Idelalisib: Practical Tools for Identifying and Managing Adverse Events in Clinical Practice
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Abstract:
Idelalisib is a first-in-class oral selective inhibitor of phosphatidylinositol 3-kinase delta, which is selectively expressed in hematopoietic cells, where it is critical to B-cell receptor signaling and B-cell development and function.Idelalisib is approved in the United States for the treatment of relapsed chronic lymphocytic leukemia (CLL; in combination with rituximab), relapsed follicular lymphoma (FL), and small lymphocytic lymphoma (SLL) and in the European Union for the treatment of CLL (in combination with rituximab).Approval was based on clinical activity in a phase II trial in indolent non-Hodgkin lymphoma and a phase III trial in CLL.Because idelalisib is a relatively new treatment option for patients with relapsed CLL, SLL, and FL, with a safety profile distinct from other agents, it is important for advanced practitioners (APs) to familiarize themselves with the adverse event (AE) profile and educate their patients as well.As active members of the oncology care team, APs can play a vital role in optimizing outcomes in patients receiving idelalisib therapy.This review will familiarize APs with the AE profile of idelalisib and provide practical information about the identification and management of AEs associated with idelalisib therapy.Keywords:
Idelalisib
Follicular lymphoma
Small-molecule kinase inhibitors, especially the two Food and Drug Administration-approved agents idelalisib and ibrutinib, have changed the treatment landscape for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). However, with these positive changes comes the new challenge of managing patients who relapse after these agents. The number of patients who have relapsed after taking idelalisib and ibrutinib is low, but as the drugs gain wider use and patients are treated for longer, this number is likely to grow. Because these patients can be challenging to manage effectively, coordinated efforts now to determine how and why patients relapse along with optimal treatment strategies are required to better serve our patients in the future. As well, identification of mechanisms of resistance is crucial to develop rational strategies for management. Current work has identified mechanisms of resistance to ibrutinib, and resistance to idelalisib is also under active investigation. In this review, we will discuss these mechanisms of resistance, as well as current and potential strategies for the management of kinase inhibitor-resistant CLL.
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"Accelerated" chronic lymphocytic leukemia/small lymphocytic lymphoma (A-CLL) is a rare histological variant of CLL/SLL, which tends to exhibit an aggressive clinical behavior compared to CLL. Due to the rarity of A-CLL (<1% of all cases), the optimal management remains ill-defined. We report two cases of A-CLL from our institution, in which both relapsed following initial chemoimmunotherapy regimens. Both patients were treated with single agent ibrutinib, a Bruton's tyrosine kinase inhibitor (BTKi), and achieved rapid, deep and durable responses. With the absence of clear guidance on A-CLL treatment, BTKi agents should be considered in the frontline treatment of A-CLL.
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Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell–cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib. While opportunistic infections and viral reactivations occur with both ibrutinib and idelalisib, these complications are less common and less severe with ibrutinib, especially when used as monotherapy without additional immunosuppressive agents. This review discusses the impact of ibrutinib and idelalisib on the immune system, including infectious and auto-immune complications as well as their specific effects on the B-cell, T-cell, and myeloid compartment.
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The clinical success of agents targeting the B-cell receptor signaling pathway in chronic lymphocytic leukemia (CLL) may also derive from disrupting the CLL microenvironment. Investigation of the immunomodulatory effects of these agents illuminates the unique immunobiology of CLL and highlights potential targets for dismantling the chronic inflammatory drive. See related article by Niemann et al., p. 1572.
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Although ibrutinib and idelalisib are profound treatment advances, they will dramatically increase individual out-of-pocket and societal costs of caring for patients with CLL.
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