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

by Selleckchem | May 18 2023

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-δi and PI3K-γi in treatment-naïve and BTKi-refractory CLL.

Experimental design: Responses to PI3K-δi, PI3K-γi, and the dual-inhibitor duvelisib in each B, T, and myeloid cell compartments of CLL were studied in vitro, and in a xenograft mouse model using primary cells from treatment-naïve and ibrutinib-resistant patients, and finally, in a patient with ibrutinib-resistant CLL treated with duvelisib.

Results: We demonstrate the essential roles of PI3K-δ for CLL B-cell survival and migration, of PI3K-γ for T-cell migration and macrophage polarization, and of dual inhibition of PI3K-δ,γ 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 PLCγ2 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-δ,γ 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.

Comments：

In this study, the researchers investigated the potential of PI3K-δi and PI3K-γi inhibitors in the treatment of chronic lymphocytic leukemia (CLL), particularly in patients who have developed resistance to BTKi therapy. The researchers conducted in vitro experiments using primary cells from treatment-naïve and ibrutinib-resistant CLL patients, as well as a xenograft mouse model and a case study of a patient with ibrutinib-resistant CLL.

The results of the study suggest that PI3K-δ is essential for CLL B-cell survival and migration, while PI3K-γ is essential for T-cell migration and macrophage polarization. Dual inhibition of PI3K-δ and PI3K-γ was found to be effective in reducing leukemia burden. Samples from patients who progressed on ibrutinib were also responsive to duvelisib therapy in a xenograft model, regardless of BTK mutations. In a case study, a patient with ibrutinib-resistant CLL responded well to single-agent duvelisib treatment, with redistribution lymphocytosis followed by partial clinical remission associated with modulation of T and myeloid cells.

Overall, the study provides evidence for the essential roles of PI3K-δ and PI3K-γ in CLL and supports the use of duvelisib as a potential therapeutic intervention for CLL patients, including those who are refractory to BTKi therapy.