Low-Dose Ruxolitinib Significantly Reduces Acute Graft-Versus-Host Disease After Haploidentical Transplantation

Clinical Summary:

• Design/Population: This multicenter, open-label trial compared low-dose ruxolitinib with mycophenolate mofetil as part of an antithymocyte globulin, calcineurin inhibitor, and short-course methotrexate prophylaxis regimen in patients undergoing first myeloablative haploidentical hematopoietic stem-cell transplantation. 
• Key Outcomes: Ruxolitinib-based prophylaxis significantly reduced grade II to IV acute graft-versus-host disease by day 100 compared with standard prophylaxis. Serious adverse events were comparable between groups, with no fatal adverse events reported in the ruxolitinib arm.
• Clinical Relevance: These findings provide randomized phase 3 evidence supporting low-dose ruxolitinib as a potential alternative to mycophenolate mofetil for acute graft-versus-host disease prophylaxis following haploidentical transplantation, with a substantial reduction in acute graft-versus-host disease and manageable toxicity. 

Results from a randomized phase 3 trial demonstrated that replacing mycophenolate mofetil with low-dose ruxolitinib as part of a multidrug prophylactic regimen significantly reduced grade II to IV acute graft-versus-host disease (GVHD) following haploidentical hematopoietic stem cell transplantation (HSCT). 

“Acute [GVHD] remains a major cause of morbidity and mortality after haploidentical [HSCT],” stated Hengwei Wu, MD, The First Affiliated Hospital, Hangzhou, China. “Ruxolitinib, a JAK 1/2 inhibitor with established activity in steroid-refractory GVHD, has shown promise for prophylaxis in early studies, but there is little evidence from randomized trials in the haploidentical HSCT setting.” 

In this open-label trial, 206 patients aged 12 to 70 years with hematologic malignancies requiring allogeneic HSCT undergoing first myeloablative haploidentical transplantation were randomized 1:1 to receive either low-dose ruxolitinib (n = 103) or standard mycophenolate mofetil (n = 103) with antithymocyte globulin, a calcineurin inhibitor, and short-course methotrexate. 

Ruxolitinib was initiated on day 1 at 5 mg twice daily for patients weighing at least 50 kg and 5 mg once daily for those weighing less than 50 kg. Treatment continued through day 60 and was subsequently tapered through day 90 in the absence of grade II to IV acute GVHD. The primary end point was the cumulative incidence of grade II to IV acute GVHD by day 100.

By day 100, the cumulative incidence of grade II to IV acute GVHD was 6.8% in the ruxolitinib arm and 36.9% in the standard prophylaxis arm. Ruxolitinib was associated with an 85% reduction in the sub distribution hazard of grade II to IV acute GVHD (sub distribution hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.07 to 0.34; P < .0001).

The most common grade 3/4 adverse events with ruxolitinib prophylaxis versus standard prophylaxis were thrombocytopenia (17% vs 11%), neutropenia (14% vs 9%), anemia (12% vs 9%), and cystitis (7% vs 10%), respectively. 

Serious adverse events occurred in 30% of patients receiving ruxolitinib-based prophylaxsis and 35% of patients receiving standard prophylaxis. No fatal adverse events occurred in the ruxolitinib arm. 

Three deaths occurred in the standard prophylaxis group, including 1 due to pulmonary infection, 1 assoicated with sepsis, bacteremia, or fungemia, and 1 due to transplant-associated thrombotic microangiopathy. No deaths were considered treatment related. 

“Low-dose ruxolitinib, used in place of mycophenolate mofetil within a backbone of prophylactic antithymocyte globulin, calcineurin inhibitor, and short-course methotrexate, reduced grade II–IV acute GVHD by day 100 after haploidentical HSCT and had manageable toxicity,” concluded Dr Wu et al. “These findings support further evaluation of targeted JAK1/2 inhibition as part of GVHD prophylaxis.” 

Source:

Wu H, Shi W, Shi Z, et al. Low-dose ruxolitinib for graft-versus-host disease prevention in haploidentical hematopoietic stem-cell transplantation: A multicenter, open-label, randomized, controlled, phase 3 trial. Lancet Haematol. Published online: August 2026. doi: 10.1016/s2352-3026(26)00167-5