Short-Course Ruxolitinib Initiated at Neutrophil Engraftment for Prevention of Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation: A Multicenter, Randomized, Open-Label, Controlled Phase II Trial

Why clinicians should know about it

• Picked for Hematology (paper of the day, 26 October 2026): Randomized trial of ruxolitinib for GVHD prevention
• Picked for Immunology and Allergy (paper of the day, 26 October 2026): Randomized trial of immunomodulation to prevent graft-versus-host disease

Abstract

BACKGROUND: Acute graft-versus-host disease (aGVHD) remains a leading cause of non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). On the cyclosporine A (CsA)/methotrexate (MTX)/mycophenolate mofetil (MMF) backbone, MMF withdrawal around engraftment creates an immunosuppression gap coinciding with peak peri-engraftment alloreactivity. OBJECTIVE: To test whether a 14-day ruxolitinib course initiated at confirmed neutrophil engraftment, within a donor-stratified MMF discontinuation schedule, reduces the 100-day cumulative incidence of grade II-IV aGVHD versus standard prophylaxis alone. STUDY DESIGN: Multicenter, randomized, open-label, phase II superiority trial (ChiCTR1900027971) at five transplant centers in North China (December 2019-August 2022). A total of 171 patients (aged 12-66 years) with hematologic malignancies or severe aplastic anemia (SAA) were randomly assigned 1:1 to ruxolitinib plus standard prophylaxis (n=86) or standard prophylaxis alone (n=85). MMF was discontinued per a donor-stratified schedule: full withdrawal at engraftment for matched sibling recipients; half-dose at engraftment, discontinuation by day +30 for matched unrelated and haploidentical recipients. Ruxolitinib (5 mg twice daily for 7 days, then 5 mg once daily for 7 days; total 105 mg) was started at confirmed neutrophil engraftment. The primary endpoint was the 100-day cumulative incidence of grade II-IV aGVHD, with death without prior aGVHD as a competing event (Fine-Gray model). Data cutoff: December 31, 2023. RESULTS: The 100-day cumulative incidence of grade II-IV aGVHD was 14.0% (12/86) versus 34.1% (29/85) (subdistribution hazard ratio [sHR] 0.35, 95% confidence interval [CI] 0.18-0.68; P=0.002), an absolute reduction of 20.1% (number needed to treat [NNT] 5.0, 95% CI 3.1-13.0). Grade III-IV aGVHD was 7.0% versus 16.5% (sHR 0.37, 95% CI 0.14-0.98; P=0.047). All 85 treated patients completed the 14-day course without dose modification; grade ≥3 adverse events within 100 days were similar between arms. Pre-transplant measurable residual disease (MRD) positivity was unbalanced between arms (63.5% vs 45.9%; P=0.032), potentially confounding survival comparisons. Two-year overall survival (OS) was 81.4% versus 82.4% (HR 0.89, 95% CI 0.45-1.75; P=0.674). Among 150 patients with hematologic malignancies, 2-year NRM was 8.1% versus 11.8% (sHR 0.63, 95% CI 0.26-1.53; P=0.308), relapse 16.2% versus 11.8% (sHR 1.11, 95% CI 0.53-2.32; P=0.782; MRD-adjusted sHR 0.95, 95% CI 0.44-2.06), disease-free survival 75.7% versus 76.3% (HR 0.92, 95% CI 0.48-1.76; P=0.834), and GVHD-free, relapse-free survival 64.9% versus 56.6% (HR 0.76, 95% CI 0.47-1.23; P=0.247). The aGVHD benefit was consistent across all prespecified subgroups (all P for interaction >0.10). CONCLUSION: Short-course ruxolitinib initiated at neutrophil engraftment reduced grade II-IV aGVHD by 20.1% (NNT 5.0), with an acceptable safety profile and no evidence of impaired graft-versus-leukemia effect after MRD balancing. Survival endpoints may be confounded by the MRD imbalance, steroid-refractory aGVHD crossover, and relapse predominance. MRD-stratified phase III trials are warranted.

Abstract as published, via PubMed.