Impact of HLA-Mismatch in Unrelated Donor Hematopoietic Stem Cell Transplantation: A Comprehensive Meta-Analysis

Background: Mismatched unrelated donor (MMURD) transplantation is widely used in patients who lack a matched unrelated donor (MUD). Despite several published observational studies, the magnitude of risk associated with 9 out of 10 MMURD transplant and that of HLA-specific mismatches is still unclear. We performed a meta-analysis to assess the difference in outcomes of MUD to those of MMURD transplant.

Methods: A comprehensive search of Medline and EMBASE was performed through April 2014. We included published manuscripts that reported outcomes of adult patients with hematologic malignancies who underwent MUD (matched at HLA-A, B, C and DRB1 at a minimum) or MMURD transplant (single antigen or allele mismatch only). The pooled relative risks (RR) from hazard ratios and risk ratios and 95% confidence intervals (CI) were estimated using a DerSimonian-Laird random-effects model. Heterogeneity was tested using the I² statistic and Cochran Q test, and sources of heterogeneity were evaluated using univariate meta-regression. Statistical analyses were performed using Stata v13.1.

Results: Twenty-two studies were included, representing 38,877 transplants. Nine out of 10 MMURD transplant was associated with a higher risk of overall mortality compared with 10 out of 10 MUD transplant (n=10; RR 1.32, 95% CI 1.17–1.49). No significant sources of heterogeneity were identified. MMURD transplant was associated with worse disease-free survival compared with MUD transplant (n=6; RR 1.20, 95% CI, 1.08–1.33). The pooled effect estimates for grade II-IV acute and chronic GVHD were 1.23 (n=4; 95% CI 0.99–1.53) and 1.08 (n=3; 95% CI 0.76–1.54) respectively. Single antigen/allele mismatches at HLA-A, B, C or DRB1 were associated with a higher risk of grade III-IV acute GVHD and overall mortality, but not chronic GVHD as compared with MUD transplant (Table). Disease-free survival was only worse for HLA-B mismatch.

Conclusion: MMURD transplant is associated with significantly higher risk of overall mortality and acute GVHD, but not chronic GVHD compared with MUD transplant. This risk is associated with HLA-A, -B, -C, and –DRB1, but not -DQB1 and -DPB1 mismatches. 

Pooled RR (95% CI)	Grade II-IV Acute GVHD	Grade III-IV Acute GVHD	Chronic GVHD	Disease-Free Survival	Overall Survival
HLA-A	1.12 (0.75 - 1.66)	1.57 (1.29 - 1.90)	0.99 (0.68 - 1.45)	1.20 (1.00 - 1.45)	1.47 (1.31 - 1.65)
HLA-B	1.41 (0.63 - 3.12)	1.67 (1.37 - 2.03)	0.87 (0.56 - 1.36)	1.20 (1.04 - 1.38)	1.33 (1.18 - 1.51)
HLA-C	1.16 (1.04 - 1.28)	1.44 (1.25 - 1.65)	1.04 (0.94 - 1.16)	1.01 (0.73 - 1.38)	1.28 (1.13 - 1.46)
HLA-DRB1	1.60 (1.23 - 2.09)	1.39 (1.13 - 1.72)	1.11 (0.68 - 1.83)	1.16 (0.94 - 1.44)	1.36 (1.22 - 1.51)
HLA-DQB1	0.89 (0.37 - 2.14)	insufficient data	insufficient data	0.99 (0.71 - 1.37)	0.95 (0.69 - 1.31)
HLA-DPB1	2.68 (1.16 - 6.19)	1.20 (0.94 - 1.52)	1.06 (0.76 - 1.46)	0.85 (0.75 - 0.97)	0.98 (0.89 - 1.07)