Treating CLL After Disease Progression on a Covalent BTK Inhibitor
Chronic lymphocytic leukaemia that progresses during or after a covalent BTK inhibitor represents a high-risk clinical situation requiring prompt reassessment of treatment strategy.
Clinical Scenario
This protocol applies to patients with chronic lymphocytic leukaemia who have received a covalent BTK inhibitor and experienced disease progression on that therapy. This population carries an elevated risk profile and specific treatment pathways are recommended to address the mechanisms of resistance and disease characteristics at relapse.
Treatment Approach
For carefully selected patients in this situation, advanced cellular therapy options may be appropriate — the suitability criteria, specific modalities, and sequencing considerations are addressed in the full protocol.
Complete regimen details, eligibility thresholds, and evidence grades are available in the structured protocol below.
References
- Patients whose CLL progresses on a covalent BTKi should be offered either a venetoclax-based regimen, irrespective of TP53 status (GRADE 1B) or Pirtobrutinib (Grade 1B, EMA, MHRA approved).
- Allogeneic stem cell transplantation remains an option for suitably fit young patients with high-risk CLL; referral should be made early, before all lines of treatment are exhausted (GRADE 2B).
- Chimeric antigen receptor T-cell (CAR-T) therapy is an area of ongoing investigation, with regulatory approval by the FDA for patients who have failed both BTKi and BCL2i therapies.
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