PI3K Inhibition Restores and Amplifies Response to Ruxolitinib in Patients with Myelofibrosis

Abstract

Purpose: 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.

Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms

“…Our multiomic and functional results identified PI3K/AKT/mTOR signaling as a key driver of platelet hyperreactivity in MPNs. The effects of dual PI3K/ mTOR inhibition by omipalisib underscores the essential role of PI3K/AKT/mTOR signaling in mediating platelet metabolism and hyperactivation in MPNs, suggesting potential therapeutic role in MPNs (49,50). We also identified metabolic changes consisting of enhanced OXPHOS and glycolysis activity in MPN platelets.…”

Benefit of Early Ruxolitinib Initiation Regardless of Fibrosis Grade in Patients with Primary Myelofibrosis: A Post Hoc Analysis of the Single-Arm Phase 3b JUMP Study

“…Furthermore, the simultaneous targeting of multiple pathways may offer a new therapeutic strategy to maximize the efficacy of JAK inhibition, particularly in patients with a loss of response to JAK inhibitors. Promising clinical outcomes were observed in patients with MF who were treated with ruxolitinib in combination with parsaclisib (PI3Kδ inhibitor), umbralisib (PI3Kδ inhibitor), pelabresib (BET inhibitor), and navitoclax (BCL-X 1 /BCL-2 inhibitor) [37][38][39][40]. Preliminary data also suggest that an investigation of the use of TP-3654 in combination with ruxolitinib is warranted [41].…”

Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers

“…It initially showed improved PFS but later demonstrated safety concerns and inferior OS [157,158]. Phase II trial investigating the addition of umbralisib to JAK1/2 (Janus Kinase 1/2) inhibitor ruxolitinib in patients with myelofibrosis (MF) demonstrated that combination treatment was well tolerated with an ORR of 37% and that umbralisib may re-sensitize patients with MF to JAK1/2 inhibitor ruxolitinib [159]. However, the FDA withdrew its approval on 1 June 2022, due to increased serious adverse events and risk of death with the use of umbralisib with updated findings from the UNITY-CLL trial [158].…”