Ruxolitinib improves response rate, failure-free survival in chronic GVHD
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Ruxolitinib appeared more effective than best available therapy for steroid-refractory or steroid-dependent chronic graft-versus-host disease, according to randomized phase 3 study results presented at TCT Meetings Digital Experience.
Researchers reported a higher overall response rate, longer failure-free survival and greater symptom improvement among patients assigned ruxolitinib (Jakafi, Incyte).
“Ruxolitinib was well-tolerated and easy for patients to take as an oral medication twice daily,” researcher Stephanie Lee, MD, MPH, professor and associate director of the clinical research division at Fred Hutchinson Cancer Research Center, told Healio. “It showed efficacy in important subgroups and the duration of response in responding patients was long. About half of people were still taking ruxolitinib at last follow-up, suggesting that patients and their doctors thought they were still deriving benefit.”
Systemic glucocorticoids are part of standard first-line treatment for chronic GVHD; however, approximately 50% of patients become refractory to or dependent on this therapy.
“Most people agree that corticosteroids are the best initial treatment,” Lee said. “But once patients need additional therapy for chronic GVHD, there isn’t an accepted standard. Ibrutinib [Imbruvica; Janssen, Pharmacyclics] was approved in August 2017 for treatment of chronic GVHD after one or more lines of prior therapy, but we need more treatment options.”
Lee and colleagues conducted the open-label REACH3 study to compare ruxolitinib, an oral inhibitor of the JAK1 and JAK2 tyrosine kinases, with best available therapy among patients with moderate or severe steroid-refractory or steroid-dependent GVHD who underwent allogeneic stem cell transplantation.
The analysis included 329 patients (median age, 49 years; range, 12-76; 61% male) with moderate (48%) or severe (52%) chronic GVHD.
Researchers randomly assigned 165 patients to ruxolitinib dosed at 10 mg twice daily. The other 164 patients received best available therapy.
Treatment lasted for six 28-day cycles, and patients continued glucocorticoids with or without calcineurin inhibitors. Trial protocol allowed for infection prophylaxis per institutional practice.
Patients assigned best available therapy who did not achieve or maintain complete response or partial response, developed toxicity or had a chronic GVHD flare were allowed to cross over to ruxolitinib on or after day 1 of the seventh cycle.
ORR at the start of the seventh cycle served as the primary endpoint. Key secondary endpoints included failure-free survival and symptom improvement, defined as a reduction of 7 or more points in total modified Lee symptom score.
Slightly more than one-third of patients (38%; n = 125) remained on assigned treatment (50% for ruxolitinib and 26% for best available therapy) at data cutoff. Sixty-one patients (37%) assigned best available therapy had crossed over to ruxolitinib. The most common reasons for treatment discontinuation included lack of efficacy (15% for ruxolitinib vs. 43% for best available therapy), adverse events (17% vs. 5%) and relapse (5% vs. 4%).
The study achieved its primary endpoint, with a significantly higher ORR among ruxolitinib-treated patients at the start of the seventh cycle (50% vs. 26%; P < .0001). Researchers also reported longer median failure-free survival (not reached vs. 5.7 months; P < .0001) and higher percentage of patients achieving improvement in modified Lee symptom score (24% vs. 11%; P = .0011) in the ruxolitinib group.
“I was pleased to see that the primary and key secondary endpoints were positive in this trial because all three endpoints ... are important and reflect different measures of successful treatment,” Lee told Healio.
Thirty-one patients (19%) assigned ruxolitinib and 27 (16%) assigned best available therapy died. The most common cause of death was chronic GVHD (13% for ruxolitinib vs. 8% for best available therapy).
A comparable percentage of patients assigned ruxolitinib and best available therapy experienced any adverse event (98% vs. 92%) or grade 3 or higher adverse events (57% vs. 58%) by the start of the seventh cycle. The most common adverse events included anemia (29% for ruxolitinib vs. 13% for best available therapy), hypertension (16% vs. 13%) and pyrexia (16% vs. 9%). More than half of patients in each group developed infections (64% for ruxolitinib vs. 56% for best available therapy), common types of which included viral (34% vs. 29%), bacterial (28% vs. 26%) and fungal (12% vs. 6%).
“This was a very large, multinational, rigorous clinical trial that required a lot of support and global collaboration to complete in a timely fashion and reach a definitive answer,” Lee told Healio. “I hope to see more chronic GVHD clinical trials like this in the future.
“Having additional agents that are more effective and less toxic to treat chronic GVHD will be a great benefit to this population,” she added. “My hope is that eventually we will see even lower morbidity and mortality from chronic GVHD if patients aren’t treated with multiple heavily immunosuppressive medications over years.”
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Zeiser R, et al. Abstract 82. Presented at: The 2021 TCT Meetings Digital Experience (virtual meeting); Feb. 8-12, 2021.
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