Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model

Purpose: Inhibitors of Bruton's tyrosine kinase (BTKi) and PI3K (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Hence, we sought evidence for essential roles of PI3K-delta i and PI3K-gamma i in treatment-naive and BTKi-refractory CLL. Experimental Design: Responses to PI3K-delta i, PI3K-gamma i, and the dual-inhibitor duvelisib in each B, T, and myeloid cell compart-ments of CLL were studied in vitro, and in a xenograft mouse model using primary cells from treatment-naive and ibrutinib-resistant patients, and finally, in a patient with ibrutinib-resistant CLL treated with duvelisib. Results: We demonstrate the essential roles of PI3K-delta for CLL B-cell survival and migration, of PI3K-gamma for T-cell migration andmacrophage polarization, and of dual inhibition of PI3K-delta,gamma for efficacious reduction of leukemia burden. We also show that samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in a xenograft model, irrespective of BTK mutations. In support of this, we report a patient with ibrutinib-resistant CLL, bearing a clone with BTK and PLC gamma 2 mutations, who responded immediately to single-agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with modulation of T and myeloid cells. Conclusions: Our data define the mechanism of action whereby dual inhibition of PI3K-delta,gamma affects CLL B-cell numbers and T and myeloid cell pro-leukemia functions and support the use of duvelisib as a valuable approach for therapeutic interventions, including for patients refractory to BTKi.