Clinical Pearls & Morning Reports

Posted by Carla Rothaus

Published May 6, 2020


Was ruxolitinib an effective therapy for glucocorticoid-refractory acute graft-versus-host disease in the trial by Zeiser et al.? 

Graft-versus-host disease (GVHD) is a significant cause of death in patients undergoing allogeneic stem-cell transplantation. Read the NEJM Original Article here.

Clinical Pearls

Q: What is the standard first-line treatment for acute GVHD?

A: A major limitation of allogeneic stem-cell transplantation is acute GVHD, a condition in which donor T cells attack host tissue, affecting multiple organs, particularly the skin, liver, and gastrointestinal tract. Standard first-line treatment is systemic, high-dose glucocorticoids; however, response ranges from approximately 60% in patients with grade II disease to 30 to 40% in patients with grade IV disease. For patients with glucocorticoid-refractory acute GVHD, no consensus exists regarding treatment, and outcomes remain poor. 

Q: Why might ruxolitinib be an effective treatment for GVHD?

A: Ruxolitinib is an oral selective inhibitor of JAK1 and JAK2 that reduces the incidence and severity of GVHD in vivo while preserving graft-versus-leukemia effects in preclinical models. The Janus kinase (JAK) and signal transducers and activators of transcription (STAT) signaling pathways play an important role in immune-cell activation and tissue inflammation during acute GVHD, including the activity of dendritic cells and neutrophil granulocytes. Tissue damage that is associated with acute GVHD is driven by inflammatory cytokines, the effects of which are mediated in part by JAKs.

Morning Report Questions 

Q: Was ruxolitinib an effective therapy for glucocorticoid-refractory acute GVHD in the trial by Zeiser et al.?

A: The primary end point was overall response at day 28, which was defined as the proportion of patients who had a complete response or partial response as compared with baseline organ staging without the use of additional systemic therapy for acute GVHD. The key secondary end point was durable overall response at day 56, which was defined as the proportion of patients in each treatment group who had response at day 28 that was maintained at day 56. Ruxolitinib therapy was associated with a significantly higher overall response at day 28 than control therapy, and the durable overall response at day 56 was also significantly higher in the ruxolitinib group than in the control group. Ruxolitinib therapy was also associated with a longer duration of response than control therapy and a longer treatment failure-free survival. Overall survival data at this point (data cutoff at day 56) are not sufficiently mature to allow conclusions to be drawn regarding survival benefit. However, the percentage of patients who died from acute GVHD did not differ substantially between the groups. 

Q: What adverse events were among the most common in association with ruxolitinib in the trial by Zeiser et al.?

A: The safety profile of ruxolitinib in this trial was consistent with the known safety profile of ruxolitinib and was as expected in patients with glucocorticoid-refractory acute GVHD. The most common events (of any grade and of grade ≥3) up to day 28 were thrombocytopenia, anemia, and cytomegalovirus infection.

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