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

Paul M. Barr, Gene B. Saylors, Stephen 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

76 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

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Barr, P. M., Saylors, G. B., Spurgeon, S., 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