Long-Term Outcomes of Immunosuppressive Therapy for Aplastic Anemia: A Single-Center Experience

AUTOIMMUNE THROMBOCYTOPENIA

ER Shilova, NA Romanenko, DA Chebykina, TV Glazanova, MN Zenina, IE Pavlova, SS Bessmeltsev

Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024

For correspondence: Elena Romanovna Shilova, MD, PhD, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024; Tel.: +7(981)129-09-77; e-mail: rniiht@mail.ru

For citation: Shilova ER, Romanenko NA, Chebykina DA, et al. Long-Term Outcomes of Immunosuppressive Therapy for Aplastic Anemia: A Single-Center Experience. Clinical oncohematology. 2023;16(3):321–30. (In Russ).

DOI: 10.21320/2500-2139-2023-16-3-321-330

ABSTRACT

Background. Bone marrow transplantation-ineligible aplastic anemia (AA) is most effectively treated with combined immunosuppressive therapy (IST). It yields remissions in most patients. However, it has such disadvantages as frequent relapses, incomplete hematologic recovery, and clonal evolution risk. Besides, АА is not always treated according to standard regimens. For different reasons, some AA patients receive delayed therapy or IST mono-treatment predominantly with cyclosporine A (CsA).

Aim. To assess long-term IST outcomes in AA patients followed-up at the Russian Research Institute of Hematology and Transfusiology for 5 years after therapy onset.

Materials & Methods. The study enrolled 30 AA patients who received IST for more than 5 years (continuous follow-up of 5.5–33 years) with monitoring of the main hemogram parameters and PNH clone size. Patients were aged 19–73 years (median 29 years). There were 8 women and 12 men. Based on international criteria, severe AA (SAA) was initially diagnosed in 18 patients, and non-severe АА (NAA) was diagnosed in 12 patients. Combined IST was administered to 22 patients (18 SAA patients and 4 NAA patients), the remaining 8 patients received ATG (n = 1) and CsA (n = 7).

Results. A response to IST was achieved in 28 (93.3 %) out of 30 patients, 16 (53.3 %) of them showed complete remission. This paper documents the characteristics of hematologic recovery depending on the compliance with standard therapy regimens, as well as on the disease variant, development of late complications and clonal evolution, characteristics of pregnancy and childbirth in 4 female patients in remission. PNH clone increased in more than a half (10 out of 16) patients whose clone was initially > 2.6 %. Long-term clonal evolution to myeloid neoplasia (13 years after IST onset) was registered in 2 (6.7 %) patients with complete AA remission. Aseptic (avascular) osteonecrosis as complication was reported in 6 (20 %) followed-up patients.

Conclusion. The results of the study highlight the importance of and the need for early start and adherence to standard combined IST regimens aimed at optimum therapeutic effect in both SAA and NAA patients, as well as for long-term follow-up of patients after completing IST.

Keywords: aplastic anemia, immunosuppressive therapy, remission, complications, clonal evolution, PNH clone, pregnancy.

