My Treatment Approach: Shared Decision-Making in CLL: Balancing Safety, Efficacy, and Patient Preference in CLL - Episode 6
BTKi Dose Modification: Preserving Efficacy While Managing Toxicity in CLL Therapy
Panelists discuss how chronic lymphocytic leukemia treatment has evolved from universal single-agent BTKi use to personalized approaches based on patient risk factors like IGHV mutation status and TP53 mutations, with growing excitement about fixed-duration oral doublet therapies combining BTKis with venetoclax that show promising efficacy despite lower MRD rates compared with antibody-containing regimens, while addressing the management of BTKi class effects including cardiovascular events, hypertension, bleeding, diarrhea, and rash through dose-modification strategies that have become preferred over drug switching, particularly for ibrutinib, where robust long-term data support maintained efficacy with dose reductions from 420 mg to 280 mg daily, though similar dose reduction evidence is less established for second-generation BTKis like acalabrutinib and zanubrutinib.
This segment discusses Bruton tyrosine kinase inhibitor (BTKi) dose-modification strategies for managing toxicity while preserving efficacy in chronic lymphocytic leukemia therapy. The experts emphasize that their approach to dose reduction has remained consistent over time, though the rationale has evolved. In 2016, when fewer treatment options were available, maintaining patients on BTKis was critical since alternative small molecule therapies weren’t accessible. Today, while more options exist, dose reduction remains a preferred first-line strategy for managing adverse events like rash, combined with patient reassurance that most adverse effects improve over time through tachyphylaxis.
The discussion reveals robust evidence supporting dose-reduction efficacy, particularly for ibrutinib. Long-term follow-up data and pharmacokinetic studies from MD Anderson demonstrate that reducing ibrutinib from 420 mg to 280 mg maintains equivalent progression-free survival and overall survival outcomes. The optimal ibrutinib dosing appears to be 2.5 to 3 mg/kg, supporting the effectiveness of reduced doses. However, if further reduction to 140 mg is necessary, experts recommend attempting re-escalation to at least 280 mg due to limited long-term data at the lowest dose level. The evidence also supports attempting dose re-escalation after adverse events resolve, though many patients can remain successful on reduced doses long-term.
Differences exist among BTKis regarding dose-modification flexibility and evidence. While ibrutinib allows flexible dose reduction while maintaining twice-daily scheduling, acalabrutinib presents challenges because it comes in only 1 dose strength, requiring conversion to once-daily dosing for reduction, which may compromise drug coverage based on pharmacokinetic data. Some evidence suggests that treatment interruptions exceeding 14 days with acalabrutinib may impact outcomes, particularly in relapsed/refractory patients. For zanubrutinib, limited dose-modification data exist, though its superior selectivity profile may provide theoretical advantages. The experts note that dose reduction is often more practical than switching therapies, involving less patient counseling and avoiding potential new adverse effects from alternative agents.
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