A 72-year-old man is diagnosed with CLL. His Rai stage is IV (haemoglobin 9.2 g/dL, platelets 88 × 10⁹/L). FISH analysis shows del(17p) and TP53 mutation. Which treatment approach is preferred according to current guidelines?

• A FCR (fludarabine, cyclophosphamide, rituximab)
• B Chlorambucil monotherapy
• C Allogeneic stem cell transplantation as upfront therapy
• D Venetoclax + obinutuzumab (fixed-duration chemo-free regimen) ✓

Explanation

Del(17p)/TP53-mutated CLL is intrinsically resistant to chemoimmunotherapy including FCR, rendering that approach ineffective. Current IWCLL and NCCN guidelines recommend BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) or the fixed-duration venetoclax + obinutuzumab regimen for this high-risk group. Venetoclax targets BCL-2 and is approved regardless of TP53 status. Chlorambucil alone has no role in symptomatic high-risk disease. Allogeneic SCT is reserved for relapsed/refractory disease after novel agents.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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