Chronic Lymphocytic Leukemia: Evolving Management With New Data From EHA 2025 - Episode 2
Choosing the Right First-Line CLL Therapy—Patient Factors and Oral Fixed-Duration Doublets
Panelists discuss how first-line chronic lymphocytic leukemia (CLL) therapy selection balances prognostic testing results with individual patient factors, weighing continuous Bruton tyrosine kinase (BTK) inhibitor therapy vs fixed-duration venetoclax-based regimens based on patient preferences for pill vs infusion treatment, comorbidities like cardiac issues, and the emerging role of oral BTK inhibitor–venetoclax doublets for appropriate candidates.
Choosing the Right First-Line CLL Therapy—Patient Factors and Oral Fixed-Duration Doublets
The current frontline treatment landscape for CLL presents clinicians with 2 primary therapeutic paradigms: continuous treatment with second-generation covalent BTK inhibitors or fixed-duration therapy with venetoclax-based combinations. Without head-to-head comparative data demonstrating superior efficacy of one approach over another, treatment selection largely depends on individual patient preferences and clinical factors. The treatment paradigm is expected to evolve over the next year as new data emerge and additional drug classes potentially receive approval for use with or without rituximab in combination regimens.
Patient-specific factors play a crucial role in therapeutic decision-making beyond genomic risk stratification. Treatment selection often centers on patient lifestyle preferences, including whether they prefer oral medication with regular clinic visits for monitoring vs infusion-based therapy with more intensive up-front scheduling. Specific clinical contraindications can guide treatment choice, such as avoiding BTK inhibitors in patients with significant cardiac arrhythmias or severe ventricular tachycardia due to potential cardiac toxicity concerns. For patients requiring anticoagulation therapy, fixed-duration approaches may be preferable to minimize bleeding risks associated with continuous BTK inhibition.
Oral doublet combinations using BTK inhibitors with venetoclax represent an emerging fixed-duration approach, although questions remain about optimal patient selection. High-risk patients with TP53 disruption, 17p deletion, and complex karyotype continue to show inferior outcomes even with these intensive regimens, suggesting a potential need for triplet combinations or more intensive therapeutic approaches in this population. The Captain study data demonstrate excellent outcomes with progression-free survival exceeding 5½ years, although results remain suboptimal for the highest-risk genomic subgroups. Most patients appear suitable candidates for oral doublet therapy regardless of IGVH mutation status, with few absolute contraindications beyond affordability concerns. Toxicity profiles have improved with better-tolerated drug combinations, making these approaches increasingly feasible for broader patient populations.
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