирогова). В тот период А. Г. Румянцев показал себя высококвалифицированным специалистом-педиатром, гематологом-иммунологом, ученым и преподавателем высшей школы. Талантливый педагог, автор и соавтор образовательных программ по лечению детских болезней, поликлинической педиатрии, педиатрической гематологии/онкологии, иммунологии/аллергологии, трансфузиологии, научный редактор базовых руководств и учебных пособий по педиатрии, детской гематологии и иммунологии." 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Alexander G. Roumiantsev, one of the most outstanding scientists, a hematologist-pediatrician of Russia, a person of the highest professional qualities and humanity. His achievements in the area are well known not only in Russia, but also worldwide. He is the President of National Association of Pediatric Oncologists and Hematologists, Chief Pediatrician of the Moscow Health Care Department, General Director of D.Rogacheva National Scientific and Practical Center of Pediatric Hematology and Oncology. A. G. Roumiantsev headed The Chair of Oncology, Hematology and Radiation Therapy at the Pediatric Faculty of N. Pirogov Russian National Research Medical University for many years.<br> <br> Alexander Grigoryevich graduated with honors from the Pediatric Faculty at the 2nd N. I. Pirogov Moscow State Medical Institute in 1971, and, in subsequent times, he was within the walls of the 2nd MOLGMI (since 1991 – Russian State Medical University, since 2011 – N. I. Pirogov Russian National Research Medical University). Over these years, А. G. Roumiantsev approved himself a highly qualified specialist in pediatrics, hematology/immunology, a skilled scientist and university professor. A gifted teacher who authored and co-authored several basic educational programs in children diseases, polyclinic pediatrics, pediatric hematology/oncology, immunology/allergology, transfusion medicine, scientific editor of some basic textbooks and teaching media in pediatrics, pediatric hematology and immunology." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1637) "This year we are celebrating the 70th Anniversary of Prof.Dr.Med. Alexander G. Roumiantsev, one of the most outstanding scientists, a hematologist-pediatrician of Russia, a person of the highest professional qualities and humanity. His achievements in the area are well known not only in Russia, but also worldwide. He is the President of National Association of Pediatric Oncologists and Hematologists, Chief Pediatrician of the Moscow Health Care Department, General Director of D.Rogacheva National Scientific and Practical Center of Pediatric Hematology and Oncology. A. G. Roumiantsev headed The Chair of Oncology, Hematology and Radiation Therapy at the Pediatric Faculty of N. Pirogov Russian National Research Medical University for many years.

Alexander Grigoryevich graduated with honors from the Pediatric Faculty at the 2nd N. I. Pirogov Moscow State Medical Institute in 1971, and, in subsequent times, he was within the walls of the 2nd MOLGMI (since 1991 – Russian State Medical University, since 2011 – N. I. Pirogov Russian National Research Medical University). Over these years, А. G. Roumiantsev approved himself a highly qualified specialist in pediatrics, hematology/immunology, a skilled scientist and university professor. A gifted teacher who authored and co-authored several basic educational programs in children diseases, polyclinic pediatrics, pediatric hematology/oncology, immunology/allergology, transfusion medicine, scientific editor of some basic textbooks and teaching media in pediatrics, pediatric hematology and immunology." 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Alexander G. Roumiantsev, one of the most outstanding scientists, a hematologist-pediatrician of Russia, a person of the highest professional qualities and humanity. His achievements in the area are well known not only in Russia, but also worldwide. He is the President of National Association of Pediatric Oncologists and Hematologists, Chief Pediatrician of the Moscow Health Care Department, General Director of D.Rogacheva National Scientific and Practical Center of Pediatric Hematology and Oncology. A. G. Roumiantsev headed The Chair of Oncology, Hematology and Radiation Therapy at the Pediatric Faculty of N. Pirogov Russian National Research Medical University for many years.<br> <br> Alexander Grigoryevich graduated with honors from the Pediatric Faculty at the 2nd N. I. Pirogov Moscow State Medical Institute in 1971, and, in subsequent times, he was within the walls of the 2nd MOLGMI (since 1991 – Russian State Medical University, since 2011 – N. I. 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Alexander Grigoryevich graduated with honors from the Pediatric Faculty at the 2nd N. I. Pirogov Moscow State Medical Institute in 1971, and, in subsequent times, he was within the walls of the 2nd MOLGMI (since 1991 – Russian State Medical University, since 2011 – N. I. Pirogov Russian National Research Medical University). Over these years, А. G. Roumiantsev approved himself a highly qualified specialist in pediatrics, hematology/immunology, a skilled scientist and university professor. 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Александр Григорьевич в 1971 г. окончил с отличием педиатрический факультет Второго Московского ордена Ленина государственного медицинского института, и в последующие годы он работал в стенах этого ВУЗа (2-го МОЛГМИ, с 1991 г. – Российского государственного медицинского университета, с 2011 г. – Российского национального исследовательского медицинского университета им. Н. И. Пирогова). В тот период А. Г. Румянцев показал себя высококвалифицированным специалистом-педиатром, гематологом-иммунологом, ученым и преподавателем высшей школы. Талантливый педагог, автор и соавтор образовательных программ по лечению детских болезней, поликлинической педиатрии, педиатрической гематологии/онкологии, иммунологии/аллергологии, трансфузиологии, научный редактор базовых руководств и учебных пособий по педиатрии, детской гематологии и иммунологии." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3053) "В этом году мы отмечаем 70-летие профессора Александра Григорьевича Румянцева – одного из выдающихся российских ученых, специалиста в области детской онкогематологии, человека высочайших профессиональных качеств и гуманности. Его достижения широко известны не только в России, но и за рубежом. Он является президентом Национальной Ассоциации детских онкологов и гематологов, главным педиатром Московского департамента здравоохранения, генеральным директором Национального научно-практического центра детской гематологии и онкологии имени Димы Рогачева. В течение многих лет А. Г. Румянцев был главой кафедры онкологии, гематологии и радиационной терапии педиатрического факультета Российского национального исследовательского медицинского университета им. Н. И. Пирогова.

Александр Григорьевич в 1971 г. окончил с отличием педиатрический факультет Второго Московского ордена Ленина государственного медицинского института, и в последующие годы он работал в стенах этого ВУЗа (2-го МОЛГМИ, с 1991 г. – Российского государственного медицинского университета, с 2011 г. – Российского национального исследовательского медицинского университета им. Н. И. Пирогова). В тот период А. Г. Румянцев показал себя высококвалифицированным специалистом-педиатром, гематологом-иммунологом, ученым и преподавателем высшей школы. Талантливый педагог, автор и соавтор образовательных программ по лечению детских болезней, поликлинической педиатрии, педиатрической гематологии/онкологии, иммунологии/аллергологии, трансфузиологии, научный редактор базовых руководств и учебных пособий по педиатрии, детской гематологии и иммунологии." } } } [1]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "29" ["~IBLOCK_SECTION_ID"]=> string(2) "29" ["ID"]=> string(3) "829" ["~ID"]=> string(3) "829" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(204) "Редкий случай пароксизмальной ночной гемоглобинурии у пациента старше 70 лет с миелодиспластическим синдромом" ["~NAME"]=> string(204) "Редкий случай пароксизмальной ночной гемоглобинурии у пациента старше 70 лет с миелодиспластическим синдромом" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "15.08.2017 14:36:41" ["~TIMESTAMP_X"]=> string(19) "15.08.2017 14:36:41" ["DETAIL_PAGE_URL"]=> string(147) "/ru/archive/tom-6-nomer-1/klinicheskie-raboty/redkiy-sluchay-paroksizmalnoy-nochnoy-gemoglobinurii-u-patsienta-starshe-70-let-s-mielodisplastiches/" ["~DETAIL_PAGE_URL"]=> string(147) "/ru/archive/tom-6-nomer-1/klinicheskie-raboty/redkiy-sluchay-paroksizmalnoy-nochnoy-gemoglobinurii-u-patsienta-starshe-70-let-s-mielodisplastiches/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(29548) "

Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired chronic disease of hematopoietic stem cells (HSC) characterized by chronic intravascular hemolysis, bone mar row failure and increased risk of thrombotic complications. PNH occurs due to a non-malignant clonal expansion of mutated HSCs with an acquired somatic X-linked mutation in the phosphatidylinositol glycan A gene (PIG-A) [2, 22]. This mutation causes altered glycosylphosphatidylinositol (GPI anchor) binding to some surface proteins, e.g., CD55 and CD 59 complement-inhibitors. Loss of these regulatory proteins predisposes for non-controlled complement activation resulting to intravascular destruction of red blood cells (RBC), thus manifesting as chronic hemolysis and progressing anemia [12, 22]. However, sole PIG-A mutation is not sufficient for expansion of a PNH clone and clinical symptoms. Precise mechanisms of the clonal expansion are not yet known, probably, being coupled to bone marrow failure [12, 21]. Such physiological mechanism is confirmed by higher incidence of PNH clone in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS) [11, 18, 27, 26, 29, 30]. 

Table 1 shows results of international clinical studies for PNH clone assessment in the patients with different MDS subtypes.

Table 1. Identification and distribution of PNH clones in the patients with different subtypes of myelodysplastic syndrome (MDS)

No of cases (reference No) Country Diagnostic technique Cells studied Sensitivity threshold Percentage of patients with detectable PNH clone (number of cases)о Distribution of PNH clones in MDS subtypes
58518
USA Flow cytometry CD59-RBCs FLAER/CD24-granulocytes FLAER/CD14-monocytes 0.01% 5.5%(32/585) LGMDSL
HGMDSL
MDS w/5q deletion
МДС, non-specified
Myelofibrosis w/myeloid metaplasia(subtype distribution not shown)
31627 Japan Flow cytometry CD59-/CD55-/CD11b+ granulocytes and CD59-/CD55-/ GP-A+ RBCs ≥0.003% granulocytes and
≥0.005% RBCs
20% (64/316) RA: 64/316 (20%)
13629 USA Flow cytometry CD55-/CD59- and/or
CD16-/CD66b-granulocytes
0.01% 6.6% (9/136) RA: 6/17 (35%)
5q:1/5 (20%)
RCMD: 2/37 (5%)
16428 Japan Flow cytometry CD59-/CD55-granulocytes and RBCs 0.003% CD55-, CD59- granulocytes and RBCs 12.8%(21-164) RA: 21/119 (17.6%)
RARS: 0/4
RAEB: 0/33
RAEBt: 0/8
2530 Turkey Flow cytometry CD55-/CD59 - leukocytes ≥ M + 1.96 x SD for controls 24% (6/25) RA: 4/17 (23.5%)
RARS: 1/2
RAEB: 1/4
CMML: 0/2
3821 Japan Flow cytometry CD55-/CD59-RBCs No data 15.7% (6/38) RA: 5/33 (15.1%)
RARS: 1/1
RAEB: 0/4

Note: PNH, paroxysmal nocturnal hemoglobinuria; MDS, Myelodysplastic syndrome ; CMML, chronic myelomonocytic leu kemia; FLAER, fluorescent aerolysine; HGMDSL, high-risk MDS; hMDS, hypoplastic MDS variant, LGMDSL, low-risk MDS; MDS-U, MDS non-classified; RA, refractory anemia; RAEB(1/2), RA with blast excess (1/2); RAEBt, RA with blast excess and acute leukemia transformation; RAMD, RA with multilineage dysplasia; RARS, RA with ring syderoblasts; RCMD, RA with multilineage dysplasia; RCMDRS, RA with multilineage dysplasia and ring syderoblasts; 5q, 5q syndrome.

As seen from a series of studies (Table 1), incidence of PNH clone in MDS patients varies from 5.5% to 24% cases (a mean of 13%). PNH manifestations are highly different, and the disease may develop at any age (a median of 30-40 years old) [8, 22]. Life-threatening complications occur, as a rule, due to uncontrollable complement-mediated hemolysis and consequent blood platelet activation [3, 10, 19]. Most common clinical symptoms include anemia (88%) [3], thrombosis (35%) [9], chronic kidney disease (64%) [10], abdominal pains (57%), lung hypertension (47%), dyspnoe (66%), dysphagia (41%), significant fatigue (96%), erectile dysfunction (47%), bone marrow failure (45%) [19, 24]. Hemoglobinuria is the most remarkable PNH symptom. It develops in nearly all patients during the disease, being, however, initially observed only in 26% of the cases [22, 24]. Thromboses represent the main reason of mortality (40 to 67% of lethal outcomes) followed by chronic kidney injury (8 to 18% of total), infections (17%), and bleedings (8%) [15, 23].

PNH symptoms exert significant negative effects upon quality of life due to anemia, transfusion dependence, abdominal and chest pain, sufficient fatique, dyspnoe which often need hospitalization and symptomatic drug medication.

PNH diagnostics may be quite difficult, due to variability of symptoms and rarity of the disorder. However, the time of diagnostics may be more rapid when using diagnostic algorithm and screening of high-risk patients [8]. Flow cytometry (FC) is considered the most sensitive and informative technique to establish PNH diagnosis. Percentage of blood cells with complete or partial GPI anchor deficiency shows the size of PNH clone, as measured by immune phenotyping performed with flow cytometry [1] /National Clinical Guidelines on PNH diagnostics and treatment specify several patient groups with different clinical traits are discerned for appropriate PNH screening [16], i.e., Coombs-negative intravascular hemolysis; hemolytic anemia associated with hemoglobinuria, iron deficiency, cytopenia and thromboses; some bone marrow failure patterns (suggested or proven aplastic anemia; myelodysplastic syndrome (refractory cytopenia with 1-,2- or 3-lineage dyspla-sia, hypoplastic MDS variant), other cytopenias with unknown etiology after detailed examination; thromboses with atypical manifestations (uncommon localization, associated hemolytic anemia and cytopenias). As suggested in the Recommendations, optimal frequency of clinical examination and PNH screening should be performed initially in cases of aplastic anemia (AA) and MDS, and then twice a year in case of initial PNH clone detection. Presence of a PNH clone in MDS patients may be of high predictive value, with respect to its future treatment strategy.

Clinical Practice Guidelines in Oncology by National Comprehensive Cancer Network (NCCN-2010) recommend screening for PNH clone and HLA-DR15 if considering MDS. These markers seem to be best predictors of response to immunosuppressive therapy, especially, for younger patients (≤60 years old) with normal cytogenetics and hypoplastic MDS variant [20].

So far, only symptomatic therapy was used for PNH therapy, i.e., iron supplement, folates, steroids, blood transfusions, anticoagulants in thrombotic episodes. Generally, the median survival for hemolytic PNH patients comprises 10 to 15 years from initial diagnosis. Thirty-five percent of these patients are lost within 5 years [8].

Hematopoietic stem cell transplantation (HSCT) is an approach which may be potentially curative in PNH. However, HSCT is known to produce high complication rates, mortality, and is performed only for certain indications in cases of hematopoietic aplasia [4, 13].

Since 2007, Eculizumab, a drug for PNH target therapy, was registered for clinical use. Eculizumab is a humanized monoclonal antibody which is able to specifically bind the С5 component of complement system, thus blocking excessive complement activation and C5-mediated hemolysis, the main affecting factor in PNH. International clinical trials and subsequent studies have shown that Eculizumab sufficiently decreased incidence of life-threatening complications (i.e., thromboses), and significantly improved survival of the PNH patients. [7, 14].

Current publications contain only few reports on successful treatment of combined PNH/MDS conditions . In available literature we did not find any data on clinical hematological remission achieved with Eculizumab therapy in patients >70 years old. Therefore, our own description of such clinical case treated by Eculizumab should have clinical practical value.

Clinical case description

Patient M., 73 years old, was admitted to a Department of Therapy in January 2016. He presented with significant fatigue, vertigo, dizziness, absence of appetite, icterus, dark urine, periodical pressing heart pain, low-grade fever over month, cough, dyspnoe upon modest physical loads. Anemic syndrome and thrombocytopenia are traced since 2006, specialized hematological examination was initiated since 2009. Bone marrow cytology showed megaloblastoid traits of erythroid cells evaluated as potential MDS markers. Glucocorticoid therapy did not provide clinical response. Special examination aiming to exclude paraneoplastic events, has shown a prostate carcinoma (рТ2с, NO, G3, R0). The patient underwent extraperitoneal endoscopic radical prostatectomy with removal of regional pelvic lymph nodes, followed by urological screening, without any specific treatment. Since June 2015, his condition became worse, due to unmotivated fatigue, episodic hematuria. In January 2016, he noted some general physical symptoms as else-where described (see above), being admitted to Therapeutic Department. On admittance, his state was moderately severe. Skin and mucosae were icteric, multiple angiokeratomas and skin papillomas were evident. Peripheral lymph nodes were not enlarged, peripheral oedemas not detected. Chest auscultation did not show rales, however, weak breathing was evident. Heart sounds were muffled, at regular beats. Liver and spleen were not enlarged. Clinical blood analysis revealed decrease Hb (60 g/L), RBCs (1.75 х10 12 /L), platelets (60х10 9 /L), leukocytes (5.4х10 9 /L), neutrophils (64% of total leukocyte counts). Urinalysis showed proteinuria 2.0 g/L, changed and fresh RBCs (100 to 120 per microscopic field), urobilinogen (3+), bilirubin (1+). Results of blood biochemistry were as follows: direct bilirubin (21 μmol /L), total bilirubin of 87 μmol /L, ALaT (31U/L), ASaT (108 U/L, LDH (2925 U/L, being much higher normal values of 125-245 U/L). On 13.01.16, ECG has shown a subendocardial anterior lateral myocardial infarction. EchoCG has shown apical hypokinesis, akinesia of anterior and anteriorseptal segments. Cor onarographic study was refused, due to thrombocytopenia and hemorrhagic risk in the patient.

In view of distinct blood changes, we looked for PNH clonal markers. Flow cytometry provided the following pattern: type I (normal) RBCs, 59.05%; type II (partial СD59 deficiency), 1.47%; type III (complete lack of СD59 ), 39.48%; monocytes with FLAER/СD14 deficiency – 92.02%; granulocytes with FLAER/СD14 mangle – 94.73%. Hence, a PNH clone was detectable among RBCs, monocytes and granulocytes in blood sample. Appropriate treatment consisted of RBC transfusions (6 standard doses), bisoprolol (5 mg), isosorbide dinitrate (20 mg twice a day) followed by improvement of physical condition. Hb increased to 90 g/L, blood bilirubin and LDH levels remained high (resp., 28 μmol /L, and 2124 U/L). The patient was discharged from the clinic. In June 2016, he was urgently admitted to the M. Zhadkevich Municipal Clinical Hospital due to worsened clinical condition, recurrent skin icterus, dark urine, fever. His initial blood sampling was impossible due to intravascular hemolysis. Urine samples were brown-colored, with abundant yellow-brownish debris seen upon microscopy. Washed RBCs were transfused at this phase. At day +2 after admission, total blood analysis showed low Hb levels (62 g/L), decreased platelet counts (62х109/L). Routine blood chemistry showed LDH activity of 7132 U/L (reference, 125 to 245 U/L), total bilirubin, 100 μMol/L (direct bilirubin, 20 μmol/L); ASAТ, 290 U/L; С-reactive protein, 150 g/L. X-ray chest examination showed pneumonia in the left lower lobe. Further transfusion therapy included 3 doses of washed RBCs, and antibacterial treatment with Amoxicilline clavulanate, and Azithromycin. Relative stabilization of clinical state was observed. However, the course of disease was complicated by significant thrombocytopenia (to 18-20х109/L), profuse nasal bleeding, instability of respiratory and cardiovascular systems, thus re-quiring therapeutic nitrates, bisoprolol, continued antibacterial and detoxication therapy. 

In view of pronounced intravascular hemolysis and generally severe condition of the patient, we then started pathogenetic treatment by Eculizumab at a dose of 600 mg at a 7-day interval. Simultaneous vaccination for meningococcal infection was performed at this time. As an outcome, the pulmonary inflammation was resolved, urinary parameters were normalized, with anemia improved to some degree (Hb level increased to 87 g/L).

Seven days after 2nd eculizumab infusion, the patient was hospitalized to the Department of Hematology of Clinical Research Center at the Moscow Health Department, to specify further therapy. Upon admission, the patient was in satisfactory condition. Skin was of normal colour, eye sclerae were subicteric, hemorrhagic syndrome was not detectable. Hemodynamics remained stable, liver, spleen were of normal size. Blood analysis showed further increased Hb level (95 g/L), erythrocytes (3.0х1012/L), platelets, 35х109/L, leukocytes (3.2х109/L); differential counts showed 48% neutrophils. Urinalysis showed low protein content (0.1 g/L), erythrocytes (1-4 per vision field). Serum indexes were as follows: total bilirubin, 21 μmol /L (direct, 2.5 μmol /L), LDH, 540 U/L (reference, 125–245 U/L).

Marrow cytology revealed 2.3% blast cells, with dysplastic traits of granulocyte lineage (Peulger-like, hyposegmentation of the nuclei), erythroid cells (megaloblasts, increased pyknosis rates), and megakaryocytic lineage (mononuclear or small megakaryocytes). Cytogenetic data exhibited complex aberrations: 45,X, -Y[16]/ 46,XY[4]nucish(DXZ1х1) [66] (DXZ1,DYZ3)x1[34]. Loss of Y chromosome was shown in 80% of the cells studied.

Hence, the following diagnosis has been established: Paroxismal nocturnal hemoglobinuria. Myelodysplastic syndrome. Refractory cytopenia with multilinear dysplasia. IPSS: intermediate 1 risk. Prostate carcinoma (рТ2с, NO,M0.G3,R0). Extraperitoneal endoscopic radical prostatectomy of 2009. Due to observed clinical effect, we decided to continue Eculizumab treatment, according to a standard schedule. This mode of therapy proved to be tolerable, without adverse events during the infusions. Time-dependent dynamics of main blood indexes and changes in leukocyte profiles during such therapy are presented at Fig.1 and Table 2.

Figure 1. Time course of hematological indexes during eculizumab therapy.

Figure 1. Time course of hematological indexes during eculizumab therapy.

Table 2. Time dynamics of leukocyte profiles during Eculizumab therapy

Table 2. Time dynamics of leukocyte profiles during Eculizumab therapy

As seen from Fig. 1, the Hb levels did gradually increase to reference values, i.e., 120-125 g/L, leukocytes, to 4.1-5.87х109. Thrombocytopenia also became clinically insignificant(53-60 х109).

LDH activity is shown to be increased in disorders accompanied by tissue damage and cell destruction. Therefore, this parameter is an important marker of tissue decay, chronical hemolysis. Fig. 2 shows changes in LDH activity during Eculizumab therapy.

Figure 2. LDH changes with time after Eculizumab treatment.

Figure 2. LDH changes with time after Eculizumab treatment.

As seen from Fig. 2, PNH progression was noted by increased LDH levels from April 2014 to February 2016. Positive dy namics of the disease was then seen as proven by decreased LDH levels and Hb normalization (Fig. 1), when continuing treatment. The patient reported improved physical condi tion, he has resumed usual physical loads. Eculizumab treat ment is continued at a dose of 900 mg once every 2 weeks.

Discussion

Historically, the PNH patients received symptomatic treat ment, e.g., transfusion of washed RBCs, anticoagulant drugs, iron supplement and folic acid, glucocorticosteroids etc. HSCT was introduced is a method of choice for PNH thera py. Despite wide use of anticoagulants in PNH for thrombo sis prophylaxis, appropriate risk in the patients remain high, thus enhancing bleeding risks as well [14]. Advent of Eculi zumab, a monoclonal antibody which inhibits complement activity, has sufficiently improved results of PNH treatment due to effective control of complement-mediated hemolysis causing thromboses, and improving total survival of the pa tients [5, 17].

HCT remains the only curative method for PNH. Accord ing to large retrospective study which involved 211 PNH patients treated with BMT, total 5-year survival in this co hort was 68%, whereas graft failure was observed in 6% of the cases. Acute or chronic GvHD was evident in one-third of the patients [4, 5]. Meanwhile, Loschi M. et al reported total 6-year survival of 92% among the patients treated by Eculizumab [17]. Hence, HSCT provides a chance for radi cal PNH treatment. However, lethality and potential compli cations of the procedure are poorly predictable, and HSCT, therefore, cannot be recommended as a first-line strategy in the patients with classic PNH [6].

In some cases, HSCT is considered an option of MDS treat ment as first-line strategy. According to National Clinical Guidelines for Diagnostics and Treatment of Adult MDS, HSCT is indicated for the patients from the Group 1-2 in termediate and high-risk IPSS scores. Cumulative mortality after allo-HSCT from HLA-identical siblings in 387 patients with MDS proved to be 37% within 3 years, whereas relapse rates were 23% during this time period, with overall 3-year survival of 40%, according to IBMTR data. The disease stage and number of blasts are more significant to the HSCT out comes. However, upper age limits for HSCT do not exceed 65-70 years [26].

Our clinical case demonstrates clinical remission in an el derly PNH patient with myelodysplastic syndrome and high comorbidity burden. This case also shows importance of im mune phenotyping for PNH clone detection in either patient with myelodysplastic syndrome. The patient had several in dications for PNH clone testing, including cytopenia due to suggested MDS syndrome, intravascular hemolysis traits, and arterial thrombosis.

It is known that poorly documented MDS may be confused with unrecognized classical PNH, since in many instances it may be interpreted as isolated cytopenia, with non-detect ed active intravascular hemolysis. In this view, our clinical observation contains sufficient criteria for MDS diagnostics, i.e., erythroid hyperplasia and dysplasia typical to PNH, along with distinct cytological features of granulocytic and megakaryocytic dysplasia, like as clonal cytogenetic aberra tion (Y chromosome loss). Certainly, therapeutic choice in such cases cannot be based on the MDS treatment standards only. One should consider rates of intravascular hemolysis and, therefore, arrange target treatment with Eculizumab, according to current clinical indications. In this case, inten sive intravascular hemolysis was followed by RBC transfu sions, being then complicated by myocardial infarction, thus being indicative for appropriate target therapy, according to current recommendations. Marked positive response to Ecu lizumab treatment confirms a leading pathogenetic role of hemolysis rather than of bone marrow failure, for the pro found anemia observed in this case. Further accumulation of blood immunophenotyping results, cytogenetic and cy tological data will specify the PNH clone frequency and its pathogenetic role in MDS.

Conflict of interest

No conflict of interests is reported.

References

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Introduction

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired chronic disease of hematopoietic stem cells (HSC) characterized by chronic intravascular hemolysis, bone mar row failure and increased risk of thrombotic complications. PNH occurs due to a non-malignant clonal expansion of mutated HSCs with an acquired somatic X-linked mutation in the phosphatidylinositol glycan A gene (PIG-A) [2, 22]. This mutation causes altered glycosylphosphatidylinositol (GPI anchor) binding to some surface proteins, e.g., CD55 and CD 59 complement-inhibitors. Loss of these regulatory proteins predisposes for non-controlled complement activation resulting to intravascular destruction of red blood cells (RBC), thus manifesting as chronic hemolysis and progressing anemia [12, 22]. However, sole PIG-A mutation is not sufficient for expansion of a PNH clone and clinical symptoms. Precise mechanisms of the clonal expansion are not yet known, probably, being coupled to bone marrow failure [12, 21]. Such physiological mechanism is confirmed by higher incidence of PNH clone in patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS) [11, 18, 27, 26, 29, 30]. 

Table 1 shows results of international clinical studies for PNH clone assessment in the patients with different MDS subtypes.

Table 1. Identification and distribution of PNH clones in the patients with different subtypes of myelodysplastic syndrome (MDS)

No of cases (reference No) Country Diagnostic technique Cells studied Sensitivity threshold Percentage of patients with detectable PNH clone (number of cases)о Distribution of PNH clones in MDS subtypes
58518
USA Flow cytometry CD59-RBCs FLAER/CD24-granulocytes FLAER/CD14-monocytes 0.01% 5.5%(32/585) LGMDSL
HGMDSL
MDS w/5q deletion
МДС, non-specified
Myelofibrosis w/myeloid metaplasia(subtype distribution not shown)
31627 Japan Flow cytometry CD59-/CD55-/CD11b+ granulocytes and CD59-/CD55-/ GP-A+ RBCs ≥0.003% granulocytes and
≥0.005% RBCs
20% (64/316) RA: 64/316 (20%)
13629 USA Flow cytometry CD55-/CD59- and/or
CD16-/CD66b-granulocytes
0.01% 6.6% (9/136) RA: 6/17 (35%)
5q:1/5 (20%)
RCMD: 2/37 (5%)
16428 Japan Flow cytometry CD59-/CD55-granulocytes and RBCs 0.003% CD55-, CD59- granulocytes and RBCs 12.8%(21-164) RA: 21/119 (17.6%)
RARS: 0/4
RAEB: 0/33
RAEBt: 0/8
2530 Turkey Flow cytometry CD55-/CD59 - leukocytes ≥ M + 1.96 x SD for controls 24% (6/25) RA: 4/17 (23.5%)
RARS: 1/2
RAEB: 1/4
CMML: 0/2
3821 Japan Flow cytometry CD55-/CD59-RBCs No data 15.7% (6/38) RA: 5/33 (15.1%)
RARS: 1/1
RAEB: 0/4

Note: PNH, paroxysmal nocturnal hemoglobinuria; MDS, Myelodysplastic syndrome ; CMML, chronic myelomonocytic leu kemia; FLAER, fluorescent aerolysine; HGMDSL, high-risk MDS; hMDS, hypoplastic MDS variant, LGMDSL, low-risk MDS; MDS-U, MDS non-classified; RA, refractory anemia; RAEB(1/2), RA with blast excess (1/2); RAEBt, RA with blast excess and acute leukemia transformation; RAMD, RA with multilineage dysplasia; RARS, RA with ring syderoblasts; RCMD, RA with multilineage dysplasia; RCMDRS, RA with multilineage dysplasia and ring syderoblasts; 5q, 5q syndrome.

As seen from a series of studies (Table 1), incidence of PNH clone in MDS patients varies from 5.5% to 24% cases (a mean of 13%). PNH manifestations are highly different, and the disease may develop at any age (a median of 30-40 years old) [8, 22]. Life-threatening complications occur, as a rule, due to uncontrollable complement-mediated hemolysis and consequent blood platelet activation [3, 10, 19]. Most common clinical symptoms include anemia (88%) [3], thrombosis (35%) [9], chronic kidney disease (64%) [10], abdominal pains (57%), lung hypertension (47%), dyspnoe (66%), dysphagia (41%), significant fatigue (96%), erectile dysfunction (47%), bone marrow failure (45%) [19, 24]. Hemoglobinuria is the most remarkable PNH symptom. It develops in nearly all patients during the disease, being, however, initially observed only in 26% of the cases [22, 24]. Thromboses represent the main reason of mortality (40 to 67% of lethal outcomes) followed by chronic kidney injury (8 to 18% of total), infections (17%), and bleedings (8%) [15, 23].

PNH symptoms exert significant negative effects upon quality of life due to anemia, transfusion dependence, abdominal and chest pain, sufficient fatique, dyspnoe which often need hospitalization and symptomatic drug medication.

PNH diagnostics may be quite difficult, due to variability of symptoms and rarity of the disorder. However, the time of diagnostics may be more rapid when using diagnostic algorithm and screening of high-risk patients [8]. Flow cytometry (FC) is considered the most sensitive and informative technique to establish PNH diagnosis. Percentage of blood cells with complete or partial GPI anchor deficiency shows the size of PNH clone, as measured by immune phenotyping performed with flow cytometry [1] /National Clinical Guidelines on PNH diagnostics and treatment specify several patient groups with different clinical traits are discerned for appropriate PNH screening [16], i.e., Coombs-negative intravascular hemolysis; hemolytic anemia associated with hemoglobinuria, iron deficiency, cytopenia and thromboses; some bone marrow failure patterns (suggested or proven aplastic anemia; myelodysplastic syndrome (refractory cytopenia with 1-,2- or 3-lineage dyspla-sia, hypoplastic MDS variant), other cytopenias with unknown etiology after detailed examination; thromboses with atypical manifestations (uncommon localization, associated hemolytic anemia and cytopenias). As suggested in the Recommendations, optimal frequency of clinical examination and PNH screening should be performed initially in cases of aplastic anemia (AA) and MDS, and then twice a year in case of initial PNH clone detection. Presence of a PNH clone in MDS patients may be of high predictive value, with respect to its future treatment strategy.

Clinical Practice Guidelines in Oncology by National Comprehensive Cancer Network (NCCN-2010) recommend screening for PNH clone and HLA-DR15 if considering MDS. These markers seem to be best predictors of response to immunosuppressive therapy, especially, for younger patients (≤60 years old) with normal cytogenetics and hypoplastic MDS variant [20].

So far, only symptomatic therapy was used for PNH therapy, i.e., iron supplement, folates, steroids, blood transfusions, anticoagulants in thrombotic episodes. Generally, the median survival for hemolytic PNH patients comprises 10 to 15 years from initial diagnosis. Thirty-five percent of these patients are lost within 5 years [8].

Hematopoietic stem cell transplantation (HSCT) is an approach which may be potentially curative in PNH. However, HSCT is known to produce high complication rates, mortality, and is performed only for certain indications in cases of hematopoietic aplasia [4, 13].

Since 2007, Eculizumab, a drug for PNH target therapy, was registered for clinical use. Eculizumab is a humanized monoclonal antibody which is able to specifically bind the С5 component of complement system, thus blocking excessive complement activation and C5-mediated hemolysis, the main affecting factor in PNH. International clinical trials and subsequent studies have shown that Eculizumab sufficiently decreased incidence of life-threatening complications (i.e., thromboses), and significantly improved survival of the PNH patients. [7, 14].

Current publications contain only few reports on successful treatment of combined PNH/MDS conditions . In available literature we did not find any data on clinical hematological remission achieved with Eculizumab therapy in patients >70 years old. Therefore, our own description of such clinical case treated by Eculizumab should have clinical practical value.

Clinical case description

Patient M., 73 years old, was admitted to a Department of Therapy in January 2016. He presented with significant fatigue, vertigo, dizziness, absence of appetite, icterus, dark urine, periodical pressing heart pain, low-grade fever over month, cough, dyspnoe upon modest physical loads. Anemic syndrome and thrombocytopenia are traced since 2006, specialized hematological examination was initiated since 2009. Bone marrow cytology showed megaloblastoid traits of erythroid cells evaluated as potential MDS markers. Glucocorticoid therapy did not provide clinical response. Special examination aiming to exclude paraneoplastic events, has shown a prostate carcinoma (рТ2с, NO, G3, R0). The patient underwent extraperitoneal endoscopic radical prostatectomy with removal of regional pelvic lymph nodes, followed by urological screening, without any specific treatment. Since June 2015, his condition became worse, due to unmotivated fatigue, episodic hematuria. In January 2016, he noted some general physical symptoms as else-where described (see above), being admitted to Therapeutic Department. On admittance, his state was moderately severe. Skin and mucosae were icteric, multiple angiokeratomas and skin papillomas were evident. Peripheral lymph nodes were not enlarged, peripheral oedemas not detected. Chest auscultation did not show rales, however, weak breathing was evident. Heart sounds were muffled, at regular beats. Liver and spleen were not enlarged. Clinical blood analysis revealed decrease Hb (60 g/L), RBCs (1.75 х10 12 /L), platelets (60х10 9 /L), leukocytes (5.4х10 9 /L), neutrophils (64% of total leukocyte counts). Urinalysis showed proteinuria 2.0 g/L, changed and fresh RBCs (100 to 120 per microscopic field), urobilinogen (3+), bilirubin (1+). Results of blood biochemistry were as follows: direct bilirubin (21 μmol /L), total bilirubin of 87 μmol /L, ALaT (31U/L), ASaT (108 U/L, LDH (2925 U/L, being much higher normal values of 125-245 U/L). On 13.01.16, ECG has shown a subendocardial anterior lateral myocardial infarction. EchoCG has shown apical hypokinesis, akinesia of anterior and anteriorseptal segments. Cor onarographic study was refused, due to thrombocytopenia and hemorrhagic risk in the patient.

In view of distinct blood changes, we looked for PNH clonal markers. Flow cytometry provided the following pattern: type I (normal) RBCs, 59.05%; type II (partial СD59 deficiency), 1.47%; type III (complete lack of СD59 ), 39.48%; monocytes with FLAER/СD14 deficiency – 92.02%; granulocytes with FLAER/СD14 mangle – 94.73%. Hence, a PNH clone was detectable among RBCs, monocytes and granulocytes in blood sample. Appropriate treatment consisted of RBC transfusions (6 standard doses), bisoprolol (5 mg), isosorbide dinitrate (20 mg twice a day) followed by improvement of physical condition. Hb increased to 90 g/L, blood bilirubin and LDH levels remained high (resp., 28 μmol /L, and 2124 U/L). The patient was discharged from the clinic. In June 2016, he was urgently admitted to the M. Zhadkevich Municipal Clinical Hospital due to worsened clinical condition, recurrent skin icterus, dark urine, fever. His initial blood sampling was impossible due to intravascular hemolysis. Urine samples were brown-colored, with abundant yellow-brownish debris seen upon microscopy. Washed RBCs were transfused at this phase. At day +2 after admission, total blood analysis showed low Hb levels (62 g/L), decreased platelet counts (62х109/L). Routine blood chemistry showed LDH activity of 7132 U/L (reference, 125 to 245 U/L), total bilirubin, 100 μMol/L (direct bilirubin, 20 μmol/L); ASAТ, 290 U/L; С-reactive protein, 150 g/L. X-ray chest examination showed pneumonia in the left lower lobe. Further transfusion therapy included 3 doses of washed RBCs, and antibacterial treatment with Amoxicilline clavulanate, and Azithromycin. Relative stabilization of clinical state was observed. However, the course of disease was complicated by significant thrombocytopenia (to 18-20х109/L), profuse nasal bleeding, instability of respiratory and cardiovascular systems, thus re-quiring therapeutic nitrates, bisoprolol, continued antibacterial and detoxication therapy. 

In view of pronounced intravascular hemolysis and generally severe condition of the patient, we then started pathogenetic treatment by Eculizumab at a dose of 600 mg at a 7-day interval. Simultaneous vaccination for meningococcal infection was performed at this time. As an outcome, the pulmonary inflammation was resolved, urinary parameters were normalized, with anemia improved to some degree (Hb level increased to 87 g/L).

Seven days after 2nd eculizumab infusion, the patient was hospitalized to the Department of Hematology of Clinical Research Center at the Moscow Health Department, to specify further therapy. Upon admission, the patient was in satisfactory condition. Skin was of normal colour, eye sclerae were subicteric, hemorrhagic syndrome was not detectable. Hemodynamics remained stable, liver, spleen were of normal size. Blood analysis showed further increased Hb level (95 g/L), erythrocytes (3.0х1012/L), platelets, 35х109/L, leukocytes (3.2х109/L); differential counts showed 48% neutrophils. Urinalysis showed low protein content (0.1 g/L), erythrocytes (1-4 per vision field). Serum indexes were as follows: total bilirubin, 21 μmol /L (direct, 2.5 μmol /L), LDH, 540 U/L (reference, 125–245 U/L).

Marrow cytology revealed 2.3% blast cells, with dysplastic traits of granulocyte lineage (Peulger-like, hyposegmentation of the nuclei), erythroid cells (megaloblasts, increased pyknosis rates), and megakaryocytic lineage (mononuclear or small megakaryocytes). Cytogenetic data exhibited complex aberrations: 45,X, -Y[16]/ 46,XY[4]nucish(DXZ1х1) [66] (DXZ1,DYZ3)x1[34]. Loss of Y chromosome was shown in 80% of the cells studied.

Hence, the following diagnosis has been established: Paroxismal nocturnal hemoglobinuria. Myelodysplastic syndrome. Refractory cytopenia with multilinear dysplasia. IPSS: intermediate 1 risk. Prostate carcinoma (рТ2с, NO,M0.G3,R0). Extraperitoneal endoscopic radical prostatectomy of 2009. Due to observed clinical effect, we decided to continue Eculizumab treatment, according to a standard schedule. This mode of therapy proved to be tolerable, without adverse events during the infusions. Time-dependent dynamics of main blood indexes and changes in leukocyte profiles during such therapy are presented at Fig.1 and Table 2.

Figure 1. Time course of hematological indexes during eculizumab therapy.

Figure 1. Time course of hematological indexes during eculizumab therapy.

Table 2. Time dynamics of leukocyte profiles during Eculizumab therapy

Table 2. Time dynamics of leukocyte profiles during Eculizumab therapy

As seen from Fig. 1, the Hb levels did gradually increase to reference values, i.e., 120-125 g/L, leukocytes, to 4.1-5.87х109. Thrombocytopenia also became clinically insignificant(53-60 х109).

LDH activity is shown to be increased in disorders accompanied by tissue damage and cell destruction. Therefore, this parameter is an important marker of tissue decay, chronical hemolysis. Fig. 2 shows changes in LDH activity during Eculizumab therapy.

Figure 2. LDH changes with time after Eculizumab treatment.

Figure 2. LDH changes with time after Eculizumab treatment.

As seen from Fig. 2, PNH progression was noted by increased LDH levels from April 2014 to February 2016. Positive dy namics of the disease was then seen as proven by decreased LDH levels and Hb normalization (Fig. 1), when continuing treatment. The patient reported improved physical condi tion, he has resumed usual physical loads. Eculizumab treat ment is continued at a dose of 900 mg once every 2 weeks.

Discussion

Historically, the PNH patients received symptomatic treat ment, e.g., transfusion of washed RBCs, anticoagulant drugs, iron supplement and folic acid, glucocorticosteroids etc. HSCT was introduced is a method of choice for PNH thera py. Despite wide use of anticoagulants in PNH for thrombo sis prophylaxis, appropriate risk in the patients remain high, thus enhancing bleeding risks as well [14]. Advent of Eculi zumab, a monoclonal antibody which inhibits complement activity, has sufficiently improved results of PNH treatment due to effective control of complement-mediated hemolysis causing thromboses, and improving total survival of the pa tients [5, 17].

