Ruxolitinib was superior to best available therapy in achieving efficacy as determined by overall response and duration of response, with acceptable safety in adolescents and adults with steroid-dependent or steroid-refractory chronic graft-vs-host disease. Findings from the phase III REACH3 trial were presented by Robert Zeiser, MD, and colleagues during the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 77).

Robert Zeiser, MD

“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 Dr. Zeiser, of University Hospital Freiburg, Germany. “It shows a significant advantage for ruxolitinib. It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”

These results were hailed as practice-changing at a pre-meeting press conference.

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

Robert Brodsky, MD

Background

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

Study Details

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

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

Efficacy Results

Patients treated with ruxolitinib achieved significantly better overall response rate at week 24: 49.7% vs 25.6%, respectively (P < .0001). Complete response rate was 6.7% vs 3%, and partial response rate was 43% vs 22.3%.

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: 24.2% vs 11% percent (P = .0011). There was a significant 63% relative improvement in failure-free survival favoring ruxolitinib at week 24 (P < .0001).

Best overall response was 76.4% vs 60%, respectively, and duration of response was also significantly longer with ruxolitinib: not reached vs 6.24 months, respectively.

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 group. Treatment discontinuations were observed in 49.7% of patients and 74.4%, respectively. There were more discontinuations in the ruxolitinib group due to adverse events (17.9% vs 4.9%) and more discontinuations due to lack of efficacy in the best available therapy group (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.

Safety and Tolerability

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

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 patients in the ruxolitinib group and 36.7% of the best available therapy group. More dose modifications due to adverse events were needed in the ruxolitinib group—37.6% vs 16.5%—as were the percentage of patients requiring discontinuation due to adverse events—16.4% vs 7%. Deaths were not significantly different between the two treatment arms.

The most frequent adverse events in the ruxolitinib arm were anemia and thrombocytopenia. The rates of grades 3 and 4 anemia were 12.7% for ruxolitinib and 7.6% for best available therapy; for grades 3 and 4 thrombocytopenia, the rates were 15.2% and 10.1%.

No significant difference was observed between treatment arms in the rate of viral or bacterial infections. A higher frequency of fungal infections was noted in the ruxolitinib arm. No significant difference was observed between the two arms for cytomegalovirus infection or reactivation.

The study authors concluded, “This is the first successful randomized phase III trial of ruxolitinib in patients with steroid-dependent or steroid-refractory chronic graft-vs-host disease. Ruxolitinib demonstrated superior efficacy vs best available therapy, measured by a higher overall response rate, longer failure-free survival rate, and greater symptom improvement. Ruxolitinib was effective for moderate or severe steroid-dependent or steroid-refractory and its safety profile is consistent with that expected for this drug and this population.”

Disclosure: For full disclosures of the study authors, visit ash.confex.com.