Ruxolitinib Data Published in NEJM Underscore ORR Benefit in Chronic GVHD, Irrespective of Organs Involved at Baseline

Robert Zeiser, MD

Ruxolitinib (Jakafi) continued to result in a significant improvement in overall response rate (ORR) compared with best available therapy (BAT) in patients with steroid-refractory/dependent chronic graft-vs-host disease (GVHD), regardless of the individual organs involved at baseline, according to findings from the phase 3 REACH3 trial (NCT03112603) published In The New England Journal of Medicine.¹

At week 24, the ORR achieved with ruxolitinib was 49.7% vs 25.6% with BAT among the 329 patients who had undergone randomization on the trial (odds ratio [OR], 2.99; P <.001). Ruxolitinib also resulted in a longer median failure-free survival than the control, at more than 18.6 months vs 5.7 months, respectively (HR, 0.37; 95% CI, 0.27-0.51; P <.001), and a higher symptom response, at 24.2% vs 11.0%, respectively (OR, 2.62; 95% CI, 1.42-4,82; P = .001).

Additionally, results from a new subgroup analysis of the trial revealed that irrespective of the organs involved at baseline, ruxolitinib produced a higher overall response than BAT at week 24. Although participants were not stratified according to organ involvement, ORs favored ruxolitinib in all organ subgroups that were examined.

“Ruxolitinib lead to a higher overall response than control therapy at week 24, regardless of organs involved, and a higher best overall response, a longer duration of response [DOR], and longer failure-free survival. The results in individual organs showed that ruxolitinib led to higher responses in most organs than control therapy,” lead study author Robert Zeiser, MD, of Albert-Ludwigs-Universität Freiburg, and colleagues, wrote. “The response in the lungs and liver was low in both treatment groups, which highlights how difficult treatment can be when these organs are affected. However, subgroup analysis of overall response according to organ involvement showed that chronic GVHD in difficult-to-treat organs did not preclude alleviation of chronic GVHD in other organs in patients receiving ruxolitinib, so the overall response was favorable.”

In the open-label, phase 3 trial, investigators set out to examine the safety and efficacy of ruxolitinib at a twice-daily dose of 10 mg vs investigator’s choice of 10 frequently used options that are considered to be BAT in patients aged 12 years or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD.

To be eligible for enrollment, patients needed to have undergone allogeneic stem cell transplantation. If they had previously received a JAK inhibitor for acute GVHD, they had to have achieved a complete or partial response to treatment. They must have discontinued treatment with the JAK inhibitor at least 8 weeks before the first dose of study treatment.

If patients had previously received 2 or more systemic therapies for chronic GVHD plus glucocorticoids with or without calcineurin inhibitors, they were excluded. Moreover, patients who had their primary cancer relapse, experienced graft loss within 6 months prior to treatment initiation, or they had active, uncontrolled infection, were also excluded.

A total of 329 participants were randomized 1:1 to receive either ruxolitinib at a twice-daily dose of 10 mg (n = 165) or BAT (n = 164), which could have included any of the following: extracorporeal photopheresis, low-dose methotrexate, mycophenolate mofetil, a mTOR inhibitor like everolimus (Afinitor) or sirolimus (Rapamune), infliximab (Remicade), rituximab (Rituxan), pentostatin (Nipent), imatinib (Gleevec), or ibrutinib (Imbruvica).

Patients were stratified based on the severity of their chronic GVHD. Participants continued to receive glucocorticoids with or without calcineurin inhibitors, and infection prophylaxis was permitted and given in accordance with local institutional guidelines.

The primary end point of the trial was overall response at week 24, and 2 important secondary end points included failure-free survival and response on the modified Lee Symptom Scale at week 24. Other end points comprised subgroup analyses of overall response, individual organ responses, best overall response at any time up to week 24, DOR, change in glucocorticoid dose over time, overall survival (OS), and changes in quality-of-life measures.

Patient characteristics were noted to be well balanced between the 2 treatment arms. The median age of stud participants was 49 years (range, 12-76) and the majority (61.1%) were male. Just under half, or 42.9%, had moderate chronic GHVD, and 56.5% had severe chronic disease. Moreover, 71.4% and 28.6% had glucocorticoid-refractory or -dependent disease, respectively.

