FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease

Abstract

On May 24, 2019, the Food and Drug Administration approved ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in adult and pediatric patients 12 years and older. Approval was based on Study INCB 18424-271 (REACH-1; NCT02953678), an open-label, single-arm, multicenter trial that included 49 patients with grades 2-4 SR-aGVHD occurring after allogeneic hematopoietic stem cell transplantation. Ruxolitinib was administered at 5 mg twice daily, with dose increases to 10 mg twice daily permitted after 3 days in the absence of toxicity. The Day-28 overall response rate was 57.1% (95% confidence interval [CI]: 42.2-71.2). The median duration of response was 0.5 months (95% CI: 0.3-2.7), and the median time from Day-28 response to either death or need for new therapy for acute GVHD was 5.7 months (95% CI: 2.2 to not estimable). Common adverse reactions included anemia, thrombocytopenia, neutropenia, infections, edema, bleeding, and elevated transaminases. Ruxolitinib is the first drug approved for treatment of SR-aGVHD. The Oncologist 2020;25:e328-e334Implications for Practice: Ruxolitinib is the first Food and Drug Administration-approved treatment for steroid-refractory acute graft-versus-host disease in adult and pediatric patients 12 years and older. Its approval provides a treatment option for the 60% of those patients who do not respond to steroid therapy.

Ruxolitinib in children with steroid‐refractory acute graft‐versus‐host disease: A retrospective multicenter study of the pediatric group of SFGM‐TC

“…A response rate of 81% in aGVHD was achieved in this study leading to promises. In May 2019, the Food and Drug administration approved ruxolitinib for steroid‐refractory aGVHD in adult and pediatric patients 12 years older based on REACH‐1 (NCT02953678) study, which showed a day‐28 overall response rate (primary endpoint) of 57.1% (95% CI, 42.2‐71.2) 13 …”

Acute Graft‐versus‐Host Disease: Emerging Insights and Updates into Detection, Prevention, and Treatment

“…The FDA-adjudicated ORR at day 28 (excluding patients who had received any other systemic therapy, n=49) was similar to the full population at 57.1% (95% CI 42.2-71.2%). 58 Six-month OS in day-28 responders (n=39) was 73.2% (95% CI 55.9-84.6%) compared with other responders (n=13) at 35.9% (95% CI 11.7-61.3%) and nonresponders (n=19) at 15.8% (95% CI 3.9-34.9%). At day 28, among patients with any response on combination therapy (n=43), 55.8% (n=24) reduced their steroid dose by ≥ 50% such that the median corticosteroid dose was 156.3 mg/day on day 1 reduced to a median of 62.5 mg/day by day 28.…”

“…57 Steroid-Refractory Acute GVHD Despite aggressive steroid treatment, response rates are poor, hovering around 40%, and most patients require second-line therapy. 16,58 Indications for an additional agent include GVHD progression after 3 days of steroids, persistent grade III GVHD not improving after 7 days of steroid, persistent grade GVHD not improving after 14 days of steroid, or inability to tolerate steroid taper. 16 Until recently, there was no standard treatment for steroid-refractory disease.…”

“…59 In May 2019, the FDA approved the first agent for this indication, ruxolitinib, an oral inhibitor of the tyrosine kinases Janus associated kinase (JAK)1 and JAK2 based on results of the REACH-1 study. 58,60 JAKs and its associated signal transducer and activator of transcription contribute to cytokine receptor signaling and the inflammatory process of acute GVHD, thus the JAK-signal transducer and activator of transcription pathway is an ideal target to block. 58 REACH-1 was a single-cohort phase II study (clinicaltrials.gov; NCT02953678) evaluating the efficacy of ruxolitinib 5 mg twice/day (or 10 mg twice/day in the absence of cytopenias) in combination with corticosteroids (methylprednisolone 2 mg/kg/day intravenous or prednisone equivalent) in patients with grades II-IV steroidrefractory acute GVHD who had failed no more than 1 other systemic treatment.…”

Metabolic reprogramming augments potency of human pSTAT3–inhibited iTregs to suppress alloreactivity

“…Moreover, pSTAT3-inhibited iTregs preserve donor antileukemia activity necessary for the beneficial graft-versus-leukemia effect. Despite recent FDA approvals for agents to treat steroid refractory acute (60) and chronic GVHD (61), advances in GVHD prevention are needed. Additionally, innovative approaches are needed in solid-organ allotransplantation to reduce dependence on broadly suppressive calcineurin inhibitors and glucocorticoids.…”