Targeting the tumor microenvironment for treating double-refractory chronic lymphocytic leukemia

• Published in: Blood Vol. 144; no. 6; pp. 601 - 614
• Main Authors: Lewis, Richard I., vom Stein, Alexander F., Hallek, Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.08.2024
• Subjects: Agammaglobulinaemia Tyrosine Kinase - antagonists & inhibitors; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Drug Resistance, Neoplasm - drug effects; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Molecular Targeted Therapy - methods; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Tumor Microenvironment - drug effects
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2023022861

The introduction of BTK inhibitors and BCL2 antagonists to the treatment of chronic lymphocytic leukemia (CLL) has revolutionized therapy and improved patient outcomes. These agents have replaced chemoimmunotherapy as standard of care. Despite this progress, a new group of patients is currently emerging, which has become refractory or intolerant to both classes of agents, creating an unmet medical need. Here, we propose that the targeted modulation of the tumor microenvironment provides new therapeutic options for this group of double-refractory patients. Furthermore, we outline a sequential strategy for tumor microenvironment-directed combination therapies in CLL that can be tested in clinical protocols. With the advent of Bruton tyrosine kinase inhibitors and the BCL2 inhibitor venetoclax as targeted therapies now central to the management of patients with chronic lymphocytic leukemia (CLL), the greatest current challenge for physicians and patients is tackling CLL that is resistant to both classes of drugs. Lewis and colleagues provide their perspective on how we should address this increasing group of patients. After reviewing the pertinent literature, the authors highlight the importance of targeting the tumor microenvironment as part of the strategy to overcome dual-refractory leukemia. They advocate for programs that first diminish the proleukemic microenvironment before rebuilding and retaining an immune system that maintains remissions.