Response to ruxolitinib durable at 8 weeks

A drug used to treat myelofibrosis and polycythemia vera demonstrated efficacy for treatment of acute graft-versus-host disease in patients who had undergone allogenic stem-cell transplantation, researchers report.

In a phase III, open-label trial that randomized 309 patients to ruxolitinib or standard therapy, ruxolitinib, a selective Janus kinas (JAK1 and JAK2) inhibitor achieved an overall response of 62% (n=96) versus 39% in the control group (n=61) at day 28, “odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001),” wrote Robert Zeiser, MD, of the department of Department of Hematology, Oncology, and Stem Cell Transplantation at University Medical Center Freiburg, Freiburg, Germany, for the REACH2 trial group. The findings were publishing online by The New England Journal of Medicine.

For 5 decades, researchers have been struggling to understand GVHD, noted Duke University’s Nelson Chao, MD, in an editorial that accompanied the study results. “The authors are to be congratulated for completing this successful randomized trial, which showed convincingly that ruxolitinib was more effective than the investigator’s choice of therapy (from a list of nine commonly used options; control group) in patients in whom glucocorticoid therapy had failed,” Chao wrote.

Standard therapy for GVHD is high dose-glucocorticoids, but “response ranges from 60% in patients with grade II disease to 30 to 40% in patients with grade IV disease.” In the REACH2 trial, the investigators randomized patients, age 12 or older, who had glucocorticoid-refractory acute GVHD following allogenic stem-cell transplantation.

“The primary end point was overall response (complete response or partial response) at day 28,” they wrote. “The key secondary end point was durable overall response at day 56.”

The researchers enrolled 309 patients from April 12, 2017 through May 30, 2019 at 105 centers in 22 countries. “A total of 104 patients (34%) had grade II acute GVHD, 136 (44%) had grade III disease, and 62 (20%) had grade IV disease,” they wrote. The median age was 54, and 59% of patients were male.

The patients were randomized to ruxolitinib (n=154) or control (n=155). “The most common initial control therapy was extracorporeal photopheresis, which was received by 41 of 150 patients (27%),” they wrote.

Among the findings:

  • 34% of ruxolitinib patients versus 19% of controls achieved a complete response.
  • In both groups, response rate was highest among patients with grade II disease at baseline (75% in the ruxolitinib group and 51% in the control group).
  • The OR for response with ruxolitinib was highest among patients with grade IV disease at baseline “(53% [16 of 30 patients] versus 23% [7 of 30 patients]; odds ratio, 3.76; 95% CI, 1.24 to 11.38).”
  • Durable response (day 56) was 40% in the ruxolitinib group versus 22% in controls (P <0.001).

“The median failure-free survival was significantly longer in the ruxolitinib group than in the control group (5.0 months vs 1.0 month; hazard ratio for relapse or progression of hematologic disease, non–relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60), and the cumulative incidence of such events at 1 month was lower in the ruxolitinib group than in the control group (18% vs 49%) and remained lower at all time points up to 18 months (61% vs 82%),” Zeiser et al reported.

There were 72 deaths in the ruxolitinib group and 77 in the control group, and acute GVHD was the leading cause of death in both arms.

The most common adverse events in the ruxolitinib group were thrombocytopenia and anemia.

In the editorial, Chao suggested that it appears “ruxolitinib exerts its major effect through JAK2 since itacitinib, a more selective and potent inhibitor of JAK1, did not lead to improved outcomes when used as first-line therapy for acute GVHD.”

He concluded, “Given the effect of ruxolitinib in controlling glucocorticoid-refractory GVHD, it is interesting that the incidence of infectious complications or relapse was apparently not greater with ruxolitinib than with control therapy, but the total follow-up time was short. Thus, as with all good research, these observations raise important questions and set the stage for further work in this area.”

  1. Be aware that the results of this open-label, randomized trial suggest ruxolitinib may be an effective and durable treatment option for glucocorticoid-refractory, acute GVHD.

  2. Note that nuxolitinib appeared to be most effective when used in patients with grade IV GVHD.

Peggy Peck, Editor-in-Chief, BreakingMED™

The REACH trial was funded by Novartis.

Zeiser reported non-financial support from Novartis, during the conduct of the study; personal fees from Incyte, personal fees from Mallinckrodt, and personal fees from Novartis outside the submitted work.

Chao reported grants and personal fees from Jazz Pharmaceuticals, grants from Novartis Pharmaceuticals, grants from Incyte corporation, and grants and personal fees from Takeda Pharmaceuticals outside the submitted work.

Cat ID: 118

Topic ID: 78,118,730,118,119,466,467,468,717,935,138,192,925