First-Line CLL Treatment Framework

Dr. Marc Hoffmann introduces the program on optimizing CLL treatment strategies, noting that CLL remains the most common adult leukemia in the Western world with approximately 20,000 new annual US diagnoses. The panel includes Drs. Catherine Coombs, Andrew Lipsky, Sameer Parikh, and Mazyar Shadman.

Two major frontline strategies dominate 2026 practice: continuous covalent BTK inhibitor therapy with zanubrutinib or acalabrutinib, and fixed-duration venetoclax-based combinations including venetoclax-obinutuzumab and the recently FDA-approved acalabrutinib-venetoclax. Additional NCCN-listed options include MRD-guided zanubrutinib-venetoclax and acalabrutinib-venetoclax-obinutuzumab triplet therapy. Chemoimmunotherapy has been largely retired.

Dr. Coombs explains her individualized approach, emphasizing there is no one-size-fits-all strategy. Key factors include patient comorbidities, concomitant medications, treatment preference (continuous therapy versus time off treatment), and underlying CLL biology, particularly TP53 status (del(17p) and/or TP53 mutation) and IGHV mutational status. True absolute contraindications are rare; severe ventricular arrhythmias may discourage BTK inhibitors, whereas severe renal impairment complicates venetoclax-based ramp-up.

Patient preference often supersedes molecular risk factors. Younger patients frequently value time off therapy despite the logistical demands of venetoclax ramp-up, whereas older patients often prefer continuous BTK inhibitor convenience but may have significant AFib concerns, though AFib risk is substantially lower with zanubrutinib and acalabrutinib compared to ibrutinib. Dr. Parikh adds that bulky lymphadenopathy exceeding 5 centimeters may favor BTK inhibitor selection given potentially superior lymph node penetration and inferior venetoclax-obinutuzumab progression-free survival (PFS) observed in CLL14 for patients with bulky disease.