Received: March 7, 2023

Accepted: June 2, 2023

Read in PDF

Статистика Plumx английский

REFERENCES

  1. Михайлова Е.А., Фидарова З.Т., Троицкая В.В. и др. Клинические рекомендации по диагностике и лечению апластической анемии (редакция 2019 г.). Гематология и трансфузиология. 2020;65(2):208–26. doi: 10.35754/0234-5730-2020-65-2-208-226.
    [Mihailova EA, Fidarova ZT, Troitskaya VV, et al. Clinical recommendations for the diagnosis and treatment of aplastic anemia (2019 edition). Russian journal of hematology and transfusiology. 2020;65(2):208–26. doi: 10.35754/0234-5730-2020-65-2-208-226. (In Russ)]
  2. Young NS, Bacigalupo A, Marsh JC. Aplastic Anemia: Pathophysiology and Treatment. Biol Blood Marrow Transplant. 2010;16(1):S119–S125. doi: 10.1016/j.bbmt.2009.09.013.
  3. Абдулкадыров К.М., Бессмельцев С.С. Апластическая анемия. М.: Наука, 1995. 231 с.
    [Abdulkadyrov KM, Bessmeltsev SS. Aplasticheskaya anemiya. (Aplastic anemia.) Moscow: Nauka Publ.; 1995. 231 p. (In Russ)]
  4. Кулагин А.Д., Лисуков И.А., Козлов Н.А. Апластическая анемия: иммунопатогенез, клиника, диагностика, лечение. Новосибирск: Наука, 2008. 236 с.
    [Kulagin AD, Lisukov IA, Kozlov NA. Aplasticheskaya anemiya: immunopatogenez, klinika, diagnostika, lechenie. (Aplastic anemia: immunopathogenesis, clinic, diagnosis, therapy.) Novosibirsk: Nauka Publ.; 2008. 236 p. (In Russ)]
  5. Михайлова Е.А., Фидарова З.Т., Устинова Е.Н. и др. Комбинированная иммуносупрессивная терапия больных апластической анемией: эффективность повторных курсов антитимоцитарного глобулина. Гематология и трансфузиология. 2014;59(4):11–8.
    [Mikhailova EA, Fidarova ZT, Ustinova EN, et al. Combined immunosuppressive therapy in patients with aplastic anemia: efficiency of repeated antithymocyte globulin courses. Gematologiya i transfuziologiya. 2014;59(4):11–8. (In Russ)]
  6. DeLatour P, 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(5):635–42. doi: 10.1002/ajh.25050
  7. Young NS. Current concepts in the pathophysiology and treatment of aplastic anemia. Hematology Am Soc Hematol Educ Program. 2013;2013(1):76–81. doi: 10.1182/asheducation-2013.1.76.
  8. Frickhofen N, Heimpel H, Kaltwasser JP, et al. Anti-thymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood. 2003;101(4):1236–42. doi: 10.1182/ blood-2002–04–1134.
  9. Marsh JC, Hows JM, Bryett KA, et al. Survival after antilymphocyte globulin therapy for aplastic anemia depends on disease severity. Blood. 1987;70(4):1046–52.
  10. Kulagin AD, Ivanova MO, Golubovskaya IK, et al. The horse ATG (ATGAM) total dose of 160 mg/kg as compared with 100 mg/kg is superior in achieving haematological response in aplastic anaemia patients. Bone Marrow Transplant. 2013;48(Suppl 2):
  11. Young N, Griffith P, Brittain E, et al. A multicenter trial of antithymocyte globulin in aplastic anemia and related diseases. Blood. 1988;72(6):1861–9.
  12. Абдулкадыров К.М., Ганапиев А.А., Шилова Е.Р. и др. Результаты лечения больных апластической анемией различными дозами антилимфоцитарного глобулина. Терапевтический архив. 1995;67(8):51–4.
    [Abdulkadyrov KM, Ganapiev AA, Shilova ER, et al. The treatment results in patients with aplastic anemia using different doses of antilymphocyte globulin. Terapevticheskii arkhiv. 1995;67(8):51–4. (In Russ)]
  13. Saracco P, Quarello P, Iori A, et al. Cyclosporin A response and dependence in children with acquired aplastic anaemia: a multicentre retrospective study with long-term observation follow up. Br J Haematol. 2008;140(2):197–205. doi: 10.1111/j.1365-2141.2007.06903.x.
  14. Scheinberg P. Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries. Br J Haematol. 2021;194(6):954–69. doi: 10.1111/bjh.17403.
  15. Olnes MJ, P. Scheinberg, KR Calvo, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367(1):11–9. doi: 10.1056/NEJMoa1200931.
  16. DeLatour RP, Kulasekararaj A, Iacobelli S, et al. Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med. 2022;386(1):11–23. doi: 10.1056/NEJMoa2109965.
  17. Camitta BM. What is the definition of cure for aplastic anemia? Acta Haematol. 2000;103(1):16–8. doi: 10.1159/000040999.
  18. Rosenfeld S, Follman D, Nuez O, et al. Antithymocyte globulin and cyclosporine for severe aplastic anemia. Association between hematologic response and long-term outcome. JAMA. 2003;289(9):1130–5. doi: 10.1001/jama.289.9.1130.
  19. Tichelli A, de Latour RP, Passweg J, et al.; SAA Working Party of the EBMT. Long-term outcome of a randomized controlled study in patients with newly diagnosed severe aplastic anemia treated with antithymocyte globulin and cyclosporine, with or without granulocyte colony-stimulating factor: a Severe Aplastic Anemia Working Party Trial from the European Group of Blood and Marrow Transplantation. Haematologica. 2020;105(5):1223–31. doi: 10.3324/haematol.2019.222562.
  20. Groarke EM, Patel BA, Shalhoub R, et al. Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia. 2022;36(9):2328–37. doi: 10.1038/s41375-022-01636-8.
