Idelalisib in the management of lymphoma

Introduction: PI3K inhibitors are an important new therapeutic option for the treatment of relapsed and refractory B-cell lymphoid malignancies. Idelalisib is a PI3Kδ inhibitor that has been approved for the treatment of lymphoma and chronic lymphocytic leukemia in the relapsed/refractory setting, and several other PI3K inhibitors are being developed targeting other isoforms of the PI3K enzyme, which results in distinct toxicities and variable efficacy in the clinical setting.Areas covered: We provide a general overview of PI3K inhibitors, recommended applications, and the mechanism and management of toxicities. We further review trials, ongoing and completed, leading to the approval of idelalisib as well other PI3K inhibitors currently in development. Articles were obtained from PubMed, and abstracts were searched for the past 5 years from the websites for ASCO, ASH, EHA, and ICML/Lugano.Expert commentary: PI3K inhibitors provide an important and powerful pharmacologic tool in the armamentarium a...

Clinical use of PI3K inhibitors in B-cell lymphoid malignancies: today and tomorrow.

Pharmacological agents that inhibit enzymes of the B-cell receptor (BCR) pathway are of increasing importance in the treatment of B-cell malignancies These include inhibitors of Bruton tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), splenic tyrosine kinase and protein kinase Cβ Two agents are already approved in the USA and Europe: ibrutinib, a BTK inhibitor, for the treatment of chronic lymphatic leukaemia (CLL), mantle cell lymphoma (MCL) and Waldenstrom's macroglobulinemia; and idelalisib, a PI3Kδ inhibitor, for the treatment of CLL and follicular lymphoma In addition, the role of these drugs in diffuse large B-cell lymphoma and marginal zone lymphoma is under investigation, as single agents and in combination with chemotherapy In CLL, both ibrutinib and idelalisib have an established role as first-line therapy in patients with del(17p), and in MCL, ibrutinib is a standard option for patients relapsing after chemoimmunotherapy Unexpected toxicities have been encountered when combining these potent new agents with other drugs, including chemotherapy and lenalidomide, and based on this experience the risks and benefits of novel combinations must be evaluated carefully In this review, we summarize the efficacy and safety results with these inhibitors and discuss novel combinations that are under study and the future role of BCR inhibitors in these disorders

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Targeting of B-cell receptor signalling in B-cell malignancies

PI3K signaling pathway in normal B cells and indolent B-cell malignancies

The phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is implicated in the pathogenesis of lymphoma. Deeper understanding of the diversity and biological impact of this pathway has led to the development of specific inhibitors to this pathway. Preclinical data in cell lines, patient samples and disease models have broadened our understanding of PI3K inhibition. Several PI3K inhibitors are currently in advanced stages of clinical development. Idelalisib is the first agent of this new substance class to be approved in chronic lymphocytic leukemia and follicular lymphoma. Other agents specifically target different PI3K isoforms and show promising clinical efficacy.

The Emerging Role of PI3K Inhibitors in the Treatment of Hematological Malignancies: Preclinical Data and Clinical Progress to Date

Results of the Mantle Cell Lymphoma Subset from a Phase 2a Study of Copanlisib, a Novel PI3K Inhibitor, in Patients with Indolent and Aggressive Lymphoma

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Results of the Mantle Cell Lymphoma Subset from a Phase 2a Study of Copanlisib, a Novel PI3K Inhibitor, in Patients with Indolent and Aggressive Lymphoma