Разработка программной терапии больных острыми миелоидными лейкозами в возрасте моложе 60 лет, основанной на принципах дифференцированного воздействия
Разработка программной терапии больных острыми миелоидными лейкозами в возрасте моложе 60 лет, основанной на принципах дифференцированного воздействия
Паровичникова Е.Н., Лукьянова И.А., Троицкая В.В., Дроков М.Ю., Кузьмина Л.А., Соколов А.Н., Кохно А.В., Фидарова З.Т., Гальцева И.В., Давыдова Ю.О, Кашлакова А.И., Грибанова Е.О., Звонков Е.Е., Сысоева Е.П., Двирнык В.Н., Обухова Т.Н., Судариков А.Б., Сидорова Ю.В., Куликов С.М, Чабаева Ю.А., Савченко В.Г. Разработка программной терапии больных острыми миелоидными лейкозами в возрасте моложе 60 лет, основанной на принципах дифференцированного воздействия. Терапевтический архив. 2021; 93 (7): 753–762. DOI: 10.26442/00403660.2021.07.200946
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Аннотация
Цель. Проанализировать результаты терапии больных острыми миелоидными лейкозами (ОМЛ) по протоколам ОМЛ-17 и модифицированному ОМЛ-17 (мОМЛ-17) в рамках двух последовательных пилотных исследований с целью разработки оптимальной химиотерапевтической стратегии в лечении больных ОМЛ в возрасте до 60 лет.
Материалы и методы. В исследование включены 89 больных ОМЛ в возрасте моложе 60 лет, получавших терапию согласно протоколам ОМЛ-17 и мОМЛ-17. Цитогенетическое и молекулярно-генетическое исследования осуществляли всем больным. Оценивали наличие мутаций в генах FLT3, NPM1, CEBPa методом фрагментного анализа. У 35 больных выполнили исследование на mutTP53, mutRUNX1 методом секвенирования нового поколения (next generation sequencing – NGS). Минимальную остаточную популяцию опухолевых клеток оценивали методом многоцветной проточной цитометрии. Статистический анализ проводили с помощью процедур пакета SAS 9.3.
Результаты. Полная ремиссия (ПР) достигнута у 89,7% больных, пролеченных по интенсивным программам, и у 52,4% больных, получивших низкодозное воздействие. Рефрактерными к терапии оказались 8,8% больных, пролеченных интенсивно, и 38% – не ответили на низкодозное воздействие. Показатель ранней летальности составил 3%. Общая и безрецидивная 3-летняя выживаемость всех больных, включенных в 2 последовательных исследования, составили 60 и 67% соответственно. Значимым стал показатель минимальной остаточной болезни (МОБ) после 1-го курса индукционной терапии. Трехлетняя безрецидивная выживаемость тех больных, у кого ПР достигнута после 1-го индукционного курса и МОБ не выявлена (получен МОБ-негативный статус), составила 90% в сравнении с 43% у тех, у кого при достижении ПР после 1-го курса определялся МОБ-позитивный статус (р=0,00001).
Заключение. Ключевой фактор, существенно влияющий на долгосрочные результаты терапии, – это показатель МОБ после 1-го курса индукции.
Ключевые слова: острые миелоидные лейкозы, минимальная остаточная болезнь, группа риска, трансплантация аллогенных стволовых кроветворных клеток
Materials and methods. The study included 89 AML patients who were aged below 60 years and received treatment within the AML-17 and mOML-17 protocols. Cytogenetic and molecular genetic studies were performed in all patients. The presence of mutations in the FLT3, NPM1, CEBPa genes was assessed by fragment analysis. 35 patients underwent a study for mutTP53, mutRUNX1 using next generation sequencing (NGS). The minimum residual population of tumor cells was evaluated by multicolor flow cytometry. Statistical analysis was performed using the procedures of the SAS 9.3 package.
Results. Complete remission (CR) was achieved in 89.7% of patients treated with intensive chemotherapy (CT) courses and in 52.4% of patients treated with low-dose CT courses. 8.8% of intensively treated patients were refractory to therapy, and 38% did not respond to low-dose exposure. The early mortality rate was 3%. The overall survival and disease-free 3-year survival for patients included in 2 consecutive studies was were 60% and 67%, respectively. The level of minimal residual disease (MRD) after the first course of induction CT was an important prognostic indicator. The three-year relapse-free survival for patients in whom CR was achieved after the first course of induction CT and in whom MRD was not detected (MRD-negative status was obtained) was 90% compared to 43% for patients who were MRD positive after the first course of induction CT (p=0.00001).
