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ABSTRACT
Introduction
The outcome of patients with lymphoid malignancies has markedly improved in recent years due to the implementation of new therapeutic options. Chronic lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin lymphomas (NHL) are characterized by the activation of the phosphatidylinositol 3-kinase (PI3 K) pathway via B-cell receptor signaling. The PI3 K delta (PI3 Kδ) p110δ isoform inhibitor, idelalisib, showed high anti-tumor activity in this group of tumors. It was the first agent from a new class of isoform-specific inhibitors to receive regulatory approvals for the treatment of refractory/relapsed CLL, as well as small lymphocytic lymphoma and follicular lymphoma.
Areas covered
In this paper, the authors provide a comprehensive overview of the activity and safety profile of idelalisib and other, newly developed PI3 K inhibitors in patients with indolent B-cell malignancies.
Expert opinion
Idelalisib is a very potent anti-lymphoma agent in CLL and other NHL. However, there are some limitations of its broad clinical use according to some important side effects observed during treatment. Consequently, the development of new PI3 K inhibitors, which will be highly active and possess better safety profiles are warranted.
Article highlights
Most, still uncurable, indolent lymphoproliferative B-cell disorders are characterized by the activation of the phosphatidylinositol 3-kinase (PI3K) pathway via B cell receptor signaling.
Idelalisib is the first clinically tested PI3K small molecule inhibitor of selective delta isoform of PI3K (PI3Kδ).
Idelalisib has shown high clinical activity in chronic lymphocytic leukemia (CLL) and was approved for the treatment of relapsed/refractory CLL as well as indolent B-cell non-Hodgkin lymphomas, such as small B-cell lymphocytic lymphoma (SLL) and follicular lymphoma (FL).
Combination of idelalisib with rituximab is used for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.
Although idelalisib has significant anti-tumor efficacy, it is important for clinicians to be aware of its adverse event profile; the major barrier in the clinical development of PI3Kδ inhibitors has been the occurrence of toxicities, primarily hepatotoxicity, pneumonitis, and colitis, with severe diarrhea.
Several new PI3K inhibitors have been developed, such as already approved for treatment of CLL and/or FL copanlisib or duvelisib, as well as those under assessment such as Gedatolisib, Buparlisib, Dactolisib, Apitolisib, Pictilisib, Taselisib or Alpelisib.
This box summarizes key points contained in the article.
Declaration of interest
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 declares that they have served as a consultant for Gilead Sciences. Another referee declares that he has served on the advisory boards and has been invited to meetings/received congress fees from Gilead Sciences, Janssen, Roche, Amgen Inc., and AbbVie. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.