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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia

Published on: September 18, 2013

Current status of phosphoinotiside-3 kinase inhibitors in blood cancers

Geoffrey Shouse¹, Olga V Danilova, Alexey V Danilov

¹City of Hope National Medical Center, Duarte, California, USA.

Current Opinion in Oncology

|July 20, 2022

Abstract

Purpose Of Review:

Treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) underwent paradigm shifts, with targeted agents rapidly displacing chemotherapy. Phosphoinotiside-3 kinase (PI3K) is essential for survival and proliferation of neoplastic B cells and has proven a tractable target in NHL, with four agents receiving FDA approval in the last decade. This review summarizes key data and challenges associated with use of PI3K inhibitors in routine practice.

Recent Findings:

Idelalisib and duvelisib are active in CLL and indolent NHL, including in patients with high-risk features. Despite differential targeting of PI3K isoforms, they exhibit comparable efficacy and adverse event profile including autoimmune events (transaminitis, colitis, pneumonitis), mediated by Treg/Th17 imbalance. Although copanlisib, a pan-PI3K inhibitor, is associated with a distinct safety profile (hyperglycemia, hypertension), preclinical studies indicate that umbralisib, a dual inhibitor of PI3Kδ and casein kinase 1ε, may have less effect on Tregs. However, both drugs may still cause immune-mediated toxicities.

Summary:

With close monitoring and management of adverse events, PI3K inhibitors continue to have a role in therapy of R/R CLL and NHL. Strategies to mitigate adverse events and increase efficacy of PI3K inhibitors include time-limited combination approaches, intermittent dosing schedules.

Insights

Phosphoinositide-3 kinase (PI3K) inhibitors are effective treatments for non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Careful management of side effects is crucial for their continued use in relapsed/refractory patients.

Area of Science:

Oncology
Pharmacology
Immunology

Background:

Targeted therapies, specifically phosphoinositide-3 kinase (PI3K) inhibitors, are revolutionizing the treatment landscape for non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), largely replacing traditional chemotherapy.
PI3K plays a critical role in the survival and proliferation of malignant B cells, making it a key therapeutic target in NHL, evidenced by four FDA-approved agents in the past decade.

Purpose of the Study:

To review essential data and discuss challenges related to the clinical application of PI3K inhibitors in the management of NHL and CLL.
To summarize the efficacy and safety profiles of currently available PI3K inhibitors in routine practice.

Main Methods:

Review of clinical trial data and real-world evidence for PI3K inhibitors in NHL and CLL.
Analysis of adverse event profiles and mechanisms of toxicity associated with PI3K inhibition.
Exploration of strategies for mitigating toxicity and enhancing efficacy.

Main Results:

Idelalisib and duvelisib demonstrate efficacy in CLL and indolent NHL, including high-risk cases, with comparable outcomes and a shared adverse event profile (autoimmune toxicities) linked to Treg/Th17 imbalance.
Copanlisib, a pan-PI3K inhibitor, presents a distinct safety profile with hyperglycemia and hypertension. Umbralisib, a dual PI3Kδ/CK1ε inhibitor, shows potential for reduced Treg effects but can still induce immune-mediated toxicities.
Despite potential immune-mediated toxicities, PI3K inhibitors remain valuable in treating relapsed/refractory (R/R) CLL and NHL.

Conclusions:

PI3K inhibitors are integral to the treatment of R/R CLL and NHL, necessitating close monitoring and proactive management of adverse events.
Strategies such as intermittent dosing and time-limited combination therapies show promise for improving the therapeutic index of PI3K inhibitors.

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