Treatment with ruxolitinib plus azacytidine yielded encouraging spleen response rates and improvement in bone marrow fibrosis among patients with myelofibrosis, according an open-label, single-arm phase 2 study.
Ruxolitinib (Jakafi, Incyte) is a first-in-class JAK1/JAK2 inhibitor approved for treatment of patients with intermediate- or high-risk myelofibrosis.
“Although ruxolitinib affords benefits in a majority of patients with myelofibrosis, activation in non-JAK pathway could lead to therapeutic resistance, suggesting a need for rationally developed combinations,” Srdan Verstovsek, MD, PhD, medical oncologist and professor in the department of leukemia at The University of Texas MD Anderson Cancer Center and a HemOnc Today Editorial Board Member, and colleagues wrote. “We hypothesized that the combination of azacytidine and ruxolitinib would target distinct clinical and pathological manifestations of myelofibrosis, resulting in synergistic efficacy.”
Verstovsek and colleagues assessed the combination in patients with intermediate- or high-risk primary myelofibrosis (n = 25), post-polycythemia vera myelofibrosis (n = 10) or post-essential thrombocythemia (n = 11) at a single institution.
“We and other groups have tried to develop combinatorial approaches by adding agents with known activity in myelofibrosis to ruxolitinib to attempt to improve the depth and duration of response, and potentially improve other myelofibrosis features such as cytopenias and bone marrow fibrosis,” Naval Daver, MD, associate professor in the leukemia department at MD Anderson Cancer Center, told HemOnc Today. “Azacytidine is well tolerated and has shown activity in myelodysplastic syndrome, acute myeloid leukemia and in myelofibrosis in a phase 1 study prompting evaluation of this combination.”
Patients received ruxolitinib twice daily in 28-day cycles for the first three cycles and azacytidine 25 mg/m2 on days 1 through 5 starting in cycle 4. Azacytidine dosing could be increased to 75 mg/m2.
Median follow-up was 28 months (range, 4-50).
Seventy-two percent of patients achieved response using International Working Group for Myelofibrosis Research and Treatment criteria. Two patients had partial remission and 31 had clinical improvement.
Median time to response was 1.8 months (range, 0.7-19).
Seven patients responded after the addition of azacytidine, with a median time to response of 4.4 months (range, 0.1-16.5).
Researchers observed more than a 50% reduction in palpable spleen length in 62% of patients at 24 weeks, and 95% maintained this at 48 weeks. The reduction occurred in 71% of patients at any time on the study.
At 24 months, 57% of patients had improvement in bone marrow reticulin fibrosis grade.
Nine percent of patients discontinued treatment due to drug-related toxicities, all cytopenias.
“This is an encouraging finding and different from what has been seen with single-agent ruxolitinib,” Daver told HemOnc Today.
Researchers observed new onset grade 3 or grade 4 anemia among 35% of patients and thrombocytopenia among 26% of patients.
“The study is ongoing and we continue to accrue patients,” Daver said. “The improvements in bone marrow fibrosis are very encouraging. The combination was tolerable with only 9% discontinuing therapy at any time, mainly due to myelosuppression. The results of this study need to be validated in a larger multicenter prospective study, either randomized or nonrandomized. We are also following the patients for survival and this will be updated in the future.” – by Cassie Homer
For more information:
Daver, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0428, Houston, Texas; email: email@example.com.
Disclosures: Verstovsek reports research funding from and a consultant role with Incyte. Please see the study for all other authors’ relevant financial disclosures.