National Marrow Donor Program–Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide

Abstract

PURPOSE Hematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT. PATIENTS AND METHODS We performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning–based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy. RESULTS Notably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS. CONCLUSION Our prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.

KIR in Allogeneic Hematopoietic Stem Cell Transplantation: Need for a Unified Paradigm for Donor Selection

“…Concerning the use of 9/10 MMUD, a high cumulative incidence of grade II–IV acute GVHD (aGVHD) was previously reported, which reached 69% in some cohorts ( 18 – 20 ) and restricted the use of such donors. Recent studies introducing PT-Cy instead of historical anti-thymoglobulins (ATG) as GVHD prophylaxis show significantly lower rates of aGVHD using 9/10 MMUD ( 21 , 22 ). One question being addressed now under clinical trials is whether haploidentical donor or 9/10 MMUD is a better alternative donor (NCT01597778, NCT03250546).…”

Is Post-Transplant Cyclophosphamide the New Methotrexate?

“…The only difference observed was a higher incidence of relapse in the PT-Cy group (HR 1.52; p = 0.02). A recent prospective, multicenter phase 2 trial for HLA-mismatched unrelated donor (UD) using PT-Cy/sirolimus/MMF and MAC (50%) or RIC (50%) conditioning showed the feasibility of alloHCT with mismatched UD [48]. All patients received bone marrow grafts.…”

“…Progress III study is currently comparing in a phase 3 trial if PT-Cy/tacro/MMF is superior to standard tacro/MTX in the RIC/PBSC setting [43]. One prospective phase 2 trial showed feasibility of PTCy/sirolimus/MMF in the setting of MMUD when using BM graft [48].…”

Abatacept for GVHD prophylaxis can reduce racial disparities by abrogating the impact of mismatching in unrelated donor stem cell transplantation

“…However, the PT-Cy patients had inferior 6-month SGFS (68% for MMUD/PT-Cy vs 97.7% for MMUD/aba). 9 Together, POC account for a large proportion of enrollment in both the ABA2 and PT-Cy trials. These studies document the emergence of multiple strategies that could make MMUD HCT an effective alternative for HCT, and, thereby, lessen disparities in outcomes affecting POC with hematologic malignancies.…”