The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia

Curr Hematol Malig Rep. 2017 Feb;12(1):11-19. doi: 10.1007/s11899-017-0359-0.


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.

Keywords: BCL-2 inhibitors; Chronic lymphocytic leukemia; Clinical trials; Venetoclax.

Publication types

  • Review

MeSH terms

  • Aniline Compounds / therapeutic use
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Bridged Bicyclo Compounds, Heterocyclic / adverse effects
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
  • Gossypol / chemistry
  • Gossypol / therapeutic use
  • Humans
  • Indoles
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Neutropenia / etiology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrroles / therapeutic use
  • Sulfonamides / adverse effects
  • Sulfonamides / therapeutic use
  • Thionucleotides / therapeutic use


  • Aniline Compounds
  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Indoles
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrroles
  • Sulfonamides
  • Thionucleotides
  • oblimersen
  • Gossypol
  • venetoclax
  • obatoclax
  • navitoclax