The Bcl-2 inhibitor venetoclax (VEN) has yielded exceptional clinical responses in chronic lymphocytic leukemia (CLL). However, de novo resistance can result in failure to achieve negative minimal residual disease and predicts poor treatment outcomes. Consequently, additional pro-apoptotic drugs, such as inhibitors of Mcl-1 and Bcl-xL, are in development. By profiling anti-apoptotic proteins using flow cytometry, we find that leukemic B-cells recently emigrated from the lymph node (LN) (CD69Pos/CXCR4Low) in vivo are enriched for cell clusters simultaneously overexpressing multiple anti-apoptotic proteins (Mcl-1high/Bcl-xLhigh/Bcl-2high), in both treated and treatment naïve CLL patients. These cells exhibited anti-apoptotic resistance to multiple BH-domain antagonists, including inhibitors of Bcl-2, Mcl-1, and Bcl-xL, when tested as single agents in a flow cytometry-based functional assay. Anti-apoptotic multi-drug resistance declines ex vivo, consistent with resistance being generated in vivo by extrinsic microenvironmental interactions. Surviving "persister" cells in patients undergoing venetoclax treatment are enriched for CLL cells displaying the functional and molecular properties of microenvironmentally-induced multi-drug resistance. Overcoming this resistance required simultaneous inhibition of multiple anti-apoptotic proteins, with potential for unwanted toxicities. Using a drug screen performed using patient PBMCs cultured in an ex vivo microenvironment model we identify novel venetoclax drug combinations that induce selective cytotoxicity in multi-drug resistant CLL cells. Thus, we demonstrate that anti-apoptotic multi-drug resistant CLL cells exist in patients de novo, and show that these cells persist during pro-apoptotic treatment such as venetoclax. We validate clinically actionable approaches to selectively deplete this reservoir in patients.

Background Immune checkpoint inhibition is part of standard systemic management for many advanced malignancies. Toxicities from this treatment approach are unpredictable, though usually reversible with management per established guidelines. Some patients suffer major morbidity and treatment-related mortality from these agents in an unpredictable manner. Cardiac and neurologic complications are rare, but can result in serious clinical consequences. Methods We describe the presentation, management, and outcomes of eight sequential cases of combined cardiac and neurologic toxicities resulting in severe illness and demonstrating lack of rapid response to immunosuppression. Results Our cohort consisted of six males and two females with an average age of 73.5 years (61–89 years). There were four patients with melanoma, and one patient each with urothelial carcinoma, renal cell carcinoma, breast cancer, and non-small cell lung cancer. Four patients received combination immunotherapy and four patients received monotherapy. The median time to presentation from treatment initiation was 27 days (11–132 days). All patients had a cardiovascular and neurologic toxicity, and most had hepatitis and myositis. The cardiac signs and symptoms were the prominent initial features of the clinical presentation. Each patient was managed by a multidisciplinary team and received a range of immunosuppressive agents. All patients died as a consequence of the immune related adverse events. Conclusions The evaluation of patients with cardiac adverse events from immunotherapy, should include assessment of overlapping toxicities such as myasthenia gravis and myositis. Providers should be aware of the potential for an extended duration of disability and slow improvement for certain toxicities as these expectations may factor prominently in goals of care decisions.

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