HCT remains the only curative method for PNH. Accord ing to large retrospective study which involved 211 PNH patients treated with BMT, total 5-year survival in this co hort was 68%, whereas graft failure was observed in 6% of the cases. Acute or chronic GvHD was evident in one-third of the patients [4, 5]. Meanwhile, Loschi M. et al reported total 6-year survival of 92% among the patients treated by Eculizumab [17]. Hence, HSCT provides a chance for radi cal PNH treatment. However, lethality and potential compli cations of the procedure are poorly predictable, and HSCT, therefore, cannot be recommended as a first-line strategy in the patients with classic PNH [6].

In some cases, HSCT is considered an option of MDS treat ment as first-line strategy. According to National Clinical Guidelines for Diagnostics and Treatment of Adult MDS, HSCT is indicated for the patients from the Group 1-2 in termediate and high-risk IPSS scores. Cumulative mortality after allo-HSCT from HLA-identical siblings in 387 patients with MDS proved to be 37% within 3 years, whereas relapse rates were 23% during this time period, with overall 3-year survival of 40%, according to IBMTR data. The disease stage and number of blasts are more significant to the HSCT out comes. However, upper age limits for HSCT do not exceed 65-70 years [26].

Our clinical case demonstrates clinical remission in an el derly PNH patient with myelodysplastic syndrome and high comorbidity burden. This case also shows importance of im mune phenotyping for PNH clone detection in either patient with myelodysplastic syndrome. The patient had several in dications for PNH clone testing, including cytopenia due to suggested MDS syndrome, intravascular hemolysis traits, and arterial thrombosis.

It is known that poorly documented MDS may be confused with unrecognized classical PNH, since in many instances it may be interpreted as isolated cytopenia, with non-detect ed active intravascular hemolysis. In this view, our clinical observation contains sufficient criteria for MDS diagnostics, i.e., erythroid hyperplasia and dysplasia typical to PNH, along with distinct cytological features of granulocytic and megakaryocytic dysplasia, like as clonal cytogenetic aberra tion (Y chromosome loss). Certainly, therapeutic choice in such cases cannot be based on the MDS treatment standards only. One should consider rates of intravascular hemolysis and, therefore, arrange target treatment with Eculizumab, according to current clinical indications. In this case, inten sive intravascular hemolysis was followed by RBC transfu sions, being then complicated by myocardial infarction, thus being indicative for appropriate target therapy, according to current recommendations. Marked positive response to Ecu lizumab treatment confirms a leading pathogenetic role of hemolysis rather than of bone marrow failure, for the pro found anemia observed in this case. Further accumulation of blood immunophenotyping results, cytogenetic and cy tological data will specify the PNH clone frequency and its pathogenetic role in MDS.

Conflict of interest

No conflict of interests is reported.

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string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11323" ["VALUE"]=> array(2) { ["TEXT"]=> string(48) "<p>Галина А. Дудина</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(36) "

Галина А. Дудина

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11324" ["VALUE"]=> array(2) { ["TEXT"]=> string(204) "<p>ГБУЗ Московский клинический научно-практический Центр департамента здравоохранения, Москва, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(192) "

ГБУЗ Московский клинический научно-практический Центр департамента здравоохранения, Москва, Россия

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Пароксизмальная ночная гемоглобинурия (ПНГ) является генетически обусловленным, приобретенным, клональным гематологическим заболеванием, при котором клетки крови утрачивают способность фиксировать на поверхности белки-ингибиторы системы компле-
мента – CD55 и CD59. Вследствие этого у больных развивается комплемент-опосредованный хронический внутрисосудистый гемолиз, наиболее тяжелым осложнением которого являются тромбозы. В рекомендациях международных групп по изучению ПНГ определены группы риска для выявления патологического клона, в число которых входят пациенты с миелодиспластическим синдромом (МДС). Приведено описание выявления клинически значимого
ПНГ-клона у пожилого пациента с миелопластическим синдромом и позитивные результаты применения патогенетического лечения экулизумабом.

Ключевые слова

Пароксизмальная ночная гемоглобинурия, миелодиспластический синдром, диагностика, экулизумаб

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Galina A. Dudina

" ["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) "11327" ["VALUE"]=> array(2) { ["TEXT"]=> string(483) "<p>Moscow Clinical Research Center, Moscow Health Department, Moscow, Russian Federation<br><br> <b>Correspondence</b<br>Dudina Galina A., PhD (Medicine), Senior Research Associate, Department of Oncohematology and Secondary Immunodeficiencies, The Moscow Clinical Research Center of Moscow Health Department, Entusiastov Ave 86, 111123, Moscow, Russian Federation<br> Phone: +7 (916) 650 8577 <br> E-mail: dudina_gal@mail.ru</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(432) "

Moscow Clinical Research Center, Moscow Health Department, Moscow, Russian Federation

CorrespondenceDudina Galina A., PhD (Medicine), Senior Research Associate, Department of Oncohematology and Secondary Immunodeficiencies, The Moscow Clinical Research Center of Moscow Health Department, Entusiastov Ave 86, 111123, Moscow, Russian Federation
Phone: +7 (916) 650 8577
E-mail: dudina_gal@mail.ru

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Paroxysmal nocturnal hemoglobinuria (PNH) is a systemic, acquired clonal hematological disorder which results from loss of complement-inhibiting proteins (CD55 and CD 59) from the blood cell surface. Therefore, such patients develop chronic complement-mediated intravascular hemolysis, with thromboses manifesting as most severe clinical complications. Recommendations of International PNH groups discern certain risk groups based on detection of a pathological cell clone, including patients with myelodysplastic syndrome (MDS). Here we describe detection of a clinically sound PNH clone in an elderly patient with MDS, as well as positive results of patho-genetic treatment with Eculizumab.

Keywords

Paroxismal nocturnal hemoglobinuria, myelodysplastic syndrome, diagnostics, Eculizumab

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Galina A. Dudina

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Galina A. Dudina

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Paroxysmal nocturnal hemoglobinuria (PNH) is a systemic, acquired clonal hematological disorder which results from loss of complement-inhibiting proteins (CD55 and CD 59) from the blood cell surface. Therefore, such patients develop chronic complement-mediated intravascular hemolysis, with thromboses manifesting as most severe clinical complications. Recommendations of International PNH groups discern certain risk groups based on detection of a pathological cell clone, including patients with myelodysplastic syndrome (MDS). Here we describe detection of a clinically sound PNH clone in an elderly patient with MDS, as well as positive results of patho-genetic treatment with Eculizumab.

Keywords

Paroxismal nocturnal hemoglobinuria, myelodysplastic syndrome, diagnostics, Eculizumab

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Paroxysmal nocturnal hemoglobinuria (PNH) is a systemic, acquired clonal hematological disorder which results from loss of complement-inhibiting proteins (CD55 and CD 59) from the blood cell surface. Therefore, such patients develop chronic complement-mediated intravascular hemolysis, with thromboses manifesting as most severe clinical complications. Recommendations of International PNH groups discern certain risk groups based on detection of a pathological cell clone, including patients with myelodysplastic syndrome (MDS). Here we describe detection of a clinically sound PNH clone in an elderly patient with MDS, as well as positive results of patho-genetic treatment with Eculizumab.

Keywords

Paroxismal nocturnal hemoglobinuria, myelodysplastic syndrome, diagnostics, Eculizumab

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Moscow Clinical Research Center, Moscow Health Department, Moscow, Russian Federation

CorrespondenceDudina Galina A., PhD (Medicine), Senior Research Associate, Department of Oncohematology and Secondary Immunodeficiencies, The Moscow Clinical Research Center of Moscow Health Department, Entusiastov Ave 86, 111123, Moscow, Russian Federation
Phone: +7 (916) 650 8577
E-mail: dudina_gal@mail.ru

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Moscow Clinical Research Center, Moscow Health Department, Moscow, Russian Federation

CorrespondenceDudina Galina A., PhD (Medicine), Senior Research Associate, Department of Oncohematology and Secondary Immunodeficiencies, The Moscow Clinical Research Center of Moscow Health Department, Entusiastov Ave 86, 111123, Moscow, Russian Federation
Phone: +7 (916) 650 8577
E-mail: dudina_gal@mail.ru

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Галина А. Дудина

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Галина А. Дудина

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Вследствие этого у больных развивается комплемент-опосредованный хронический внутрисосудистый гемолиз, наиболее тяжелым осложнением которого являются тромбозы. В рекомендациях международных групп по изучению ПНГ определены группы риска для выявления патологического клона, в число которых входят пациенты с миелодиспластическим синдромом (МДС). Приведено описание выявления клинически значимого <br>ПНГ-клона у пожилого пациента с миелопластическим синдромом и позитивные результаты применения патогенетического лечения экулизумабом. </p> <h3>Ключевые слова</h3> <p> Пароксизмальная ночная гемоглобинурия, миелодиспластический синдром, диагностика, экулизумаб </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1728) "

Пароксизмальная ночная гемоглобинурия (ПНГ) является генетически обусловленным, приобретенным, клональным гематологическим заболеванием, при котором клетки крови утрачивают способность фиксировать на поверхности белки-ингибиторы системы компле-
мента – CD55 и CD59. Вследствие этого у больных развивается комплемент-опосредованный хронический внутрисосудистый гемолиз, наиболее тяжелым осложнением которого являются тромбозы. В рекомендациях международных групп по изучению ПНГ определены группы риска для выявления патологического клона, в число которых входят пациенты с миелодиспластическим синдромом (МДС). Приведено описание выявления клинически значимого
ПНГ-клона у пожилого пациента с миелопластическим синдромом и позитивные результаты применения патогенетического лечения экулизумабом.

Ключевые слова

Пароксизмальная ночная гемоглобинурия, миелодиспластический синдром, диагностика, экулизумаб

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1728) "

Пароксизмальная ночная гемоглобинурия (ПНГ) является генетически обусловленным, приобретенным, клональным гематологическим заболеванием, при котором клетки крови утрачивают способность фиксировать на поверхности белки-ингибиторы системы компле-
мента – CD55 и CD59. Вследствие этого у больных развивается комплемент-опосредованный хронический внутрисосудистый гемолиз, наиболее тяжелым осложнением которого являются тромбозы. В рекомендациях международных групп по изучению ПНГ определены группы риска для выявления патологического клона, в число которых входят пациенты с миелодиспластическим синдромом (МДС). Приведено описание выявления клинически значимого
ПНГ-клона у пожилого пациента с миелопластическим синдромом и позитивные результаты применения патогенетического лечения экулизумабом.

Ключевые слова

Пароксизмальная ночная гемоглобинурия, миелодиспластический синдром, диагностика, экулизумаб

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ГБУЗ Московский клинический научно-практический Центр департамента здравоохранения, Москва, Россия

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ГБУЗ Московский клинический научно-практический Центр департамента здравоохранения, Москва, Россия

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Introduction

Novel achievements in fundamental molecular biology have expanded and deepened our knowledge on the wide vari- ety diseases molecular pathogenesis and created new tools aimed at the correction of identified pathogenic factors. The development of genome editing has changed the concept of available target for therapeutic correction. Introduction of techniques for highly precise and safe introduction of dou- ble-stranded breaks in human DNA followed by natural DNA repair mechanisms has changed current approaches to gene therapy and opens new horizons in the treatment of numerous diseases, including cancer.
It is known that there are at least 10000 human diseases caused by single gene mutations (monogenic diseases). Due to the wide use of next-generation sequencing, the number of detectable monogenic diseases tends to increase [10]. In despite of the monogenic diseases rarity, they affect over 400 million people worldwide. For some patients allogeneic he- matopoietic stem cell transplantation (allo-HSCT) may be applicable to cure their genetic disease, but the majority of patients are incurable now. Genome editing for the treatment of monogenic diseases is a conceptually simple approach (genome editing can be used to correct the underlying ge- netic aberrations), but its basic potential power focused on the mechanism providing more than merely modifying of the causative mutation. Genome editing is a method that can make more sophisticated and nuanced genomic chang- es, which can be used to cure more common diseases or to modify their course [22].

Genome editing in human: how does it work

There are different tools developed for the genome editing. The most popular among them are Zinc-finger Nucleas- es (ZFN), Transcription Activator-Like Effector Nucleases (TALEN), as well as Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR/Cas9) systems. These systems are common in their structural features which include a spe- cific DNA-binding segments and nuclease domain.

The main principle of genome editing is specific recognition of a target locus, based on genomic sequence authenticity with highly precised introduction of DNA breaks in the required genome site. Using artificially produced DNA sequences, we can direct our molecular instruments to any DNA locus thus selecting a target to correct. By nuclease domain activation in the case of nucleases listed above, a double-stranded break is introduced to genomic DNA of the target cell. The targeted DNA break generally affects a neighbor segment of the DNA-binding domain. Such endonuclease-based procedure causes stable, heritable changes of the target gene sequence and/or its expression in the cell. After introducing double-stranded breaks, one may give a rise to short insertions or deletions (indels) in the gene causing its functional inactivation (a ‘knockout’ procedure) due to the genetic code frameshift. Such inaccurate repair of the DNA occurs in the absence of homologous donor DNA and is reffered as non-homologous DNA end joining (NHEJ). By contrary, when exploiting a proper mechanism of homology-directed repair (HDR) of a double-stranded break, which reproduces precise copies of sister chromatids or exogenous DNA template, we are able to overwrite, i.e., to precisely introduce a correct nucleotide sequence or integrate a new gene (transgene), with high degree of accuracy. For this purpose, we need to bring a donor DNA segment for its insertion to the site of double-stranded breakage. Such template will be replicated during the homologous breakage repair.

Among the most important principles of the site-specific nuclease application the safety holds a specific place. In particular, the safety can be obtained, for example, by the transient expression of gene editing system components after the nuclease-encoding mRNA transfection. Once the mRNA is translated and the nuclease protein maturated, the RNA rapidly and entirely degraded within the cell In a natural way. In this respect, the only challenge is to deliver a nuclease-encoding genetic construct to the target cells. A simple and safe solution is to use viral vectors that are unable to integrate into the human genome, being intended only for transportation of viral genetic construct to the cell. However, there are some limitations, due to the size of this construct and cell tropism of transporter viruses and due to their toxicity for certain cell and tissue types. However, this way is plausible and practically applicable for in vivo administration. Physical methods of the DNA transfection represent a simpler and safer approach, i.e., phagocytosis, lipofection, electroporation, which also have their practical limitations. Clinically aimed genome editing in humans was applied for isolated cells taken from the human body and, after appropriate manipulations, returned to the host. The ex vivo protocols presume high enrichment of a distinct cell population, such as lymphocytes and hematopoietic stem cells (HSCs). The lymphocytes are obtained from peripheral blood, whereas stem cells could be enriched from bone marrow, umbilical blood, or peripheral blood from mobilized donors. The hematopoietic stem cell isolation is accomplished by additional separation procedures, in order to get a pure progenitor population. Cryoconservation of the cells with good viability followed by their intravenous infusion is widely used in the routine clinical practice over 50 years of the bone marrow transplantation. Hematopoietic stem cells are one of the most popular and promising target for gene therapy protocols, due to their tissue-specific homing, ability for differentiation and production of various blood cells, as well as broad clinical experience with their transplantation [11] (Fig. 1).

Figure 1. Flow-chart of genome editing procedure for treatment of monogenic diseases based on hematopoietic stem cell transplantation (adapted from [11])
Figure 1. Flow-chart of genome editing procedure for treatment of monogenic diseases based on hematopoietic stem cell transplantation (adapted from [11])

Potential therapeutic applications of genome editing

Discussion on therapeutic applications of the genome editing in human could be chronologically divided into three parts, i.e., current fields of genome editing, close future of the methodology, and its long-range prospective in the human diseases therapy. State of the art. HIV treatment is a leading field among different approaches to therapeutic usage of genome editing, with six already registered clinical trials (all of them are based on ZFN platform), and a number of pre-clinical and experimental data. A clinical case of a ‘Berlin patient’ proved to be a countdown point: an allogeneic HSC transplant to the HIV-infected patient with acute leukemia from a donor homozygous for CCR5delta32 mutation caused cure from both hematological malignancy and HIV infection [8,9]. People with naturally occurred mutation of both CCR5 alleles are non-susceptible to HIV infection. Unfortunately, the CCR 5delta32 homozygotes make <1% of Caucasian population, minimizing chances for finding an HLA-compatible donor with such a genetic defect [13,17]. Moreover, allogeneic HSCT is not an obligatory indication for HIV infection treatment, due to a sufficient procedure-related mortality. It is possible for only a group of HIV-associated complications such as hematological malignances.

Meanwhile, this successful transplantation has confirmed a critical significance of CCR5 for primary infection and development of the HIV-associated disease, thus starting a new path of clinical research. Therefore, first experience of genome editing in humans was obtained in patients suffer ing from HIV. These experiments became able due to wellknown target gene, i.e., CCR5 that should be knocked out, thus simulating a known mutation causing HIV resistance. Similarly, the target T lymphocytes were selected because this cell population is a main host for HIV. Critical decrease of CD4+ T cells in humans is an evident reason for morbidity and mortality in HIV patients. Moreover, novel modalities are required for HIV treatment, due to high social significance of this infection. A private company Sangamo Biosciences is now leading in ZFN-directed genome editing of T lymphocytes and HSCs. Higher transfection efficiency (>50%) and rare off-target gene modification were demonstrated during pre-clinical studies of CCR5 knockout in T cells and hematopoietic stem cells. Modified HSC were transplanted to humanized NSG mice and showed their ability for a normal hematopoiesis recovery. Moreover, upon HIV infection of transplanted animals, a selective advantage in survival was noted for the modified cells, as well as HIV resistance of T cell populations and decreased viral load in the animals. [6,11]. Sangamo has initiated several clinical trials with this technology, including those using HSCT following a conditioning regimen. As of today, over 80 patients with HIV are enrolled into clinical studies with infusion of the ‘edited’ human T cells and withdrawal of HAART. Results of 2 nd phase will be published in the near future. 

Other gene editing systems are also actively used for CCR5 knockout. For example, highly effective CCR5 modification was demonstrated for human T lymphocytes using TALENbased approach [18,19]. Preliminary results from a joint research group of the First Palvov State Medical University of St. Petersburg and Hamburg University have shown 40 per cent efficiency for the CCR5 gene modification using CCR5Uco-TALEN system (on behalf of CIC725, unpublished data). Similar results of CCR5 gene knockout by means of CRISPR/Cas9 enzyme system have been published, where the 27% efficiency in hematopoietic stem cells was observed, with preserved viability, proliferative and differentiation capacity of the cells. Interestingly, in silico estimation predicted a significant number of homologous CCR5 sites with highrate off-target effects. However, their real occurrence proved to be as low as 0.6% [16]. 

Close future. Currently, we are waiting for launching several clinical protocols with genome-edited cells. All of them concern treatment of monogenic diseases, due to presence of distinct target gene loci to be corrected, and because of well-designed HSC transplantation method. 

According to WHO, thousands of inherited monogenic disorders are known at the present time. Despite extreme rarity of distinct conditions, a summary prevalence of the monogenic disorders is up to 1% of total birth rates, i.e., hundreds of thousands new cases each year and the allogeneic HSCT is the one of potentially curative approach to the therapy of some types of these diseases. Due to the problems with HSC genome editing, most appropriate clinical protocols are at the stage of early pre-clinical and experimental studies with both cellular and animal models. At a longer range, these experiments should increase the gene editing efficiency to required clinical applications, aiming for safe and radical treatment of human inherited diseases [11].

Primary immune deficiencies (PID) could represent a good example of gene therapy implementations. Severe combined immune deficiencies (SCID) represent the most significant patient group. X-SCID is the most common genetic form of this disorder, caused by interleukin-2γ receptor (IL2RG) gene mutations. Several research groups have successfully used a ZFN system for induction of HDR in the IL2RG locus in different human cell types including HSCs and embryonic stem cells [4,14]. E.g., a copy of IL2RG was integrated into the HSC genome by means of ZFN nucleases. Integration efficiency was about 6% for ILRG2-containing cassette, showing only negligible off-target effects. Following grafting of the modified cells into a murine NSG model, a full-scale recovery of hemopoiesis with multi-lineage differentiation of immune populations were detected,. In spite of low integration efficiency of the functional gene cassette, the workers point to a selective advantage of genetically modified blood progenitors, along with reconstitution of the IL2RG function. Safety of the protocol is even increased, due to absence of special HSCT conditioning in this group of patients with immunodeficiencies [4].

Chronic granulomatous disease (CGD) is another impor tant clinical form of PID. It is characterized by deficient synthesis of reactive oxygen species (ROS) in phagocytic cells due to NOX2 gene mutation. Successful CGD gene correction by means of retroviral gene therapy was overshadowed by evident proto-oncogene activation followed by their clonal selection. An attempt of controlled gp91phox transgene integration to a safe AAVS1 region, using induced pluripotent stem cells (iPSCs) obtained from the patient’s HSCs was undertaken. The study has demonstrated an increased gp91phox mRNA levels in iPSCs subjected to genome editing, with subsequent differentiation to functional granulocytes with restored ROS production. Virtually all the modified cell clones contained a gp91phox cassette in AAVS1 locus. However, ca. 50% of them exhibited other integration sites. The study has shown an increased total efficiency and bi-allelic TALEN-induced modification (60%) as compared to 48% with ZFN system [3]. Now more safe self-inactivating RV vectors (SIN-gRV) are in Phase I/II clinical trials for PIDs. They show comparable efficiency and the absence of events related to clonal expansion [1,26].

Hyper-IgM syndrome is another disorder from the PID group. A recent report has demonstrated an in situ HDR insertion to CD40L in human lymphocytes using a TALEN system, thus making first step to the gene correction in human hematopoietic cells. The most important achievement was retaining of natural regulatory elements, profile and expression kinetics of the gene transduced, together with restored B cell function [7].

Hemoglobinopathies. Beta-thalassemia is a group of inher itable blood diseases caused by HBB gene defect, character ized by decreased or absent synthesis of hemoglobin beta protein chains. As of today, allo-HSCT is the only available method to treat these disorders. Some studies show that HBB genomic locus coils should be specifically and effectively modified by ZFN [27], TALEN, or CRISPR/Cas9 systems [3,22]. Using native patient-derived iPSCs treated with TALEN system, in situ correction of HBB gene was performed. HDR efficiency was not high for the system developed; however the HBB-integrated clones demonstrated normal karyotype, retained pluripotency and, upon induction to differentiation, produced hematopoietic progenitors able for erythropoiesis with normal beta-globin expression. Off-target activity of TALEN was not detected during the cell modification [15].
A recent study reported efficiency of CRISPR/Cas9 system for correction of HBB in iPSCs|: up to 57% of the clones showed modification of at least one HBB allele in experimental series, as well as minimal off-target activity [28].

Sickle-cell anemia is a widely spread inherited hemoglobin disorder caused by structural defect of hemoglobin chain (HBB mutation) that leads to abnormal HbS production. Correction of this specific defect by means of genome editing tools was also successfully demonstrated [17]. Another recent study applied ZFN system for repair of specific mutation in CD34+ cells from the patients. The given work yielded promising results, i.e., the HDR efficiency was up 18% in the CD34+ populations from sickle-cell anemia subjects. Restoration of normal Hb synthesis was confirmed in the gene-modified cells. Since only 10 to 30% of progenitor cell population is required for sufficient erythropoiesis, the efficiency of genome editing is close to the levels plausible for clinical usage. Therefore, an appropriate clinical protocol will be probably initiated in sooner time [5].

HSC pathology. Fanconi anemia occurs due to deficient proteins belonging to a DNA repair cluster . Quite recently, an in situ successful correction of FANCC gene was carried out in a primary culture of the patients’ fibroblasts using CRISPR/Cas9 nucleases and CRISPR/Cas9 nickases followed by transformation of modified cells to iPSCs [20].

Of interest was a significant preference of nickase system for homology-directed repair (HDR), whereas classical nucleases favored NHEJ repair mechanisms. Generally, the CRISPR/Cas9 nuclease activity, if measured by cell modification, proved to be ca. 5%, including a small number of cells with HDR. The given efficiency rate is much lower than the required for clinical trials. The procedure needs selection of clones with successful gene integration.
In vivo genome editing is connected with elaboration of effective gene delivery, using a safe virus-based vector. The first upcoming clinical study is scheduled and will include hemo philia B treatment. A transgene of blood coagulation factor IX modified by genome editing will be introduced to genome of hepatocytes. The substitute gene, i.e., factor IX gene, is introduced to the target locus under albumin promoter, thus inducing factor IX protein synthesis by the human host liver. Albumin promoter was chosen as the safest and most synthesis-efficient segment of hepatocyte genome. The manipulations have to proceed as follows: the patient is infused intravenously with two viruses. The first virus produces zinc nucleases that incise the albumin gene, followed by effects of second virus that encodes the transgene incorporated into the genome [12]. Efficiency and safety of the method are shown at preclinical phase. An application for clinical use of this method has been considered and endorsed by the USA Food and drug administration (FDA).

Cancer immunotherapy. The most important developments in genome editing are directed to combat malignant tumors. By means of genome editing, novel mechanisms of tumor cell functioning are discovered, and tumor models are designed for pathogenetic analysis and studies of new medical drugs. So far, further breakthrough in oncology is connected with mechanistic studies of tumor avoidance from natural immune surveillance and achievements in the field of genetic engineering, i.e. production of T lymphocytes with chimeric antigenic receptors (CAR-T). The T cell modifications by means of genome editing are coupled to design of CAR-T cells. Appropriate gene editing procedures enable safe enhancement of antitumor effect. Nowadays, successful clinical use of CAR-T designed with TALEN technology was demonstrated in seven pediatric patients with acute lymphoblastic leukemia at London clinics [23,24]. Hence, expectations for gene editing in oncology are rather broad. In the nearest future, we can expect CAR-T cells after multiple editing (e.g., with combined changes in the genes encoding ТCR, PD1 receptors and CTLC4 receptors). Clinical application of this data is possible without a delay upon discerning new tumor resistance mechanisms based on genome editing.

Prospective of human genome editing can be focused on breaking immune histocompatibility differences are extremely valuable in organ and tissue transplants field. The “edited” animals, e.g., pigs, may become versatile donors for humans taking into account their organ physiology and structure. One may imagine soon occurring farms for transgenic pigs that could be used as compatible graft donors for humans. This kind of pigs already exists and was a subject to multiple genome editing and knockout of immune sur veillance genes thus making them plausible for xenogeneic transplants [25].

In summary, the mentioned preclinical studies with site-specific genome editing systems are challenged by the issues of procedure efficiency. Human immune populations and hematopoietic cells are among the most demanded cell editing targets. Low HDR efficiency appears to be an important problem for HSC modification, as well as loss of multilineage differentiation potential upon genetic manipulations, as well as low expansion rates of in vitro modified cells. Over last years, the field of genome editing has been developed very rapidly. Currently, there are several alternative recognized tools tested for genome editing which are based on site-specific nuclease effects. A number of research groups are working on the efficiency, safety and simplified design for these tools. Recent clinical studies have shown that the gene editing has already reached pharmacological level in terms of efficiency, specificity, delivery rates, and considered by appropriate regulatory institutes both in USA and Europe. Due to many years of fundamental studies, some specific genes responsible for certain genetic disorders were discovered.

The nucleases that are able to precisely knockout target genes were discovered as well. The ex vivo experiments showed potential ability to use the modified cells in vivo, by means of cellular therapy and HSCT procedures.

Despite some difficulties, preclinical studies of genome editing are bringing medical science to a new level. Clinical implications of genome editing based on transplantation of distinct cell populations (e.g., HSCs) are quite promising and potentially successful.

Acknowledgements

We would like to thank all clinical and laboratory staff of R. Gorbacheva Memorial Research Institute of Children’s Oncology, Hematology and Transplantation at the First Pavlov State Medical University of St. Petersburg. We also are grateful for useful support and cooperation in the field of hematopoietic stem cell research to Prof. Gerard Wagemaker; to Prof. Boris Fehse for cooperation in genome editing research; as well as to Prof. Fyodor D. Urnov for personal communications in the field of genome editing. We would like to express our sincere gratitude to Prof. Alexey B. Chuhlovin for advices in writing of the article, and Dr. Olga Ponomarenko for assistance and consulting.

Conflicts of interest

No conflict interests are declared

References

  1. Booth C., Gaspar H.B., Thrasher A.J. Treating Immuno deficiency through HSC Gene Therapy. Trends Mol. Med. 2016;22:317–327. doi: 10.1016/j.molmed.2016.02.002

  2. Cradick TJ, Fine EJ, Antico CJ, Bao G. CRISPR/Cas9 systems targeting β-globin and CCR5 genes have substantial off-target activity. Nucleic Acids Res. 2013;41:9584–9592

  3. Dreyer AK, Hoffmann D, Lachmann N, Ackermann M, Steinemann D, Timm B, Siler U,Reichenbach J, Grez M, Moritz T, et al. TALEN-mediated functional correction of X-linked chronic granulomatous disease in patient-derived induced pluripotent stem cells. Biomaterials 2015;69:191– 200. doi: 10.1016/j.biomaterials.2015.07.057.

  4. Genovese P, Schiroli G, Escobar G, Targeted genome editing in human repopulating haematopoietic stem cells Nature. 2014 Jun 12;510(7504):235-40. doi: 10.1038/na ture13420. Epub 2014 May 28.

  5. Hoban MD, Cost GJ, Mendel MC, et al. Correction of the sickle cell disease mutation in human hematopoietic stem/ progenitor cells. Blood. 2015;125(17):2597-2604.Hoban MD, Cost GJ, Mendel MC, et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood. 2015;125(17):2597-2604.

  6. Holt N, Wang J, Kim K, Friedman G, Wang X, Taupin V, et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol (2010) 28(8):839–47.10.1038/nbt.1663

  7. Hubbard, N., Hagin, D., Sommer, K., Song, Y., Khan, I., Clough, C., Ochs, H. D., Rawlings, D. J., Scharenberg, A. M., & Torgerson, T. R. (2016). Targeted gene editing restores reg ulated CD40L function in X-linked hyper-IgM syndrome. Blood, 127(21), 2513-2522. Accessed March 20, 2017. DOI: 10.1182/blood-2015-11-683235

  8. Hütter G, Nowak D, Mossner M et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009; 360:692–8

  9. Hütter G, Thiel E. Allogeneic transplantation of CCR5 deficient progenitor cells in a patient with HIV infection – an update after 3 years and the search for patient no. 2. AIDS 2011; 25:273–4.

  10. Johnston JJ, Lewis KL, Ng D, Singh LN, Wynter J, Brew er C, et al. Individualized iterative phenotyping for ge nome-wide analysis of loss-of-function mutations. Am J Hum Genet. 2015;96:913–25.

  11. Lepik, K.V., Popova, M.O., Shakirova, A.I., Sergeev, V.S., Potter, A.Y., Barkhatov, I.M., Fehse, B., Afanasyev, B.V. Site-specific genome editing for hematopoetic stem cells transplantation-based gene therapy approaches (2016) Genes and Cells, 11 (2), pp. 21-29.

  12. Li H, Haurigot V, Doyon Y, et al. In vivo genome editing restores hemostasis in a mouse model of hemophilia. Nature. 2011;475(7355):217-221. doi:10.1038/nature10177.

  13. Libert F, Cochaux P, Beckman G, et al. The CCR5-Δ32 mutation conferring protection against HIV-1 in Caucasian populations has a single and recent origin in Northeastern Europe. Hum Mol Genet 1998;7:399–406.

  14. Lombardo A, Genovese P, Beausejour CM, Colleoni S, Lee YL, Kim KA, et al. Gene editing in human stem cells using zinc finger nucleases and integrase-defective lenti viral vector delivery. Nat Biotechnol (2007)25(11):1298– 306.10.1038/nbt1353

  15. Ma N, Liao B, Zhang H, et al. Transcription activator-like effector nuclease (TALEN)-mediated gene correction in in tegration-free beta-thalassemia induced pluripotent stem cells. J Biol Chem. 2013;288:34671–34679.

  16. Mandal PK, Ferreira LMR, Collins R, et al. Efficient ab lation of genes in human hematopoietic stem and effector cells using CRISPR/Cas9. Cell stem cell. 2014;15(5):643-652. doi:10.1016/j.stem.2014.10.004.

  17. Marmor M, Sheppard HW, Donnell D, et al. Homozy gous and heterozygous CCR5-D32 genotypes are associated with resistance to HIV infection. JAIDS 2001;27:472–81.

  18. Mock U, Hauber I, Fehse B Digital PCR to assess gene-ed iting frequencies mediated by designer nucleases. Nature Protocols 11, 598–615, (2016). doi:10.1038/nprot.2016.027

  19. Mock U, Machowicz R, Hauber I, et al. mRNA transfec tion of a novel TAL effector nuclease (TALEN) facilitates ef ficient knockout of HIV co-receptor CCR5. Nucleic Acids Research. 2015;43(11):5560-5571. doi:10.1093/nar/gkv469.

  20. Osborn MJ, Gabriel R, Webber BR, et al. Fanconi Anemia Gene Editing by the CRISPR/Cas9 System. Human Gene Therapy. 2015;26(2):114-126. doi:10.1089/hum.2014.111.

  21. Patsali P, Mussolino C, Stephanou C, et al. Towards per sonalized gene therapy for β-thalassemia in Cyprus; Pre sented at: American Society for Gene and Cell Therapy 19th Annual Congress; Washington, DC. May 23, 2014. Abstract number 692. Molecular Therapy, Volume 22, S268.

  22. Porteus MH. Towards a new era in medicine: therapeutic genome editing. Genome Biology. 2015;16:286. doi:10.1186/ s13059-015-0859-y.

  23. Qasim, W., Amrolia, P. J., Samarasinghe, S., et al. (2015). First Clinical Application of Talen Engineered Universal CAR19 T Cells in B-ALL. Blood, 126(23), 2046. Accessed March 20, 2017.

  24. Reardon S. Leukaemia success heralds wave of gene-ed iting therapies. One-year-old girl treated as plans to inject DNA-cutting technology directly into patients’ bodies take shape. Nature 527, 146–147 (09 November 2015). doi:10.1038/ nature.2015.18737. http://www.nature.com/news/leukaemia success-heralds-wave-of-gene-editing-therapies-1.18737

  25. Reardon S. New life for pig-to-human transplants. Gene-editing technologies have breathed life into the lan guishing field of xenotransplantation. Nature 527, 152–154 (12 November 2015) doi:10.1038/527152a. http://www.nature. com/news/new-life-for-pig-to-human-transplants-1.18768

  26. Touzot F, Hacein-Bey-Abina S, Fischer A, Cavazzana M. Gene therapy for inherited immunodeficiency. Expert Opin Biol Ther (2014) 14(6):789–98.10.1517/14712598.2014.895811

  27. Voit RA, Hendel A, Pruett-Miller SM, Porteus MH. Nu clease-mediated gene editing by homologous recombination of the human globin locus. Nucleic Acids Res. 2014;42:1365– 1378

  28. Yang Y, Zhang X, Yi L et al. Naïve Induced Pluripotent Stem Cells Generated From β-Thalassemia Fibroblasts Allow Efficient Gene Correction With CRISPR/Cas9 Stem Cells Transl Med. 2016 Jan;5(1):8-19. doi: 10.5966/sctm.2015 0157

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Introduction

Novel achievements in fundamental molecular biology have expanded and deepened our knowledge on the wide vari- ety diseases molecular pathogenesis and created new tools aimed at the correction of identified pathogenic factors. The development of genome editing has changed the concept of available target for therapeutic correction. Introduction of techniques for highly precise and safe introduction of dou- ble-stranded breaks in human DNA followed by natural DNA repair mechanisms has changed current approaches to gene therapy and opens new horizons in the treatment of numerous diseases, including cancer.
It is known that there are at least 10000 human diseases caused by single gene mutations (monogenic diseases). Due to the wide use of next-generation sequencing, the number of detectable monogenic diseases tends to increase [10]. In despite of the monogenic diseases rarity, they affect over 400 million people worldwide. For some patients allogeneic he- matopoietic stem cell transplantation (allo-HSCT) may be applicable to cure their genetic disease, but the majority of patients are incurable now. Genome editing for the treatment of monogenic diseases is a conceptually simple approach (genome editing can be used to correct the underlying ge- netic aberrations), but its basic potential power focused on the mechanism providing more than merely modifying of the causative mutation. Genome editing is a method that can make more sophisticated and nuanced genomic chang- es, which can be used to cure more common diseases or to modify their course [22].

Genome editing in human: how does it work

There are different tools developed for the genome editing. The most popular among them are Zinc-finger Nucleas- es (ZFN), Transcription Activator-Like Effector Nucleases (TALEN), as well as Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR/Cas9) systems. These systems are common in their structural features which include a spe- cific DNA-binding segments and nuclease domain.

The main principle of genome editing is specific recognition of a target locus, based on genomic sequence authenticity with highly precised introduction of DNA breaks in the required genome site. Using artificially produced DNA sequences, we can direct our molecular instruments to any DNA locus thus selecting a target to correct. By nuclease domain activation in the case of nucleases listed above, a double-stranded break is introduced to genomic DNA of the target cell. The targeted DNA break generally affects a neighbor segment of the DNA-binding domain. Such endonuclease-based procedure causes stable, heritable changes of the target gene sequence and/or its expression in the cell. After introducing double-stranded breaks, one may give a rise to short insertions or deletions (indels) in the gene causing its functional inactivation (a ‘knockout’ procedure) due to the genetic code frameshift. Such inaccurate repair of the DNA occurs in the absence of homologous donor DNA and is reffered as non-homologous DNA end joining (NHEJ). By contrary, when exploiting a proper mechanism of homology-directed repair (HDR) of a double-stranded break, which reproduces precise copies of sister chromatids or exogenous DNA template, we are able to overwrite, i.e., to precisely introduce a correct nucleotide sequence or integrate a new gene (transgene), with high degree of accuracy. For this purpose, we need to bring a donor DNA segment for its insertion to the site of double-stranded breakage. Such template will be replicated during the homologous breakage repair.

Among the most important principles of the site-specific nuclease application the safety holds a specific place. In particular, the safety can be obtained, for example, by the transient expression of gene editing system components after the nuclease-encoding mRNA transfection. Once the mRNA is translated and the nuclease protein maturated, the RNA rapidly and entirely degraded within the cell In a natural way. In this respect, the only challenge is to deliver a nuclease-encoding genetic construct to the target cells. A simple and safe solution is to use viral vectors that are unable to integrate into the human genome, being intended only for transportation of viral genetic construct to the cell. However, there are some limitations, due to the size of this construct and cell tropism of transporter viruses and due to their toxicity for certain cell and tissue types. However, this way is plausible and practically applicable for in vivo administration. Physical methods of the DNA transfection represent a simpler and safer approach, i.e., phagocytosis, lipofection, electroporation, which also have their practical limitations. Clinically aimed genome editing in humans was applied for isolated cells taken from the human body and, after appropriate manipulations, returned to the host. The ex vivo protocols presume high enrichment of a distinct cell population, such as lymphocytes and hematopoietic stem cells (HSCs). The lymphocytes are obtained from peripheral blood, whereas stem cells could be enriched from bone marrow, umbilical blood, or peripheral blood from mobilized donors. The hematopoietic stem cell isolation is accomplished by additional separation procedures, in order to get a pure progenitor population. Cryoconservation of the cells with good viability followed by their intravenous infusion is widely used in the routine clinical practice over 50 years of the bone marrow transplantation. Hematopoietic stem cells are one of the most popular and promising target for gene therapy protocols, due to their tissue-specific homing, ability for differentiation and production of various blood cells, as well as broad clinical experience with their transplantation [11] (Fig. 1).

Figure 1. Flow-chart of genome editing procedure for treatment of monogenic diseases based on hematopoietic stem cell transplantation (adapted from [11])
Figure 1. Flow-chart of genome editing procedure for treatment of monogenic diseases based on hematopoietic stem cell transplantation (adapted from [11])

Potential therapeutic applications of genome editing

Discussion on therapeutic applications of the genome editing in human could be chronologically divided into three parts, i.e., current fields of genome editing, close future of the methodology, and its long-range prospective in the human diseases therapy. State of the art. HIV treatment is a leading field among different approaches to therapeutic usage of genome editing, with six already registered clinical trials (all of them are based on ZFN platform), and a number of pre-clinical and experimental data. A clinical case of a ‘Berlin patient’ proved to be a countdown point: an allogeneic HSC transplant to the HIV-infected patient with acute leukemia from a donor homozygous for CCR5delta32 mutation caused cure from both hematological malignancy and HIV infection [8,9]. People with naturally occurred mutation of both CCR5 alleles are non-susceptible to HIV infection. Unfortunately, the CCR 5delta32 homozygotes make <1% of Caucasian population, minimizing chances for finding an HLA-compatible donor with such a genetic defect [13,17]. Moreover, allogeneic HSCT is not an obligatory indication for HIV infection treatment, due to a sufficient procedure-related mortality. It is possible for only a group of HIV-associated complications such as hematological malignances.

Meanwhile, this successful transplantation has confirmed a critical significance of CCR5 for primary infection and development of the HIV-associated disease, thus starting a new path of clinical research. Therefore, first experience of genome editing in humans was obtained in patients suffer ing from HIV. These experiments became able due to wellknown target gene, i.e., CCR5 that should be knocked out, thus simulating a known mutation causing HIV resistance. Similarly, the target T lymphocytes were selected because this cell population is a main host for HIV. Critical decrease of CD4+ T cells in humans is an evident reason for morbidity and mortality in HIV patients. Moreover, novel modalities are required for HIV treatment, due to high social significance of this infection. A private company Sangamo Biosciences is now leading in ZFN-directed genome editing of T lymphocytes and HSCs. Higher transfection efficiency (>50%) and rare off-target gene modification were demonstrated during pre-clinical studies of CCR5 knockout in T cells and hematopoietic stem cells. Modified HSC were transplanted to humanized NSG mice and showed their ability for a normal hematopoiesis recovery. Moreover, upon HIV infection of transplanted animals, a selective advantage in survival was noted for the modified cells, as well as HIV resistance of T cell populations and decreased viral load in the animals. [6,11]. Sangamo has initiated several clinical trials with this technology, including those using HSCT following a conditioning regimen. As of today, over 80 patients with HIV are enrolled into clinical studies with infusion of the ‘edited’ human T cells and withdrawal of HAART. Results of 2 nd phase will be published in the near future. 

