Иммуносупрессивная терапия больных апластической анемией: успехи и неудачи (одноцентровое исследование 2007–2016 гг.) - Журнал Терапевтический архив №7 Вопросы гематологии 2020

Иммуносупрессивная терапия больных апластической анемией: успехи и неудачи (одноцентровое исследование 2007–2016 гг.)

Михайлова Е.А., Фидарова З.Т., Абрамова А.В. и др. Иммуносупрессивная терапия больных апластической анемией: успехи и неудачи (одноцентровое исследование 2007–2016 гг.). Терапевтический архив. 2020; 92 (7): 4–9.
DOI: 10.26442/00403660.2020.07.000756

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Mikhaylova E.A., Fidarova Z.T., Abramova A.V., et al. Immunosupressive therapy of aplastic anemia patients: successes and failures (single center experiment 2007–2016). Therapeutic Archive. 2020; 92 (7): 4–9. DOI: 10.26442/00403660.2020.07.000756

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Аннотация

Современные программы лечения больных апластической анемией (АА) включают два основных терапевтических направления: трансплантацию аллогенного костного мозга и комбинированную иммуносупрессивную терапию (ИСТ). Методом выбора для большинства взрослых больных АА остается комбинированная ИСТ. В данную работу первоначально включены 130 пациентов с АА, получавших ИСТ в ФГБУ «НМИЦ гематологии» в 2007–2016 гг., анализ эффективности ИСТ проводился у 120 больных. Медиана возраста составила 25 (17–65) лет, 70 мужчин и 50 женщин, у 66% больных диагностирована тяжелая АА и у 34% – нетяжелая. Анализ эффективности ИСТ выполнялся у 120 больных АА. В группу анализа не включены 8 больных тяжелой АА, умерших в течение первых 3 мес от начала лечения от тяжелых инфекционных осложнений (ранние смерти – 6,2%), и 2 больных АА, течение заболевания которых неизвестно. Медиана продолжительности наблюдения – 55 (6–120) мес. Клон пароксизмальной ночной гемоглобинурии выявлен у 67% больных АА, медиана его размера по гранулоцитам – 2,5 (0,01–99,5)%. Лечение проводилось по классическому протоколу комбинированной ИСТ: лошадиный антитимоцитарный глобулин (АТГ) и циклоспорин А. У 87% больных достигнут положительный ответ на комбинированную ИСТ. Для получения положительного ответа оказалось достаточным проведение одного курса терапии АТГ 74% больных, 2 курсов АТГ – 24%, и 2% потребовалось 3 курса АТГ. У большинства больных (93%) гематологический ответ получен через 3–6 мес от начала лечения. Поэтому 3–6-й месяцы после 1-го курса АТГ при отсутствии ответа на 1-ю линию терапии можно считать оптимальным сроком проведения 2-го курса АТГ. Такая тактика позволяет получить ответ еще у 58% больных, не ответивших на 1-й курс терапии АТГ. Вероятность 10-летней общей выживаемости составила 90% (95% доверительный интервал 83,6–96,2).

Ключевые слова: идиопатическая апластическая анемия, приобретенная апластическая анемия, иммуносупрессивная терапия, антитимоцитарный глобулин, клон пароксизмальной ночной гемоглобинурии.

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Treatment programs for patients with acquired aplastic anemia include two main therapeutic options: allogeneic bone marrow transplantation and combined immunosuppressive therapy (IST). However, combined IST remains the method of choice for most adult AA patients. This study included 120 AA patients who received IST at the National Research Center for Hematology in 2007–2016. The analysis was applied to 120 patients. Median age was 25 (17–65) years, M/F: 66/54, SAA/NSAA: 66%/34%. Effectiveness of IST was carried out in 120 patients with AA. This group did not include 8 SAA patients who died during the first 3 months from the start of treatment from severe infectious complications (early deaths – 6.2%) and 2 AA patients who dropped out of surveillance. The observation time was 55 (6–120) months. Paroxysmal nocturnal hemoglobinuria (PNH clone) was detected in 67% of AA patients. The median PNH clone size (granulocytes) was 2.5 (0.01–99.5)%. The treatment was according to the classical protocol of combined IST: horse antithymocytic globulin and cyclosporin A. Most of patients (87%) responded to combined immunosuppressive therapy. To achieve a positive response, it was sufficient to conduct one course of ATG to 64% of patients, two courses of ATG – 24% of patients and 2% of patients responded only after the third course of ATG. A positive response after the first course was obtained in 64% of patients included in the analysis. Most of the responding patients (93%) achieve a positive response after 3–6 months from the start of treatment. Therefore, the 3rd–6th months after the first course of ATG in the absence of an answer to the first line of therapy can be considered the optimal time for the second course of ATG. This tactic allows to get an answer in another 58% of patients who did not respond to the first course of ATG. The probability of an overall 10-year survival rate was 90% (95% confidence interval 83.6–96.2).

