Case Discussion: High-Risk CLL with del(17p) and Clinical Summary

Dr. Lipsky presents a second case of a 72-year-old man with symptomatic CLL requiring therapy. High-risk molecular features include del(17p), unmutated IGHV, and complex karyotype (more than 3 abnormalities on stimulated karyotype). Relevant comorbidities include well-controlled hypertension and migraines, multiple concomitant medications, and limited caregiver support. Laboratory findings show white blood cell count 145,000, anemia, thrombocytopenia, elevated beta-2 microglobulin and LDH, creatinine reflecting CKD stage 3 (GFR 52), and imaging demonstrating massive lymphadenopathy up to 10 cm with marked splenomegaly 12 cm below costal margin and B symptoms.

Dr. Shadman emphasizes first ruling out Richter's transformation given B symptoms and weight loss; PET scan and potential excisional biopsy are warranted before proceeding. Once confirmed as CLL, his approach weighs 3 domains. For efficacy, zanubrutinib monotherapy has the largest evidence base for TP53-aberrant frontline patients, favoring continuous BTKi therapy.

For safety, the well-controlled hypertension history doesn't exclude covalent BTKis but warrants close monitoring; the migraine history prompts consideration between acalabrutinib (which can cause headaches early) and zanubrutinib. Multiple medications require pharmacist-led drug interaction review, and anticoagulant or antiplatelet medications should be critically reassessed given BTKi bleeding risk.

Limited caregiver support significantly favors continuous BTKi therapy over time-limited venetoclax-based combinations requiring frequent ramp-up visits. Bulky disease further supports BTK inhibition. The closing summary reviews key data discussed: SEQUOIA 78-month follow-up data showing PFS2 and post-progression treatment patterns, pirtobrutinib pooled frontline data, the established sequencing principle that covalent-to-non-covalent BTKi switching is supported while the reverse is not, and the observation that fixed-duration options are expanding but longest follow-up data for high-risk disease continues to favor continuous BTKi therapy.