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

Jennifer R. Brown, John C. Byrd, Steven E. Coutre, Don M. Benson, Ian W. Flinn, Nina D. Wagner-Johnston, Stephen Spurgeon, Brad S. Kahl, Celeste Bello, Heather K. Webb, Dave M. Johnson, Sissy Peterman, Daniel Li, Thomas M. Jahn, Brian J. Lannutti, Roger G. Ulrich, Albert S. Yu, Langdon L. Miller, Richard R. Furman

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Abstract

In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kd, 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 PI3Kd 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 PI3Kd 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.

Original languageEnglish (US)
Pages (from-to)3390-3397
Number of pages8
JournalBlood
Volume123
Issue number22
DOIs
StatePublished - May 29 2014

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Phosphatidylinositol 3-Kinase
B-Cell Chronic Lymphocytic Leukemia
Refractory materials
Therapeutics
Phosphorylation
idelalisib
Chemokines
Disease-Free Survival
Diarrhea
Pneumonia
Fever
Phosphotransferases
Lipids
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Brown, J. R., Byrd, J. C., Coutre, S. E., Benson, D. M., Flinn, I. W., Wagner-Johnston, N. D., ... Furman, R. R. (2014). Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood, 123(22), 3390-3397. https://doi.org/10.1182/blood-2013-11-535047

Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. / Brown, Jennifer R.; Byrd, John C.; Coutre, Steven E.; Benson, Don M.; Flinn, Ian W.; Wagner-Johnston, Nina D.; Spurgeon, Stephen; 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.

In: Blood, Vol. 123, No. 22, 29.05.2014, p. 3390-3397.

Research output: Contribution to journalArticle

Brown, JR, Byrd, JC, Coutre, SE, Benson, DM, Flinn, IW, Wagner-Johnston, ND, Spurgeon, S, Kahl, BS, Bello, C, Webb, HK, Johnson, DM, Peterman, S, Li, D, Jahn, TM, Lannutti, BJ, Ulrich, RG, Yu, AS, Miller, LL & Furman, RR 2014, 'Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia', Blood, vol. 123, no. 22, pp. 3390-3397. https://doi.org/10.1182/blood-2013-11-535047
Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014 May 29;123(22):3390-3397. https://doi.org/10.1182/blood-2013-11-535047
Brown, Jennifer R. ; Byrd, John C. ; Coutre, Steven E. ; Benson, Don M. ; Flinn, Ian W. ; Wagner-Johnston, Nina D. ; Spurgeon, Stephen ; 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. / Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. In: Blood. 2014 ; Vol. 123, No. 22. pp. 3390-3397.
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abstract = "In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kd, 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 PI3Kd 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 PI3Kd 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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AU - Flinn, Ian W.

AU - Wagner-Johnston, Nina D.

AU - Spurgeon, Stephen

AU - Kahl, Brad S.

AU - Bello, Celeste

AU - Webb, Heather K.

AU - Johnson, Dave M.

AU - Peterman, Sissy

AU - Li, Daniel

AU - Jahn, Thomas M.

AU - Lannutti, Brian J.

AU - Ulrich, Roger G.

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AU - Furman, Richard R.

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