Background
Phase III multicenter RCT (BMT CTN 0402), N=304 adults undergoing matched related donor allogeneic HCT. Tested tacrolimus/sirolimus vs tacrolimus/methotrexate as acute GVHD prophylaxis.
Interventions and follow up
Arm A: Tacrolimus + sirolimus (Tac/Sir).
Arm B: Tacrolimus + methotrexate (Tac/Mtx).
Primary endpoint: Day 114 grade II–IV acute GVHD-free survival (intention-to-treat).
mFollow up: 2 years.
Arm B: Tacrolimus + methotrexate (Tac/Mtx).
Primary endpoint: Day 114 grade II–IV acute GVHD-free survival (intention-to-treat).
mFollow up: 2 years.
Results
Day 114 grade II–IV aGVHD-free survival: 67% (Tac/Sir) vs 62% (Tac/Mtx), P=.38 (NS, negative primary).
Grade II–IV aGVHD: 26% vs 34%, P=.48.
Neutrophil engraftment: 14 vs 16 days, P<.001.
Platelet engraftment: 16 vs 19 days, P=.03.
2-yr cGVHD: 53% vs 45%, P=.06.
2-yr RFS: 53% vs 54%, P=.77.
2-yr OS: 59% vs 63%, P=.36.
NRM/TRM: NR.
Grade II–IV aGVHD: 26% vs 34%, P=.48.
Neutrophil engraftment: 14 vs 16 days, P<.001.
Platelet engraftment: 16 vs 19 days, P=.03.
2-yr cGVHD: 53% vs 45%, P=.06.
2-yr RFS: 53% vs 54%, P=.77.
2-yr OS: 59% vs 63%, P=.36.
NRM/TRM: NR.
Adverse events
Mucositis: Less severe with Tac/Sir (peak Oral Mucositis Assessment Scale 0.70 vs 0.96, P<.001).
Other toxicities: Similar between arms; no excess thrombotic microangiopathy or veno-occlusive disease attributable to sirolimus.
Other toxicities: Similar between arms; no excess thrombotic microangiopathy or veno-occlusive disease attributable to sirolimus.
Conclusions
Tacrolimus/sirolimus did not improve acute GVHD-free survival over tacrolimus/methotrexate (negative primary), but with similar long-term outcomes, faster engraftment, and less mucositis it is an acceptable methotrexate-free alternative after matched related donor HCT.
Key Limitations
Negative primary endpoint. Limited to matched related donors; not generalizable to unrelated/haploidentical settings. Pre-dates the post-transplant cyclophosphamide era now standard for many transplants.
Clinical Context
Established tacrolimus/sirolimus as a recognized calcineurin-based, methotrexate-sparing prophylaxis option, useful where methotrexate mucotoxicity is a concern. Subsequent BMT CTN 1703 made PTCy-tacrolimus-MMF the preferred standard for reduced-intensity HCT.