  21. Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172(2):187–207. doi: 10.1111/bjh.13853.
  22. Кулагин А.Д., Лисуков И.А., Птушкин В.В. и др. Национальные клинические рекомендации по диагностике и лечению пароксизмальной ночной гемоглобинурии. Онкогематология. 2014;9(2):20–8. doi: 10.17650/1818-8346-2014-9-2-20-28.
    [Kulagin AD, Lisukov IA, Ptushkin VV, et al. National clinical guidelines for the diagnosis and treatment of paroxysmal nocturnal hemoglobinuria. Oncohematology. 2014;9(2):20–8. doi: 10.17650/1818-8346-2014-9-2-20-28. (In Russ)]
  23. Borowitz, MJ, Craig, FE, Digiuseppe JA, et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom. 2012;78(4):211–30. doi: 10.1002/cyto.b.20525.
  24. Шилова Е.Р., Глазанова Т.В., Кострома И.И. и др. Клональная эволюция апластической анемии (краткий обзор литературы и описание собственного клинического наблюдения). Клиническая онкогематология. 2022;15(3):298–306. doi: 10.21320/2500-2139-2022-15-3-298-306.
    [Shilova ER, Glazanova TV, Kostroma II, et al. Clonal Evolution of Aplastic Anemia: A Brief Literature Review and a Case Report. Clinical oncohematology. 2022;15(3):298–306. doi: 10.21320/2500-2139-2022-15-3-298-306. (In Russ)]
  25. Кулагин А.Д. Клинико-гематологические и иммунологические критерии долгосрочного прогноза приобретенной апластической анемии: Дис.… д-ра мед. наук. СПб., 2015.
    [Kulagin AD. Kliniko-gematologicheskie i immunologicheskie kriterii dolgosrochnogo prognoza priobretennoi aplasticheskoi anemii. (Clinical, hematological, and immunological criteria for long-term prognosis of acquired aplastic anemia.) [dissertation] Saint Petersburg; 2015. (In Russ)]
  26. Scheinberg P, Rios OJ, Scheinberg P, et al. Prolonged cyclosporine administration after antithymocyte globulin delays but does not prevent relapse in severe aplastic anemia. Am J Hematol. 2014;89(6):571–4. doi: 10.1002/ajh.2369.
  27. Kulagin A, Lisukov I, Ivanova M, et al. Prognostic value of paroxysmal nocturnal haemoglobinurea clone presence in aplastic anaemia patients treated with combined immunosuppression: results of two-centre prospective study. Br J Haematol. 2014;164(4):546–54. doi: 10.1111/bjh.12661.
  28. Фидарова З.Т., Михайлова Е.А., Гальцева И.В. и др. Динамика ПНГ-клона у больных апластической анемией в процессе иммуносупрессивной терапии. Клиническая лабораторная диагностика. 2016;61(8):490–4. doi: 10.18821/0869-2084-2016-61-8-490-494.
    [Fidarova ZT, Mikhailova EA, Galtseva IV, et al. The dynamics of paroxysmal nocturnal hemoglobinuria clone in patients with aplastic anemia in process of immune suppressive therapy. Klinicheskaya laboratornaya diagnostika. 2016;61(8):490–4. doi: 10.18821/0869-2084-2016-61-8-490-494. (In Russ)]
  29. Шилова Е.Р., Глазанова Т.В., Чубукина Ж.В. и др. Пароксизмальная ночная гемоглобинурия у пациентов с апластической анемией: проблемы, особенности, анализ клинического наблюдения. Клиническая онкогематология. 2019;12(3):319–28. doi: 10.21320/2500-2139-2019-12-3-319-328.
    [Shilova ER, Glazanova TV, Chubukina ZhV, et al. Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia: Challenges, Characteristics, and Analysis of Clinical Experience. Clinical oncohematology. 2019;12(3):319–28. doi: 10.21320/2500-2139-2019-12-3-319-328. (In Russ)]
  30. Wanachiwanawin W, Siripanyaphinyo U, Piyawattanasakul N, Kinoshita T. A cohort study of the nature of paroxysmal nocturnal hemoglobinuria clones and PIG-A mutations in patients with aplastic anemia. Eur J Haematol. 2006;76(6):502–9. doi: 10.1111/j.0902-4441.2005.t01-1-EJH2467.
  31. Marsh JC, Kulasekararaj AG. Management of the refractory aplastic anemia patient: what are the options? Blood. 2013;122(2):3561–7. doi: 10.1182/blood-2013-05-498279.
  32. Ogawa S. Clonal hematopoiesis in acquired aplastic anemia. 2016;128(3):337–47. doi: 10.1182/blood-2016-01-636381.
  33. Sun L, Babushok DV. Secondary myelodysplastic syndrome and leukemia in acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria. Blood. 2020;136(1):36–49. doi: 10.1182/blood.2019000940.
  34. Kojima S, Ohara A, Tsuchida M, еt al. Risk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosupressive therapy in children. Blood. 2002;100(3):786–90. doi: 10.1182/blood.v100.3.786.
  35. Korkama E-S, Armstrong A-E, Jarva H, еt al. Spontaneous remission in paroxysmal nocturnal hemoglobinuria-return to health or transition into malignancy? Front Immunol. 2018;9:1749. doi: 10.3389/fimmu.2018.01749.
  36. Golubovskaya IK, Kulagin AD, Rudnitskaya YV, et al. Myelodysplastic syndrome/acute myeloid leukemia evolving from aplastic anemia: Efficacy of hematopoietic stem cell transplantation. Cell Ther Transplant. 2018;2(23):36–44. doi: 10.18620/ctt-1866-8836-2018-7-2-36-44.
  37. Tichelli, A, Soci, G, Marsh, JC, et al. Outcome of Pregnancy and Disease Course among Women with Aplastic Anemia Treated with Immunosuppression. Ann Intern Med. 2002;137(3):164–72. doi: 10.7326/0003-4819-137-3-200208060-00008.