Venetoclax, approved for CLL and AML with specific mutations, induces apoptosis by a mechanism distinct from classical cytotoxics. Its target and primary clinical risk is:

• A Activates p53-dependent apoptosis; primary risk is febrile neutropenia from p53 activation in normal haematopoietic progenitors
• B Inhibits MDM2, stabilising p53 and triggering widespread apoptosis; primary risk is hepatotoxicity
• C Directly crosslinks DNA in malignant lymphocytes; primary risk is haemorrhagic cystitis
• D Inhibits BCL-2 antiapoptotic protein, releasing pro-apoptotic proteins (BAX/BAK) to trigger mitochondrial outer membrane permeabilisation; primary risk is tumour lysis syndrome (TLS) ✓

Explanation

Venetoclax is a selective BCL-2 (B-cell lymphoma 2) homology domain 3 (BH3) mimetic that binds the hydrophobic groove of BCL-2 protein, displacing pro-apoptotic proteins (BAX, BAK, BIM) from BCL-2's inhibitory grasp. The released BAX and BAK then insert into the mitochondrial outer membrane, causing permeabilisation and release of cytochrome c — initiating the intrinsic apoptotic cascade. CLL cells are highly BCL-2 dependent ('BCL-2 primed'), making venetoclax highly active. The rapid tumour cell lysis in CLL causes significant tumour lysis syndrome (TLS) risk, necessitating dose ramp-up, prophylaxis with allopurinol/rasburicase, and monitoring. MDM2 inhibitors (e.g. navtemadlin) are a separate class.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.