Background
Multicenter, prospective, open-label, randomized phase 2 noninferiority trial (NCT04669210) comparing a calcineurin-free regimen — post-transplant cyclophosphamide plus ruxolitinib (PTCy-Ruxo) — versus conventional PTCy + tacrolimus + mycophenolate mofetil (PTCy-Tac-MMF) for GVHD prophylaxis after unrelated or haploidentical donor alloHCT. 128 adults with AML or ALL in complete remission were randomized 1:1, stratified by donor type and disease risk index.
Interventions and follow up
Arm A (PTCy-Ruxo): Cyclophosphamide 50 mg/kg IV days +3 and +4 + ruxolitinib 5 mg TID during conditioning and days +5 to +21, then 5 mg BID days +22 to +150 (no calcineurin inhibitor, no MMF)
Arm B (PTCy-Tac-MMF): Cyclophosphamide 50 mg/kg IV days +3 and +4 + tacrolimus (target 5–15 ng/mL) + MMF 30 mg/kg/day PO (10/10 HLA matched) or 45 mg/kg/day PO (<10/10 HLA matched) days +5 to +35
Primary endpoint: Cumulative incidence of grade II–IV acute GVHD at day +125 (noninferiority margin 10%, one-sided α 2.5%)
Median follow-up: 2 years
Arm B (PTCy-Tac-MMF): Cyclophosphamide 50 mg/kg IV days +3 and +4 + tacrolimus (target 5–15 ng/mL) + MMF 30 mg/kg/day PO (10/10 HLA matched) or 45 mg/kg/day PO (<10/10 HLA matched) days +5 to +35
Primary endpoint: Cumulative incidence of grade II–IV acute GVHD at day +125 (noninferiority margin 10%, one-sided α 2.5%)
Median follow-up: 2 years
Results
Grade II–IV aGVHD at day +125 (PTCy-Ruxo vs PTCy-Tac-MMF): 12.9% vs 21.2%, risk difference −8.3% (95% CI −21.2% to +4.6%), noninferiority P=.0041 (superiority P=.20)
Moderate–severe cGVHD at 2 years: 24.2% vs 39.5%, risk difference −15.2% (95% CI −31.1% to +0.7%), noninferiority P=.0012 (superiority P=.09)
Overall survival: 80.6% vs 72.5%, P=.28
GVHD-free, relapse-free survival (GRFS): 61.3% vs 48.1%, P=.19
Non-relapse mortality / relapse: NR
Moderate–severe cGVHD at 2 years: 24.2% vs 39.5%, risk difference −15.2% (95% CI −31.1% to +0.7%), noninferiority P=.0012 (superiority P=.09)
Overall survival: 80.6% vs 72.5%, P=.28
GVHD-free, relapse-free survival (GRFS): 61.3% vs 48.1%, P=.19
Non-relapse mortality / relapse: NR
Adverse events
Renal/endothelial: Grade 2–4 acute kidney injury 1.6% vs 12.1%, P=.02; endothelial complications 1.6% vs 13.6%, P=.01
Hematologic: Severe poor graft function 21.1% vs 42.6%, P=.01; cytopenias expected with both regimens
Infectious: No significant difference in infectious complications reported
Hematologic: Severe poor graft function 21.1% vs 42.6%, P=.01; cytopenias expected with both regimens
Infectious: No significant difference in infectious complications reported
Conclusions
PTCy-Ruxo was noninferior to standard PTCy-Tac-MMF for prevention of grade II–IV acute GVHD at day +125 in unrelated and haploidentical donor alloHCT, with a similarly favorable cGVHD profile and an improved safety profile (less AKI, fewer endothelial complications, less severe poor graft function). PTCy-Ruxo warrants further study as a calcineurin-free alternative on a PTCy backbone.
Key Limitations
Single-country (Russia) phase 2 trial — external validity awaits multinational replication. Restricted to AML/ALL in complete remission; no data in lymphoma, myeloma, or MDS. Both arms received PTCy, so the trial does not establish whether ruxolitinib without PTCy would suffice. Powered for noninferiority, not superiority — numerical advantages in OS, GRFS, and cGVHD did not reach significance. Optimal ruxolitinib duration beyond day +150 not addressed.
Clinical Context
First randomized comparison of two PTCy-anchored prophylaxis regimens, supporting a calcineurin-sparing strategy in alloHCT. ASTCT guidance positions PTCy-based prophylaxis as standard following BMT CTN 1703; PTCy-Ruxo may evolve into an alternative for patients with calcineurin-related toxicities, particularly TMA-prone or renally fragile recipients. Findings parallel growing enthusiasm for JAK1/2 inhibition in GVHD prevention.