Immunosuppressive therapy combining anti-thymocyte globulin and cyclosporine A in childhood acquired aplastic anaemia – long term-outcomes and risks

Czech version

Authors: M. Suková ¹; E. Mejstříková ²; V. Campr ³; E. Vodičková ⁴; P. Smíšek ¹; P. Keslová ¹; P. Sedláček ¹; L. Šrámková ¹; V. Vávra ¹; E. Pindurová ¹; Z. Zemanová ⁵; J. Starý ¹
Authors‘ workplace: Klinika dětské hematologie a onkologie, 2. lékařská fakulta UK a FN v Motole, Praha ¹; Laboratoř průtokové cytometrie CLIP, 2. lékařská fakulta UK a FN v Motole, Praha ²; Ústav lékařské patologie, 2. lékařská fakulta UK a FN v Motole, Praha ³; Oddělení klinické hematologie FN v Motole, Praha ⁴; Laboratoř nádorové cytogenetiky, 1. lékařská fakulta UK, Praha ⁵
Published in: Transfuze Hematol. dnes,18, 2012, No. 3, p. 112-123.
Category: Comprehensive Reports, Original Papers, Case Reports

Overview

In patients with acquired aplastic anaemia (AA), autoimmunity has been shown to play an important role in the pathogenesis. Therefore immunosuppressive therapy combining cyclosporine A (CsA) and antithymocyte globulin (ATG) is currently a standard treatment regimen for paediatric patients with AA, if a matched sibling donor is not available. Response rate approximately 70% and a 10-20% risk of clonal evolution (paroxysmal nocturnal haemoglobinuria, myelodysplastic syndrome, acute myeloid leukaemia) are the main limitations of IST compared to allogeneic stem cell transplantation (MSD-SCT). Long-term experience with AA management is presented through a cohort of paediatric patients diagnosed with aplastic anaemia between 1996 and 2009 in the Czech Republic. A total of 72 children with a median age of 10.5 yrs (1.6-17.9 yrs) met the criteria of aplastic anaemia. First-line therapy followed HLA-identical sibling donor availability - 18 patients underwent MSD-SCT and 54 were given immunosuppressive therapy (IST). Overall survival (OS) at a median follow-up of 7 years was 96±3.5% in the SCT group and 92±3.8% in the IST group. There was a significant difference between 7-year EFS in the SCT group (92.3±7.4%) and in the IST group (58±7.1%). Overall response to IST was 76%. Cummulative relapse rate 22%, with 75% probability of response to repeated courses of IST. First-line IST failure and relapse treatment non-response in 12 patients was managed by stem cell transplantation from an alternative donor (MUD-SCT) followed by 5-year OS 80%. No MDS/AML clonal transformation was registered within a 7-year median follow-up after IST. PNH clonal evolution was registered in 7 out of 37 evaluated patients (19%) at a median interval of 108 months from start of IST. Five of these patients presented with clinical or laboratory symptoms of PNH including two thrombotic events. Only two patients were asymptomatic, with a subclinical course typical of PNH/AA syndrome. The cumulative risk of PNH evolution following immunosuppressive treatment for aplastic anaemia is 2.2%...4.6% ...7.2%...19.8% 2, 4, 6 and 10 years from start of treatment. IST should be considered an effective alternative first-line therapy for paediatric aplastic anaemia, with acceptable toxicity facilitating at least temporary disease control in patients lacking a matched sibling donor. From a long-term perspective not relapses, but PNH clonal evolution including symptomatic haemolytic and thrombotic forms are of a major concern in therapy consequencies.

Key words:
aplastic anaemia, immunosuppressive therapy, antithymocyte globulin, response, relapse, PNH, clonal evolution

Sources

1. Young NS, Calado RT, Scheinberg P, et al. Current concepts in the patophysiology and treatment of aplastic anemia. Blood 2006; 108: 2509-2519.

2. Hrodek O, Hyniová H, Chudomel V. Dřeňové útlumy u dětí. Čs Pediatrie 1982; 37: 562-570.

3. Davies JK, Guinan EC. An update on the management of severe idiopathic aplastic anaemia in children. Br J Haematol 2007; 136: 549-564.

4. Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmeier H. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood 2003; 101: 1236-1242.

5. Fuhrer M, Burdech S, Ebell W, et al. Relapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience. German/Austrian Pediatric Aplastic Anemia Working Group. Klin Pediatr 1998; 210: 173-179.

6. Kojima S, Horine K, Inaba J, et al. Long term outcome of acquired aplastic anaemia in children: comparison between immunosuppressive therapy and bone marrow transplantation. Br J Haematol 2000; 111: 321-328.

7. Tichelli A, Gratwohl A, Nissen C, et al. Late clonal complications in severe aplastic anemia. Leuk Lymphoma 1994; 12: 167-175.

8. Socie G, Rosenfeld S, Frickhofen N, et al. Late clonal diseases of treated aplastic anemia. Semin Hematol 2000; 37: 91-101.

9. Kojima S, Ohara A, Tsuchida M, et al. Risk factors for evolution of acquired aplastic anaemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood 2002; 100: 766-790.

10. Fuhrer M, Rampf U, Baumann I, et al. Immunosuppressive therapy for aplastic anemia in children: a more severe disease predicts better survival. Blood 2005; 106: 2102-2104.

