PI3K-Delta Inhibitor Idelalisib Produces High Response Rates in Relapsed Indolent Lymphoma


Key Points

  • Idelalisib produced high response rates in extensively pretreated patents with relapsed/refractory indolent non-Hodgkin lymphoma.
  • The safety profile was acceptable and differed from that of other active agents.

Phosphatidylinositol 3-kinase (PI3K)-delta mediates B-cell receptor signaling and microenvironment support signals that promote the growth and survival of malignant B lymphocytes. In a phase II study reported in The New England Journal of Medicine, Gopal et al found that the PI3K-delta inhibitor idelalisib produced a high response rate with acceptable toxicity in patients with relapsed/refractory indolent non-Hodgkin lymphomas.

Study Details

In the study, 125 patients with indolent non-Hodgkin lymphomas who had no response to or relapse within 6 months after treatment with rituximab (Rituxan) and an alkylating agent received oral idelalisib at 150 mg twice daily until disease progression or withdrawal from the study. The primary endpoint was overall response rate.

Patients had a median age of 64 years; 64% were male; 58% had follicular lymphoma, 22% small lymphocytic lymphoma, 12% marginal-zone lymphoma, and 8% lymphoplasmacytic lymphoma with or without Waldenström’s macroglobulinemia; 89% had stage III or IV disease, 30% had elevated lactate dehydrogenase, and 26% had bulky disease. The median number of prior treatment regimens was four (range, 2–12), and and prior therapy consisted of rituximab in all patients, an alkylating agent in all patients, bendamustine in 65%, anthracycline in 63%, purine analog in 34%, and stem cell transplantation in 11%. Disease was refractory to rituximab in all patients, to alkylating agents in 99%, and to the combination in 86%, and 79% had disease refractory to two or more prior regimens.


On the basis of independent review committee assessment, the response rate was 57%, including complete response in 6% and a minor response in one patient with Waldenström’s macroglobulinemia. Response rates were consistent across subgroups, including rates of 54% in follicular lymphoma, 61% in small lymphocytic lymphoma, 47% in marginal-zone lymphoma, and 80% in lymphoplasmacytic lymphoma, 50% in patients with less than four prior therapies and 62% in those with at least four prior therapies, 57% among both patients with and without prior bendamustine, 50% and 59% in those without and with bendamustine refractoriness, and 55% and 69% those refractory and not refractory to last therapy.

Median time to response was 1.9 months and median duration of response was 12.5 months (range, 0.03–14.8 months), greater than the duration of 5.9 months in the group of 28 patients with response to their most recent therapy.

Median follow-up was 9.7 months. Median progression-free survival was 11.0 months (range, 0.03–16.6 months), with 47% of the patients remaining progression-free at 48 weeks. At the time of analysis, median overall survival was 20.3 months (range, 0.7–22.0 months), with 1-year overall survival of 80%.


The most common adverse events of any grade were neutropenia (56%), increased ALT (47%), diarrhea (43%), and increased AST (35%). Grade 3 or higher adverse events occurred in 54% of patients, with the most common being neutropenia (27%), increased ALT (13%), diarrhea (13%), increased AST (8%), and pneumonia (7%). Adverse events led to discontinuation of idelalisib in 20% of patients, including elevated ALT/AST in 4%, colitis in 3%, and pneumonia, pneumonitis, diarrhea, and neutropenia in 2% each. Idelalisib dose reduction was required in 34% of patients, most commonly due to ALT/AST elevation, diarrhea, and neutropenia. The most common serious adverse events were pyrexia (10%), pneumonia (7%), diarrhea (7%), colitis (4%), dehydration (3%), febrile neutropenia (3%), acute renal failure (2%), and pneumonitis (2%). In all patients with grade 1 or 2 ALT/AST elevations, levels returned to normal ranges despite continued treatment.

The investigators concluded, “In 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…. The toxicity profile does not generally overlap with that of most other active agents and may allow the development of more highly active combination regimens.”

The study was funded by Gilead Sciences and Calistoga Pharmaceuticals (acquired by Gilead Sciences in 2011), a National Institutes of Health grant, and Frank and Betty Vandermeer. For full disclosures of the study authors, visit

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