Ruxolitinib plus steroids for acute graft versus host disease: a multicenter, randomized, phase 3 trial

Abstract

Newly diagnosed patients with high-risk acute graft-versus-host disease (aGVHD) often experience poor clinical outcomes and low complete remission rates. Ruxolitinib with corticosteroids showed promising efficacy in improving response and failure free survival in our phase I study. This study (ClinicalTrials.gov: NCT04061876) sought to evaluate the safety and effectiveness of combining ruxolitinib (RUX, 5 mg/day) with corticosteroids (1 mg/kg/day methylprednisolone, RUX/steroids combined group) versus using methylprednisolone alone (2 mg/kg/day, steroids-only group). Newly diagnosed patients with intermediate- or high-risk aGVHD were included, with risk levels classified by either the Minnesota aGVHD Risk Score or biomarker assessment. Patients were randomized in a ratio of 1:1 into 2 groups: 99 patients received RUX combined with methylprednisolone, while the other 99 received methylprednisolone alone as the initial treatment. The RUX/steroids group showed a significantly higher overall response rate (ORR) on day 28 (92.9%) compared to the steroids-only group (70.7%, Odds Ratio [OR] = 5.8; 95% Confidence Interval [CI], 2.4-14.0; P < 0.001). Similarly, the ORR on day 56 was higher in the RUX/steroids group (85.9% vs. 46.5%; OR = 7.07; 95% CI, 3.36-15.75; P < 0.001). Additionally, the 18-month failure-free survival was significantly better in the RUX/steroids group (57.2%) compared to the steroids-only group (33.3%; Hazard Ratio = 0.46; 95% CI, 0.31-0.68; P < 0.001). Adverse events (AEs) frequencies were comparable between both groups, with the exception of fewer grade 4 AEs in the RUX/steroids group (26.3% vs. 50.5% P = 0.005). To our knowledge, this study is the first prospective, randomized controlled trial to demonstrate that adding ruxolitinib to the standard methylprednisolone regimen provides an effective and safe first-line treatment for newly diagnosed high-risk acute GVHD.

Fig. 1

Study design and consort diagram. a Flow chart of treatment schedule. Newly diagnosed intermediate or high-risk acute graft-versus-host disease (aGVHD) patients underwent randomization and treatment of RUX/steroids combined or steroids only regimen after aGVHD risk evaluation. The medication of conditioning, GVHD prophylaxis regimen, and taper process of aGVHD treatment were described detail in “Methods”. Patients were monitored for safety, treatment response, and clinical endpoints. “Day”, “Week”, and “Year” referred to time after aGVHD treatment. b Enrollment of patients into the study. ATG anti-thymocyte globulin; CMV cytomegalovirus; CsA cyclosporine A; DLI donor lymphocyte infusion; EBV Epstein–Barr virus; GVHD graft versus host disease; MRD measurable residual disease; PTLD post-transplantation lymphoproliferative disorder; RUX ruxolitinib

Fig. 2

Overall response at day 28 and day 56. The primary endpoint was an overall response (complete or partial response) on day 28 (a), and the secondary endpoint was a overall response on day 56 (b). Two-sided P values were calculated using a stratified Cochran–Mantel–Haenszel test

Fig. 3

Duration of response (a) and failure-free survival (b)