A combination strategy to target pathophysiology of chronic lymphocytic leukemia

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PROJECT SUMMARY Survival of chronic lymphocytic leukemia (CLL) cells is largely due to B-cell receptor (BCR) signaling and to the anti-apoptotic function of BCL-2 family proteins. The BCR pathway is critical for the proliferation, maintenance, and survival of B-cells. Bruton’s tyrosine kinase (BTK) is pivotal in the BCR axis and is activated when BCR is stimulated. Due to its critical role in BCR axis signaling and importance of the BCR pathway in B-cells, BTK is an attractive therapeutic target and ibrutinib (IBR) was approved for CLL. The dependency of CLL cells on BCL- 2 protein for survival makes BCL-2 antagonists such as venetoclax (VEN) optimal combination partners for BTK inhibitors. Acalabrutinib (ACA) is a second-generation more selective BTK inhibitor that irreversibly binds to Cys-481 in the BTK kinase domain and potently blocks its enzymatic activity. ACA demonstrated compelling activity in the clinic and during Phase I trials, and it became clear that this oral drug is highly effective with greater selectivity than first-generation inhibitor IBR. However, clinically, patients rarely achieve complete remissions (CR) or cures, and continuous use of the drug or combination strategies are needed. Similar to BCR targeting, BCL-2 inhibitor, VEN, was effective in the clinic but with limited CRs. Based on our preclinical investigations and three distinct rationales, we designed and initiated a clinical trial combining IBR and VEN in CLL. Rationales included decline in MCL-1 survival protein in CLL cells following IBR treatment, mobilization of CLL cells from lymph nodes to circulating blood after IBR, and potential decreased incidence of VEN-induced tumor lysis syndrome due to debulking of tumor by IBR. Data demonstrated a dramatic increase in CR rates compared with IBR or VEN monotherapy as well as achievement of undetectable measurable residual disease in 2/3 of previously untreated patients. Based on this data we hypothesized that more selective BTK inhibitor ACA combined with VEN may be more effective strategy for CLL with greater response rates. A clinical protocol (NCT04169737) has been established and initiated to evaluate the efficacy of the combination treatment with or without obinutuzumab treatment-naïve and previously treated cohorts. In this proposal, we will focus only on the ACA+VEN combination (i.e. without obinutuzumab). Through this trial, we will obtain samples during treatment to evaluate the components that contribute to response to therapy. In Aim 1, we will conduct pharmacodynamic analyses during therapy to determine the impact of VEN addition to ACA. Plasma pharmacokinetics of each drug will be measured, and molecular endpoints will be compared using RNAseq and proteomics analyses. For Aim 2, we will compare the combination of ACA/VEN combination against IBR/VEN for non-inferiority. These analyses will include pharmacodynamic analysis, -omics and biomarker comparisons using retrospective data from IBR/VEN combination with the ongoing ACA/VEN clinical trial. We have prior data from untreated (n=120) and previously treated (n=80) CLL patients on IBR/VEN trial. Ultimately, the goals of this proposal are to identify hallmarks and biomarkers of response and resistance that may lead to more effective treatment of CLL.