Venetoclax (ABT-199) is a highly selective BCL-2 inhibitor used in CLL. The tumor lysis syndrome risk with venetoclax is particularly high because:

• A Venetoclax also inhibits BCL-XL in red blood cells, causing hemolysis that adds uric acid to tumor lysis burden
• B Venetoclax induces neutrophil extracellular trap (NET) formation that traps and destroys leukemic cells en masse
• C CLL cells release HMGB1 during necrotic death triggered by venetoclax, causing systemic inflammatory response mimicking TLS
• D CLL cells overexpress BCL-2 and are primed for apoptosis ('poised to die') — upon BCL-2 blockade, massive synchronous apoptosis of a large tumor burden releases uric acid, potassium, and phosphate ✓

Explanation

BCL-2 is overexpressed in CLL B-cells and sequesters pro-apoptotic proteins (BAX, BAK, BIM) at the mitochondrial outer membrane. CLL cells are described as 'primed for apoptosis' — a concept called mitochondrial priming — meaning they are poised at the threshold of apoptosis, held back only by BCL-2. When venetoclax releases BIM and other BH3-only proteins from BCL-2, it triggers immediate and synchronous apoptosis of billions of CLL cells, releasing massive amounts of intracellular contents (potassium, phosphate, uric acid, calcium), causing tumor lysis syndrome. Venetoclax's ramp-up dosing strategy (5 mg → 20 → 50 → 100 → 400 mg over 5 weeks) with aggressive TLS prophylaxis was specifically designed to mitigate this risk.

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

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Written and medically reviewed by the StethoPrep medical team.