Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia.

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Citation

Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, Spurgeon SE, Kahl BS, Bello C, Webb HK, Johnson DM, Peterman S, Li D, Jahn TM, Lannutti BJ, Ulrich RG, Yu AS, Miller LL, Furman RR

Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia.

Blood. 2014 May 29;123(22):3390-7. doi: 10.1182/blood-2013-11-535047. Epub 2014 Mar 10.

PubMed ID
24615777 [ View in PubMed
]
Abstract

In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kdelta, 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 PI3Kdelta 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 PI3Kdelta 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.

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