Among those who were randomized to the control arm, 34.8% received extracorporeal photopheresis, 22.2% were given mycophenolate mofetil, and 17.1% received ibrutinib. About half of the participants were given calcineurin inhibitors during the trial.

At a median follow-up of 57.3 weeks, 38.0% of patients were still receiving treatment. However, 49.7% and 74.4% discontinued treatment with ruxolitinib or BAT, respectively. The most common reasons for discontinuation in the investigative and control arms, respectively, included lack of efficacy (14.5% vs 42.7%), toxicities (17.0% vs 4.9%), and relapse of underlying disease (5.5% vs 4.3%). Additionally, 37.2% of patients crossed over from the control arm to receive ruxolitinib.

Additional data indicated that the probability for failure-free survival at 6 months was higher with ruxolitinib vs BAT, at 74.9% (95% CI, 67.5%-80.9%) and 44.5% (95% CI, 36.5%-52.1%), respectively.

A best overall response up to week 24 was reported in 76.4% and 60.4% of patients in the investigative and control arms, respectively (OR, 2.17; 95% CI, 1.34-3.52; risk ratio, 1.24; 95% CI, 1.07-1.43; P = .001). Among responders, the estimated probability of maintaining response to treatment at 1 year in the ruxolitinib and BAT arms was 68.5% (95% CI, 58.9%-76.3%) and 40.3% (95% CI, 30.3%-50.2%), respectively.

Participants who crossed over to the investigative arm (n = 61) also experienced a response, with a best overall response of 78.7% at the time of data cutoff; 4 of these patients achieved a complete response to ruxolitinib and 44 experienced a partial response.

At data cutoff, the OS data were not mature and had had not yet been reached in either arm (HR, 1.09; 95% CI, 0.65-1.82). At 12 months, the estimated probability of survival in the ruxolitinib and BAT arms was 81.4% (95% CI, 74.1%-86.8%) and 83.8% (95% CI, 76.5%-89.0%), respectively.

The safety analysis included 165 patients from the investigative arm and 158 from the control arm; these patients had received at least 1 dose of study treatment up to week 24. Any-grade toxicities were experienced by 97.6% of those who were given ruxolitinib and 91.8% of those who received BAT.

Rates of grade 3 or higher adverse effects (AEs) were 57.0% and 57.6% in the investigative and control arms, respectively. The most frequently reported grade 3 or higher AEs in these arms were thrombocytopenia (15.2% vs 10.1%, respectively), anemia (12.7% vs 7.6%), neutropenia (8.5% vs 3.8%), and pneumonia (8.5% vs 9.5%). Additionally, 33.3% and 36.7% of those in the ruxolitinib and BAT arms, respectively, experienced serious AEs.

Moreover, 16.4% of patients who received ruxolitinib discontinued treatment because of toxicities vs 7.0% of those who received BAT. In the investigative and control arms, 37.6% and 16.5% of patients, respectively, experienced AEs that resulted in dose adjustments or interruptions.

Infections were reported in 63.6% of those given ruxolitinib and 56.3% of those who received BAT; these effects were grade 3 in severity in 19.4% and 18.4% of patients, respectively. The most frequently reported infections were viral (33.9% vs 29.1%, respectively), followed by bacterial (27.9% vs 25.9%) and fungal (11.5% vs 5.7%).

Slightly more patients who received ruxolitinib vs BAT had died, at 18.8% vs 16.5%, respectively. Deaths were mostly attributed to complications caused by chronic GVHD or treatment (13.3%, ruxolitinib; 7.9%, BAT, including 2 deaths following crossover to ruxolitinib) or infections (1.2% vs 3.7%, respectively).

“Our trial showed that among patients with moderate or severe chronic GVHD in whom glucocorticoids produced an inadequate response, ruxolitinib was superior to control therapies, as evidenced by a greater overall response, longer failure-free survival, and greater reduction in symptoms,” the study authors concluded. “Patients receiving ruxolitinib had a higher incidence of grade 3 or worse thrombocytopenia and anemia than those receiving control therapy; no new safety signals were observed.”

Reference

1. Zeiser R, Polverelli N, Hashmi SK, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228-238. doi:10.1056/NEJMoa2033122