11. Lee JJ, Kook H, Chung IJ, et al. Telomere length changes in patients with aplastic anaemia. Br J Haematol 2001; 112: 1026-1030.

12. Calado RT, Young NS. Telomere maintenance and human bone marrow failure. Blood 2008; 111: 4446-4455.

13. Scheinberg P, Cooper JN, Sloand EM, et al. Association of telomerase length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA 2010; 304: 1358-1364.

14. Young NS, Maciejewski JP, Sloand E, et al. The ralationship of aplastic anemia and PNH: Int J Hematol 2002; 76 (suppl 2): 168-172.

15. Maciejewski JP, Rivera C, Kook H, Dunn D, Young NS. Relationship between bone marrow failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-deficient clonek. Br J Haematol 2001; 115: 1015-1022.

16. Scheinberg P, Male M, Nunez O, Young NS. PNH clones in severe aplastic anemia patients treated with horse antithymocyte globuline plus cyclosporine A. Haematologica 2010; 95: 1075-1080.

17. Ware RE, Hall SE, Rosse WF. Paroxysmal nocturnal hemoglobinuria with onset in childhood and adolescence. N Engl J Med 1991; 325: 991-996.

18. van den Heuvel-Eibrink M, Bredius RG, Winkel MI, et al. Childhood paroxysmal nocturnal haemoglobinuria, a report of 11 cases in the Netherlands. Br J Haematol 2005; 128: 571-577.

19. Timeus F, Crescenzi O, Saracco P, et al. PNH clones in children wth acquired aplastic anemia - a prospective single centre study. Br J Haematol 2010; 150: 483-485.

20. Rosenfeld S, Fellmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia – association between hematologic response and long-term outcome. JAMA 2003; 289: 1130-1135.

21. Young NS. Paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes: clonal expansion of PIG-A mutant hematopoietic cells in bone marrow faiilure. Haematologica 2009; 94: 3-7.

22. de Latour Peffault R, Mary JY, Socie G, et al. Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 2008; 118: 3099-3106.

23. Starý J, Sedláček P, Kobylka P, et al. Významný pokrok v léčbě získané aplastické anémie u dětí v 90. letech. Čs Pediatrie 1998; 53: 260-266.

24. Saracco P, Quarello P, Zecca M, et al. Cyclosporine A response and dependence in children with acquired aplastic anemia - a multicentre retrospective study with long-term follow-up. Br J Haematol 2008; 140: 197-205.

25. Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood 1995; 85: 3367-3377.

26. Stadler M, Germing U, Kliche KO, et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patiens with low-risk myelodysplastic syndromes. Leukemia 2004; 18: 460-465.

27. Hall SE, Rosse WF. The use of monoclonal antibodies and flow cytometry in the diagnosis of paroxysmal nocturnal hemoglobinuria. Blood 1996; 87: 5332-5340.

28. Mortazavi Y, Merk B, Macintosh J, et al. The spectrum of PIG-A gene mutations in AA/PNH: a high incidence of multiple mutations and evidence of a mutational hot spot. Blood 2003; 101: 2833-2841.

29. Kaplan E, Meier P. Nonparametric estimation for incomplete observations. JASA 1958; 53: 457-481.

30. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163-170.

31. Gooley TA, Leisenring W, Crowley J, et al. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Ass 1999; 18: 695-706.

32. Pindurová E, Sedláček P, Keslová P, et al. Úloha alogenní transplantace buněk krvetvorby v léčbě získané aplastické anémie u dětí – zkušenost v České republice v letech 1991–2007. Transfuze hematol dnes 2011; 17: 122-129.

33. Tichelli A, Schrezenmeier H, Socié G, et al. A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood 2011; 117: 4434-4441.

34. Maciejewski JP, Selleri C. Evolution of clonal cytogenetic abnormalities in aplastic anemia. Leuk Lymphoma 2004; 45: 433-440.

35. Sloand EM, Kim S, Fuhrer M, et al. Fas-mediated apoptosis is important in regulative cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities. Blood 2002; 100: 4427-4432.

35. Locasciulli A, Oneto R, Bacigalupo A, et al. Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Bone and Marrow Transplantation (EBMT). Haematologica 2007; 92: 11-18.

36. Scheinberg P, Nunez O, Young NS. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med 2011; 365: 430-438.

37. Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol 2009; 144: 206-216.

38. Bacigalupo A, Socie G, Lanino E, et al. Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party. Haematologica 2010; 95: 976-982.

39. Tichelli A, Passweg J, Issen C, et al. Repeated treatment with horse antithymocyte globuline for severe aplastic anemia. Br J Haematol 1998; 100: 393-400.

40. Hill A, Richards SJ, Hillmen P. Recent developments in the understanding and management of paroxysmal nocturnal hemoglobinuria. Br J Haematol 2007; 137: 181-192.

41. Parker Ch, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria, Blood 2001; 106: 3699-3709.

Labels

Haematology Internal medicine Clinical oncology

Dasatinib in second line treatment of chronic myeloid leukaemia in patients with imatinib resistance or intolerance treated at the Clinic of Haematology and Transfusiology Bratislava between 2007 and 2011

Assessment of extramedullary leukemic infiltration in childhood acute lymphoblastic leukemia and its clinical use. Review and original data

A rare case of intestinal bleeding in patient with colorectal carcinoma on anticoagulation treatment

Article was published in

Transfusion and Haematology Today

2012 Issue 3