Posttransplant cyclophosphamide (PTCy) has been increasingly used in unrelated donor (URD) hematopoietic cell transplantation (HCT) based on two phase III trials that have compared PTCy with conventional prophylaxis. However, a robust comparison with anti-thymocyte globulin (ATG) is not available.

Compare PTCy and ATG in patients undergoing URD HCT.

This registry-based cohort study included patients who underwent hematopoietic cell transplantation in the United States from 2017 to 2021. Data were sourced from a Center for International Blood and Marrow Transplant Research (CIBMTR) registry database. We included patients diagnosed with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) who received HCT using matched or mismatched URD HCT with PTCy or ATG (those receiving both were excluded). The primary outcomes were relapse-free survival (RFS) and moderate to severe chronic GVHD (mod/sev cGVHD). Secondary outcomes included overall survival (OS), relapse (REL), non-relapse mortality (NRM), and grades II-IV and III-IV acute GVHD (aGVHD II-IV and aGVHD III-IV). Univariable analysis was performed with Kaplan-Meier and cumulative incidence curves and compared with the logrank and Gray tests, respectively. Multivariable analyses were performed using cause-specific Cox models controlling for patient age and sex, disease, conditioning regimen, graft source, donor age, HLA match, and year of transplant. All analyses were conducted with R, version 4.1.1, from the R Foundation for Statistical Computing, Vienna, Austria.

With a median follow-up of 36 months, 4,750 patients were included (2,271 with PTCy and 2,479 with ATG). The median age was 61 years (range: 18-81), and 44% were female. AML was the most common diagnosis (54%), followed by MDS (30%) and ALL (16%). 45% received a myeloablative conditioning regimen, and peripheral blood was the preferred graft source (90%). Except for HLA matching (HLA 7/8 in 26% of the PTCy group and 9% in the ATG group) and the year of transplant (PTCy was more common in later years), all variables were well-balanced. 2y-RFS was 49% for PTCy and 43% for ATG (p = 0.001). 2y-mod/sev cGVHD was 12% for PTCy and 23% for ATG (p < 0.001). RFS improved with PTCy (HR = 0.83, 95%CI 0.76-0.91, p<0.001) as well as mod/sev cGVHD (HR = 0.45, 95%CI 0.38-0.53, p < 0.001), compared to ATG. OS also improved (HR = 0.77, 95%CI 0.70-0.85, p < 0.001), mainly because of lower NRM (HR = 0.66, 95%CI 0.58-0.76, p < 0.001). There was no effect on relapse (HR = 0.95, 95%CI 0.85-1.07, p = 0.44). Grades II-IV (HR = 0.60, 95%CI 0.54-0.67, p < 0.001) and III-IV aGVHD (HR = 0.44, 95%CI 0.36-0.55, p < 0.001) were also less common with PTCy compared to ATG. The same results held when (1) HLA 7/8 mismatched HCT were excluded or (2) when analyses were stratified by transplant year.

Within this large and contemporary CIBTMR database, outcomes with PTCy-based GVHD prophylaxis were better than ATG in every studied aspect except relapse, leading to higher RFS and OS and improved GVHD control. Although registry-based, the groups were well-balanced, and the large patient cohort (nearly 5,000 individuals) enabled us to develop a Cox model that controlled for all possible confounding factors, minimizing bias. Our findings suggest that PTCy should be preferred over ATG in unrelated donor transplantation.