MRD-driven treatment strategies in CLL: Current practice, limitations, and emerging paradigms.

Measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL) has evolved from a research tool to a central endpoint in modern clinical trials and is increasingly shaping treatment individualization. During the chemoimmunotherapy era, a strong association between MRD status and long-term outcomes positioned MRD as a surrogate marker for remission durability in selected contexts. With the widespread adoption of targeted therapies, however, the clinical meaning of MRD has become treatment-class and biology dependent. In time-limited venetoclax-based regimens, achieving undetectable MRD (uMRD) strongly predicts durable off-treatment remission. In contrast, in continuous BTK inhibitor-based therapy, conventional MRD thresholds are less prognostic, and durable disease control can occur despite persistent low-level disease. This review summarizes the current technical landscape of MRD assessment, including major testing platforms, sensitivity thresholds, and specimen considerations, and highlights practical factors that influence interpretation in routine practice and clinical trials. The role of MRD across contemporary therapeutic classes is examined, with particular emphasis on emerging combination strategies. Results from MRD-guided combination trials demonstrate that tailoring treatment duration to depth and trajectory of MRD clearance is feasible, safe, and capable of producing outstanding long-term outcomes, including survival rates exceeding those achieved with prior standards. These data provide the strongest prospective evidence to date that MRD can function not merely as a prognostic marker, but as a therapeutic guide when applied within regimens capable of deep disease eradication. Interpretation of MRD in biologically defined subgroups, including TP53-disrupted and IGHV-unmutated disease, as well as its evolving role following immune-based therapies, is also considered. We address the principal barriers to routine clinical implementation, along with the key questions being addressed by ongoing randomized studies that will determine whether MRD fully transitions from a prognostic biomarker to a practical therapeutic guide in CLL.