When chronic graft-versus-host disease (cGVHD) develops as a complication of allogeneic hematopoietic stem cell transplant (alloHSCT), treatment options are limited. New findings show that ruxolitinib (Jakafi) was superior to standard therapy in reducing symptoms of cGVHD in the second-line setting, and the results are potentially practice changing.
The new data, from the REACH3 trial, were presented at the annual meeting of the American Society of Hematology (ASH), held virtually this year.
This trial is “almost certainly a practice changer,” commented Robert Brodsky, MD, ASH secretary, during a press preview webinar.
Chronic GVHD occurs in approximately 30%-70% of patients who undergo alloSCT, and “has been really hard to treat,” said Brodsky, from Johns Hopkins University School of Medicine, Baltimore, Maryland. “Steroids are the first-line treatment, but after that, nothing else has shown any improvement and even steroids don’t work that well.”
Of the patients assessed, 50% of those who received ruxolitinib responded to therapy compared with only 25% who received standard therapies.
“This is the first multicenter randomized controlled trial for chronic GVHD that is positive,” said senior study author Robert Zeiser, PhD, of University Medical Center, 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.”
Ruxolitinib, a JAK inhibitor first marketed for use in myelofibrosis, is already approved for acute GVHD. The US Food and Drug Administration approved that indication last year on the basis of data from two previous trials, REACH 1 and REACH 2. The trials found that ruxolitinib was superior to best available therapy for treating patients with acute GVHD.
Superior to Best Available Therapy
In the current REACH 3 study, Zeiser and colleagues compared ruxolitinib with best available therapy in 329 patients with moderate-to-severe cGVHD (both steroid dependent and steroid resistant).
All patients had undergone alloSCT and were randomly assigned to ruxolitinib (10 mg twice daily) for six 28-day cycles or investigator-selected best available therapy (BAT), of which there were 10 options. Patients continued receiving their regimen of corticosteroids, and viral prophylaxis and antibiotics were allowed as needed for infection prevention and treatment.
The study permitted crossover: patients on BAT were allowed to start on ruxolitinib on or after cycle 7 day 1 for patients who did not achieve or maintain a response, developed toxicity to BAT, or had a cGVHD flare.
The study met its primary endpoint of overall response rate (ORR), with a clear and substantial improvement among patients taking ruxolitinib (50% vs 26%; odds ratio, 2.99; P < .0001a), Zeiser noted. The complete response rate was also higher (7% vs 3%).
Both key secondary endpoints also showed that ruxolitinib was superior to BAT. Failure-free survival was significantly longer in the ruxolitinib group (median not reached vs 5.7 months; hazard ratio, 0.370; P < .0001). There was also an improvement in symptoms based on changes in the modified Lee symptom score (mLSS; 0 [no symptoms] to 100 [worst symptoms]) at cycle 7 day 1; the results show that the mLSS responder rate was higher in patients on ruxolitinib (24% vs 11%; odds ratio, 2.62; P = .0011).
A total of 31 patients in the ruxolitinib group died (19%) along with 27 in the BAT group (16%), with the cGVHD as the main cause of death.
Adverse events were comparable in both groups (ruxolitinib 98% [grade ≥ 3, 57%]; BAT, 92% [grade ≥ 3, 58%], with the most common being anemia (29% vs 13%), hypertension (16% vs 13%), pyrexia (16% vs 9%), and ALT increase (15% vs 4%).
More Options for Patients
“The addition of ruxolitinib is definitely practice changing for this very difficult to treat population,” commented James Essell, MD, medical director of the Blood Cancer Center at Mercy Health, Cincinnati, Ohio, who was not involved in the study.
However, he added that “more options are still required, as evidenced by the continued deaths of patients despite this new option.”
Essell pointed out that ibrutinib (Imbruvica) is already approved for the treatment of cGVHD. “Ruxolitinib offers another option for treating this group of patients,” he said, and predicted that “it will be used frequently and has a different toxicity profile, ultimately improving the care for patients with cGVHD.”
It is likely that ruxolitinib will be considered earlier in the treatment of cGVHD to avoid the toxicity of chronic steroid use, he added, but price is a consideration. “The cost of ruxolitinib is over 200 times more than prednisone, limiting the adoption front line without a clinical trial.”
Another expert approached for comment was enthusiastic. “The abstract gave good evidence and efficacy with chronic GVHD,” said Ryotaro Nakamura, MD, associate professor of hematology & hematopoietic cell transplantation at City of Hope, Duarte, California. He noted that there have been two previous REACH trials which showed a benefit for ruxolitinib in acute GVHD.
What this means is that there is now global evidence that ruxolitinib is better than anything else so far, he said, and this latest trial is just part of the “practice-changing data,” from the three studies. “It is practice changing in that it is providing options now for these patients,” he said.
Zeiser has disclosed relationships with Incyte, Novartis and Mallinckrodt; other authors have also disclosed relationships with industry as noted in the abstract. Essell and Nakamura have disclosed no relevant financial relationships.
American Society of Hematology 2020 Annual Meting: Abstract 77. Presented December 4, 2020.