Chronic Lymphocytic Leukemia: Evolving Management With New Data From EHA 2025 - Episode 13
Reevaluating Risk in Relapsed CLL—the Role of Biomarkers and Treatment History
Panelists discuss how biomarker retesting at relapse should include cytogenetics and fluorescence in situ hybridization to detect clonal evolution, Bruton tyrosine kinase (BTK) resistance mutations in patients progressing on BTK inhibitors, and molecular panels to identify new mutations that may predict transformation risk. Real-world registry data demonstrate that venetoclax-based therapy remains highly effective after BTK inhibitor progression, with progression-free survival of 30 to 35 months, providing crucial benchmarks for treatment sequencing decisions in the absence of prospective clinical trial data.
Reevaluating Risk in Relapsed CLL—the Role of Biomarkers and Treatment History
Biomarker reassessment at the time of relapse represents a critical component of treatment planning, as disease characteristics can evolve during treatment and impact subsequent therapeutic decisions. Although IGVH mutation status remains stable over time, cytogenetic abnormalities can change significantly, with patients potentially developing new high-risk features such as 17p deletion or complex karyotype that were not present at initial diagnosis. This evolution from standard-risk to high-risk disease biology directly influences treatment selection and expected outcomes for subsequent therapy lines. Although some argue that biomarker reassessment may be less relevant given the effectiveness of targeted therapies, understanding the current risk profile helps clinicians counsel patients about treatment duration expectations and tailor therapeutic approaches accordingly.
Resistance mutation testing has become increasingly important for patients experiencing progression on BTK inhibitor therapy, particularly for identifying specific BTK resistance mutations that may inform future treatment decisions. Although many patients may not have identifiable resistance mutations at progression, testing provides valuable information for potential treatment sequencing strategies as more data become available about mutation-specific therapeutic approaches. Comprehensive molecular panels help identify new mutations that may have developed during treatment, including those associated with increased transformation risk, providing crucial prognostic information for immediate treatment planning and long-term disease monitoring strategies.
Real-world evidence addressing treatment sequencing after frontline BTK inhibitor therapy has provided essential benchmarks for clinical practice, particularly regarding venetoclax-based therapy effectiveness in this setting. Analysis of registry data from academic centers examining patients who progressed directly on BTK inhibitors and subsequently received venetoclax-based treatment revealed progression-free survival outcomes of 30 to 35 months, demonstrating robust efficacy in this challenging patient population. These real-world data are particularly valuable given the absence of prospective clinical trials specifically addressing this sequence, as pivotal venetoclax studies excluded patients with prior BTK inhibitor exposure. The registry-based approach provides high-quality evidence to inform treatment decisions while acknowledging that these patients represent some of the most difficult cases to treat, having experienced progression rather than discontinuation due to intolerance on their frontline therapy.
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