Concomitant phosphatidylinositol 3-kinase delta (PI3Kδ) and (spleen tyrosine kinase) SYK inhibition with idelalisib plus entospletinib resulted in a high rate of treatment-emergent pneumonitis, a study published in the journal Blood has shown.1

Although agents that target B-cell receptor signaling have changed the treatment landscape of relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and only provide partial responses in many instances. Because preclinical data have demonstrated synergistic activity with PI3Kδ and SYK inhibition, researchers sought to evaluate the efficacy and safety of idelalisib and entospletinib.

For the phase 2 trial, researchers enrolled patients with relapsed or refractory CLL or NHL. All participants underwent dose escalation with each agent.

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Results showed that 60% and 36% of patients with CLL and follicular lymphoma, respectively, achieved objective responses after a median treatment exposure of 10 weeks.

However, the study was closed early because 18% of patients developed treatment-emergent pneumonitis, of which 11 of the 12 cases were severe. Most patients recovered with supportive care and systemic steroids, but 2 patients died as a result of treatment-induced pneumonitis.

Investigators found that interferon γ and interleukins 6, 7, and 8 increased over time in patients who developed pneumonitis, which may be useful for biomarker monitoring.

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“Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring,” the authors concluded. “These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity.”


  1. Barr PM, Saylors GB, Spurgeon SE, et al. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL [published online ahead of print March 11, 2016]. Blood. doi: 10.1182/blood-2015-12-683516.