Other gene editing systems are also actively used for CCR5 knockout. For example, highly effective CCR5 modification was demonstrated for human T lymphocytes using TALENbased approach [18,19]. Preliminary results from a joint research group of the First Palvov State Medical University of St. Petersburg and Hamburg University have shown 40 per cent efficiency for the CCR5 gene modification using CCR5Uco-TALEN system (on behalf of CIC725, unpublished data). Similar results of CCR5 gene knockout by means of CRISPR/Cas9 enzyme system have been published, where the 27% efficiency in hematopoietic stem cells was observed, with preserved viability, proliferative and differentiation capacity of the cells. Interestingly, in silico estimation predicted a significant number of homologous CCR5 sites with highrate off-target effects. However, their real occurrence proved to be as low as 0.6% [16]. 

Close future. Currently, we are waiting for launching several clinical protocols with genome-edited cells. All of them concern treatment of monogenic diseases, due to presence of distinct target gene loci to be corrected, and because of well-designed HSC transplantation method. 

According to WHO, thousands of inherited monogenic disorders are known at the present time. Despite extreme rarity of distinct conditions, a summary prevalence of the monogenic disorders is up to 1% of total birth rates, i.e., hundreds of thousands new cases each year and the allogeneic HSCT is the one of potentially curative approach to the therapy of some types of these diseases. Due to the problems with HSC genome editing, most appropriate clinical protocols are at the stage of early pre-clinical and experimental studies with both cellular and animal models. At a longer range, these experiments should increase the gene editing efficiency to required clinical applications, aiming for safe and radical treatment of human inherited diseases [11].

Primary immune deficiencies (PID) could represent a good example of gene therapy implementations. Severe combined immune deficiencies (SCID) represent the most significant patient group. X-SCID is the most common genetic form of this disorder, caused by interleukin-2γ receptor (IL2RG) gene mutations. Several research groups have successfully used a ZFN system for induction of HDR in the IL2RG locus in different human cell types including HSCs and embryonic stem cells [4,14]. E.g., a copy of IL2RG was integrated into the HSC genome by means of ZFN nucleases. Integration efficiency was about 6% for ILRG2-containing cassette, showing only negligible off-target effects. Following grafting of the modified cells into a murine NSG model, a full-scale recovery of hemopoiesis with multi-lineage differentiation of immune populations were detected,. In spite of low integration efficiency of the functional gene cassette, the workers point to a selective advantage of genetically modified blood progenitors, along with reconstitution of the IL2RG function. Safety of the protocol is even increased, due to absence of special HSCT conditioning in this group of patients with immunodeficiencies [4].

Chronic granulomatous disease (CGD) is another impor tant clinical form of PID. It is characterized by deficient synthesis of reactive oxygen species (ROS) in phagocytic cells due to NOX2 gene mutation. Successful CGD gene correction by means of retroviral gene therapy was overshadowed by evident proto-oncogene activation followed by their clonal selection. An attempt of controlled gp91phox transgene integration to a safe AAVS1 region, using induced pluripotent stem cells (iPSCs) obtained from the patient’s HSCs was undertaken. The study has demonstrated an increased gp91phox mRNA levels in iPSCs subjected to genome editing, with subsequent differentiation to functional granulocytes with restored ROS production. Virtually all the modified cell clones contained a gp91phox cassette in AAVS1 locus. However, ca. 50% of them exhibited other integration sites. The study has shown an increased total efficiency and bi-allelic TALEN-induced modification (60%) as compared to 48% with ZFN system [3]. Now more safe self-inactivating RV vectors (SIN-gRV) are in Phase I/II clinical trials for PIDs. They show comparable efficiency and the absence of events related to clonal expansion [1,26].

Hyper-IgM syndrome is another disorder from the PID group. A recent report has demonstrated an in situ HDR insertion to CD40L in human lymphocytes using a TALEN system, thus making first step to the gene correction in human hematopoietic cells. The most important achievement was retaining of natural regulatory elements, profile and expression kinetics of the gene transduced, together with restored B cell function [7].

Hemoglobinopathies. Beta-thalassemia is a group of inher itable blood diseases caused by HBB gene defect, character ized by decreased or absent synthesis of hemoglobin beta protein chains. As of today, allo-HSCT is the only available method to treat these disorders. Some studies show that HBB genomic locus coils should be specifically and effectively modified by ZFN [27], TALEN, or CRISPR/Cas9 systems [3,22]. Using native patient-derived iPSCs treated with TALEN system, in situ correction of HBB gene was performed. HDR efficiency was not high for the system developed; however the HBB-integrated clones demonstrated normal karyotype, retained pluripotency and, upon induction to differentiation, produced hematopoietic progenitors able for erythropoiesis with normal beta-globin expression. Off-target activity of TALEN was not detected during the cell modification [15].
A recent study reported efficiency of CRISPR/Cas9 system for correction of HBB in iPSCs|: up to 57% of the clones showed modification of at least one HBB allele in experimental series, as well as minimal off-target activity [28].

Sickle-cell anemia is a widely spread inherited hemoglobin disorder caused by structural defect of hemoglobin chain (HBB mutation) that leads to abnormal HbS production. Correction of this specific defect by means of genome editing tools was also successfully demonstrated [17]. Another recent study applied ZFN system for repair of specific mutation in CD34+ cells from the patients. The given work yielded promising results, i.e., the HDR efficiency was up 18% in the CD34+ populations from sickle-cell anemia subjects. Restoration of normal Hb synthesis was confirmed in the gene-modified cells. Since only 10 to 30% of progenitor cell population is required for sufficient erythropoiesis, the efficiency of genome editing is close to the levels plausible for clinical usage. Therefore, an appropriate clinical protocol will be probably initiated in sooner time [5].

HSC pathology. Fanconi anemia occurs due to deficient proteins belonging to a DNA repair cluster . Quite recently, an in situ successful correction of FANCC gene was carried out in a primary culture of the patients’ fibroblasts using CRISPR/Cas9 nucleases and CRISPR/Cas9 nickases followed by transformation of modified cells to iPSCs [20].

Of interest was a significant preference of nickase system for homology-directed repair (HDR), whereas classical nucleases favored NHEJ repair mechanisms. Generally, the CRISPR/Cas9 nuclease activity, if measured by cell modification, proved to be ca. 5%, including a small number of cells with HDR. The given efficiency rate is much lower than the required for clinical trials. The procedure needs selection of clones with successful gene integration.
In vivo genome editing is connected with elaboration of effective gene delivery, using a safe virus-based vector. The first upcoming clinical study is scheduled and will include hemo philia B treatment. A transgene of blood coagulation factor IX modified by genome editing will be introduced to genome of hepatocytes. The substitute gene, i.e., factor IX gene, is introduced to the target locus under albumin promoter, thus inducing factor IX protein synthesis by the human host liver. Albumin promoter was chosen as the safest and most synthesis-efficient segment of hepatocyte genome. The manipulations have to proceed as follows: the patient is infused intravenously with two viruses. The first virus produces zinc nucleases that incise the albumin gene, followed by effects of second virus that encodes the transgene incorporated into the genome [12]. Efficiency and safety of the method are shown at preclinical phase. An application for clinical use of this method has been considered and endorsed by the USA Food and drug administration (FDA).

Cancer immunotherapy. The most important developments in genome editing are directed to combat malignant tumors. By means of genome editing, novel mechanisms of tumor cell functioning are discovered, and tumor models are designed for pathogenetic analysis and studies of new medical drugs. So far, further breakthrough in oncology is connected with mechanistic studies of tumor avoidance from natural immune surveillance and achievements in the field of genetic engineering, i.e. production of T lymphocytes with chimeric antigenic receptors (CAR-T). The T cell modifications by means of genome editing are coupled to design of CAR-T cells. Appropriate gene editing procedures enable safe enhancement of antitumor effect. Nowadays, successful clinical use of CAR-T designed with TALEN technology was demonstrated in seven pediatric patients with acute lymphoblastic leukemia at London clinics [23,24]. Hence, expectations for gene editing in oncology are rather broad. In the nearest future, we can expect CAR-T cells after multiple editing (e.g., with combined changes in the genes encoding ТCR, PD1 receptors and CTLC4 receptors). Clinical application of this data is possible without a delay upon discerning new tumor resistance mechanisms based on genome editing.

Prospective of human genome editing can be focused on breaking immune histocompatibility differences are extremely valuable in organ and tissue transplants field. The “edited” animals, e.g., pigs, may become versatile donors for humans taking into account their organ physiology and structure. One may imagine soon occurring farms for transgenic pigs that could be used as compatible graft donors for humans. This kind of pigs already exists and was a subject to multiple genome editing and knockout of immune sur veillance genes thus making them plausible for xenogeneic transplants [25].

In summary, the mentioned preclinical studies with site-specific genome editing systems are challenged by the issues of procedure efficiency. Human immune populations and hematopoietic cells are among the most demanded cell editing targets. Low HDR efficiency appears to be an important problem for HSC modification, as well as loss of multilineage differentiation potential upon genetic manipulations, as well as low expansion rates of in vitro modified cells. Over last years, the field of genome editing has been developed very rapidly. Currently, there are several alternative recognized tools tested for genome editing which are based on site-specific nuclease effects. A number of research groups are working on the efficiency, safety and simplified design for these tools. Recent clinical studies have shown that the gene editing has already reached pharmacological level in terms of efficiency, specificity, delivery rates, and considered by appropriate regulatory institutes both in USA and Europe. Due to many years of fundamental studies, some specific genes responsible for certain genetic disorders were discovered.

The nucleases that are able to precisely knockout target genes were discovered as well. The ex vivo experiments showed potential ability to use the modified cells in vivo, by means of cellular therapy and HSCT procedures.

Despite some difficulties, preclinical studies of genome editing are bringing medical science to a new level. Clinical implications of genome editing based on transplantation of distinct cell populations (e.g., HSCs) are quite promising and potentially successful.

Acknowledgements

We would like to thank all clinical and laboratory staff of R. Gorbacheva Memorial Research Institute of Children’s Oncology, Hematology and Transplantation at the First Pavlov State Medical University of St. Petersburg. We also are grateful for useful support and cooperation in the field of hematopoietic stem cell research to Prof. Gerard Wagemaker; to Prof. Boris Fehse for cooperation in genome editing research; as well as to Prof. Fyodor D. Urnov for personal communications in the field of genome editing. We would like to express our sincere gratitude to Prof. Alexey B. Chuhlovin for advices in writing of the article, and Dr. Olga Ponomarenko for assistance and consulting.

Conflicts of interest

No conflict interests are declared

References

  1. Booth C., Gaspar H.B., Thrasher A.J. Treating Immuno deficiency through HSC Gene Therapy. Trends Mol. Med. 2016;22:317–327. doi: 10.1016/j.molmed.2016.02.002

  2. Cradick TJ, Fine EJ, Antico CJ, Bao G. CRISPR/Cas9 systems targeting β-globin and CCR5 genes have substantial off-target activity. Nucleic Acids Res. 2013;41:9584–9592

  3. Dreyer AK, Hoffmann D, Lachmann N, Ackermann M, Steinemann D, Timm B, Siler U,Reichenbach J, Grez M, Moritz T, et al. TALEN-mediated functional correction of X-linked chronic granulomatous disease in patient-derived induced pluripotent stem cells. Biomaterials 2015;69:191– 200. doi: 10.1016/j.biomaterials.2015.07.057.

  4. Genovese P, Schiroli G, Escobar G, Targeted genome editing in human repopulating haematopoietic stem cells Nature. 2014 Jun 12;510(7504):235-40. doi: 10.1038/na ture13420. Epub 2014 May 28.

  5. Hoban MD, Cost GJ, Mendel MC, et al. Correction of the sickle cell disease mutation in human hematopoietic stem/ progenitor cells. Blood. 2015;125(17):2597-2604.Hoban MD, Cost GJ, Mendel MC, et al. Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells. Blood. 2015;125(17):2597-2604.

  6. Holt N, Wang J, Kim K, Friedman G, Wang X, Taupin V, et al. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol (2010) 28(8):839–47.10.1038/nbt.1663

  7. Hubbard, N., Hagin, D., Sommer, K., Song, Y., Khan, I., Clough, C., Ochs, H. D., Rawlings, D. J., Scharenberg, A. M., & Torgerson, T. R. (2016). Targeted gene editing restores reg ulated CD40L function in X-linked hyper-IgM syndrome. Blood, 127(21), 2513-2522. Accessed March 20, 2017. DOI: 10.1182/blood-2015-11-683235

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Р. М. Горбачевой, Первый Санкт-Петербургский Государственный Медицинский Университет им. акад. И. П. Павлова, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(318) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский Государственный Медицинский Университет им. акад. И. П. Павлова, 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) "11299" ["VALUE"]=> array(2) { ["TEXT"]=> string(2113) "Редактирование генома – это революционная технология. Она представляет собой процесс внесения точных изменений нуклеотидной последовательности генома любого организма. Редактирование генома предоставляет мощный инструмент исправления генетических ошибок в нуклеотидной последовательности ДНК, и переворачивает концепцию доступной мишени для терапевтической коррекции. Создание высокоточного и безопасного метода для внесения одно- и двухцепочечных разрывов в ДНК человека с последующим использованием природных механизмов восстановления ДНК влияет на современные подходы к генной терапии и открывает новые горизонты в лечении многочисленных заболеваний. Редактирование генома разрабатывается для лечения моногенных заболеваний, инфекционных заболеваний и злокачественных опухолей. Данный обзор посвящен терапевтическому применению редактирования генома у человека. <h3>Ключевые слова</h3> Редактирование генома, гемопоэтические стволовые клетки, ZFN, TALEN, CRISPR-Cas9, трансплантация гемопоэтических стволовых клеток, ТГСК, ВИЧ, наследственные заболевания, моногенные заболевания, рак, опухоли кроветворной и лимфатической ткани." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2101) "Редактирование генома – это революционная технология. Она представляет собой процесс внесения точных изменений нуклеотидной последовательности генома любого организма. Редактирование генома предоставляет мощный инструмент исправления генетических ошибок в нуклеотидной последовательности ДНК, и переворачивает концепцию доступной мишени для терапевтической коррекции. Создание высокоточного и безопасного метода для внесения одно- и двухцепочечных разрывов в ДНК человека с последующим использованием природных механизмов восстановления ДНК влияет на современные подходы к генной терапии и открывает новые горизонты в лечении многочисленных заболеваний. Редактирование генома разрабатывается для лечения моногенных заболеваний, инфекционных заболеваний и злокачественных опухолей. Данный обзор посвящен терапевтическому применению редактирования генома у человека.

Ключевые слова

Редактирование генома, гемопоэтические стволовые клетки, ZFN, TALEN, CRISPR-Cas9, трансплантация гемопоэтических стволовых клеток, ТГСК, ВИЧ, наследственные заболевания, моногенные заболевания, рак, опухоли кроветворной и лимфатической ткани." 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Popova, Kirill V. Lepik, Vladislav S. Sergeev, Alena I. Shakirova, Alisa Y. Potter, Albert R. Muslimov, Ildar M. Barkhatov, 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(153) "Marina O. Popova, Kirill V. Lepik, Vladislav S. Sergeev, Alena I. Shakirova, Alisa Y. Potter, Albert R. Muslimov, Ildar M. Barkhatov, 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) "11301" ["VALUE"]=> array(2) { ["TEXT"]=> string(550) "Raisa Gorbacheva Memorial Research Institute of Children’s Oncology, Hematology and Transplantation, The First St. Petersburg Pavlov State Medical University, St. Petersburg, Russia<br> Dr. Marina O. Popova, PhD, R. Gorbacheva Memorial Research Institute of Children’s Oncology, Hematology and Transplantation, The First Pavlov State Medical University of St. Petersburg, Russia, 12 Roentgen St., 197022, St. Petersburg, Russia<br> Phone: +7 (812) 233-29-25 (office), +7 (911) 711-39-77 (mobile) E-mail: marina.popova.spb@gmail.com" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(538) "Raisa Gorbacheva Memorial Research Institute of Children’s Oncology, Hematology and Transplantation, The First St. Petersburg Pavlov State Medical University, St. Petersburg, Russia
Dr. Marina O. Popova, PhD, R. Gorbacheva Memorial Research Institute of Children’s Oncology, Hematology and Transplantation, The First Pavlov State Medical University of St. Petersburg, Russia, 12 Roentgen St., 197022, St. Petersburg, Russia
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Keywords

Genome editing, hematopoietic stem cells, ZFN, TALEN, CRISPR-Cas9, hematopoietic stem cell transplantation, HSCT, HIV, inherited diseases, monogenic diseases, cancer, hematological malignancies." 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Popova, Kirill V. Lepik, Vladislav S. Sergeev, Alena I. Shakirova, Alisa Y. Potter, Albert R. Muslimov, Ildar M. Barkhatov, 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(153) "Marina O. Popova, Kirill V. Lepik, Vladislav S. Sergeev, Alena I. Shakirova, Alisa Y. Potter, Albert R. Muslimov, Ildar M. Barkhatov, 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(153) "Marina O. Popova, Kirill V. Lepik, Vladislav S. Sergeev, Alena I. Shakirova, Alisa Y. Potter, Albert R. Muslimov, Ildar M. Barkhatov, Boris V. 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This scientific breakthrough provides a powerful tool for the errors correction in the nucleotide sequence of DNA. The development of the genome editing has inverted the concept of an available target for the therapeutic correction. The opportunity of highly precise and safe entering of single- and double-stranded breaks into the human DNA followed by natural DNA repair mechanisms has changed current approaches of the gene therapy and opened up new horizons in the treatment of numerous diseases. Genome editing is being developed to treat not only monogenic diseases but also infectious diseases and cancer. In the current review, we discuss the therapeutic application of genome editing. <h3>Keywords</h3> Genome editing, hematopoietic stem cells, ZFN, TALEN, CRISPR-Cas9, hematopoietic stem cell transplantation, HSCT, HIV, inherited diseases, monogenic diseases, cancer, hematological malignancies." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1059) "Genome editing is a breakthrough technology which consists of the process of precise modifications introduction into the genome of any organism. This scientific breakthrough provides a powerful tool for the errors correction in the nucleotide sequence of DNA. The development of the genome editing has inverted the concept of an available target for the therapeutic correction. The opportunity of highly precise and safe entering of single- and double-stranded breaks into the human DNA followed by natural DNA repair mechanisms has changed current approaches of the gene therapy and opened up new horizons in the treatment of numerous diseases. Genome editing is being developed to treat not only monogenic diseases but also infectious diseases and cancer. In the current review, we discuss the therapeutic application of genome editing.

Keywords

Genome editing, hematopoietic stem cells, ZFN, TALEN, CRISPR-Cas9, hematopoietic stem cell transplantation, HSCT, HIV, inherited diseases, monogenic diseases, cancer, hematological malignancies." ["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(1059) "Genome editing is a breakthrough technology which consists of the process of precise modifications introduction into the genome of any organism. This scientific breakthrough provides a powerful tool for the errors correction in the nucleotide sequence of DNA. The development of the genome editing has inverted the concept of an available target for the therapeutic correction. The opportunity of highly precise and safe entering of single- and double-stranded breaks into the human DNA followed by natural DNA repair mechanisms has changed current approaches of the gene therapy and opened up new horizons in the treatment of numerous diseases. Genome editing is being developed to treat not only monogenic diseases but also infectious diseases and cancer. In the current review, we discuss the therapeutic application of genome editing.

Keywords

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Dr. Marina O. Popova, PhD, R. Gorbacheva Memorial Research Institute of Children’s Oncology, Hematology and Transplantation, The First Pavlov State Medical University of St. Petersburg, Russia, 12 Roentgen St., 197022, St. Petersburg, Russia
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Dr. Marina O. Popova, PhD, R. Gorbacheva Memorial Research Institute of Children’s Oncology, Hematology and Transplantation, The First Pavlov State Medical University of St. Petersburg, Russia, 12 Roentgen St., 197022, St. Petersburg, Russia
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Создание высокоточного и безопасного метода для внесения одно- и двухцепочечных разрывов в ДНК человека с последующим использованием природных механизмов восстановления ДНК влияет на современные подходы к генной терапии и открывает новые горизонты в лечении многочисленных заболеваний. Редактирование генома разрабатывается для лечения моногенных заболеваний, инфекционных заболеваний и злокачественных опухолей. Данный обзор посвящен терапевтическому применению редактирования генома у человека.

Ключевые слова

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Ключевые слова

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It took millions of years for apes to evolve into humans.
It may take only a century for humans to change again.
Unknown author

Recent  advent  and  subsequent  improvements  in  genome editing  techniques  have  dramatically  changed  public  attitudes  towards  implementation  of  biotechnology  and  created  novel  opportunities  for  a  variety  of  technological  startup companies. None of the most influential publications in the world have overlooked growing interest for for genome editing  in  various  fields  of  medicine,  agriculture,  industrial biotech, etc. Booming headlines have announced future victories  over  severe  diseases,  comparing  recent  achievements in genetic engineering to invention of electricity, antibiotics, rocketry, and the Internet. A total of 1 billion US dollars has already  been  invested  into  these  studies,  including  venture capital and other funding sources. How reasonable could the high expectations of scientific, clinical and business communities be? What obstacles should researchers and industries anticipate on their way to the market? Is this potential really high, or is it another soap bubble from the modern biotech?

Since 2005, as the term ‘Genome editing’ was coined [1], the field has developed, both in academic and industrial circles, towards  the  more  efficient  targeted  nucleases  which  should possess  optimal  specificity,  cost  efficiency,  and  provide  reproducible results. These advances resulted in development of the three main groups of relevant enzymes, i.e., zinc finger nucleases (ZFN), Transcription activator-like effector nucleases (TALEN), and CRISPR/Сas enzyme systems (CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; Cas, a CRISPR-associated protein). High accuracy of specific genome  targeting  by  means  of  these  molecular  lancets  led to present-day discovery of a novel research area which was designated as ‘gene surgery’.

Broad outlooks of gene surgery have drawn immediate interest, first of all, in the medical field. Over the last decade, significant increase in the number of companies using different genome editing techniques has been observed. Their aim is to  develop  novel  therapies  for  inherited  monogenic,  oncological and viral diseases. For instance, Sangamo Biosciences has developed a proprietary genome editing technology using  ZFN  system,  and  succeeded  in  Phase  I  clinical  studies with HIV-infected patients, then extending potential indications  to  hemophilias,  hemoglobinopathies,  etc.  [2].  French company Cellectis  is  developing  TALEN  in  immuno-oncology.  The  idea  is  to  edit  immune  cells  for  treatment  of  hemato-oncological disorders and some solid tumors [3]. The Editas  Medicine activities  are  focused  on  genetic  diseases, e.g.  their  first  clinical  trial  scheduled  for  2017  will  concern Leber’s amaurosis, a rare clinical form of blindness [4]. Caribou Biosciences studies different options for CRISPR-based technologies in medicine, agriculture, biological studies and industry,  [5]  whereas Intellia  Therapeutics,  their  affiliated company, is seeking for ex vivo and in  vivo genome editing for a number of clinical conditions [6]. CRISPR Therapeutics are focused on three main topics, (1) ex vivo gene editing of hematopoietic  stem  cells;  (2) in  vivo gene  editing  for  liver diseases; (3) additional in vivo programs targeting other or gan systems, such as muscle and lung [7].

All  things  considered,  there  is  a  new  ‘gold  rush’,  this  time centered on gene therapy. Investments to each of these companies  are  estimated  in  dozens  and  hundreds  millions  US dollars,  whereas  capitalization  of  the  most  advanced  firms exceeds a billion USD. Meanwhile, appropriate clinical studies  with  different  targeted  nucleases  enrolled  less  than  100 patients  with  viral  and  oncological  diseases  [8,  9].  To  date, several other clinical studies are endorsed [10], and vast majority  of  companies  are  only  in  the  process  of  approaching clinical  phase.  Moreover,  big  industry,  e.g., Novartis, Astra Zeneca, Bayer, has also entered the game.

Several start-ups involved in genome editing have emerged in Russia. They are employed for medical applications of genome editing technologies. For instance, two Skolkovo resident companies are performing these activities, i.e., AGCT with a flagship project of hematopoietic stem cells gene editing aimed for the treatment of HIV-associated tumors [11], and the Gene Therapy Centre.

It is commonly known that intellectual property is the main asset of any company active in biotechnology and largely determines  its  market  price  and  value.  Proprietary  rights  for ZFN and TALEN are already established by the main players, thus  forcing  emerging  companies  to  license  the  main  patents, or to create new inventive solutions. Meanwhile, an uncertainty with intellectual property for CRISPR is characterized as a “patent battle” by most experts in the field. In May 2012,  Jennifer  Doudna,  employed  at  the  UC  Berkeley  filed a  provisional  patent  application  describing  a  new in  vitro gene editing technique, jointly with Emmanuelle Charpentier (University of Vienna at that time) and other colleagues. In December 2012, Feng Zhang from the Broad Institute in Boston  filed  a  provisional  patent  application  for  the  specific use of CRISPR/Cas system exclusively in eukaryotic cells. Results  of  the  both  studies  were  reported  in Science in  August 2012 and February 2013, respectively [12, 13].

The first patent was finalized in March 2013, and the second one was finalized seven months later. However, the Broad Institute and MIT’s joint patent was granted first in April 2014, due to the fast track requested by Zhang at the United States Patent and Trademark Office (USPTO). A year later, the UC Berkeley  claimed  to  the  USPTO  on  the  patent  interference right,  demanding,  at  least,  partial  edition  of  the  patent  applied  by  Zhang,  based  upon  the  evidence  that  CRISPR  use in eukaryotic cells presumed an obvious extension of the in vitro studies  by  Doudna  and  Charpentier.  Over  2016,  a  big investigation has proceeded including analysis of a thousand of relevant documents offered by the both sides. The discussion is still ongoing, and appropriate decision is expected not earlier that in 2017.

However,  despite  the  lack  of  clear-cut  rights  for  intellectual  property,  and  uncertainty  of patent  landscape,  about  ten emerging biotechnological companies based on CRISPR/Cas techniques  have  raised  significant  funding  over  last  years. Some  of  them  have  already  licensed  intellectual  property from  their  current  owners  while  others  are  awaiting  decisions on the legal conflicts. It is still unknown whether these decisions  will  influence  the  marketing  processes  and  if  the CRISPR-based genome editing will be widely available in the future. Currently three companies are leading in the field of CRISPR/Cas-based  technologies  applications  in  medicine, i.e., Editas  Medicine,  with  Zhang  as  a  co-founder, CRISPR Therapeutics,  co-founded  by  Charpentier,  and Intellia  Therapeutics,  an  affiliated  company  by Caribou  Biosciences,  with Doudna as a co-founder. Great expectations placed on these technologies are counterpoised by many open questions of the novel therapies efficacy  and  safety.  Definite  answers  will  be  obtained  only  in  the course of clinical trials which will determine successfulness of either research team.

In  2016,  the  story  with  CAR-T  (Т  lymphocytes  with  chimeric  antigen  receptors)  has  forced  the market  players  and general  public  to  realize  potential  serious  consequences of  novel  over-estimated  approaches.  A  clinical  trial  performed  by Juno  Therapeutics was  discontinued  in  July,  due to severe neurotoxicity (i.e. cerebral edema) and lethal outcomes in three patients with acute lymphoblastic leukemia. This  event  caused  immediate  reaction  among  investors,  researchers  and  society.  The  questions  were  raised  on  ethics and design of clinical studies by sponsors keeping the novel production  technologies  as  a  commercial  secret,  as  well  as claims for transparency from all the stakeholders, especially, in advanced fields of medicine [14]. The reasons were soon specified, the study protocol was amended appropriately, and so the trial was resumed. In November, however, two more lethal  outcomes  were  reported  by  similar  reasons,  with  repeated  discontinuation  of  the  clinical  trial.  Despite  certain concerns,  the  challenges  were  only  transient,  both  for Juno Therapeutics,  and  their  competitors  developing  CAR-T  for other applications (Kite Pharma, for non-Hodgkin lymphoma, Novartis), and the first approval of this technology is expected in the US in early 2017. Outlooks for the CRISPR technology application for CAR-T production resulted into several joint R&D programs: Editas Medicine in cooperation with Juno Therapeutics are developing  novel  gene-engineered  Т  cells  for  cancer  immunotherapy,  whereas Novartis combined  their  efforts  with Intellia Therapeutics,  with  a  purpose  of  editing  hematopoietic  stem cells and design of novel CAR-T cells. Complex  approval  procedures  represent  additional  barriers for commercialization of new technologies, due to high-degree regulation in medicine and legal specifications in different  countries.  Moreover,  some  open  questions  remain,  e.g., the  issues  of  pricing,  optimized  manufacturing  and  quality control  for  the  personalized  products.  Advances  in  technologies  definitely  result  into  changes  and  improvement  of regulatory  standards.  This  is  already  true  for  gene  therapy legislation in the USA and the EU [15, 16]. Moreover, some special procedures for registration of breakthrough technologies are available in these countries, e.g., Prime in European Medical Agency (EMA), and Breakthrough Designation and Fast  Track in  Food  and  Drug  Administration  (FDA,  USA). In  Russian  Federation,  the  Federal  Law On  Biomedical  Cellular  Products was  issued  in  2016  [17],  which  has  fixed  the regulatory frames for ex vivo gene editing technologies. Regulations for in vivo gene therapeutic techniques are generally determined in the Federal Law On Medicinal Drug Controls [18].  Emergence  of  novel  technologies  poses  questions  not only to the researchers but for the regulatory bodies as well. Certainly,  a  dialogue  between  the  industry  and  regulators may  accelerate  clinical  implementation  of  novel  promising technologies  aimed  for  the  future  treatment  of  serious  and life-threatening diseases.

Rapid development and growing interest in genome editing have  drawn  attention  of  the  community  to  this  technology, both in the view of potential treatment advances of many severe disorders, as well as a source of numerous ethical dilemmas. The main aspect may concern opportunities for germinal  cell  and  embryos  editing  at  the  preimplantation  stage. Just  in  February  2016,  Kathy  Niakan  from  Francis  Crick Institute obtained the first British licence for editing human embryos  limited  by  research  purposes  only,  in  order  to  investigate fundamental mechanisms of normal and disturbed embryogenesis [19]. Quite recently, two research teams from China  have  reported  the  first  successful  cases  of  human embryo  editing  [20].  In  the  first  case,  the  gene  editing  was performed  due  to  an  inherited  blood  disorder,  and,  in  the second  case,  the  procedure  induced  resistance  against  HIV. In both cases, the embryos were non-viable and were eliminated within several days. These events caused vivid discussions on rationale and relevance of human genome editing. On  the  one  hand,  such  approach  may  potentially  cure  the child of an inherited disease, or make him non-susceptible to many infections. On the other hand, it may result in severe complications, since long-term effects of such interventions are still unknown. Moreover, there are concerns that in the future these procedures could be used for the consumer purposes,  e.g.  choice  of  eye  color,  or  mental  characteristics  of the subject.

Modern  legislation  on  the  embryo  editing  varies  in  different countries, from total ban to biased interpretation of legal standards  [21].  Hence,  there  is  no  answer  to  a  question  on the birthplace of the first “edited” child. The opinion leaders in this field have already replied to the social challenges and provided their comments, with respect to prospects of gene editing in germinal cells and embryos [22].

Technological breakthroughs, especially, in the field of biology  and  medicine,  reveal  a  number  of attractive  outlooks, along  with  potential  hazards.  Only  long-term  studies  may answer many current questions concerning human genome editing and we are lucky to live at the moment when we can observe and influence these changes.

Conflict of interests

The author has no conflicts of interest to be declared.

References

1. Urnov  FD,  Miller  JC,  Lee  YL,  Beausejour  CM,  Rock JM,  Augustus  S,  Jamieson  AC,  Porteus  MH,  Gregory  PD, Holmes   MC.   Highly   efficient   endogenous   human   gene  correction  using  designed  zinc-finger  nucleases.  Nature. 2005;435(7042):646-651.

2. http:www.sangamo.com/

3. http:www.cellectis.com/

4. http:www.editasmedicine.com/

5. http:cariboubio.com/

6. http:www.intelliatx.com/

7. http:crisprtx.com

8. Tebas  P,  Stein  D,  Tang  WW,  Frank  I,  Wang  SQ,  Lee  G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH. Gene editing of CCR5  in  autologous  CD4  T  cells  of  persons  infected  with HIV. N Engl J Med  2014; 370(10):901-910.

9. Cyranoski D. CRISPR gene-editing tested in a person for the first time. Nature. 2016; 539:479.

10. Reardon  S.  First  CRISPR  clinical  trial  gets  green  light from US panel. Nature News. Jun 22, 2016.

11. http:agct.bio

12. Jinek  M,  Chylinski  K,  Fonfara  I,  Hauer  M,  Doudna  JA, Charpentier  E.  A  programmable  dual-RNA-guided  DNA endonuclease in adaptive bacterial immunity. Science. 2012; 337(6096):816-21.

13. Cong  L,  Ran  FA,  Cox  D,  Lin  S,  Barretto  R,  Habib  N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. Multiplex Genome  Engineering  Using  CRISPR/Cas  Systems.  Science 2013; 339(6121):819-23.

14. Hey SP, Kesselheim AS. The FDA, Juno Therapeutics, and the ethical imperative of transparency. BMJ. 2016;354:i4435.

15. EMA: Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products, 2015

16. FDA Guidance: Preclinical assessment of investigational cellular  and  gene  therapy  products,  2013;  Potency  tests  for cellular and gene therapy products, 2014.

17. Russian Federal Law On Biomedical Cellular Products of 23/06/2016, No.180-ФЗ (as amended for 2016, in Russian).

18. Russian  Federal  Law  On  Medicinal  Drug  Controls  of 12/04/2010, No.61-ФЗ (as amended for 2016, in Russian).

19. http:www.bbc.com/news/health-35301238

20. Callawey E. Second Chinese team reports gene editing in human embryos. Nature News. Apr 8, 2016.

21. Araki M., Ishii T. International regulatory landscape and integration of corrective genome editing into in vitro fertilization. Reprod. Biol. Endocrinol. 2014; 12:108.

22. Bosley KS, Botchan M, Bredenoord AL, Carroll D, Charo RA, Charpentier E, Cohen R, Corn J, Doudna J, Feng G, Greely  HT,  Isasi  R,  Ji  W,  Kim  J-S,  Knoppers  B,  Lanphier  E, Li  J,  Lovell-Badge  R,  Martin  GS,  Moreno  J,  Naldini  L,  Pera M,  Perry  ACF,  Venter  JC,  Zhang  F,  et  al.  CRISPR  germline engineering – the community speaks. Nature Biotechnology. 2015; 33:478–486.

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It took millions of years for apes to evolve into humans.
It may take only a century for humans to change again.
Unknown author

Recent  advent  and  subsequent  improvements  in  genome editing  techniques  have  dramatically  changed  public  attitudes  towards  implementation  of  biotechnology  and  created  novel  opportunities  for  a  variety  of  technological  startup companies. None of the most influential publications in the world have overlooked growing interest for for genome editing  in  various  fields  of  medicine,  agriculture,  industrial biotech, etc. Booming headlines have announced future victories  over  severe  diseases,  comparing  recent  achievements in genetic engineering to invention of electricity, antibiotics, rocketry, and the Internet. A total of 1 billion US dollars has already  been  invested  into  these  studies,  including  venture capital and other funding sources. How reasonable could the high expectations of scientific, clinical and business communities be? What obstacles should researchers and industries anticipate on their way to the market? Is this potential really high, or is it another soap bubble from the modern biotech?

Since 2005, as the term ‘Genome editing’ was coined [1], the field has developed, both in academic and industrial circles, towards  the  more  efficient  targeted  nucleases  which  should possess  optimal  specificity,  cost  efficiency,  and  provide  reproducible results. These advances resulted in development of the three main groups of relevant enzymes, i.e., zinc finger nucleases (ZFN), Transcription activator-like effector nucleases (TALEN), and CRISPR/Сas enzyme systems (CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; Cas, a CRISPR-associated protein). High accuracy of specific genome  targeting  by  means  of  these  molecular  lancets  led to present-day discovery of a novel research area which was designated as ‘gene surgery’.

Broad outlooks of gene surgery have drawn immediate interest, first of all, in the medical field. Over the last decade, significant increase in the number of companies using different genome editing techniques has been observed. Their aim is to  develop  novel  therapies  for  inherited  monogenic,  oncological and viral diseases. For instance, Sangamo Biosciences has developed a proprietary genome editing technology using  ZFN  system,  and  succeeded  in  Phase  I  clinical  studies with HIV-infected patients, then extending potential indications  to  hemophilias,  hemoglobinopathies,  etc.  [2].  French company Cellectis  is  developing  TALEN  in  immuno-oncology.  The  idea  is  to  edit  immune  cells  for  treatment  of  hemato-oncological disorders and some solid tumors [3]. The Editas  Medicine activities  are  focused  on  genetic  diseases, e.g.  their  first  clinical  trial  scheduled  for  2017  will  concern Leber’s amaurosis, a rare clinical form of blindness [4]. Caribou Biosciences studies different options for CRISPR-based technologies in medicine, agriculture, biological studies and industry,  [5]  whereas Intellia  Therapeutics,  their  affiliated company, is seeking for ex vivo and in  vivo genome editing for a number of clinical conditions [6]. CRISPR Therapeutics are focused on three main topics, (1) ex vivo gene editing of hematopoietic  stem  cells;  (2) in  vivo gene  editing  for  liver diseases; (3) additional in vivo programs targeting other or gan systems, such as muscle and lung [7].

All  things  considered,  there  is  a  new  ‘gold  rush’,  this  time centered on gene therapy. Investments to each of these companies  are  estimated  in  dozens  and  hundreds  millions  US dollars,  whereas  capitalization  of  the  most  advanced  firms exceeds a billion USD. Meanwhile, appropriate clinical studies  with  different  targeted  nucleases  enrolled  less  than  100 patients  with  viral  and  oncological  diseases  [8,  9].  To  date, several other clinical studies are endorsed [10], and vast majority  of  companies  are  only  in  the  process  of  approaching clinical  phase.  Moreover,  big  industry,  e.g., Novartis, Astra Zeneca, Bayer, has also entered the game.

Several start-ups involved in genome editing have emerged in Russia. They are employed for medical applications of genome editing technologies. For instance, two Skolkovo resident companies are performing these activities, i.e., AGCT with a flagship project of hematopoietic stem cells gene editing aimed for the treatment of HIV-associated tumors [11], and the Gene Therapy Centre.

It is commonly known that intellectual property is the main asset of any company active in biotechnology and largely determines  its  market  price  and  value.  Proprietary  rights  for ZFN and TALEN are already established by the main players, thus  forcing  emerging  companies  to  license  the  main  patents, or to create new inventive solutions. Meanwhile, an uncertainty with intellectual property for CRISPR is characterized as a “patent battle” by most experts in the field. In May 2012,  Jennifer  Doudna,  employed  at  the  UC  Berkeley  filed a  provisional  patent  application  describing  a  new in  vitro gene editing technique, jointly with Emmanuelle Charpentier (University of Vienna at that time) and other colleagues. In December 2012, Feng Zhang from the Broad Institute in Boston  filed  a  provisional  patent  application  for  the  specific use of CRISPR/Cas system exclusively in eukaryotic cells. Results  of  the  both  studies  were  reported  in Science in  August 2012 and February 2013, respectively [12, 13].

The first patent was finalized in March 2013, and the second one was finalized seven months later. However, the Broad Institute and MIT’s joint patent was granted first in April 2014, due to the fast track requested by Zhang at the United States Patent and Trademark Office (USPTO). A year later, the UC Berkeley  claimed  to  the  USPTO  on  the  patent  interference right,  demanding,  at  least,  partial  edition  of  the  patent  applied  by  Zhang,  based  upon  the  evidence  that  CRISPR  use in eukaryotic cells presumed an obvious extension of the in vitro studies  by  Doudna  and  Charpentier.  Over  2016,  a  big investigation has proceeded including analysis of a thousand of relevant documents offered by the both sides. The discussion is still ongoing, and appropriate decision is expected not earlier that in 2017.

However,  despite  the  lack  of  clear-cut  rights  for  intellectual  property,  and  uncertainty  of patent  landscape,  about  ten emerging biotechnological companies based on CRISPR/Cas techniques  have  raised  significant  funding  over  last  years. Some  of  them  have  already  licensed  intellectual  property from  their  current  owners  while  others  are  awaiting  decisions on the legal conflicts. It is still unknown whether these decisions  will  influence  the  marketing  processes  and  if  the CRISPR-based genome editing will be widely available in the future. Currently three companies are leading in the field of CRISPR/Cas-based  technologies  applications  in  medicine, i.e., Editas  Medicine,  with  Zhang  as  a  co-founder, CRISPR Therapeutics,  co-founded  by  Charpentier,  and Intellia  Therapeutics,  an  affiliated  company  by Caribou  Biosciences,  with Doudna as a co-founder. Great expectations placed on these technologies are counterpoised by many open questions of the novel therapies efficacy  and  safety.  Definite  answers  will  be  obtained  only  in  the course of clinical trials which will determine successfulness of either research team.

