Post-transplant cyclophosphamide vs tacrolimus/methotrexate: Improved GRFS, reduced NRM, and less severe GVHD in myeloablative HLA-matched allogeneic transplantation

Abstract

Abstract Background: Graft-versus-host disease (GVHD) has been a significant barrier to successful myeloablative (MAC) allogeneic hematopoietic cell transplantation (HCT). Traditional GVHD prophylaxis with calcineurin inhibitor [tacrolimus (TAC) or cyclosporin] and methotrexate (MTX) is associated with substantial GVHD. Recent studies suggest that regimens incorporating post-transplant cyclophosphamide (PTCy) result in improved GVHD-free-relapse-free survival (GRFS) with lower non-relapse mortality (NRM) and less severe GVHD after MAC HCT with HLA-matched donors. Methods: We conducted a retrospective cohort study of 237 adult patients (pts) 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. Pts were evaluated based on GVHD prophylaxis: PTCy/TAC/mycophenolate mofetil (MMF) or TAC/MTX. The choice of MAC regimen and GVHD prophylaxis followed institutional protocols and physician discretion. The primary endpoint was GRFS, defined as time from HCT to the earliest occurrence of grade III-IV acute GVHD (aGVHD) as defined by MAGIC criteria, moderate-to-severe chronic GVHD (cGVHD) per NIH criteria, morphologic relapse, or death. Secondary endpoints included overall survival (OS), progression-free survival (PFS), cGVHD-free survival, cumulative incidence of grade II–IV and III–IV aGVHD at D+90, and cumulative incidence of moderate-to-severe cGVHD, NRM, and leukemia relapse at 1 year. Survival outcomes were estimated using the Kaplan–Meier method and compared using log-rank tests. Cumulative incidence functions accounted for competing risks and were compared using Gray's test. Measurable residual disease (MRD) in AML was evaluated by flow cytometry (sensitivity 10-4), FLT3-ITD and/or NPM1 by NGS/PCR; for ALL, NGS or BCR::ABL1 PCR were also considered. Results: Of 237 pts, 46 received PTCy/TAC/MMF and 191 received TAC/MTX. Baseline characteristics including age, sex, race/ethnicity, remission status, and pre-HCT MRD were comparable between groups. Chemotherapy-only regimens were used in 74%; TBI-based regimens were used in 26%. The PTCy group included 41% ALL and 59% AML; TAC/MTX group included 28% ALL and 72% AML. Among ALL pts, Ph-like status was higher in the PTCy group (8.1% vs 1.6%, p = 0.026). AML pts had comparable ELN 2022 risk distributions between groups. Median follow-up was 2.5 years (interquartile range, 1–5.4 years). The 1-year GRFS trended higher with PTCy versus TAC/MTX (63.5% vs 50.2%, p = 0.09). OS and PFS were similar between PTCy and TAC/MTX (OS: 93.3% vs. 82.1%, p = 0.2; PFS: 70.2% vs. 74.8%, p = 0.6, respectively). PTCy yielded superior 1-year chronic GVHD-free survival (86.3% vs 61.7%, p = 0.006). The cumulative incidence of grade II-IV and III-IV aGVHD trended lower with PTCy (13.0% and 4.3%) compared to TAC/MTX (28.4% and 12.6%, p = 0.057 and 0.076). Moderate-to-severe cGVHD at 1 year was significantly lower in the PTCy group (7% vs 21%, p = 0.02). The cumulative incidence of NRM at 1 year was also significantly lower with PTCy than with TAC/MTX (2.2% vs 10.5%, p = 0.04). However, cumulative incidence of relapse at one year trended higher with PTCy (27.6% vs 14.7%, p = 0.06). We then evaluated outcomes of PTCy vs TAC/MTX stratified by pre-HCT MRD (n=81 MRD+; n=125 MRD-). Among MRD+ pts, 1-year GFRS was similar between PTCy and TAC/MTX (41.7% vs 39.5%, p = 0.6); among MRD- pts, 1-year GRFS was numerically higher for PTCy (75.4% vs 58.2%, p = 0.2). Cumulative incidence of grade II-IV and III-IV aGVHD, cGVHD, and NRM all trended lower with PTCy vs TAC/MTX in both MRD+ and MRD- cohorts. The cumulative incidence of relapse at 1 year among MRD+ pts was higher with PTCy vs TAC/MTX (51.9% vs 23.3%, p = 0.05); no differences were observed in MRD- pts (14.1% vs 9%, p = 0.41). OS and PFS were similar for PTCy vs TAC/MTX regardless of MRD status.Conclusion: Our single-center experience corroborates recent randomized data (Curtis NEJM 2025), demonstrating superior GRFS and GVHD rates for PTCy-based GVHD prophylaxis compared with historical TAC/MTX in MAC HLA-matched alloHCT for AML/ALL. PTCy regimens resulted in less clinically significant GVHD and lower NRM; however, we observed a trend towards increased relapse, especially among patients with detectable MRD pre-HCT. Future studies should focus on optimizing anti-leukemic strategies to further mitigate relapse risk in PTCy-based HCT.