Greater HLA Disparity Is Associated with Reduced Risk of Relapse and Improved Event-Free Survival after Nonmyeloablative, HLA-Haploidentical BMT with Post-Transplantation High-Dose Cyclophosphamide
Authors: Kasamon Yvette L. , Leffell Mary S. , Kowalski Jeanne , Tsai Hua-Ling , Rossiter Nancy , Morris Lawrence E. , Crilley Pamela A. , Luznik Leo , Bolaños-Meade Javier , O’Donnell Paul V. , Ambinder Richard F. , Jones Richard J. , Fuchs Ephraim J. 
Published: April 2020

Abstract
Background: Although a lower relapse risk has been reported after allogeneic BMT with increasing HLA disparity, this potential benefit has been offset by higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM). However, it is possible that the type of GVHD prophylaxis could influence the balance between GVHD toxicity and relapse.
Patients and methods: We retrospectively analyzed the outcomes of 185 patients with poor-risk hematologic malignancies enrolled on three similar clinical trials of related-donor, haploidentical BMT incorporating high-dose post-transplantation cyclophosphamide (Cy) for GVHD and graft rejection prophylaxis (as published in BBMT2008;14:641–50). Molecular typing was at an allele level for HLA-A, -B, -Cw, and -DRB1 and at an allele group level for -DQB1. All received Cy (14.5 mg/kg IV on days −6, −5), fludarabine (30 mg/m2 IV on days −6 to −2), total body irradiation (200 cGy on day −1), and non-T-cell depleted bone marrow infusion. GVHD prophylaxis consisted of Cy (50 mg/kg IV) either once (on day 3; n = 48) or twice (on days 3, 4; n = 137), mycophenolate mofetil for 35 days, and tacrolimus for up to 6 months, with filgrastim begun after the last dose of Cy. Most patients (median age 50, range 1–71) had advanced disease and 49 (26%) had failed autologous BMT. Diagnoses were MDS (22), CMML (3), acute leukemia or lymphoblastic lymphoma (58), CML (11), CLL (15), multiple myeloma (9), non-Hodgkin lymphoma (42), and Hodgkin lymphoma (25).
Results: Median follow-up after BMT is 20 months (range, 2–71 months) in those without events. Nonengraftment attributed to primary graft failure or to residual bone marrow malignancy occurred in 29 of 177 evaluable patients (16%). Cumulative incidences of grade II–IV acute GVHD and chronic GVHD were 31% and 15%, respectively. Cumulative incidences of NRM and relapse or progression at one year were 15% and 50%, respectively. Actuarial event-free survival (EFS) at one year was 35%, with grade II–IV acute GVHD by day 100 associated with a trend toward lower cumulative incidence of relapse (p = 0.08) but a significantly higher cumulative incidence of NRM (p = 0.002) on subgroup analysis. Notably, increasing degrees of HLA mismatch at either class I or class II loci had no significant effect on cumulative incidence of acute or chronic GVHD or NRM. In contrast, the presence of a DRB1 antigen mismatch in the GVH, but not host-versus-graft (HVG), direction was associated with a significantly lower cumulative incidence of relapse (Figure a; p = 0.04) and improved EFS (Figure c; p = 0.009), whereas DQB1 antigen and class II allele mismatch status had no effect. Additionally, the presence of two or more class I allele mismatches (composite of A, B, and Cw) in either direction was associated with a significantly lower cumulative incidence of relapse (Figure b; p = 0.045 for GVH direction, p = 0.01 for HVG direction) and improved EFS (Figure d; p = 0.07 for GVH direction, p = 0.001 for HVG direction).
Conclusion: Greater HLA disparity appears to be beneficial after nonmyeloablative, HLA-haploidentical BMT that incorporates high-dose post-transplantation Cy. These results suggest an anti-tumor effect of partially HLA-mismatched BMT that is irrespective of clinically significant GVHD. Potential effectors of anti-tumor immunity include HLA-DRB1 reactive CD4+ T-cells, class I reactive CD8+ T-cells, and/or natural killer cells recognizing missing self. Since most patients have several potential HLA-haploidentical related donors, the results support a strategy of choosing a donor who is incompatible for both HLA-DRB1 antigen and multiple HLA class I alleles.
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