Ruxolitinib effective, safe for glucocorticoid-refractory acute GVHD
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Ruxolitinib appeared to be more effective than common treatments for patients with glucocorticoid-refractory acute graft-versus-host disease, according to results of a randomized phase 3 study published in The New England Journal of Medicine.
“So far, there is no standard treatment for patients with GVHD who do not respond to glucocorticoid,” Robert Zeiser, MD, professor of hematology and oncology at University Medical Center Freiburg in Germany, told Healio. “I am convinced that ruxolitinib will become the standard therapy for these patients.”
About half of allogeneic stem cell transplant recipients develop GVHD, which is a substantial cause of death among these patients, according to study background.
A previous phase 2 trial showed ruxolitinib (Jakafi, Incyte), a selective Janus kinase (JAK1 and JAK2) inhibitor, may be effective for patients with glucocorticoid-refractory acute GVHD.
In the current multicenter, open-label trial, Zeiser and colleagues randomly assigned 309 patients (median age, 54 years; range, 12-73) with glucocorticoid-refractory acute GVHD after allogeneic stem cell transplantation to oral ruxolitinib dosed at 10 mg twice daily (n = 154) or to investigator’s choice of therapy from a list of nine commonly used medications (control group; n = 155).
The control therapies included antithymocyte globulin, extracorporeal photopheresis, mesenchymal stromal cells, low-dose methotrexate, mycophenolate mofetil, everolimus (Afinitor, Novartis), sirolimus, etanercept and infliximab.
Overall response at day 28 served as the study’s primary endpoint. Durable overall response at day 56 served as a secondary endpoint.
Median follow-up was 5.04 months for the ruxolitinib group and 3.58 months for the control group.
Results showed a superior ORR in the ruxolitinib group at day 28 compared with the control group (62% vs. 39%; OR = 2.64; 95% CI, 1.65-4.22). Forty-nine patients crossed over to ruxolitinib on or after day 28.
The ruxolitinib group also had a higher rate of durable overall response at day 56 vs. the control group (40% vs. 22%; OR = 2.38; 95% CI, 1.43-3.94).
Researchers reported an estimated cumulative incidence of loss of response of 10% in the ruxolitinib group and 39% in the control group at 6 months. Additionally, researchers observed longer median failure-free survival with ruxolitinib compared with the control therapies (5 months vs. 1 months; HR = 0.46; 95% CI, 0.35-0.6 for relapse or progression of hematologic disease, nonrelapse-related death, or addition of new systemic therapy for acute GVHD).
Moreover, the ruxolitinib group experienced longer median OS than the control group (11.1 months vs. 6.5 months; HR = 0.83; 95% CI, 0.6-1.15).
Common adverse events up to day 28 included thrombocytopenia (33% ruxolitinib group vs. 18% control group), anemia (30% vs. 28%) and cytomegalovirus infection (26% vs. 21%).
“The results of this trial support previously reported findings with ruxolitinib in patients with glucocorticoid-refractory acute GVHD,” Zeiser and colleagues wrote. “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.”
Potential targets of ruxolitinib include neutrophils, macrophages and dendritic cells in which JAK1 and JAK2 mediate signaling, Nelson Chao, MD, professor of medicine, immunology and pathology and chief of the division of cell therapy at Duke University School of Medicine, wrote in an accompanying editorial. Previous studies have suggested neutrophils play a key role in the pathogenesis of acute GVHD, and ruxolitinib has demonstrated an ability to prevent the upregulation of several proinflammatory cytokines in human macrophages, Chao noted.
“Cytokine regulation contributes to the anti-inflammatory effect of ruxolitinib,” he wrote. “Another important open question concerns the effect of ruxolitinib on the B-cell population, since optimal B-cell activity requires a complex interplay of inputs from a variety of T cells, including effector T cells and regulatory T cells. Given the effect of ruxolitinib in controlling glucocorticoid-refractory GVHD, it is interesting that the incidence of infectious complications or relapse was apparently not greater with ruxolitinib than with control therapy, but the total follow-up time was short. Thus, as with all good research, these observations raise important questions and set the stage for further work in this area.” – by John DeRosier
For more information:
Robert Zeiser, MD, can be reached at robert.zeiser@uniklinik-freiburg.de.
Disclosures: Novartis supported this study. Zeiser reports personal fees from Incyte, Mallinckrodt and Novartis. Please see the study for all other authors’ relevant financial disclosures. Chao reports research funding and personal fees from Jazz Pharmaceuticals and Takeda, and research funding from Incyte and Novartis.
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Chao N. N Engl J Med. 2020:doi:10.1056/NEJMe2003331.
Zeiser R, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1917635.
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