Updates in acquired aplastic anemia: Can we do more for our patients?


The purpose of this work is to present the results of allogeneic stem cell transplantation as therapy for patients diagnosed with acquired aplastic anemia in the Department of Bone Marrow Transplantation of Fundeni Clinical Institute and to elaborate an algorithm of treatment in aplastic anemia starting with the observations obtained from our clinical practice and following the European treatment guidelines in this group of patients.

Aplastic Anemia (AA) is a rare hematological disease characterized by pancytopenia and a hypocellular bone marrow. The paradigm of bone marrow failure syndromes, aplastic anemia is a diagnosis of exclusion despite the precision of its diagnosis criteria. Although AA is not a malignant disease, but an autoimmune disorder, the grave consequences of pancytopenia and clonal transformation into acute leukemia make it a potentially fatal condition.

The management of AA patients is challenging and necessitates a very well established treatment plan from the diagnosis.

We present the treatment algorithm for AA patients with recommendations based on both recent guidelines in the field and on our experience treating AA patients with allogeneic stem cell transplant. Therapeutic procedure algorithm comprises different approaches for different patient populations, age categories and availability of immunosuppression therapy or different types of donors.

According to the recent EBMT recommendations the treatment of choice for young patients (younger than 40 years) who have a matched sibling donor is hematopoietic stem cell transplantation (HSCT). For those patients who don’t have a matched sibling donor or are not candidates for HSCT due to older age, the immunosuppression with ATG and cyclosporine is an efficient treatment. The supportive care has an important role and the patients with aplastic anemia should be managed by a multidisciplinary team. For patients older than 40 years, the choice between immunosuppressive therapy (IST) and upfront transplant with HLA identical sibling donor remains a key question. However, the standard approaches for this category of patients is front line immunosuppression with ATG and cyclosporine and if they become refractory to at least one course of IST the allogeneic stem cell transplant using fludarabine-based conditioning is the second-line treatment option.

In our institution there were eleven AA patients treated with allogeneic stem cell transplantation from 2009 till 2015. They were all young patients with age between 19 and 42 years old and all had severe acquired aplastic anemia with transfusion dependence. Six cases were transplanted from a matched sibling donor and five patients had undergone an unrelated matched donor transplant. The allogeneic HSCT procedure was done both as front line therapy in the case of three patients and as second treatment choice in the rest of eight patients. Four patients died, three of them due to transplant related toxicity and one patient experienced severe autoimmune reaction with transfusion inefficacy complicated with intracerebral haemorrhage at four months from transplant.

In our opinion the most challenging aspect in treating AA patients is choosing the best treatment option taking into account the patient age and performance status, the severity of the disease and the availability of a donor for allogeneic HSCT.

Although the treatment strategy must be individualized in every patient case, it is necessary to make a standardization of treatment procedures in AA and to follow the evidence based recommendations available in the management of this rare disease.

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  • 1. Passweg J, et al. The complete treatment algorithm for SAA, EBMT, 2012, 1-41.

  • 2. Sureda A, et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2015, Bone Marrow Transplantation (2015), 1-20.

  • 3. Schrezenmeier et al. Aplastic Anemia- Diagnostics and Therapy of Acquired Aplastic Anemia, 2012, 1-15

  • 4. Passweg JR, et al. Aplastic Anemia: First-line Treatment by Immunosuppression and Sibling Marrow Transplantation, ASH, 2010.

  • 5. Guinan E. Diagnosis and Management of Aplastic Anemia, ASH, 2011.

  • 6. DeZern AE, Brodsky R. Clinical management of aplastic anemia, Expert Rev Hematol. 2011 Apr; 4(2): 221-230.

  • 7. 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 Blood and Marrow Transplantation (EBMT) Haematologica. 2007;92(1):11-18. Guidance for immunosuppressive therapy or bone marrow transplantation as first-line therapy.

  • 8. Lawler M, McCann SR, Marsh JC, et al. Serial chimerism analyses indicate that mixed haemopoietic chimerism influences the probability of graft rejection and disease recurrence following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA): indication for routine assessment of chimerism post SCT for SAA. Br. J. Haematol. 2009;144(6):933-945.

  • 9. Schrezenmeier H, Passweg JR, Marsh JC, et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood. 2007;110:1397-1400.

  • 10. Kahl C, Leisenring W, Deeg HJ, et al. Cyclophosphamide and anti-thymocyte globulin as a conditioning regimen for allogeneic marrow transplantation in patients with aplastic anaemia: a long-term follow-up. Br. J. Haematol. 2005;130(5):747-751.

  • 11. Bacigalupo A. Bone marrow transplantation for severe aplastic anemia from HLA identical siblings. Haematologica. 1999;84(1):2-4.

  • 12. Champlin RE, Perez WS, Passweg JR, et al. Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens. Blood. 2007;109(10):4582-4585.

  • 13. Al-Zahrani H, Nassar A, Al-Mohareb F, et al. Fludarabine based conditioning chemotherapy for allogeneic hematopoietic stem cell transplantation in acquired severe aplastic anemia. Biol. Blood Marrow Transplant. 2010 DOI: 10.1016/j. bbmt.2010.08.013.

