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Ruxolitinib-azacytidine combination shows ‘synergistic efficacy’ for myelofibrosis
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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:
Naval Daver, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0428, Houston, Texas; email: ndaver@mdanderson.org.
Disclosures: Verstovsek reports research funding from and a consultant role with Incyte. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Myelofibrosis, whether primary or having evolved from pre-existing polycythemia vera or essential thrombocythemia, remains a difficult therapeutic challenge in 2018. The burden of a patient having myelofibrosis — a clonal progressive myeloproliferative neoplasm — can be multifaceted and include frequently problematic splenomegaly, difficult myelofibrosis-associated symptoms (splenomegaly, pruritus, bone pain, fatigue, night sweats and pathologic weight loss), cytopenias with associated complications (primarily anemia and thrombocytopenia), and premature death through either progressive debilitation from myelofibrosis or from evolution to high-risk acute myeloid leukemia.
The clinical management of myelofibrosis in 2018, according to current National Comprehensive Cancer Network guidelines, is either allogeneic stem cell transplant for good candidates of intermediate or high risk, or the JAK1/JAK2 inhibitor ruxolitinib, the sole approved agent for this indication for over 6 years. Whereas allogenic stem cell transplant has been utilized by less than 10% of patients with myelofibrosis for many reasons, the benefits of ruxolitinib have been several, including decreased myelofibrosis-associated symptoms, improvements in splenomegaly and prolonged survival. Despite the numerous benefits of ruxolitinib, limitations include the lack of a “plateau” to myelofibrosis survival with the agent, as well as an inability to avoid progression to AML.
Combination therapies, with a ruxolitinib backbone, have been of great interest in myelofibrosis to augment the benefits of therapy in either an additive or synergistic fashion. Combination approaches have included agents to improve anemia — danazol, lenalidomide (Revlimid, Celgene), sotatercept (ACE-011; Acceleron Pharma, Celgene) or luspatercept (ACE-536; Acceleron Pharma, Celgene) — novel pathway inhibitors (PI3 kinase, PIM kinase, etc), as well as other approaches.
The recently published manuscript in Blood by Masarova and colleagues relays the successful experience of the combination of the hypomethylating agent azacitidine with ruxolitinib. These trial results are noteworthy for several reasons, including the practical applicability by commercial availability of azacitidine, as well as activity of that agent in myelodysplastic syndrome-associated cytopenias and delay in transformation to AML. First, their experience suggested patients did better by addition of azacitidine after a 3-month run-in of ruxolitinib, perhaps helping to decrease cytopenias at onset. Second, they demonstrated the additive value of azacitidine by one-third of their responses occurring only after starting azacitidine. Third, in a nonrandomized fashion, the rates of overall response, as well as decreases in bone marrow fibrosis, suggested the combination is likely superior to ruxolitinib alone compared with historical data.
These aggregate data suggest this combination is worthy of further testing with natural groups for consideration, including those with higher-risk disease (in nontransplant candidates), greater baseline splenomegaly, only a partial response after 3 months of ruxolitinib and increased blasts as baseline. NCCN guidelines for myelofibrosis do include the addition of azacitidine to ruxolitinib in advanced patients, with increasing blasts, who do not have access to clinical trials. Further delineation of the exact extent — and candidates — for consideration of combination ruxolitinib-azacitidine will need to be determined through further prospective clinical trials.
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