Dual Inhibition of PI3K-{delta} and PI3K-{gamma} By Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Patient-Derived Xenograft Model

In conclusion, DUV inhibits the in vivo survival and proliferation of leukemic B cells from CLL patients, including those who have progressed on ibrutinib. Dual PI3K- and - inhibition is more effective at inhibiting CLL B cells in vivo than PI3K- inhibition alone. Moreover, PI3K- inhibition shifts macrophage polarization away from a CLL-supportive M2 phenotype. Thus, DUV exerts inhibitory effects on CLL B cells and on CLL-supporting T and myeloid cells. Overall, these findings elucidate the non-redundant roles of PI3K- and - in CLL and demonstrate the potent antitumor activity of dual PI3K isoform inhibition by DUV in ibrutinib-resistant patient CLL cells in vivo. Further investigation of DUV as a therapeutic option for patients who are refractory to or intolerant of ibrutinib or other BTK inhibitors is ongoing in a phase 2 clinical trial (BRIO; NCT03370185).DisclosuresChen: Janssen: Research Funding; ArgenX: Research Funding; Beigene: Research Funding; Pharmacyclics: Research Funding; Verastem: Research Funding. Kutok: Infinity Pharmaceuticals: Employment, Equity Ownership. Barrientos: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weaver: Verastem Oncology: Employment, Other: Stockholder; Agios Pharmaceut...

Source: Blood - November 21, 2018 Category: Hematology Authors: Chen, S.-S., Kutok, J. L., Ferrer, G., Ravichandran, P., Ibrahim, M., Kieso, Y., Barrientos, J. C., Weaver, D. T., Pachter, J. A., Rai, K. R., Chiorazzi, N. Tags: 642. CLL: Therapy, excluding Transplantation: Poster III Source Type: research