Ruxolitinib in Combination with Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Vs-Host Disease: Results from the Phase 2 REACH1 Trial

Abstract

Introduction Acute graft-vs-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Less than 50% of patients (pts) achieve sustained responses with first-line corticosteroid (CS) treatment. Retrospective studies demonstrated clinical benefit with the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib (RUX) in pts with steroid-refractory (SR) aGVHD. Objectives To present updated results from REACH1 (NCT02953678), a phase 2 trial evaluating RUX plus CS in SR aGVHD. Methods REACH1 was a single-arm, open-label, multicenter study. Eligible pts were aged ≥12 years and developed grade II–IV SR aGVHD following allo-HSCT from any donor source for hematologic malignancies. SR aGVHD was defined as GVHD that progressed after 3 days or had not improved after 7 days of primary treatment with methylprednisolone ≥2 mg/kg/d (or equivalent), development of GVHD in another organ after receiving ≥1 mg/kg/d methylprednisolone for skin or skin plus upper gastrointestinal GVHD, or inability to tolerate CS taper. Pts received RUX 5 mg twice daily (BID), with optional increase to 10 mg BID in the absence of cytopenias. The primary endpoint was Day 28 overall response rate (ORR), and the key secondary endpoint was 6-month duration of response (DOR). ORR was defined as the proportion of patients demonstrating a complete response (CR), very good partial response, or partial response. Results The study enrolled 71 pts. Median age was 58 years, and 49.3% were male. Treatment was ongoing in 11 pts (15.5%) at data cutoff (2 Jul 2018). At Day 28, ORR was 54.9% (CR, 26.8%). Responses were observed irrespective of aGVHD grade and SR criteria (Figure 1). Best ORR at any time during treatment was 73.2% (CR, 56.3%). Median (range) time to response was 7 (6–49) days. Median DOR with minimum 6 months follow-up was 345 days for both Day 28 responders (Figure 2) and for pts who had a best overall response at any time during treatment . Four pts (5.6%) had malignancy relapse. Nonrelapse mortality at 6 months was 44.4%. Median overall survival had not been reached for Day 28 responders (Figure 3). The most frequently reported hematologic treatment-emergent adverse events (TEAEs) were anemia (64.8%), thrombocytopenia (62.0%), and neutropenia (47.9%). Cytomegalovirus infection (12.7%), sepsis (12.7%), and bacteremia (9.9%) were the most frequently reported infections. Fatal RUX-related TEAEs were sepsis and pulmonary hemorrhage (1 pt each) and were attributed to both RUX and CS. Conclusion In this first prospective trial of RUX in SR aGVHD, ORR was 54.9% by Day 28 and 73.2% at any time during treatment. Responses were rapid and durable. The AE profile was consistent with expectations for RUX and pts with SR aGVHD. RUX represents a promising therapeutic strategy.