Conclusion. The key factor that significantly affects the long-term results of therapy is the rate of MRD after the first course of induction CT.
Keywords: acute myeloid leukemia, minimal residual disease, risk group, transplantation of allogeneic hematopoietic stem cells
Материалы и методы. В исследование включены 89 больных ОМЛ в возрасте моложе 60 лет, получавших терапию согласно протоколам ОМЛ-17 и мОМЛ-17. Цитогенетическое и молекулярно-генетическое исследования осуществляли всем больным. Оценивали наличие мутаций в генах FLT3, NPM1, CEBPa методом фрагментного анализа. У 35 больных выполнили исследование на mutTP53, mutRUNX1 методом секвенирования нового поколения (next generation sequencing – NGS). Минимальную остаточную популяцию опухолевых клеток оценивали методом многоцветной проточной цитометрии. Статистический анализ проводили с помощью процедур пакета SAS 9.3.
Результаты. Полная ремиссия (ПР) достигнута у 89,7% больных, пролеченных по интенсивным программам, и у 52,4% больных, получивших низкодозное воздействие. Рефрактерными к терапии оказались 8,8% больных, пролеченных интенсивно, и 38% – не ответили на низкодозное воздействие. Показатель ранней летальности составил 3%. Общая и безрецидивная 3-летняя выживаемость всех больных, включенных в 2 последовательных исследования, составили 60 и 67% соответственно. Значимым стал показатель минимальной остаточной болезни (МОБ) после 1-го курса индукционной терапии. Трехлетняя безрецидивная выживаемость тех больных, у кого ПР достигнута после 1-го индукционного курса и МОБ не выявлена (получен МОБ-негативный статус), составила 90% в сравнении с 43% у тех, у кого при достижении ПР после 1-го курса определялся МОБ-позитивный статус (р=0,00001).
Заключение. Ключевой фактор, существенно влияющий на долгосрочные результаты терапии, – это показатель МОБ после 1-го курса индукции.
Ключевые слова: острые миелоидные лейкозы, минимальная остаточная болезнь, группа риска, трансплантация аллогенных стволовых кроветворных клеток
________________________________________________
Materials and methods. The study included 89 AML patients who were aged below 60 years and received treatment within the AML-17 and mOML-17 protocols. Cytogenetic and molecular genetic studies were performed in all patients. The presence of mutations in the FLT3, NPM1, CEBPa genes was assessed by fragment analysis. 35 patients underwent a study for mutTP53, mutRUNX1 using next generation sequencing (NGS). The minimum residual population of tumor cells was evaluated by multicolor flow cytometry. Statistical analysis was performed using the procedures of the SAS 9.3 package.
Results. Complete remission (CR) was achieved in 89.7% of patients treated with intensive chemotherapy (CT) courses and in 52.4% of patients treated with low-dose CT courses. 8.8% of intensively treated patients were refractory to therapy, and 38% did not respond to low-dose exposure. The early mortality rate was 3%. The overall survival and disease-free 3-year survival for patients included in 2 consecutive studies was were 60% and 67%, respectively. The level of minimal residual disease (MRD) after the first course of induction CT was an important prognostic indicator. The three-year relapse-free survival for patients in whom CR was achieved after the first course of induction CT and in whom MRD was not detected (MRD-negative status was obtained) was 90% compared to 43% for patients who were MRD positive after the first course of induction CT (p=0.00001).
Conclusion. The key factor that significantly affects the long-term results of therapy is the rate of MRD after the first course of induction CT.