In  2016,  the  story  with  CAR-T  (Т  lymphocytes  with  chimeric  antigen  receptors)  has  forced  the market  players  and general  public  to  realize  potential  serious  consequences of  novel  over-estimated  approaches.  A  clinical  trial  performed  by Juno  Therapeutics was  discontinued  in  July,  due to severe neurotoxicity (i.e. cerebral edema) and lethal outcomes in three patients with acute lymphoblastic leukemia. This  event  caused  immediate  reaction  among  investors,  researchers  and  society.  The  questions  were  raised  on  ethics and design of clinical studies by sponsors keeping the novel production  technologies  as  a  commercial  secret,  as  well  as claims for transparency from all the stakeholders, especially, in advanced fields of medicine [14]. The reasons were soon specified, the study protocol was amended appropriately, and so the trial was resumed. In November, however, two more lethal  outcomes  were  reported  by  similar  reasons,  with  repeated  discontinuation  of  the  clinical  trial.  Despite  certain concerns,  the  challenges  were  only  transient,  both  for Juno Therapeutics,  and  their  competitors  developing  CAR-T  for other applications (Kite Pharma, for non-Hodgkin lymphoma, Novartis), and the first approval of this technology is expected in the US in early 2017. Outlooks for the CRISPR technology application for CAR-T production resulted into several joint R&D programs: Editas Medicine in cooperation with Juno Therapeutics are developing  novel  gene-engineered  Т  cells  for  cancer  immunotherapy,  whereas Novartis combined  their  efforts  with Intellia Therapeutics,  with  a  purpose  of  editing  hematopoietic  stem cells and design of novel CAR-T cells. Complex  approval  procedures  represent  additional  barriers for commercialization of new technologies, due to high-degree regulation in medicine and legal specifications in different  countries.  Moreover,  some  open  questions  remain,  e.g., the  issues  of  pricing,  optimized  manufacturing  and  quality control  for  the  personalized  products.  Advances  in  technologies  definitely  result  into  changes  and  improvement  of regulatory  standards.  This  is  already  true  for  gene  therapy legislation in the USA and the EU [15, 16]. Moreover, some special procedures for registration of breakthrough technologies are available in these countries, e.g., Prime in European Medical Agency (EMA), and Breakthrough Designation and Fast  Track in  Food  and  Drug  Administration  (FDA,  USA). In  Russian  Federation,  the  Federal  Law On  Biomedical  Cellular  Products was  issued  in  2016  [17],  which  has  fixed  the regulatory frames for ex vivo gene editing technologies. Regulations for in vivo gene therapeutic techniques are generally determined in the Federal Law On Medicinal Drug Controls [18].  Emergence  of  novel  technologies  poses  questions  not only to the researchers but for the regulatory bodies as well. Certainly,  a  dialogue  between  the  industry  and  regulators may  accelerate  clinical  implementation  of  novel  promising technologies  aimed  for  the  future  treatment  of  serious  and life-threatening diseases.

Rapid development and growing interest in genome editing have  drawn  attention  of  the  community  to  this  technology, both in the view of potential treatment advances of many severe disorders, as well as a source of numerous ethical dilemmas. The main aspect may concern opportunities for germinal  cell  and  embryos  editing  at  the  preimplantation  stage. Just  in  February  2016,  Kathy  Niakan  from  Francis  Crick Institute obtained the first British licence for editing human embryos  limited  by  research  purposes  only,  in  order  to  investigate fundamental mechanisms of normal and disturbed embryogenesis [19]. Quite recently, two research teams from China  have  reported  the  first  successful  cases  of  human embryo  editing  [20].  In  the  first  case,  the  gene  editing  was performed  due  to  an  inherited  blood  disorder,  and,  in  the second  case,  the  procedure  induced  resistance  against  HIV. In both cases, the embryos were non-viable and were eliminated within several days. These events caused vivid discussions on rationale and relevance of human genome editing. On  the  one  hand,  such  approach  may  potentially  cure  the child of an inherited disease, or make him non-susceptible to many infections. On the other hand, it may result in severe complications, since long-term effects of such interventions are still unknown. Moreover, there are concerns that in the future these procedures could be used for the consumer purposes,  e.g.  choice  of  eye  color,  or  mental  characteristics  of the subject.

Modern  legislation  on  the  embryo  editing  varies  in  different countries, from total ban to biased interpretation of legal standards  [21].  Hence,  there  is  no  answer  to  a  question  on the birthplace of the first “edited” child. The opinion leaders in this field have already replied to the social challenges and provided their comments, with respect to prospects of gene editing in germinal cells and embryos [22].

Technological breakthroughs, especially, in the field of biology  and  medicine,  reveal  a  number  of attractive  outlooks, along  with  potential  hazards.  Only  long-term  studies  may answer many current questions concerning human genome editing and we are lucky to live at the moment when we can observe and influence these changes.

Conflict of interests

The author has no conflicts of interest to be declared.

References

1. Urnov  FD,  Miller  JC,  Lee  YL,  Beausejour  CM,  Rock JM,  Augustus  S,  Jamieson  AC,  Porteus  MH,  Gregory  PD, Holmes   MC.   Highly   efficient   endogenous   human   gene  correction  using  designed  zinc-finger  nucleases.  Nature. 2005;435(7042):646-651.

2. http:www.sangamo.com/

3. http:www.cellectis.com/

4. http:www.editasmedicine.com/

5. http:cariboubio.com/

6. http:www.intelliatx.com/

7. http:crisprtx.com

8. Tebas  P,  Stein  D,  Tang  WW,  Frank  I,  Wang  SQ,  Lee  G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH. Gene editing of CCR5  in  autologous  CD4  T  cells  of  persons  infected  with HIV. N Engl J Med  2014; 370(10):901-910.

9. Cyranoski D. CRISPR gene-editing tested in a person for the first time. Nature. 2016; 539:479.

10. Reardon  S.  First  CRISPR  clinical  trial  gets  green  light from US panel. Nature News. Jun 22, 2016.

11. http:agct.bio

12. Jinek  M,  Chylinski  K,  Fonfara  I,  Hauer  M,  Doudna  JA, Charpentier  E.  A  programmable  dual-RNA-guided  DNA endonuclease in adaptive bacterial immunity. Science. 2012; 337(6096):816-21.

13. Cong  L,  Ran  FA,  Cox  D,  Lin  S,  Barretto  R,  Habib  N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. Multiplex Genome  Engineering  Using  CRISPR/Cas  Systems.  Science 2013; 339(6121):819-23.

14. Hey SP, Kesselheim AS. The FDA, Juno Therapeutics, and the ethical imperative of transparency. BMJ. 2016;354:i4435.

15. EMA: Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products, 2015

16. FDA Guidance: Preclinical assessment of investigational cellular  and  gene  therapy  products,  2013;  Potency  tests  for cellular and gene therapy products, 2014.

17. Russian Federal Law On Biomedical Cellular Products of 23/06/2016, No.180-ФЗ (as amended for 2016, in Russian).

18. Russian  Federal  Law  On  Medicinal  Drug  Controls  of 12/04/2010, No.61-ФЗ (as amended for 2016, in Russian).

19. http:www.bbc.com/news/health-35301238

20. Callawey E. Second Chinese team reports gene editing in human embryos. Nature News. Apr 8, 2016.

21. Araki M., Ishii T. International regulatory landscape and integration of corrective genome editing into in vitro fertilization. Reprod. Biol. Endocrinol. 2014; 12:108.

22. Bosley KS, Botchan M, Bredenoord AL, Carroll D, Charo RA, Charpentier E, Cohen R, Corn J, Doudna J, Feng G, Greely  HT,  Isasi  R,  Ji  W,  Kim  J-S,  Knoppers  B,  Lanphier  E, Li  J,  Lovell-Badge  R,  Martin  GS,  Moreno  J,  Naldini  L,  Pera M,  Perry  ACF,  Venter  JC,  Zhang  F,  et  al.  CRISPR  germline engineering – the community speaks. Nature Biotechnology. 2015; 33:478–486.

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Кристина А. Ходова

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Инновационный центр «Сколково», Москва, Российская Федерация

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Появление и совершенствование доступных технологий направленного редактирования генома открыло новые возможности для их потенциального терапевтического применения в различных областях медицины. Несмотря на ранние стадии большинства разработок в этой области, они могут изменить не только подходы к лечению многих тяжелых заболеваний, но и уже влияют на формирование рыночного ландшафта и развитие общества в целом. Основной вопрос состоит в том, насколько оправданы надежды ученых, разработчиков и инвесторов на эти продукты и результаты,
и какие основные риски ожидают на пути регистрации и внедрения нового продукта в клиническую практику.

Ключевые слова

Редактирование генома, инвестиции, стартапы, исследования и разработки, интеллектуальная собственность.

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Kristina A. Khodova

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Skolkovo Foundation, Moscow, Russia

Correspondence
Dr. Kristina A. Khodova, Skolkovo Innovation Center, Nobel Street 5, 143026, Moscow, Russia
Phone: +7 (916) 438-29-54
E-mail: kris.khodova@gmail.com

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Recent improvements in targeted genome editing technologies have opened new potential therapeutic applications in different medical conditions. Despite the fact that most of these technologies are still at early implementation phase, they already demonstrate a high therapeutic potential which may change treatment methodology for many severe diseases, and exert a significant influence upon market landscape and human population in general. However, some major issues and risks remain in the field, i.e., whether appropriate products and results will meet expectations of scientists, engineers and investors, and what risks could be anticipated for the registration procedures and introduction of original products into clinical practice.

Keywords

Genome editing, investment, startups, research & development, intellectual property.

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Kristina A. Khodova

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Kristina A. Khodova

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Recent improvements in targeted genome editing technologies have opened new potential therapeutic applications in different medical conditions. Despite the fact that most of these technologies are still at early implementation phase, they already demonstrate a high therapeutic potential which may change treatment methodology for many severe diseases, and exert a significant influence upon market landscape and human population in general. However, some major issues and risks remain in the field, i.e., whether appropriate products and results will meet expectations of scientists, engineers and investors, and what risks could be anticipated for the registration procedures and introduction of original products into clinical practice.

Keywords

Genome editing, investment, startups, research & development, intellectual property.

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Recent improvements in targeted genome editing technologies have opened new potential therapeutic applications in different medical conditions. Despite the fact that most of these technologies are still at early implementation phase, they already demonstrate a high therapeutic potential which may change treatment methodology for many severe diseases, and exert a significant influence upon market landscape and human population in general. However, some major issues and risks remain in the field, i.e., whether appropriate products and results will meet expectations of scientists, engineers and investors, and what risks could be anticipated for the registration procedures and introduction of original products into clinical practice.

Keywords

Genome editing, investment, startups, research & development, intellectual property.

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Skolkovo Foundation, Moscow, Russia

Correspondence
Dr. Kristina A. Khodova, Skolkovo Innovation Center, Nobel Street 5, 143026, Moscow, Russia
Phone: +7 (916) 438-29-54
E-mail: kris.khodova@gmail.com

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Skolkovo Foundation, Moscow, Russia

Correspondence
Dr. Kristina A. Khodova, Skolkovo Innovation Center, Nobel Street 5, 143026, Moscow, Russia
Phone: +7 (916) 438-29-54
E-mail: kris.khodova@gmail.com

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Кристина А. Ходова

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Кристина А. Ходова

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Несмотря на ранние стадии большинства разработок в этой области, они могут изменить не только подходы к лечению многих тяжелых заболеваний, но и уже влияют на формирование рыночного ландшафта и развитие общества в целом. Основной вопрос состоит в том, насколько оправданы надежды ученых, разработчиков и инвесторов на эти продукты и результаты, <br>и какие основные риски ожидают на пути регистрации и внедрения нового продукта в клиническую практику. </p> <h3>Ключевые слова</h3> <p>Редактирование генома, инвестиции, стартапы, исследования и разработки, интеллектуальная собственность.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1454) "

Появление и совершенствование доступных технологий направленного редактирования генома открыло новые возможности для их потенциального терапевтического применения в различных областях медицины. Несмотря на ранние стадии большинства разработок в этой области, они могут изменить не только подходы к лечению многих тяжелых заболеваний, но и уже влияют на формирование рыночного ландшафта и развитие общества в целом. Основной вопрос состоит в том, насколько оправданы надежды ученых, разработчиков и инвесторов на эти продукты и результаты,
и какие основные риски ожидают на пути регистрации и внедрения нового продукта в клиническую практику.

Ключевые слова

Редактирование генома, инвестиции, стартапы, исследования и разработки, интеллектуальная собственность.

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Появление и совершенствование доступных технологий направленного редактирования генома открыло новые возможности для их потенциального терапевтического применения в различных областях медицины. Несмотря на ранние стадии большинства разработок в этой области, они могут изменить не только подходы к лечению многих тяжелых заболеваний, но и уже влияют на формирование рыночного ландшафта и развитие общества в целом. Основной вопрос состоит в том, насколько оправданы надежды ученых, разработчиков и инвесторов на эти продукты и результаты,
и какие основные риски ожидают на пути регистрации и внедрения нового продукта в клиническую практику.

Ключевые слова

Редактирование генома, инвестиции, стартапы, исследования и разработки, интеллектуальная собственность.

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Инновационный центр «Сколково», Москва, Российская Федерация

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Инновационный центр «Сколково», Москва, Российская Федерация

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Introduction

Ph1-positive acute lymphoblastic leukemia (Ph+ALL) ranks a special place among lymphoid tumors. Initially, Ph1 positivity in ALL cells seemed an unexpected finding, since it challenged a specificity of t(9;22) translocation for chronic myeloid leukemia [17]. Afterwards, upon data gaining, it has become clear that Ph+ ALL may occur in all age groups, being more common in aged people, with minimal rates shown for children. Its prevalence is as high as 20% among adult ALL patients [15]. Until more recent times, the Ph+ ALL was considered an extremely unfavorable clinical variant with respect to all known treatment modes including hematopoietic stem cell transplantation (HSCT) [15]. This problem was solved as soon as different tyrosine kinase inhibitor drugs (TKIs) were introduced to clinics, thus enabling stable molecular remissions of the disease [3,6,13,18], and their usage for successful HSCT [2,16,23] including autologous (auto-) HSCTs [4,7,8,25]. ACA in Ph+ ALL are commonly seen, being described for 30-60% of the cases [5, 11, 14, 24]. Evaluation of allo-HSCT outcomes has shown that their prognosis depends on presence or absence of additional chromosome aberrations in cases of Ph1 chromosome positivity [1]. Moreover, it should be kept in mind that the ACA in Ph+ ALL patients could not be definitive. In particular, efficiency of chemotherapy and HSCT may be very good in cases of Ph1 chromosome combined with high hyperdiploidy [22]. We have previously confirmed it in our studies [9]. Such clinical aspect seems to be of high importance, in view of revisiting auto-HSCT for Ph+ ALL treatment [7,8,25].

Our study concerned a retrospective analysis of allo-HSCT performed in a mixed cohort of children and adults with Ph+ ALL who exhibited different clinical, transplant and cytogenetic characteristics.

Patients and Methods

The study was performed in a group of sixty-five patients with Ph+ ALL who underwent allo-HSCT at the First St. Petersburg I. Pavlov State Medical University over 2008 to 2015. We have used short-term 24-hour culturing of bone marrow  cells  without  mitogen  stimulation.  Cytogenetic  studies were carried out with a GTG chromosome staining using a standard technique [9]. Fluorescent in situ hybridization (FISH) with specific DNA probes proceeded according to the manufacturers’ protocols (MetaSystems, Germany; CytoCell, Great Britain). Interpretation of chromosomal aberrations was performed in accordance with an International System for Human Cytogenetic Nomenclature [20]. Evaluation of overall survival (OS) and event-free survival (EFS) was carried out in the patients with different demographic and clinical characteristics including gender and age, donor type, clinical state at the HSCT, conditioning regimen, source of stem cells and number of stem cells transplanted. The overall survival (OS) has been determined as the time period passed since HSCT to the patient’s death (for any reasons), or until the last examination date. Event-free survival (EFS) was evaluated as a time from HSCT to any adverse event (non-achievement of remission post-transplant, relapse, or death for any reasons), or till the last examination date. Statistical evaluation was performed with digital package ‘R’, version 3.1.1. (The R Foundation for Statistical Computing, Vienna Austria 2012). Survival curves have been plotted, according to Kaplan-Meier analysis. The survival plots were compared by means of a log-rank test; confidence levels by p<0,05 were considered significant. Multivariate analysis has been performed by the Cox regression model.

Results

The group of patients included 26 females (40%), and 39 males (60%), at the age between 5 and 48 years (a median of 26 years). Table 1 represents clinical and transplantation characteristics of the cohort under study. Thirty-one patients (48%) received allo-HSCT in the 1st remission, 20 subjects (31%) were transplanted in the 2nd remission, whereas 14 (21%) of the patients underwent allo-HSCT in active stage of the disorder. Bone marrow was a source of stem cells in 31 patients (48%), whereas peripheral blood stem cell transplants were used in 32 subjects (49%). Two patients got stem cells from the both sources. Reduced-intensity conditioning regimens (RIC) were used in 36 cases (55%), myeloablative treatment, in 29 cases (45%). Eighteen patients (28%) had HLA-identical sibling in their families; whereas 42 patients (65%) could be transplanted from HLA-matched unrelated donors found in an international registry. In 5 cases (7%), a related haploidentical HSCT was performed, since HLAmatched donor was absent in the family or blood donor Registries.

Table 1. Clinical and transplantation characteristics of Ph+ ALL patients under study

table-1-clinical-and-transplantation.jpg

Cytogenetic characteristics of Ph-positive ALL

Primary diagnosis of Ph+ ALL was established by a standard cytogenetic examination performed in 53 (80%) of the patients. In 12 subjects (18%), the diagnosis was based on a fusion chimeric BCR-ABL gene found by FISH technique and chimeric bcr/abl transcript (р190 and/or p210) revealed with PCR.

Afterwards, we considered karyotypic changes in 53 patients with described pre-transplant cytogenetics. A t(9;22) (q34;q11) translocation, as sole karyotypic aberration, has been revealed in 33 patients, including 9 children (38%) and 24 (62%) adults. Accessory chromosomal anomalies were found in 20 patients, 5 (33%), in children and 15 (67%) in adults. The cytogenetic data for the 20 patients with additional chromosomal aberrations (ACA) are represented in Table 2. Both quantitative and structural ACA have been detected. Numerical abnormalities beared, mainly, on the chromosomes 1, 7, 8, 9, 10, being found in 12 out of 20 cases (60%). Trisomy 1 was nonrandom, being found in 2 patients (No5, 6). Similar repeated findings were made for trisomy10 (No4, 20), trisomy 22 (No4, 16), monosomy 7 (No8, 12). Trisomy 2 (in No20), trisomy 17 and 19 (No2), monosomy 9 (No16) were revealed in single patients.

Table 2. Karyotypes of the patients with Ph+ ALL with additional chromosomal abnormalities (ACA)

table-2-karyotypes-of-the-patients.jpg

Note: additional chromosomal abnormalities are marked red.

Additional structural aberrations [except of t(9;22)] were registered in 20 patients. These were unbalanced in 16 of 20 cases (80%). Meanwhile, only 4 patients (20%) exhibited reciprocal translocations. Detailed evaluation of the chromosomal alterations, i.e., complete or partial monosomies and trisomies, is represented in Fig.1. Chromosomes 5, 7, 9, 2, 1, 17, 22 were most commonly involved into additional structural rearrangements. E.g., deletions and translocations in the short arm (p) of the chromosome 9 were observed in 4 patients out of 20 (No1, 5, 9, 15); reciprocal and unbalanced translocations with involvement of 7p were found in 3 cases (No17, 18, 19). Interstitial deletions and unbalanced translocations under involvement of 5q have been registered in 4 patients (No2, 4, 17, 18); deletions/translocations with chromosome 1, in 3 cases (No1, 6, 18); deletions and translocations of the chromosome 2, in 4 subjects (No1, 11, 17, 18). A structurally changed chromosome 17 was noted in 2 cases, as an isochromosome 17q (No2), or as a partner in unbalanced translocation (No4). An accessory derivate of the chromosome 22 was revealed in two patients (No14, 16). Unbalanced rearrangements involving other chromocomes occured occasionally.

A karyotype with three and more chromosomal aberrations was revealed in 13 patients (20%). As an example, the karyograms with a variant t(21;9;22)(q22;q34;q11) translocation and compound chromosomal abnormalities are presented on Fig. 2. The latter include ‘jumping’ segments (1q, 8q, 1q8q) to the partner chromosomes 1, 4, 5, 14, 19, 21 in a patient with chemoresistant Ph+ ALL (No18).

figure-1-figure-illustrates-the-additional-cytogenetic-alterations.jpg

Figure 1. Figure illustrates the additional cytogenetic alterations in the cohort of Ph-positive ALL with the support of CYDAS (http://www.cydas.org/OnlineAnalysis/) [12]. Chromosomal gains are marked in green to the right, losses in red to the left. The thickness of the bars represents the number of cases showing the respective chromosomal gain or loss.

figure-2-karyograms-of-a-bone-marrow-cells.jpg

Figure 2. Karyograms of a bone marrow cells from a patient with chemoresistant Ph+ ALL and complex chromosomal abnormalities including a variant translocation t(21;9;22) and ‘jumping’ segments (1q, 8q, 1q-8q) to the partner chromosomes 1, 4, 5, 14, 21 (A,B – GTG banding; C,D, multi-coloured FISH).

Effects of cytogenetic, clinical and transplantation parameters upon clinical outcomes of allo-HSCT in the Ph+ALL patients

Furthermore, we performed an OS and EFS analysis in the patients different for their clinical and biological characteristics, e.g., gender, age, disease state, donor type, conditioning regimen, source of stem cells, presence of additional chromosomal aberrations and complex karyotypic abnormalities (≥3 per a karyotype). ///
A univariate analysis (Table 3) has shown significant differences in OS and EFS after allo-HSCT for the patients differing in their clinical stage at transplantation (for EFS only), donor type, as well as for groups with ACA, complex chromosomal aberrations (≥3 per karyotype), or ACA-free.

Table 3. Univariate analysis of overall survival (OS) and event-free survival (EFS) for the patients under study

table-3-intestinal-microbiota-diversity-by-weber-et-al.jpg

Our data suggest that clinical efficiency was higher for transplantations performed at the 1st remission (for EFS only), in cases of matched related and unrelated donors, in absence of ACA in karyotype (for OS only), and, in particular, for complex chromosome aberrations (for OS only) (Fig. 3, 4). Meanwhile, no significant differences were obtained in the patients differing for their age, gender, conditioning regimens, stem cell source, time period from initial diagnosis to HSCT, and amount of transplanted CD34+ cells.

figure-3-overall-survival.jpg

Figure 3. Overall survival after allo-HSCT in Ph+ ALL patients dependent on the presence of additional chromosomal abnormalities [except of t(9;22)] (left); and presence of ≥3 additional chromosomal aberrations (right).

figure-4-event-free-survival.jpg

Figure 4. Event-free survival after allo-HSCT in Ph+ ALL patients dependent on clinical stage at time of HSCT.

The results of multivariate analysis (Table 4) have shown that a presence of ≥3 chromosomal abnormalities in karyotype is an independent predictor for OS in ALL patients with t(9;22)/BCR-ABL translocation. Meanwhile, clinical stage at the time of allo-HSCT seems to be an independent predictor of event-free survival (EFS) of these patients.

Table 4. Multivariate analysis of survival predictors post-HSCT in Ph’-positive ALL

table-4-multivariate-analysis.jpg

Discussion

Our study has confirmed recent conclusions on predictive significance of ACA in Ph+ALL patients [1]. According to several studies [5, 24], ACA in Ph+ ALL took place in 30-60% of these patients, and some of them underwent HSCT. As a rule, ACA affect chromosome pairs 7 to 9, 21 and 22 [11, 24]. Since advent of tyrosine kinase inhibitors (TKIs), predictive significance shifted towards ACA of chromosomes 9 and 22, making questionable a predictive role of other chromosomes. [21]. In our cohort, the structural changes in chromosomes 9 and 22 with 9p deletion and accessory Ph’-chromosome encountered in 6 patients. Moreover, ACA included also structural changes of chromosomes 5 (n=4), 7 (n=3), 1 (n=3), 17 (n=2) and some others. When discussing a role of ACA in Ph+ ALL patients, one should mention that some of them, by contrary, might lengthen OS and EFS. In particular, such situation is typical to the patients with a combination of one or two Ph1-cromosomes with high hyperdiploid karyotype [5, 19, 22]. In most of them, it was rather easy to achieve complete remission, due to positive predictive effect of high hyperdiploidy. Such patients were absent from our cohort. In the past, however, we have observed several ALL patients with two Ph’ chromosomes and high hyperdiploid karyotype who developed complete remission, even at standard chemotherapy, without TKI’s, with subsequent consolidation by means of autologous HSCT [9]. Some workers presume that only a combination of glucocorticoids and TKI’s is today sufficient to achieve a molecular remission, which could be fixed with auto-transplant [4, 7, 8]. As seen from our results, this cohort is heterogeneous, with respect to cytogenetic and prognostic parameters. Hence, appropriate therapy should be differentiated and based on cytogenetic data. In case of “favorable” combination of Ph’ chromosome and high hyperdiploid karyotype, the patients should be initially prepared by glucocorticoids and TKI’s (without application of ), then followed by auto-HSCT. What concerns more toxic protocols of therapy followed by auto-HSCT, they should be used, first of all, for treating the patients with other ACA types. Moreover, chemotherapy causes both de novo chromosome damage in Ph+ cells, and triggers a complex, prognostically adverse process of clonal evolution [10]. A resulting delay with HSCT in adult patients with Ph+ALL also remains unacceptable.

Conclusion

Our  data  show  broad  cytogenetic  heterogeneity  among  leukemia patients with Ph+ ALL before HSCT. A significant subgroup exhibits additional chromosomal abnormalities which are associated with inferior clinical outcomes post-transplant. This phenomenon can be due to clonal evolution of malignant karyotype, or chemotherapy performed before HSCT, thus requiring further studies in the field.

Conflict of interest

All the authors have no conflict of interest to declare.

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  3. Chiaretti S, Foa R. Management of adult Ph-positive acute lymphoblastic leukemia. Hematology 2015;2015:406-413.

  4. Ding Z, Han MZ, Chen SL, MA QL, Wei JL, Pang AM, Zhang XY, Liang C, Yao JF, Cao YG, Feng SZ, Jiang EL. Outcomes of Adults with Acute Lymphoblastic Leukemia After Autologous Hematopoietic Stem Cell Transplantation and the Significance of Pretransplantation Minimal Residual Disease: Analysis from a Single Center of China. Chin Med J 2015;128(15):2065-2071.

  5. Dombret H, Gabert J, Boiron JM, Rigal-Huguet F, Blaise D, Thomas X, Delannoy A, Buzyn A, Bilhou-Nabera C, Cayuela JM, Fenaux P, Bourhis JH, Fegueux N, Charrin C, Boucheux C, Lheritier V, Esperou H, Macintyre E, Vernant JP, Fiere D. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia – results of the prospective multicenter LALA-94 trial. Blood 2002;100(7):2357-2366.

  6. Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993:  addition  of  imatinib  to  a  standard  treatment  regimen  enhances  long-term  outcomes  in  Philadelphia positive acute lymphoblastic leukemia. Blood 2014;123(6):843-850.

  7. Giebel S, Labopin M, Gorin NC, Caillot D, Leguay Th, Schaap N, Michallet M, Dombret H, Mohty M. Improving results of autologous stem cell transplantation for Philadelphia-positive acute lymphoblastic leukaemia in the era of tyrosine kinase inhibitors: A report from the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Eur J Cancer 2014;50(2):411-417.

  8. Giebel S, Labopin M,  Potter M,  Poiré X,  Sengeloev H,  Socié G,  Huynh A,  Afanasyev BV, Schanz U,  Ringden O,  Kalhs P,  Beelen DW,  Campos AM.,  Masszi T,  Mohty M, Nagler A. Comparable Results of Autologous and Allogeneic Hematopoietic Stem Cell Transplantation for Adult Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia in First Complete Molecular Remission: An Analysis By the Acute Leukemia Working Party of the EBMT. Blood 2016;128(26):512.

  9. Gindina TL, Mamaev NN, Barkhatov IM, Solomonova EV, Semyenova EV, Zubarovskaya LS, Morozova EV, Rudnitskaya YuV, Poppova MO, Alexeev SM, Uspenskaya OS, Bondarenko SN, Afanasyev BV. Complex chromosome changes in patients with recurrent acute leukemias after allogeneic hematopoietic stem cell transplantation. Ther Arkh 2012;84(8):61-66 [In Russia].

  10. Gindina TL, Mamaev NN, Bondarenko SN, Semenova EV, Nikolaeva ES, Vlasova ME, Stancheva NV, Slesarchuk OA, Vavilov SN, Morozova EV, Alyanskiy AL, Afanasyev BV. Complex chromosomal aberrations in patients with post-transplantation replases of acute leukemias: clinical and theoretical aspects. Klin. Onkogematol. 2015;8(1):69-77.

  11. Heerema NA, Harbott J, Galimberti S, Camitta BM, Gaynon PS, Janka-Schaub G, Kamps W, Basso G, Pui CH, Schrappe M, Auclerc MF, Carroll AJ, Conter V, Harrison CJ, Pullen J, Raimondi SC, Richards S, Riehm H, Sather HN, Shuster JJ, Silverman LB, Valsecchi MG, Arico M. Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome. Leukemia 2004;18(4):693-702.

  12. Hiller B, Bradtke J, Balz H, Rieder H. CyDAS: a cytogenetic data analysis system. Bioinformatics. 2005;21(7):1282-1283.

  13. Kebriaei P, Saliba r, Rondon G, Chiattone A, Luthra R, Anderlini P, Andersson B, Shpall E, Popat U, Jones R, Worth L, Ravandi F, Thomas D, O’Brien S, Kantarjian H, de Lima M, Giralt S, Champlin R. Long-term follow-up of allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: impact of tyrosine kinase inhibitors on treatment outcomes. Biol Blood Marrow Transplant 2012;18(4):584-592.

  14. Ko BS, Tang JL, Lee FY, Liu MC, Tsai W, Chen YC, Wang CH, Sheng MC, Lin DT, Lin KH, Tien HF. Additional chromosomal abnormalities and variability of BCR breakpoints in Philadelphia chromosome/BCR-ABL-positive acute lymphoblastic leukemia in Taiwan. Am J Hematol 2002;71(4):291-299.

  15. Moorman AV. The clinical relevance of chromosomal and genomic abnormalities in B-cell precursor acute lymphoblastic leukaemia. Blood Reviews 2012;26(3):123-135.

  16. Parma  M,  Vigano  C,  Fumagalli  M,  Collnaghi  F,  Colombo A, Mottadelli F, Rossi V, Elli E, Terruzzi E, Belotti A, Cazzaniga G, Pogliani EM, Pioltelli P. Good outcome for very high risk adult B-cell acute lymphoblastic leukemia carrying genetic abnormalities t(4;11)(q21;q23) or t(9;22)(q34;q11), if promptly submitted to allogeneic transplantation, after obtaining a good molecular remission. Mediterr J Hematol Infect Dis 2015;7(1):e2015041.

  17. Propp S, Lizzi FA. Philadelphia chromosome in acute lymphocytic leukemia. Blood 1970;36(3):353-360.

  18. Ribera JM, Garcia O, Montesinos P, Brunet S, Abella E, Barrios M, Gonzales-Campos J, Bravo P, Hernandez-Rivas JM. Treatment of young patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia using increased dose of imatinib and deintensified chemotherapy before allogeneic stem cell transplantation. Br J Haematol 2012;159(1):78-81.

  19. Rieder H, Lufwig WD, Gassmann W, Maurer J, Janssen JW, Gokbudet N, Schwartz S, Thiel E, Loffler H, Bartram CR, Hoelzer D, Fonatsch C. Prognostic significance of additional chromosome abnormalities in adult patients with Philadelphia chromosome positive acute lymphoblastic leukaemia. Br J Haematol 1996;95(4):678-691.

  20. Schaffer L., McGovan-Jordan J., Schmid M. ISCN. An international System for Human Cytogenetic Nomenclature. S. Karger, Basel. Switzerland, 2013, p.140

  21. Short NY, Kantarjian HM, Sasaki K, Ravandi F, Ko H, Yin CC, Garcia-Manero G, Cortes JE, Garris R, O’Brien SM, Patel K, Khouri M, Thomas D, Jain N, Kadia TM, Daver N, Benton CB, Issa GC, Konopleva M, Jabbour E. Poor outcomes associated with +der(22)t(9;22) and -9/9p in patients with Philadelphia chromosome positive acute lymphobladstic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor. Amer J Haematol. 2017;92(3):238-243.

  22. Tauro S, McMullan D, Griffits M, Craddock C, Mahendra P. High-hyperploidy in Philadelphia positive adult acute lymphoblastic leukemia: case-series and review of literature. Bone Marrow Transplant 2003;31(9):763-766.

  23. Wang L, Liu D-H. Tyrosine kinase inhibitor for treatment of adult allogeneic hematopoietic stem cell transplantation candidate with Philadelphia positive acute lymphoblastic leukemia. Chinese Medical Journal 2017;130(2):127-129.

  24. Wetzler M, Dodge RK, Mrozek K, Stewart CC, Caroll AJ, Tantravahi R, Vardiman JW, Larson RA, Bloomfield CD. Additional cytogenetic abnormalities in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: a study of the Cancer and Leukemia Group B. Leukemia 2004;124(3):275-288.

  25. Wetzler M, Watson D, Stock W, Koval G, Mulkey FA, Hoke EE, McCarty JM, Blum WG, Powell BL, Marcucci G, Bloomfield CD, Linker CA, Larson RA. Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of GALGB Sudy 10001 (Alliance). Haematologica 2014;99(1):111-115.

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Introduction

Ph1-positive acute lymphoblastic leukemia (Ph+ALL) ranks a special place among lymphoid tumors. Initially, Ph1 positivity in ALL cells seemed an unexpected finding, since it challenged a specificity of t(9;22) translocation for chronic myeloid leukemia [17]. Afterwards, upon data gaining, it has become clear that Ph+ ALL may occur in all age groups, being more common in aged people, with minimal rates shown for children. Its prevalence is as high as 20% among adult ALL patients [15]. Until more recent times, the Ph+ ALL was considered an extremely unfavorable clinical variant with respect to all known treatment modes including hematopoietic stem cell transplantation (HSCT) [15]. This problem was solved as soon as different tyrosine kinase inhibitor drugs (TKIs) were introduced to clinics, thus enabling stable molecular remissions of the disease [3,6,13,18], and their usage for successful HSCT [2,16,23] including autologous (auto-) HSCTs [4,7,8,25]. ACA in Ph+ ALL are commonly seen, being described for 30-60% of the cases [5, 11, 14, 24]. Evaluation of allo-HSCT outcomes has shown that their prognosis depends on presence or absence of additional chromosome aberrations in cases of Ph1 chromosome positivity [1]. Moreover, it should be kept in mind that the ACA in Ph+ ALL patients could not be definitive. In particular, efficiency of chemotherapy and HSCT may be very good in cases of Ph1 chromosome combined with high hyperdiploidy [22]. We have previously confirmed it in our studies [9]. Such clinical aspect seems to be of high importance, in view of revisiting auto-HSCT for Ph+ ALL treatment [7,8,25].

Our study concerned a retrospective analysis of allo-HSCT performed in a mixed cohort of children and adults with Ph+ ALL who exhibited different clinical, transplant and cytogenetic characteristics.

Patients and Methods

The study was performed in a group of sixty-five patients with Ph+ ALL who underwent allo-HSCT at the First St. Petersburg I. Pavlov State Medical University over 2008 to 2015. We have used short-term 24-hour culturing of bone marrow  cells  without  mitogen  stimulation.  Cytogenetic  studies were carried out with a GTG chromosome staining using a standard technique [9]. Fluorescent in situ hybridization (FISH) with specific DNA probes proceeded according to the manufacturers’ protocols (MetaSystems, Germany; CytoCell, Great Britain). Interpretation of chromosomal aberrations was performed in accordance with an International System for Human Cytogenetic Nomenclature [20]. Evaluation of overall survival (OS) and event-free survival (EFS) was carried out in the patients with different demographic and clinical characteristics including gender and age, donor type, clinical state at the HSCT, conditioning regimen, source of stem cells and number of stem cells transplanted. The overall survival (OS) has been determined as the time period passed since HSCT to the patient’s death (for any reasons), or until the last examination date. Event-free survival (EFS) was evaluated as a time from HSCT to any adverse event (non-achievement of remission post-transplant, relapse, or death for any reasons), or till the last examination date. Statistical evaluation was performed with digital package ‘R’, version 3.1.1. (The R Foundation for Statistical Computing, Vienna Austria 2012). Survival curves have been plotted, according to Kaplan-Meier analysis. The survival plots were compared by means of a log-rank test; confidence levels by p<0,05 were considered significant. Multivariate analysis has been performed by the Cox regression model.

Results

The group of patients included 26 females (40%), and 39 males (60%), at the age between 5 and 48 years (a median of 26 years). Table 1 represents clinical and transplantation characteristics of the cohort under study. Thirty-one patients (48%) received allo-HSCT in the 1st remission, 20 subjects (31%) were transplanted in the 2nd remission, whereas 14 (21%) of the patients underwent allo-HSCT in active stage of the disorder. Bone marrow was a source of stem cells in 31 patients (48%), whereas peripheral blood stem cell transplants were used in 32 subjects (49%). Two patients got stem cells from the both sources. Reduced-intensity conditioning regimens (RIC) were used in 36 cases (55%), myeloablative treatment, in 29 cases (45%). Eighteen patients (28%) had HLA-identical sibling in their families; whereas 42 patients (65%) could be transplanted from HLA-matched unrelated donors found in an international registry. In 5 cases (7%), a related haploidentical HSCT was performed, since HLAmatched donor was absent in the family or blood donor Registries.

Table 1. Clinical and transplantation characteristics of Ph+ ALL patients under study

table-1-clinical-and-transplantation.jpg

Cytogenetic characteristics of Ph-positive ALL

Primary diagnosis of Ph+ ALL was established by a standard cytogenetic examination performed in 53 (80%) of the patients. In 12 subjects (18%), the diagnosis was based on a fusion chimeric BCR-ABL gene found by FISH technique and chimeric bcr/abl transcript (р190 and/or p210) revealed with PCR.

Afterwards, we considered karyotypic changes in 53 patients with described pre-transplant cytogenetics. A t(9;22) (q34;q11) translocation, as sole karyotypic aberration, has been revealed in 33 patients, including 9 children (38%) and 24 (62%) adults. Accessory chromosomal anomalies were found in 20 patients, 5 (33%), in children and 15 (67%) in adults. The cytogenetic data for the 20 patients with additional chromosomal aberrations (ACA) are represented in Table 2. Both quantitative and structural ACA have been detected. Numerical abnormalities beared, mainly, on the chromosomes 1, 7, 8, 9, 10, being found in 12 out of 20 cases (60%). Trisomy 1 was nonrandom, being found in 2 patients (No5, 6). Similar repeated findings were made for trisomy10 (No4, 20), trisomy 22 (No4, 16), monosomy 7 (No8, 12). Trisomy 2 (in No20), trisomy 17 and 19 (No2), monosomy 9 (No16) were revealed in single patients.

Table 2. Karyotypes of the patients with Ph+ ALL with additional chromosomal abnormalities (ACA)

table-2-karyotypes-of-the-patients.jpg

Note: additional chromosomal abnormalities are marked red.

Additional structural aberrations [except of t(9;22)] were registered in 20 patients. These were unbalanced in 16 of 20 cases (80%). Meanwhile, only 4 patients (20%) exhibited reciprocal translocations. Detailed evaluation of the chromosomal alterations, i.e., complete or partial monosomies and trisomies, is represented in Fig.1. Chromosomes 5, 7, 9, 2, 1, 17, 22 were most commonly involved into additional structural rearrangements. E.g., deletions and translocations in the short arm (p) of the chromosome 9 were observed in 4 patients out of 20 (No1, 5, 9, 15); reciprocal and unbalanced translocations with involvement of 7p were found in 3 cases (No17, 18, 19). Interstitial deletions and unbalanced translocations under involvement of 5q have been registered in 4 patients (No2, 4, 17, 18); deletions/translocations with chromosome 1, in 3 cases (No1, 6, 18); deletions and translocations of the chromosome 2, in 4 subjects (No1, 11, 17, 18). A structurally changed chromosome 17 was noted in 2 cases, as an isochromosome 17q (No2), or as a partner in unbalanced translocation (No4). An accessory derivate of the chromosome 22 was revealed in two patients (No14, 16). Unbalanced rearrangements involving other chromocomes occured occasionally.

A karyotype with three and more chromosomal aberrations was revealed in 13 patients (20%). As an example, the karyograms with a variant t(21;9;22)(q22;q34;q11) translocation and compound chromosomal abnormalities are presented on Fig. 2. The latter include ‘jumping’ segments (1q, 8q, 1q8q) to the partner chromosomes 1, 4, 5, 14, 19, 21 in a patient with chemoresistant Ph+ ALL (No18).

figure-1-figure-illustrates-the-additional-cytogenetic-alterations.jpg

Figure 1. Figure illustrates the additional cytogenetic alterations in the cohort of Ph-positive ALL with the support of CYDAS (http://www.cydas.org/OnlineAnalysis/) [12]. Chromosomal gains are marked in green to the right, losses in red to the left. The thickness of the bars represents the number of cases showing the respective chromosomal gain or loss.

figure-2-karyograms-of-a-bone-marrow-cells.jpg

Figure 2. Karyograms of a bone marrow cells from a patient with chemoresistant Ph+ ALL and complex chromosomal abnormalities including a variant translocation t(21;9;22) and ‘jumping’ segments (1q, 8q, 1q-8q) to the partner chromosomes 1, 4, 5, 14, 21 (A,B – GTG banding; C,D, multi-coloured FISH).

Effects of cytogenetic, clinical and transplantation parameters upon clinical outcomes of allo-HSCT in the Ph+ALL patients

Furthermore, we performed an OS and EFS analysis in the patients different for their clinical and biological characteristics, e.g., gender, age, disease state, donor type, conditioning regimen, source of stem cells, presence of additional chromosomal aberrations and complex karyotypic abnormalities (≥3 per a karyotype). ///
A univariate analysis (Table 3) has shown significant differences in OS and EFS after allo-HSCT for the patients differing in their clinical stage at transplantation (for EFS only), donor type, as well as for groups with ACA, complex chromosomal aberrations (≥3 per karyotype), or ACA-free.

