Association of Rh Mismatch with Primary Graft Failure and Overall Survival in Allogeneic Hematopoietic Stem Cell Recipients with Acute Leukemia, a CIBMTR Analysis

Background:

ABO-mismatch between donor and recipient can influence outcomes in allogeneic stem cell transplant (Allo-SCT) but relatively less is known about the impact of Rh-mismatch (Rh-Mm) on outcomes. Conflicting data also exists regarding the association of Rh-Mm with allo-SCT outcomes, e.g., a Japanese registry study (Konuma et al. 2023) found no association between Rh-Mm and OS, but a German study (Erker et al. 2005) found association of Rh-Mm with poor OS. Given different outcomes, and varying geography, using a larger CIBMTR (Center for International Blood and Marrow Transplant Research) dataset published by Subramanian et al. 2023, we sought to determine the association of Rh-Mm with primary graft failure (PGF) and OS.

Methods:

Adult patients with acute leukemia (ALL and AML) who received allo-SCT between 2008 and 2018 from an HLA matched siblings (HMS) or matched unrelated donor (MUD) and had Rh-Mm status available were included in the final analysis. Donor-recipient Rh-Mm status was categorized into 4 groups, (+/+), (+/-), (-/+) and (-/-). Descriptive statistics were conducted across Rh-Mm groups using Chi-square/Fisher’s exact test, and ANOVA/Kruskal Wallis tests as applicable. Primary and secondary outcomes were association of PGF and OS with Rh-Mm status. PGF was defined as no neutrophil recovery by day +28 post-allo-SCT. For the binary variable of PGF and time to event variable of death, logistic regression and Cox proportional hazard models were conducted, respectively. Unadjusted and adjusted models (after adjusting for significant confounders) were performed to calculate odds (OR) and hazard ratios (HR) of PGF and OS for Rh-Mm and a two-sided p-value<0.05 was considered significant. Analysis was performed using SAS, version 9.3, Copyright (c) 2016 by SAS Institute Inc., Cary, NC, USA.

Results:

Among 4945 allo-SCT recipients, 3775 (76.3%) had Rh-Mm of +/+, 472 (9.5%) +/-, 507 (10.3%) -/+ and 191 (3.9%)-/-. Sex distribution among the 4 groups was similar but +/+ group had a lower proportion of Whites vs other groups, p <.0001. Recipient/donor age, donor-recipient sex, KPS, conditioning regimen, disease type (AML vs. ALL), graft type (bone marrow vs. peripheral blood), disease status, PGF rates and the year of transplant were not significantly different across groups. Rh-Mm groups were different in terms of HCT-comorbidity index (HCT-CI), GVHD prophylaxis, donor type (HMS vs. MUD), donor-recipient CMV status and ABO mismatch status. In unadjusted logistic model, ORs of PGF (not significant) for Rh-Mm +/-, -/+ and -/- when compared with +/+ were 1.39 (95% CI: 0.86-2.26, p: 0.236), 0.83 (95% CI: 0.46- 1.48, p:0.265) and 1.19 (95% CI: 0.55- 2.60, p:0.747), respectively. After adjusting for significant confounders such as disease-status, GVHD prophylaxis, conditioning regimen, graft type and ABO mismatch status, Rh-Mm was not significantly associated with PGF. In unadjusted cox proportional hazard model, HRs of deaths (not significant) for +/-, -/+ and -/- were 0.97 (95% CI: 0.85-1.11, p:0.655), 1.00 (95% CI: 0.88-1.13, p: 0.999), and 0 .98 (95% CI: 0.80-1.19, p:0.800), respectively. After adjusting for significant confounders such as recipient age, sex, ABO mismatch, HCT-CI, KPS, ALL vs. AML, disease status, GVHD prophylaxis, conditioning regimen, graft type and the year of transplant, Rh-Mm was not significantly associated with OS.

Conclusion:

In one of the largest retrospective analyses to date, we found that Rh mismatch in acute leukemia patients undergoing allo-SCT patients is not associated with primary graft failure or overall survival. Our study confirms the findings of some prior retrospective studies.