Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

Abstract

BACKGROUNDAcute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stemcell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODSWe conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTSA total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, nonrelapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONSRuxolitinib 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. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.

Hepatitis E virus is an infrequent but potentially serious infection in allogeneic hematopoietic stem cell transplant recipients

“…Several different therapies have been used over the years with varying efficacy but none of these have been shown to be clearly superior. Ruxolitinib has recently been shown in randomized controlled trials to be more effective than "best available therapy" and is now seen as the primary choice for treatment of steroid refractory acute GVHD 9 . Other promising options are mesenchymal stem cells, especially in children, and photopheresis.…”

Targeting Histone Deacetylases to Modulate Graft-Versus-Host Disease and Graft-Versus-Leukemia

“…JAK inhibition is one of the promising therapeutic strategies in the prevention and treatment of GvHD since pre-clinical animal studies with JAK inhibitors demonstrated a significant reduction of GvHD while maintaining or enhancing immune reconstitution compared to control groups [124,125,149,150]. Consistent with these pre-clinical studies, ruxolitinib was highly effective for steroid-refractory GvHD [151,152]. Similarly, the first prospective clinical trial with a JAK inhibitor, itacitinib (a selective JAK 1 inhibitor; ClinicalTrials.gov #NCT03139604), demonstrated encouraging efficacy in acute GvHD patients [153].…”

Translational and clinical advances in acute graft-versus-host disease

“…Rux was superior in terms of ORR; however, there was no difference in cumulative incidence of 18-month NRM. 91 Infections and cytopenias remain limiting toxicities. The FDA has approved Rux for SR aGvHD.…”