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

• DOI: 10.1158/1078-0432.c.6637754.v1
• Publication Date: 2023-05-10T13:39:10Z
• Authors: Tamara K. Moyo; Ashwin Kishtagari; Matthew T. Villaume; Brandon McMahon; Sanjay R. Mohan; Tess Stopczynski; Sheau-Chiann Chen; Run Fan; Yuankai Huo; Hyeonsoo Moon; Yucheng Tang; Cosmin A. Bejan; Merrida Childress; Ingrid Anderson; Kyle Rawling; Rhea M. Simons; Ashley Moncrief; Rebekah Caza; Laura Dugger; Aunshka Collins; Channing V. Dudley; P. Brent Ferrell; Michael Byrne; Stephen A. Strick...; Gregory D. Ayers; Bennett A. Landman; Emily F. Mason; Ruben A. Mesa; Jeanne M. Palmer; Laura C. Michaelis; Michael R. Savona
• Keywords: Ruxolitinib

<div>AbstractPurpose:<p>Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of <i>JAK2</i><sup>V617F</sup>-mutant cell lines.</p>Patients Methods:<p>In phase I dose-escalation -expansion study, we evaluated the safety efficacy selective umbralisib, in combination ruxolitinib MF who had suboptimal response lost ruxolitinib. Enrolled subjects were required be on stable dose ≥8 weeks continue MTD at study enrollment. The recommended umbralisib was determined using modified 3+3 design. Safety, pharmacokinetics, outcomes evaluated, spleen size measured novel automated digital atlas.</p>Results:<p>Thirty-seven (median age, 67 years) prior exposure enrolled. A total 2 treated 800 mg experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities seen lower doses. Two (5%) achieved durable complete response, 12 (32%) met International Working Group-Myeloproliferative Neoplasms Research Treatment criteria clinical improvement. With median follow-up 50.3 months censored patients, overall survival greater than 70% after years follow-up.</p>Conclusions:<p>Adding well tolerated may resensitize without unacceptable rates adverse events earlier generation inhibitors. Randomized trials testing treatment should pursued.</p></div>