Foundations · Year 1 · from Foundations
Case 3: Venetoclax for Chronic Lymphocytic Leukemia (BH3 Mimetic Therapy)
Clinical Image
Source: Wikipedia - Chronic lymphocytic leukemia - CC BY-SA 3.0
Case Presentation
A 72-year-old man with chronic lymphocytic leukemia (CLL) has progressed through multiple prior therapies including chemoimmunotherapy and ibrutinib. His disease has acquired a TP53 deletion, associated with treatment resistance. He is started on venetoclax, a selective Bcl-2 inhibitor, combined with rituximab. The oncologist explains that CLL cells are heavily dependent on Bcl-2 for survival. Venetoclax is a BH3 mimetic, a small molecule designed to mimic the BH3 domain of pro-apoptotic proteins. It binds to the hydrophobic groove of Bcl-2 where pro-apoptotic proteins normally bind, displacing sequestered Bax and Bak. The freed Bax and Bak oligomerize, causing MOMP, cytochrome c release, apoptosome formation, and caspase activation, restoring the apoptotic pathway. He is warned about tumor lysis syndrome (TLS) due to rapid cell death and started on dose ramp-up with aggressive hydration and monitoring. He achieves deep remission with undetectable minimal residual disease. This case demonstrates how understanding apoptosis mechanisms has led to effective targeted therapies that exploit cancer cell dependencies.
Key Learning Points
- BH3 mimetics like venetoclax work by binding anti-apoptotic Bcl-2 family proteins, displacing sequestered pro-apoptotic Bax and Bak to restore the intrinsic apoptotic pathway
- Cancer cells often become "addicted" to anti-apoptotic proteins for survival; targeting these dependencies can be therapeutically effective even in chemotherapy-resistant disease
- Tumor lysis syndrome risk with venetoclax reflects the rapid, massive cell death induced by restoring apoptosis; careful dose escalation and monitoring are required