Table 3. Univariate analysis of overall survival (OS) and event-free survival (EFS) for the patients under study

table-3-intestinal-microbiota-diversity-by-weber-et-al.jpg

Our data suggest that clinical efficiency was higher for transplantations performed at the 1st remission (for EFS only), in cases of matched related and unrelated donors, in absence of ACA in karyotype (for OS only), and, in particular, for complex chromosome aberrations (for OS only) (Fig. 3, 4). Meanwhile, no significant differences were obtained in the patients differing for their age, gender, conditioning regimens, stem cell source, time period from initial diagnosis to HSCT, and amount of transplanted CD34+ cells.

figure-3-overall-survival.jpg

Figure 3. Overall survival after allo-HSCT in Ph+ ALL patients dependent on the presence of additional chromosomal abnormalities [except of t(9;22)] (left); and presence of ≥3 additional chromosomal aberrations (right).

figure-4-event-free-survival.jpg

Figure 4. Event-free survival after allo-HSCT in Ph+ ALL patients dependent on clinical stage at time of HSCT.

The results of multivariate analysis (Table 4) have shown that a presence of ≥3 chromosomal abnormalities in karyotype is an independent predictor for OS in ALL patients with t(9;22)/BCR-ABL translocation. Meanwhile, clinical stage at the time of allo-HSCT seems to be an independent predictor of event-free survival (EFS) of these patients.

Table 4. Multivariate analysis of survival predictors post-HSCT in Ph’-positive ALL

table-4-multivariate-analysis.jpg

Discussion

Our study has confirmed recent conclusions on predictive significance of ACA in Ph+ALL patients [1]. According to several studies [5, 24], ACA in Ph+ ALL took place in 30-60% of these patients, and some of them underwent HSCT. As a rule, ACA affect chromosome pairs 7 to 9, 21 and 22 [11, 24]. Since advent of tyrosine kinase inhibitors (TKIs), predictive significance shifted towards ACA of chromosomes 9 and 22, making questionable a predictive role of other chromosomes. [21]. In our cohort, the structural changes in chromosomes 9 and 22 with 9p deletion and accessory Ph’-chromosome encountered in 6 patients. Moreover, ACA included also structural changes of chromosomes 5 (n=4), 7 (n=3), 1 (n=3), 17 (n=2) and some others. When discussing a role of ACA in Ph+ ALL patients, one should mention that some of them, by contrary, might lengthen OS and EFS. In particular, such situation is typical to the patients with a combination of one or two Ph1-cromosomes with high hyperdiploid karyotype [5, 19, 22]. In most of them, it was rather easy to achieve complete remission, due to positive predictive effect of high hyperdiploidy. Such patients were absent from our cohort. In the past, however, we have observed several ALL patients with two Ph’ chromosomes and high hyperdiploid karyotype who developed complete remission, even at standard chemotherapy, without TKI’s, with subsequent consolidation by means of autologous HSCT [9]. Some workers presume that only a combination of glucocorticoids and TKI’s is today sufficient to achieve a molecular remission, which could be fixed with auto-transplant [4, 7, 8]. As seen from our results, this cohort is heterogeneous, with respect to cytogenetic and prognostic parameters. Hence, appropriate therapy should be differentiated and based on cytogenetic data. In case of “favorable” combination of Ph’ chromosome and high hyperdiploid karyotype, the patients should be initially prepared by glucocorticoids and TKI’s (without application of ), then followed by auto-HSCT. What concerns more toxic protocols of therapy followed by auto-HSCT, they should be used, first of all, for treating the patients with other ACA types. Moreover, chemotherapy causes both de novo chromosome damage in Ph+ cells, and triggers a complex, prognostically adverse process of clonal evolution [10]. A resulting delay with HSCT in adult patients with Ph+ALL also remains unacceptable.

Conclusion

Our  data  show  broad  cytogenetic  heterogeneity  among  leukemia patients with Ph+ ALL before HSCT. A significant subgroup exhibits additional chromosomal abnormalities which are associated with inferior clinical outcomes post-transplant. This phenomenon can be due to clonal evolution of malignant karyotype, or chemotherapy performed before HSCT, thus requiring further studies in the field.

Conflict of interest

All the authors have no conflict of interest to declare.

References

  1. Aldoss I, Stiller T, Cao TM, Palmer JM, Thomas SH, Forman SJ, Pullarkat V. Impact of additional cytogenetic abnormalities in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia undergoing allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2015;21(7):1326-1329.

  2. Cai WZ, Cen JN, Chen J, Fu CC, Han Y, Jin ZM, Ma X, Miao M, Qin HY, Tang XW, Xue SL, Sun AN, Chen SN, Wu DP. Major molecular response prior to allogeneic hematopoietic stem cell transplantation predicts better outcome in adult Philadelphia-positive acute lymphoblastic leukemia in first remission. Bone Marrow Transplant 2017;52(3):470-472.

  3. Chiaretti S, Foa R. Management of adult Ph-positive acute lymphoblastic leukemia. Hematology 2015;2015:406-413.

  4. Ding Z, Han MZ, Chen SL, MA QL, Wei JL, Pang AM, Zhang XY, Liang C, Yao JF, Cao YG, Feng SZ, Jiang EL. Outcomes of Adults with Acute Lymphoblastic Leukemia After Autologous Hematopoietic Stem Cell Transplantation and the Significance of Pretransplantation Minimal Residual Disease: Analysis from a Single Center of China. Chin Med J 2015;128(15):2065-2071.

  5. Dombret H, Gabert J, Boiron JM, Rigal-Huguet F, Blaise D, Thomas X, Delannoy A, Buzyn A, Bilhou-Nabera C, Cayuela JM, Fenaux P, Bourhis JH, Fegueux N, Charrin C, Boucheux C, Lheritier V, Esperou H, Macintyre E, Vernant JP, Fiere D. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia – results of the prospective multicenter LALA-94 trial. Blood 2002;100(7):2357-2366.

  6. Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993:  addition  of  imatinib  to  a  standard  treatment  regimen  enhances  long-term  outcomes  in  Philadelphia positive acute lymphoblastic leukemia. Blood 2014;123(6):843-850.

  7. Giebel S, Labopin M, Gorin NC, Caillot D, Leguay Th, Schaap N, Michallet M, Dombret H, Mohty M. Improving results of autologous stem cell transplantation for Philadelphia-positive acute lymphoblastic leukaemia in the era of tyrosine kinase inhibitors: A report from the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Eur J Cancer 2014;50(2):411-417.

  8. Giebel S, Labopin M,  Potter M,  Poiré X,  Sengeloev H,  Socié G,  Huynh A,  Afanasyev BV, Schanz U,  Ringden O,  Kalhs P,  Beelen DW,  Campos AM.,  Masszi T,  Mohty M, Nagler A. Comparable Results of Autologous and Allogeneic Hematopoietic Stem Cell Transplantation for Adult Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia in First Complete Molecular Remission: An Analysis By the Acute Leukemia Working Party of the EBMT. Blood 2016;128(26):512.

  9. Gindina TL, Mamaev NN, Barkhatov IM, Solomonova EV, Semyenova EV, Zubarovskaya LS, Morozova EV, Rudnitskaya YuV, Poppova MO, Alexeev SM, Uspenskaya OS, Bondarenko SN, Afanasyev BV. Complex chromosome changes in patients with recurrent acute leukemias after allogeneic hematopoietic stem cell transplantation. Ther Arkh 2012;84(8):61-66 [In Russia].

  10. Gindina TL, Mamaev NN, Bondarenko SN, Semenova EV, Nikolaeva ES, Vlasova ME, Stancheva NV, Slesarchuk OA, Vavilov SN, Morozova EV, Alyanskiy AL, Afanasyev BV. Complex chromosomal aberrations in patients with post-transplantation replases of acute leukemias: clinical and theoretical aspects. Klin. Onkogematol. 2015;8(1):69-77.

  11. Heerema NA, Harbott J, Galimberti S, Camitta BM, Gaynon PS, Janka-Schaub G, Kamps W, Basso G, Pui CH, Schrappe M, Auclerc MF, Carroll AJ, Conter V, Harrison CJ, Pullen J, Raimondi SC, Richards S, Riehm H, Sather HN, Shuster JJ, Silverman LB, Valsecchi MG, Arico M. Secondary cytogenetic aberrations in childhood Philadelphia chromosome positive acute lymphoblastic leukemia are nonrandom and may be associated with outcome. Leukemia 2004;18(4):693-702.

  12. Hiller B, Bradtke J, Balz H, Rieder H. CyDAS: a cytogenetic data analysis system. Bioinformatics. 2005;21(7):1282-1283.

  13. Kebriaei P, Saliba r, Rondon G, Chiattone A, Luthra R, Anderlini P, Andersson B, Shpall E, Popat U, Jones R, Worth L, Ravandi F, Thomas D, O’Brien S, Kantarjian H, de Lima M, Giralt S, Champlin R. Long-term follow-up of allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: impact of tyrosine kinase inhibitors on treatment outcomes. Biol Blood Marrow Transplant 2012;18(4):584-592.

  14. Ko BS, Tang JL, Lee FY, Liu MC, Tsai W, Chen YC, Wang CH, Sheng MC, Lin DT, Lin KH, Tien HF. Additional chromosomal abnormalities and variability of BCR breakpoints in Philadelphia chromosome/BCR-ABL-positive acute lymphoblastic leukemia in Taiwan. Am J Hematol 2002;71(4):291-299.

  15. Moorman AV. The clinical relevance of chromosomal and genomic abnormalities in B-cell precursor acute lymphoblastic leukaemia. Blood Reviews 2012;26(3):123-135.

  16. Parma  M,  Vigano  C,  Fumagalli  M,  Collnaghi  F,  Colombo A, Mottadelli F, Rossi V, Elli E, Terruzzi E, Belotti A, Cazzaniga G, Pogliani EM, Pioltelli P. Good outcome for very high risk adult B-cell acute lymphoblastic leukemia carrying genetic abnormalities t(4;11)(q21;q23) or t(9;22)(q34;q11), if promptly submitted to allogeneic transplantation, after obtaining a good molecular remission. Mediterr J Hematol Infect Dis 2015;7(1):e2015041.

  17. Propp S, Lizzi FA. Philadelphia chromosome in acute lymphocytic leukemia. Blood 1970;36(3):353-360.

  18. Ribera JM, Garcia O, Montesinos P, Brunet S, Abella E, Barrios M, Gonzales-Campos J, Bravo P, Hernandez-Rivas JM. Treatment of young patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia using increased dose of imatinib and deintensified chemotherapy before allogeneic stem cell transplantation. Br J Haematol 2012;159(1):78-81.

  19. Rieder H, Lufwig WD, Gassmann W, Maurer J, Janssen JW, Gokbudet N, Schwartz S, Thiel E, Loffler H, Bartram CR, Hoelzer D, Fonatsch C. Prognostic significance of additional chromosome abnormalities in adult patients with Philadelphia chromosome positive acute lymphoblastic leukaemia. Br J Haematol 1996;95(4):678-691.

  20. Schaffer L., McGovan-Jordan J., Schmid M. ISCN. An international System for Human Cytogenetic Nomenclature. S. Karger, Basel. Switzerland, 2013, p.140

  21. Short NY, Kantarjian HM, Sasaki K, Ravandi F, Ko H, Yin CC, Garcia-Manero G, Cortes JE, Garris R, O’Brien SM, Patel K, Khouri M, Thomas D, Jain N, Kadia TM, Daver N, Benton CB, Issa GC, Konopleva M, Jabbour E. Poor outcomes associated with +der(22)t(9;22) and -9/9p in patients with Philadelphia chromosome positive acute lymphobladstic leukemia receiving chemotherapy plus a tyrosine kinase inhibitor. Amer J Haematol. 2017;92(3):238-243.

  22. Tauro S, McMullan D, Griffits M, Craddock C, Mahendra P. High-hyperploidy in Philadelphia positive adult acute lymphoblastic leukemia: case-series and review of literature. Bone Marrow Transplant 2003;31(9):763-766.

  23. Wang L, Liu D-H. Tyrosine kinase inhibitor for treatment of adult allogeneic hematopoietic stem cell transplantation candidate with Philadelphia positive acute lymphoblastic leukemia. Chinese Medical Journal 2017;130(2):127-129.

  24. Wetzler M, Dodge RK, Mrozek K, Stewart CC, Caroll AJ, Tantravahi R, Vardiman JW, Larson RA, Bloomfield CD. Additional cytogenetic abnormalities in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia: a study of the Cancer and Leukemia Group B. Leukemia 2004;124(3):275-288.

  25. Wetzler M, Watson D, Stock W, Koval G, Mulkey FA, Hoke EE, McCarty JM, Blum WG, Powell BL, Marcucci G, Bloomfield CD, Linker CA, Larson RA. Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of GALGB Sudy 10001 (Alliance). Haematologica 2014;99(1):111-115.

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Недавнее исследование [1] показало, что ДХА оказывают неблагоприятный эффект на результаты трансплантации у взрослых больных Ph+ ОЛЛ.<br> <h3>Пациенты и методы</h3> Проведен ретроспективный анализ результатов лечения смешанной когорты больных Ph+ ОЛЛ, 19 детей и 46 взрослых, которым алло-ТГСК была выполнена в нашем университете в период с 2008 по 2015 годы. Среди 65 больных Ph+ ОЛЛ, данные стандартного цитогенетического исследования перед алло-ТГСК были доступны у 53 больных. <br> <h3>Результаты</h3> Тридцать три из 53 больных (51%) имели изолированную транслокацию t(9;22). ДХА были выявлены у 20/53 (31%) больных, включая 13/53 (20%) больных с 3 и более хромосомными аномалиями. Наиболее частыми хромосомами, вовлекающимися в дополнительные нарушения были 1, 5, 7, 9, 22. Структурные аномалии из числа ДХА были несбалансированными у 16 (80%) больных, в то время только 4 (20%) больных имели сбалансированные транслокации. При однофакторном анализе прогностическими факторами, связанными с лучшей ОВ и БСВ были тип донора (совместимый родственный/совместимый неродственный vs. гаплоидентичный; p=0,02), клинический статус на момент ТГСК (1 ремиссия vs. другой статус; p=0,01, только для БСВ), дополнительные хромосомные аномалии (ДХА- vs. ДХА+; p=0,04, только для ОВ) и, особенно, комплексные хромосомные аномалии (&lt;3ХА vs ≥3ХА; p=0,01, только для ОВ). Согласно многофакторному анализу независимыми прогностическими факторами клинических исходов являются комплексные хромосомные аномалии на кариотип (HR 2,79, 95% ДИ 1,23-6,34; р=0,01, только для ОВ) и клинический статус на момент ТГСК (HR 2,15, 95% ДИ 1,13-4,09; р=0,01, только для БСВ).<br> <h3>Заключение</h3> Исследование показало, что комплексные хромосомные аномалии и статус заболевания на момент ТГСК являются независимыми прогностическими факторами в смешанной когорте больных Ph+ ОЛЛ, леченных ТГСК. <br> <h3>Ключевые слова</h3> Острый лимфобластный лейкоз, Ph1-позитивный, алло-ТГСК, дополнительные хромосомные аномалии." 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Афанасьев" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11007" ["VALUE"]=> array(2) { ["TEXT"]=> string(420) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии ПДО, Первый Санкт-Петербургский Государственный медицинский университет им. акад. И. П. Павлова" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(420) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии ПДО, Первый Санкт-Петербургский Государственный медицинский университет им. акад. И. П. Павлова" ["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) "11008" ["VALUE"]=> array(2) { ["TEXT"]=> string(4093) "<h3>Резюме</h3> Дополнительные хромосомные аномалии (ДХА) при Ph-позитивном остром лимфобластном лейкозе (Ph+ ОЛЛ) встречаются довольно часто, однако, их прогностическое значение в эру тирозин-киназных ингибиторов и аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) до конца не изучено. Недавнее исследование [1] показало, что ДХА оказывают неблагоприятный эффект на результаты трансплантации у взрослых больных Ph+ ОЛЛ.<br> <h3>Пациенты и методы</h3> Проведен ретроспективный анализ результатов лечения смешанной когорты больных Ph+ ОЛЛ, 19 детей и 46 взрослых, которым алло-ТГСК была выполнена в нашем университете в период с 2008 по 2015 годы. Среди 65 больных Ph+ ОЛЛ, данные стандартного цитогенетического исследования перед алло-ТГСК были доступны у 53 больных. <br> <h3>Результаты</h3> Тридцать три из 53 больных (51%) имели изолированную транслокацию t(9;22). ДХА были выявлены у 20/53 (31%) больных, включая 13/53 (20%) больных с 3 и более хромосомными аномалиями. Наиболее частыми хромосомами, вовлекающимися в дополнительные нарушения были 1, 5, 7, 9, 22. Структурные аномалии из числа ДХА были несбалансированными у 16 (80%) больных, в то время только 4 (20%) больных имели сбалансированные транслокации. При однофакторном анализе прогностическими факторами, связанными с лучшей ОВ и БСВ были тип донора (совместимый родственный/совместимый неродственный vs. гаплоидентичный; p=0,02), клинический статус на момент ТГСК (1 ремиссия vs. другой статус; p=0,01, только для БСВ), дополнительные хромосомные аномалии (ДХА- vs. ДХА+; p=0,04, только для ОВ) и, особенно, комплексные хромосомные аномалии (&lt;3ХА vs ≥3ХА; p=0,01, только для ОВ). Согласно многофакторному анализу независимыми прогностическими факторами клинических исходов являются комплексные хромосомные аномалии на кариотип (HR 2,79, 95% ДИ 1,23-6,34; р=0,01, только для ОВ) и клинический статус на момент ТГСК (HR 2,15, 95% ДИ 1,13-4,09; р=0,01, только для БСВ).<br> <h3>Заключение</h3> Исследование показало, что комплексные хромосомные аномалии и статус заболевания на момент ТГСК являются независимыми прогностическими факторами в смешанной когорте больных Ph+ ОЛЛ, леченных ТГСК. <br> <h3>Ключевые слова</h3> Острый лимфобластный лейкоз, Ph1-позитивный, алло-ТГСК, дополнительные хромосомные аномалии." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4005) "

Резюме

Дополнительные хромосомные аномалии (ДХА) при Ph-позитивном остром лимфобластном лейкозе (Ph+ ОЛЛ) встречаются довольно часто, однако, их прогностическое значение в эру тирозин-киназных ингибиторов и аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) до конца не изучено. Недавнее исследование [1] показало, что ДХА оказывают неблагоприятный эффект на результаты трансплантации у взрослых больных Ph+ ОЛЛ.

Пациенты и методы

Проведен ретроспективный анализ результатов лечения смешанной когорты больных Ph+ ОЛЛ, 19 детей и 46 взрослых, которым алло-ТГСК была выполнена в нашем университете в период с 2008 по 2015 годы. Среди 65 больных Ph+ ОЛЛ, данные стандартного цитогенетического исследования перед алло-ТГСК были доступны у 53 больных.

Результаты

Тридцать три из 53 больных (51%) имели изолированную транслокацию t(9;22). ДХА были выявлены у 20/53 (31%) больных, включая 13/53 (20%) больных с 3 и более хромосомными аномалиями. Наиболее частыми хромосомами, вовлекающимися в дополнительные нарушения были 1, 5, 7, 9, 22. Структурные аномалии из числа ДХА были несбалансированными у 16 (80%) больных, в то время только 4 (20%) больных имели сбалансированные транслокации. При однофакторном анализе прогностическими факторами, связанными с лучшей ОВ и БСВ были тип донора (совместимый родственный/совместимый неродственный vs. гаплоидентичный; p=0,02), клинический статус на момент ТГСК (1 ремиссия vs. другой статус; p=0,01, только для БСВ), дополнительные хромосомные аномалии (ДХА- vs. ДХА+; p=0,04, только для ОВ) и, особенно, комплексные хромосомные аномалии (<3ХА vs ≥3ХА; p=0,01, только для ОВ). Согласно многофакторному анализу независимыми прогностическими факторами клинических исходов являются комплексные хромосомные аномалии на кариотип (HR 2,79, 95% ДИ 1,23-6,34; р=0,01, только для ОВ) и клинический статус на момент ТГСК (HR 2,15, 95% ДИ 1,13-4,09; р=0,01, только для БСВ).

Заключение

Исследование показало, что комплексные хромосомные аномалии и статус заболевания на момент ТГСК являются независимыми прогностическими факторами в смешанной когорте больных Ph+ ОЛЛ, леченных ТГСК.

Ключевые слова

Острый лимфобластный лейкоз, Ph1-позитивный, алло-ТГСК, дополнительные хромосомные аномалии." 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Gindina, Nikolai N. Mamaev, Elena S. Nikolaeva, Irina A. Petrova, Elena I. Darskaya, Olga V. Pirogova, Yana V. Gudozhnikova, Olesya V. Paina, Alexander L. Alyanskyi, Sergey N. Bondarenko, 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(242) "Tatiana L. Gindina, Nikolai N. Mamaev, Elena S. Nikolaeva, Irina A. Petrova, Elena I. Darskaya, Olga V. Pirogova, Yana V. Gudozhnikova, Olesya V. Paina, Alexander L. Alyanskyi, Sergey N. Bondarenko, 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) "11033" ["VALUE"]=> array(2) { ["TEXT"]=> string(241) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Department of Hematology, Transfusiology and Transplantation, The First St. Petersburg I. Pavlov State Medical 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(241) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Department of Hematology, Transfusiology and Transplantation, The First St. Petersburg I. Pavlov State Medical 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) "11034" ["VALUE"]=> array(2) { ["TEXT"]=> string(2343) "Additional chromosomal abnormalities (ACA) are rather common in Ph+ acute lymphoblastic leukemia (ALL). However, their prognostic significance in the era of protein tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still poorly known. A recent study [1] has shown that ACA exert unfavorable effect upon HSCT results in adult patients with Ph+ALL. <h3>Patients and methods</h3> We have performed a retrospective analysis of treatment results for a mixed cohort of the patients with Ph+ ALL, including 19 children (aged 5 – 18 y.o.) and 46 adults (aged 19 – 57 y.o.) who received allo-HSCT at our Institute over 2008 to 2015. Among sixty-five subjects with Ph+ ALL, the results of standard cytogenetic studies were available for 53 patients. <h3>Results</h3> Thirty-three patients of 53 (51%) exhibited an isolated t(9;22) translocation. ACA were revealed in 20/53 patients (31%), including 13/53 (20%) subjects with 3 and more chromosome abnormalities. Chromosomes 1, 5, 7, 8, 9, 22 were most commonly affected with additional anomalies. Structural abnormalities attributable to ACA were imbalanced in 16 patients (80%), whereas only 4 patients (20%) showed balanced translocations. In a univariate analysis, significance was shown for the donor type (matched related and unrelated vs haploidentical, p=0.02), clinical stage at HSCT (1st remission vs other stages, p=0.01, for EFS only), additional chromosomal abnormalities (ACA-negative vs ACA-positive, p=0.04, for OS only), and, in particular, complex chromosomal aberrations (<3 anomalies vs ≥3 anomalies, p=0.01, for OS only). According to multivariate analysis, the number of additional chromosomal abnormalities per karyotype (HR 2.79, 95% CI 1.23-6.34; р=0.01, for OS only) and clinical stage at HSCT (HR 2.15, 95% CI 1.13-4.09; р=0.01, for EFS only) are independent prognostic factors for clinical outcomes. <h3>Conclusion</h3> The study has shown that complex chromosomal anomalies and the stage of disease at the moment of HSCT are independent prognostic factors in a mixed cohort of Ph+ ALL patients treated with hematopoietic stem cell transplantation. <h3>Keywords</h3> Acute lymphoblastic leukemia, Ph1-positive, allo-HSCT, additional chromosomal abnormalities. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2292) "Additional chromosomal abnormalities (ACA) are rather common in Ph+ acute lymphoblastic leukemia (ALL). However, their prognostic significance in the era of protein tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still poorly known. A recent study [1] has shown that ACA exert unfavorable effect upon HSCT results in adult patients with Ph+ALL.

Patients and methods

We have performed a retrospective analysis of treatment results for a mixed cohort of the patients with Ph+ ALL, including 19 children (aged 5 – 18 y.o.) and 46 adults (aged 19 – 57 y.o.) who received allo-HSCT at our Institute over 2008 to 2015. Among sixty-five subjects with Ph+ ALL, the results of standard cytogenetic studies were available for 53 patients.

Results

Thirty-three patients of 53 (51%) exhibited an isolated t(9;22) translocation. ACA were revealed in 20/53 patients (31%), including 13/53 (20%) subjects with 3 and more chromosome abnormalities. Chromosomes 1, 5, 7, 8, 9, 22 were most commonly affected with additional anomalies. Structural abnormalities attributable to ACA were imbalanced in 16 patients (80%), whereas only 4 patients (20%) showed balanced translocations. In a univariate analysis, significance was shown for the donor type (matched related and unrelated vs haploidentical, p=0.02), clinical stage at HSCT (1st remission vs other stages, p=0.01, for EFS only), additional chromosomal abnormalities (ACA-negative vs ACA-positive, p=0.04, for OS only), and, in particular, complex chromosomal aberrations (<3 anomalies vs ≥3 anomalies, p=0.01, for OS only). According to multivariate analysis, the number of additional chromosomal abnormalities per karyotype (HR 2.79, 95% CI 1.23-6.34; р=0.01, for OS only) and clinical stage at HSCT (HR 2.15, 95% CI 1.13-4.09; р=0.01, for EFS only) are independent prognostic factors for clinical outcomes.

Conclusion

The study has shown that complex chromosomal anomalies and the stage of disease at the moment of HSCT are independent prognostic factors in a mixed cohort of Ph+ ALL patients treated with hematopoietic stem cell transplantation.

Keywords

Acute lymphoblastic leukemia, Ph1-positive, allo-HSCT, additional chromosomal abnormalities. 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Gindina, Nikolai N. Mamaev, Elena S. Nikolaeva, Irina A. Petrova, Elena I. Darskaya, Olga V. Pirogova, Yana V. Gudozhnikova, Olesya V. Paina, Alexander L. Alyanskyi, Sergey N. Bondarenko, 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(242) "Tatiana L. Gindina, Nikolai N. Mamaev, Elena S. Nikolaeva, Irina A. Petrova, Elena I. Darskaya, Olga V. Pirogova, Yana V. Gudozhnikova, Olesya V. Paina, Alexander L. Alyanskyi, Sergey N. Bondarenko, Ludmila S. Zubarovskaya, Boris V. Afanasyev" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(6) "Author" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(242) "Tatiana L. Gindina, Nikolai N. Mamaev, Elena S. Nikolaeva, Irina A. Petrova, Elena I. Darskaya, Olga V. Pirogova, Yana V. Gudozhnikova, Olesya V. Paina, Alexander L. Alyanskyi, Sergey N. Bondarenko, Ludmila S. Zubarovskaya, Boris V. Afanasyev" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11034" ["VALUE"]=> array(2) { ["TEXT"]=> string(2343) "Additional chromosomal abnormalities (ACA) are rather common in Ph+ acute lymphoblastic leukemia (ALL). However, their prognostic significance in the era of protein tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still poorly known. A recent study [1] has shown that ACA exert unfavorable effect upon HSCT results in adult patients with Ph+ALL. <h3>Patients and methods</h3> We have performed a retrospective analysis of treatment results for a mixed cohort of the patients with Ph+ ALL, including 19 children (aged 5 – 18 y.o.) and 46 adults (aged 19 – 57 y.o.) who received allo-HSCT at our Institute over 2008 to 2015. Among sixty-five subjects with Ph+ ALL, the results of standard cytogenetic studies were available for 53 patients. <h3>Results</h3> Thirty-three patients of 53 (51%) exhibited an isolated t(9;22) translocation. ACA were revealed in 20/53 patients (31%), including 13/53 (20%) subjects with 3 and more chromosome abnormalities. Chromosomes 1, 5, 7, 8, 9, 22 were most commonly affected with additional anomalies. Structural abnormalities attributable to ACA were imbalanced in 16 patients (80%), whereas only 4 patients (20%) showed balanced translocations. In a univariate analysis, significance was shown for the donor type (matched related and unrelated vs haploidentical, p=0.02), clinical stage at HSCT (1st remission vs other stages, p=0.01, for EFS only), additional chromosomal abnormalities (ACA-negative vs ACA-positive, p=0.04, for OS only), and, in particular, complex chromosomal aberrations (<3 anomalies vs ≥3 anomalies, p=0.01, for OS only). According to multivariate analysis, the number of additional chromosomal abnormalities per karyotype (HR 2.79, 95% CI 1.23-6.34; р=0.01, for OS only) and clinical stage at HSCT (HR 2.15, 95% CI 1.13-4.09; р=0.01, for EFS only) are independent prognostic factors for clinical outcomes. <h3>Conclusion</h3> The study has shown that complex chromosomal anomalies and the stage of disease at the moment of HSCT are independent prognostic factors in a mixed cohort of Ph+ ALL patients treated with hematopoietic stem cell transplantation. <h3>Keywords</h3> Acute lymphoblastic leukemia, Ph1-positive, allo-HSCT, additional chromosomal abnormalities. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2292) "Additional chromosomal abnormalities (ACA) are rather common in Ph+ acute lymphoblastic leukemia (ALL). However, their prognostic significance in the era of protein tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still poorly known. A recent study [1] has shown that ACA exert unfavorable effect upon HSCT results in adult patients with Ph+ALL.

Patients and methods

We have performed a retrospective analysis of treatment results for a mixed cohort of the patients with Ph+ ALL, including 19 children (aged 5 – 18 y.o.) and 46 adults (aged 19 – 57 y.o.) who received allo-HSCT at our Institute over 2008 to 2015. Among sixty-five subjects with Ph+ ALL, the results of standard cytogenetic studies were available for 53 patients.

Results

Thirty-three patients of 53 (51%) exhibited an isolated t(9;22) translocation. ACA were revealed in 20/53 patients (31%), including 13/53 (20%) subjects with 3 and more chromosome abnormalities. Chromosomes 1, 5, 7, 8, 9, 22 were most commonly affected with additional anomalies. Structural abnormalities attributable to ACA were imbalanced in 16 patients (80%), whereas only 4 patients (20%) showed balanced translocations. In a univariate analysis, significance was shown for the donor type (matched related and unrelated vs haploidentical, p=0.02), clinical stage at HSCT (1st remission vs other stages, p=0.01, for EFS only), additional chromosomal abnormalities (ACA-negative vs ACA-positive, p=0.04, for OS only), and, in particular, complex chromosomal aberrations (<3 anomalies vs ≥3 anomalies, p=0.01, for OS only). According to multivariate analysis, the number of additional chromosomal abnormalities per karyotype (HR 2.79, 95% CI 1.23-6.34; р=0.01, for OS only) and clinical stage at HSCT (HR 2.15, 95% CI 1.13-4.09; р=0.01, for EFS only) are independent prognostic factors for clinical outcomes.

Conclusion

The study has shown that complex chromosomal anomalies and the stage of disease at the moment of HSCT are independent prognostic factors in a mixed cohort of Ph+ ALL patients treated with hematopoietic stem cell transplantation.

Keywords

Acute lymphoblastic leukemia, Ph1-positive, allo-HSCT, additional chromosomal abnormalities. " ["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(2292) "Additional chromosomal abnormalities (ACA) are rather common in Ph+ acute lymphoblastic leukemia (ALL). However, their prognostic significance in the era of protein tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still poorly known. A recent study [1] has shown that ACA exert unfavorable effect upon HSCT results in adult patients with Ph+ALL.

Patients and methods

We have performed a retrospective analysis of treatment results for a mixed cohort of the patients with Ph+ ALL, including 19 children (aged 5 – 18 y.o.) and 46 adults (aged 19 – 57 y.o.) who received allo-HSCT at our Institute over 2008 to 2015. Among sixty-five subjects with Ph+ ALL, the results of standard cytogenetic studies were available for 53 patients.

Results

Thirty-three patients of 53 (51%) exhibited an isolated t(9;22) translocation. ACA were revealed in 20/53 patients (31%), including 13/53 (20%) subjects with 3 and more chromosome abnormalities. Chromosomes 1, 5, 7, 8, 9, 22 were most commonly affected with additional anomalies. Structural abnormalities attributable to ACA were imbalanced in 16 patients (80%), whereas only 4 patients (20%) showed balanced translocations. In a univariate analysis, significance was shown for the donor type (matched related and unrelated vs haploidentical, p=0.02), clinical stage at HSCT (1st remission vs other stages, p=0.01, for EFS only), additional chromosomal abnormalities (ACA-negative vs ACA-positive, p=0.04, for OS only), and, in particular, complex chromosomal aberrations (<3 anomalies vs ≥3 anomalies, p=0.01, for OS only). According to multivariate analysis, the number of additional chromosomal abnormalities per karyotype (HR 2.79, 95% CI 1.23-6.34; р=0.01, for OS only) and clinical stage at HSCT (HR 2.15, 95% CI 1.13-4.09; р=0.01, for EFS only) are independent prognostic factors for clinical outcomes.

Conclusion

The study has shown that complex chromosomal anomalies and the stage of disease at the moment of HSCT are independent prognostic factors in a mixed cohort of Ph+ ALL patients treated with hematopoietic stem cell transplantation.

Keywords

Acute lymphoblastic leukemia, Ph1-positive, allo-HSCT, additional chromosomal abnormalities. 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Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Department of Hematology, Transfusiology and Transplantation, The First St. Petersburg I. Pavlov State Medical 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(241) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Department of Hematology, Transfusiology and Transplantation, The First St. Petersburg I. Pavlov State Medical 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(241) "R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, Department of Hematology, Transfusiology and Transplantation, The First St. Petersburg I. Pavlov State Medical University, St. Petersburg, Russia" } ["AUTHOR_RU"]=> array(37) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11006" ["VALUE"]=> array(2) { ["TEXT"]=> string(416) "Татьяна Л. Гиндина, Николай Н. Мамаев, Елена С. Николаева, Ирина А. Петрова, Елена И. Дарская, Ольга В. Пирогова, Яна В. Гудожникова, Олеся В. Паина, Александр Л. Алянский, Сергей Н. Бондаренко, 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(416) "Татьяна Л. Гиндина, Николай Н. Мамаев, Елена С. Николаева, Ирина А. Петрова, Елена И. Дарская, Ольга В. Пирогова, Яна В. Гудожникова, Олеся В. Паина, Александр Л. Алянский, Сергей Н. Бондаренко, 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(416) "Татьяна Л. Гиндина, Николай Н. Мамаев, Елена С. Николаева, Ирина А. Петрова, Елена И. Дарская, Ольга В. Пирогова, Яна В. Гудожникова, Олеся В. Паина, Александр Л. Алянский, Сергей Н. Бондаренко, Людмила С. Зубаровская, Борис В. Афанасьев" } ["SUBMITTED"]=> array(37) { ["ID"]=> string(2) "20" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Дата подачи" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "SUBMITTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "20" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11001" ["VALUE"]=> string(10) "17.02.2017" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "17.02.2017" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "17.02.2017" } ["ACCEPTED"]=> array(37) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11002" ["VALUE"]=> string(10) "17.02.2017" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "17.02.2017" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "17.02.2017" } ["PUBLISHED"]=> array(37) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11003" ["VALUE"]=> string(10) "10.03.2017" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "10.03.2017" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Дата публикации" ["~DEFAULT_VALUE"]=> NULL ["DISPLAY_VALUE"]=> string(10) "10.03.2017" } ["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) "11008" ["VALUE"]=> array(2) { ["TEXT"]=> string(4093) "<h3>Резюме</h3> Дополнительные хромосомные аномалии (ДХА) при Ph-позитивном остром лимфобластном лейкозе (Ph+ ОЛЛ) встречаются довольно часто, однако, их прогностическое значение в эру тирозин-киназных ингибиторов и аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) до конца не изучено. Недавнее исследование [1] показало, что ДХА оказывают неблагоприятный эффект на результаты трансплантации у взрослых больных Ph+ ОЛЛ.<br> <h3>Пациенты и методы</h3> Проведен ретроспективный анализ результатов лечения смешанной когорты больных Ph+ ОЛЛ, 19 детей и 46 взрослых, которым алло-ТГСК была выполнена в нашем университете в период с 2008 по 2015 годы. Среди 65 больных Ph+ ОЛЛ, данные стандартного цитогенетического исследования перед алло-ТГСК были доступны у 53 больных. <br> <h3>Результаты</h3> Тридцать три из 53 больных (51%) имели изолированную транслокацию t(9;22). ДХА были выявлены у 20/53 (31%) больных, включая 13/53 (20%) больных с 3 и более хромосомными аномалиями. Наиболее частыми хромосомами, вовлекающимися в дополнительные нарушения были 1, 5, 7, 9, 22. Структурные аномалии из числа ДХА были несбалансированными у 16 (80%) больных, в то время только 4 (20%) больных имели сбалансированные транслокации. При однофакторном анализе прогностическими факторами, связанными с лучшей ОВ и БСВ были тип донора (совместимый родственный/совместимый неродственный vs. гаплоидентичный; p=0,02), клинический статус на момент ТГСК (1 ремиссия vs. другой статус; p=0,01, только для БСВ), дополнительные хромосомные аномалии (ДХА- vs. ДХА+; p=0,04, только для ОВ) и, особенно, комплексные хромосомные аномалии (&lt;3ХА vs ≥3ХА; p=0,01, только для ОВ). Согласно многофакторному анализу независимыми прогностическими факторами клинических исходов являются комплексные хромосомные аномалии на кариотип (HR 2,79, 95% ДИ 1,23-6,34; р=0,01, только для ОВ) и клинический статус на момент ТГСК (HR 2,15, 95% ДИ 1,13-4,09; р=0,01, только для БСВ).<br> <h3>Заключение</h3> Исследование показало, что комплексные хромосомные аномалии и статус заболевания на момент ТГСК являются независимыми прогностическими факторами в смешанной когорте больных Ph+ ОЛЛ, леченных ТГСК. <br> <h3>Ключевые слова</h3> Острый лимфобластный лейкоз, Ph1-позитивный, алло-ТГСК, дополнительные хромосомные аномалии." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(4005) "

Резюме

Дополнительные хромосомные аномалии (ДХА) при Ph-позитивном остром лимфобластном лейкозе (Ph+ ОЛЛ) встречаются довольно часто, однако, их прогностическое значение в эру тирозин-киназных ингибиторов и аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) до конца не изучено. Недавнее исследование [1] показало, что ДХА оказывают неблагоприятный эффект на результаты трансплантации у взрослых больных Ph+ ОЛЛ.

Пациенты и методы

Проведен ретроспективный анализ результатов лечения смешанной когорты больных Ph+ ОЛЛ, 19 детей и 46 взрослых, которым алло-ТГСК была выполнена в нашем университете в период с 2008 по 2015 годы. Среди 65 больных Ph+ ОЛЛ, данные стандартного цитогенетического исследования перед алло-ТГСК были доступны у 53 больных.

Результаты

Тридцать три из 53 больных (51%) имели изолированную транслокацию t(9;22). ДХА были выявлены у 20/53 (31%) больных, включая 13/53 (20%) больных с 3 и более хромосомными аномалиями. Наиболее частыми хромосомами, вовлекающимися в дополнительные нарушения были 1, 5, 7, 9, 22. Структурные аномалии из числа ДХА были несбалансированными у 16 (80%) больных, в то время только 4 (20%) больных имели сбалансированные транслокации. При однофакторном анализе прогностическими факторами, связанными с лучшей ОВ и БСВ были тип донора (совместимый родственный/совместимый неродственный vs. гаплоидентичный; p=0,02), клинический статус на момент ТГСК (1 ремиссия vs. другой статус; p=0,01, только для БСВ), дополнительные хромосомные аномалии (ДХА- vs. ДХА+; p=0,04, только для ОВ) и, особенно, комплексные хромосомные аномалии (<3ХА vs ≥3ХА; p=0,01, только для ОВ). Согласно многофакторному анализу независимыми прогностическими факторами клинических исходов являются комплексные хромосомные аномалии на кариотип (HR 2,79, 95% ДИ 1,23-6,34; р=0,01, только для ОВ) и клинический статус на момент ТГСК (HR 2,15, 95% ДИ 1,13-4,09; р=0,01, только для БСВ).

Заключение

Исследование показало, что комплексные хромосомные аномалии и статус заболевания на момент ТГСК являются независимыми прогностическими факторами в смешанной когорте больных Ph+ ОЛЛ, леченных ТГСК.

Ключевые слова

Острый лимфобластный лейкоз, Ph1-позитивный, алло-ТГСК, дополнительные хромосомные аномалии." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(4005) "

Резюме

Дополнительные хромосомные аномалии (ДХА) при Ph-позитивном остром лимфобластном лейкозе (Ph+ ОЛЛ) встречаются довольно часто, однако, их прогностическое значение в эру тирозин-киназных ингибиторов и аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) до конца не изучено. Недавнее исследование [1] показало, что ДХА оказывают неблагоприятный эффект на результаты трансплантации у взрослых больных Ph+ ОЛЛ.

Пациенты и методы

Проведен ретроспективный анализ результатов лечения смешанной когорты больных Ph+ ОЛЛ, 19 детей и 46 взрослых, которым алло-ТГСК была выполнена в нашем университете в период с 2008 по 2015 годы. Среди 65 больных Ph+ ОЛЛ, данные стандартного цитогенетического исследования перед алло-ТГСК были доступны у 53 больных.

