Superior Chronic Graft-versus-Host Disease-Free Survival with Post-Transplant Cyclophosphamide Relative to Tacrolimus/Methotrexate in Myeloablative HLA-Matched Allogeneic Hematopoietic Cell Transplantation.

Graft-versus-host disease (GVHD) has been a significant barrier to successful myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT). Traditional GVHD prophylaxis with a calcineurin inhibitor and methotrexate (TAC/MTX) is associated with substantial GVHD. Controversy exists over whether post-transplantation cyclophosphamide (PTCy) should replace TAC/MTX as the standard of care for MAC HCT using HLA-matched donors. We conducted a retrospective cohort study of 237 adult patients with acute myeloid leukemia (AML; n = 164) or acute lymphoblastic leukemia (ALL; n = 73) who underwent MAC followed by HLA-matched HCT at our center between 2018 and 2025. Patients were evaluated based on GVHD prophylaxis received: PTCy/TAC/mycophenolate mofetil (MMF) or TAC/MTX. Kaplan-Meier and competing-risks methods were applied, with outcomes further stratified by pre-HCT measurable residual disease (MRD). Of the 237 patients, 46 received PTCy/TAC/MMF and 191 received TAC/MTX. Baseline characteristics, remission status, and pre-HCT MRD were comparable in the 2 groups. One-year chronic GVHD-free survival was significantly superior with PTCy compared to TAC/MTX (86.3% versus 61.7%; P = .006), attributed to significantly lower moderate to severe chronic GVHD at 1 year (7% versus 21%; P = .02) and significantly lower NRM at 1 year (2.2% versus 10.5%; P = .04) with PTCy. Overall survival (OS) and progression-free survival (PFS) were similar in the PTCy and TAC/MTX groups (OS: 93.3% versus 82.1%, P = .2; PFS: 70.2% versus 74.8%, P = .6). One-year GVHD-free, relapse-free survival (GRFS) trended higher in the PTCy group (63.5% versus 50.2%; P = .09). We then evaluated the outcomes in the 2 groups stratified by pre-HCT MRD status (PTCy: MRD+ 35% [n = 16]; MRD-, 63% [n = 29]; unknown, 2% [n = 1]; TAC/MTX: MRD+, 34% [n = 65]; MRD-, 50% [n = 96]; unknown, 16% [n = 30]). Similar trends toward superior rates of GVHD, NRM, and GRFS were observed following PTCy in both the MRD+ and MRD- cohorts. The cumulative incidence of relapse at 1 year did not differ between PTCy and TAC/MTX among MRD- patients (14.1% versus 9%; P = .41); however, we observed a strikingly high incidence of relapse among MRD+ patients treated with PTCy relative to TAC/MTX (51.9% versus 23.3%; P = .06). In this single-center analysis, PTCy-based GVHD prophylaxis demonstrated superior chronic GVHD-free survival, significantly reduced NRM, and a trend toward higher GRFS compared with TAC/MTX in MAC HLA-matched HCT for acute leukemia. However, a suggestion of increased relapse, particularly among patients with detectable MRD before HCT, warrants further investigation. Integrating enhanced antileukemic strategies with PTCy platforms may optimize long-term outcomes. © 2026 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.