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Ruxolitinib (Jakafi) topped best available therapy as a second-line treatment for patients with moderate to severe chronic graft-vs-host disease (GVHD) after allogeneic stem-cell transplantation, the randomized REACH3 study showed.

The phase III trial met its primary endpoint, with a week-24 overall response rate of 49.7% with the Janus kinase (JAK) 1/2 inhibitor compared to 25.6% in the control arm (OR 2.99, 95% CI 1.86-4.80, P<0.0001), reported Robert Zeiser, MD, of the University of Freiburg in Germany.

Median failure-free survival -- a secondary endpoint defined as no recurrence of underlying disease, need for another systemic GVHD treatment, or death -- was not reached in the ruxolitinib arm compared to 5.7 months with best available therapy (HR 0.370, 95% CI 0.268-0.510, P<0.0001), according to findings presented at the American Society of Hematology (ASH) virtual meeting.

"This is the first successful randomized phase III trial in adolescent and adult patients with chronic graft-vs-host disease with an inadequate response to corticosteroids," Zeiser said during an ASH press briefing.

Chronic GVHD is a life-threatening complication that occurs in anywhere from 30%-70% of patients who undergo allogeneic stem-cell transplantation, Zeiser explained.

"Currently, standard first-line therapy consists of systemic corticosteroids," he said. "However, only 50% of patients respond, while the others become steroid refractory or steroid dependent."

In the study, a higher proportion of patients on ruxolitinib had improved symptoms compared to the control group (24.2% vs 11.0%), as measured by a 7-point total symptom score reduction from baseline on the modified Lee Symptom Score (OR 2.62, 95% CI 1.42-4.82, P=0.0011).

Best overall response, using NIH criteria, also favored the ruxolitinib group (76.4% vs 60.4%; OR 2.17, 95% CI 1.34-3.52), and included complete responses in 12.1% and 6.7%. Median duration of response was not reached with the study drug, compared to 6.24 months with best available therapy.

At 24 weeks, twice as many patients in the ruxolitinib arm had a complete response compared to controls (6.7% vs 3.0%) and twice as many remained on treatment (50.3% vs 25.6%, respectively).

"The results represent a major step forward for patients with chronic graft-vs-host disease that is not resolved by taking corticosteroids," said press briefing moderator Lisa Hicks, MD, of St. Michael's Hospital in Toronto.

REACH3 enrolled 329 patients, ages 12 and over, who developed steroid-refractory or steroid-dependent chronic GVHD following allogeneic hematopoietic cell transplant and randomized them 1:1 to either ruxolitinib (10 mg twice daily) or best available treatment.

Baseline characteristics were well matched with respect to age (median age of about 50), sex (56%-66% men), chronic GVHD severity (severe in 54%-59%), and criteria for being steroid refractory or dependent, said Zeiser. Patients were also well matched for donor type, cytomegalovirus (CMV) status, and time from chronic GVHD onset to randomization (roughy 6 months in both arms). CMV reactivation occurred in 5.5% of patients on the study drug versus 8.2% of controls.

Eligibility requirements included evidence of myeloid and platelet engraftment, and patients in either arm were allowed to continue receiving steroids with or without a calcineurin inhibitor. At 24 weeks, patients in the control arm could crossover to ruxolitinib, 37% of whom did.

"Importantly, the safety profile for ruxolitinib was consistent with previous observations," said Zeiser.

Nearly all patients in the two arms experienced an adverse event (AE) of any grade (98% in ruxolitinib arm vs 92% in control arm). Grade ≥3 AEs were similar (57% vs 58%), as were serious AEs (33% vs 37%). Treatment discontinuation for toxicity occurred in 17% of patient on ruxolitinib and 5% of those on best available therapy, and dose modifications due to AEs occurred in 37% and 17%, respectively.

Grade ≥3 AEs that were more frequent in the study arm included anemia (12.7% vs 7.6%) and thrombocytopenia (15.2% vs 10.1%), noted Zeiser. There were no significant differences in infections overall, though there was a trend toward higher fungal infections in the ruxolitinib arm (11.5% vs 5.7%). Deaths overall occurred in 18.8% of patients on the ruxolitinib arm versus 16.5% in the control arm, which was not significantly different.

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