Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy Journal Article
| Authors: | Mato, A. R.; Ghosh, N.; Schuster, S. J.; Lamanna, N.; Pagel, J. M.; Flinn, I. W.; Barrientos, J. C.; Rai, K. R.; Reeves, J. A.; Cheson, B. D.; Barr, P. M.; Kambhampati, S.; Lansigan, F.; Pu, J. J.; Skarbnik, A. P.; Roeker, L.; Fonseca, G. A.; Sitlinger, A.; Hamadeh, I. S.; Dorsey, C.; LaRatta, N.; Weissbrot, H.; Luning Prak, E. T.; Tsao, P.; Paskalis, D.; Sportelli, P.; Miskin, H. P.; Weiss, M. S.; Svoboda, J.; Brander, D. M. |
| Article Title: | Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy |
| Abstract: | 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. © 2021 American Society of Hematology |
| Journal Title: | Blood |
| Volume: | 137 |
| Issue: | 20 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2021-05-20 |
| Start Page: | 2817 |
| End Page: | 2826 |
| Language: | English |
| DOI: | 10.1182/blood.2020007376 |
| PUBMED: | 33259589 |
| PROVIDER: | scopus |
| PMCID: | PMC8574211 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2021 -- Source: Scopus |
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