Keywords: acute myeloid leukemia, minimal residual disease, risk group, transplantation of allogeneic hematopoietic stem cells
Список литературы
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4. Ye XN, Zhou XP, Wei JY, et al. Epigenetic priming with decitabine followed by low-dose idarubicin/cytarabine has an increased anti-leukemic effect compared to traditional chemotherapy in high-risk myeloid neoplasms. Leuk Lymphoma. 2016;57(6):1311-8. DOI:10.3109/10428194.2015.1091931
5. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-240. DOI:10.1182/blood-2016-03-643544
6. Anelli L, Pasciolla C, Zagaria A, et al. Monosomal karyotype in myeloid neoplasias: a literature review. Onco Targets Ther. 2017;10:2163-71. DOI:10.2147/OTT.S133937
7. Brands-Nijenhuis AV, Labopin M, Schouten HC, et al. Monosomal karyotype as an adverse prognostic factor in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem-cell transplantation in first complete remission: a retrospective survey on behalf of the ALWP of the EBMT. Haematologica. 2016;101(2):248-55. DOI:10.3324/haematol.2015.132654
8. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016;374:2209-21. DOI:10.1056/NEJMoa1516192
9. Rogers HJ, Vardiman JW, Anastasi J, et al. Complex or monosomal karyotype and not blast percentageis associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014;99(5):821-9.
DOI:10.3324/haematol.2013.096420
10. Паровичникова Е.Н., Лукьянова И.А., Троицкая В.В., и др. Результаты программной терапии острых миелоидных лейкозов в ФГБУ «НМИЦ гематологии» Минздрава России. Терапевтический архив. 2018;90(7):14-22 [Parovichnikova EN, Lukianova IA, Troitskaya VV, et al. Results of program acute myeloid leukemia therapy use in National medical research center for hematology of the Ministry of Health of Russian Federation. Terapevticheskii Arkhiv (Ter. Arkh.). 2018;90(7):14‑22 (in Russian)]. DOI:10.26442/terarkh201890714-22
11. Büchner T, Berdel WE, Schoch C, et al. Double induction containing either two courses or one course of high-dose cytarabine plus mitoxantrone and postremission therapy by either autologous stem-cell transplantation or by prolonged maintenance for acute myeloid leukemia. J Clin Oncol. 2006;24(16):2480-9. DOI:10.1200/JCO.2005.04.5013
12. Baron F, Stevens-Kroef M, Kicinski M, et al. Impact of induction regimen and allogeneic hematopoietic cell transplantation on outcome in younger adults with acute myeloid leukemia with a monosomal karyotype. Haematologica. 2019;104(6):1168-75. DOI:10.3324/haematol.2018.204826
13. Büchner T, Hiddemann W, Berdel WE, et al. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol. 2003;21(24):4496-504. DOI:10.1200/JCO.2003.02.133
14. Schmid C, Schleuning M, Tischer J, et al. Early allo-SCT for AML with a complex aberrant karyotype – results from a prospective pilot study. Bone Marrow Transplant. 2012;47:46-53. DOI:10.1038/bmt.2011.15
15. van Gelder M, de Wreede LC, Schetelig J, et al. Monosomal karyotype predicts poor survival after allogeneic stem cell transplantation in chromosome 7 abnormal myelodysplastic syndrome and secondary acute myeloid leukemia. Leukemia. 2013;27(4):879-88. DOI:10.1038/leu.2012.297
16. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. DOI:10.1182/blood-2018-08-868752
17. Bazarbachi A, Bug G, Baron F, et al. Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3-internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2020;105(6):1507‑16. DOI:10.3324/haematol.2019.243410
2. Pollyea DA, Bixby D, Perl A, et al. NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021. J Natl Compr Canc Netw. 2021 Jan 6;19(1):16-27. doi: 10.6004/jnccn.2021.0002.
3. Cornelissen JJ, Gratwohl A, Schlenk RF, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012;9(10):579-90. DOI:10.1038/nrclinonc.2012.150
4. Ye XN, Zhou XP, Wei JY, et al. Epigenetic priming with decitabine followed by low-dose idarubicin/cytarabine has an increased anti-leukemic effect compared to traditional chemotherapy in high-risk myeloid neoplasms. Leuk Lymphoma. 2016;57(6):1311-8. DOI:10.3109/10428194.2015.1091931
5. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-240. DOI:10.1182/blood-2016-03-643544
6. Anelli L, Pasciolla C, Zagaria A, et al. Monosomal karyotype in myeloid neoplasias: a literature review. Onco Targets Ther. 2017;10:2163-71. DOI:10.2147/OTT.S133937
7. Brands-Nijenhuis AV, Labopin M, Schouten HC, et al. Monosomal karyotype as an adverse prognostic factor in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem-cell transplantation in first complete remission: a retrospective survey on behalf of the ALWP of the EBMT. Haematologica. 2016;101(2):248-55. DOI:10.3324/haematol.2015.132654
8. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016;374:2209-21. DOI:10.1056/NEJMoa1516192
9. Rogers HJ, Vardiman JW, Anastasi J, et al. Complex or monosomal karyotype and not blast percentageis associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014;99(5):821-9.
