Title: When Matched Donors Are Not Available: The Emerging Role of Haploidentical Transplantation in Severe Aplastic Anaemia
Submitted by Gonzalo Daniel Bentolila
Physician expert perspectives: Gonzalo Daniel Bentolila
Medical Faculty, HSCT Unit, Fundaleu (Fundación contra la Leucemia), Buenos Aires, Argentina.
A previously healthy 19-year-old female, without history of exposure to toxic agents, presented in March 2022 with fatigue and easy bruising. Initial laboratory evaluation showed pancytopenia: hemoglobin 6.2 g/dL, white blood cells 2.38 × 10⁹/L (27% neutrophils; absolute neutrophil count: 642/μL), platelets 22 × 10⁹/L, and reticulocyte count <1%. Haptoglobin and LDH levels were normal.
Peripheral blood flow cytometry revealed no evidence of clonal hematopoiesis, although 1.9% of mature neutrophils lacked CD16 expression. Bone marrow biopsy demonstrated marked hypocellularity (20%) with prominent adipose tissue and scattered CD34⁺ cells (~1%), without fibrosis or iron overload. Cytogenetic analysis showed a normal female karyotype: 46,XX [20]. The diagnosis was confirmed with two additional bone marrow biopsies.
Flow cytometry for PNH identified minor clones in multiple lineages: erythrocytes (9.3%), monocytes (14.4%), neutrophils (10.8%), basophils (13.9%), and eosinophils (13.2%). Next-generation sequencing using a myeloid panel detected no pathogenic variants.
She has no matched sibling donor; only a 6/12 HLA-matched brother identified at high-resolution typing, and preliminary searches found no fully matched unrelated donor (MUD).
Overall, these findings are consistent with a hypocellular bone marrow failure syndrome, most compatible with severe aplastic anemia associated with a minor PNH clone, without evidence of hemolysis, myeloid malignancy, or clonal evolution.
Which of the following is the most appropriate next step in management for this patient?
A. Observation and repeat bone marrow biopsy in 3 months
B. Start high-dose corticosteroids
C. Initiate immunosuppressive therapy with antithymocyte globulin (ATG) and cyclosporine
D. Begin eltrombopag monotherapy
E. Refer for haploidentical donor hematopoietic stem cell transplantation
Expert Perspective by Gonzalo Bentolila
Severe aplastic anemia (SAA) is a rare but life-threatening bone marrow failure syndrome characterized by pancytopenia and marked hypocellularity. Allogeneic hematopoietic cell transplantation (HCT) remains the only curative therapy, particularly in young and fit patients. While a matched sibling donor (MSD) is the preferred option, haploidentical HCT with post-transplant cyclophosphamide (haplo-HCT + PTCy) has become a feasible and increasingly adopted strategy in patients lacking MSD or matched unrelated donors (MUD).
The 2024 ASTCT guidelines recommend that in patients under 50 without MSD, alternative donor HCT—including MUD and haplo-HCT—should be prioritized over immunosuppressive therapy (IST), provided the transplant is performed in experienced centers (1). This represents a shift from the traditional algorithm in which IST precedes consideration of transplant in the absence of an MSD.
Bonfim et al. reported on 78 patients with SAA who underwent haplo-HCT with PTCy across multiple Brazilian centers. The 1-year overall survival (OS) was 81%, with event-free survival (EFS) of 71%. Graft failure or poor graft function occurred in 21%, particularly in patients not previously exposed to ATG or alemtuzumab. Improved outcomes were observed in those who received 300–400 cGy total body irradiation (TBI) or cyclophosphamide 50 mg/kg in the conditioning regimen. The addition of ATG, in contrast, did not reduce the risk of graft failure. Acute GVHD grade II-IV occurred in 16% and chronic GVHD in 10% (2).
