Ruxolitinib Efficacious, Safe in Patients with Chronic Graft-Versus-Host Disease


Patients with glucocorticoid-refractory or -dependent chronic GVHD are more likely to experience complete or partial response with the JAK inhibitor than with control therapies.


Robert Zeiser, MD

New phase 3 data show that ruxolitinib could be highly beneficial in patients with glucocorticoid-refractory or -dependent chronic graft-versus-host disease (GVHD), a significant complication of allogenic stem-cell transplantation.

In the REACH3 study, a team, led by Robert Zeiser, MD, of the University of Freiburg, Germany, assessed the efficacy and safety of ruxotilinib 10 mg twice daily in patients with moderate-to-severe glucocorticoid-refractory or -dependent chronic GVHD.

“Preclinical studies showed that Janus kinase 1 and 2 (JAK1–JAK2) signaling is crucial in the steps leading to inflammation and tissue damage in acute GVHD and chronic GVHD15-19 and that ruxolitinib, a JAK1–JAK2 inhibitor, was an effective treatment in a mouse model of chronic GVHD,” Zeiser and colleagues wrote.

“In addition,” they continued, “a retrospective survey showed ruxolitinib led to high response and 6-month survival rates in patients with acute or chronic GVHD who were heavily pretreated.”

The Study

The investigators enrolled a total of 329 patients, all of whom were ≥12 years of age. Patients were then randomized 1:1 to receive either ruxolitinib or control therapy, which was chosen from the 10 most commonly used options and considered best available care.

The most utilized control therapies in the study were extracorporeal photopheresis (34.8%), mycophenolate mofetil (22.2%), and ibrutinib (17.1%). Roughly 50% of all patients also received calcineurin inhibitors during the trial period.

As such, all patients received their assigned therapy for ≥6 cycles (consisting of 28 days).

The primary outcome sought by Zeiser and team was overall response, complete and partial, at week 24. Secondary endpoints included failure-free survival and an improved score on the modified Lee Symptom scale at week 24 — defined as ≥7-point reduction from baseline in total symptom score.

Patients who achieved response by the endpoint could reduce glucocorticoid, calcineurin inhibitors, ruxolitinib dosing. Those who did not respond to treatment, had unacceptable side effects, or had a GVHD flare-up were able to begin a new control therapy.

The team used the Cochran–Mantel–Haenszel chi-square test, stratified according to severity of chronic GVHD, in order to compare overall responses and responses on the modified Lee Symptom Scale between groups. Further, they used a stratified log-rank test to compare failure-free survival.


Data showed that a greater number of patients responded to ruxolitinib than the control group at week 24 (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001).

Further, ruxolitinib was associated with a longer median failure-free survival versus control (18.6 months vs. 5.7 months; hazard ratio [HR], 0.37; P<0.001). Patients receiving the JAK also had higher symptom response compared to control (24.2% vs. 11.0%; odds ratio [OR]. 2.62; P = 0.001).

The team calculated probability of failure-free survival at 6 months, estimating higher values with ruxolitinib (74.9%; 95% CI, 67.5 to 80.9) than the control therapy (44.5%; 95% CI, 36.5 to 52.1).

Additionally, the response on the modified Lee Symptom Scale at 24 weeks was also higher in the ruxolitinib cohort than in the control cohort.

In terms of safety, the most commonly reported adverse events of grade 3 or higher up at week 24 were thrombocytopenia (15.2% in ruxolitinib group; 10.1% in control group) and anemia (12.7% and 7.6%, respectively). The incidence of cytomegalovirus infections and reactivations was comparable between groups.

“Our trial showed that among patients with moderate or severe chronic GVHD in whom glucocorticoids produced an inadequate response, ruxolitinib was superior to control therapies, as evidenced by a greater overall response, longer failure-free survival, and greater reduction in symptoms,” Zeiser and colleagues concluded.

Currently, ruxolitinib is approved in the United States for the treatment of glucocorticoid-refractory acute GVHD in patients 12 years of age or older. This approval was supported by findings from the phase 2 REACH1 study, showing ruxolitinib linked to high response rates in the patient population.

The study, “Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease,” was published online in The England Journal of Medicine.

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