Advances in CLL Monitoring and Prognosis

Sanam Loghavi, MD, assistant professor, Department of Hematopathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, discusses the essential genetic and molecular evaluations for newly diagnosed chronic lymphocytic leukemia (CLL) and how these findings guide treatment selection and prognosis. She outlines the importance of sequencing the immunoglobulin heavy chain variable region (IGHV) to determine whether the gene is mutated or unmutated. Unmutated IGHV (<2% deviation from germline) is associated with reduced responsiveness to chemoimmunotherapy and worse outcomes.

Dr. Loghavi emphasizes the role of identifying somatic mutations, particularly TP53 mutations, which confer resistance to standard chemoimmunotherapy due to impaired apoptosis pathways. These cases often require targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors. She also highlights the significance of assessing clonal complexity using various modalities, including fluorescence in situ hybridization to detect TP53 deletions, since not all alterations are point mutations.

The discussion transitions to measurable residual disease (MRD) monitoring, which has become a cornerstone in the management of CLL. Earlier MRD detection relied on flow cytometry with a sensitivity of approximately 10⁻⁴ (one in 10,000 cells). Advances in next-generation sequencing now allow sensitivity to 10⁻⁶, enabling detection of very small residual disease burdens. However, questions remain regarding the prognostic thresholds for MRD positivity and the optimal point for discontinuing therapy.

Dr. Loghavi notes that while modern therapies and MRD-guided surveillance have markedly improved patient outcomes, a subset of patients, especially those with TP53 mutations or other adverse genetic markers, continue to experience aggressive disease. Ongoing research aims to determine how to eradicate persistent CLL clones effectively while minimizing treatment-related toxicity.