Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial

Abstract

Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.

Conflict of interest statement

Conflict-of-interest disclosure: M.J. reports receiving consulting fees from Incyte Corporation, Kadmon, and Genentech and receiving institutional research support from Mallinckrodt and Janssen. M.-A.P. reports receiving institutional research support for clinical trials from Incyte Corporation; honoraria from AbbVie, Bellicum, Bristol-Myers Squibb, Incyte Corporation, Merck, Novartis, Nektar Therapeutics, and Takeda; serving on data and safety monitoring boards for Servier and Medigene; and serving on scientific advisory boards for MolMed and NexImmune. M.A.S. reports receiving personal fees and research grant support from Incyte Corporation, Amgen, AbbVie, Astellas, Pfizer, Sanofi/Genzyme, Takeda, and Merck; receiving personal fees from Partners Therapeutics, FlatIron, and NovoNordisk; and receiving research grant support from Seattle Genetics, PBD Inc, Genentech, Cellect, Fortis Therapeutics, Bristol-Myers Squibb, and Celgene. H.A. reports receiving consulting fees from Incyte Corporation. N.N.S. reports receiving consulting fees from Incyte Corporation; serving on scientific advisory boards for Kite, Juno, and Cellectar; and receiving institutional research support for clinical trials from Miltenyi Biotec. Y.-B.C. reports receiving consulting fees from Incyte Corporation, Takeda, Magenta, and Kiadis and serving on data and safety monitoring boards for Actinium, Equillium, and AbbVie; S.F. reports receiving personal fees and other support for serving on advisory boards and speakers’ bureaus for Amgen, Incyte Corporation, Jazz Pharmaceuticals, Gilead, GlaxoSmithKline, Novartis, Bristol-Myers Squibb, and Pfizer; and receiving personal fees and other support for serving on a speakers’ bureau for Stemline Pharmaceuticals, Janssen Pharmaceuticals, Takeda Pharmaceuticals, and Karyopharm. F.W.D., M.C.A., and C.T. report employment by and stock ownership in Incyte Corporation. M.D.H. reports employment by and stock ownership in Incyte Corporation and has a patent pending for Biomarkers for Graft Versus Host Disease. H.J.K. served on an advisory board and received research funding from Incyte Corporation. L.C.-S. declares no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Response outcomes. (A) Duration of response (time from first response until GVHD progression or death) in day 28 responders and other responders (patients who responded at any time during treatment). The data cutoff was 2 July 2018. (B) Subgroup analysis of day 28 ORR. Acute GVHD response was assessed using standardized objective criteria per MAGIC guidelines. *After primary treatment with methylprednisolone ≥2 mg/kg per day. †In another organ in patients who previously received corticosteroids (≥1 mg/kg per day methylprednisolone) for skin or skin plus upper GI GVHD.

Figure 2.

OS and NRM. (A) Kaplan-Meier estimates of OS in patients by response status (day 28 responders, other responders, nonresponders). OS was defined as the time from first ruxolitinib treatment to death for any cause. The data cutoff was 2 July 2018. (B) OS by aGVHD grade at enrollment. aGVHD grade at enrollment was significantly associated with OS by log-rank test in the Kaplan-Meier analysis (P = .021). In model-based analysis of OS by Cox regression, aGVHD grade III/IV was again significantly associated with reduced OS (aGVHD grade III/IV vs grade II [reference]; HR, 0.334; 95% CI, 0.150-0.747; P = .0076). (C) NRM by response status. The 6-month cumulative incidence rate for NRM was 44.4% (95% CI, 32.5%-55.7%) for the entire patient cohort, 21.2% (95% CI, 9.9%-35.2%) for day 28 responders, 64.1% (95% CI, 31.5%-84.3%) for other responders, and 78.9% (95% CI, 53.2%-91.5%) for nonresponders. The 12-month cumulative incidence rate for NRM was 52.9% (95% CI, 39.6%-64.5%) for all patients, 28.2% (95% CI, 14.5%-43.6%) for day 28 responders, and 84.2% (95% CI, 58.7%-94.6%) for nonresponders. The 12-month NRM rate for other responders was not evaluable.

Figure 2.

OS and NRM. (A) Kaplan-Meier estimates of OS in patients by response status (day 28 responders, other responders, nonresponders). OS was defined as the time from first ruxolitinib treatment to death for any cause. The data cutoff was 2 July 2018. (B) OS by aGVHD grade at enrollment. aGVHD grade at enrollment was significantly associated with OS by log-rank test in the Kaplan-Meier analysis (P = .021). In model-based analysis of OS by Cox regression, aGVHD grade III/IV was again significantly associated with reduced OS (aGVHD grade III/IV vs grade II [reference]; HR, 0.334; 95% CI, 0.150-0.747; P = .0076). (C) NRM by response status. The 6-month cumulative incidence rate for NRM was 44.4% (95% CI, 32.5%-55.7%) for the entire patient cohort, 21.2% (95% CI, 9.9%-35.2%) for day 28 responders, 64.1% (95% CI, 31.5%-84.3%) for other responders, and 78.9% (95% CI, 53.2%-91.5%) for nonresponders. The 12-month cumulative incidence rate for NRM was 52.9% (95% CI, 39.6%-64.5%) for all patients, 28.2% (95% CI, 14.5%-43.6%) for day 28 responders, and 84.2% (95% CI, 58.7%-94.6%) for nonresponders. The 12-month NRM rate for other responders was not evaluable.

Figure 3.

Average corticosteroid dose over time. The average corticosteroid dose in milligrams per day at days 1, 14, 28, 56, 100, and 180 is displayed for patients who continued receiving ruxolitinib treatment. Data shown indicate median (horizontal line), mean (diamond), 75th and 25th quartiles (upper and lower boundaries, respectively), and minimum (lower error bar)/maximum (upper error bar).