A Phase 3 trial published in The Lancet Haematology showed that low-dose ruxolitinib reduced grade II-IV acute graft-versus-host disease to 6.8% after haploidentical HSCT, outperforming standard prophylaxis with manageable safety.
Written By: Meghana Jinka, PharmD
Reviewed By: Pharmacally Editorial Team
A Phase 3 trial published in The Lancet Haematology has shown that low-dose ruxolitinib significantly reduced the incidence of acute graft-versus-host disease (GVHD) following haploidentical hematopoietic stem cell transplantation (HSCT). In the multicenter randomized study, replacing mycophenolate mofetil with the JAK1/2 inhibitor ruxolitinib within a standard prophylactic regimen lowered the cumulative incidence of grade II-IV acute GVHD by day 100 from 36.9% to 6.8%, while maintaining a manageable safety profile.
Acute GVHD continues to limit outcomes after haploidentical HSCT despite advances in donor selection and immunosuppressive regimens. Researchers found that incorporating the Janus kinase (JAK) 1/2 inhibitor ruxolitinib into a prophylactic regimen of antithymocyte globulin (ATG), a calcineurin inhibitor, and short-course methotrexate reduced clinically significant acute GVHD by more than 80% compared with the current standard approach using mycophenolate mofetil.
Targeting JAK Signaling to Prevent Acute GVHD
Ruxolitinib inhibits JAK1 and JAK2, key signaling proteins involved in inflammatory cytokine pathways that drive immune activation and tissue injury in GVHD. The drug is already approved for steroid-refractory acute GVHD, but evidence supporting its use before disease onset has remained limited, particularly in patients undergoing haploidentical transplantation.
Haploidentical HSCT has expanded donor availability for patients with hematologic malignancies, but the procedure carries a substantial risk of acute GVHD. Preventing this complication without increasing infection risk or impairing engraftment remains a major clinical priority.
Phase 3 Trial Demonstrated Marked Reduction in Acute GVHD
The open label, randomized, controlled Phase 3 trial (NCT04838704) enrolled 215 patients across five transplant centers in China between April 2021 and December 2023. Eligible participants were aged 12 to 70 years with hematologic malignancies requiring their first myeloablative haploidentical HSCT.
After exclusions for protocol deviations, 206 patients were included in the modified intention-to-treat analysis, with 103 patients assigned to each treatment group.
Patients in the experimental arm received low-dose oral ruxolitinib beginning on day 1 after transplantation alongside ATG, a calcineurin inhibitor, and short-course methotrexate. Treatment continued through day 60 and was tapered to day 90 in patients who remained free of grade II-IV acute GVHD. The control group received standard prophylaxis replacing ruxolitinib with mycophenolate mofetil.
The primary endpoint was the cumulative incidence of grade II-IV acute GVHD by day 100.
Results strongly favored ruxolitinib prophylaxis. Grade II-IV acute GVHD developed in only seven patients, corresponding to a cumulative incidence of 6.8%, compared with 38 patients and a cumulative incidence of 36.9% in the standard prophylaxis group. This translated to an 85% relative reduction in risk (subdistribution hazard ratio 0.15; 95% CI 0.07-0.34; p<0.0001).
Among surviving patients, the median follow-up reached 26.4 months.
Safety Profile Remained Manageable
The safety profile was consistent with expectations for patients undergoing intensive transplantation.
The most common grade 3 or 4 adverse events in the ruxolitinib group included thrombocytopenia (17%), neutropenia (14%), anemia (12%), and cystitis (7%). Comparable rates were observed in the standard prophylaxis arm.
Serious adverse events occurred in 30% of patients receiving ruxolitinib and 35% of those receiving standard prophylaxis.
No fatal adverse events occurred in the ruxolitinib group. Three deaths were reported in the control group due to pulmonary infection, severe bloodstream infection, and transplant-associated thrombotic microangiopathy. Investigators determined that none of the deaths were related to the assigned prophylactic treatment.
Findings Support a New Preventive Strategy
The investigators concluded that replacing mycophenolate mofetil with low-dose ruxolitinib within a standard ATG-based prophylactic regimen substantially reduced clinically significant acute GVHD while maintaining an acceptable safety profile.
The findings provide the strongest randomized evidence to date supporting JAK1/2 inhibition as part of first-line GVHD prevention after haploidentical HSCT. Additional studies in broader transplant populations and longer-term follow-up will help determine whether this strategy can improve long-term survival, reduce chronic GVHD, and influence future transplant practice guidelines.
Reference
About the Writer
Meghana Jinka (LinkedIn) is a PharmD graduate with a strong interest in clinical pharmacy, clinical research, pharmacovigilance, and medical writing. She has developed expertise in evaluating scientific literature, interpreting clinical data, and communicating complex medical information in a clear and accessible manner. Through clinical training, patient counseling, and healthcare awareness activities, she has gained practical experience in evidence-based medicine and patient-centered care. Passionate about healthcare communication, Meghana is committed to developing accurate, engaging, and evidence-based healthcare documents that support healthcare professionals and the wider community.