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You Make the Call: Would you proceed with a 7/8 matched unrelated donor alloHCT in a patient with severe acquired aplastic anemia?

February 1, 2024

February 2024

Amy E. DeZern, MD, MHS  Director, Bone Marrow Failure and MDS Program  Professor of Oncology and Medicine

Amy E. DeZern, MD, MHS

Director, Bone Marrow Failure and MDS Program

Professor of Oncology and Medicine

Johns Hopkins University School of Medicine


Charlotte M. Story, MD Hematology Fellow Johns Hopkins University School of Medicine

Charlotte M. Story, MD

Hematology Fellow

Johns Hopkins University School of Medicine




I have a 66-year-old female patient who was diagnosed with severe acquired aplastic anemia. Her bone marrow biopsy was hypocellular as expected and did not show concerning myeloid mutations. Her karyotype and fluorescence in situ hybridization panel for myelodysplastic syndromes were normal. She had a small paroxysmal nocturnal hemoglobinuria (PNH) clone. She received horse anti-thymocyte globulin (hATG), cyclosporine, and a limited course of eltrombopag because of issues with insurance coverage. She had what seemed like a partial response initially. Unfortunately, at six months post-treatment, she did not have full count recovery or transfusion independence. Her platelets remain consistently in the low 20,000/mL range, but she has not needed a transfusion. Her absolute neutrophil count ranges between 800 and 1,200 µL. Her hemoglobin (Hb)/retic remain low, and she needs packed red blood cells every few weeks to keep her Hb greater than 7.0 g/dL. She has no past medical history and is an incredibly fit 66-year-old.

Initially, I was considering an allogeneic hematopoietic cell transplant (alloHCT) as second-line therapy (rather than rabbit ATG [rATG]); however, we have limited “good” donor options. Her brother is in his early 60s and is a haploidentical match. The best matched unrelated donors that we have are 9/10 (7/8) matches, but all are young donors who are willing and able to donate bone marrow. I have not had a good experience with patients who fail second-line rATG and then go to transplant for third-line treatment. She appears to be doing incredibly well, but I wish the donor options were better. Would you proceed with a 7/8 matched unrelated donor alloHCT in this setting or plan for second-line rATG?


Aplastic anemia (AA) is characterized by the loss of multipotent hematopoietic stem cells, which results in varying degrees of pancytopenia and trilineage bone marrow hypoplasia. AA can be acquired or inherited. The diagnosis of acquired AA is supported by this patient’s age (past the typical age of presentation of most inherited marrow failure conditions), the presence of a paroxysmal nocturnal hemoglo­binuria (PNH) clone, and the absence of findings characteristic of myelodysplastic syndromes. Acquired AA is frequently associated with a PNH clone, often without evidence of classical PNH disease. It is thought that the autoimmune assault on the hematopoietic progenitors is less effective against a PNH clone, as these lack the glycosylphosphatidylinositol- anchored proteins (CD55 and CD59) for complement binding. This permits the PNH clone to evade autoimmunity and proliferate preferentially to detection level.1

In a patient over 40 years old with severe acquired AA (SAA), the standard of care is upfront treatment with immunosuppressive therapy (IST) with or without the addition of the thrombopoietin receptor agonist eltrombopag. The response rates to IST are somewhat lackluster (as demonstrated in this case), and the long-term survival is around 58% in patients over 40 years of age.2 Given the low event-free survival post-IST, it is prudent at diagnosis to initiate typing of the patient and family members in any patient who is a potential transplant candidate in case of future need, such as relapse or primary refractory disease after IST.

In this patient with refractory AA, treatment options include further IST or allogeneic bone marrow transplant (BMT). Repeat rabbit anti-thymocyte globulin  has response rates as low as 30% to 35% with short duration, and relapses are common.3,4 Clonal evolution in older patients with repeated IST courses also remains a concern.

