In the phase III REACH2 trial reported in TheNew England Journal of Medicine, Robert Zeiser, MD, of the Department of Hematology, Oncology, and Stem Cell Transplantation, University Medical Center Freiburg, Germany, and colleagues found that the JAK1/2 inhibitor ruxolitinib improved response rate vs investigator’s choice of therapy in patients with glucocorticoid-refractory acute graft-vs-host disease after allogeneic stem cell transplantation (SCT).1
Study Details
In the open-label trial, 309 patients aged ≥ 12 years from sites in 22 countries were randomly assigned between April 2017 and May 2019 to receive ruxolitinib at 10 mg twice daily (n = 154) or investigator’s choice of therapy among nine commonly used options (control group, n = 155) for up to 24 weeks. Eligible patients had received allogeneic SCT (any donor source, any stem cell source) and had grade II to IV glucocorticoid-refractory acute graft-vs-host disease requiring the use of systemic immunosuppressive therapy. Randomization was stratified by grade of acute graft-vs-host disease. Treatment options in the control group consisted of antithymocyte globulin, extracorporeal photopheresis, mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil, mTOR inhibitor (everolimus or sirolimus), etanercept, or infliximab.
Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia…than that observed with control therapy.— Robert Zeiser, MD, and colleagues
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The primary endpoint was overall response of graft-vs-host disease at day 28. The key secondary endpoint was durable overall response at day 56. Response was defined as complete or partial vs baseline organ staging without the use of additional systemic therapy. Complete response was defined as a score of 0 for acute graft-vs-host disease grading in all evaluable organs, indicating complete resolution of all signs and symptoms. Partial response was defined as improvement of one stage in one or more involved organs without disease progression in other organs or sites.
For the ruxolitinib vs control groups, the median age was 53 vs 54 years; 60% vs 59% were male; 72% vs 66% were white and 12% vs 19% were Asian. The numbers of patients with grade II, III, and IV acute graft-vs-host disease were 53 vs 53, 71 vs 72, and 30 vs 30.
Among all patients, malignancies included leukemias or myelodysplastic syndrome (MDS) in 81%, including acute myeloid leukemia in 39%, acute lymphoblastic leukemia in 13%, and MDS in 18%; and lymphoproliferative malignancies in 14%, including non-Hodgkin lymphoma in 9% and Hodgkin lymphoma in 3%. The most commonly used therapies in the control group (patients could receive more than one option) were extracorporeal photopheresis (31%), mycophenolate mofetil (22%), etanercept (21%), and antithymocyte globulin (16%).
Response Rates
Response at day 28 was observed in 96 patients (62%) in the ruxolitinib group vs 61 patients (39%) in the control group (odds ratio [OR] = 2.64, P < .001), with a complete response observed in 53 patients (34%) vs 30 patients (19%). By baseline grade, overall response rates were 75% vs 51% among patients with grade II (OR = 2.96, 95% confidence interval [CI] = 1.30–6.76), 56% vs 38% among those with grade III (OR = 2.15, 95% CI = 1.10–4.20), and 53% vs 23% among those with grade IV acute graft-vs-host disease (OR = 3.76, 95% CI = 1.24–113.8).
Durable response at day 56 was observed in 40% vs 22% of patients (OR = 2.38, P < .001), including durable complete response in 27% vs 16%. Response at any time up to and including day 28 and before the start of additional systemic therapy was observed in 82% vs 61% of patients (OR = 3.07, 95% CI = 1.80–5.25).
The estimated cumulative incidence of loss of response at 6 months was 10% vs 39%. By day 56, 21% vs 14% had discontinued glucocorticoid treatment. Median failure-free survival was 5 months vs 1 month, with the hazard ratio for relapse or progression of hematologic disease, non-relapse–related death, or addition of new systemic therapy for acute graft-vs-host disease (failure events) being 0.46 (95% CI = 0.35–0.60); the cumulative incidence of these events was 18% vs 49% at 28 days and remained lower in the ruxolitinib group at all time points through 18 months (61% vs 82% at 18 months). At 18 months, the cumulative incidence of cancer relapse or disease progression was 19% vs 13%, and the cumulative incidence of non-relapse–related mortality was 49% vs 51%. Median overall survival was 11.1 months vs 6.5 months (HR = 0.83, 95% CI = 0.60–1.15). Death attributed to acute graft-vs-host disease occurred in 22% vs 25% of patients.
Adverse Events
The median duration of exposure to study therapy was 63 days (range = 6–396 days) in the ruxolitinib group and 29 days (range = 1–188 days) in the control group.
Through day 28, the most common adverse events of any grade in the ruxolitinib group were thrombocytopenia (33% vs 18% in the control group; grade ≥ 3 in 27% vs 15%), anemia (30% vs 28%; grade ≥ 3 in 22% vs 19%), and cytomegalovirus infection (26% vs 21%; grade ≥ 3 in 7% vs 8%). Grade ≥ 3 infections occurred in 22% vs 19% of patients by day 28 and in 37% vs 28% by data cutoff (July 2019). At data cutoff, grade ≥ 3 bleeding had occurred in 12% vs 7% of patients. Serious adverse events occurred in 38% vs 34% of patients. Up to day 28, adverse events led to treatment discontinuation in 11% vs 5% of patients.
The investigators concluded: “Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy.”
DISCLOSURE: Dr. Zeiser has received speaker fees from Novartis, Incyte, and Mallinckrodt. For full disclosures of the study authors, visit nejm.org.
REFERENCE
1. Zeiser R, von Bubnoff N, Butler J, et al: Ruxolitinib for glucocorticoid-refractory acute graft-vs-host disease. N Engl J Med 382:1800-1810, 2020.
