Phase 2 study of idelalisib and entospletinib: Pneumonitis limits combination therapy in relapsed refractory CLL and NHL

Paul M. Barr, Gene B. Saylors, Stephen E. Spurgeon, Bruce D. Cheson, Daniel R. Greenwald, Susan M. O'Brien, Andre K.D. Liem, Rosemary E. Mclntyre, Adarsh Joshi, Esteban Abella-Dominicis, Michael J. Hawkins, Anita Reddy, Julie Di Paolo, Hank Lee, Joyce He, Jing Hu, Lyndah K. Dreiling, Jonathan W. Friedberg

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase δ and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment-emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-γ and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470.

Original languageEnglish (US)
Pages (from-to)2411-2415
Number of pages5
JournalBlood
Volume127
Issue number20
DOIs
StatePublished - May 19 2016

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Barr, P. M., Saylors, G. B., Spurgeon, S. E., Cheson, B. D., Greenwald, D. R., O'Brien, S. M., Liem, A. K. D., Mclntyre, R. E., Joshi, A., Abella-Dominicis, E., Hawkins, M. J., Reddy, A., Paolo, J. D., Lee, H., He, J., Hu, J., Dreiling, L. K., & Friedberg, J. W. (2016). Phase 2 study of idelalisib and entospletinib: Pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood, 127(20), 2411-2415. https://doi.org/10.1182/blood-2015-12-683516