Chronic Lymphocytic Leukemia: Evolving Management With New Data From EHA 2025 - Episode 16
Additional Considerations in Sequencing Relapsed/Refractory CLL
Panelists discuss how sequencing therapy after covalent Bruton tyrosine kinase (BTK) inhibitor progression involves choosing between noncovalent BTK inhibitors like pirtobrutinib or venetoclax-based therapy, with the traditional approach favoring venetoclax second-line followed by pirtobrutinib third-line based on available data, while acknowledging that current studies reflect heavily pretreated patients and may not represent the superior outcomes expected in earlier-line settings, and highlight promising early results from zanubrutinib plus venetoclax combinations showing 96% overall response rates and high undetectable minimal residual disease rates in phase 1 studies.
Additional Considerations in Sequencing Relapsed/Refractory CLL
Treatment sequencing decisions after covalent BTK inhibitor progression present complex clinical challenges, with multiple viable options but limited comparative data to guide optimal approaches. The traditional developmental pathway suggests a natural sequence from covalent BTK inhibitors to BCL2 inhibitor therapy, followed by noncovalent BTK inhibitors like pirtobrutinib. This approach is supported by substantial prospective and retrospective data demonstrating venetoclax efficacy after BTK inhibitor progression, combined with evidence showing pirtobrutinib effectiveness following venetoclax treatment. However, direct progression from covalent to noncovalent BTK inhibitors represents an alternative strategy supported by the BRUIN 3-to-1 study, although long-term follow-up data comparing these sequencing approaches remain limited.
A critical limitation in current evidence stems from the patient populations studied in pivotal trials, which predominantly included heavily pretreated patients with multiple prior therapies, often including chemotherapy. These data may not accurately reflect outcomes for patients receiving modern sequencing in earlier treatment lines, where patients transition directly from frontline covalent BTK inhibitor therapy to second-line treatment without extensive prior exposure. The median progression-free survival of approximately 30 months observed with venetoclax after covalent BTK inhibitors in registry studies, although encouraging, must be interpreted cautiously given the heavily pretreated nature of these cohorts. Patients receiving venetoclax as true second-line therapy after single-agent BTK inhibitor progression would likely achieve superior outcomes.
Emerging combination approaches, including pirtobrutinib plus naveclax, represent promising future treatment options that may reshape sequencing considerations. Early phase 1 data from this combination demonstrate excellent safety profiles without dose-limiting toxicities, along with impressive efficacy, including 96% overall response rates and 50% complete response rates. The achievement of undetectable minimal residual disease in approximately 50% to 60% of patients at the 10–4 level represents particularly encouraging findings for fixed-duration combination approaches. The ongoing SEQUEL trial comparing pirtobrutinib plus naveclax to standard options will provide crucial comparative efficacy data. As these novel combinations mature and gain regulatory approval, they may offer superior outcomes that could influence optimal sequencing strategies for patients with relapsed/refractory chronic lymphocytic leukemia (CLL).
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