Keywords: idiopathic aplastic anemia, acquired aplastic anemia, immunosuppressive therapy, antithymocyte globulin, paroxysmal nocturnal hemoglobinuria, cyclosporin A.

Список литературы

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2. Kordasti S, Costantini B, Seidl T, et al. Deep phenotyping of tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment. Blood. 2016;128:1193-205. doi: 10.1182/blood-2016-03-703702
3. Risitano AM, Maciejewski JP, Green S, et al. In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing. Lancet (London, England). 2004;364:35564. doi: 10.1016/S0140-6736(04)16724-X
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8. Scheinberg P. Aplastic anemia: therapeutic updates in immunosuppression and transplantation. Hematology Am Soc Hematol Educ Program. 2012;2012:292-300. doi: 10.1182/asheducation-2012.1.292
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doi: 10.1182/blood-2016-08-693481
12. Peffault de Latour R, Tabrizi R, Marcais A, et al. Nationwide survey on the use of horse antithymocyte globulins (ATGAM) in patients with acquired aplastic anemia: A report on behalf of the French Reference Center for Aplastic Anemia. Am J Hematol. 2018;93:635-42. doi: 10.1002/ajh.25050
13. Alashkar F, Oelmuller M, Herich-Terhurne D, et al. Immunosuppressive therapy (IST) in adult patients with acquired aplastic anemia (AA): A single-center experience over the past 15 years. Eur J Haematol. 2019;103:18-25. doi: 10.1111/ejh.13235
14. Kulagin A, Lisukov I, Ivanova M, et al. Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: Results of two-centre prospective study. Br J Haematol. 2014;164:546-54. doi: 10.1111/bjh.12661
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Br J Haematol. 2009;144:206-16. doi: 10.1111/j.1365-2141.2008.07450.x
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22. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818-25. doi: 10.1182/blood-2013-10-534743
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25. Scheinberg P. Activity of eltrombopag in severe aplastic anemia. Blood Adv. 2018;2:450-6. doi: 10.1182/bloodadvances.2018020248

