Background: In BMT CTN 1703, post-transplant cyclophosphamide (PTCy)-based prophylaxis significantly improved GVHD-free, relapse-free survival (GRFS) compared to standard prophylaxis with tacrolimus and methotrexate (MTX), while overall survival (OS), disease-free survival (DFS), relapse, and treatment-related mortality (TRM) did not differ significantly. The trial enrolled adults undergoing reduced-intensity conditioning (RIC) hematopoietic cell transplantation (HCT) for hematologic malignancies with well-matched donors, excluding myeloablative conditioning (MAC) or in-vivo T-cell depletion with anti-thymocyte globulin (ATG). The current study evaluates myeloablative HCT outcomes following PTCy-based versus CNI/MTX-based GVHD prophylaxis, with or without ATG, using the Center for International Blood & Marrow Transplant Research (CIBMTR) database.

Methods: The primary objective was to compare the 2-year GRFS between PTCy-based and CNI/MTX-based GVHD prophylaxis, with and without ATG. Secondary objectives included OS, DFS, TRM, relapse, acute GVHD (aGVHD II-IV and III-IV), and chronic GVHD requiring immunosuppression (cGVHD). Adult patients (18≤ age <70 years) with hematologic malignancies (AML or ALL in CR1 or CR2, MDS) undergoing first HCT from an HLA-matched sibling (MSD) or unrelated donor (MUD) between 2014-2022, using a PBSC graft and MAC regimen were included (n=8272). Cox proportional hazards models were used to assess associations. Proportional hazards assumptions were tested using time-dependent covariates; violations were addressed by stratification. Stepwise backward selection was used to build outcome-specific models. Interactions were tested at p<0.01, and no significant interactions were detected. All models were adjusted for center effects. A significance level of 0.01 was used to account for multiple testing.

Results: The study included three cohorts: PTCy-based (n=1360, reference), CNI/MTX with ATG (n=1543), and CNI/MTX without ATG (n=5369). Median age at HCT 50.6 years for the study population, and similar in all three cohorts. Most patients were non-Hispanic white, with slight male predominance across all three groups (55%). AML was the predominant diagnosis in the three cohorts (54-59%). MUD was more common in the PTCy (68%) and CNI/MTX/ATG (95%) groups, while in the CNI/MTX cohort 47% had a MUD and 53% MSD. More grafts were cryopreserved in the PTCy cohort (45%) compared to 24% and 22% in the CNI/MTX/ATG and CNI/MTX cohorts, respectively. PTCy use increased since 2019 compared to CNI/MTX+/-ATG.

At 2 years, GRFS was significantly higher in PTCy cohort (41.2%; 95% confidence interval [CI], 38.5-43.9), compared to CNI/MTX/ATG (25.8%; 95%CI, 23.5-28.1), and CNI/MTX cohorts (17.5%; 95%CI ,16.5-18.5), p<0.001. In multivariable regression analysis (MVA), compared to PTCy-based, patients receiving CNI/MTX prophylaxis had lower GRFS [HR 1.74 (1.58-1.92), p<0.0001], higher aGVHD II-IV [HR 1.62 (1.35-1.94), p<0.0001] and III-IV [HR 1.97 (1.50-2.60), p<0.0001], higher cGVHD requiring immunosuppression [HR 2.82 (2.25-3.53), p<0.0001], higher TRM [HR 1.69 (1.40-2.05), p<0.0001], higher relapse risk within the first 4 months [HR 1.38 (1.17-1.63), p=0.0001] but lower relapse risk after 4 months [HR 0.80 (0.70-0.91), p=0.0007] and lower OS [HR 1.20 (1.07-1.34), p=0.0016]. Compared to PTCy-based, patients with CNI/MTX/ATG prophylaxis had inferior GRFS [Hazard ratio (HR) 1.47 (1.27-1.70, p<0.0001)], higher aGVHD II-IV [HR 1.51 (1.17-1.95), p=0.0015], cGVHD requiring immune suppression [HR 1.73 (1.28-2.33), p=0.0003] and higher relapse risk within the first 4 months [HR 1.50 (1.17-1.93), p=0.0016]. DFS did not differ between cohorts. The association of PTCy with higher GRFS was consistent in subgroup analyses restricted to MUD and MSD, as well as in sensitivity analyses limited to transplants performed between 2019 and 2022.

Conclusions: In this large registry-based study of adult patients undergoing MAC allogeneic HLA-matched HCT, PTCy-based GVHD prophylaxis was associated with superior GRFS compared to CNI/MTX with and without ATG. This benefit resulted from a decrease in both grade III-IV aGVHD and cGVHD requiring immune suppression, along with lower TRM. While there was no difference in DFS, OS was higher in the patients receiving PTCy-based prophylaxis. These results support the use of PTCy-based prophylaxis in the myeloablative setting for adults with AML or ALL in remission, or with MDS.

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2025
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