Ruxolitinib in GVHD Reveals Lower Risk of Relapse, Longer Duration of Response

Findings from the phase 3 REACH2 trial (NCT02913261) demonstrated a lower risk of relapse and longer median duration of response (DOR) with ruxolitinib (Jakafi) vs best available therapy (BAT) in patients with steroid-refractory acute graft-versus-host disease (GVHD).

Patients who received ruxolitinib experienced a longer median DOR compared with BAT, at 163 days (range, 22-623) versus 101 days (range, 10-456), respectively, according to results presented during the 47th Annual Meeting of The European Society for Blood and Marrow Transplantation.¹ Additionally, the ruxolitinib cohort had a lower probability of loss of response at both 6 months (8.73%) and 12 months (10.16%) versus the BAT arm (37.34% and 37.34%, respectively).

Moreover, the median failure-free survival (FFS) was more than 3 times longer in the ruxolitinib arm versus the BAT arm, at 4.86 months and 1.02 months, respectively (HR, 0.49; 95% CI, 0.37-0.63). The agent also resulted in fewer incidences of hematologic disease progression or relapse, nonrelapse mortality (NRM), or the addition of new systemic treatments. Ruxolitinib also demonstrated a longer median event-free survival (EFS) versus BAT, at 8.18 months and 4.17 months, respectively (HR, 0.80; 95% CI, 0.60-1.08); this translated to a 20% reduction in the risk of hematologic relapse or progression, graft failure, or death because of any cause.

The risk of malignancy relapse or progression was relatively low in both cohorts. The probability of events at 6 months in the ruxolitinib arm was 8.5% versus 13.5% in the BAT arm; at 12 months, these rates were 11.1% and 15.1%, respectively. The cumulative incidence of NRM proved to have similar event rates over time in both treatment arms. The probability of events at 6 months in the investigative and control arms were 37.7% versus 42.4%, respectively; at 12 months, these rates were 43.8% and 46.5%, respectively.

“The ruxolitinib-treated patients had a longer DOR compared with [those who received] BAT,” Mohamad Mohty, MD, PhD, a professor of hematology and head of the Department of Hematology and Cellular Therapy at Saint-Antoine Hospital and University Pierre and Marie Curie in Paris, France, said during the presentation. “They have a longer median FFS, a longer EFS, and more pronounced improvement in health outcomes [with ruxolitinib].…This is really good news for our patients who are struggling with… post allogeneic stem cell transplantation.”

In May 2019, ruxolitinib was approved by the FDA for use in patients with steroid-refractory acute GVHD, making it the only agent to receive regulatory approval for this patient population.2 The initial results of the phase 3 REACH2 study, which enrolled 309 patients, indicated that ruxolitinib demonstrated superiority over BAT3 ; the agent elicited an overall response rate (ORR) of 62.3% at day 28 versus 39.4% with BAT (P<.001). At day 56, the ORRs in the investigative and control arms were 39.6% and 21.9%, respectively (P<.001). No unexpected safety signals were reported with ruxolitinib, and cytopenias were the most common adverse effect (AE) observed with its use.

To be eligible for participation on the REACH2 trial, patients needed to be 12 years or older, have steroid-refractory acute GVHD, and have progressed following 3 or more days of high-dose systemic steroid therapy with or without calcineurin inhibitors (CNIs), had a lack of response after 7 days, or had progressed while being treated with a steroid taper. Evidence of myeloid and platelet count engraftment was also required.

Participants were randomized 1:1 to receive either 10 mg of ruxolitinib twice daily and steroids with or without CNI (n = 154) or BAT and steroids with or without CNI (n = 155). Patients were stratified by acute GVHD grade. Investigators planned for follow-up at 6 months, 9 months, 12 months, 18 months, and 24 months. Notably, the study allowed for crossover to ruxolitinib.

Key secondary end points evaluated after 6 months of follow-up included DOR, FFS, EFS, malignancy relapse/progression, NRM, patient-reported outcomes (PROs), corticosteroid dose, chronic GVHD crossover, and safety.

Overall survival data are not yet mature but are expected to be presented during the study’s final analysis, according to Mohty.

The median age of participants was 53.25 years, and the majority of patients were male. Thirtythree percent of patients had grade 2 disease, 44.4% had grade 3 disease, and 20.4% had grade IV disease. The majority (62.3%) of patients on the ruxolitinib arm had acute GVHD organ involvement in the lower gastrointestinal tract; the same was true for the BAT arm (74.2%). Moreover, 30.5% of those in the ruxolitinib arm experienced failure during the steroid taper versus 31.6% of those in the BAT arm.