________________________________________________

1. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108:2509-19. doi: 10.1182/blood-2006-03-010777
2. Kordasti S, Costantini B, Seidl T, et al. Deep phenotyping of tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment. Blood. 2016;128:1193-205. doi: 10.1182/blood-2016-03-703702
3. Risitano AM, Maciejewski JP, Green S, et al. In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing. Lancet (London, England). 2004;364:35564.
doi: 10.1016/S0140-6736(04)16724-X
4. Medinger M, Drexler B, Lengerke C, Passweg J. Pathogenesis of acquired aplastic anemia and the role of the bone marrow microenvironment. Front Oncol. 2018;8:1-10. doi: 10.3389/fonc.2018.00587
5. Young NS. Aplastic Anemia. N Engl J Med. 2018;379:1643-56.
doi: 10.1056/NEJMra1413485
6. Luzzatto L, Risitano AM. Advances in understanding the pathogenesis of acquired aplastic anaemia. Br J Haematol. 2018;182:758-76. doi: 10.1111/bjh.15443
7. Bacigalupo A, Giammarco S, Sica S, et al. Bone marrow transplantation versus immunosuppressive therapy in patients with acquired severe aplastic anemia. Int J Hematol. 2016;104:168-74. doi: 10.1007/s12185-016-2037-8
8. Scheinberg P. Aplastic anemia: therapeutic updates in immunosuppression and transplantation. Hematology Am Soc Hematol Educ Program. 2012;2012:292-300. doi: 10.1182/asheducation-2012.1.292
9. Townsley DM, Winkler T. Nontransplant therapy for bone marrow failure. ASH Educ Progr B. 2016;2016:83-9. doi: 10.1182/asheducation-2016.1.83
10. Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172:187-207. doi: 10.1111/bjh.13853
11. Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017;129:1428-36. doi: 10.1182/blood-2016-08-693481
12. Peffault de Latour R, Tabrizi R, Marcais A, et al. Nationwide survey on the use of horse antithymocyte globulins (ATGAM) in patients with acquired aplastic anemia: A report on behalf of the French Reference Center for Aplastic Anemia. Am J Hematol. 2018;93:635-42. doi: 10.1002/ajh.25050
13. Alashkar F, Oelmuller M, Herich-Terhurne D, et al. Immunosuppressive therapy (IST) in adult patients with acquired aplastic anemia (AA): A single-center experience over the past 15 years. Eur J Haematol. 2019;103:18-25. doi: 10.1111/ejh.13235
14. Kulagin A, Lisukov I, Ivanova M, et al. Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anaemia patients treated with combined immunosuppression: Results of two-centre prospective study. Br J Haematol. 2014;164:546-54. doi: 10.1111/bjh.12661
15. Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009;144:206-16. doi: 10.1111/j.1365-2141.2008.07450.x
16. Scheinberg P, Cooper JN, Sloand EM, et al. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA. 2010;304:1358-64.
doi: 10.1001/jama.2010.1376
17. Bacigalupo A. Antithymocyte globulin and transplants for aplastic anemia. Haematologica. 2017;102:1137-8. doi: 10.3324/haematol.
2017.171538
18. Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365:430-8. doi: 10.1056/NEJMoa1103975
19. Mikhailova EA, Fidarova ZT, Ustinova EN, et al. Combined immunosuppressive therapy of aplastic anemia: repeated courses of horse antithymocytic globulin. Gematologiya i transfusiologiya. 2014;59:11-8 (In Russ.)
20. Mikhailova EA, Fidarova ZT, Troitskaya VV, et al. Protocol of progamm treatment aplastic anemia patients: combined immunosupressive therapy. In Algoritmy diagnostiki i protokoly lechenia zabolevaniy sistemy krovi. Moscow: Practika, 2018; p. 213-30 (In Russ.)
21. Desmond R, Townsley DM, Dunbar C, Young NS. Eltrombopag in Aplastic Anemia. Semin Hematol. 2015;52(1):31-7. doi: 10.1053/
j.seminhematol.2014.10.002
22. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818-25. doi: 10.1182/blood-2013-10-534743
23. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11-9. doi: 10.1056/NEJMoa1200931
24. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017;376:1540-50. doi: 10.1056/NEJMoa1613878
25. Scheinberg P. Activity of eltrombopag in severe aplastic anemia. Blood Adv. 2018;2:450-6. doi: 10.1182/bloodadvances.2018020248

Авторы

Е.А. Михайлова, З.Т. Фидарова, А.В. Абрамова, А.В. Лучкин, В.В. Троицкая, В.Н. Двирнык, И.В. Гальцева, Г.А. Клясова, А.М. Ковригина, С.М. Куликов, Ю.А. Чабаева, Е.Н. Паровичникова, В.Г. Савченко, Т.Н. Обухова

ФГБУ «Национальный медицинский исследовательский центр гематологии» Минздрава России, Москва, Россия

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E.A. Mikhaylova, Z.T. Fidarova, A.V. Abramova, A.V. Luchkin, V.V. Troitskaya, V.N. Dvirnyk, I.V. Galtseva, G.A. Kliasova, A.M. Kovrigina, S.M. Kulikov, Iu.А. Chabaeva, E.N. Parovichnikova, V.G. Savchenko, T.N. Obukhova

National Research Center for Hematology, Moscow, Russia

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