A 72-year-old woman with previously treated CLL (fludarabine, cyclophosphamide, rituximab - FCR) relapses with progressive lymphocytosis and lymphadenopathy at 24 months. TP53 mutation is confirmed. The MOST appropriate salvage therapy is:

• A Repeat FCR chemoimmunotherapy
• B Idelalisib + rituximab
• C Chlorambucil + obinutuzumab
• D Ibrutinib (BTK inhibitor) monotherapy ✓

Explanation

TP53-mutated/deleted CLL (del 17p) is defined by chemoimmunotherapy resistance as TP53 is required for DNA damage-induced apoptosis that underpins the efficacy of alkylating agents and purine analogues. Ibrutinib (BTK inhibitor) and venetoclax (BCL2 inhibitor) are the preferred agents as they bypass the TP53 pathway. Ibrutinib is approved first-line and in relapsed/refractory TP53-mutated CLL and produces durable responses. FCR repeat is ineffective in TP53-mutated disease. Chlorambucil + obinutuzumab has inferior outcomes in TP53-mutated disease. Idelalisib + rituximab is an option but BTK inhibition is generally preferred.

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

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Written and medically reviewed by the StethoPrep medical team.