The PI3Kδ inhibitor idelalisib has activity in previously treated B-cell non-Hodgkin lymphomas.

  • Major finding: The PI3Kδ inhibitor idelalisib has activity in previously treated B-cell non-Hodgkin lymphomas.

  • Approach: A phase II trial evaluated idelalisib in patients who were refractory to rituximab and an alkylating agent.

  • Impact: Idelalisib may be an effective therapy for indolent non-Hodgkin lymphoma regardless of subtype.

The δ isoform of phosphatidylinositol 3-kinase (PI3Kδ) acts downstream of the B-cell receptor and other cytokine, chemokine, and integrin receptors to regulate B-cell development and function. Given that PI3Kδ activity is largely restricted to hematopoietic cells and often upregulated in B-cell malignancies, this PI3K isoform represents a promising therapeutic target. Gopal and colleagues report results from a single-group, open-label, phase II study of the orally bioavailable PI3Kδ inhibitor idelalisib in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphomas, including follicular lymphoma, small lymphocytic lymphoma, marginal-zone lymphoma, and lymphoplasmacytic lymphoma with or without Waldenström macroglobulinemia. Eligible patients had been previously treated with at least two systemic therapies, and their disease had either failed to respond or progressed within 6 months following treatment with rituximab and an alkylating agent, which are commonly used as first-line and subsequent therapy. The primary endpoint was the overall response rate, and secondary endpoints included the time to response, duration of response, progression-free survival, overall survival, and safety. Of 122 evaluable patients, lymph node size was reduced in 110 (90%) patients, with 71 (57%) meeting the criteria for an objective response. Response rates were similar across the lymphoma subtypes. The median time to response was 1.9 months, and the median duration of response was 12.5 months, indicating that continued administration of idelalisib can lead to rapid, durable responses in patients with indolent B-cell non-Hodgkin lymphomas. The median progression-free survival was 11.0 months, and the median overall survival was 20.3 months. Idelalisib had a favorable safety profile in this patient population, with a low incidence of clinically significant hematologic toxic effects or severe adverse events and low rates of discontinuation due to toxicity. The findings that idelalisib is well tolerated and has single-agent activity in indolent non-Hodgkin lymphomas support further evaluation of this drug in larger, controlled trials.

Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014 Jan 22 [Epub ahead of print].

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