Approved and emerging PI3K inhibitors for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma

ABSTRACT

Introduction

PI3K inhibition with idelalisib (at that time CAL-101) was at the forefront of the development of molecularly targeted therapies in Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Leukemia (SLL) and follicular lymphoma. However, after initial approval, subsequent trials identified specific immune-mediated and infectious toxicity that led to a reduced use and stopped the further development of this agent. PI3K inhibition as a treatment paradigm fell out of favor compared to other developments such as BTK or BCL2 inhibitors.

Areas covered

This review provides an overview of the experience with approved PI3Ki, including long-term experience, and highlights the current PI3Ki developments in CLL, B-cell and T-Cell Non-Hodgkin’s Lymphoma.

Expert opinion

With careful monitoring and prophylaxis usage of the first-generation PI3K inhibitor, idelalisib, in the approved indications, it is safe and remains an option in higher line therapy after the failure of other novel agents and/or chemoimmunotherapy. New developments with next-generation PI3K inhibitors of improved tolerability and sustained efficacy reignited the treatment principle and already led to newly approved therapeutic options for patients. Certainly, the authors here believe that PI3K inhibitors as a monotherapy and in combination with other agents is currently a rapidly evolving field in cancer treatment.

KEYWORDS:

• CLL
• NHL
• PI3K inhibitors
• idelalisib
• umbralisib

Article highlights

• The improved understanding of CLL/lymphoma pathogenesis led to the development of PI3K targeted therapies inhibiting survival and proliferation signals transduced particularly by the B-cell receptor.

• Idelalisib was the first PI3K inhibitor to be approved for the treatment of relapsed CLL and follicular lymphoma. However, severe infections and long-term immune-related toxicities prevented further drug development.

• Several next-generation PI3Ki with a higher selectivity for the PI3Kδ isoform or modifying off-targeted activity were developed leading to novel treatment approaches.

• Duvelisib is a dual inhibitor of PI3Kδ and γ potentially modifying the tumor-protective microenvironment. Promising activity was observed in B-NHL and T-NHL, an area of high unmet need.

• Umbralisib is a highly selective PI3Kδ inhibitor and an inhibitor of casein kinase-1ε with promising activity. Umbralisib was safely combined with other targeted agents and is currently intensely studied in CLL and B-NHL.

• The improvements of next-generation PI3Ki offer the opportunity to combine and sequence targeted agents with the aim to achieve long-term disease remission or approach the ultimate goal of cure.

This box summarizes key points contained in the article.

Declaration of Interest

S Stilgenbauer has received honoraria for consultancy, for serving as an Advisory board member and for speaking, as well as having received research grants and travel support from: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GlaxoSmithKline, Hoffmann La-Roche, Janssen, Novartis, Mundipharma and Pharmacyclics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

One referee has served on the advisory boards of Celgene/Juno and Regeneron. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript was not funded.