Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia

• Published in: Blood Vol. 123; no. 22; pp. 3390 - 3397
• Main Authors: Brown, Jennifer R., Byrd, John C., Coutre, Steven E., Benson, Don M., Flinn, Ian W., Wagner-Johnston, Nina D., Spurgeon, Stephen E., Kahl, Brad S., Bello, Celeste, Webb, Heather K., Johnson, Dave M., Peterman, Sissy, Li, Daniel, Jahn, Thomas M., Lannutti, Brian J., Ulrich, Roger G., Yu, Albert S., Miller, Langdon L., Furman, Richard R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29-05-2014; American Society of Hematology
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Clinical Trials and Observations; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Phosphoinositide-3 Kinase Inhibitors; Purines - administration & dosage; Purines - adverse effects; Purines - pharmacokinetics; Purines - therapeutic use; Quinazolinones - administration & dosage; Quinazolinones - adverse effects; Quinazolinones - pharmacokinetics; Quinazolinones - therapeutic use; Recurrence; Treatment Outcome
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2013-11-535047

In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kδ, was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutations (24%). Patients were treated at 6 dose levels of oral idelalisib (range 50-350 mg once or twice daily) and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines. The most commonly observed grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis.1,2 The median progression-free survival for all patients was 15.8 months. This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These trials were registered at clinicaltrials.gov as #NCT00710528 and #NCT01090414.
•Idelalisib was evaluated in 54 patients with heavily pretreated chronic lymphocytic leukemia, and target inhibition was documented in vivo.•Oral idelalisib therapy demonstrated a favorable safety profile and rapidly induced durable disease control in the majority of patients.