Ruxolitinib effective as second-line therapy for chronic GVHD
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Ruxolitinib conferred a higher overall response rate than best available therapy for certain patients with chronic graft-versus-host disease, according to results of an analysis presented at the virtual ASH Annual Meeting and Exposition.
The randomized, phase 3 REACH3 trial evaluated ruxolitinib (Jakafi, Incyte) — an oral Janus kinase 1/2 inhibitor — vs. investigator's choice of best available therapy among patients with steroid-refractory or steroid-dependent chronic GVHD after undergoing allogeneic hematopoietic stem cell transplantation.
Chronic GVHD occurs in approximately 30% to 70% of patients who undergo allogeneic HSCT, according to Robert Zeiser, PhD, head of the section of tumor immunology and immune modulation at University of Freiburg Medical Center.
Historically, first-line treatment for chronic GVHD has been steroids, which nearly half of patients become refractory to or dependent upon to treat their symptoms, Zeiser said during a presentation.
“No standard second-line treatment for [chronic GVHD] has been defined so far, and there have not yet been any successful, large-scale randomized studies in this setting,” he said.
The REACH3 trial included 329 patients (median age, 49 years; range, 12-76; 61% male) who underwent allogeneic HSCT and developed moderate or severe chronic GVHD. Researchers randomly assigned patients to either ruxolitinib dosed at 10 mg twice daily (n = 165) or an investigator-selected best available therapy from one of 10 therapy options (n = 164).
Baseline patient characteristics were similar between the ruxolitinib and best available therapy groups and were closely matched for age, sex, severity of chronic GVHD (moderate, 41.2% vs. 44.5%; severe, 58.8% vs. 54.9%) and modified Lee symptom scale score (median, 18.67 vs. 18.54).
Patients underwent six 28-day cycles of treatment and could remain on regimens of corticosteroids and/or calcineurin inhibitors. They also were permitted to receive antivirals and antibiotics to prevent infection.
Patients were allowed to cross over from the best available therapy group to the ruxolitinib group on or after day 1 of cycle seven if they did not achieve or maintain a complete or partial response to therapy, developed toxicity to therapy or had a chronic GVHD flare.
ORR at week 24, which included the sum of complete and partial responses as determined by NIH consensus criteria for response, served as the primary endpoint. Secondary endpoints included failure-free survival and improvement in symptoms based on changes in modified Lee symptom scale score at 24-week follow-up.
One hundred twenty-five patients (38%) remained on treatment at data cutoff on May 8. Eighty-two patients (49.7%) in the ruxolitinib group and 122 patients (74.4%) in the best available therapy group discontinued treatment due to reasons that included lack of efficacy (14.5% in the ruxolitinib group vs. 42.7% receiving best available therapy), adverse events (17% vs. 4.9%) and disease relapse (5.5% vs. 4.3%).
Sixty-one patients (37.2%) crossed over to ruxolitinib.
Results showed the study met its primary efficacy endpoint of significantly higher ORR at week 24 with ruxolitinib vs. best available therapy (49.7% vs 25.6%; OR = 2.99; 95% CI, 1.86-4.8).
The complete response rate also was higher in the ruxolitinib group (6.7% vs. 3%), which demonstrated significantly longer median failure-free survival (not reached vs 5.7 months; HR = 0.37; 95% CI, 0.268-0.51) and greater improvement in modified Lee symptom score response rate (24% vs. 11%; OR = 2.62; 95% CI, 1.42-4.82).
The safety analysis showed the ruxolitinib and best available therapy groups had similar rates of adverse events of any grade (97.6% vs. 91.8%) and of grade 3 or greater (57% vs. 57.6%). The most common adverse events included anemia (29.1% vs. 12.7%), hypertension (15.8% vs. 12.7%), pyrexia (15.8% vs. 9.5%) and increased alanine transaminase levels (15.2% vs. 4.4%).
Sixty-four percent of patients in the ruxolitinib group experienced an infection compared with 56% of the best available therapy group. These included fungal (11.5% vs. 5.7%), viral (33.9% vs 29.1%) and bacterial (27.9% vs 25.9%) infections.
Thirty-one patients (18.8%) in the ruxolitinib group and 27 patients (16.5%) in the best available therapy group died as of data cutoff; the primary cause of death was chronic GVHD for 22 patients (13%) in the ruxolitinib group and 13 patients (8%) in the best available therapy group.
“The safety profile of ruxolitinib was consistent with previous observations and with what is expected in patients with chronic GVHD,” Zeiser said.
He added that this was the first successful randomized phase 3 trial among adolescents and adults with chronic GVHD who had an inadequate response to corticosteroids.
“Ruxolitinib is the first agent to demonstrate superior efficacy to [best available therapy] in a phase 3 trial,” he said.
In an ASH press release, Zeiser said the results of this study, coupled with the lack of approved second-line therapies for chronic GVHD, should lead to changes in clinical practice.
“[This study] shows a significant advantage for ruxolitinib,” he said in the release. “It is likely that this trial will lead to approval for this indication and change the guidelines for the treatment of this disease.”
Perspective
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Lisa Hicks, MD
This is the first successful phase 3 trial of a second-line treatment for chronic GVHD in adults and adolescents. The results represent a major step forward for patients with chronic GVHD that does not resolve when taking corticosteroids.
This study provides more evidence that an additional drug — ruxolitinib — can be used to treat chronic GVHD and has immediate implications for the clinical environment.
Perspective
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This randomized trial conducted in Europe establishes ruxolitinib as a standard of care, as it was very well-tolerated and demonstrated a significant benefit over best available therapy.
However, some issues with the are worth mentioning. Some of the criteria used for refractory disease are not necessarily standard. Lack of response or disease progression after just 1 week might have been just a little short. Rather, disease persistence requiring high doses of steroids for more than 4 weeks is a standard criterion. Also, the best-available-therapy group did not include ibrutinib (Imbruvica; Pharmacyclics, Janssen) or belumosudil (KD025, Kadmon Holdings), data for which also were presented at this ASH meeting. Lastly, there were some outliers, such as patients who had around 2,000 days of treatment before they started ruxolitinib, and you have to wonder how they developed GVHD over that period of time.
It was interesting that the study included patients with reflares, or those who had to go back up on their dose of prednisone after an unsuccessful attempt to taper their steroids. Of note, this trial had a crossover design, so at the 6-month mark patients on best available therapy who had not responded were allowed to get ruxolitinib. That takes away from the effect a little bit, but it’s appropriate for this type of disorder, because there is no good treatment.
All in all, the investigators have to be commended, because these are challenging studies to conduct. They noticed a significant benefit, and I think it establishes ruxolitinib as a standard of care for patients with chronic GVHD who are failing steroid therapy.
Memorial Sloan Kettering Cancer Center
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Zeiser R, et al. Abstract 77. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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