From Time‐Limited Therapy to Treatment‐Free Observation: The Evolving Role of MRD in CLL Management

The integration of measurable residual disease (MRD) into the management of chronic lymphocytic leukemia (CLL) has emerged as a major advance in risk stratification and trial design, particularly in the context of time-limited, targeted regimens. High-sensitivity MRD assessment, enabled by multicolor flow cytometry, allele-specific oligonucleotide PCR, and next-generation sequencing (NGS), provides a robust, quantifiable measure for depth of remission and long-term outcomes. Landmark trials—including CLL14, MURANO, CAPTIVATE, and GLOW—have consistently demonstrated that achieving undetectable MRD (uMRD) strongly predicts prolonged progression-free survival (PFS) and overall survival (OS), within a range of chemoimmunotherapy and venetoclax-based time-limited regimens. In selected clinical trials, MRD assessment has been prospectively incorporated into strategies exploring time-limited therapy and MRD-adapted discontinuation, although routine MRD-guided decision-making in clinical practice remains investigational. CLL research is increasingly focused on treatment-free observation in select patients achieving deep and sustained remissions, with MRD playing a central prognostic role. Emerging technologies, including circulating tumor DNA (ctDNA) monitoring and artificial intelligence (AI)-driven predictive modeling, promise to further refine risk stratification and personalize therapy. This review summarizes the current evidence supporting MRD as a prognostic biomarker and clinical trial endpoint, discusses investigational MRD-adapted strategies, and outlines future directions—including ctDNA and AI-based tools—that may ultimately support more individualized treatment duration and treatment-free observation in CLL.