Background
Phase II/III, open-label RCT (BMT CTN 1301). 304 patients with hematologic malignancies undergoing HLA-matched related (MRD) or unrelated (MUD) donor PBSC allo-HCT. Compared tacrolimus + sirolimus (Tac/Sir), a calcineurin-free mTOR inhibitor regimen, versus tacrolimus + methotrexate (Tac/MTX). Rationale: sirolimus inhibits T-cell proliferation via a distinct mechanism and may reduce GVHD without impairing graft-versus-leukemia.
Interventions and follow up
Arm A (Tac/Sir): tacrolimus (target 8–12 ng/mL) + sirolimus (target 3–12 ng/mL, day −3 to +100 with taper)
Arm B (Tac/MTX): tacrolimus (target 8–12 ng/mL) + methotrexate 15mg/m² day +1, 10mg/m² days +3, +6, +11
Primary endpoint: Grade II–IV acute GVHD at day +114
Median follow up: 60 months
Arm B (Tac/MTX): tacrolimus (target 8–12 ng/mL) + methotrexate 15mg/m² day +1, 10mg/m² days +3, +6, +11
Primary endpoint: Grade II–IV acute GVHD at day +114
Median follow up: 60 months
Results
Grade II–IV acute GVHD: 26.1% (Tac/Sir) vs 29.2% (Tac/MTX) — HR 0.85, 95% CI 0.57–1.27, P=.43, NS
Grade III–IV acute GVHD: 9.1% vs 11.2% — NS
2-year chronic GVHD: 40.3% (Tac/Sir) vs 52.9% (Tac/MTX) — P=.04
2-year OS: 60.5% vs 59.3% — NS
2-year relapse: 23.4% vs 20.1% — NS
Thrombotic microangiopathy: 5.3% (Tac/Sir) vs 1.3% (Tac/MTX) — P=.06
Grade III–IV acute GVHD: 9.1% vs 11.2% — NS
2-year chronic GVHD: 40.3% (Tac/Sir) vs 52.9% (Tac/MTX) — P=.04
2-year OS: 60.5% vs 59.3% — NS
2-year relapse: 23.4% vs 20.1% — NS
Thrombotic microangiopathy: 5.3% (Tac/Sir) vs 1.3% (Tac/MTX) — P=.06
Adverse events
Vascular/metabolic: Tac/Sir higher TMA (5.3% vs 1.3%) and hypertriglyceridemia (22% vs 4%)
Mucosal: grade ≥3 mucositis lower with Tac/Sir (no methotrexate) 12% vs 27%, P<.001
Engraftment/infection: delayed engraftment median 16 vs 14 days (NS); infection rates similar
Mucosal: grade ≥3 mucositis lower with Tac/Sir (no methotrexate) 12% vs 27%, P<.001
Engraftment/infection: delayed engraftment median 16 vs 14 days (NS); infection rates similar
Conclusions
Tac/Sir did not significantly reduce acute GVHD vs Tac/MTX but was associated with significantly lower chronic GVHD and less mucositis. Increased TMA risk warrants monitoring. Tac/Sir is an acceptable alternative to Tac/MTX for selected patients, particularly those at high risk for mucositis.
Key Limitations
The primary endpoint (acute GVHD) was not met, making this a technically negative trial for its stated purpose; chronic GVHD reduction was a secondary endpoint. The TMA signal (5.3% vs 1.3%) raises safety concerns given the sirolimus–calcineurin inhibitor combination's nephrotoxic and vascular effects. With BMT CTN 1703 (PTCy), Tac/Sir has been largely superseded for matched-donor PBSC HCT.
Clinical Context
BMT CTN 1301 validated Tac/Sir as an alternative to Tac/MTX with lower mucositis and chronic GVHD, but it was not superior on the primary acute GVHD endpoint. Following BMT CTN 1703, PTCy-based prophylaxis is the preferred standard for matched PBSC allo-HCT per ASTCT practice. Tac/Sir remains in use at some centers, particularly for MRD or BM transplants, with TMA monitoring required.