A 70-year-old man is diagnosed with chronic lymphocytic leukemia (CLL). FISH shows del(17p) with TP53 mutation. IgHV mutation status is unmutated. He has symptomatic disease (Rai Stage III). According to current guidelines, what is the preferred first-line therapy?

• A FCR (fludarabine + cyclophosphamide + rituximab)
• B Ibrutinib monotherapy
• C Venetoclax + obinutuzumab ✓
• D Chlorambucil + anti-CD20 antibody

Explanation

Del(17p)/TP53 mutation confers high-risk CLL with resistance to chemoimmunotherapy (including FCR, which is contraindicated). Venetoclax (BCL-2 inhibitor) + obinutuzumab (anti-CD20) is the preferred first-line for del(17p)/TP53-mutated CLL per IWCLL and EMA/FDA approvals, based on CLL14 trial data showing superior PFS over chlorambucil-obinutuzumab. Ibrutinib (BTK inhibitor) is an equally valid alternative. FCR is specifically avoided in del(17p) due to TP53-dependent apoptosis pathway disruption impairing response to DNA damage.

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

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Written and medically reviewed by the StethoPrep medical team.