“[The baseline characteristics] were very well balanced between treatment arms, especially the—and this is of importance when it comes to acute GVHD—organ involvement,” Mohty noted

In the ruxolitinib arm, 1.9% of patients are receiving ongoing treatment, 22.7% completed treatment, and 75.3% discontinued treatment. The most common reasons for discontinuation included lack of efficacy (20.8%), AEs (17.5%), and death (16.2%). By comparison, no patients in the BAT arm are still receiving treatment, 13.5% completed treatment, and 86.5% discontinued treatment. Here, 44.5% discontinued due to lack of efficacy, 13.5% due to death, and 8.4% due to disease relapse. Notably, 31.6% of patients from the BAT cohort crossed over to receive ruxolitinib.

Additionally, Mohty spoke to the results of a PRO analysis from the study. “Quality of life is very important when it comes to GVHD.” Mohty said. “The mean EQ-5D-5L scores improved in both treatment arms at week 24; however, this improvement was more pronounced in the ruxolitinib arm. This is in line with the data that [have been] previously described.”

Key secondary findings indicated that 22.1% of patients in the ruxolitinib arm and 14.8% of those in the BAT arm had completed steroid taper by day 56 (odds ratio, 1.63; 95% CI, 0.91-2.92). Moreover, the ruxolitinib cohort had more patients completely tapered off steroids at day 56 versus the BAT cohort.

Notably, 29.2% and 18.7% of patients in the investigative and control arms, respectively, had developed chronic GVHD, although fewer severe cases were observed in the ruxolitinib arm (4 vs 7, respectively). Patients who crossed over to the ruxolitinib arm experienced responses that were consistent with what had been reported in the primary analysis of ruxolitinib, with an ORR at crossover day 28 of 67.3% and 42.9% at crossover day 56.

Regarding safety, patients in the ruxolitinib arm (n = 152) had a median duration of exposure of 63.0 months (range, 6.0-463.0 months) versus 29.0 (range, 1.0-188.0 months) in the BAT arm (n = 150). Any-grade toxicities were reported in 99.3% of those given ruxolitinib versus 98.7% of those given BAT; 91.4% versus 87.3% of patients, respectively, experienced grade 3 AEs. Slightly more patients in the investigative arm experienced serious AEs versus those in the control arm, at 66.4% versus 53.3%, respectively (TABLE1 ).

Additionally, more patients who received ruxolitinib experienced toxicities that resulted in discontinuation versus those given BAT, at 27.0% versus 9.3%, respectively. Just slightly less than 55% of patients on the investigative arm experienced toxicities that led to dose modifications versus 13.3% of those on the control arm.

“We didn’t see any new safety signals with this longer follow-up,” Mohty said. “The toxicity profile of ruxolitinib reflects the longer treatment duration compared with the control BAT arm.”

The most common all-grade AEs associated with ruxolitinib included thrombocytopenia (234.9/100 patient treatment years [PTY]), anemia (181.7/100 PTY), and neutropenia (131.3/100 PTY), with common grade 3 or higher AEs including thrombocytopenia (200.3/100 PTY), anemia (181.7/100 PTY), and neutropenia (131.3/100 PTY). The most frequently experienced any-grade AEs in the BAT arm were anemia (216/100 PTY), thrombocytopenia (211.9/100 PTY), and cytomegalovirus infection (169.8/100 PTY), with common grade 3 or higher AEs including thrombocytopenia (178.9/100 PTY), anemia (148.6/100 PTY), and neutropenia (115.6/100 PTY).

Other all-grade AEs associated with ruxolitinib included diarrhea (56.6/100 PTY), hypomagnesemia (53.0/100 PTY), and hypertension (48.2/100 PTY), with other grade 3 or higher AEs including white blood cell count decrease (46.2/100 PTY), sepsis (26.0/100 PTY), and hypertension (21.2/100 PTY).

_References:

_{1. Mohty M. Ruxolitinib vs best available therapy in patients with steroid-refractory acute graft-vs-host-disease: 6-month follow-up from the randomized, phase 3 REACH2 study. Presented at: European Society for Blood and Marrow Transplantation 47th Annual Meeting; March 14-17, 2021; virtual. Accessed March 16, 2021. Abstract OS8-4. http://bit. ly/3cExjUv}

_{2. FDA approves Jakafi (ruxolitinib) for the treatment of patients with acute graft-versus-host disease. News release. Incyte Corporation. May 24, 2019. Accessed March 16, 2021. http://bit.ly/38LNX3t}

_{3. Zeiser R, von Bubnoff N, Butler J, et al; REACH2 Trial Group. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N Engl J Med. 2020;382(19):1800-1810. doi:10.1056/NEJMoa1917635}