Результаты

Тридцать три из 53 больных (51%) имели изолированную транслокацию t(9;22). ДХА были выявлены у 20/53 (31%) больных, включая 13/53 (20%) больных с 3 и более хромосомными аномалиями. Наиболее частыми хромосомами, вовлекающимися в дополнительные нарушения были 1, 5, 7, 9, 22. Структурные аномалии из числа ДХА были несбалансированными у 16 (80%) больных, в то время только 4 (20%) больных имели сбалансированные транслокации. При однофакторном анализе прогностическими факторами, связанными с лучшей ОВ и БСВ были тип донора (совместимый родственный/совместимый неродственный vs. гаплоидентичный; p=0,02), клинический статус на момент ТГСК (1 ремиссия vs. другой статус; p=0,01, только для БСВ), дополнительные хромосомные аномалии (ДХА- vs. ДХА+; p=0,04, только для ОВ) и, особенно, комплексные хромосомные аномалии (<3ХА vs ≥3ХА; p=0,01, только для ОВ). Согласно многофакторному анализу независимыми прогностическими факторами клинических исходов являются комплексные хромосомные аномалии на кариотип (HR 2,79, 95% ДИ 1,23-6,34; р=0,01, только для ОВ) и клинический статус на момент ТГСК (HR 2,15, 95% ДИ 1,13-4,09; р=0,01, только для БСВ).

Заключение

Исследование показало, что комплексные хромосомные аномалии и статус заболевания на момент ТГСК являются независимыми прогностическими факторами в смешанной когорте больных Ph+ ОЛЛ, леченных ТГСК.

Ключевые слова

Острый лимфобластный лейкоз, Ph1-позитивный, алло-ТГСК, дополнительные хромосомные аномалии." } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11007" ["VALUE"]=> array(2) { ["TEXT"]=> string(420) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии ПДО, Первый Санкт-Петербургский Государственный медицинский университет им. акад. И. П. Павлова" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(420) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии ПДО, Первый Санкт-Петербургский Государственный медицинский университет им. акад. И. П. Павлова" ["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(420) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой; кафедра гематологии, трансфузиологии и трансплантологии ПДО, Первый Санкт-Петербургский Государственный медицинский университет им. акад. И. П. Павлова" } } } [5]=> array(49) { ["IBLOCK_SECTION_ID"]=> string(2) "32" ["~IBLOCK_SECTION_ID"]=> string(2) "32" ["ID"]=> string(3) "826" ["~ID"]=> string(3) "826" ["IBLOCK_ID"]=> string(1) "2" ["~IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(252) "Опыт Астаны: отдел онкогематологии и трансплан- тации костного мозга, Национальный исследова - тельский Центр онкологии и трансплантации" ["~NAME"]=> string(252) "Опыт Астаны: отдел онкогематологии и трансплан- тации костного мозга, Национальный исследова - тельский Центр онкологии и трансплантации" ["ACTIVE_FROM"]=> NULL ["~ACTIVE_FROM"]=> NULL ["TIMESTAMP_X"]=> string(19) "15.06.2017 22:34:06" ["~TIMESTAMP_X"]=> string(19) "15.06.2017 22:34:06" ["DETAIL_PAGE_URL"]=> string(147) "/ru/archive/tom-6-nomer-1/klinicheskie-stati/opyt-astany-otdel-onkogematologii-i-transplan-tatsii-kostnogo-mozga-natsionalnyy-issledova-telskiy-ts/" ["~DETAIL_PAGE_URL"]=> string(147) "/ru/archive/tom-6-nomer-1/klinicheskie-stati/opyt-astany-otdel-onkogematologii-i-transplan-tatsii-kostnogo-mozga-natsionalnyy-issledova-telskiy-ts/" ["LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["~LIST_PAGE_URL"]=> string(12) "/ru/archive/" ["DETAIL_TEXT"]=> string(26726) "

Introduction

The Unit of Oncohematology and Bone Marrow Transplantation  (BMT)  was  arranged  on  basis  of  the  Republican  Research Center of Hospital Emergencies SC (Astana, Republic of Kazakhstan) in August 2010, using previous clinical experience  of  the  regional  hematologists.  At  the  beginning,  our  unit consisted of ten hospital beds for chemotherapy of leukemia  and  lymphomas.  First  bone  marrow  transplantation  in  Kazakhstan  was  performed  just  on  the  basis  of  our  specialized unit. Time sequence of our main advances is shown in Table 1.

Table 1. Main steps in development of Oncohematology Unit

table-1-main-steps-in-development-of-oncohematology-unit.jpg

Invaluable  support  and  contribution  to  the  development  of  the  BMT  Unit  should  be  mentioned.  Our  activities  were  supported  by  Professor  Boris  Afanasyev,  Director,  R.  Gorbacheva  Memorial  Research  Institute  of  Children  Oncology, Hematology and Transplantation at the St. Petersburg I. Pavlov  State  Medical  University.  Several  leading  specialists  from the Gorbacheva Institute, e.g., Professor Alexander D. Kulagin, Dr. Sergey N. Bondarenko, Dr. Vladimir N. Vavilov worked hardly at Astana, in order to consult severe patients, arrange  optimal  transplantation  regimens,  analyze  difficult  clinical cases, perform master classes and conferences. This collaboration  has  been  sufficiently  promoted  by  Dr.  Irina  Pivovarova whose contribution to these advances should be highly evaluated.

Since  01.03.2013,  the  Department  was  rearranged  to  the  Unit  of  Hemoblastoses,  Hematopoietic  Aplasias  and  BMT,  followed by extension to 25 beds, with appropriately trained staff.  The  unit  is  a  part  of  Hematology  and  Transfusiology  Department.

Deep renovation of the hospital building (April to September 2013) resulted into opening of aseptic wards with laminar air flow, including BMT unit with six beds and an intensive care unit of four hospital beds.

In September 2013, the Institute of Children Oncology, Hematology  and  Transplantation  (St.  Petersburg,  Russia),  together with our Department, performed the VII Memorial R. Gorbacheva International Symposium with a main topic: Hematopoietic Stem Cell Transplantation in Children and Adults. This event has promoted further development of BMT in Republic of Kazakhstan, and broadening of international cooperation  in  the  field.  Due  to  these  advances,  Kazakhstan  first  appeared at the EBMT map, with a total of 46 transplants in 2013 (Fig. 1). The Memorial Symposium attracted prominent specialists from Europe and USA (Fig. 2, 3).

Figure 1. Allogeneic stem cell transplants per 10,000,000 inhabitants: an EBMT map for 2013 (EBMT Report, 2013).

Figure 1. Allogeneic stem cell transplants per 10,000,000 inhabitants: an EBMT map for 2013 (EBMT Report, 2013).

figure-2-participants-at-the-vii-r-gorbacheva-memori-.jpg

Figure 2. Participants at the VII R. Gorbacheva Memorial International Symposium in Hematology and transplantation in Astana (September 2013).

figure-3-international-team-of-hematologists-visiting-the-new-bmt-department-in-astana.jpg

Figure 3. International team of hematologists visiting the new BMT Department in Astana (September 2013).

Since July 4, 2014, a Clinical Department with 69 beds was arranged,  and  the  Centre  was  renamed  to  the  National  Research Centre for Oncology and Transplantation SC. An oncohematological and BMT Department consisted of a Transfusion Unit and Oncohematology Unit with an intensive care ward  (4  beds).  20.09.2016,  the  Department  was  rearranged  once again, with a Unit of Oncohematological Resuscitation and Intensive Care for 6 beds established.

Clinical activities

Composition  of  hematological  disorders  treated  at  the  Department changed over years, however, with acute leukemias (AL)  taking  a  leading  place  (54.8%).  Meanwhile,  this  ratio  is increased by 10% in 2015, as compared to 2013, with increased admittance of the patients with acute lymphoblastic leukemias  (increase  by  16.6%  against  2013),  mainly,  due  to  introduction  of  continuous  treatment  protocols,  including  high-dose consolidation phase.

Since 2016, we noted higher admission for the patients with acute promyelocytic leukemia, due to improved diagnostics of  this  leukemia  type,  e.g.,  molecular  genetic  studies  performed  by  FISH  assays  at  the  laboratory  in  St.  Petersburg  (Russia).  The  most  significant  admittance  growth  was  for  bone marrow harvesting, i.e., from 9 cases in 2013 to 55 in 2016,  due  to  establishment  and  development  of  bone  marrow transplantation in the country.

Along with leukemias, we observed a significant increase in hospitalized  patients  with  lymphoproliferative  disorders  is,  i.e.,  with  non-Hodgkin’s  lymphomas  (from  18  to  85  cases),  Hodgkin’s  disease  (from  8  to  60  cases),  and  with  multiple  myeloma (from 23 to 100 subjects).

Bone marrow transplantation

The first bone marrow transplantation at our clinic was performed in 2010. In further time, a weak growth in HSCT was noted,  i.e.,  only  six  in  2011  (including  1  allogeneic  related,  and  1  haploidentical;  nine,  in  2012  (5  allogeneic  and  4,  autologous).  Since  2013,  after  opening  a  clean  block  (6  beds),  we have sufficiently increased the BMT number, i.e., 18 BMT (5 auto, 9 allogeneic compatible, and 4 haploidentical transplants); in 2014, 46 (5 auto-, 9 allogeneic and 4 haploidentical). During next years, a stabilization in HSCT amounts is observed: 2015, 54 BMT, 2016, 52 BMT (Fig.4).

Bone  marrow  was  used  as  a  source  of  stem  cells  in  71  cases  (71 donors for allo-HSCT in 69 recipients), whereas peripheral stem cells were harvested in 73 cases (15 donors for 15 recipients of allo-BMT, and 58 marrow harvests for autologous BMT). Poor stem cell mobilizing ability was revealed in multiple  myeloma  (1  case  after  Cyclophosphamide  injections)  and  2  lymphoma  patients  (DHAP-treatment).  Better  HSC  mobilization  was  performed  with  Etoposide  (in  myeloma  case), and in 1 patient, G-CSF was applied as hemostimulant. In 40 cases, both primed BM and PBSCs were infused to the patients.  Peripheral  stem  cell  harvesting  was  performed  at  the Center of Blood Transfusion in Astana by means of obsolete collection devices (Haemonetics MCS+). At initial steps of  our  transplantation  activities,  we  obtained  inferior  stem  cell harvests, therefore infusing additional amounts of native bone marrow cells. However, the situation has changed since 2016,  after  installation  of  new  equipment  (Terumo  Spectra  Optia), we are able to yield sufficient amounts of peripheral stem cells for transplantation.

figure-4-total-bmt-figures-by-years-at-the-center-of-oncohematology-and-bone-marrow-transplantation.jpg

Figure  4.  Total  BMT  figures  by  years  at  the  Center  of  Oncohematology  and  Bone  Marrow  Transplantation  (Astana,  Kazakhstan).  A  total  of  186  transplants  were  performed. Abscissa, number of transplants; ordinate, year of observation.

The  total  amounts  of  HSCT  do  not  meet  appropriate  Kazakhstan requirements. As seen from EBMT Reports, most European countries perform over 100 transplants per 10 Mio persons. To reach this level, we should make about 200 transplants annually (Table 2).

Table 2. Estimated BMT requirements for Republic of Kazakhstan

table-2-estimated-bmt-requirements-for-republic-of-kazakhstan.jpg

Donor availability

The  ratio  of  haploidentical  transplants  performed  in  our  clinic is increased from 4 BMTs (2013) to 23 transplants in 2015. (Fig. 5). A significant growth in haplo-HSCT is noted in 2015 (23 BMTs, 43%) as compared to 2014 (9 BMTs, 19% of total). However, a lack for HLA-identical donors was evident. According to ASBMT, about 70% of the patients with malignant blood disorder do not have available HLA-identical related donor [1]. A median tine for searching an unrelated donor is ca. 4 months in 50-60% of cases. This term is too long, due to risk of the disease relapse.

There  is  an  imbalance  for  different  BMT  types  (Fig.  6).  The  number of auto-BMT, according to EBMT data, twice exceeds allo-BMT  numbers.  Relative  number  of  auto-BMT  (24%  in  2015)  is  minimal  at  the  Oncohematology  and  Bone  Marrow  Transplantation Department, compared to other types. Haplo-BMT  (43%)  and  allogeneic  BMT  (33)  are  prevailing  here.  Such an imbalance occurs due to deficiency of transplantation beds, low activities of regions by the patient stratification and their selection for bone marrow transplantation.

Therefore,  we  considered  arrangement  of  a  local  hematopoietic stem cell donor registry as a possible solution of this problem. This Registry was established in 2013. Consolidated registry of Russian Federation and Kazakh Republic have been created year later, and, currently, 5500 potential donors from Kazakhstan are introduced to this database. In 2014, a first HLA-identical donor from Kazakhstan was activated in this Registry, and the first unrelated allogeneic transplantation  from  this  donor  was  performed  02.09.2016  at  out  Department.  Arrangement  and  advances  of  the  Bone  Marrow  Donor  Registry  in  our  Republic  are  closely  associated  with  collaboration  and  advices  from  Dr.  Alexander  L.  Alyansky,  Chief of a big Donor Registry at the R. Gorbacheva Research Institute of Children Oncology, Hematology and Transplantation (St. Petersburg).

figure-5-ratios-of-different-transplant-types.jpg

Figure 5. Ratios of different transplant types.

figure-6-time-dynamics-of-bmts-by-several-years-with-respect-to-the-bmt-types.jpg

Figure 6. Time dynamics of BMTs by several years, with respect to the BMT types.

Clinical results of BMT procedures

In 2015, we have performed analysis of total survival among the BMT patients (Fig. 7). This analysis shows a significantly higher  total  survival  in  a  group  of  patients  after  allo-BMT  performed  in  the  1st  remission,  as  compared  to  survival  in  the  group  after  allogeneic  BMT  carried  out  in  the  absence  of remission, i.e., 59% vs 20%. Overall survival after haploidentical BMT is also higher in the patients transplanted in 1st remission, as compared to the patients, undergoing BMT out of remission (41% vs 23%).

Clinical results of BMT proceduresIn 2015, we have performed analysis of total survival among the BMT patients (Fig. 7). This analysis shows a significantly higher  total  survival  in  a  group  of  patients  after  allo-BMT  performed  in  the  1st  remission,  as  compared  to  survival  in  the  group  after  allogeneic  BMT  carried  out  in  the  absence  of remission, i.e., 59% vs 20%. Overall survival after haploidentical BMT is also higher in the patients transplanted in 1st remission, as compared to the patients, undergoing BMT out of remission (41% vs 23%).

figure-7-total-survival-after-allogeneic-bmt-and-haplo-bm.jpg

Figure 7. Total survival after allogeneic BMT and haplo-BMT in the patients with acute leukemias dependent on the state of disease by the time of transplant.

Overall survival (OS) was also determined in a group of patients with acute myeloblastic leukemia. We compared 3 patient groups, Group1, patients receiving chemotherapy only; Group 2 obtained BMT in remission, and Group3, patients receiving  an  off-remission  BMT  (Fig.7).  Overall  survival  among  patients  from  the  2nd  group  was  sufficiently  higher  than  for  groups  1  and  3,  i.e.,  10%  vs  60%.  However,  OS  among  the  patients  after  BMT  beyond  remission  was  twofold higher than among subjects getting chemotherapy only (20% vs 10%).

Preliminary  analysis  of  overall  survival  among  acute  leukemia patients (observed for 30 months in haplo-HSCT, or 40 months in allo-HSCT) has shown an important role of the disease status by the time of BMT, thus being in full accordance with available international data. Our results should be further  analysed  for  5-year  survival  in  a  group  of  ≥30  patients [2, 3, 4].

figure-8-overall-survival-among-patients-with-acute-leukemias-aml-and-all.jpg

Figure 8. Overall survival among patients with acute leukemias (AML and ALL), when performing standard chemotherapy (left) and allo-HSCT at our BMT Department (right).

Despite the arrangement of ‘clean unit’, and BMT numbers increased to 54 in 2015, high requirements for transplantation remain in the country. E.g., according to statistical data (Table 2), 152 patients in Kazakhstan need BMT yearly, either allogeneic  or  autologous  procedure.  Acute  leukemias  (77  BMTs  per year) are most common at our Department, including 29 ALL cases and 48 AML patients. Multiple myeloma takes next position (31 BMT annually), followed by aplastic anemia (14 BMTs),  myelodysplastic  syndromes  (n=12)  and  non-Hodgkin’s  lymphomas  (n=12),  as  well  as  Hodgkin’s  lymphoma  (6  BMTs yearly). To cover these requirements, we are planning increase in patient places (beds), with subsequent expansion of the ‘clean’ space from 6 to 15 beds.

Cooperation with clinics abroad

A  big  contribution  to  development  of  the  Oncohematology  Department  and  BMT  activity  was  made  by  the  staff  of  the R. Gorbacheva Research Institute of Children Oncology, Hematology and Transplantation at the First I. Pavlov State Medical  University  (St.  Petersburg,  Russia),  having  been  provided over last years. Over 2014-2015, we have trained in St.  Petersburg  four  clinicians  in  Hematology  at  a  postgraduate  course  Current  Hematology  and  Bone  Marrow  Transplantation;  two  clinical  laboratory  doctors  for  diagnostics  of  malignant  blood  disorders,  trained  a  laboratory  doctor  in  clinical  cytogenetics.  Our  collaborators  from  Gorbacheva Institute have teached a specialist in hematopoietic stem cells harvesting, treatment and cryoconservation; performed educational courses for 5 clinical hematolologists at the VIII and  IX  R.  Gorbacheva  Memorial  Symposia  (2014,  2015,  St. Petersburg).

Moreover,  some  specialists  from  St.  Petersburg  R.  Gorbacheva  Memorial  Institute  performed  in  Kazakhstan  several seminars and master classes over 2014, e.g., in flow cytometry for detection of minimal residual disease (Babenko Elena  V.,  2014);  arrangement  of  hematological  services  in  Kazakhstan  (Morozova  Elena  V.,  Bondarenko  Sergey  N.,  Darskaya  Elena  I.);  a  4-week  tutorial  concerning  Basics  of  Modern Diagnostics and Treatment in Oncohematology which took place in Almaty (Kazakhstan).

A  special  longitudinal  cooperation  is  performed  in  the  field  of  arrangement  of  a  Bone  Marrow  Donor  Registry  in  Kazakhstan  Republic.  A  common  Russian-Kazakh  donor  search platform is arranged in order to recruit bone marrow donors from Russian Registry for Kazakh patients.

Some   other   tutorials   were   performed   in   2015,   including   a   school   for   paroxysmal   nocturnal   hemoglobinuria   (Babenko E. V., Kulagin A. D., held in St. Petersburg), a master class by E. V. Babenko concerning immune phenotyping of PNH markers (April 2015, Astana, Kazakhstan); an expert council on invasive fungal invasions in hematology (13 May, 2015, Research Institute of Pediatrics and Children Surgery, Prof.  K.  O.  Omarova,  N.  N.  Klimko,  PhD  M.  O.  Popova). A  tutorial  “Hematopoietic  stem  cell  transplantation  in  the  children  with  oncohematological  diseases  and  orphan  diseases” was performed on May 25-30, 2015, in Astana, led by Dr. S. N. Bondarenko), followed by a master class: Arrangement  of  a  Bone  Marrow  Donor  Registry  (May  26-28,  2015,  Astanа, led by Dr. A. L. Alyansky).Further prospectivesFuture cooperation between the 1st St. Petersburg State Medical  I.  Pavlov  University  and  hematological  institutions  in  St. Petersburg and Kazakhstan in the field of hematopoietic transplantation should be developed in the abovementioned directions:

  1. Hematopoietic  transplantation  in  pediatric  practice  and  adult patients.

    1. Further development of diagnostic base in oncohematology  (morphology,  immunohistochemistry,  immune  phenotyping, cytogenetics, molecular diagnostics).

    2. Unified and improved diagnostic and therapeutic protocols, in order to assess and treat tumor and non-tumor blood diseases.

    3. Orphan dieases (diagnostics, registries, bone marrow transplantation, target therapy).

  2. Functioning of a common Bone Marrow Donor Registry.

Our plans for the nearest future are connected with meeting the requirements of Kazakh patients in transplantation assistance, e.g., an increase of clinical facilities by 5 hospital beds, and  opening  a  special  block  for  therapy  of  lymphoproliferative disorders with 15 beds, as well as expansion of critical care unit to 9 beds. Increasing number of patients needs arrangement of outpatient service and polyclinics.

Conflicts of interest

The authors have no conflict of interest to declare.

References

  1. Bayraktar  UD,  Champlin  RE,  Ciurea  SO.  Progress  in  haploidentical stem cell transplantation. Biol Blood Marrow Transplant 2012; 18:372-380.

  2. Olifirovich A, Pivovarova I, Kemaykin V, Klodzinskiy A, Nemerovchenko  A,  Tussipova  A,  Vildanova  R,  Sataeva  M,  Kolesnev A, Iskakova A. Remission at secondary acute myeloid leukemia after haploidentical stem cells microtransplantation (a clinical case); Abstract XXXV World Congress International Society of Hematology, Sept. 4-7, Beijing, China, 2014: 133, ЕР-05-001.

  3. Pivovarova  IA,  Klodzinsky  AA,  Kemaikin  VM,  Olifirovich  AA,  Kolesnev  AV,  Iskakova  AM,  Sataeva  MS.  Lethality  trends  after  haploidentical  hematopoietic  stem  cell  transplantation.  Kazakhstanskaya  Transplantologiya,  2014;  No1:46-53.

  4. Vildanova   R,   Pivovarova   I,   Klodzinskiy   A,   Kemaikin  V,  Kolesnev  A,  Sataeva  M,  Iskakova  A,  Olifirovich  A,  Tussipova  A,  Nemerovchenko  A.  BeEAM  as  conditioning  regimen for haploidentical bone marrow transplantation in patients  with  Ph-positive  ALL  (two  case  reports);  Abstract  XXXV  World  Congress  International  Society  of  Hematology, Sept. 4-7, Beijing, China, 2014: 124, ЕР-04-001.

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Introduction

The Unit of Oncohematology and Bone Marrow Transplantation  (BMT)  was  arranged  on  basis  of  the  Republican  Research Center of Hospital Emergencies SC (Astana, Republic of Kazakhstan) in August 2010, using previous clinical experience  of  the  regional  hematologists.  At  the  beginning,  our  unit consisted of ten hospital beds for chemotherapy of leukemia  and  lymphomas.  First  bone  marrow  transplantation  in  Kazakhstan  was  performed  just  on  the  basis  of  our  specialized unit. Time sequence of our main advances is shown in Table 1.

Table 1. Main steps in development of Oncohematology Unit

table-1-main-steps-in-development-of-oncohematology-unit.jpg

Invaluable  support  and  contribution  to  the  development  of  the  BMT  Unit  should  be  mentioned.  Our  activities  were  supported  by  Professor  Boris  Afanasyev,  Director,  R.  Gorbacheva  Memorial  Research  Institute  of  Children  Oncology, Hematology and Transplantation at the St. Petersburg I. Pavlov  State  Medical  University.  Several  leading  specialists  from the Gorbacheva Institute, e.g., Professor Alexander D. Kulagin, Dr. Sergey N. Bondarenko, Dr. Vladimir N. Vavilov worked hardly at Astana, in order to consult severe patients, arrange  optimal  transplantation  regimens,  analyze  difficult  clinical cases, perform master classes and conferences. This collaboration  has  been  sufficiently  promoted  by  Dr.  Irina  Pivovarova whose contribution to these advances should be highly evaluated.

Since  01.03.2013,  the  Department  was  rearranged  to  the  Unit  of  Hemoblastoses,  Hematopoietic  Aplasias  and  BMT,  followed by extension to 25 beds, with appropriately trained staff.  The  unit  is  a  part  of  Hematology  and  Transfusiology  Department.

Deep renovation of the hospital building (April to September 2013) resulted into opening of aseptic wards with laminar air flow, including BMT unit with six beds and an intensive care unit of four hospital beds.

In September 2013, the Institute of Children Oncology, Hematology  and  Transplantation  (St.  Petersburg,  Russia),  together with our Department, performed the VII Memorial R. Gorbacheva International Symposium with a main topic: Hematopoietic Stem Cell Transplantation in Children and Adults. This event has promoted further development of BMT in Republic of Kazakhstan, and broadening of international cooperation  in  the  field.  Due  to  these  advances,  Kazakhstan  first  appeared at the EBMT map, with a total of 46 transplants in 2013 (Fig. 1). The Memorial Symposium attracted prominent specialists from Europe and USA (Fig. 2, 3).

Figure 1. Allogeneic stem cell transplants per 10,000,000 inhabitants: an EBMT map for 2013 (EBMT Report, 2013).

Figure 1. Allogeneic stem cell transplants per 10,000,000 inhabitants: an EBMT map for 2013 (EBMT Report, 2013).

figure-2-participants-at-the-vii-r-gorbacheva-memori-.jpg

Figure 2. Participants at the VII R. Gorbacheva Memorial International Symposium in Hematology and transplantation in Astana (September 2013).

figure-3-international-team-of-hematologists-visiting-the-new-bmt-department-in-astana.jpg

Figure 3. International team of hematologists visiting the new BMT Department in Astana (September 2013).

Since July 4, 2014, a Clinical Department with 69 beds was arranged,  and  the  Centre  was  renamed  to  the  National  Research Centre for Oncology and Transplantation SC. An oncohematological and BMT Department consisted of a Transfusion Unit and Oncohematology Unit with an intensive care ward  (4  beds).  20.09.2016,  the  Department  was  rearranged  once again, with a Unit of Oncohematological Resuscitation and Intensive Care for 6 beds established.

Clinical activities

Composition  of  hematological  disorders  treated  at  the  Department changed over years, however, with acute leukemias (AL)  taking  a  leading  place  (54.8%).  Meanwhile,  this  ratio  is increased by 10% in 2015, as compared to 2013, with increased admittance of the patients with acute lymphoblastic leukemias  (increase  by  16.6%  against  2013),  mainly,  due  to  introduction  of  continuous  treatment  protocols,  including  high-dose consolidation phase.

Since 2016, we noted higher admission for the patients with acute promyelocytic leukemia, due to improved diagnostics of  this  leukemia  type,  e.g.,  molecular  genetic  studies  performed  by  FISH  assays  at  the  laboratory  in  St.  Petersburg  (Russia).  The  most  significant  admittance  growth  was  for  bone marrow harvesting, i.e., from 9 cases in 2013 to 55 in 2016,  due  to  establishment  and  development  of  bone  marrow transplantation in the country.

Along with leukemias, we observed a significant increase in hospitalized  patients  with  lymphoproliferative  disorders  is,  i.e.,  with  non-Hodgkin’s  lymphomas  (from  18  to  85  cases),  Hodgkin’s  disease  (from  8  to  60  cases),  and  with  multiple  myeloma (from 23 to 100 subjects).

Bone marrow transplantation

The first bone marrow transplantation at our clinic was performed in 2010. In further time, a weak growth in HSCT was noted,  i.e.,  only  six  in  2011  (including  1  allogeneic  related,  and  1  haploidentical;  nine,  in  2012  (5  allogeneic  and  4,  autologous).  Since  2013,  after  opening  a  clean  block  (6  beds),  we have sufficiently increased the BMT number, i.e., 18 BMT (5 auto, 9 allogeneic compatible, and 4 haploidentical transplants); in 2014, 46 (5 auto-, 9 allogeneic and 4 haploidentical). During next years, a stabilization in HSCT amounts is observed: 2015, 54 BMT, 2016, 52 BMT (Fig.4).

Bone  marrow  was  used  as  a  source  of  stem  cells  in  71  cases  (71 donors for allo-HSCT in 69 recipients), whereas peripheral stem cells were harvested in 73 cases (15 donors for 15 recipients of allo-BMT, and 58 marrow harvests for autologous BMT). Poor stem cell mobilizing ability was revealed in multiple  myeloma  (1  case  after  Cyclophosphamide  injections)  and  2  lymphoma  patients  (DHAP-treatment).  Better  HSC  mobilization  was  performed  with  Etoposide  (in  myeloma  case), and in 1 patient, G-CSF was applied as hemostimulant. In 40 cases, both primed BM and PBSCs were infused to the patients.  Peripheral  stem  cell  harvesting  was  performed  at  the Center of Blood Transfusion in Astana by means of obsolete collection devices (Haemonetics MCS+). At initial steps of  our  transplantation  activities,  we  obtained  inferior  stem  cell harvests, therefore infusing additional amounts of native bone marrow cells. However, the situation has changed since 2016,  after  installation  of  new  equipment  (Terumo  Spectra  Optia), we are able to yield sufficient amounts of peripheral stem cells for transplantation.

figure-4-total-bmt-figures-by-years-at-the-center-of-oncohematology-and-bone-marrow-transplantation.jpg

Figure  4.  Total  BMT  figures  by  years  at  the  Center  of  Oncohematology  and  Bone  Marrow  Transplantation  (Astana,  Kazakhstan).  A  total  of  186  transplants  were  performed. Abscissa, number of transplants; ordinate, year of observation.

The  total  amounts  of  HSCT  do  not  meet  appropriate  Kazakhstan requirements. As seen from EBMT Reports, most European countries perform over 100 transplants per 10 Mio persons. To reach this level, we should make about 200 transplants annually (Table 2).

Table 2. Estimated BMT requirements for Republic of Kazakhstan

table-2-estimated-bmt-requirements-for-republic-of-kazakhstan.jpg

Donor availability

The  ratio  of  haploidentical  transplants  performed  in  our  clinic is increased from 4 BMTs (2013) to 23 transplants in 2015. (Fig. 5). A significant growth in haplo-HSCT is noted in 2015 (23 BMTs, 43%) as compared to 2014 (9 BMTs, 19% of total). However, a lack for HLA-identical donors was evident. According to ASBMT, about 70% of the patients with malignant blood disorder do not have available HLA-identical related donor [1]. A median tine for searching an unrelated donor is ca. 4 months in 50-60% of cases. This term is too long, due to risk of the disease relapse.

There  is  an  imbalance  for  different  BMT  types  (Fig.  6).  The  number of auto-BMT, according to EBMT data, twice exceeds allo-BMT  numbers.  Relative  number  of  auto-BMT  (24%  in  2015)  is  minimal  at  the  Oncohematology  and  Bone  Marrow  Transplantation Department, compared to other types. Haplo-BMT  (43%)  and  allogeneic  BMT  (33)  are  prevailing  here.  Such an imbalance occurs due to deficiency of transplantation beds, low activities of regions by the patient stratification and their selection for bone marrow transplantation.

Therefore,  we  considered  arrangement  of  a  local  hematopoietic stem cell donor registry as a possible solution of this problem. This Registry was established in 2013. Consolidated registry of Russian Federation and Kazakh Republic have been created year later, and, currently, 5500 potential donors from Kazakhstan are introduced to this database. In 2014, a first HLA-identical donor from Kazakhstan was activated in this Registry, and the first unrelated allogeneic transplantation  from  this  donor  was  performed  02.09.2016  at  out  Department.  Arrangement  and  advances  of  the  Bone  Marrow  Donor  Registry  in  our  Republic  are  closely  associated  with  collaboration  and  advices  from  Dr.  Alexander  L.  Alyansky,  Chief of a big Donor Registry at the R. Gorbacheva Research Institute of Children Oncology, Hematology and Transplantation (St. Petersburg).

figure-5-ratios-of-different-transplant-types.jpg

Figure 5. Ratios of different transplant types.

figure-6-time-dynamics-of-bmts-by-several-years-with-respect-to-the-bmt-types.jpg

Figure 6. Time dynamics of BMTs by several years, with respect to the BMT types.

Clinical results of BMT procedures

In 2015, we have performed analysis of total survival among the BMT patients (Fig. 7). This analysis shows a significantly higher  total  survival  in  a  group  of  patients  after  allo-BMT  performed  in  the  1st  remission,  as  compared  to  survival  in  the  group  after  allogeneic  BMT  carried  out  in  the  absence  of remission, i.e., 59% vs 20%. Overall survival after haploidentical BMT is also higher in the patients transplanted in 1st remission, as compared to the patients, undergoing BMT out of remission (41% vs 23%).

Clinical results of BMT proceduresIn 2015, we have performed analysis of total survival among the BMT patients (Fig. 7). This analysis shows a significantly higher  total  survival  in  a  group  of  patients  after  allo-BMT  performed  in  the  1st  remission,  as  compared  to  survival  in  the  group  after  allogeneic  BMT  carried  out  in  the  absence  of remission, i.e., 59% vs 20%. Overall survival after haploidentical BMT is also higher in the patients transplanted in 1st remission, as compared to the patients, undergoing BMT out of remission (41% vs 23%).

figure-7-total-survival-after-allogeneic-bmt-and-haplo-bm.jpg

Figure 7. Total survival after allogeneic BMT and haplo-BMT in the patients with acute leukemias dependent on the state of disease by the time of transplant.

Overall survival (OS) was also determined in a group of patients with acute myeloblastic leukemia. We compared 3 patient groups, Group1, patients receiving chemotherapy only; Group 2 obtained BMT in remission, and Group3, patients receiving  an  off-remission  BMT  (Fig.7).  Overall  survival  among  patients  from  the  2nd  group  was  sufficiently  higher  than  for  groups  1  and  3,  i.e.,  10%  vs  60%.  However,  OS  among  the  patients  after  BMT  beyond  remission  was  twofold higher than among subjects getting chemotherapy only (20% vs 10%).

Preliminary  analysis  of  overall  survival  among  acute  leukemia patients (observed for 30 months in haplo-HSCT, or 40 months in allo-HSCT) has shown an important role of the disease status by the time of BMT, thus being in full accordance with available international data. Our results should be further  analysed  for  5-year  survival  in  a  group  of  ≥30  patients [2, 3, 4].

figure-8-overall-survival-among-patients-with-acute-leukemias-aml-and-all.jpg

Figure 8. Overall survival among patients with acute leukemias (AML and ALL), when performing standard chemotherapy (left) and allo-HSCT at our BMT Department (right).

Despite the arrangement of ‘clean unit’, and BMT numbers increased to 54 in 2015, high requirements for transplantation remain in the country. E.g., according to statistical data (Table 2), 152 patients in Kazakhstan need BMT yearly, either allogeneic  or  autologous  procedure.  Acute  leukemias  (77  BMTs  per year) are most common at our Department, including 29 ALL cases and 48 AML patients. Multiple myeloma takes next position (31 BMT annually), followed by aplastic anemia (14 BMTs),  myelodysplastic  syndromes  (n=12)  and  non-Hodgkin’s  lymphomas  (n=12),  as  well  as  Hodgkin’s  lymphoma  (6  BMTs yearly). To cover these requirements, we are planning increase in patient places (beds), with subsequent expansion of the ‘clean’ space from 6 to 15 beds.

Cooperation with clinics abroad

A  big  contribution  to  development  of  the  Oncohematology  Department  and  BMT  activity  was  made  by  the  staff  of  the R. Gorbacheva Research Institute of Children Oncology, Hematology and Transplantation at the First I. Pavlov State Medical  University  (St.  Petersburg,  Russia),  having  been  provided over last years. Over 2014-2015, we have trained in St.  Petersburg  four  clinicians  in  Hematology  at  a  postgraduate  course  Current  Hematology  and  Bone  Marrow  Transplantation;  two  clinical  laboratory  doctors  for  diagnostics  of  malignant  blood  disorders,  trained  a  laboratory  doctor  in  clinical  cytogenetics.  Our  collaborators  from  Gorbacheva Institute have teached a specialist in hematopoietic stem cells harvesting, treatment and cryoconservation; performed educational courses for 5 clinical hematolologists at the VIII and  IX  R.  Gorbacheva  Memorial  Symposia  (2014,  2015,  St. Petersburg).

Moreover,  some  specialists  from  St.  Petersburg  R.  Gorbacheva  Memorial  Institute  performed  in  Kazakhstan  several seminars and master classes over 2014, e.g., in flow cytometry for detection of minimal residual disease (Babenko Elena  V.,  2014);  arrangement  of  hematological  services  in  Kazakhstan  (Morozova  Elena  V.,  Bondarenko  Sergey  N.,  Darskaya  Elena  I.);  a  4-week  tutorial  concerning  Basics  of  Modern Diagnostics and Treatment in Oncohematology which took place in Almaty (Kazakhstan).

A  special  longitudinal  cooperation  is  performed  in  the  field  of  arrangement  of  a  Bone  Marrow  Donor  Registry  in  Kazakhstan  Republic.  A  common  Russian-Kazakh  donor  search platform is arranged in order to recruit bone marrow donors from Russian Registry for Kazakh patients.

Some   other   tutorials   were   performed   in   2015,   including   a   school   for   paroxysmal   nocturnal   hemoglobinuria   (Babenko E. V., Kulagin A. D., held in St. Petersburg), a master class by E. V. Babenko concerning immune phenotyping of PNH markers (April 2015, Astana, Kazakhstan); an expert council on invasive fungal invasions in hematology (13 May, 2015, Research Institute of Pediatrics and Children Surgery, Prof.  K.  O.  Omarova,  N.  N.  Klimko,  PhD  M.  O.  Popova). A  tutorial  “Hematopoietic  stem  cell  transplantation  in  the  children  with  oncohematological  diseases  and  orphan  diseases” was performed on May 25-30, 2015, in Astana, led by Dr. S. N. Bondarenko), followed by a master class: Arrangement  of  a  Bone  Marrow  Donor  Registry  (May  26-28,  2015,  Astanа, led by Dr. A. L. Alyansky).Further prospectivesFuture cooperation between the 1st St. Petersburg State Medical  I.  Pavlov  University  and  hematological  institutions  in  St. Petersburg and Kazakhstan in the field of hematopoietic transplantation should be developed in the abovementioned directions:

  1. Hematopoietic  transplantation  in  pediatric  practice  and  adult patients.

    1. Further development of diagnostic base in oncohematology  (morphology,  immunohistochemistry,  immune  phenotyping, cytogenetics, molecular diagnostics).

    2. Unified and improved diagnostic and therapeutic protocols, in order to assess and treat tumor and non-tumor blood diseases.

    3. Orphan dieases (diagnostics, registries, bone marrow transplantation, target therapy).

  2. Functioning of a common Bone Marrow Donor Registry.

Our plans for the nearest future are connected with meeting the requirements of Kazakh patients in transplantation assistance, e.g., an increase of clinical facilities by 5 hospital beds, and  opening  a  special  block  for  therapy  of  lymphoproliferative disorders with 15 beds, as well as expansion of critical care unit to 9 beds. Increasing number of patients needs arrangement of outpatient service and polyclinics.

Conflicts of interest

The authors have no conflict of interest to declare.

References

  1. Bayraktar  UD,  Champlin  RE,  Ciurea  SO.  Progress  in  haploidentical stem cell transplantation. Biol Blood Marrow Transplant 2012; 18:372-380.

  2. Olifirovich A, Pivovarova I, Kemaykin V, Klodzinskiy A, Nemerovchenko  A,  Tussipova  A,  Vildanova  R,  Sataeva  M,  Kolesnev A, Iskakova A. Remission at secondary acute myeloid leukemia after haploidentical stem cells microtransplantation (a clinical case); Abstract XXXV World Congress International Society of Hematology, Sept. 4-7, Beijing, China, 2014: 133, ЕР-05-001.

  3. Pivovarova  IA,  Klodzinsky  AA,  Kemaikin  VM,  Olifirovich  AA,  Kolesnev  AV,  Iskakova  AM,  Sataeva  MS.  Lethality  trends  after  haploidentical  hematopoietic  stem  cell  transplantation.  Kazakhstanskaya  Transplantologiya,  2014;  No1:46-53.

  4. Vildanova   R,   Pivovarova   I,   Klodzinskiy   A,   Kemaikin  V,  Kolesnev  A,  Sataeva  M,  Iskakova  A,  Olifirovich  A,  Tussipova  A,  Nemerovchenko  A.  BeEAM  as  conditioning  regimen for haploidentical bone marrow transplantation in patients  with  Ph-positive  ALL  (two  case  reports);  Abstract  XXXV  World  Congress  International  Society  of  Hematology, Sept. 4-7, Beijing, China, 2014: 124, ЕР-04-001.

