The combination of cyclophosphamide and cyclosporin has emerged as a potential new standard of care for preventing graft-versus-host disease (GVHD) in patients with aggressive blood cancers undergoing stem cell transplantation, according to results from the phase 3 BM12 CAST trial presented at the European Hematology Association 2025 Congress and simultaneously published in The New England Journal of Medicine.
The randomized trial demonstrated that cyclophosphamide plus cyclosporin significantly improved GVHD-free relapse-free survival compared with the current standard prophylaxis of cyclosporin plus methotrexate in patients receiving transplants from matched related blood stem cell donors.
Significant Improvement in Primary Endpoint
The study's primary endpoint showed compelling results, with median GVHD-free relapse-free survival reaching 26.2 months (95% CI, 9.1-not reached) in the cyclophosphamide plus cyclosporin arm (n = 66) compared with 6.4 months (95% CI, 5.6-83) with standard cyclosporin/methotrexate (n = 68), representing a hazard ratio of 0.42 (95% CI, 0.27-0.66).
At three years, 49.1% (95% CI, 36%-61%) of patients treated with posttransplant cyclophosphamide and cyclosporin remained free from GVHD compared with 14.2% (95% CI, 6%-25%) for those who received cyclosporin/methotrexate.
"Cyclosporin and cyclophosphamide offer a new standard of care for prevention of GVHD for patients with aggressive blood cancers undergoing transplant from a matched related blood stem cell donor," said lead study author David Curtis, MBBS, PhD, FRACP, FRCPA, a clinical hematologist and director of Malignant Hematology Research at the Australian Centre for Blood Disease, Monash University, Alfred Hospital, in Melbourne, Australia.
Promising Overall Survival Trends
While overall survival data remain immature, early results favor the cyclophosphamide plus cyclosporin regimen. The 2-year overall survival rates were 83% with cyclosporin/cyclophosphamide and 71% with cyclosporin/methotrexate (HR 0.59; 95% CI, 0.29-1.19).
Study Design and Patient Population
The cooperative group study, conducted with the Australasian Leukaemia & Lymphoma Group (ALLG), enrolled 134 patients with acute leukemia or myelodysplastic syndrome across 10 different transplant centers in Australia and New Zealand. Investigators sought to determine if replacing methotrexate with cyclophosphamide could improve GVHD prevention in patients posttransplant.
Eligible patients were between 18 and 70 years old, had previously undergone an allogeneic stem cell transplant from a matched related donor, and had an aggressive blood cancer. Patients were followed for three years, with the primary endpoint being GVHD-free relapse-free survival.
Safety Profile and Adverse Events
The safety profile of the new combination proved favorable, with researchers noting no increase in adverse effects, particularly cardiotoxicity, which is typically a concern in this patient population. The cumulative incidence of grade 3/4 acute GVHD at three months was 3% (95% CI, 1%-10%) with cyclophosphamide/cyclosporin compared with 10% (95% CI, 4%-19%) with methotrexate/cyclosporin. After the first 100 days following transplant, the rates of serious adverse events were similar across both treatment arms.
Clinical Significance
For patients with aggressive blood cancers, allogeneic stem cell transplantation provides curative potential; however, GVHD poses a significant treatment burden, and effective options are needed beyond the current combination of cyclosporin plus methotrexate, which is mechanistically designed to suppress the donor immune system.
"Our cooperative group is very proud to have delivered such an impactful clinical trial for patients that undergo bone marrow transplantation," said Delaine Smith, chief executive officer of ALLG. "Prof Curtis has led a highly motivated research team across Australia and New Zealand, and their efforts have catapulted this century's biggest improvement in bone marrow transplantation. We are thrilled that patients around the world will now have better treatment… better lives."
Curtis emphasized that "the study demonstrates the power of cooperative group clinical trials in addressing patient-specific care and outcomes."
