Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma

Abstract

Key Points This clinical study assessed idelalisib, a selective PI3Kδ inhibitor, in 64 patients with relapsed, indolent non-Hodgkin lymphoma. Idelalisib treatment rapidly induced durable disease responses in heavily pretreated patients with a favorable safety profile.

Ibrutinib and idelalisib target B cell receptor- but not CXCL12/CXCR4-controlled integrin-mediated adhesion in Waldenstrom macroglobulinemia

“…[1][2][3] Very recently, ibrutinib became the first FDA-and EMA-approved treatment for WM patients. Herein, we investigated the molecular and cellular mechanisms underlying the clinical efficacy of ibrutinib and idelalisib in WM patients.…”

BCR pathway inhibition as therapy for chronic lymphocytic leukemia and lymphoplasmacytic lymphoma

“…Treatment-induced lymphocytosis was not seen in patients with LPL. 56 In mantle cell lymphoma (MCL), ibrutinib transiently increased the ALC (Ն50% increase and Ͼ5000 cells/L) in 34% of patients. 57 Decreased cell adhesion and reduced homing and migration of CLL cells are the likely factors contributing to lymphocytosis in patients treated with kinase inhibitors.…”

“…Based on consistent reductions in lymphadenopathy, long PFS, and pharmacokinetic considerations, a dose of 150 mg twice daily was chosen for future studies. 56 Safety. The phase 1 dose escalation study conducted across a wide range of hematologic malignancies enrolled 54 patients with relapsed/refractory CLL.…”

“…In addition, PI3K␣ can also participate in BCR signaling and promote cell survival (reviewed previously 39 ). In a dose escalation phase 1 study of oral idelalisib in indolent NHL, 56 MCL 80 and CLL 52 patients were treated at 6 dose levels ranging from 50 to 350 mg once or twice daily, and remained on continuous therapy while deriving clinical benefit. No maximum tolerated dose was established.…”

Role of the tumor microenvironment in mature B-cell lymphoid malignancies

“…It has demonstrated excellent clinical activity in patients with relapsed/refractory CLL/small lymphocytic lymphoma and FL, indications for which it has gained approval from both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). [119][120][121] PI3Kδ is expressed by both normal and malignant lymphoid cells, and PI3k inhibition by idelalisib in vitro leads to induction of apoptosis. 122 Like ibrutinib, idelalisib interferes with pro-survival microenvironment-derived signals, chemotaxis and adhesion.…”