Ruxolitinib plus etanercept showed positive results for the treatment of steroid-refractory severe acute graft-versus-host disease.
A new study is making the case for using ruxolitinib in combination with etanercept for the treatment of steroid-refractory severe acute graft-versus-host disease (SR-aGHVD), which affects approximately half of patients with severe aGVHD, a significant cause of morbidity and mortality after allogeneic stem cell transplantation (allo-SCT).
The treatment combination showed promising results in 64 patients with grade 3-4 SR-aGVHD after allo-SCT, with 61.2% of patients still alive at 2 years.
With a historical 6-month survival rate of approximately 49% and long-term survival rates ranging from just 5% to 30% among patients with SR-aGVHD, the study findings could have important implications as researchers try to pinpoint an effective treatment for these patients who show resistance to first-line steroids.
“There is preclinical evidence that interferon-gamma receptor (INFγR) pathway mediated by Janus kinase (JAK) signaling is predominantly involved in GVHD,” explained the researchers of the current study. “And, JAK1/2 inhibition does not impair the acquisition of donor T-cell alloreactivity and preserve the beneficial graft vs leukemia (GvL) effective in vivo. This suggests a potential role of ruxolitinib, a selective JAK 1/2 inhibitor in the prevention treatment of GVHD.”
Building off this preclinical evidence, the researchers conducted their phase 2 multicenter study in which patients received ruxolitinib and etanercept after failing to respond to corticosteroids. Most of these patients (76.6%) had aGVHD involving at least 2 of their organs, including the skin (57 patients), the gut (47 patients), and the liver (35 patients).
The treatment combination elicited a response in an overwhelming majority of patients, with an overall response rate of 87.5% by day 28. The responses included 47 (73.4%) complete responses (CRs) and 9 (14.1%) partial responses (PRs).
The researchers noted that this was higher than the ORR seen with ruxolitinib monotherapy in the REACH-1 study. In addition to adding a second immunosuppressive drug, the current study had a younger group of patients than the REACH-1 trial (median 29 years versus 58 years, respectively), which could explain the differences in response rates.
By day 56 in the current study, there were 52 patients still alive, 45 of which had a CR; this included 2 patients who evolved from a PR to a CR.
“Using univariate and multivariate analysis, we found three elements that may impair the response to this anti-GVHD regimen, gut Enterobacteriaceae colonization, delayed therapy, and development of stages 3-4 liver GVHD,” wrote the researchers. “Gut Enterobacteriaceae colonization makes this anti-GVHD treatment more complicated, probably because ruxolitinib itself induces infectious tolerance, quickly worsens the gut infection and sometimes causes bloodstream infection, which was seen in seven cases in our cohort.”
During the course of therapy, 39.1% of patients experienced at least 1 severe infectious episode, of which pulmonary infections were most frequent (23.4%), followed by bacterial infections, invasive pulmonary fungal diseases, cytomegalovirus pneumonia, and miliary tuberculosis.
The most common hematologic toxicity was grade 2-4 cytopenia, which was reversible by GVHD recovery or by tapering of ruxolitinib. Any grade anemia, leukopenia, or thrombocytopenia occurred in 51.6%, 43.8%, and 50.0% of patients, respectively. Severe anemia, leukopenia, or thrombocytopenia (grades 3-4) occurred in 29.7%, 26.6%, and 39.1%, respectively.
The researchers noted that cytopenias preceded the treatment combination in nearly half of the patients. Additionally, the rate of cytopenias was not unexpectedly high, leading the researchers to believe it was more related to GVHD itself and subsequent infections.
Reference
Zhao Y, Hengwei Wu, Shi J, et al. Ruxolitinib combined with etanercept induce a rapid response to corticosteroid-refractory severe acute graft vs host disease after allogeneic stem cell transplantation: Results of a multi- center prospective study. Am J Hematol. Published online June 8, 2020. doi: 10.1002/ajh.25898.
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