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

Refractory chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation remains a leading cause of late morbidity and mortality for transplant survivors. Therapeutic targeting of the JAK-STAT pathway has proved to be an effective approach for cGVHD, however toxicities and short response durability have been limiting use of available agents. The safety and efficacy of the JAK 1/2 inhibitor baricitinib was investigated in patients with severe cGVHD refractory to at least two lines of therapy. This single center phase 1/2 study (NCT0275973) enrolled twenty-four adult patients who received two dose levels of baricitinib of 2- and 4-mg daily in an intra-patient dose escalation study design. No dose limiting toxicities were observed at either dose level. ORR at 6-months was 76.2% (95%CI, 52.8-91.8), with responses observed across all involved organs including sclerotic skin and pulmonary. Median FFS 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 (pSTAT) 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 severely affected cohort of cGVHD patients, warranting further evaluation in earlier line and larger scale studies.