Dataset Information

The Evolving Use of Phosphatidylinositol 3-Kinase Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.

ABSTRACT: B cells express 4 phosphatidylinositol 3-kinase (PI3K) isoforms and have a dependence on p110δ for survival. The design of isoform-selective inhibitors is possible, and pharmacologic inhibition of p110δ is toxic to neoplastic chronic lymphocytic leukemia (CLL) cells for both cell-intrinsic and cell-extrinsic reasons. Idelalisib is a first-in-class p110δ inhibitor that exhibits efficacy for the treatment of relapsed CLL irrespective of adverse prognostic features. Duvelisib is a p110γ/δ inhibitor with a similar efficacy and safety profile to idelalisib. Recent data indicate that umbralisib, a p110δ/CK-1ε dual inhibitor, is safe and effective when administered to patients with CLL.

SUBMITTER: Lampson BL

PROVIDER: S-EPMC8239250 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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The Evolving Use of Phosphatidylinositol 3-Kinase Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.

Lampson Benjamin L BL Brown Jennifer R JR

Hematology/oncology clinics of North America 20210527 4

B cells express 4 phosphatidylinositol 3-kinase (PI3K) isoforms and have a dependence on p110δ for survival. The design of isoform-selective inhibitors is possible, and pharmacologic inhibition of p110δ is toxic to neoplastic chronic lymphocytic leukemia (CLL) cells for both cell-intrinsic and cell-extrinsic reasons. Idelalisib is a first-in-class p110δ inhibitor that exhibits efficacy for the treatment of relapsed CLL irrespective of adverse prognostic features. Duvelisib is a p110γ/δ inhibitor ...[more]

PMID: 34174987

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Project description:Covalent Bruton's tyrosine kinase inhibitors (cBTKi) have led to a paradigm shift in the treatment of chronic lymphocytic leukemia (CLL). These targeted oral therapies are administered as standard treatments in both the front-line and relapsed and/or refractory settings. Given their administration as a continuous therapy with a "treat-to-progression" strategy, limitations of their use include discontinuation due to toxicity or from progression of the disease. Non-covalent Bruton's tyrosine kinase inhibitors (ncBTKi) distinguish themselves by binding reversibly to the BTK target, which may address the limitations of toxicity and acquired resistance seen with cBTKi. Several ncBTKis have been studied preclinically and in clinical trials, including pirtobrutinib and nemtabrutinib. Pirtobrutinib, which is now FDA approved for relapsed and/or refractory mantle cell lymphoma (MCL), has shown outstanding safety and preliminary efficacy in CLL in phase 1 and 2 clinical trials, with phase 3 trials underway. This agent may fill an unmet medical need for CLL patients requiring treatment after a cBTKi. Pirtobrutinib is particularly promising for the treatment of "double exposed" CLL, defined as CLL requiring treatment after both a cBTKi and venetoclax. Some patients have now developedacquired resistance to pirtobrutinib, and resistance mechanisms (including novel acquired mutations in BTK outside of the C481 position) have been recently described. Further study regarding the mechanisms of resistance to pirtobrutinib in patients without prior cBTKi exposure, as well as the potential for cross-resistance between cBTKi and ncBTKis, may be important to help inform where ncBTKis will ultimately fit in the treatment sequencing paradigm for CLL. An emerging clinical challenge is the treatment of CLL after ncBTKi discontinuation. Novel therapeutic strategies are being investigated to address the treatment of patients following disease progression on ncBTKis. Such strategies include novel agents (BTK degraders, bispecific antibody therapy, CAR T-cell therapy, PKC-beta inhibitors) as well as combination approaches incorporating a ncBTKi (e.g., pirtobrutinib and venetoclax) that may help overcome this acquired resistance.

Dataset Information

The Evolving Use of Phosphatidylinositol 3-Kinase Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.

Publications

The Evolving Use of Phosphatidylinositol 3-Kinase Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.

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