Survival and Engraftment Post Allogeneic Hematopoietic Stem Cell Transplantation: ABO Mismatch Matters in RIC

Introduction: ABO blood group incompatibility is not a barrier to allogeneic hematopoietic stem cell transplantation (allo-HCT). This may be observed in about half of all allo-HCT with differing degrees of mismatch (mm) i.e. major, minor, or bidirectional. Despite numerous factors affecting allo-HCT outcomes, the impact of donor-recipient ABO mm is not well characterized. Methods: To investigate the association between ABO mm and allo-HCT outcomes in patients receiving post-transplant cyclophosphamide (PTCy) graft versus host disease (GVHD) prophylaxis, we retrospectively analyzed patients undergoing allo-HCT between October 2015 & December 2023. Cumulative incidences were analyzed using competing risk models. Multivariable Cox regression analysis (MVA) assessed risk factors for overall survival (OS) and GVHD-free/relapse-free survival (GRFS). Fine-gray regression was used for non-relapse mortality (NRM), cumulative incidence of relapse (CIR), GVHD, and primary graft failure (PGF). A p-value of <0.05 was considered statistically significant, and analyses were conducted using EZR (version 1.62). Results: A total of 1089 patients [median age 59 years (IQR 47-66); male, 57%] underwent allo-HCT. The predominant indication for allo-HCT was acute myeloid leukemia (n=543, 49%). Most received a graft from a matched unrelated donor (n=540, 49.6%). The KPS was >80% in 900 (82.6%) patients and the HCT-CI score was <3 in 80.3%. The conditioning regimen was reduced intensity (RIC) in 801 (73.5%). Peripheral blood grafts were used in 98% of the cases, the median CD34+ cell dose was 7.4x106/kg (IQR 5.6-8.4). Most patients received fresh grafts (n=847, 77.8%). ABO-matched grafts were used in 646 patients (59%), 212 (20%) had a minor mm, 175 (16%) had a major mm, and 56 (5%) had bidirectional mm. The 2-year OS for recipients of a major ABO-mm graft was 57.7% (49.7-64.9) vs 64.9% (61.4-68.2) for ABO-matched grafts [HR 1.32 (1.1-1.6), p=0.003]. The incidence of PGF at D+100 was 4.6% (2.2-8.5) for major mm grafts and 1.9% (1.1-2.9) for ABO-matched grafts [HR 2.88 (1.2 - 6.7); p=0.01]. Platelet engraftment occurred at a median of 23 days (20-26) in patients with major mm and 20 days (19-21) for ABO-matched grafts (p=0.005). There was no significant difference in the rate of neutrophil engraftment. By D+30, 95.4% (90.4-97.8) of major mm recipients had engrafted compared to 95.1% (93.4-96.3) of ABO-matched recipients. The median day of neutrophil engraftment was day 18 (17-19) for both groups (p=0.93). The D+100, grade III-IV aGVHD was 6.1% (3.1-10.5) and 6.6% (5-8.5), for major mm and ABO-matched grafts, respectively (p=0.71). At 2-years, moderate-severe cGVHD was 19% (13.1-25.7) vs 17.7% (15-20.6) for major mm and ABO-matched grafts, respectively (p=0.79). There was no significant difference in NRM at 1 year between patients with major mm [18.8% (13.3-25.1)] and those with ABO-matched grafts [16.5% (14.1-19.1), p=0.07]. The CIR at 2-years was comparable between the two groups [22.5% (16.4-29.2) vs 23.1% (20.2-26.1); p=0.94]. The GRFS at 12 and 24 months was 41.4% (33 - 48) and 35.7% (28 - 43) respectively in the ABO mm group, compared to 47.8% (44 - 51) and 43.8% (40 - 47) in those with ABO-matched grafts (p=0.16). MVA identified major ABO mm, recipient age, HLA-mismatch, and a diagnosis of myelofibrosis as predictors for PGF and delayed platelet engraftment. Recipient age, HLA-mismatch, use of cryopreserved grafts, KPS <90%, HCTCI>3, and high-very high DRI were predictors for OS. In the RIC subgroup (n=801, 73.6%), the 2-year OS for major mm grafts was 54% (44.9-62.3) vs 61.3% (57.2-65.1) for ABO-matched grafts [HR 1.32 (1.1-1.7), p=0.04]. The incidence of PGF was 5.2% (2.3-9.9) for major mm grafts vs 2.4% (1.4-3.8) for ABO-matched grafts [HR 2.49 (1.1 - 6.1); p=0.04]. In patients with major mm grafts, platelet engraftment occurred at a median of 23 days (21-26) vs 21 days (20-22) for ABO-matched grafts (p=0.01). Major ABO mm was predictive of delayed platelet engraftment on MVA. The effects of ABO mm on OS, PGF, and platelet engraftment were not demonstrated in patients receiving myeloablative conditioning. Conclusion: Major ABO mismatch is associated with higher PGF rates, and delayed platelet engraftment, particularly in patients receiving RIC and PTCy-based GVHD prophylaxis. However, ABO mismatch does not significantly affect OS, NRM. CIR, neutrophil engraftment, or the incidence of GVHD.

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