Biomarker Interpretation and High-Risk Disease Definitions in CLL

Dr. Shadman explains that high-risk definitions evolve as treatments change. During the chemoimmunotherapy era, del(11q) was considered high risk due to shorter chemotherapy responses, but this marker is no longer predictively significant in the targeted therapy era. TP53 aberrations, including TP53 mutation and del(17p) collectively, remain both prognostic and predictive even with current best therapies, with differences becoming apparent after sufficient follow-up.

Dr. Lipsky clarifies the distinction between prognostic and predictive biomarkers, emphasizing this is unusually important in CLL. Prognostic biomarkers describe natural disease history (for example, SF3B1 mutation predicting shorter time to first treatment), whereas predictive biomarkers indicate differential treatment outcomes under specific therapies. This distinction matters because a biomarker's predictive value is treatment-dependent.

For TP53 aberrations, occurring in approximately 8% of frontline patients and up to 40% after multiple treatment lines, the data strongly favor continuous covalent BTKi therapy. Patients with TP53 aberrations receiving venetoclax-obinutuzumab may achieve median progression-free survival (PFS) around 4 years, whereas zanubrutinib data shows median PFS not yet reached, with 64% of patients free from progression or death at 6 years.

For IGHV mutational status, Dr. Lipsky notes that unmutated IGHV doesn't exclude any option but does predict different outcomes by treatment strategy. With zanubrutinib monotherapy, IGHV-mutated and unmutated patients show no significant PFS difference at 6 years. With time-limited venetoclax-based therapy, unmutated patients may achieve approximately 5.5 years of PFS versus 9 years for mutated patients based on CLL14 study 9-year follow-up data. Patient preference, however, ultimately drives treatment selection.