PB1870 IBRUTINIB PLUS VENETOCLAX SYNERGISTICALLY REDUCES SIGNALING AND VIABILITY IN CLL: IMPLICATIONS FOR BIOMARKER DISCOVERY

Abstract

Background:Recently, several small molecule drugs have been approved for the treatment of chronic lymphocytic leukemia (CLL). These drugs have significantly improved the management of this patient group. However, knowledge about how to combine the novel therapies for optimal effects and what patients will best benefit from them is still lacking.Aims:The aims of this study were to investigate whether drug synergies can be identified by single cell signaling analyses, and to identify potential signaling biomarkers for response to therapy.Methods:We investigated the effects of idelalisib, ibrutinib and venetoclax on 35 protein epitopes by phospho flow cytometry in CLL patient samples. Cell viability was monitored with internal markers for apoptosis in the phospho flow assays and with independent drug sensitivity screens.Results:The activity of proteins in the B cell receptor signalosome and the phosphatidylinositol 3‐kinase pathway were altered upon drug exposure. Combined treatment with ibrutinib and venetoclax give promising results in clinical studies and we show that this combination exerted synergistic inhibitory effects both on cell signaling (Figure 1a) and on cell viability (Figure 1a, b). Our analyses indicate that the standard dosages of ibrutinib and venetoclax can be lowered without loss of efficacy, potentially reducing drug costs and toxicities. Observed correlation between cell signaling and cell viability indicates that signaling molecules could serve as biomarkers to predict response to therapy.Summary/Conclusion:We suggest that phospho flow should be considered as a novel approach for dose and synergy prediction in a precision medicine setting for CLL.image