Treatment Sequencing and Real-World Evidence in CLL

Dr. Coombs frames sequencing philosophy around patient age and disease trajectory. For 90-year-old patients, single-agent BTK inhibitor therapy with minimal visits represents ideal care without complex sequencing consideration. For patients in their 30s to 50s, the goal is achieving long-term disease control potentially spanning decades, requiring deliberate preservation of subsequent treatment options.

She expresses concern about moving pirtobrutinib to earlier lines in younger patients due to potential shared resistance pathways with covalent BTK inhibitors, though covalent-after-non-covalent sequencing lacks evidence and should not be routinely attempted, the reverse order (covalent then non-covalent) is established. Venetoclax's entirely different mechanism of action allows flexible sequencing before or after BTK inhibitors with no theoretical cross-resistance, supported by growing trial and real-world evidence.

Dr. Lipsky acknowledges the fundamental limitation of designing optimal sequencing studies in CLL. By the time results mature 15 to 20 years later, the treatments being studied may be obsolete. The field's current luxury of multiple effective options means most sequencing decisions avoid catastrophic outcomes.

Dr. Shadman reviews Komodo Health real-world comparative effectiveness data presented at EHA and ASCO comparing zanubrutinib versus acalabrutinib in treatment-naïve CLL, showing zanubrutinib-favoring trends consistent with previous cross-trial comparisons and indirect comparative analyses. He notes real-world databases provide valuable population-level evidence confirming clinical trial signals, particularly for questions like BTK inhibitor selection where head-to-head randomized evidence is limited.