REACH3 Trial Yields Positive Outcomes Among Patients With GVHD Taking Ruxolitinib

Incyte’s Jakafi (ruxolitinib) led to significantly greater overall response, failure-free survival, and symptoms response among patients with glucocorticoid-refractory or -dependent chronic graft-vs-host disease (GVHD) compared with those who received standard second-line therapy, according to new study results published in The New England Journal of Medicine.

However, incidence of thrombocytopenia and anemia was higher in the group that received ruxolitinib.

Although standard first-line treatment for GVHD is systemic glucocorticoids, around 50% of patients will become glucocorticoid-refractory or glucocorticoid-dependent, which can increase the risk of poor outcomes.

“Preclinical studies showed that Janus kinase 1 and 2 (JAK1–JAK2) signaling is crucial in the steps leading to inflammation and tissue damage in acute GVHD and chronic GVHD and that ruxolitinib, a JAK1–JAK2 inhibitor, was an effective treatment in a mouse model of chronic GVHD,” researchers said.

To determine the effects of ruxolitinib compared with an investigator’s choice of therapy from 10 commonly used options among these patients, researchers conducted REACH3, a phase 3 multicenter randomized trial. Previous data from REACH1 and REACH2 show the treatment yielded high response rates.

The main control therapies administered were extracorporeal photopheresis, mycophenolate mofetil, and ibrutinib; half of participants received calcineurin inhibitors throughout the duration of the trial.

All individuals included in the trial (n = 329) were 12 years or older and had moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. “Patients were randomly assigned in a 1:1 ratio to receive ruxolitinib at a dose of 10 mg twice daily or therapy chosen by the investigators from a list of 10 commonly used options… and were stratified according to the severity of their chronic GVHD,” authors said.

The assigned treatment was administered for at least 6 cycles at 28 days per cycle. If patients reported unacceptable adverse effects or chronic GVHD progressed, treatment was discontinued.

Individuals also continued to receive glucocorticoids with or without calcineurin inhibitors, but these treatments were tapered throughout the trial based on patients’ responses.

Median patient age was 49 years, and the majority (61.1%) were male. Of the patients included, 42.9% had moderate chronic GVHD, 56.5% had severe chronic GVHD, 71.4% had glucocorticoid-refractory disease, and 28.6% had glucocorticoid-dependent disease.

“At data cutoff (May 8, 2020; median follow-up, 57.3 weeks), 125 patients (38.0%) continued to receive the randomized treatment; 82 patients (49.7%) discontinued ruxolitinib and 122 patients (74.4%) discontinued control therapy,” the authors wrote. Lack of efficacy, adverse events, and relapse of underlying disease were the main reasons for discontinuation reported.

Analyses revealed:

• Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio [OR], 2.99; P < .001).
• A best overall response up to week 24 was observed in 76.4% of patients in the ruxolitinib group and in 60.4% in the control group (OR, 2.17; 95% CI, 1.34-3.52).
• 11 patients (6.7%) in the ruxolitinib group and 5 (3.0%) in the control group had a complete response.
• Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; HR, 0.37; P < .001) and higher symptom response (24.2% vs. 11.0%; OR, 2.62; P = .001).
• The most common (occurring in ≥10% patients) adverse events of grade 3 or higher up to week 24 were thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively).
• Patients who crossed over from control therapy to ruxolitinib (n = 61) had a response, with a best overall response at data cutoff in 78.7% (4 with a complete response and 44 with a partial response).
• Results in individual organs showed that ruxolitinib led to higher responses in most organs than control therapy.

Eleven deaths were reported as being related to the trial drug, with 7 (4.2%) among those who received ruxolitinib and 4 (2.5%) among those treated with control therapies.

Data showed that incidence of cytomegalovirus infections and reactivations was similar in the 2 groups. “Given the risk of infections, patients treated with ruxolitinib should receive prophylaxis against infection, and a low threshold for evaluation of new signs and symptoms should be adopted,” authors suggested.

These data will serve as the basis for a supplemental New Drug Application for ruxolitinib, currently undergoing review with the FDA, Incyte said in a statement. The drug has a Prescription Drug User Fee Act date of September 22, 2021.

Reference

Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. Published online July 15, 2021. doi:10.1056/NEJMoa2033122