The FDA has approved ruxolitinib (Jakafi®, Incyte Corporation), a JAK1/JAK2 inhibitor, for the treatment of steroid-refractory acute graft-versus-host disease (GVHD) in adults and in children age 12 and older.
Graft-versus-host disease is a complication of allogeneic hematopoietic stem cell transplantation (HSCT), a procedure involving the transfer of stem cells from a healthy donor to a patient with a hematologic malignancy following high-intensity chemotherapy or radiation. In GVHD, the donated stem cells view the patient's healthy cells as foreign invaders and therefore attack the patient's organs and tissues. This condition can range in severity from mild to life-threatening.
Ruxolitinib was approved following a priority review based on the phase 2 REACH1 trial (NCT02953678), which enrolled patients with steroid-refractory grade 2 to 4 acute GVHD, graded according to the Mount Sinai Acute GVHD International Consortium criteria, following allogeneic HSCT. Patients were excluded from the trial if they had undergone more than one allogeneic HSCT, if they were receiving more than one systemic treatment in addition to corticosteroids for acute GVHD, if they had chronic GVHD including overlap syndrome, or if they had severe organ failure, relapse of their primary disease, splenectomy, active uncontrolled infection, treatment with corticosteroids within seven days of enrollment for any indications besides GVHD, JAK inhibitor treatment following allogeneic HSCT, or any other investigational treatment with 21 days or five half-lives of enrollment.
The trial's primary end point was overall response rate—defined as the proportion of patients with a complete response, very good partial response, or partial response—at day 28. The key secondary end point was six-month duration of response. The trial enrolled 71 patients, including 49 who were refractory to steroids alone, 12 with at least two prior anti-GVHD therapies, and 10 who did not meet the FDA criteria for steroid-refractory disease.
Among the 49 patients with steroid-refractory GVHD, at day 28, ruxolitinib produced overall response rates of 100% for grade 2 GVHD, 40.7% for grade 3 GVHD, and 44.4% for grade 4 GVHD. The median duration of response, as calculated from response at day 28 to progression, new salvage therapy, or death from any cause, was 16 days. The median time from ruxolitinib response at day 28 to death or need for either new salvage therapy or increase in steroids was 173 days. Among all 71 study participants, the most common hematologic adverse reactions included anemia (75%), thrombocytopenia (75%), and neutropenia (58%), while the most frequent nonhematologic adverse reactions were infections (55%) and edema (51%).
For patients with GVHD, the recommended starting dose of ruxolitinib is 5 mg, administered orally twice daily.
"The ultimate goal of GVHD therapy is not just to control the disease process, but to facilitate true immunotolerance that will allow patients to be successfully weaned off of therapy without residual GVHD side effects, while maintaining the beneficial [graft-versus-leukemia] effect," state the study authors, led by Madan Jagasia, MBBS, MS, Chief Medical Officer of the Vanderbilt-Ingram Cancer Center, in their publication in Immunotherapy.
"Further advancement of the field will require a well-coordinated, systematic, international effort," the authors conclude. "We expect ruxolitinib will be integrated into this targeted approach as a standard-of-care therapy for [steroid-refractory acute GVHD] and [chronic GVHD] patients."
For More Information
Clinicaltrials.gov (2019). A study of ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute graft-versus-host disease (REACH1). NLM identifier: NCT02953678.
Jagasia M, Zeiser R, Arbushites M, et al (2018). Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials. Immunotherapy, 10(5):391-402. DOI:10.2217/imt-2017-0156
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