Optimizing novel agent combination therapy for previously untreated, high risk chronic lymphocytic leukemia

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SUMMARY/ABSTRACT Patients with high-risk TP53 aberrant chronic lymphocytic leukemia (CLL) have a shorter survival than other CLL patients. We previously found that the BTK inhibitor acalabrutinib (A) and the BCL-2 inhibitor venetoclax (V) are highly effective at killing CLL cells ex vivo. We developed AVO, a new time-limited triplet combination regimen combining AV with an anti-CD20 antibody obinutuzumab (O). The AVO clinical trial and correlative laboratory studies on primary samples from this trial comprise the key elements of this project. The first aim of the project is to determine the efficacy of the AVO combination regimen in patients with previously untreated TP53 aberrant CLL. We hypothesize that AVO will be a highly efficacious and well- tolerated novel agent triplet regimen, with individualized therapy duration guided by achievement of undetectable minimal residual disease (uMRD). This hypothesis will be tested through determining the proportion of patients who achieve complete response (CR) with uMRD, as well as characterizing the safety of the regimen, in an investigator-initiated, phase 2, multicenter clinical trial of AVO in patients with previously untreated CLL. The second aim of the project is to assess whether MRD clonal dynamics, pre-treatment mitochondrial priming, or genomic complexity predict clinical response to AVO. We will utilize a next-generation sequencing (NGS) based technology, Adaptive ClonoSEQ, to assess whether MRD clonal dynamics with this assay can more accurately predict survival and guide treatment duration decisions compared with conventional flow cytometry- based MRD. Through functional interrogation of CLL cell mitochondria by BH3 profiling, we hypothesize that patients with higher levels of mitochondrial priming at baseline and/or early on treatment will achieve a higher rate of CR with uMRD on AVO. Genomic predictors of response will also be assessed through stimulated karyotype and mutational profiling with a 95-gene NGS ‘rapid heme panel’ (RHP). The third aim of the project is to elucidate mechanisms of resistance to AVO, including acquired somatic mutations, modulation in mitochondrial priming, alterations in phosphorylation, and kinase activity. We will use RHP to evaluate the pattern of somatic mutations as they develop. We will also evaluate whether CLL cells that are typically dependent on BCL-2 at baseline will develop alternative survival dependencies on other anti- apoptotic proteins at progression. In addition, we will assess whether BCL-2 family protein phosphorylation may represent a functional resistance mechanism, and whether PP2A activators can help reverse this and thereby restore sensitivity. And we will use high-throughput kinase activity mapping (HT-KAM) to identify which kinases are activated in resistant patients to identify new, potentially therapeutically actionable targets. Elucidating resistance mechanisms will inform the design of future novel agent combination therapy trials, with the goal of decreasing the risk of acquired therapy resistance in CLL and eventually other B cell malignancies.