title: The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.
abstract: The BCL-2 family of proteins integrates pro- and anti-apoptotic signals within the cell and is responsible for initiation of caspase-dependent apoptosis. Chronic lymphocytic leukemia (CLL) cells are particularly dependent on the anti-apoptotic protein BCL-2 for their survival, making this an attractive therapeutic target in CLL. Several early efforts to create inhibitors of the anti-apoptotic family members faced significant challenges, but eventually, the BCL-2 specific inhibitor venetoclax moved forward in CLL. Overall and complete response rates to venetoclax monotherapy in relapsed, refractory CLL are approximately 80 and 20%, respectively, even in patients with high-risk 17p deletion. Toxicities have been manageable and include neutropenia, diarrhea, and nausea. The risk of tumor lysis syndrome (TLS), seen in early experience with the drug, has been mitigated by the use of appropriate TLS risk assessment, prophylaxis, and management. Future studies of venetoclax will focus on combination approaches, predictive biomarker discovery, and mechanisms of resistance.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Lampson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. matthew_davids@dfci.harvard.edu.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Davids
mesh_terms: D000814:Aniline Compounds / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000627:therapeutic use; D006072:Gossypol / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007211:Indoles; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D009503:Neutropenia / Q000209:etiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use; D013873:Thionucleotides / Q000627:therapeutic use
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D013449:Sulfonamides; D013873:Thionucleotides; C408162:oblimersen; D006072:Gossypol; C579720:venetoclax; C520962:obatoclax; C528561:navitoclax
keywords: BCL-2 inhibitors; Chronic lymphocytic leukemia; Clinical trials; Venetoclax