Meta-Analysis of HLA-Mismatched Compared to HLA-Matched Hematopoietic Stem Cell Transplantation
Authors: Kekre Natasha , Mak Kimberley , Binder Moritz , Brånvall Elsa , Ishii Kazusa , Stopsack Konrad , Cutler Corey S 
Published: October 2019

Abstract
Background: Mismatched unrelated donor (MMURD) transplantation is widely accepted as an alternative donor source in patients who lack a matched unrelated donor (MUD). The magnitude of risk of adverse outcomes associated with HLA mismatching in the unrelated donor setting is not known. We performed a systematic review and meta-analysis to assess the difference in outcomes of MUD transplants with those of MMURD transplants in adults with hematologic malignancies.
Methods: A comprehensive search of Medline and EMBASE was performed through April 2014. Studies eligible for inclusion were published manuscripts that reported overall survival of adult patients with hematologic malignancies who underwent MUD (10 out of 10 matched at HLA-A, B, C, DRB1, and DQB1) or MMURD transplants (9 out of 10 single antigen or allele mismatch). Study selection, data extraction and quality assessment were completed independently by two reviewers, and disagreements were resolved by a third reviewer. The pooled relative risks (RR) from hazard ratios and risk ratios and 95% confidence intervals (CI) were estimated using a random-effects model (DerSimonian and Laird method). Heterogeneity was tested using the I2 statistic and Cochran Q test, and the sources of heterogeneity were evaluated using univariate meta-regression. Analysis of publication bias, sensitivity analysis, and cumulative meta-analysis were used to test reliability. Statistical analyses were performed using Stata version 13.1.
Results: There were 10 studies eligible for inclusion for the primary analysis of overall mortality. Single allele or antigen MMURD transplants were associated with significantly higher risk of overall mortality compared to MUD transplants (RR 1.32, 95% CI 1.17–1.49, p<0.001). There was substantial heterogeneity across studies (I2= 59.8%, p=0.006). None of the predefined covariates, including publication year, follow-up duration, age, sex, graft source, conditioning regimen, T-cell depletion, and geographical region of study were shown to be significantly contributing to heterogeneity. There was no statistically significant evidence of publication bias by Egger's test (p=0.082) or funnel plot analysis. Sensitivity analysis omitting each study individually did not substantially change the pooled effect estimate. Cumulative meta-analysis indicated no change in the magnitude of the pooled effect with time.
MMURD transplants were associated with significantly lower disease-free survival compared to MUD transplants (n=6; RR 1.20, 95% CI, 1.08–1.33, p=0.001; I2= 0.0%). The pooled effect estimate for acute grade II-IV graft-versus-host disease (GVHD) was borderline significant (n=4; RR 1.23, 95% CI, 0.99–1.53, p=0.061; I2= 0.0%). The pooled effect estimate for chronic GVHD was not significant (n=3; RR 1.08, 95% CI, 0.76–1.54, p=0.679; I2= 32.1%).
Conclusion: HLA-mismatched unrelated donor transplants are associated with significantly higher risk of overall mortality compared to HLA-matched unrelated donor transplants. The principal cause of adverse outcomes does not however appear to be completely related to excess GVHD.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.