DOI:10.3324/haematol.2013.096420
10. Parovichnikova EN, Lukianova IA, Troitskaya VV, et al. Results of program acute myeloid leukemia therapy use in National medical research center for hematology of the Ministry of Health of Russian Federation. Terapevticheskii Arkhiv (Ter. Arkh.). 2018;90(7):14‑22 (in Russian) DOI:10.26442/terarkh201890714-22
11. Büchner T, Berdel WE, Schoch C, et al. Double induction containing either two courses or one course of high-dose cytarabine plus mitoxantrone and postremission therapy by either autologous stem-cell transplantation or by prolonged maintenance for acute myeloid leukemia. J Clin Oncol. 2006;24(16):2480-9. DOI:10.1200/JCO.2005.04.5013
12. Baron F, Stevens-Kroef M, Kicinski M, et al. Impact of induction regimen and allogeneic hematopoietic cell transplantation on outcome in younger adults with acute myeloid leukemia with a monosomal karyotype. Haematologica. 2019;104(6):1168-75. DOI:10.3324/haematol.2018.204826
13. Büchner T, Hiddemann W, Berdel WE, et al. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol. 2003;21(24):4496-504. DOI:10.1200/JCO.2003.02.133
14. Schmid C, Schleuning M, Tischer J, et al. Early allo-SCT for AML with a complex aberrant karyotype – results from a prospective pilot study. Bone Marrow Transplant. 2012;47:46-53. DOI:10.1038/bmt.2011.15
15. van Gelder M, de Wreede LC, Schetelig J, et al. Monosomal karyotype predicts poor survival after allogeneic stem cell transplantation in chromosome 7 abnormal myelodysplastic syndrome and secondary acute myeloid leukemia. Leukemia. 2013;27(4):879-88. DOI:10.1038/leu.2012.297
16. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. DOI:10.1182/blood-2018-08-868752
17. Bazarbachi A, Bug G, Baron F, et al. Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3-internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2020;105(6):1507‑16. DOI:10.3324/haematol.2019.243410
2. Pollyea DA, Bixby D, Perl A, et al. NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021. J Natl Compr Canc Netw. 2021 Jan 6;19(1):16-27. doi: 10.6004/jnccn.2021.0002.
3. Cornelissen JJ, Gratwohl A, Schlenk RF, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012;9(10):579-90. DOI:10.1038/nrclinonc.2012.150
4. Ye XN, Zhou XP, Wei JY, et al. Epigenetic priming with decitabine followed by low-dose idarubicin/cytarabine has an increased anti-leukemic effect compared to traditional chemotherapy in high-risk myeloid neoplasms. Leuk Lymphoma. 2016;57(6):1311-8. DOI:10.3109/10428194.2015.1091931
5. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-240. DOI:10.1182/blood-2016-03-643544
6. Anelli L, Pasciolla C, Zagaria A, et al. Monosomal karyotype in myeloid neoplasias: a literature review. Onco Targets Ther. 2017;10:2163-71. DOI:10.2147/OTT.S133937
7. Brands-Nijenhuis AV, Labopin M, Schouten HC, et al. Monosomal karyotype as an adverse prognostic factor in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem-cell transplantation in first complete remission: a retrospective survey on behalf of the ALWP of the EBMT. Haematologica. 2016;101(2):248-55. DOI:10.3324/haematol.2015.132654
8. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016;374:2209-21. DOI:10.1056/NEJMoa1516192
9. Rogers HJ, Vardiman JW, Anastasi J, et al. Complex or monosomal karyotype and not blast percentageis associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome patients with inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Marrow Pathology Group study. Haematologica. 2014;99(5):821-9.
