Major Histocompatibility Mismatch and Donor Choice for Second Allogeneic Bone Marrow Transplantation

Abstract

Large alternative donor pools provide the potential for selecting a different donor for a second allogeneic (allo) bone or marrow transplant (BMT). As HLA disparity may contribute to the graft-versus-tumor effect, utilizing new mismatched haplotype donors may potentially improve the antitumor activity for relapsed hematologic malignancies despite a previous alloBMT. Data from patients who received a second alloBMT for relapsed hematologic malignancies at Johns Hopkins were analyzed. Outcomes were compared between patients who received a second allograft with the same MHC composition and those who received an allograft with a new mismatched haplotype. Loss of heterozygosity analysis was performed for patients with acute myeloid leukemia (AML) whose first allograft was haploidentical. Between 2005 and 2015, 40 patients received a second BMT for a relapsed hematologic malignancy. The median follow-up is 750 (range, 26 to 2950) days. The median overall survival (OS) in the cohort is 928 days (95% confidence interval [CI], 602 to not reached [NR]); median event-free survival (EFS) for the cohort is 500 days (95% CI, 355 to NR). The 4-year OS is 40% (95% CI, 25% to 64%), and the 4-year EFS is 36% (95% CI, 24% to 55%). The cumulative incidence of nonrelapsed mortality by 2 years was 27% (95% CI, 13% to 42%). The cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) at 100 days was 15% (95% CI, 4% to 26%); the cumulative incidence of extensive chronic GVHD at 2 years was 22% (95% CI, 9% to 36%). The median survival was 552 days (95% CI, 376 to 2950+) in the group who underwent transplantation with a second allograft that did not harbor a new mismatched haplotype, while it was not reached in the group whose allograft contained a new mismatched haplotype (hazard ratio [HR], .36; 95% CI, .14 to .9; P = .02). EFS was also longer in the group who received an allograft containing a new mismatched haplotype, (NR versus 401 days; HR, .50; 95% CI, .22 to 1.14; P = .09). Although the allograft for this patient's second BMT contained a new mismatched haplotype, AML nevertheless relapsed a second time. Second BMTs are feasible and provide a reasonable chance of long-term survival. An allograft with a new mismatched haplotype may improve outcomes after second BMTs for relapsed hematologic malignancies.

Keywords: HLA loss; Haploidentical; Post-transplant cyclophosphamide; Relapse; Second transplantations.

Figure 1

OS (A) and EFS (B). The median OS for the cohort is 928 days (95% CI 602 – NR); median EFS for the cohort is 500 days (95% CI 355-NR).

Figure 2

Cumulative incidence of relapse at 2 years was 33% (95% CI 18–48%), and the cumulative incidence of NRM by 2 years was 27% (95% CI 13–42%) for the cohort

Figure 3

Matching pathway

Figure 4

OS (A) and EFS (B) by exposure to new haplotype. The median survival was 552 days (95% CI 376–2950+) in the group transplanted with a second graft that did not harbor a new mismatched haplotype, while it was not reached in the group whose allograft contained a new mismatched haplotype (HR 0.36, 95% CI 0.14 – 0.9; p=0.02). The median event free survival was also longer in the group who received an allograft containing a new mismatched haplotype (NR versus 401 days, HR 0.50, 95% CI .22–1.14, p=0.09)