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Кемайкин, Анастасия A. Олифирович, Александр В. Колеснев, Анатолий В. Немеровченко, Рузаль Ф. Вильданова, Ольга В. Гайнутдинова, Адия А. Тусипова, Аяужан Е. Есимбекова, Алия K. Баймурзина, Айзат С. Сулейменова, Ольга O. Лесечко, Гульназ Д. Ансатбаева, Мария С. Алимбетова" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(494) "Вадим М. Кемайкин, Анастасия A. Олифирович, Александр В. Колеснев, Анатолий В. Немеровченко, Рузаль Ф. Вильданова, Ольга В. Гайнутдинова, Адия А. Тусипова, Аяужан Е. Есимбекова, Алия K. Баймурзина, Айзат С. Сулейменова, Ольга O. Лесечко, Гульназ Д. Ансатбаева, Мария С. 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С июля 2014 г. организован клинический департамент на 60 коек, и было учреждено АО «Национальный научный Центр онкологии и трансплантации». С 2010 по 2016 гг. начали внедряться различные типы трансплантации гемопоэтических стволовых клеток (ТГСК) – от аутологичной ТКМ до аллогенной ТГСК от совместимых доноров (33% в 2016 г.) и гаплоидентичной ТГСК (43% от общего числа пересадок в 2016 г.). Всего с 2010 г. в отделении проведены 186 ТГСК. Костный мозг в качестве трансплантата использовали в 71 случае (71 донор для алло-ТГСК 69 реципиентам), тогда как периферические стволовые клетки заготавливали в 73 случаях (15 доноров для алло-ТГСК), и 58 заготовок костного мозга для аутологичных ТКМ). Особый вклад в развитие нашей клиники ТКМ и регистра доноров костного мозга внесли ведущие специалисты НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой в Санкт-Петербурге. Эти мероприятия по обучению и образованию позволили организовать эффективную структуру для ТГСК за 3 года. Такая помощь оказывалась по линии консультирования тяжелых клинических случаев, назначения оптимальных режимов трансплантации, анализа сложных клинических случаев, в виде конференций и мастер-классов. <br> <h3>Ключевые слова</h3> Трансплантация гемопоэтических стволовых клеток, организация клиники, Астана, казахстанский опыт.<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2797) "

Резюме

Отделение  онкогематологии  и  трансплантации  костного мозга (ТКМ) было организовано на базе Республиканского научного центра неотложной медицинской помощи (Астана, Республика Казахстан) в августе 2010 г. С июля 2014 г. организован клинический департамент на 60 коек, и было учреждено АО «Национальный научный Центр онкологии и трансплантации». С 2010 по 2016 гг. начали внедряться различные типы трансплантации гемопоэтических стволовых клеток (ТГСК) – от аутологичной ТКМ до аллогенной ТГСК от совместимых доноров (33% в 2016 г.) и гаплоидентичной ТГСК (43% от общего числа пересадок в 2016 г.). Всего с 2010 г. в отделении проведены 186 ТГСК. Костный мозг в качестве трансплантата использовали в 71 случае (71 донор для алло-ТГСК 69 реципиентам), тогда как периферические стволовые клетки заготавливали в 73 случаях (15 доноров для алло-ТГСК), и 58 заготовок костного мозга для аутологичных ТКМ). Особый вклад в развитие нашей клиники ТКМ и регистра доноров костного мозга внесли ведущие специалисты НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой в Санкт-Петербурге. Эти мероприятия по обучению и образованию позволили организовать эффективную структуру для ТГСК за 3 года. Такая помощь оказывалась по линии консультирования тяжелых клинических случаев, назначения оптимальных режимов трансплантации, анализа сложных клинических случаев, в виде конференций и мастер-классов.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, организация клиники, Астана, казахстанский опыт.
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Dr. Vadim M. Kemaikin, Chief, BMT Department, National Research Centre for Oncology and Transplantation, Kerey, Zhanibek Khanov st., 3, Astana, 010000, Republic of Kazakhstan
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Keywords

Hematopoietic stem cell transplantation, clinical advancements, Astana, Republic of Kazakhstan. 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Kemaikin, Anastasiya A. Olifirovich, Alexandr V. Kolesnev, Anatoliy V. Nemerovchenko, Ruzal F. Vildanova, Olga V. Gainutdinova, Adiya A. Tusipova, Ayauzhan E. Esimbekova, Aliya K. Baimursina, Ayzat S. Suleimenova, Olga O. Lesechko, Gulnaz D. Ansatbaeva, Mariya S. Alimbetova" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(283) "Vadim M. Kemaikin, Anastasiya A. Olifirovich, Alexandr V. Kolesnev, Anatoliy V. Nemerovchenko, Ruzal F. Vildanova, Olga V. Gainutdinova, Adiya A. Tusipova, Ayauzhan E. Esimbekova, Aliya K. Baimursina, Ayzat S. Suleimenova, Olga O. Lesechko, Gulnaz D. Ansatbaeva, Mariya S. Alimbetova" ["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(283) "Vadim M. Kemaikin, Anastasiya A. 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This assistance was performed in order to consult severe patients, arrange optimal transplantation regimens, analyze difficult clinical cases, perform master classes and conferences.

Keywords

Hematopoietic stem cell transplantation, clinical advancements, Astana, Republic of Kazakhstan. " ["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(1520) "The Unit of Oncohematology and Bone Marrow Transplantation (BMT) was arranged on basis of the Republican Research Center of Hospital Emergencies SC (Astana, Republic of Kazakhstan) in August 2010. Since July 2014, a Clinical Department with 69 beds was arranged, and National Research Center for Oncology and Transplantation SC was arranged. From 2010 to 2016, the modalities of hematopoietic stem cell transplantation have been advanced, from autologous BMT to allogeneic hematopoietic stem cell transplants (HSCT) from matched donors (33%), and haploidentical HSCTs (43% in 2016), a total of 186 transpants. Bone marrow was used as a source of stem cells in 71 cases (71 donors for allo-HSCT in 69 recipients), whereas peripheral stem cells were harvested in 73 cases (15 donors for 15 recipients of allo-BMT, and 58 marrow harvests for autologous BMT). In particular, our BMT clinic and Bone Marrow Donor Registry developed with invaluable support and contribution by the leading specialists from R. Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation at the St. Petersburg. This system of education and training allowed to arrange an effective HSCT structure within 3 years. This assistance was performed in order to consult severe patients, arrange optimal transplantation regimens, analyze difficult clinical cases, perform master classes and conferences.

Keywords

Hematopoietic stem cell transplantation, clinical advancements, Astana, Republic of Kazakhstan. " } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11180" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-1-30-36" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-1-30-36" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-1-30-36" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11181" ["VALUE"]=> string(137) "Astana experience: Department of Oncohematology and Bone Marrow Transplantation, National Research Center of Oncology and Transplantation" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(137) "Astana experience: Department of Oncohematology and Bone Marrow Transplantation, National Research Center of Oncology and Transplantation" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(137) "Astana experience: Department of Oncohematology and Bone Marrow Transplantation, National Research Center of Oncology and Transplantation" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11257" ["VALUE"]=> array(2) { ["TEXT"]=> string(387) "Bone Marrow Transplantation Department, National Research Center for Oncology and Transplantation, Astana, Republic of Kazakhstan<br> Dr. Vadim M. Kemaikin, Chief, BMT Department, National Research Centre for Oncology and Transplantation, Kerey, Zhanibek Khanov st., 3, Astana, 010000, Republic of Kazakhstan<br> Phone: +7 7172 70 29 41 E-mail: hematology.astana@gmail.com" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(375) "Bone Marrow Transplantation Department, National Research Center for Oncology and Transplantation, Astana, Republic of Kazakhstan
Dr. Vadim M. Kemaikin, Chief, BMT Department, National Research Centre for Oncology and Transplantation, Kerey, Zhanibek Khanov st., 3, Astana, 010000, Republic of Kazakhstan
Phone: +7 7172 70 29 41 E-mail: hematology.astana@gmail.com" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(375) "Bone Marrow Transplantation Department, National Research Center for Oncology and Transplantation, Astana, Republic of Kazakhstan
Dr. Vadim M. Kemaikin, Chief, BMT Department, National Research Centre for Oncology and Transplantation, Kerey, Zhanibek Khanov st., 3, Astana, 010000, Republic of Kazakhstan
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Кемайкин, Анастасия A. Олифирович, Александр В. Колеснев, Анатолий В. Немеровченко, Рузаль Ф. Вильданова, Ольга В. Гайнутдинова, Адия А. Тусипова, Аяужан Е. Есимбекова, Алия K. Баймурзина, Айзат С. Сулейменова, Ольга O. Лесечко, Гульназ Д. Ансатбаева, Мария С. Алимбетова" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(494) "Вадим М. Кемайкин, Анастасия A. Олифирович, Александр В. Колеснев, Анатолий В. Немеровченко, Рузаль Ф. Вильданова, Ольга В. Гайнутдинова, Адия А. Тусипова, Аяужан Е. Есимбекова, Алия K. Баймурзина, Айзат С. Сулейменова, Ольга O. Лесечко, Гульназ Д. Ансатбаева, Мария С. Алимбетова" ["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(494) "Вадим М. Кемайкин, Анастасия A. 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С июля 2014 г. организован клинический департамент на 60 коек, и было учреждено АО «Национальный научный Центр онкологии и трансплантации». С 2010 по 2016 гг. начали внедряться различные типы трансплантации гемопоэтических стволовых клеток (ТГСК) – от аутологичной ТКМ до аллогенной ТГСК от совместимых доноров (33% в 2016 г.) и гаплоидентичной ТГСК (43% от общего числа пересадок в 2016 г.). Всего с 2010 г. в отделении проведены 186 ТГСК. Костный мозг в качестве трансплантата использовали в 71 случае (71 донор для алло-ТГСК 69 реципиентам), тогда как периферические стволовые клетки заготавливали в 73 случаях (15 доноров для алло-ТГСК), и 58 заготовок костного мозга для аутологичных ТКМ). Особый вклад в развитие нашей клиники ТКМ и регистра доноров костного мозга внесли ведущие специалисты НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой в Санкт-Петербурге. Эти мероприятия по обучению и образованию позволили организовать эффективную структуру для ТГСК за 3 года. Такая помощь оказывалась по линии консультирования тяжелых клинических случаев, назначения оптимальных режимов трансплантации, анализа сложных клинических случаев, в виде конференций и мастер-классов. <br> <h3>Ключевые слова</h3> Трансплантация гемопоэтических стволовых клеток, организация клиники, Астана, казахстанский опыт.<br>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2797) "

Резюме

Отделение  онкогематологии  и  трансплантации  костного мозга (ТКМ) было организовано на базе Республиканского научного центра неотложной медицинской помощи (Астана, Республика Казахстан) в августе 2010 г. С июля 2014 г. организован клинический департамент на 60 коек, и было учреждено АО «Национальный научный Центр онкологии и трансплантации». С 2010 по 2016 гг. начали внедряться различные типы трансплантации гемопоэтических стволовых клеток (ТГСК) – от аутологичной ТКМ до аллогенной ТГСК от совместимых доноров (33% в 2016 г.) и гаплоидентичной ТГСК (43% от общего числа пересадок в 2016 г.). Всего с 2010 г. в отделении проведены 186 ТГСК. Костный мозг в качестве трансплантата использовали в 71 случае (71 донор для алло-ТГСК 69 реципиентам), тогда как периферические стволовые клетки заготавливали в 73 случаях (15 доноров для алло-ТГСК), и 58 заготовок костного мозга для аутологичных ТКМ). Особый вклад в развитие нашей клиники ТКМ и регистра доноров костного мозга внесли ведущие специалисты НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой в Санкт-Петербурге. Эти мероприятия по обучению и образованию позволили организовать эффективную структуру для ТГСК за 3 года. Такая помощь оказывалась по линии консультирования тяжелых клинических случаев, назначения оптимальных режимов трансплантации, анализа сложных клинических случаев, в виде конференций и мастер-классов.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, организация клиники, Астана, казахстанский опыт.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2797) "

Резюме

Отделение  онкогематологии  и  трансплантации  костного мозга (ТКМ) было организовано на базе Республиканского научного центра неотложной медицинской помощи (Астана, Республика Казахстан) в августе 2010 г. С июля 2014 г. организован клинический департамент на 60 коек, и было учреждено АО «Национальный научный Центр онкологии и трансплантации». С 2010 по 2016 гг. начали внедряться различные типы трансплантации гемопоэтических стволовых клеток (ТГСК) – от аутологичной ТКМ до аллогенной ТГСК от совместимых доноров (33% в 2016 г.) и гаплоидентичной ТГСК (43% от общего числа пересадок в 2016 г.). Всего с 2010 г. в отделении проведены 186 ТГСК. Костный мозг в качестве трансплантата использовали в 71 случае (71 донор для алло-ТГСК 69 реципиентам), тогда как периферические стволовые клетки заготавливали в 73 случаях (15 доноров для алло-ТГСК), и 58 заготовок костного мозга для аутологичных ТКМ). Особый вклад в развитие нашей клиники ТКМ и регистра доноров костного мозга внесли ведущие специалисты НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой в Санкт-Петербурге. Эти мероприятия по обучению и образованию позволили организовать эффективную структуру для ТГСК за 3 года. Такая помощь оказывалась по линии консультирования тяжелых клинических случаев, назначения оптимальных режимов трансплантации, анализа сложных клинических случаев, в виде конференций и мастер-классов.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, организация клиники, Астана, казахстанский опыт.
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Gastrointestinal damage after HSCT

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is an effective method of treatment of some solid tumors, hematological, autoimmune and hereditary diseases in children and adults, which is based on providing preceding conditioning (cytostatic and/or radiation therapy) with further intravenous administration of hematopoietic stem cells, to restore bone marrow function in cases of its damage or malfunction [24].

Primary disease status at the time of therapy initiation, and degree of HLA—compatibility between the stem cell recipient fections, in particular — pseudo—membranous colitis associated with Clostridium difi'icile which often occur after massive antibiotic therapy. Elimination of normal intestinal microbiota is a sufficient risk factor for GIT GVHD, pseudo—membranous colitis and antibiotic—associated diarrhea post—HSCT. Fecal microbiota transplantation (FMT) from healthy donors allows restoration of a physiological microbial Variability and functional activity of intestinal microbiota leading to eradication of pathogenic microorganisms, therefore abrogating infectious complications.

The efficacy of HSCT is limited by several main factors. First of all, primary or secondary resistance to chemotherapy confers high risk of progression or relapse of underlying disease in the posttransplant period. Second, is the frequent mortality from septic complications of nosocomial multi—drug resistant strains of bacteria, including prevalent Clostridium difi'icile, Klebsiella pneumonia, Pseudomonas aeruginosa and Vancomycin—resistant (VRE). Third, it is immune complications, such as acute and chronic “graft versus host” disease (GVHD), occurring due to affection of recipient tissues and organs by lymphocytes of donor origin [1].

GvHD pathogenesis is based on damage of recipient tissues  that  are  recognized  as  antigens  by  immune  competent  cells   of  the  donor  [6].  GvHD  plays  a  key  role  in  post-transplan- tation  mortality  and  patient’s  quality  of  life.  Most  suscepti- ble tissues to damage usually have high proliferative activity,  such as skin cells, enterocytes and endothelium of small bile  ducts of the liver. In this case, intestinal stem cells and their  niche (Paneth cells) are primary targets of intestinal GvHD,  along with dysbiosis of intestinal microbiota leading to dys- function  of  enterocytes,  bacterial  colonization  and,  conse- quently,  potentiation  of  systemic  inflammatory  response   [18,26]. Intestinal GvHD is manifested by symptoms of diarrhea in its secretory form. This complication is associated by  morphologically seen infiltration of cytotoxic intraepithelial  lymphocytes (CD8+), with damage to mucous epithelial cells  of stomach and/or intestine. Appropriate histological chang- es can vary from lymphoid infiltration of intestinal mucosa  to total destruction of crypts and formation of extensive ne- crotic-ulcerous defects (Fig.1) [13].

figure-1-histology-changes-in-acute-“graft-versus-host-disease”-of-intestine.jpg

Figure 1. Histology changes in acute “graft versus host disease” of intestine [13].
A. Mild degree: focal intraepithelial lymphocytic infiltration (1-2-3 cells, arrows) in part glands with intact integrity and struc- ture of the glands of the mucous membrane.
B. Medium degree: common uneven, often quite abundant lymphocytic infiltration with formation of nuclear foci rexis of epi- thelial cells (arrow) and small foci of subtotal or total destruction of some glands.
C. Severe degree: larger areas of destruction of the mucous membrane, the bottom of defects is loose immature granulation tissue (top right, arrow). Remaining glands are with symptoms of subtotal or total destruction (dotted arrows) or with nuclear rexis of epithelial cells (arrows).

In most cases, gastrointestinal tract (GIT) is a primary organ damaged, thus resulting to enhanced inflammation of immune origin, serious diarrhea, due to GVHD manifestation, and intestinal infections, in particular, pseudo—membranous colitis associated with Clostridium difi'icile associated with massive antibiotic therapy. Consequent elimination of normal intestinal microbiota is among main risk factors for GVHD of GIT, pseudo—membranous colitis and antibiotic—associated diarrhea after HSCT. Frequency of deaths after HSCT is known to be significantly higher in patients with skewed biodiversity of normal microbiota [11].

Intestinal damage after HSCT is clinically manifesting by a maldigestion syndrome which includes anorexia, nausea, vomiting, abdominal pain and diarrhea. These symptoms quickly lead to malfunction of intestinal barrier function, reduced adaptation reserves of the organism, development of protein—energy malnutrition and cachexia.

There are several reasons for high mortality in patients undergoing allo—HSCT. First, long period of pancytopenia which is associated with severe infection complications and requires administration of broad—spectrum antibiotics, which, in turn, leads to partial elimination or lack of normal intestinal microbiota, selection for multi—drug resistant bacterial strains, their subsequent expansion and dominance over normal microbiota (Tab. 1) [20]. Second, intensive chemotherapy and allo—HSCT in most cases leads to altered structure and decreased protective functions of intestinal wall, which is clinically expressed as mucositis which results from direct toxic effects of chemotherapy upon epithelial and Vascular structures of intestine, causing invasion of pathogenic microorganisms into the intestinal wall, in the presence of neutropenia and developing GVHD.

Table 1. Intestinal microbiota: alterations during antibiotic treatment, adapted from Peterson C. et al [20].

table-1-intestinal-microbiota-alterations-during-antibiotic-treatment.jpg

Thus, currently available drugs and technologies for treat- ment Of infectious complications and GVHD do not solve the problem Of early mortality among hematological patients after allo-HSCT. Those patients with severe damage Of di- gestive system are at high risk Of fatal outcome, due to infec- tious complications, metabolic disorders, massive intestinal bleeding and increasing cacheXia, even if achieving com- plete remission Of underlying malignant disease following a successful HSCT.

Positive effects of directed microbiota correction

There are conflicting reports on clinical effects Of intestinal microbiota correction. Some Of these approaches have, how- ever, shown their ability tO prevent complications occurring after organ and cell transplantation (Tab. 2).

Table 2. Results of gut microbial interventions upon results of cell/organ transplantation based on review by Wang et al. [29]

table-2-results-of-gut-microbial-interventions-upon-results-of-cell organ-transplantation.jpg

Human microbiota

Human intestinal microbiota represents a broad set of obligatory and facultative microorganisms that can cause disease in case of suppressed immunity or immunological incompatibility in the host.

There are two kinds of microorganisms classified by their location in the gut: luminal microbiota, which is located in the intestine indigestible dietary fiber and mucosal, adjacent to epithelial cells of the intestine, being integrated into parietal mucin layer. Both luminal and mucosal microbiota may impact the condition of human body, due to their regulatory interactions, and perform many metabolic effects such as detoxification, suppression of pathogenic microorganisms, regulation of immune system, regeneration of epithelium, synthesis of certain Vitamins and essential amino acids, fat metabolism, etc. Dominating intestinal bacteria include 5 types: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria and Verrucomicrobia. Among them, two types of microbes (Bifidobacterium and Lactobacillus) play a crucial role in development of microbiota till the moment of birth (Tab.3).

Table 3. Intestinal microbiota diversity, by Weber et. al. [30]

table-3-intestinal-microbiota-diversity-by-weber-et-al.jpg

Stable composition of intestinal microbiota and regulation of local immune system reactivity are considered the key aspect for its functional activities. One should take into account of short chain fatty acids (acetate, propionate, butyrate) and antimicrobial peptides produced in situ, regulation of formation of T—regulatory cells (Treg) and IgA in bacteria from intestinal lumen. At the level of lamina propria, metabolic maintenance of transforming growth factor (TGFB), integrin CtE (CD103*), dendritic cells, Treg and T—helper (Th17) producing IL—10, IL—22 are important regenerative factors of epithelial cells. At the level of mesenteric lymph node, one should discuss interaction with innate lymphoid cells via a RORyt nuclear receptor, which reduces local inflammation [29]. Preservation of these interactions allows the growth suppression of pathogenic microbiota, eliminate endogenous and exogenous pathogens, maintain structural integrity of intestinal epithelium.

Variability evaluation of intestinal microbiota

Until now, qualitative identification of composed intestinal microbiota, especially anaerobic microorganisms, represents the main problem in diagnostics of many human bacteria that are undetectable by classical bacteriological methods. Implementation of fecal microbiota transplantation (FMT) procedure into clinical practice and its scientific rationale were largely possible due to development of the microbe identification methods by genome next—generation sequencing (NGS) of bacterial DNAs, and, to a lesser extent, by multiplex real—time polymerase chain (e.g. Colonoflor—16) [8]. Development of the s.c. shotgun next—generation sequencing based on differential analysis of bacterial 16S ribosomal RNA and identification of distinct molecular isolates allowed precise DNA profiling of microbiota composition from donor and recipient, therefore, characterizing the most appropriate fecal donors, and evaluating microbiological results of the treatment [16]. This sequencing procedure consists of 4 successive stages: selection of microbial DNAs from feces, amplification by PCR V4—5 plots of the 16S rRNA gene, sequencing, comparing individual results with a database of previously studied samples, for example, from the NCBI Sequence Read Archive database.

Quantitative 16S RNA analysis in patients with sepsis has revealed sufficient shifts of the main microbial types in the stool samples from the intensive care patients [34]. The workers observed scewed diversity of main microbial communities (1 to 4 bacterial taxa) in 30% of the patients. Bacteria associated with the genera Enterococcus and Staphylococcus and the family Enterobacteriaceae comprised the majority of these communities.

As seen from the Figure 2, normal stool specimens (H1, H2, H3, H4, and H5) were characterized by prevalence of Firmicutes and, in most cases, Bacteroidetes, without Proteobacterial abundance (Fig 2. 1A). In a half of ICU patients (ICU1, ICU4, ICU6, ICU9, ICU11, and ICU15), either Proteobacteria or Firmicutes organisms were totally dominant from at least one time point of stool collection (Fig. 1B and C).

In ICU1, ICU11, and ICU15, the authors observed drastic changes in microbial ratios, with Firmicutes being completely replaced by Proteobacteria. The latter phylum predominated also in most stool samples of the patients ICU6 (Fig 2. 1B) and ICU4 (Fig 2. 1C).

figure-2-composition--of-the-gut-microbiome-.jpg

Figure 2. Composition of the gut microbiome at the phylum level determined by molecular analysis of stool samples collected from healthy controls (A), de- ceased ICU patients with severe sepsis (black circles on the time line) (B), and recovered ICU patients (green circles) (C). Dates of stool collection are displayed in numbered quadrants [34].

Hence, the gross shifts in microbial composition in critically ill patients with clinical signs of sepsis are, mainly, unidirectional, leading to exhaustion of large microbial philae. However, these changes seem to be quite heterogenous and need further clarification for bacterial types associated with worse clinical prognosis.

Under common clinical conditions, however, diagnostics of bacterial dysbiosis is performed for planning different therapeutic measures, including clinical FMT effects. Evaluation of gastrointestinal microflora and mucosa is, generally, performed by means of the following microbiological methods:

— conventional bacteriological tests (microscopy, seeding, assessment of antibiotic resistance).

— biopsy of stomach and/or intestine mucosa with subsequent histology and immunophenotyping of local lymphocytes; verification of infectious lesions at the intestinal mucosa;

— definition of Clostridium difi'icile toxin A and B in stool;

— fecal calprotectin in stool etc.

Fecal microbiota transplantation

In the recent years, FMT was actively developing as a meth- od  to  restore  functional  and  anatomical  integrity  of  intes- tinal  microbiota  in  appropriate  clinical  situations  (Fig.3)   [12,14,21,].

Typical  changes  of  intestinal  microbiota  in  inflammatory   bowel  diseases  include  reduced  diversity  of  obligate  micro- organisms, especially, deficiency of Firmicutes and Bacteroidetes [3]. Ultimately, this leads to lack of butyrate synthesis  by Faecalibacterium  prausnitzii.  This  metabolite  is  a  local  anti-inflammatory agent, acting via IL-8 inhibition [25]. The main known mechanisms of FMT action include com- petition for nutrients, direct inhibition of excessive pathogen  growth,  modulation  of  host  immune  system  by  interaction   with  normal  microbiota.  FMT  seems  to  be  more  effective,   than use of probiotic preparations, in restoring altered intes- tinal microbiota, since the latter is unable to colonize intesti- nal space for an extended period.

FMT also allows correction of both microbiota in digestive  ways,  and  microbial  spectrum  of  other  body  areas  (mouth,   lungs, urinary routes, etc.) to less pathogenic species which  are  more  sensitive  to  antibiotics.  This  effect  can  be  used  to   eradicate   antibiotic-resistant   pathogenic   bacteria   strains    based  on  natural  competition  and  antagonism  between  the   microorganisms [8].

In 2014, a meta-analysis of clinical studies showed that FMT  was effective in 87% of diarrhea cases (a total of 536 patients)  caused  by  Clostridium  difficile,  with  primary  resistance  to   prior  therapy  with  metronidazole  and  vancomycin  [2].  The   transplant administration route was an important factor af- fecting  treatment  outcomes,  i.e.,  the  microflora  delivery  to   the  stomach  yielded  81%  of  clinical  success;  to  duodenum,   86%; via  ascending  part  of  the  colon  (with  fibrocolonosco- py),  93%  response;  to  descending  colon  by  means  of  deep   enema, 84% of successful treatment.

A subsequent review article discussed 45 clinical studies (112  patients), showing ambiguous FMT efficiency in inflamma- tory bowel disease, i.e., only 0 to 68% of the patients achieved  clinical remission [22]. The authors noted that possible fail- ure of FMT could be connected, on the one hand, with poor  state of donor’s microbiota, especially, reduced microbial di- versity.  On  the  other  hand,  severe  malfunction  of  patient’s   GIT with high values of the Mayo scores could also influence  the outcomes.

The attempts of clinical FMT implementation are carried out  not only in clinical conditions related to intestinal infections,  but also presumed irregularities between altered microbiota  and immune system imbalance, such as irritable bowel syn- drome, rheumatoid arthritis, diabetes type 2, autism, chronic  fatigue syndrome, multiple sclerosis and Parkinson’s disease  [5]. There are single reports on FMT performed in order to  treat sepsis with multiple organ dysfunction syndrome, and  to eliminate vancomycin-resistant bacteria [32].

figure-3-fecal-microbiota-transplantation-scheme.jpg

Figure 3. Fecal microbiota transplantation scheme [15].

Increasing number of clinical research reporting successful outcomes of FMT in various diseases is accompanied by arrangement of the first specialized biobank in 2012. This USA—based facility was established for storage of fecal samples for FMT. Currently, the biobank is linked to more than 750 clinics at all the 50 USA states providing an opportunity for a constant access to the samples of donor fecal microbiota. The method was adopted and regulated by the US Food and Drug Administration (FDA). In 2013, this body has approved FMT as a therapeutic method for treatment of refractory infections associated with Clostridi'um difi'icile, for controlled clinical studies (“policy with respect to the investigational new drug requirements for use of fecal microbiota transplantation to treat Clostridi'um difi'ici'le infection not responding to standard treatment”) [27].

On the basis of clinical research, FMT was included to the Guidelines issued by European Society of Clinical Microbiology and Infectious Diseases (ECMID) concerning treatment of Vancomycin—resistant (VRE) infections caused by Clostridium difi'icile, at the AI level of evidence [4]. However, infections associated with Clostridi'um difi'icile, are just among potential indications for the FMT usage. Similarly, the FMT use was approved by the European Crohn’s and Colitis Organization as an approach to treatment of chronic nonspecific inflammatory bowel diseases [21].

Similarly, FMT can significantly modulate immune function and have positive effects on other GIT inflammatory processes of immune origin, in particular, resistant graft—versushost—disease GVHD of intestine. In fact, several researchers confirm that preventive use of FMT leads to a decreased risk of infectious complications during treatment of hematological diseases [16].

Despite some encouraging results of FMT—assisted treatment, it is still rarely used in severely immunocompromised patients, e.g., after alloHSCT. This may be due to low performance status of HSCT recipients, severely damaged gastrointestinal mucosa associated with infectious complications and risk of microbial dissemination with a transplanted donor microbiota. However, it is important to mention, that the transplanted microorganisms potentially substitute multi—drug resistant flora due to natural antagonism and improve the control over infectious complications with standard antibiotics.

Donor selection and transplant delivery of fecal microbiota

Optimal donor selection for FMT is still an uncertain aspect in FMT implementation. Some medical, ethical and economic issues should be resolved, e.g., which kind of graft will be indicated in certain cases, either being related, unrelated or autologous. From economic and ethical viewpoints, an optimal solution is to use autologous source of transplant. However, qualitative composition of a patient’s microbiota is often changed dramatically after previous courses of chemoand antibiotic therapy. Allogeneic donors may be found among healthy relatives: mother, father, siblings. However, “healthy” donor is not yet proven to be the best option for HSCT patient. Development of relevant biobanks will help to resolve the problem of a donor search/selection.

To perform a successful FMT, it is necessary to follow several factors. First of all, an accurate donor selection, must match, on the one hand, classical infectious requirements for allogeneic donor, and should not have any GIT comorbidities or oncologic diseases. On the other hand, the transplant should possess a normally present, diverse intestinal microbiota free of certain virulent pathogens. The standard technology of graft preparation should be used. Is it well developed and tested depending on the form of its delivery, and necessity of long—term storage [28].

Another important factor determining efficiency depends on the transplant delivery route. Currently, there are several options: introduction of donor microbiota to the upper GIT by means of oral capsules; bringing it to the stomach via a gastroscope channel; microbiota delivery to duodenal space with a nasointestinal tube or PEG gastrostomy; delivery to colon, using deep enema, or by means of colonoscopy [33]. Each method has its indications and advantages but, from the point of “engraftment” probability, a multiple delivery to the coecal region by means of colonoscopy is now considered to be the most effective approach (93%). The delivery technologies evolve continuously, aiming at both improving efficiency and increasing patient comfort. E.g., transendoscopic delivery to the cecum with pin—assisted tube fixation, and use of oral capsules are the most promising procedures now [19]. Another important question is the necessity of anesthesia upon delivery of donor’s transplant. In our opinion, the use of medical sedation is required not only for children, but in adults as well, for ethical reasons and better compliance.

Of the new trends, different methods of preparing matrices for transplanted microorganisms should be mentioned, for example, usage of pectin carriers, to increase fermentation activity of the dietary fibers, with synthesis of short chain fatty acids, thus allowing faster multiplication of the donor microorganisms [31].

Features of fecal microbiota transplantation in hematopoietic stem cell transplantation

Allo—HSCT negatively influences patient’s normal microbiota, due to a number of specific factors, e.g., low—microbial diets, often leading to the development of malnutrition; intestinal decontamination associated with eradication of obligate microorganisms, application of cytotoxic drugs and/ or radiation that damage GIT epithelial cells. Along with antibiotic therapy, the above factors lead to severe alterations of bacterial microbiota, development of pathogenic multidrug—resistant microbiota, presumably increasing the risk of acute GVHD [10,23].

Worldwide clinical experience shows, that GVHD of intestine treatment with basic immunosuppressive drugs of different generations is often insufficient to prevent excessive inflammatory response and relief of a diarrhea syndrome. Systemic antibiotic therapy, oral decontamination with non—absorbable antibiotics is ineffective for a significant number of patients with detectable colonization with Clostridium diffici'le. Up to 40% of patients with infection associated with Clostridium difi'icile, are resistant to metronidazole or vancomycin therapy [7]. Massive use of antibiotics post—HSCT leads to significant disturbances of intestinal microbiota homeostasis, whereas use of probiotic bacterial formulae may be ineffective due to their inability to colonize the intestinal spaces for an extended time period.

According to our data, diarrhea after allo—HSCT is observed in 79% of cases and can persist for several months, thus eventually leading to development of cachexia and lethal infectious complications. At the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation, we have a successful experience of FMT in four patients after allo—HSCT — adults (n:2) and children (n:2) with prolonged severe diarrheal syndrome, due to immune and infectious complications [8].

Hence, the general idea of using FMT in HSCT looks promising in many aspects: prevention and treatment of infectious complications, prophylaxis of a malabsorption syndrome, and prevention of cachexia, as well as the treatment of steroid—resistant intestinal forms of acute GVHD [12].

Conclusion

A significantly decreased survival is observed in cases of post—HSCT infectious complications resistant to standard antimicrobial therapy, due to increasing mortality caused by septic conditions, usually associated with pathogenic microorganisms: Klebsiella pneumoniae, Pseudomonas aeruginosa, Clostridium difi'icile, Acinetobacter baumannii. Prolonged antibiotic therapy seems to be a key factor leading to multi—drug resistance of some gut bacteria which in turn, may be a trigger to a severe GVHD. Development of intestinal GVHD in most cases leads to the inability of adequate nutrition, along with a maldigestion and malabsorption syndrome, which ultimately leads to protein—energy malnutrition, cachexia and reduced quality of life. Both in sepsis and GVHD, severe changes are observed in qualitative composition and ratios of microbiota living in human gut and other areas of the body.

Initial clinical experience with effective and safe FMT treatment in heavily pretreated category of patients allows to consider this method complementary additional or, in some cases, an alternative technology of therapy for infectious and immune complications after allo—HSCT. FMT results into changes of intestinal microbiota composition, which may help to eradicate multi—drug resistant gut infections, e.g., Clostridium difi'icile, Klebsiella pneumoniae, to reduce antibiotic—associated diarrhea, to replace resistant bacterial species in other areas of the body, and to change microbial profile to a less—virulent landscape.

Further implementation of FMT in clinical practice requires a detailed study, including optimization of criteria for the therapy initiation, selection of the most matched donors by means of multiplex DNA diagnostics, or next—generation DNA sequencing of microbiota, evaluation of long—term efficacy and safety of the transplants.

Conflict of interests

The authors have no conflict of interest to declare.

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  22. Rossen NG, McDonald IK, deVries EM, D’Haens GR, de Vos WM, Zoetendal EG, Ponsioen CY. Faecal microbiota transplantation as novel therapy in gastroenterology: A systematic review. World I Gastroenterol 2015; 21:5359—5371.

  23. Shono Y. Intestinal microbiota related effects on graft versus host disease. Int I Hematol 2015; 101; 428—437.

  24. Slavin, S. New strategies for bone marrow transplantation. Curr Opin Immunol 2000; 12: 542—551.

  25. Sokol H. Faecalibacterium prausnitzii is an anti—inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Nat Acad Sci USA 2008; 105(43): 16731—16736.

  26. Teshima T, Reddy P, Zeiser R. Acute graft—versus—host disease: novel biological insights. Biol Blood Marrow Transplant 2016; 22(1):11—16.

  27. US. Food and Drug Administration. Guidance for Industry. Enforcement policy regarding investigational new drug requirements for use of fecal microbiota for transplantation to treat Clostridium difficile infection not responsive to standard therapies. Dept Health and Human Services, Iuly 2013. http://www.fda.goV/BiologicsBloodVaccines/ GuidanceComplianceRegulatoryInformation/Guidances/ Vaccines/ucm361379.htm

  28. van Nood E, Speelman P, Kuijper EI, Keller II. Struggling with recurrent Clostridium difficile infections: is donor faeces the solution? Eurosurveillance 2009; 14(34):1—6.

  29. Wang M], Xu S, Ren Z, Iiang I, Zheng S. Gut microbiota and allogeneic transplantation. I Transl Med 2015; 13(275): 2— 1 1.

  30. Weber D., Ienq R., Hiergeist A., Oefner P, Dettmer K., Weber M., Koestler I., Gessner A., Taur Y., van den Brink M., Pamer E., Wolff D., Hahn I., Herr W, Holler E. Early systemic broad spectrum antibiotic treatment increases risk of graft versus host disease and treatment—related mortality after allogeneic stem cell transplantation — possible role of indirect effects by microbiome disruption. Bone Marrow Transplant 2016; 51(1); 3—4.

  31. Wei Y. Pectin enhances the effect of fecal microbiota transplantation in ulcerative colitis by delaying the loss of diversity of gut flora. BMC Microbiol 2016; 16: 1—9.

  32. Wei Y. Successful treatment with fecal microbiota transplantation in patients with multiple organ dysfunction syndrome and diarrhea following severe sepsis. Critical Care 2016; 20: 332.

  33. Youngster 1. Oral, frozen fecal microbiota transplant (FMT) capsules for recurrent Clostridium difficile infection. BMC Medicine 2016; 14:134.

  34. Zaborin A, Smith D, Garfield K, Quensen J, Shakhsheer B,  Kade  M,  Tirrell  M,  Tiedje  J,  Gilbert  JA,  Zaborina  O,  Alverdy  JC.  Membership  and  behavior  of  ultra-low-diversity pathogen communities present in the gut of humans during prolonged critical illness. MBio 2014; 5(5): e01361-14.

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Gastrointestinal damage after HSCT

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is an effective method of treatment of some solid tumors, hematological, autoimmune and hereditary diseases in children and adults, which is based on providing preceding conditioning (cytostatic and/or radiation therapy) with further intravenous administration of hematopoietic stem cells, to restore bone marrow function in cases of its damage or malfunction [24].

Primary disease status at the time of therapy initiation, and degree of HLA—compatibility between the stem cell recipient fections, in particular — pseudo—membranous colitis associated with Clostridium difi'icile which often occur after massive antibiotic therapy. Elimination of normal intestinal microbiota is a sufficient risk factor for GIT GVHD, pseudo—membranous colitis and antibiotic—associated diarrhea post—HSCT. Fecal microbiota transplantation (FMT) from healthy donors allows restoration of a physiological microbial Variability and functional activity of intestinal microbiota leading to eradication of pathogenic microorganisms, therefore abrogating infectious complications.

The efficacy of HSCT is limited by several main factors. First of all, primary or secondary resistance to chemotherapy confers high risk of progression or relapse of underlying disease in the posttransplant period. Second, is the frequent mortality from septic complications of nosocomial multi—drug resistant strains of bacteria, including prevalent Clostridium difi'icile, Klebsiella pneumonia, Pseudomonas aeruginosa and Vancomycin—resistant (VRE). Third, it is immune complications, such as acute and chronic “graft versus host” disease (GVHD), occurring due to affection of recipient tissues and organs by lymphocytes of donor origin [1].

GvHD pathogenesis is based on damage of recipient tissues  that  are  recognized  as  antigens  by  immune  competent  cells   of  the  donor  [6].  GvHD  plays  a  key  role  in  post-transplan- tation  mortality  and  patient’s  quality  of  life.  Most  suscepti- ble tissues to damage usually have high proliferative activity,  such as skin cells, enterocytes and endothelium of small bile  ducts of the liver. In this case, intestinal stem cells and their  niche (Paneth cells) are primary targets of intestinal GvHD,  along with dysbiosis of intestinal microbiota leading to dys- function  of  enterocytes,  bacterial  colonization  and,  conse- quently,  potentiation  of  systemic  inflammatory  response   [18,26]. Intestinal GvHD is manifested by symptoms of diarrhea in its secretory form. This complication is associated by  morphologically seen infiltration of cytotoxic intraepithelial  lymphocytes (CD8+), with damage to mucous epithelial cells  of stomach and/or intestine. Appropriate histological chang- es can vary from lymphoid infiltration of intestinal mucosa  to total destruction of crypts and formation of extensive ne- crotic-ulcerous defects (Fig.1) [13].

figure-1-histology-changes-in-acute-“graft-versus-host-disease”-of-intestine.jpg

Figure 1. Histology changes in acute “graft versus host disease” of intestine [13].
A. Mild degree: focal intraepithelial lymphocytic infiltration (1-2-3 cells, arrows) in part glands with intact integrity and struc- ture of the glands of the mucous membrane.
B. Medium degree: common uneven, often quite abundant lymphocytic infiltration with formation of nuclear foci rexis of epi- thelial cells (arrow) and small foci of subtotal or total destruction of some glands.
C. Severe degree: larger areas of destruction of the mucous membrane, the bottom of defects is loose immature granulation tissue (top right, arrow). Remaining glands are with symptoms of subtotal or total destruction (dotted arrows) or with nuclear rexis of epithelial cells (arrows).

In most cases, gastrointestinal tract (GIT) is a primary organ damaged, thus resulting to enhanced inflammation of immune origin, serious diarrhea, due to GVHD manifestation, and intestinal infections, in particular, pseudo—membranous colitis associated with Clostridium difi'icile associated with massive antibiotic therapy. Consequent elimination of normal intestinal microbiota is among main risk factors for GVHD of GIT, pseudo—membranous colitis and antibiotic—associated diarrhea after HSCT. Frequency of deaths after HSCT is known to be significantly higher in patients with skewed biodiversity of normal microbiota [11].

Intestinal damage after HSCT is clinically manifesting by a maldigestion syndrome which includes anorexia, nausea, vomiting, abdominal pain and diarrhea. These symptoms quickly lead to malfunction of intestinal barrier function, reduced adaptation reserves of the organism, development of protein—energy malnutrition and cachexia.

There are several reasons for high mortality in patients undergoing allo—HSCT. First, long period of pancytopenia which is associated with severe infection complications and requires administration of broad—spectrum antibiotics, which, in turn, leads to partial elimination or lack of normal intestinal microbiota, selection for multi—drug resistant bacterial strains, their subsequent expansion and dominance over normal microbiota (Tab. 1) [20]. Second, intensive chemotherapy and allo—HSCT in most cases leads to altered structure and decreased protective functions of intestinal wall, which is clinically expressed as mucositis which results from direct toxic effects of chemotherapy upon epithelial and Vascular structures of intestine, causing invasion of pathogenic microorganisms into the intestinal wall, in the presence of neutropenia and developing GVHD.

Table 1. Intestinal microbiota: alterations during antibiotic treatment, adapted from Peterson C. et al [20].

table-1-intestinal-microbiota-alterations-during-antibiotic-treatment.jpg

Thus, currently available drugs and technologies for treat- ment Of infectious complications and GVHD do not solve the problem Of early mortality among hematological patients after allo-HSCT. Those patients with severe damage Of di- gestive system are at high risk Of fatal outcome, due to infec- tious complications, metabolic disorders, massive intestinal bleeding and increasing cacheXia, even if achieving com- plete remission Of underlying malignant disease following a successful HSCT.

Positive effects of directed microbiota correction

There are conflicting reports on clinical effects Of intestinal microbiota correction. Some Of these approaches have, how- ever, shown their ability tO prevent complications occurring after organ and cell transplantation (Tab. 2).

Table 2. Results of gut microbial interventions upon results of cell/organ transplantation based on review by Wang et al. [29]

table-2-results-of-gut-microbial-interventions-upon-results-of-cell organ-transplantation.jpg

Human microbiota

Human intestinal microbiota represents a broad set of obligatory and facultative microorganisms that can cause disease in case of suppressed immunity or immunological incompatibility in the host.