  • 14. Maury S, et al. Improving outcome of patients older than 30 years receiving HLAidentical sibling HSCT for severe acquired aplastic anemia using fludarabine-based conditioning: a comparison with conventional conditioning regimen. Haematologica. 2009.

  • 15. Srinivasan R, Takahashi Y, McCoy JP, et al. Overcoming graft rejection in heavily transfused and allo-immunised patients with bone marrow failure syndromes using fludarabine-based haematopoietic cell transplantation. Br. J. Haematol. 2006;133(3):305-314.

  • 16. Deeg HJ, O'Donnell M, Tolar J, Agarwal R, Harris RE, Feig SA, et al. Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy. Blood. 2006 Sep 1;108(5):1485-91.

  • 17. Maury S, Balere-Appert ML, Chir Z, Boiron JM, Galambrun C, Yakouben K, et al. Unrelated stem cell transplantation for severe acquired aplastic anemia: improved outcome in the era of high-resolution HLA matching between donor and recipient. Haematologica. 2007 May;92(5):589-96.

  • 18. Young N, Bacigalupo A, Marsh J. Aplastic Anemia: Pathophysiology and Treatment. Biol Blood Marrow Transplant. 2009 Sep 23.

  • 19. Viollier R, Passweg J, Gregor M, et al. Quality-adjusted survival analysis shows differences in outcome after immunosuppression or bone marrow transplantation in aplastic anemia. Ann. Hematol. 2005;84(1):47-55.

  • 20. Siegal D, Xu W, Sutherland R J Kuruvilla, J H Lipton, M Minden, H Messner, V Gupta. Graft-versus-host disease following marrow transplantation for aplastic anemia: different impact of two GVHD prevention strategies. Bone Marrow Transplantation 2008; 42, 51 - 56.

  • 21. 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 Blood and Marrow Transplantation (EBMT) Haematologica. 2007;92(1):11-18.

  • 22. Peinemann F, Grouven U, Kroger N, Pittler M, Zschorlich B, Lange S. Unrelated donor stem cell transplantation in acquired severe aplastic anemia: a systematic review. Haematologica. 2009;94(12):1732-1742.

  • 23. Viollier R, Socie G, Tichelli A, et al. Recent improvement in outcome of unrelated donor transplantation for aplastic anemia. Bone Marrow Transplant. 2008;41(1):45-50.

  • 24. Bacigalupo A, Socie G, Lanino E, et al. Fludarabine, cyclophosphamide, anti-thymocyte 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(6):976-982.

  • 25. Gafter-Gvili A, Ram R, Gurion R, et al. ATG plus cyclosporine reduces all-cause mortality in patients with severe aplastic anemia-systematic review and meta-analysis. ActaHaematol. 2008;120(4):237-243.

  • 26. Marsh J, Schrezenmeier H, Marin P, et al. Prospective randomized multicenter study comparing cyclosporin alone versus the combination of anti-thymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. Blood. 1999;93(7):2191-2195.

  • 27. Scheinberg P, Nunez O, Wu C, Young NS. Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolatemofetil. Br. J. Haematol. 2006;133(6):606-611

  • 28. Kao SY, Xu W, Brandwein JM, et al. Outcomes of older patients (> or = 60 years) with acquired aplastic anaemia treated with immunosuppressive therapy. Br. J. Haematol. 2008;143(5):738-743.

  • 29. Rosenfeld S, Follmann D, Nunez O, Young NS. Anti-thymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. 2003;289(9):1130-1135. Randomized trial showing anti-thymocyte globulin and cyclosporine as combination immunosuppressive therapy.

  • 30. Scheinberg P, Nunez O, Wu C, Young NS. Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolatemofetil. Br. J. Haematol. 2006;133(6):606-611.

  • 31. Gluckman E, Rokicka-Milewka R, Hann I, Nikiforakis E, Tavakoli F, Cohen-Scali S, Bacigalupo A. Results and follow-up of a phase III randomized study of recombinant humangranulocyte stimulating factor as support for immunosuppressive therapy in patients with severe aplastic anaemia. Br J Haematol. 2002;119(4):1075-82.

  • 32. Ohara A, Kojima S, Hamajima N, et al. Myelodysplastic syndrome and acute myelogenousleukemia as a late clonal complication in children with acquired aplastic anemia. Blood. 1997;90(3):1009-1013.

  • 33. Brodsky RA, Chen AR, Dorr D, et al. High-dose cyclophosphamide for severe aplastic anemia: long-term followup. Blood. 2010;115(11):2136-2141.

  • 34. Gómez-Almaguer D, Jaime-Pérez JC, Garza-Rodríguez V, Chapa-Rodríguez A, Tarín-Arzaga L, Herrera-Garza JL, Ruiz-Argüelles GJ, López-Otero A, González-Llano O, Rodríguez-Romo L. (2009) Subcutaneous alemtuzumab plus cyclosporine for the treatment of aplastic anemia. Annals of Haematology, DOI 10.1007/s00277-009-0816-5.

  • 35. Risitano AM, et al. on behalf of the Working Party Severe Aplastic Anemia (WPSAA) of the European Group for Blood and Marrow Transplantation (EBMT). Alemtuzumab Is Safe And Effective As Immunosuppressive Treatment For Aplastic Anemia And Single-Lineage Marrow Failure: A Pilot Study And A Survey From The EBMT WPSAA. British Journal of Haematology, 2010.


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