Baricitinib for refractory chronic graft-versus-host disease: results of a phase 1/2 study

ABSTRACT: Refractory chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation remains a leading cause of late morbidity and mortality among transplant survivors. Therapeutic targeting of the Janus kinase (JAK)-STAT pathway has proved to be an effective approach for cGVHD; however, toxicities and short response durability have limited the use of available agents. The safety and efficacy of the JAK 1/2 inhibitor baricitinib were investigated in patients with severe cGVHD refractory to at least 2 lines of therapy. This single-center phase 1/2 study enrolled 24 adult patients who received 2 dose levels (DLs) of baricitinib, 2 and 4 mg daily, in an intrapatient dose escalation study design. No dose-limiting toxicities were observed at either DL. Overall response rate at 6 months was 76.2% (95% confidence interval [CI], 52.8-91.8), with responses observed across all involved organs, including sclerotic skin and pulmonary. Median failure-free survival was 19 months (95% CI, 11-26), with no deaths or malignancy relapse on treatment. Clinically meaningful improvements in patient-reported and functional outcomes were seen in this highly morbid cohort. Immune correlative studies showed that baricitinib induced significant reductions in cytokine-induced signaling (STAT phosphorylation) in both CD4+ and CD8+ T cells and in proinflammatory cytokine secretion. Baricitinib was well tolerated and exhibited a high rate of durable responses in a cohort of patients with severe cGVHD, warranting further evaluation in earlier-line and larger-scale studies. This trial was registered at www.clinicaltrials.gov as NCT02759731.