Jakafi remains the mainstay for treating myelofibrosis (MF) patients with symptomatic splenomegaly and constitutional symptoms. There remains an unmet need to improve response rates and or the durability of benefit. Resistance to Jakafi could be primary with lack of initial response or secondary failure losing the response. A subset of patients also achieves suboptimal responses.
Navitoclax is a novel small-molecule that targets and binds with high affinity to multiple anti-apoptotic B-cell lymphoma 2 (BCL2) family proteins. Preclinical studies show cytotoxic activity of navitoclax against myeloproliferative neoplasm-derived cell lines. Researchers evaluated the combination of navitoclax with Jakafi in patients with MF.
Results from a phase II study of Navitoclax combined with Jakafi in patients with myelofibrosis was conducted and results updated at American Society of Hematology. Eligible received at least 12 weeks of continuous Jakafi therapy followed by a starting dose of 50 mg navitoclax once-daily combined with the current stable dose of Jakafi. Weekly intra-patient dose-escalation of navitoclax was allowed to a maximum daily dose of 300 mg based on tolerability and platelet count. The study enrolled 34 patients with a median age of 68. Patients had a median duration of prior Jakafi exposure of 745 days and over half had high molecular risk mutations.
At the time of this analysis, 24 patients were evaluable. Overall, the therapy was well tolerated, and a majority of patients experienced symptomatic improvement; 29% of patients achieved a spleen volume reduction 42% and a decrease in cancer driver mutations observed in 42% of patients. Twenty-nine percent of patients experienced improvements in bone marrow fibrosis of at least 1 grade at any time.
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Navitoclax in combination with Jakafi was well tolerated with clinically meaningful spleen responses, allelic burden reductions, TSS improvements, and encouraging improvements in bone marrow fibrosis in paients with MF who have received prior treatment with Jakafi. The combination is moving forward in a Phase 3 Study comparing navitoclax and Jakafi to best available therapy in MF patients (TRANSFORM-2)