In a prospective trial, DeZern et al. evaluated upfront haplo-HCT in patients with SAA using uniform non-myeloablative conditioning (fludarabine, cyclophosphamide, and TBI 200 or 400 cGy) with PTCy. One-, two-, and three-year OS reached 92%. Critically, graft failure was entirely prevented in those who received TBI 400 cGy. This trial also highlighted the broader applicability of haplo-HCT: over a third of patients were from ethnic backgrounds underrepresented in donor registries (3).
Bacigalupo and Giammarco reviewed outcomes from 375 patients undergoing haplo-HCT for SAA and reported 1-year OS of 83% and engraftment rates of 94%, with acceptable GVHD incidence. Among young adults (median age 27), survival approached 87%. These results confirmed that haplo-HCT offers outcomes comparable to MSD transplantation and is particularly relevant in settings where donor registries are limited (4).
While IST (horse ATG + cyclosporine ± eltrombopag) remains widely used, particularly in older adults or settings with limited transplant access, its limitations include relapse, refractoriness, and the risk of late clonal evolution(5). The increasing success of haplo-HCT challenges the traditional stepwise algorithm (IST first, then transplant upon failure), especially in younger patients.
An important argument for upfront HCT over IST lies in its potential to prevent clonal evolution. Georges et al. emphasize that delaying HCT until after IST failure can expose patients to cumulative transfusion burden, risk of sensitization, and higher rates of secondary myeloid neoplasms (sMN). They advocate for early transplantation in biologically fit patients, highlighting that survival and failure-free survival are higher with upfront transplant strategies (6).
This rationale is further supported by molecular data from Gurnari et al., who analyzed 1,008 patients with AA or PNH. The 10-year cumulative incidence of clonal evolution to MDS/AML was 11.6%, increasing to 20% in patients over 35 and to 15.7% in those with incomplete response to IST. Importantly, none of the 117 patients who received upfront allogeneic HCT developed malignant clonal evolution. High-risk sMN was associated with poor-risk mutations (ASXL1, SETBP1, RUNX1) and del(7/7q), often evolving from earlier immune escape clones. These findings support the hypothesis that early HCT may alter the natural history of AA and prevent transformation (7).
Taken together, these data strongly support haplo-HCT with PTCy as a valid and effective first-line approach in selected SAA patients without MSD or MUD. The choice of conditioning regimen and graft source is critical—TBI 300–400 cGy or higher-dose cyclophosphamide improves engraftment, and bone marrow is preferred over peripheral blood to reduce GVHD. The use of unmanipulated grafts and PTCy has simplified logistics and expanded transplant accessibility worldwide.
In conclusion, haplo-HCT with PTCy offers not only curative potential but may also mitigate the long-term risk of clonal evolution. For young, fit patients with SAA lacking a matched donor, this strategy should be actively considered as upfront therapy in transplant-experienced centers.
Correct answer - E
References:
- DeZern AE, Broglie L, Kennedy-Nasser A, et al. Allogeneic Hematopoietic Cell Transplantation for the Treatment of Severe Aplastic Anemia: Guidelines from the ASTCT. Transplant Cell Ther. 2024;30(4):220.e1–220.e13.
- Bonfim C, Arcuri L, Nabhan S, et al. Haploidentical HSCT with PTCy for Severe Aplastic Anemia: A Brazilian Multicenter Experience. Biol Blood Marrow Transplant. 2024.
- DeZern AE, Zahurak M, Symons H, et al. Alternative Donor Transplantation for Refractory SAA Using PTCy. Biol Blood Marrow Transplant. 2017;23(3):498–504.
- Bacigalupo A, Giammarco S. Haploidentical Donor Transplants for Severe Aplastic Anemia. Semin Hematol. 2019;56(3):190–193.
- Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, et al. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med. 2022 Jan 6;386(1):11–23.
- Georges GE, Doney KC, Storb R. Allogeneic Bone Marrow Transplantation as First-Line Treatment for SAA. Blood Adv. 2018;2(15):2020–2028.
- Gurnari C, Pagliuca S, Prata PH, et al. Determinants of Clonal Evolution in Aplastic Anemia and PNH. J Clin Oncol. 2023;41(1):132–142.
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