Alternative Donor Transplantation for Severe Aplastic Anemia: A Comparative Study of the Saawp EBMT
Authors: Montoro Juan , Eikema Dirk-Jan , Tuffnell Joe , Potter Victoria , Kalwak Krzysztof , Halkes Stijn , Kulagin Aleksandr , Collin Matthew P. , Wynn Robert , Robinson Stephen , Nicholson Emma , Sengeloev Henrik , Clay Jennifer , Halahleh Khaled , Skorobogatova Elena , Passweg Jakob , Mielke Stephan , Ryhanen Samppa , Carpenter Ben , Gedde-Dahl Tobias , Tholouli Eleni , Fanin Renato , Lewalle Philippe , Kulasekararaj Austin , Risitano Antonio M , Peffault De Latour Regis 
Published: December 2023

Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT
INTRODUCTION
Allogeneic stem cell transplantation (allo-SCT) from an HLA-matched sibling donor (MSD) is considered the standard of care for younger patients with severe aplastic anemia (SAA). For patients lacking a suitable MSD, matched unrelated donors (MUD) have increasingly been used for SAA patients who do not respond to immunosuppressive therapy. However, a significant number of SAA patients who require allo-SCT are unable to access a fully HLA-matched unrelated donor or experience delays in finding one. In such cases, other alternative options, such as mismatched unrelated donors (MMUD), and haploidentical family donors (Haplo), have been explored.
Limited research exists on MUD, MMUD, and Haplo allo-SCT efficacy and safety in SAA. Drawing definitive conclusions for the optimal alternative donor transplant approach remains challenging.
This study compares the outcomes of allo-SCT from MUD, MMUD, and Haplo donors in patients with SAA from the SAAWP EBMT.
PATIENTS AND METHODS
Inclusion criteria
All patients diagnosed with SAA who underwent their first allo-SCT between January 2012 and December 2021 from either a MUD, MMUD or Haplo, were included. Only transplants from Haplo donors who received post-transplant cyclophosphamide (PTCy) as prophylaxis for graft-versus-host disease (GVHD) were considered.
Statistical Analysis
The study utilized statistical methods such as Kaplan-Meier estimation, Log-Rank test, competing risks analysis, and Cox proportional hazards regression. The analyses included OS, EFS, GRFS, NRM, aGVHD, cGVHD, and graft failure. The statistical software R and relevant packages were used.
RESULTS
Patient and Transplantation Characteristics
Table 1 summarizes patient and transplant characteristics for the 1652 participants.
Engraftment
Neutrophil recovery at 28 days was 85% (95% CI; 83-87) for MUD, 84% (95% CI; 80-88) for MMUD, and 75% (95% CI; 69-81) for Haplo (p = 0.033). Platelet engraftment at 100 days was 88% (95% CI; 86-91) for MUD, 82% (95% CI; 78-87) for MMUD and 72% (95% CI; 65-78) for Haplo (p &lt; 0.001).
Graft failure
The 1-year cumulative incidence of primary graft failure (PGF) for the MUD, MMUD, and Haplo cohorts was 4% (95% CI; 3-6%), 5% (95% CI; 3-8%) and 16% (95% CI; 11-21%), respectively (p &lt; 0.001). In multivariable analysis, compared with MUD, Haplo (HR, 3.72; 95% CI, 1.97-7.03; p&lt;0.001) was associated with a higher PGF. Other predictors for a higher PGF are shown in Table 2.
GVHD
The cumulative incidence of aGVHD grades II-IV at 100 days for the MUD, MMUD, and Haplo cohorts was 13% (95% CI; 11-15), 22% (95% CI; 17-26), and 18% (95% CI; 13-24), respectively (p &lt; 0.001). In multivariable analysis, MMUD was associated with an increased risk of aGVHD grades II-IV, when compared with MUD (HR 1.97; 95% CI, 1.4-2.77; p &lt; 0.001). Other predictors associated with a higher risk of aGVHD grades II-IV are shown in Table 2.
The 3-year cumulative incidence of cGVHD for the MUD, MMUD, and Haplo cohorts was 18% (95% CI; 15-20), 19% (95% CI; 14-24), and 18% (95% CI; 11-24), respectively (p = 0.9).
NRM
The 3-year cumulative incidence of NRM was 12% (95% CI; 10-14) for MUD, 17% (95% CI; 13-22) for MMUD, and 22% (95% CI; 15-28) for Haplo (p &lt; 0.001).
Survival
The 3-year EFS for the MUD, MMUD, and Haplo cohorts was 73% (95% CI; 71-76), 64% (95% CI; 59-70), and 53% (95% CI; 46-61), respectively (p &lt; 0.001), whereas OS was 81% (95% CI; 79-84), 74% (95% CI; 69-79), and 63% (95% CI; 54-71), respectively (p &lt; 0.001). In multivariable analysis, compared to MUD, MMUD (HR, 1.54; 95% CI, 1.12-2.11; p = 0.007) and Haplo (HR, 1.97; 95% CI, 1.35-2.86; p&lt;0.001) were associated with worse survival. Other predictors for a worse OS are shown in Table 2.
The 3-year GRFS for the MUD, MMUD, and Haplo cohorts was 71% (95% CI; 68-74), 66% (95% CI; 60-72), and 53% (95% CI; 44-61), respectively (p &lt; 0.001). In multivariable analysis, compared with MUD, MMUD (HR, 1.42; 95% CI, 1.1-1.82; p = 0.006) and Haplo (HR, 1.71; 95% CI, 1.27-2.31; p&lt;0.001) were associated with worse GRFS. Other factors associated with a worse GRFS are shown in Table 2.
CONCLUSION
In conclusion, our study supports MUD transplantation as the preferred option for SAA patients without a MSD. While MMUD and Haplo transplants are feasible, MMUD appears more favorable than Haplo, even in the era of PTCy.