Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy

Anthony R. Mato, Nilanjan Ghosh, Stephen J. Schuster, Nicole Lamanna, John M. Pagel, Ian W. Flinn, Jacqueline C. Barrientos, Kanti R. Rai, James A. Reeves, Bruce D. Cheson, Paul M. Barr, Suman Kambhampati, Frederick Lansigan, Jeffrey J. Pu, Alan P. Skarbnik, Lindsey Roeker, Gustavo A. Fonseca, Andrea Sitlinger, Issam S. Hamadeh, Colleen DorseyNicole LaRatta, Hanna Weissbrot, Eline T. Luning Prak, Patricia Tsao, Dana Paskalis, Peter Sportelli, Hari P. Miskin, Michael S. Weiss, Jakub Svoboda, Danielle M. Brander

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1–not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki–intolerant CLL population can result in durable well-tolerated responses.

Original languageEnglish (US)
Pages (from-to)2817-2826
Number of pages10
Issue number20
StatePublished - May 20 2021
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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