Ruxolitinib Exceeds Response, Survival, and Symptom Burden End Points in Chronic GVHD

Stephanie J. Lee, MD

The overall response rate (ORR) of ruxolitinib (Jakafi) was significantly higher than best available therapy (BAT), 49.7% versus 25.6% (odds ratio [OR], 2.99; 95% CI, 0.86-4.80; P < .0001), respectively, in adolescent and adult patients with chronic graft-versus-host disease (cGVHD), according to findings presented by Stephanie J. Lee, MD, MPH, at the 2021 Transplantation and Cellular Therapy Meetings.¹

Results from the phase 3, randomized REACH3 trial (NCT03112603) further demonstrated the benefit of ruxolitinib over BAT in rates for failure-free survival (FFS), symptom improvement, and duration of response.

“This is the first successful randomized phase 3 trial in adolescent and adult patients with cGVHD who had an inadequate response to steroids,” said Lee, professor and associate director in the clinical research division, Fred Hutch in Seattle, Washington. Standard first-line therapy for cGVHD consists of systemic steroids; however, about half of patients become steroid refractory or dependent and no standard second-line treatment has been defined.^2,3

In the trial, 329 patients were randomized to receive 10 mg of ruxolitinib twice a day (n = 165) with or without steroids and a calcineurin inhibitor or BAT (n = 164). “The Investigators had to select the [BAT] before randomization, and they selected one agent from a list of 10. Options included extracorporeal photopheresis, ibrutinib [Imbruvica], methotrexate, and others,” Lee said.

Patients who were randomized to BAT, and who either had an inadequate response, experienced a flare, or who could not tolerate BAT, were allowed to cross over to the ruxolitinib arm after week 24.

The primary end point was ORR, defined as complete or partial response, which was assessed at week 24. There were also 2 key secondary end points. The first was FFS, defined as the time until the need for additional systemic treatment for cGVHD, relapse, or death. The second was symptom burden, defined by the modified Lee Symptom Scale (mLSS).

Patient characteristics at baseline were balanced between the 2 arms. Specifically, patients in both arms had similar ages, sex, and cGVHD severity, with more than half of patients in each arm experiencing severe disease. Patients were also similar regarding refractory or steroid dependent cGVHD and in terms of time from cGVHD onset to randomization, the stem cell source, the donor type, and the donor and recipient cytomegalovirus match.

At the time of primary analysis at week 24, patient disposition demonstrated that about half (50.3%) of patients in the ruxolitinib group were still receiving the agent, whereas 49.7% had stopped treatment. The primary reason for ruxolitinib discontinuation was adverse events (AEs) and lack of efficacy. In contrast, in the BAT group, 25.6% of patients were still on treatment, whereas 74.4% of patients had discontinued therapy primarily because of lack of efficacy.

“In all, 37.2% of patients who were randomized to BAT crossed over to the ruxolitinib arm,” Lee said.

The ORR was significantly higher in the ruxolitinib arm compared with BAT. Specifically, 49.7% of patients in the ruxolitinib arm responded, including 43% who had a partial response, and 6.7%, who had a complete response. In the BAT arm, 25.6% of people responded with 22.6% of patients having a partial response and 3% having a complete response.

“This resulted in an odds ratio of 2.99, which was highly statistically significant in favor of the ruxolitinib arm,” Lee said.

Median FFS was longer in the ruxolitinib arm compared with BAT. In the ruxolitinib arm, FFS was not reached compared with 5.7 months for the BAT arm (HR, 0.37; 95% CI, 0.268-0.510; P < .0001). Similarly, the mLSS response in the ruxolitinib arm was greater than that of the BAT arm, with 24.2% of patients in the treatment arm reaching a clinically meaningful decrease in symptoms compared with 11% of patients in the BAT arm (OR, 2.62; 95% CI, 1.42-4.82; P = .0011).

Best overall response was higher in the ruxolitinib arm compared with the BAT arm, 76.4% versus 60.4%. respectively (OR, 2.17; 95% CI, 1.34-3.52) and the median duration of best overall response was 6.24 months in the BAT arm but not reached in the ruxolitinib arm.

Patients in both arms exhibited similar rates of AEs. Any-grade AEs were slightly higher in the ruxolitinib arm (97.6%) versus the BAT arm (91.8%), but rates for grade 3 or higher AEs were 57% in the ruxolitinib arm and 57.6% in the BAT arm. Serious AEs were higher in the BAT arm (36.7%) compared with the ruxolitinib arm (33.3%). Rates of death up to data cutoff were also similar. In the ruxolitinib arm, risk of death was 18.8% versus 16.5% in the BAT arm.

Regarding AEs that occurred in more than 10% of patients by data cutoff, cytopenias were the most common AEs in the ruxolitinib arm. In the ruxolitinib arm, any-grade anemia was 29.1% and grade 3 or greater anemia was 12.7%. In the BAT arm, any-grade anemia was 12.7% and grade 3 or greater anemia was 7.6%. In the ruxolitinib arm, 21.2% of patients had any-grade thrombocytopenia and 15.2% had grade 3 or greater. In the BAT arm, 14.6% had any-grade thrombocytopenia, whereas 10.1% had grade 3 or greater.

Lee said there were no difference between the 2 arms in terms of gastrointestinal AEs, infections, laboratory abnormalities, or other AEs.

Viral infections were the most common type of infection with 33.9% of patients in the ruxolitinib arm and 29.1% in the BAT arm observed. Overall, 27.9% of patients in the ruxolitinib arm and 25.9% of the BAT arm reported bacterial infections and 11.5% of patients in the ruxolitinib arm and 5.7% in the BAT arm reported fungal infections. Regarding cytomegalovirus infection/reactivation, Lee said that 5.5% of patients in the ruxolitinib arm and 8.2% of patients in the BAT arm experienced this AE.

“Importantly, the safety profile of ruxolitinib was consistent with previous observations and with what is expected in patients with cGVHD,” said Lee.

The phase 3 REACH3 trial met all its end points with ruxolitinib exhibiting higher ORRs, improvement in FFS, greater symptom improvement, and a longer duration of response compared with BAT, Lee concluded.

_REFERENCES:

_{1. Lee S. Ruxolitinib vs best available therapy in patients with glucocorticoid-refractory chronic graft-vs-host disease: primary findings from the phase 3, randomized REACH3 study. Presented at: 2021 Transplantation and Cellular Therapy Meetings; February 8-12, 2021; virtual. Abstract 82.}

_{2. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565-2579. doi:10.1056/NEJMra1703472}

_{3. Axt L, Naumann A, Toennies J, et al. Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2019;54(11):1805-1814. doi:10.1038/s41409-019-0544-y}