Ruxolitinib Elicits High Responses in Steroid-Refractory aGVHD, Regardless of Organ Involvement

The overall response rate (ORR) achieved with ruxolitinib (Jakafi) at day 28 proved to be higher than what was achieved with best available therapy (BAT) in patients with steroid-refractory acute graft-vs-host disease (aGVHD), irrespective of organ involvement, according to data from a post-hoc analysis of the phase 3 REACH2 trial (NCT03112603).¹

The findings, which were presented during the EBMT 48th Annual Meeting, indicated that the ORR elicited with ruxolitinib (n = 96) among those who had lower gastrointestinal (GI) tract involvement at day 28 was 57% vs 33% with BAT (n = 115; odds ratio [OR], 2.70; 95% CI, 1.54-4.74). In those with skin involvement, the ORRs with ruxolitinib (n = 93) and BAT (n = 74) were 72% and 47%, respectively (OR, 2.99; 95% CI, 1.55-5.79).

Moreover, in those with upper GI involvement, ruxolitinib (n = 28) induced an ORR of 68% vs 38% with BAT (n = 37; OR, 3.35; 95% CI, 1.19-9.44). Lastly, in patients who had liver involvement, the ORRs achieved with ruxolitinib (n = 36) and BAT (n = 26) were 44% and 19%, respectively (OR, 4.04; 95% CI, 1.16-14.09).

“From this post-hoc analysis, [we learned that] in patients with steroid-refractory aGVHD, the response rates were higher with ruxolitinib compared with BAT, regardless of organ involvement, and it is also true when considering aGVHD grade—all of this is good news,” lead study author Mohamad Mohty, MD, of the Haematology and Cellular Therapy Department, of Saint-Antoine and Sorbonne University, said in a presentation on the data.

For patients with aGVHD, standard initial treatment is corticosteroids, which are known to have a heavy toxicity burden. Moreover, 35% to 60% of patients become refractory to this approach. Those with steroid-refractory aGVHD often present with or progress to severe disease, and the mortality rate in these patients is 70% or higher.

The multicenter, randomized, open-label REACH2 trial enrolled patients with grade II to IV steroid-refractory aGVHD who were at least 12 years of age and who had evidence of myeloid and platelet engraftment. If patients had active uncontrolled infection, severe organ failure, overlap syndrome, or had failed previous allogeneic hematopoietic stem cell transplant within 6 months, or disease relapse, they were excluded.²

Study participants were randomized 1:1 to receive either oral ruxolitinib at a twice-daily dose of 10 mg or investigator’s choice of therapy, which could have included antithymocyte globulin, extracorporeal photopheresis, mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil, an mTOR inhibitor in the form of everolimus (Afinitor) or sirolimus (Rapamune), etanercept (Enbrel), or infliximab (Remicade).

Study participants received treatment for up to 24 weeks. Randomization was stratified according to grade of aGVHD at baseline (II vs III vs IV). Notably, standard supportive therapy was permitted in both treatment arms, as well as the continued use of calcineurin inhibitors and glucocorticoids.

The primary end point of the trial was ORR at day 28, and a key secondary end point was durable ORR at day 56. Other secondary end points included 6-month overall survival and non-relapse mortality.

At a data cutoff date of July 25, 2019, a total of 309 patients underwent randomization; 154 patients received ruxolitinib and 155 patients were given BAT. The median age in the investigative arm was 52.5 years (range, 12-73) vs 54.0 years (range, 13-71) in the control arm; 59.7% and 58.7% of patients, respectively, were male. The majority of patients were White.

In the ruxolitinib arm, 34.4% of patients had grade II acute GVHD at randomization, 46.1% had grade III disease, and 19.5% had grade IV disease; these rates were 34.2%, 46.5%, and 19.4%, respectively, in the BAT arm. Of those in the investigative arm, 62.3% had lower GI involvement, 60.4% had skin involvement, 18.2% had upper GI involvement, and 23.4% had liver involvement. Of those in the control arm, 74.2% of patients had lower GI involvement, 47.7% had skin involvement, and 23.9% had upper GI involvement, and 16.8% had liver involvement.

Data showed that the ORR with ruxolitinib was significantly higher with ruxolitinib than it was with BAT at day 28 and day 56. Day-28 ORRs in the investigative (n = 154) and control (n = 155) arms were 62% and 39%, respectively (OR, 2.64; 95% CI, 1.65-4.22; P < .001). Of those who responded to ruxolitinib, 34% achieved a complete response (CR) and 28% experienced a partial response (PR). Among those who responded to BAT, the CR and PR rates were 19% and 20%, respectively.

The ORR achieved with ruxolitinib at day 56 was 40% vs 22% with BAT (P < .001). Of those who responded to treatment in the investigative arm, the CR rate was 27% and the PR rate was 13%. Of the responders in the control arm, the CR and PR rates were 16% and 6%, respectively.

Notably, the ORR was higher with ruxolitinib vs BAT, irrespective of acute GVHD grade. Among those with grade II disease who received ruxolitinib (n = 53), the ORR was 75%, vs 51% with BAT (n = 53; OR, 2.96; 95% CI, 1.30-6.76). Among those with grade III disease, the ORRs achieved with ruxolitinib (n = 71) and BAT (n = 72) were 56% and 38%, respectively (OR, 2.15; 95% CI, 1.10-4.20). In those who had grade IV disease, the ORR with ruxolitinib (n = 30) was 53% vs 23% with BAT (n = 30; OR, 3.76; 95% CI, 1.24-11.38).

For the post-hoc subgroup analysis by organ class, investigators examined day-28 ORR by aGVHD involvement in 4 organ classes: lower GI, skin, upper GI, and liver. They also evaluated the percentage of patients with a 1-stage-or-more improvement from baseline by organ class at day 28 and day 56, excluding those with stage 0 disease at baseline.

Additional data presented during the meeting showed that a greater proportion of patients in the ruxolitinib arm experienced an improvement of 1 stage or more from baseline at day 28 and day 56 than those in the BAT arm, across the 4 organ classes examined.

In May 2019, the FDA approved ruxolitinib for the treatment of adult and pediatric patients aged 12 years and older who had steroid-refractory aGVHD.³ The regulatory decision was supported by findings from the phase 2 REACH1 trial, which showed that when ruxolitinib was combined with corticosteroids, it induced an ORR of 57% at day 28 with a CR rate of 31% in this patient population.

References

1. Mohty M, Zeiser R, Galvin J, et al. Ruxolitinib vs best available therapy in patients with steroid-refractory acute graft-vs-host disease: a comparison of response by organ class from the randomized, phase 3 REACH2 study. Presented at: EBMT 48th Annual Meeting; March 19-23, 2022; virtual. Abstract OS10-03.
2. Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host fisease. N Engl J Med. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635
3. FDA approves Jakafi (ruxolitinib) for the treatment of patients with acute graft-versus-host disease. News release. FDA; May 24, 2019. Accessed April 15, 2022. https://bit.ly/3xtTRnd