Data from PI3K Inhibition Restores and Amplifies Response to Ruxolitinib in patients with Myelofibrosis

AbstractPurpose: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (PMF), or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F mutant cell lines. Patients and Methods: In a phase I dose-escalation and expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor umbralisib in combination with ruxolitinib in MF patients who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that maximally tolerated dose at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. Results: Thirty-seven MF patients with prior exposure to ruxolitinib were enrolled. 2 patients treated with 800mg umbralisib experienced reversible Grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved complete response (CR), and 12 patients (32%) met the IWG-MRT response criteria of clinical improvement (CI). With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. Conclusions: Adding umbralisib to ruxolitinib in patients was well-tolerated and may re-sensitize MF patients to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors.