Editor's Note: The 30th European Hematology Association (EHA) Annual Meeting 2025 was grandly held in Milan, Italy, gathering top experts from the global hematology community to discuss and share the latest research progress and cutting-edge technologies in the field. During the Plenary Session, Professor David Curtis from the Australasian Leukaemia and Lymphoma Group (ALLG), on behalf of his team, announced the first results of the ALLG BM12 CAST clinical trial. This Phase III randomized controlled trial, focusing on peripheral blood stem cell transplantation from matched sibling donors, provides powerful "practice-changing" evidence to solve the challenge of Graft-versus-Host Disease (GVHD) prophylaxis, a problem that has puzzled clinicians for nearly forty years, sparking significant interest and heated discussion among attendees.

Even in matched sibling donor stem cell transplantation, considered the optimal donor source, clinically significant GVHD remains a major cause of post-transplant morbidity and mortality. Although treatment options for GVHD are increasing, achieving durable and complete remission remains difficult. Therefore, exploring a new strategy that can effectively prevent GVHD without increasing the risk of infection and relapse has become an urgent problem for the hematology community to overcome.

For nearly four decades, a combination of a calcineurin inhibitor and an anti-metabolite has been the cornerstone of GVHD prophylaxis in sibling donor transplantation. Although some centers add anti-thymocyte globulin (ATG), its optimal dosage, formulation, and the potential for increased risks of infection and relapse remain controversial. In recent years, the application of Post-transplant Cyclophosphamide (PTCy) has become increasingly widespread, based on the success of two large randomized trials. However, these studies primarily included unrelated donors and did not cover younger patients receiving myeloablative conditioning, leaving the precise efficacy of PTCy in sibling donor transplantation unclear.

To fill this gap in evidence-based medicine, the ALLG initiated and completed the CAST study. The study aimed to evaluate the efficacy and safety of PTCy in matched sibling donor peripheral blood stem cell transplantation, covering a wide range of patients receiving both myeloablative and reduced-intensity conditioning.

CAST Study Design: The First Randomized Trial of PTCy Focused on Sibling Donor Peripheral Blood Transplantation

The CAST study is a prospective, multi-center, open-label, Phase III randomized controlled trial designed to compare the superiority of a PTCy plus cyclosporin regimen against the standard regimen of cyclosporin plus methotrexate for GVHD prophylaxis.

Between April 2019 and January 2024, the study enrolled 134 patients undergoing transplantation for acute leukemia (in remission) or myelodysplasia at 8 centers in Australia and 2 centers in New Zealand. Patients were randomized 1:1 into two groups:Standard Prophylaxis Group: Received cyclosporin and methotrexate.Experimental Group: Received PTCy and cyclosporin. Notably, mycophenolate was not added to this regimen.

The primary endpoint of the study was Graft-versus-host-disease-free, Relapse-free Survival (GRFS), defined as the time to the first occurrence of grade III-IV acute GVHD, moderate-to-severe chronic GVHD, morphological relapse, or death from any cause. For patients without an event, the median follow-up was 36 months.

Key Research Findings: PTCy Regimen Significantly Improves GRFS and Relapse-Free Survival

The results of the CAST study are inspiring, with the experimental arm demonstrating overwhelming advantages across multiple key endpoints.

First, the PTCy regimen achieved tremendous success in GVHD prevention. The cumulative incidence curves showed that both acute and chronic GVHD rates were significantly lower in the experimental group compared to the standard group. Throughout the follow-up period, no grade IV acute GVHD occurred in the PTCy group, and only one patient developed severe chronic GVHD.

Regarding the primary endpoint of GRFS, the PTCy regimen delivered substantial clinical benefits. Data showed that at 3 years post-transplant, the GRFS rate in the PTCy group was as high as 49%, compared to only 14% in the standard therapy group, a difference of high statistical significance. Subgroup analyses further confirmed that the benefits of PTCy were highly significant regardless of patient age or the intensity of the conditioning regimen.

More importantly, this excellent GVHD control did not come at the cost of increased relapse. The data revealed that the two-year Relapse-free Survival (RFS) rate in the PTCy group was 74%, significantly higher than the 59% in the standard group. Although the improvement in Overall Survival (OS) has not yet reached statistical significance, a positive trend of fewer deaths was observed in the PTCy group, with zero deaths attributable to GVHD and only half the number of deaths due to infection compared to the standard group.

Safety and Clinical Significance: PTCy Regimen is Well-Tolerated, Driving a Paradigm Shift in Practice

In addition to its outstanding efficacy, the safety profile of the PTCy regimen was equally impressive. Professor David Curtis emphasized that the experimental regimen was very well-tolerated. Within the first 100 days post-transplant, no increased toxicity was observed, apart from a 3-day delay in platelet engraftment. Regarding grade III or higher non-hematologic adverse events, there was no increase in the rates of infection or ICU admission in the PTCy group. Of particular note, severe hemorrhagic cystitis, a clinical concern associated with cyclophosphamide, did not occur, and only two cases of serious cardiac events were observed. Professor Curtis speculated that the favorable tolerability of the regimen might be related to the omission of mycophenolate. During the subsequent Q&A session, Professor Curtis addressed questions regarding the optimal timing and dosage of PTCy, the possibility of omitting immunosuppressants, and long-term complications. He pointed out that the CAST study used a fixed dose of 50mg/kg, and its excellent safety profile provides confidence for its clinical application. Regarding long-term complications, as data collection was censored at 100 days post-transplant, long-term data are not yet available. However, the team has preserved all molecular data for future in-depth analysis of specific subgroups, such as those with TP53 mutations.

Summary and Outlook

In conclusion, the ALLG BM12 CAST study clearly demonstrates that for patients receiving matched sibling donor peripheral blood stem cell transplantation (including younger patients undergoing myeloablative conditioning), the two-drug “PTCy + cyclosporin” regimen is significantly superior to the traditional standard prophylaxis in improving GRFS. This regimen is not only excellently tolerated without increasing early toxicity or relapse risk, but it also translates into a significant improvement in relapse-free survival through effective control of GVHD.

This “simple, inexpensive, yet practice-changing” research outcome establishes a new standard for GVHD prophylaxis in the global field of sibling donor transplantation. It not only provides clinicians with a superior treatment option but also once again highlights the critical value and immense contribution of clinical collaborative research groups like the ALLG in the global landscape of oncology and hematology research.