Patients and Overall Outcomes
Baseline characteristics of the patients and transplants are provided in , for the group overall (n = 185) and according to the number of HLA mismatches.
The median age was 50, similar proportions had lymphoid (57%) and myeloid diseases, and over one-quarter (27%) had received previous BMT. The actuarial EFS at 1 year was 35%, with a median follow-up of 20 months in those without events and 6 months overall (range, < 1 to 71 months). The cumulative incidence of NRM was 6% at day 100 and 15% at 1 year. Graft failure with or without residual bone marrow malignancy occurred in 29 of 177 evaluable patients (16%). Cumulative incidences of acute grade II–IV GVHD and chronic GVHD were 31% and 15%, respectively.
Composite Analysis of Total HLA Mismatches
A univariate analysis of total mismatches at HLA-A, -B, -Cw, and -DRB1 in relation to transplant outcomes is presented in . On univariate analysis, having 3 or 4 total antigen mismatches in any direction was not associated with inferior EFS (HR .67, P = .09), compared with having fewer antigen mismatches (). There was no statistically significant difference found in the cumulative incidence of relapse or of NRM (). Notably, having more antigen mismatches was not associated with a statistically significant difference in the risk of acute grade II–IV GVHD (HR .89, P = .68; ). Analyses of chronic GVHD are not presented because it occurred in only 26 patients without competing risks.
Univariate Analysis of HLA Disparity in Relation to Transplant Outcomes
Figure 1 Outcomes according to donor-recipient HLA mismatching. A, Event-free survival and B, cumulative incidences of relapse and nonrelapse mortality according to the number of antigen mismatches in either direction. C, Cumulative incidence of acute grade II–IV (more ...)
We also performed a univariate analysis of outcomes according to the total number of antigen mismatches treated as continuous covariates (i.e., 0, 1, 2, 3, or 4 mismatches). For EFS, each additional degree of mismatch in any direction was nondetrimental, with an observed protective effect (HR 0.80, 95% CI .66 – .96, P = .02). Additionally, with this approach we found no statistically significant difference in the cumulative incidence of relapse (HR 0.86, 95% CI .69 – 1.06, P = 0.16) or NRM (HR 0.82, 95% CI .56 – 1.21, P = 0.33), nor was there a statistically significant difference found in the risk of acute grade II–IV GVHD with each additional degree of GVH-direction mismatch (HR 0.87, 95% CI .70 – 1.09, P = 0.24).
presents a univariate analysis of other variables that could influence EFS including age, disease type, donor characteristics, and graft characteristics. There was no statistically significant difference in EFS between patients age 50–59 versus < 50 (data not shown), whereas patient age ≥ 60 was associated with an inferior EFS (HR 1.64, P = .01) as was having a female donor for a male recipient (HR 1.47, P = .04). The adverse impact on EFS was not accounted for by a significantly increased risk of acute grade II–IV GVHD (for age ≥ 60, HR 1.18 for acute GVHD, 95% CI .66 – 2.09, P = .57; and for female donor/male recipient, HR .76, 95% CI .42 – 1.37, P = .37). On a multivariate analysis of EFS that included these variables, having 3 or 4 total antigen mismatches, as compared with fewer mismatches, was not detrimental and appeared protective (HR .60, P = .03; ).
Univariate Analysis of Event-Free Survival for Variables Other Than HLA Mismatching
Multivariate Analysis of Event-Free Survival
There were no statistically significant differences in patient or transplant characteristics between those having more versus fewer total antigen mismatches (). In the group with more antigen mismatches, there was a tendency toward more patients receiving a maternal graft or receiving two doses of posttransplantation Cy. Inclusion of these factors in this multivariate model did not change the outcome (data not shown).
Similarly, the presence of a greater number of allele mismatches was not associated with inferior outcomes. Having more allele mismatches was associated with a tendency toward lower relapse risk on univariate analysis (HR .58, P = .11, for 3 or 4 versus fewer mismatches; ), and was not detrimental and appeared protective on multivariate analysis of EFS (HR .55, P = .03; ). However, we found no significantly increased risk of acute grade II–IV GVHD associated with having 3 or 4, as compared with fewer, total allele mismatches on univariate analysis (HR 1.03, P = .94).
Total Mismatches According to Vector
Overall outcomes are also presented according to the direction of the mismatch (). Such analyses help to address whether the observed effects of HLA disparity are due to imbalances in clinically significant mismatches. For example, having more HVG-direction mismatches may be less clinically significant than GVH-direction mismatches. On univariate analysis, no statistically significant association was found between the total number of antigen or allele mismatches in the GVH direction (3 or 4 versus fewer) and relapse, NRM, or EFS (). In the HVG direction, more mismatches were associated with a nondetrimental and possibly protective effect on relapse risk and EFS (). However, because of the tight correlation between GVH- and HVG-direction mismatches at single loci, their relative contributions cannot be dissociated.
The probability of graft failure was examined with respect to the number of antigen mismatches in the HVG direction. A higher incidence of graft failure (recorded as a yes/no) was observed in those having 3 or 4 antigen mismatches in the HVG direction compared with fewer mismatches (130 and 47 evaluable patients per group, respectively). The difference was not statistically significant (odds ratio 1.91, 95% CI .68 – 5.31, P = .22) although analysis is limited by sample size. By treating the number of HVG-direction mismatches as continuous covariates, no statistically significant trend was found with respect to modeling the probability of graft failure (P = .62).
Mismatch Analysis According to HLA Locus
To further investigate whether the observed nondeleterious effects of HLA disparity on EFS reflect skewing of clinically significant variables, overall outcomes were analyzed separately at class I and at HLA-DRB1 ( and ).
The presence of two or more class I antigen mismatches in any direction was associated with a lower risk of relapse on univariate analysis (HR .55, P = .04), and a lower risk for an event on multivariate analysis (HR .53, P = .02). In the GVH direction, on univariate analysis there was no detrimental effect of more class I antigen mismatches on overall outcome (HR .78, P = .26 for EFS) or on the risk of acute grade II–IV GVHD (HR .84, P = .59), and there was a tendency toward lower risk of relapse (HR .70, P = .13). In the HVG direction, more class I antigen mismatching was also associated with a lower risk of relapse (HR .55, P = .02) and a lower risk for an event (HR .60, P = .02) on univariate analysis.
Likewise, HLA-DRB1 antigen mismatching was not associated with inferior outcomes. On univariate analysis (), DRB1 antigen mismatching in the GVH direction was associated with a lower risk of relapse (HR .65, P = .04), a similar risk of acute grade II–IV GVHD (HR 1.06, P = .84), and an improved EFS (HR .62, P = .009). On multivariate analysis of EFS (), an HLA-DRB1 antigen mismatch in the GVH direction and two or more class I antigen mismatches in any direction appeared protective.