Background
Phase III multicenter open-label RCT (ALLG BM12 CAST, Australasian Leukaemia and Lymphoma Group), N=134 adults undergoing matched related donor (MRD) peripheral-blood SCT after myeloablative or reduced-intensity conditioning for high-risk blood cancers. Tested whether PTCy added to a calcineurin inhibitor improves GVHD-free, relapse-free survival vs the standard calcineurin inhibitor + antimetabolite backbone.
Interventions and follow up
Arm A: PTCy 50 mg/kg days +3/+4 + cyclosporin (experimental prophylaxis), n=66.
Arm B: Cyclosporin + methotrexate (standard prophylaxis), n=68.
Primary endpoint: GVHD-free, relapse-free survival (GRFS).
mFollow up: NR.
Arm B: Cyclosporin + methotrexate (standard prophylaxis), n=68.
Primary endpoint: GVHD-free, relapse-free survival (GRFS).
mFollow up: NR.
Results
GRFS (median): 26.2 months (95% CI 9.1–NR) with PTCy-cyclosporin vs 6.4 months (95% CI 5.6–8.3); P<.001.
3-yr GRFS: 49% (95% CI 36–61) vs 14% (95% CI 6–25); HR for GVHD, relapse, or death 0.42 (95% CI 0.27–0.66).
Grade III–IV acute GVHD (day 100): 3% (95% CI 1–10) vs 10% (95% CI 4–19).
2-yr OS: 83% vs 71%; HR for death 0.59 (95% CI 0.29–1.19).
3-yr GRFS: 49% (95% CI 36–61) vs 14% (95% CI 6–25); HR for GVHD, relapse, or death 0.42 (95% CI 0.27–0.66).
Grade III–IV acute GVHD (day 100): 3% (95% CI 1–10) vs 10% (95% CI 4–19).
2-yr OS: 83% vs 71%; HR for death 0.59 (95% CI 0.29–1.19).
Adverse events
Serious adverse events: Similar incidence between groups during the first 100 days after SCT.
Acute GVHD / early toxicity: PTCy-cyclosporin reduced grade III–IV acute GVHD without an apparent increase in early serious toxicity or non-relapse events.
Acute GVHD / early toxicity: PTCy-cyclosporin reduced grade III–IV acute GVHD without an apparent increase in early serious toxicity or non-relapse events.
Conclusions
Adding post-transplant cyclophosphamide to a calcineurin inhibitor (replacing methotrexate) produced significantly longer GVHD-free, relapse-free survival than standard cyclosporin-methotrexate after matched related donor transplantation, across both reduced-intensity and myeloablative conditioning. This is the first randomized evidence supporting PTCy specifically in the MRD and MAC settings using a simplified dual-drug regimen.
Key Limitations
Modest sample size (N=134), open-label design. OS difference did not reach significance (HR 0.59, 95% CI crossing 1). Used cyclosporin rather than tacrolimus as the calcineurin backbone, which may limit direct comparison with tacrolimus-based standards.
Clinical Context
Extends PTCy-based prophylaxis — established in haploidentical and unrelated donor HCT (BMT CTN 1703) — into the matched related donor setting across both MAC and RIC. Supports incorporation of PTCy on a calcineurin backbone as a simplified GVHD-prophylaxis option within ASTCT/EBMT practice.