Background
Multicenter prospective open-label phase 2 noninferiority RCT (NCT04669210), N=128 adults with AML or ALL in complete remission undergoing unrelated or haploidentical HCT. Tested calcineurin-free PTCy + ruxolitinib vs standard PTCy + tacrolimus + MMF for GVHD prophylaxis.
Interventions and follow up
Arm A: PTCy 50 mg/kg days +3/+4 + ruxolitinib (5 mg TID during conditioning and days +5 to +21, then 5 mg BID days +22 to +150).
Arm B: PTCy 50 mg/kg days +3/+4 + tacrolimus (target 5–15 ng/mL) + mycophenolate mofetil.
Primary endpoint: Noninferiority for grade II–IV acute GVHD at day +125 (noninferiority margin 10%).
mFollow up: 2-year outcomes reported.
Arm B: PTCy 50 mg/kg days +3/+4 + tacrolimus (target 5–15 ng/mL) + mycophenolate mofetil.
Primary endpoint: Noninferiority for grade II–IV acute GVHD at day +125 (noninferiority margin 10%).
mFollow up: 2-year outcomes reported.
Results
Grade II–IV aGVHD (day +125): 12.9% (PTCy-Ruxo) vs 21.2% (PTCy-Tac-MMF); risk difference −8.3% (95% CI −21.2 to 4.6); noninferiority P=.0041 (superiority P=.20).
Moderate-severe cGVHD (2-yr): 24.2% vs 39.5%; noninferiority P=.0012 (superiority P=.09).
2-yr OS: 80.6% vs 72.5%; P=.28.
GRFS: 61.3% vs 48.1%; P=.19.
NRM / relapse: NR.
Moderate-severe cGVHD (2-yr): 24.2% vs 39.5%; noninferiority P=.0012 (superiority P=.09).
2-yr OS: 80.6% vs 72.5%; P=.28.
GRFS: 61.3% vs 48.1%; P=.19.
NRM / relapse: NR.
Adverse events
Renal: Grade 2–4 acute kidney injury 1.6% (PTCy-Ruxo) vs 12.1%; P=.02.
Endothelial: Endothelial complications 1.6% vs 13.6%; P=.01.
Graft function: Severe poor graft function 21.1% vs 42.6%; P=.01.
Endothelial: Endothelial complications 1.6% vs 13.6%; P=.01.
Graft function: Severe poor graft function 21.1% vs 42.6%; P=.01.
Conclusions
PTCy-ruxolitinib was noninferior to PTCy-tacrolimus-MMF for grade II–IV acute GVHD prevention in unrelated and haploidentical HCT, with noninferior chronic GVHD and a markedly better safety profile. This calcineurin-free regimen warrants further exploration.
Key Limitations
Single-country phase 2 trial; external validity awaits multinational replication. Restricted to AML/ALL in complete remission. Powered for noninferiority, not superiority — numerical OS/GRFS/cGVHD advantages not significant. Both arms used PTCy, so ruxolitinib-alone efficacy is not addressed.
Clinical Context
First randomized comparison of two PTCy-anchored prophylaxis regimens, supporting a calcineurin-sparing strategy. PTCy-Tac-MMF remains the established standard (BMT CTN 1703); PTCy-Ruxo may evolve into an alternative for calcineurin-related toxicity, particularly TMA-prone or renally fragile recipients.