Ruxolitinib Improves Outcomes in Patients With Steroid-Refractory or Steroid-Dependent Graft-vs-Host Disease

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Ruxolitinib was superior to best available therapy in achieving efficacy as determined by best overall response and duration of response, with acceptable safety in adolescents and adults with steroid-dependent or steroid-refractory chronic graft-vs-host disease effects. These findings were shown in the phase III REACH3 trial presented at the virtual 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.1

“Ruxolitinib is the first agent to demonstrate superior efficacy to best available therapy in a phase III trial of patients with chronic graft-vs-host disease and an inadequate response to steroids,” stated lead author Robert Zeiser, MD, of the University Medical Center Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”

Robert Zeiser, MD

Robert Zeiser, MD

Robert A. Brodsky, MD

Robert A. Brodsky, MD

These results were hailed as practice-changing at a premeeting press conference. “This is the first successful phase III trial in chronic graft-vs-host disease ever,” stated ASH Secretary Robert A. Brodsky, MD, Professor and Director of the Division of Hematology at Johns Hopkins School of Medicine, Baltimore. “Results suggest that ruxolitinib is a viable second-line treatment for patients whose symptoms are not fully resolved with corticosteroids.”


As Dr. Zeiser explained, graft-vs-host disease occurs in approximately 30% to 70% of patients who undergo allogeneic stem cell transplant and is a leading cause of nonrelapse mortality and morbidity in those patients. Standard first-line therapy consists of systemic steroids, but about 50% of patients will become steroid-dependent or steroid-refractory. There is no standard second-line treatment, and prior to REACH3, no successful, large-scale randomized controlled trials were conducted in this setting. Thus, ruxolitinib fulfills an unmet need, according to the results presented at the ASH Annual Meeting.

Study Details

REACH3 randomly assigned patients 1:1 to receive ruxolitinib at 10 mg twice daily (n = 165) vs best available therapy (n = 164) with steroids plus or minus a calcineurin inhibitor. Patients enrolled in the trial had to be at least 12 years old, have steroid-dependent or steroid-refractory chronic graft-vs-host disease, and evidence of myeloid and platelet engraftment.

Steroid dependence or refractoriness was defined as lack or response or disease progression after prednisone at 1 mg/d or higher for 1 week or more; or disease progression without improvement on prednisone at ≥ 0.5/mg/kg/d or 1 mg/kg every other day for 4 weeks or longer; or increase in the prednisone dose to > 0.25 mg/kg/d after two unsuccessful attempts to taper the dose.

“Safety is important because patients with chronic graft-vs-host disease are susceptible to infections.”
— Robert Zeiser, MD

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The primary efficacy period was up to week 24, when the overall response rate was assessed using National Institutes of Health criteria. After week 24, crossover to ruxolitinib was allowed during an extension phase that lasted until week 156 (end of treatment). The safety follow-up period was an additional 30 days.

Baseline characteristics were well matched for age, gender, severity of graft-vs-host disease, and criteria for steroid-dependent or steroid-refractory graft-vs-host disease. Patients were also well matched at baseline for stem cell source, donor type, and donor/recipient cytomegalovirus type.

At the end of the study, ongoing treatment was reported in 50.3% of the ruxolitinib group and 25.6% of the best available therapy control group. Treatment discontinuations were observed in 49.7% and 74.4%, respectively. There were more treatment discontinuations in the ruxolitinib group due to adverse events (17.9% vs 4.9%) and more treatment discontinuations due to lack of efficacy in the control arm (14.5% vs 42.7%). More than one-third of patients treated with best available therapy (37.2%) crossed over to ruxolitinib during the extension phase of the study.

Ruxolitinib achieved a significantly better overall response rate at week 24: 49.7% vs 25.6%, respectively (P < .0001). The complete response rate was 6.7% vs 3%, and the partial response rate was 43% vs 22%.

According to the modified Lee Symptom Scale at week 24, ruxolitinib-treated patients had a significantly greater improvement in symptoms compared with those treated with best available therapy: 24% vs 11% (P = .0011). There was a significant 63% relative improvement in failure-free survival favoring ruxolitinib at week 24 (P < .0001).

Safety and Tolerability

“Safety is important because patients with chronic graft-vs-host disease are susceptible to infections,” Dr. Zeiser explained.

The rates of adverse events of any grade and grade 3 or higher were similar in both arms of the study. Serious adverse events were reported in 33% of the ruxolitinib group and 36.7% of the best available therapy group. More dose modifications due to adverse events were needed in ruxolitinib-treated patients: 37.6% and 16.5%, respectively, and the percentage of patients requiring treatment discontinuation due to adverse events was higher in the ruxolitinib group: 16% and 7%. Deaths were not significantly different between the two treatment arms.


  • A 30-item scale developed to measure the symptoms of chronic graft-vs-host disease.
  • Original 30-item scale was based on a 1-month recall period; the modified 28-item scale (deleting items based on supportive care needs, not symptoms) uses a 7-day recall period.

The most frequent adverse events in the ruxolitinib arm were anemia and thrombocytopenia. The incidence of grade 3 or 4 anemia was 12.7% with ruxolitinib and 7.6% with best available therapy; and the rate of grade 3 or 4 thrombocytopenia was 15.2% and 10.1%, respectively.

No significant difference was observed between treatment arms in the rate of viral or bacterial infections, but a trend toward greater frequency of fungal infections was seen in the ruxolitinib arm. No significant difference was observed between the two arms for cytomegalovirus infection or reactivation.

Comment on Study

Zachariah DeFilipp, MD, of Harvard Medical School, who was not involved in this study, said these results are a step forward.

He commented: “Chronic graft-vs-host disease has long been recognized as a major long-term complication of allogeneic stem cell transplant. The treatment landscape is evolving in recent years, with a number of targeted agents being investigated. REACH3 is the only randomized study to date comparing available therapies for steroid-refractory or -dependent chronic graft-vs-host disease; it demonstrated a clinically meaningful improvement with the use of ruxolitinib in this setting. This study further supports the clinical efficacy of JAK inhibition in the treatment of graft-vs-host disease, following the U.S. Food and Drug Administration approval of ruxolitinib for steroid-refractory acute graft-vs-host disease.”

Zachariah DeFilipp, MD

Zachariah DeFilipp, MD

Dr. DeFilipp cited potential areas of further study, such as patient- and disease-related factors, including organ-specific responses, which may predict patients who are most likely to respond to ruxolitinib; and continued follow-up to evaluate the duration of response.

“REACH3 will result in increased clinical use of ruxolitinib in the treatment of chronic graft-vs-host disease,” he predicted. He added that future studies will likely look at other uses of JAK inhibition, either alone or in combination with other targeted agents, in multiple settings during and after transplant. 

DISCLOSURE: Dr. Zeiser has served as an advisor or consultant to Novartis, Mallinckrodt Pharmaceuticals, and Incyte. Dr. Brodsky has received honoraria from UpToDate; and has served as an advisor or consultant to and received research funding from Achillion Pharmaceuticals and Alexion Pharmaceuticals. Dr. DeFilipp has served as an advisor or consultant to Syndax Pharmaceuticals and has received research funding from Incyte and Regimmune.


1. Zeiser R, Polverelli N, Ram R, et al: Ruxolitinib versus best available therapy in patients with steroid-refractory/steroid-dependent chronic graft-vs-host disease: Primary findings from the phase 3 randomized REACH3 study. 2020 ASH Annual Meeting & Exposition. Abstract 77. Presented December 5, 2020.