Treatment for relapsed or refractory (R/R) AA most often hinges on the patient’s transplant eligibility. For those who are transplant eligible, donor availability is no longer the limitation that it was historically. Adoption of post-transplantation cyclophosphamide (PT-CY)-based graft-versus-host disease (GVHD) prophylaxis yields excellent long-term survival rates with low toxicity. This platform allows the use of alternative donors to human leukocyte antigen (HLA)-identical siblings such as haploidentical, matched unrelated, and even mismatched unrelated donors with very favorable results. The CHAMP study, for which this patient would have been eligible, was a multicenter phase II clinical trial examining outcomes in patients with R/R AA who underwent haploidentical transplant.5 This study demonstrated a one-year overall survival (OS) of 81%.5 Patients up to age 75 were included, and 16% of the cohort were ages 60 to 69. Longer-term data from registry-based studies have shown similar long-term survival between upfront haploidentical and identical sibling donor transplant, albeit in a younger patient population.6 A single institution experience with haploidentical transplantation for SAA demonstrated a two-year OS of 94% and cumulative incidence of grade 2 to 4 acute GVHD of 11% by day 100 using PT-CY.7 Haploidentical donors for refractory patients in this series were ages 23 to 71.

This patient’s haploidentical donor is older, which may confer increased risk of graft failure, post-transplant infections, GVHD, and even decreased OS.8 The ability to control the graft harvest with a related haploidentical donor must be balanced with the rising complication risk seen with increasing donor age. It is worth highlighting that second-degree relatives are often forgotten resources in the haploidentical donor search, and grandchildren, nieces, nephews, and even great-grandchildren can be queried for donor eligibility. However, this patient also has several younger, unrelated donors who are 9/10 (7/8) matches. Since the advent of PT-CY, there have been multiple prospective studies that have shown the safety of partially “mismatched” grafts, and that 7/8-matched grafts can perform similarly to 8/8-matched grafts.9,10

After ensuring that a complete search for the best available haploidentical donor was not fruitful, we would move forward with a 7/8- or 9/10-unrelated donor transplant with a bone marrow graft source. Pursuit of further IST may cause additional toxicity and delay or even prevent BMT as a potentially curative therapy.


  1. Fattizzo B, Ireland R, Dunlop A, et al. Clinical and prognostic significance of small paroxysmal nocturnal hemoglobinuria clones in myelodysplastic syndrome and aplastic anemia. Leukemia. 2021;35(11):3223-3231.
  2. Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017;129(11):1428-1436.
  3. Marsh JCW, Kulasekararaj AG. Management of the refractory aplastic anemia patient: what are the options? Hematology Am Soc Hematol Educ Program. 2013;2013(1):87-94.
  4. Scheinberg P, Nunez O, Young NS. Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia. Br J Haematol. 2006;133(6):622-627.
  5. DeZern AE, Eapen M, Wu J, et al. Haploidentical bone marrow transplantation in patients with relapsed or refractory severe aplastic anaemia in the USA (BMT CTN 1502): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2022;9(9):e660-e669.
  6. Xu ZL, Xu LP, Wu DP, et al. Comparable long-term outcomes between upfront haploidentical and identical sibling donor transplant in aplastic anemia: a national registry-based study. Haematologica. 2022;107(12):2918-2927.
  7. DeZern AE, Zahurak ML, Symons HJ, et al. Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide. Blood Adv. 2020;4(8):1770-1779.
  8. Arai Y, Kondo T, Yamazaki H, et al. Allogeneic unrelated bone marrow transplantation from older donors results in worse prognosis in recipients with aplastic anemia. Haematologica. 2016;101(5):644-652.
  9. Shaw BE, Jimenez-Jimenez AM, Burns LJ, et al. National Marrow Donor Program-sponsored multicenter, phase II trial of HLA-mismatched unrelated donor bone marrow transplantation using post-transplant cyclophosphamide. J Clin Oncol. 2021;39(18):1971-1982.
  10. Shaw BE, Jimenez-Jimenez AM, Burns LJ, et al. Three-year outcomes in recipients of mismatched unrelated bone marrow donor transplants using post-transplantation cyclophosphamide: follow-up from a National Marrow Donor Program-sponsored prospective clinical trial. Transplant Cell Ther. 2023;29(3):208.e1-208.e6.


I was referred an 18-year-old collegiate basketball player who has had three episodes of right thigh hematoma after trauma, the first of which occurred in 2020. He then had two repeat injuries in 2023 after receiving a knee to the thigh. He has a prolonged partial thromboplastin time. His factor VIII and IX levels are normal, and factor XI is 43%. He has no family history of bleeding disorders and wants to return to play. Is it reasonable to recommend prophylactic fresh frozen plasma prior to games, or is treatment with injury only recommended? Would prophylactic recombinant factor VIIa or tranexamic acid be appropriate treatment options? Should this patient be precluded from play?

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Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.


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