PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma

BackgroundPhosphatidylinositol-3-kinase delta (PI3K) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3K inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas. MethodsIn this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety. ResultsThe median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenstrom's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%). ConclusionsIn this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.) Idelalisib, which inhibits PI3K isoform delta, produced antitumor responses in nearly 60% of pretreated patients with indolent non-Hodgkin's lymphomas. Responses lasted a median of 11 months. Grade 3 or higher toxic effects were seen in 13 to 27% of patients. Indolent non-Hodgkin's lymphomas constitute approximately one third of all cases of non-Hodgkin's lymphoma and include follicular lymphoma, small lymphocytic lymphoma, marginal-zone lymphoma, and lymphoplasmacytic lymphoma with or without Waldenstrom's macroglobulinemia.(1)-(3) It was estimated that approximately 20,000 people in the United States were diagnosed with indolent non-Hodgkin's lymphoma in 2012 and that approximately 7000 died of this disease.(4),(5) The mainstay of treatment for indolent non-Hodgkin's lymphoma is an anti-CD20 antibody (primarily rituximab) in combination with chemotherapy consisting of alkylating agents, anthracyclines, antimitotic agents, or purine analogues. Although the current treatments for indolent non-Hodgkin's lymphomas are initially effective in inducing ...