Prevention of graft-vs-host disease was far superior with a cyclophosphamide/cyclosporin-based regimen than with standard prophylaxis in patients receiving a matched-sibling donor stem cell transplant in a large Australian randomized trial, investigators reported at the European Hematology Association (EHA) 2025 Congress.1 The study, which many experts believe may change the standard of care, was published simultaneously in TheNew England Journal of Medicine.2
In the randomized phase III ALLG BM12 CAST trial, patients treated with cyclophosphamide plus cyclosporin, compared with those receiving cyclosporin plus methotrexate, remained free of graft-vs-host disease or disease relapse for a median of 26.2 months as compared with 6.4 months (P < .001). At 3 years, 49% and 14%, respectively, were free of graft-vs-host disease and relapse, meeting the study’s primary endpoint, according to David Curtis, MBBS, PhD, FRACP, FRCPA, of Alfred Health in Melbourne, Australia, who presented the findings during the EHA 2025 Congress Plenary Session.
David Curtis, MBBS, PhD, FRACP, FRCPA
Dr. Curtis said the findings establish cyclophosphamide plus single-agent calcineurin inhibition as the new standard for graft-vs-host disease prophylaxis after matched related-donor transplantation. “This could be the nail in the coffin for standard graft-vs-host disease prophylaxis, which is a calcium inhibitor and an antimetabolite for matched donor transplants, which has been used for 40 years. These data support changing practice, as they have already changed practice in Australia,” he told journalists at a press briefing.
Rates of grade III or IV acute graft-vs-host disease at 3 months were 3% with cyclophosphamide/cyclosporin prophylaxis and 10% with standard prophylaxis. The hazard ratio (HR) for graft-vs-host disease, relapse, or death was 0.42 (95% confidence interval [CI] = 0.27–0.66). At 2 years, the overall survival rate was 83% vs 71%, respectively (HR = 0.59; 95% CI = 0.29–1.19). The incidence of serious adverse events was similar in the two groups in the first 100 days after stem cell transplantation. Infections were not increased in the experimental arm, and the actual benefit observed on relapse-free survival was noteworthy, according to Dr. Curtis. “This is probably the first randomized study of graft-vs-host disease prophylaxis that shows the benefit [of prophylaxis] for relapse-free survival.”
Need for a New Approach
Although peripheral blood stem cell transplant from matched related donors may cure many hematologic cancers, graft-vs-host disease confers a morbidity and mortality risk for 20% to 50% of patients, the researchers noted. The historical standard for graft-vs-host disease prophylaxis has been combination therapy with a calcineurin inhibitor (cyclosporin or tacrolimus) and an antimetabolite (methotrexate or mycophenolate mofetil), for immune suppression. “But this is only partially effective,” explained Dr. Curtis, “with about one in four patients either succumbing to or living with long-term illness due to graft-vs-host disease. We need more effective methods to reduce the risk for graft-vs-host disease without increasing the risk for infection or relapse.”
About the Study
Various combinations of agents have been evaluated in different transplant populations, with varying levels of success. The multicenter CAST trial sought to resolve these uncertainties in 134 adults undergoing myeloablative or reduced-intensity conditioning before stem cell transplants from matched related donors.2 The median age of patients was 56; approximately 60% had acute myeloid leukemia, 22% had acute lymphoblastic leukemia, 16% had myelodysplastic syndrome, 60% had intermediate-risk disease status, and almost 30% had high- or very high–risk disease. Patients were randomly assigned to receive posttransplant cyclophosphamide/cyclosporin or cyclosporin/methotrexate.
“The difference with previous studies is that here we don’t use an antimetabolite, so there’s no mycophenolate or methotrexate, and I think that’s been the key for making this regimen much more tolerable. The other important aspect of this study is that we’ve shown it [this regimen] can be used for young people receiving myeloablative conditioning,” Dr. Curtis said.
Multiple analyses of the data showed consistent superiority of the cyclophosphamide/cyclosporin prophylaxis, regardless of patient age, intensity of conditioning regimen, use of a female donor for a male recipient, comorbidity score, or disease risk index. Neutrophil engraftment was not delayed with the experimental approach, and the time to platelet recovery was just 3 days longer.
DISCLOSURE: Dr. Curtis reported no conflicts of interest.
REFERENCES
1. Curtis D, Purtill D, Lewis C, et al: A phase 3 randomised trial of post-transplant cyclophosphamide for GVHD prophylaxis in matched sibling donor peripheral blood stem cell transplantation: The ALLG BM12 CAST trial. EHA 2025 Congress. Abstract S103. Presented June 14, 2025.
2. Curtis DJ, Patil SS, Reynolds J, et al: Graft-versus-host disease prophylaxis with cyclophosphamide and cyclosporin. N Engl J Med. June 13, 2025 (early release online).