DOI:10.3324/haematol.2013.096420
10. Паровичникова Е.Н., Лукьянова И.А., Троицкая В.В., и др. Результаты программной терапии острых миелоидных лейкозов в ФГБУ «НМИЦ гематологии» Минздрава России. Терапевтический архив. 2018;90(7):14-22 [Parovichnikova EN, Lukianova IA, Troitskaya VV, et al. Results of program acute myeloid leukemia therapy use in National medical research center for hematology of the Ministry of Health of Russian Federation. Terapevticheskii Arkhiv (Ter. Arkh.). 2018;90(7):14‑22 (in Russian)]. DOI:10.26442/terarkh201890714-22
11. Büchner T, Berdel WE, Schoch C, et al. Double induction containing either two courses or one course of high-dose cytarabine plus mitoxantrone and postremission therapy by either autologous stem-cell transplantation or by prolonged maintenance for acute myeloid leukemia. J Clin Oncol. 2006;24(16):2480-9. DOI:10.1200/JCO.2005.04.5013
12. Baron F, Stevens-Kroef M, Kicinski M, et al. Impact of induction regimen and allogeneic hematopoietic cell transplantation on outcome in younger adults with acute myeloid leukemia with a monosomal karyotype. Haematologica. 2019;104(6):1168-75. DOI:10.3324/haematol.2018.204826
13. Büchner T, Hiddemann W, Berdel WE, et al. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol. 2003;21(24):4496-504. DOI:10.1200/JCO.2003.02.133
14. Schmid C, Schleuning M, Tischer J, et al. Early allo-SCT for AML with a complex aberrant karyotype – results from a prospective pilot study. Bone Marrow Transplant. 2012;47:46-53. DOI:10.1038/bmt.2011.15
15. van Gelder M, de Wreede LC, Schetelig J, et al. Monosomal karyotype predicts poor survival after allogeneic stem cell transplantation in chromosome 7 abnormal myelodysplastic syndrome and secondary acute myeloid leukemia. Leukemia. 2013;27(4):879-88. DOI:10.1038/leu.2012.297
16. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. DOI:10.1182/blood-2018-08-868752
17. Bazarbachi A, Bug G, Baron F, et al. Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3-internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. 2020;105(6):1507‑16. DOI:10.3324/haematol.2019.243410
________________________________________________
2. Pollyea DA, Bixby D, Perl A, et al. NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021. J Natl Compr Canc Netw. 2021 Jan 6;19(1):16-27. doi: 10.6004/jnccn.2021.0002.
3. Cornelissen JJ, Gratwohl A, Schlenk RF, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol. 2012;9(10):579-90. DOI:10.1038/nrclinonc.2012.150
4. Ye XN, Zhou XP, Wei JY, et al. Epigenetic priming with decitabine followed by low-dose idarubicin/cytarabine has an increased anti-leukemic effect compared to traditional chemotherapy in high-risk myeloid neoplasms. Leuk Lymphoma. 2016;57(6):1311-8. DOI:10.3109/10428194.2015.1091931
5. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-240. DOI:10.1182/blood-2016-03-643544
6. Anelli L, Pasciolla C, Zagaria A, et al. Monosomal karyotype in myeloid neoplasias: a literature review. Onco Targets Ther. 2017;10:2163-71. DOI:10.2147/OTT.S133937
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Авторы
Е.Н. Паровичникова*, И.А. Лукьянова, В.В. Троицкая, М.Ю. Дроков, Л.А. Кузьмина, А.Н. Соколов, А.В. Кохно, З.Т. Фидарова, И.В. Гальцева, Ю.О. Давыдова, А.И. Кашлакова, Е.О. Грибанова, Е.Е. Звонков, Е.П. Сысоева, В.Н. Двирнык, Т.Н. Обухова, А.Б. Судариков, Ю.В. Сидорова, С.М. Куликов, Ю.А. Чабаева, В.Г. Савченко
ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия
*elenap@blood.ru
National Research Center for Hematology, Moscow, Russia
*elenap@blood.ru
ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия
*elenap@blood.ru
________________________________________________
National Research Center for Hematology, Moscow, Russia
*elenap@blood.ru
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