There are two kinds of microorganisms classified by their location in the gut: luminal microbiota, which is located in the intestine indigestible dietary fiber and mucosal, adjacent to epithelial cells of the intestine, being integrated into parietal mucin layer. Both luminal and mucosal microbiota may impact the condition of human body, due to their regulatory interactions, and perform many metabolic effects such as detoxification, suppression of pathogenic microorganisms, regulation of immune system, regeneration of epithelium, synthesis of certain Vitamins and essential amino acids, fat metabolism, etc. Dominating intestinal bacteria include 5 types: Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria and Verrucomicrobia. Among them, two types of microbes (Bifidobacterium and Lactobacillus) play a crucial role in development of microbiota till the moment of birth (Tab.3).

Table 3. Intestinal microbiota diversity, by Weber et. al. [30]

table-3-intestinal-microbiota-diversity-by-weber-et-al.jpg

Stable composition of intestinal microbiota and regulation of local immune system reactivity are considered the key aspect for its functional activities. One should take into account of short chain fatty acids (acetate, propionate, butyrate) and antimicrobial peptides produced in situ, regulation of formation of T—regulatory cells (Treg) and IgA in bacteria from intestinal lumen. At the level of lamina propria, metabolic maintenance of transforming growth factor (TGFB), integrin CtE (CD103*), dendritic cells, Treg and T—helper (Th17) producing IL—10, IL—22 are important regenerative factors of epithelial cells. At the level of mesenteric lymph node, one should discuss interaction with innate lymphoid cells via a RORyt nuclear receptor, which reduces local inflammation [29]. Preservation of these interactions allows the growth suppression of pathogenic microbiota, eliminate endogenous and exogenous pathogens, maintain structural integrity of intestinal epithelium.

Variability evaluation of intestinal microbiota

Until now, qualitative identification of composed intestinal microbiota, especially anaerobic microorganisms, represents the main problem in diagnostics of many human bacteria that are undetectable by classical bacteriological methods. Implementation of fecal microbiota transplantation (FMT) procedure into clinical practice and its scientific rationale were largely possible due to development of the microbe identification methods by genome next—generation sequencing (NGS) of bacterial DNAs, and, to a lesser extent, by multiplex real—time polymerase chain (e.g. Colonoflor—16) [8]. Development of the s.c. shotgun next—generation sequencing based on differential analysis of bacterial 16S ribosomal RNA and identification of distinct molecular isolates allowed precise DNA profiling of microbiota composition from donor and recipient, therefore, characterizing the most appropriate fecal donors, and evaluating microbiological results of the treatment [16]. This sequencing procedure consists of 4 successive stages: selection of microbial DNAs from feces, amplification by PCR V4—5 plots of the 16S rRNA gene, sequencing, comparing individual results with a database of previously studied samples, for example, from the NCBI Sequence Read Archive database.

Quantitative 16S RNA analysis in patients with sepsis has revealed sufficient shifts of the main microbial types in the stool samples from the intensive care patients [34]. The workers observed scewed diversity of main microbial communities (1 to 4 bacterial taxa) in 30% of the patients. Bacteria associated with the genera Enterococcus and Staphylococcus and the family Enterobacteriaceae comprised the majority of these communities.

As seen from the Figure 2, normal stool specimens (H1, H2, H3, H4, and H5) were characterized by prevalence of Firmicutes and, in most cases, Bacteroidetes, without Proteobacterial abundance (Fig 2. 1A). In a half of ICU patients (ICU1, ICU4, ICU6, ICU9, ICU11, and ICU15), either Proteobacteria or Firmicutes organisms were totally dominant from at least one time point of stool collection (Fig. 1B and C).

In ICU1, ICU11, and ICU15, the authors observed drastic changes in microbial ratios, with Firmicutes being completely replaced by Proteobacteria. The latter phylum predominated also in most stool samples of the patients ICU6 (Fig 2. 1B) and ICU4 (Fig 2. 1C).

figure-2-composition--of-the-gut-microbiome-.jpg

Figure 2. Composition of the gut microbiome at the phylum level determined by molecular analysis of stool samples collected from healthy controls (A), de- ceased ICU patients with severe sepsis (black circles on the time line) (B), and recovered ICU patients (green circles) (C). Dates of stool collection are displayed in numbered quadrants [34].

Hence, the gross shifts in microbial composition in critically ill patients with clinical signs of sepsis are, mainly, unidirectional, leading to exhaustion of large microbial philae. However, these changes seem to be quite heterogenous and need further clarification for bacterial types associated with worse clinical prognosis.

Under common clinical conditions, however, diagnostics of bacterial dysbiosis is performed for planning different therapeutic measures, including clinical FMT effects. Evaluation of gastrointestinal microflora and mucosa is, generally, performed by means of the following microbiological methods:

— conventional bacteriological tests (microscopy, seeding, assessment of antibiotic resistance).

— biopsy of stomach and/or intestine mucosa with subsequent histology and immunophenotyping of local lymphocytes; verification of infectious lesions at the intestinal mucosa;

— definition of Clostridium difi'icile toxin A and B in stool;

— fecal calprotectin in stool etc.

Fecal microbiota transplantation

In the recent years, FMT was actively developing as a meth- od  to  restore  functional  and  anatomical  integrity  of  intes- tinal  microbiota  in  appropriate  clinical  situations  (Fig.3)   [12,14,21,].

Typical  changes  of  intestinal  microbiota  in  inflammatory   bowel  diseases  include  reduced  diversity  of  obligate  micro- organisms, especially, deficiency of Firmicutes and Bacteroidetes [3]. Ultimately, this leads to lack of butyrate synthesis  by Faecalibacterium  prausnitzii.  This  metabolite  is  a  local  anti-inflammatory agent, acting via IL-8 inhibition [25]. The main known mechanisms of FMT action include com- petition for nutrients, direct inhibition of excessive pathogen  growth,  modulation  of  host  immune  system  by  interaction   with  normal  microbiota.  FMT  seems  to  be  more  effective,   than use of probiotic preparations, in restoring altered intes- tinal microbiota, since the latter is unable to colonize intesti- nal space for an extended period.

FMT also allows correction of both microbiota in digestive  ways,  and  microbial  spectrum  of  other  body  areas  (mouth,   lungs, urinary routes, etc.) to less pathogenic species which  are  more  sensitive  to  antibiotics.  This  effect  can  be  used  to   eradicate   antibiotic-resistant   pathogenic   bacteria   strains    based  on  natural  competition  and  antagonism  between  the   microorganisms [8].

In 2014, a meta-analysis of clinical studies showed that FMT  was effective in 87% of diarrhea cases (a total of 536 patients)  caused  by  Clostridium  difficile,  with  primary  resistance  to   prior  therapy  with  metronidazole  and  vancomycin  [2].  The   transplant administration route was an important factor af- fecting  treatment  outcomes,  i.e.,  the  microflora  delivery  to   the  stomach  yielded  81%  of  clinical  success;  to  duodenum,   86%; via  ascending  part  of  the  colon  (with  fibrocolonosco- py),  93%  response;  to  descending  colon  by  means  of  deep   enema, 84% of successful treatment.

A subsequent review article discussed 45 clinical studies (112  patients), showing ambiguous FMT efficiency in inflamma- tory bowel disease, i.e., only 0 to 68% of the patients achieved  clinical remission [22]. The authors noted that possible fail- ure of FMT could be connected, on the one hand, with poor  state of donor’s microbiota, especially, reduced microbial di- versity.  On  the  other  hand,  severe  malfunction  of  patient’s   GIT with high values of the Mayo scores could also influence  the outcomes.

The attempts of clinical FMT implementation are carried out  not only in clinical conditions related to intestinal infections,  but also presumed irregularities between altered microbiota  and immune system imbalance, such as irritable bowel syn- drome, rheumatoid arthritis, diabetes type 2, autism, chronic  fatigue syndrome, multiple sclerosis and Parkinson’s disease  [5]. There are single reports on FMT performed in order to  treat sepsis with multiple organ dysfunction syndrome, and  to eliminate vancomycin-resistant bacteria [32].

figure-3-fecal-microbiota-transplantation-scheme.jpg

Figure 3. Fecal microbiota transplantation scheme [15].

Increasing number of clinical research reporting successful outcomes of FMT in various diseases is accompanied by arrangement of the first specialized biobank in 2012. This USA—based facility was established for storage of fecal samples for FMT. Currently, the biobank is linked to more than 750 clinics at all the 50 USA states providing an opportunity for a constant access to the samples of donor fecal microbiota. The method was adopted and regulated by the US Food and Drug Administration (FDA). In 2013, this body has approved FMT as a therapeutic method for treatment of refractory infections associated with Clostridi'um difi'icile, for controlled clinical studies (“policy with respect to the investigational new drug requirements for use of fecal microbiota transplantation to treat Clostridi'um difi'ici'le infection not responding to standard treatment”) [27].

On the basis of clinical research, FMT was included to the Guidelines issued by European Society of Clinical Microbiology and Infectious Diseases (ECMID) concerning treatment of Vancomycin—resistant (VRE) infections caused by Clostridium difi'icile, at the AI level of evidence [4]. However, infections associated with Clostridi'um difi'icile, are just among potential indications for the FMT usage. Similarly, the FMT use was approved by the European Crohn’s and Colitis Organization as an approach to treatment of chronic nonspecific inflammatory bowel diseases [21].

Similarly, FMT can significantly modulate immune function and have positive effects on other GIT inflammatory processes of immune origin, in particular, resistant graft—versushost—disease GVHD of intestine. In fact, several researchers confirm that preventive use of FMT leads to a decreased risk of infectious complications during treatment of hematological diseases [16].

Despite some encouraging results of FMT—assisted treatment, it is still rarely used in severely immunocompromised patients, e.g., after alloHSCT. This may be due to low performance status of HSCT recipients, severely damaged gastrointestinal mucosa associated with infectious complications and risk of microbial dissemination with a transplanted donor microbiota. However, it is important to mention, that the transplanted microorganisms potentially substitute multi—drug resistant flora due to natural antagonism and improve the control over infectious complications with standard antibiotics.

Donor selection and transplant delivery of fecal microbiota

Optimal donor selection for FMT is still an uncertain aspect in FMT implementation. Some medical, ethical and economic issues should be resolved, e.g., which kind of graft will be indicated in certain cases, either being related, unrelated or autologous. From economic and ethical viewpoints, an optimal solution is to use autologous source of transplant. However, qualitative composition of a patient’s microbiota is often changed dramatically after previous courses of chemoand antibiotic therapy. Allogeneic donors may be found among healthy relatives: mother, father, siblings. However, “healthy” donor is not yet proven to be the best option for HSCT patient. Development of relevant biobanks will help to resolve the problem of a donor search/selection.

To perform a successful FMT, it is necessary to follow several factors. First of all, an accurate donor selection, must match, on the one hand, classical infectious requirements for allogeneic donor, and should not have any GIT comorbidities or oncologic diseases. On the other hand, the transplant should possess a normally present, diverse intestinal microbiota free of certain virulent pathogens. The standard technology of graft preparation should be used. Is it well developed and tested depending on the form of its delivery, and necessity of long—term storage [28].

Another important factor determining efficiency depends on the transplant delivery route. Currently, there are several options: introduction of donor microbiota to the upper GIT by means of oral capsules; bringing it to the stomach via a gastroscope channel; microbiota delivery to duodenal space with a nasointestinal tube or PEG gastrostomy; delivery to colon, using deep enema, or by means of colonoscopy [33]. Each method has its indications and advantages but, from the point of “engraftment” probability, a multiple delivery to the coecal region by means of colonoscopy is now considered to be the most effective approach (93%). The delivery technologies evolve continuously, aiming at both improving efficiency and increasing patient comfort. E.g., transendoscopic delivery to the cecum with pin—assisted tube fixation, and use of oral capsules are the most promising procedures now [19]. Another important question is the necessity of anesthesia upon delivery of donor’s transplant. In our opinion, the use of medical sedation is required not only for children, but in adults as well, for ethical reasons and better compliance.

Of the new trends, different methods of preparing matrices for transplanted microorganisms should be mentioned, for example, usage of pectin carriers, to increase fermentation activity of the dietary fibers, with synthesis of short chain fatty acids, thus allowing faster multiplication of the donor microorganisms [31].

Features of fecal microbiota transplantation in hematopoietic stem cell transplantation

Allo—HSCT negatively influences patient’s normal microbiota, due to a number of specific factors, e.g., low—microbial diets, often leading to the development of malnutrition; intestinal decontamination associated with eradication of obligate microorganisms, application of cytotoxic drugs and/ or radiation that damage GIT epithelial cells. Along with antibiotic therapy, the above factors lead to severe alterations of bacterial microbiota, development of pathogenic multidrug—resistant microbiota, presumably increasing the risk of acute GVHD [10,23].

Worldwide clinical experience shows, that GVHD of intestine treatment with basic immunosuppressive drugs of different generations is often insufficient to prevent excessive inflammatory response and relief of a diarrhea syndrome. Systemic antibiotic therapy, oral decontamination with non—absorbable antibiotics is ineffective for a significant number of patients with detectable colonization with Clostridium diffici'le. Up to 40% of patients with infection associated with Clostridium difi'icile, are resistant to metronidazole or vancomycin therapy [7]. Massive use of antibiotics post—HSCT leads to significant disturbances of intestinal microbiota homeostasis, whereas use of probiotic bacterial formulae may be ineffective due to their inability to colonize the intestinal spaces for an extended time period.

According to our data, diarrhea after allo—HSCT is observed in 79% of cases and can persist for several months, thus eventually leading to development of cachexia and lethal infectious complications. At the R. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation, we have a successful experience of FMT in four patients after allo—HSCT — adults (n:2) and children (n:2) with prolonged severe diarrheal syndrome, due to immune and infectious complications [8].

Hence, the general idea of using FMT in HSCT looks promising in many aspects: prevention and treatment of infectious complications, prophylaxis of a malabsorption syndrome, and prevention of cachexia, as well as the treatment of steroid—resistant intestinal forms of acute GVHD [12].

Conclusion

A significantly decreased survival is observed in cases of post—HSCT infectious complications resistant to standard antimicrobial therapy, due to increasing mortality caused by septic conditions, usually associated with pathogenic microorganisms: Klebsiella pneumoniae, Pseudomonas aeruginosa, Clostridium difi'icile, Acinetobacter baumannii. Prolonged antibiotic therapy seems to be a key factor leading to multi—drug resistance of some gut bacteria which in turn, may be a trigger to a severe GVHD. Development of intestinal GVHD in most cases leads to the inability of adequate nutrition, along with a maldigestion and malabsorption syndrome, which ultimately leads to protein—energy malnutrition, cachexia and reduced quality of life. Both in sepsis and GVHD, severe changes are observed in qualitative composition and ratios of microbiota living in human gut and other areas of the body.

Initial clinical experience with effective and safe FMT treatment in heavily pretreated category of patients allows to consider this method complementary additional or, in some cases, an alternative technology of therapy for infectious and immune complications after allo—HSCT. FMT results into changes of intestinal microbiota composition, which may help to eradicate multi—drug resistant gut infections, e.g., Clostridium difi'icile, Klebsiella pneumoniae, to reduce antibiotic—associated diarrhea, to replace resistant bacterial species in other areas of the body, and to change microbial profile to a less—virulent landscape.

Further implementation of FMT in clinical practice requires a detailed study, including optimization of criteria for the therapy initiation, selection of the most matched donors by means of multiplex DNA diagnostics, or next—generation DNA sequencing of microbiota, evaluation of long—term efficacy and safety of the transplants.

Conflict of interests

The authors have no conflict of interest to declare.

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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) "11124" ["VALUE"]=> array(2) { ["TEXT"]=> string(2901) "Резюме Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) – радикальный метод лечения онкогематологических и наследственных заболеваний у взрослых и детей. Несмотря на свою эффективность, ТГСК ассоциирована со значительным числом жизнеугрожающих осложнений. Главные причины неудачи лечения – это летальность от септических осложнений, вызванных нозокомиальными поли- и панрезистентными штаммами бактерий, среди которых превалирует Clostridium difficile и Klebsiella pneumoniae, и иммунных осложнений, таких как острая и хроническая реакция «трансплантат против хозяина» (РТПХ), в основе которой лежит поражение органов пациента лимфоцитами донора. В большинстве случаев первичным органом-мишенью является желудочно-кишечный тракт (ЖКТ) в результате развития неконтролируемого воспаления и тяжелой диареи при РТПХ, а также кишечных инфекций, в частности – псевдомембранозного колита ассоциированного с Clostridium difficile на фоне массивной антибиотикотерапии. Одним из основных факторов риска развития РТПХ с вовлечением ЖКТ, псевдомембранозного колита и антибиотико-ассоциированной диареи после ТГСК считают элиминацию нормальной микробиоты кишечника. Трансплантация фекальной микробиоты (ТФМ) здорового донора позволяет восстановить физиологическое микробное разнообразие и функциональную активность микробиоты кишечника и может приводить к эрадикации патогенных микроорганизмов, тем самым купируя инфекционные осложнения. <h3>Ключевые слова</h3> Трансплантация фекальной микробиоты, трансплантация гемопоэтических стволовых клеток, антибиотикорезистентность." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2889) "Резюме Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) – радикальный метод лечения онкогематологических и наследственных заболеваний у взрослых и детей. Несмотря на свою эффективность, ТГСК ассоциирована со значительным числом жизнеугрожающих осложнений. Главные причины неудачи лечения – это летальность от септических осложнений, вызванных нозокомиальными поли- и панрезистентными штаммами бактерий, среди которых превалирует Clostridium difficile и Klebsiella pneumoniae, и иммунных осложнений, таких как острая и хроническая реакция «трансплантат против хозяина» (РТПХ), в основе которой лежит поражение органов пациента лимфоцитами донора. В большинстве случаев первичным органом-мишенью является желудочно-кишечный тракт (ЖКТ) в результате развития неконтролируемого воспаления и тяжелой диареи при РТПХ, а также кишечных инфекций, в частности – псевдомембранозного колита ассоциированного с Clostridium difficile на фоне массивной антибиотикотерапии. Одним из основных факторов риска развития РТПХ с вовлечением ЖКТ, псевдомембранозного колита и антибиотико-ассоциированной диареи после ТГСК считают элиминацию нормальной микробиоты кишечника. Трансплантация фекальной микробиоты (ТФМ) здорового донора позволяет восстановить физиологическое микробное разнообразие и функциональную активность микробиоты кишечника и может приводить к эрадикации патогенных микроорганизмов, тем самым купируя инфекционные осложнения.

Ключевые слова

Трансплантация фекальной микробиоты, трансплантация гемопоэтических стволовых клеток, антибиотикорезистентность." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["DOI"]=> array(36) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11066" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-1-20-29" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-1-20-29" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_EN"]=> array(36) { ["ID"]=> string(2) "37" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(6) "Author" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "37" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11118" ["VALUE"]=> array(2) { ["TEXT"]=> string(73) "Maxim A. Kucher, Oleg V. Goloschapov, 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(73) "Maxim A. Kucher, Oleg V. Goloschapov, 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) "11119" ["VALUE"]=> array(2) { ["TEXT"]=> string(555) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation, The First State I. Pavlov Medical University, St. Petersburg, Russia;<br> Dr. Maxim A. Kucher, Head, Department of Clinical Nutrition, R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; The First State I. Pavlov Medical University, St. Petersburg, Russia, L. Tolstoy St. 6-8, 197022<br> Phone: 8 (812) 338 6260, +7 (921) 993 9902 E-mail: doctorkucher@yandex.ru" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(543) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation, The First State I. Pavlov Medical University, St. Petersburg, Russia;
Dr. Maxim A. Kucher, Head, Department of Clinical Nutrition, R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; The First State I. Pavlov Medical University, St. Petersburg, Russia, L. Tolstoy St. 6-8, 197022
Phone: 8 (812) 338 6260, +7 (921) 993 9902 E-mail: doctorkucher@yandex.ru" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Organization" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_EN"]=> array(36) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11120" ["VALUE"]=> array(2) { ["TEXT"]=> string(1529) "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method of treatment for hematological, malignant and hereditary diseases in adults and children. Despite its efficiency, HSCT is associated with several potential life-threatening complications. Mortality from bloodstream infections is the main limiting factor for HSCT. Those are caused by bacterial strains refractory to antimicrobial treatment, e.g., Clostridium difficile and Klebsiella pneumoniae, and due to immune complications, such as acute and chronic “graft versus host disease” (GvHD), which represents a conflict between donor lymphocytes and patients’ tissues. In most cases, gastrointestinal tract (GIT) is primarily damaged post-HSCT, as a result of enhanced inflammation, serious diarrhea manifesting in GvHD and intestinal infections, in particular – pseudo-membranous colitis associated with Clostridium difficile which often occur after massive antibiotic therapy. Elimination of normal intestinal microbiota is a sufficient risk factor for GIT GvHD, pseudo-membranous colitis and antibiotic-associated diarrhea post-HSCT. Fecal microbiota transplantation (FMT) from healthy donors allows restoration of a physiological microbial variability and functional activity of intestinal microbiota leading to eradication of pathogenic microorganisms, therefore abrogating infectious complications. <h3>Keywords</h3> Fecal microbiota transplantation, hematopoietic stem cell transplantation, antibiotic resistance. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1517) "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method of treatment for hematological, malignant and hereditary diseases in adults and children. Despite its efficiency, HSCT is associated with several potential life-threatening complications. Mortality from bloodstream infections is the main limiting factor for HSCT. Those are caused by bacterial strains refractory to antimicrobial treatment, e.g., Clostridium difficile and Klebsiella pneumoniae, and due to immune complications, such as acute and chronic “graft versus host disease” (GvHD), which represents a conflict between donor lymphocytes and patients’ tissues. In most cases, gastrointestinal tract (GIT) is primarily damaged post-HSCT, as a result of enhanced inflammation, serious diarrhea manifesting in GvHD and intestinal infections, in particular – pseudo-membranous colitis associated with Clostridium difficile which often occur after massive antibiotic therapy. Elimination of normal intestinal microbiota is a sufficient risk factor for GIT GvHD, pseudo-membranous colitis and antibiotic-associated diarrhea post-HSCT. Fecal microbiota transplantation (FMT) from healthy donors allows restoration of a physiological microbial variability and functional activity of intestinal microbiota leading to eradication of pathogenic microorganisms, therefore abrogating infectious complications.

Keywords

Fecal microbiota transplantation, hematopoietic stem cell transplantation, antibiotic resistance. 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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) "11120" ["VALUE"]=> array(2) { ["TEXT"]=> string(1529) "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method of treatment for hematological, malignant and hereditary diseases in adults and children. Despite its efficiency, HSCT is associated with several potential life-threatening complications. Mortality from bloodstream infections is the main limiting factor for HSCT. Those are caused by bacterial strains refractory to antimicrobial treatment, e.g., Clostridium difficile and Klebsiella pneumoniae, and due to immune complications, such as acute and chronic “graft versus host disease” (GvHD), which represents a conflict between donor lymphocytes and patients’ tissues. In most cases, gastrointestinal tract (GIT) is primarily damaged post-HSCT, as a result of enhanced inflammation, serious diarrhea manifesting in GvHD and intestinal infections, in particular – pseudo-membranous colitis associated with Clostridium difficile which often occur after massive antibiotic therapy. Elimination of normal intestinal microbiota is a sufficient risk factor for GIT GvHD, pseudo-membranous colitis and antibiotic-associated diarrhea post-HSCT. Fecal microbiota transplantation (FMT) from healthy donors allows restoration of a physiological microbial variability and functional activity of intestinal microbiota leading to eradication of pathogenic microorganisms, therefore abrogating infectious complications. <h3>Keywords</h3> Fecal microbiota transplantation, hematopoietic stem cell transplantation, antibiotic resistance. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1517) "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method of treatment for hematological, malignant and hereditary diseases in adults and children. Despite its efficiency, HSCT is associated with several potential life-threatening complications. Mortality from bloodstream infections is the main limiting factor for HSCT. Those are caused by bacterial strains refractory to antimicrobial treatment, e.g., Clostridium difficile and Klebsiella pneumoniae, and due to immune complications, such as acute and chronic “graft versus host disease” (GvHD), which represents a conflict between donor lymphocytes and patients’ tissues. In most cases, gastrointestinal tract (GIT) is primarily damaged post-HSCT, as a result of enhanced inflammation, serious diarrhea manifesting in GvHD and intestinal infections, in particular – pseudo-membranous colitis associated with Clostridium difficile which often occur after massive antibiotic therapy. Elimination of normal intestinal microbiota is a sufficient risk factor for GIT GvHD, pseudo-membranous colitis and antibiotic-associated diarrhea post-HSCT. Fecal microbiota transplantation (FMT) from healthy donors allows restoration of a physiological microbial variability and functional activity of intestinal microbiota leading to eradication of pathogenic microorganisms, therefore abrogating infectious complications.

Keywords

Fecal microbiota transplantation, hematopoietic stem cell transplantation, antibiotic resistance. " ["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(1517) "Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective method of treatment for hematological, malignant and hereditary diseases in adults and children. Despite its efficiency, HSCT is associated with several potential life-threatening complications. Mortality from bloodstream infections is the main limiting factor for HSCT. Those are caused by bacterial strains refractory to antimicrobial treatment, e.g., Clostridium difficile and Klebsiella pneumoniae, and due to immune complications, such as acute and chronic “graft versus host disease” (GvHD), which represents a conflict between donor lymphocytes and patients’ tissues. In most cases, gastrointestinal tract (GIT) is primarily damaged post-HSCT, as a result of enhanced inflammation, serious diarrhea manifesting in GvHD and intestinal infections, in particular – pseudo-membranous colitis associated with Clostridium difficile which often occur after massive antibiotic therapy. Elimination of normal intestinal microbiota is a sufficient risk factor for GIT GvHD, pseudo-membranous colitis and antibiotic-associated diarrhea post-HSCT. Fecal microbiota transplantation (FMT) from healthy donors allows restoration of a physiological microbial variability and functional activity of intestinal microbiota leading to eradication of pathogenic microorganisms, therefore abrogating infectious complications.

Keywords

Fecal microbiota transplantation, hematopoietic stem cell transplantation, antibiotic resistance. " } ["DOI"]=> array(37) { ["ID"]=> string(2) "28" ["TIMESTAMP_X"]=> string(19) "2016-04-06 14:11:12" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(3) "DOI" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(3) "DOI" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "28" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11066" ["VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-1-20-29" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-1-20-29" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(3) "DOI" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(37) "10.18620/ctt-1866-8836-2017-6-1-20-29" } ["NAME_EN"]=> array(37) { ["ID"]=> string(2) "40" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:49:47" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(4) "Name" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(7) "NAME_EN" ["DEFAULT_VALUE"]=> string(0) "" ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "80" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "40" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> NULL ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11067" ["VALUE"]=> string(114) " Fecal microbiota transplantation as a method to treat complications after hematopoietic stem cell transplantation" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(114) " Fecal microbiota transplantation as a method to treat complications after hematopoietic stem cell transplantation" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(4) "Name" ["~DEFAULT_VALUE"]=> string(0) "" ["DISPLAY_VALUE"]=> string(114) " Fecal microbiota transplantation as a method to treat complications after hematopoietic stem cell transplantation" } ["ORGANIZATION_EN"]=> array(37) { ["ID"]=> string(2) "38" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Organization" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "38" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11119" ["VALUE"]=> array(2) { ["TEXT"]=> string(555) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation, The First State I. Pavlov Medical University, St. Petersburg, Russia;<br> Dr. Maxim A. Kucher, Head, Department of Clinical Nutrition, R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; The First State I. Pavlov Medical University, St. Petersburg, Russia, L. Tolstoy St. 6-8, 197022<br> Phone: 8 (812) 338 6260, +7 (921) 993 9902 E-mail: doctorkucher@yandex.ru" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(543) "R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; Chair of Hematology, Transfusiology and Transplantation, The First State I. Pavlov Medical University, St. Petersburg, Russia;
Dr. Maxim A. Kucher, Head, Department of Clinical Nutrition, R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; The First State I. Pavlov Medical University, St. Petersburg, Russia, L. Tolstoy St. 6-8, 197022
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Dr. Maxim A. Kucher, Head, Department of Clinical Nutrition, R. Gorbacheva Memorial Institute of Children Oncology, Hematology and Transplantation; The First State I. Pavlov Medical University, St. Petersburg, Russia, L. Tolstoy St. 6-8, 197022
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Несмотря на свою эффективность, ТГСК ассоциирована со значительным числом жизнеугрожающих осложнений. Главные причины неудачи лечения – это летальность от септических осложнений, вызванных нозокомиальными поли- и панрезистентными штаммами бактерий, среди которых превалирует Clostridium difficile и Klebsiella pneumoniae, и иммунных осложнений, таких как острая и хроническая реакция «трансплантат против хозяина» (РТПХ), в основе которой лежит поражение органов пациента лимфоцитами донора. В большинстве случаев первичным органом-мишенью является желудочно-кишечный тракт (ЖКТ) в результате развития неконтролируемого воспаления и тяжелой диареи при РТПХ, а также кишечных инфекций, в частности – псевдомембранозного колита ассоциированного с Clostridium difficile на фоне массивной антибиотикотерапии. Одним из основных факторов риска развития РТПХ с вовлечением ЖКТ, псевдомембранозного колита и антибиотико-ассоциированной диареи после ТГСК считают элиминацию нормальной микробиоты кишечника. 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Главные причины неудачи лечения – это летальность от септических осложнений, вызванных нозокомиальными поли- и панрезистентными штаммами бактерий, среди которых превалирует Clostridium difficile и Klebsiella pneumoniae, и иммунных осложнений, таких как острая и хроническая реакция «трансплантат против хозяина» (РТПХ), в основе которой лежит поражение органов пациента лимфоцитами донора. В большинстве случаев первичным органом-мишенью является желудочно-кишечный тракт (ЖКТ) в результате развития неконтролируемого воспаления и тяжелой диареи при РТПХ, а также кишечных инфекций, в частности – псевдомембранозного колита ассоциированного с Clostridium difficile на фоне массивной антибиотикотерапии. Одним из основных факторов риска развития РТПХ с вовлечением ЖКТ, псевдомембранозного колита и антибиотико-ассоциированной диареи после ТГСК считают элиминацию нормальной микробиоты кишечника. Трансплантация фекальной микробиоты (ТФМ) здорового донора позволяет восстановить физиологическое микробное разнообразие и функциональную активность микробиоты кишечника и может приводить к эрадикации патогенных микроорганизмов, тем самым купируя инфекционные осложнения.

Ключевые слова

Трансплантация фекальной микробиоты, трансплантация гемопоэтических стволовых клеток, антибиотикорезистентность." ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(2889) "Резюме Аллогенная трансплантация гемопоэтических стволовых клеток (ТГСК) – радикальный метод лечения онкогематологических и наследственных заболеваний у взрослых и детей. Несмотря на свою эффективность, ТГСК ассоциирована со значительным числом жизнеугрожающих осложнений. Главные причины неудачи лечения – это летальность от септических осложнений, вызванных нозокомиальными поли- и панрезистентными штаммами бактерий, среди которых превалирует Clostridium difficile и Klebsiella pneumoniae, и иммунных осложнений, таких как острая и хроническая реакция «трансплантат против хозяина» (РТПХ), в основе которой лежит поражение органов пациента лимфоцитами донора. В большинстве случаев первичным органом-мишенью является желудочно-кишечный тракт (ЖКТ) в результате развития неконтролируемого воспаления и тяжелой диареи при РТПХ, а также кишечных инфекций, в частности – псевдомембранозного колита ассоциированного с Clostridium difficile на фоне массивной антибиотикотерапии. Одним из основных факторов риска развития РТПХ с вовлечением ЖКТ, псевдомембранозного колита и антибиотико-ассоциированной диареи после ТГСК считают элиминацию нормальной микробиоты кишечника. Трансплантация фекальной микробиоты (ТФМ) здорового донора позволяет восстановить физиологическое микробное разнообразие и функциональную активность микробиоты кишечника и может приводить к эрадикации патогенных микроорганизмов, тем самым купируя инфекционные осложнения.

Ключевые слова

Трансплантация фекальной микробиоты, трансплантация гемопоэтических стволовых клеток, антибиотикорезистентность." } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "11123" ["VALUE"]=> array(2) { ["TEXT"]=> string(445) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Кафедра гематологии, трансфузиологии и трансплантологии, 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(445) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Кафедра гематологии, трансфузиологии и трансплантологии, 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" } ["DISPLAY_VALUE"]=> string(445) "НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Кафедра гематологии, трансфузиологии и трансплантологии, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия" } } } }
Том 6, Номер 1
31.03.2017 08:23:00
Том 6, Номер 1
Главный редактор
Афанасьев Б. В. (Санкт-Петербург, Россия)
Со-редакторы
Вагемакер Г (Роттердам, Нидерланды)
Цандер А. Р. (Гамбург, Германия)
Заместитель главного редактора
Фезе Б. (Гамбург, Германия)
Ответственный редактор
Чухловин А. Б. (Санкт-Петербург, Россия)
Редакционная коллегия
Алейникова О. В. (Минск, Беларусь)
Борсет М. (Трондхейм, Норвегия)
Галибин О. В. (Санкт-Петербург, Россия)
Зубаровская Л. С. (Санкт-Петербург, Россия)
Климко Н. Н. (Санкт-Петербург, Россия)
Кольб Х. (Мюнхен, Германия)
Крегер Н. (Гамбург, Германия)
Кулагин А. Д. (Санкт-Петербург, Россия)
Ланге К. (Гамбург, Германия)
Мамаев Н. Н. (Санкт-Петербург, Россия)
Михайлова Н. Б. (Санкт-Петербург, Россия)
Моисеев И. С. (Санкт-Петербург, Россия)
Наглер А. (Тель-Авив, Израиль)
Немков А. С. (Санкт-Петербург, Россия)
Парамонов И. В. (Киров, Россия)
Румянцев А. Г. (Москва, Россия)
Савченко В. Г. (Москва, Россия)
Смирнов А. В. (Санкт-Петербург, Россия)
Усс А. Л. (Минск, Беларусь)
Фиббе В. (Лейден, Нидерланды)
Хельтцер Д. (Франкфурт-на-Майне, Германия)
Чечеткин А. В. (Санкт-Петербург, Россия)

Учредители журнала:
Университетский медицинский центр Гамбург-Эппендорф (Германия),
Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова (Россия) и Фонд развития
трансплантации костного мозга, Санкт-Петербург

Издание зарегистрировано:
В Федеральной службе по надзору за соблюдением законодательства в сфере массовых коммуникаций и охране культурного наследия, Свидетельство о регистрации ПИ No ФС-22142 от 27 октября 2005 г.

Архив журнала КТТ:
http://cttjournal.com/archive.html?&L=1

Обзор выпуска
Алексей Б. Чухловин

Настоящий выпуск CTT касается различных областей трансплантологии. Так, специальная редакционная статья, написанная Б. В. Афанасьевым, посвящена 70-летию профессора Александра Григорьевича Румянцева – выдающегося российского специалиста в области детской гематологии.

В числе клинических работ, исследование Татьяны Л. Гиндиной показывает негативное прогностическое значение комплексного кариотипа лейкозных клеток. Число таких хромосомных аномалий на кариотип, а также стадия заболевания оказались независимыми прогностическими факторами при анализе смешанной группы больных Ph+ острым лимфобластным лейкозом на момент трансплантации гемопоэтических стволовых клеток (ТГСК). Статья описывает различные хромосомные аберрации при остром лейкозе и рассматривает их подробно.

Следующая статья Максима А. Кучера и соавт. представляет и обосновывает популярную теорию тесных связей между кишечной микробиотой и клиническими рисками после ТГСК. Эта гипотеза следует из наличия определенных корреляций между кишечным дисбиозом и клиническими эпизодами хронических воспалительных заболеваний кишечника. Установление биологического разнообразия и преобладания различных видов бактерий после ТГСК может быть важным средством определения микробной активации в качестве фактора усиления реакции трансплантат против хозяина (РТПХ). Авторы представляют свои первые результаты о трансплантации фекальной микрофлоры в случаях осложненной ТГСК, с целью предотвращения или лечения тяжелых форм острой РТПХ.

Клинический отчет Вадима М. Кемайкина и соавт. (Астана, Республика Казахстан) отражает их опыт в начальной организации службы трансплантации костного мозга на базе Центра неотложной медицинской помощи Астаны. После 6 лет развития скромное отделение для ауто-ТГСК превратилось в современный специализированный отдел для проведения различных типов ТГСК, включая гаплоидентичную трансплантацию, с хорошими исходами у пациентов.

Пароксизмальная ночная гемоглобинурия (ПНГ), клональная мембранопатия системы крови, относится к состояниям, потенциально излечимых посредством ТГСК. Для улучшения прогноза и качества жизни у таких пациентов и других больных с наличием ПНГ-клонов возможно применение Экулизумаба – моноклонального антитела против компонента комплемента. Лечебный эффект от инфузии препарата состоит в блокаде комплемент-опосредованного внутрисосудистого гемолиза эритроцитов. В своем сообщении, Галина А.Дудина описала поучительный случай ПНГ у пожилого пациента с МДС, который успешно лечился Экулизумабом, поскольку ТГСК не была показана из-за пожилого возраста и большого числа тяжелых сопутствующих заболеваний.

Среди экспериментальных работ мы хотели бы порекомендовать обзор Марины О. Поповой и соавт., где обсуждаются вопросы потенциального клинического применения редактирования генов для лечения генетических заболеваний. Авторы касаются методологии целенаправленной процедуры редактирования гена in vitro с использованием лентивирусных векторов. Далее авторы описывают возможные моногенные заболевания, находящиеся на разных фазах клинических испытаний с применеием генной терапии, в том числе – такиe известные синдромы, как первичные иммунодефициты, бета-талассемию и др.

Последнее краткое сообщение отражает точку зрения Кристины Ходовой – эксперта по иммуногенетике и внедрению методов генной терапии – на бизнес-перспективы генной терапии. Автор рассматривает целый ряд различных подходов к генной терапии, соответствующие патентные случаи, существующие перспективы и возможности дальнейших инвестиций в эти исследования.

Редакционная статья

Юбилей А. Г. Румянцева (70-летие)
Профессор Борис В. Афанасьев, главный редактор журнала «Клеточная Терапия и Трансплантация», Директор НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Санкт-Петербург

Клинические работы

Экспериментальные исследования

Клиническое применение редактирования генома для лечения заболеваний человека
Марина О. Попова, Кирилл В. Лепик, Владислав С. Сергеев, Алена И. Шакирова, Алиса Я. Поттер, Альберт Р. Муслимов, Ильдар М. Бархатов, Борис В. Афанасьев

Краткие сообщения

Клинические статьи

Pезультаты аллогенной трансплантации гемопоэ - тических стволовых клеток в смешанной когорте больных с Ph-позитивным острым лимфобластным лейкозом
Татьяна Л. Гиндина, Николай Н. Мамаев, Елена С. Николаева, Ирина А. Петрова, Елена И. Дарская, Ольга В. Пирогова, Яна В. Гудожникова, Олеся В. Паина, Александр Л. Алянский, Сергей Н. Бондаренко, Людмила С. Зубаровская, Борис В. Афанасьев
Опыт Астаны: отдел онкогематологии и трансплан- тации костного мозга, Национальный исследова - тельский Центр онкологии и трансплантации
Вадим М. Кемайкин, Анастасия A. Олифирович, Александр В. Колеснев, Анатолий В. Немеровченко, Рузаль Ф. Вильданова, Ольга В. Гайнутдинова, Адия А. Тусипова, Аяужан Е. Есимбекова, Алия K. Баймурзина, Айзат С. Сулейменова, Ольга O. Лесечко, Гульназ Д. Ансатбаева, Мария С. Алимбетова

Редакционная статья

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 <br>
Александр  Григорьевич  в  1971  г.  окончил  с  отличием педиатрический факультет Второго Московского ордена Ленина государственного медицинского института, и в последующие годы он работал в стенах этого ВУЗа (2-го МОЛГМИ, с 1991 г. – Российского государственного медицинского университета, с 2011 г. – Российского национального исследовательского медицинского университета  им.  Н.  И.  Пирогова).  В  тот  период  А.  Г.  Румянцев  показал   себя   высококвалифицированным   специалистом-педиатром,  гематологом-иммунологом,  ученым  и  преподавателем  высшей  школы.  Талантливый  педагог, автор  и  соавтор  образовательных  программ  по  лечению   детских   болезней,   поликлинической   педиатрии,  педиатрической гематологии/онкологии, иммунологии/аллергологии,  трансфузиологии,  научный  редактор  базовых  руководств  и  учебных  пособий  по  педиатрии,  детской гематологии и иммунологии.
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                    [TEXT] => В этом году мы отмечаем 70-летие профессора Александра Григорьевича Румянцева – одного из выдающихся российских ученых, специалиста в области детской онкогематологии, человека высочайших профессиональных качеств и гуманности. Его достижения широко известны не только в России, но и за рубежом. Он является президентом Национальной Ассоциации детских онкологов и гематологов, главным педиатром Московского департамента здравоохранения, генеральным директором Национального научно-практического центра детской гематологии и онкологии имени Димы Рогачева. В течение многих лет А. Г. Румянцев был главой кафедры онкологии, гематологии и радиационной терапии педиатрического факультета Российского национального исследовательского медицинского университета им. Н. И. Пирогова.

Александр Григорьевич в 1971 г. окончил с отличием педиатрический факультет Второго Московского ордена Ленина государственного медицинского института, и в последующие годы он работал в стенах этого ВУЗа (2-го МОЛГМИ, с 1991 г. – Российского государственного медицинского университета, с 2011 г. – Российского национального исследовательского медицинского университета им. Н. И. Пирогова). В тот период А. Г. Румянцев показал себя высококвалифицированным специалистом-педиатром, гематологом-иммунологом, ученым и преподавателем высшей школы. Талантливый педагог, автор и соавтор образовательных программ по лечению детских болезней, поликлинической педиатрии, педиатрической гематологии/онкологии, иммунологии/аллергологии, трансфузиологии, научный редактор базовых руководств и учебных пособий по педиатрии, детской гематологии и иммунологии. [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