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Blood ; 137(20): 2817-2826, 2021 05 20.
Article in English | MEDLINE | ID: mdl-33259589

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 Î´ (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.


Subject(s)
Antineoplastic Agents/therapeutic use , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Neoplasm Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Adenine/adverse effects , Adenine/analogs & derivatives , Adenine/therapeutic use , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Cardiovascular Diseases/chemically induced , Drug Eruptions/etiology , Drug Resistance, Neoplasm , Female , Gastrointestinal Diseases/chemically induced , Heterocyclic Compounds, 4 or More Rings/adverse effects , Humans , Kaplan-Meier Estimate , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Piperidines/adverse effects , Piperidines/therapeutic use , Progression-Free Survival , Protein Kinase Inhibitors/adverse effects
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