Clinical Scenario Presentation and Treatment Approach for Progressive Disease

Dr. Marin Xavier and Dr. Raji Shameem introduce their discussion on optimizing second-line therapy in CLL after covalent BTK inhibitor (BTKi) exposure. They present the first scenario involving a 66-year-old man diagnosed with CLL 5 years ago, IGHVunmutated without TP53 mutation at diagnosis, who received first-line continuous covalent BTKi therapy for 4 years achieving partial response.

The patient currently experiences progressive lymphadenopathy and rising absolute lymphocyte count with ECOG performance status 1, no active B symptoms, white blood cell count of 72,000 (increased from 35,000), hemoglobin 11.4 g/dL, and platelets 145,000. CT imaging shows enlarging cervical and abdominal nodes with largest measuring 4.2 cm. Mutational testing revealed BTKC481S mutation and acquired TP53 mutation. The patient has no significant cardiovascular history and expresses preference for similar treatment if possible, having tolerated current therapy well.

Dr. Shameem emphasizes this represents a common clinical scenario where patients receive frontline covalent BTKis and progress, creating challenging second-line treatment decisions. Initial assessment involves confirming true progression based on progressive lymphadenopathy and rising absolute lymphocyte count, which this patient demonstrates despite absence of B symptoms and only mild anemia with normal platelet count. Patient baseline comorbidities require evaluation, including cardiac history, atrial fibrillation status, anticoagulation use, and renal function, particularly when considering BCL-2 inhibitor (BCL-2i)-based therapy regimens due to tumor lysis syndrome risk.

Patient preference represents a crucial decision-making factor, with this patient expressing desire for similar therapy suggesting inclination toward continued oral targeted therapy rather than alternative approaches. Dr. Shameem suggests that for CLL, patient preference often dictates treatment selection, acknowledging that many patients become accustomed to continuous oral dosing convenience and seek familiar approaches upon progression.