Case Discussion: Treatment-Naïve Patient with CLL with Unmutated IGHV

Dr. Shadman presents a case of a 68-year-old woman with symptomatic CLL requiring treatment. She has unmutated IGHV but no del(17p) or TP53 mutation, ECOG performance status 0, no significant comorbidities, and prefers oral therapy. She is professionally active, works full-time, and lives far from the clinic with strong preference for minimal clinic visits. Laboratory findings show white blood cell count 85,000, hemoglobin 9.2 g/dL, platelets 95,000, with bulky lymphadenopathy and enlarged spleen on examination.

Dr. Lipsky notes that no treatment options are excluded by her molecular profile: all strategies including continuous and time-limited approaches remain available. The most influential factor in this case is her geographic distance and preference for minimal clinic visits, which biases against venetoclax-based strategies requiring frequent in-person ramp-up visits, particularly given her bulky disease placing her in a higher tumor lysis syndrome risk category.

From an efficacy standpoint, her unmutated IGHV is informative for time-limited therapy: CLL14 9-year follow-up data suggests approximately 5.5 years of PFS for unmutated patients versus 9 years for mutated patients with venetoclax-obinutuzumab. With zanubrutinib monotherapy from SEQUOIA data, IGHV-mutated and unmutated patients show no statistically significant PFS difference at 6 years, making BTKi monotherapy the more straightforward recommendation given her logistical preferences and bulky disease.

A practical BTKi approach allows flexible visit spacing after initiation (seeing the patient in 1 to 2 weeks for initial count monitoring, then monthly, then every few months), aligning well with her preference to minimize clinic visits while ensuring adequate safety monitoring.