Managing Early Relapse of CLL & Treatment Selection After Frontline Therapy

This segment examines the management of patients who relapse after frontline therapy, a growing area of complexity given the expanding number of targeted agents and sequencing considerations. The panel begins by distinguishing between patients relapsing after BTKi therapy versus those whose initial regimen was venetoclax-based and time-limited.

For patients progressing after a covalent BTKi, venetoclax-based combinations remain the preferred next step, supported by robust clinical experience and durable remissions. The faculty notes that intolerance versus progression matters: patients who stop a BTKi due to toxicity may have different subsequent treatment expectations than those progressing biologically. In contrast, patients relapsing after fixed-duration venetoclax can often be treated effectively with a covalent BTKi, and sequencing between classes generally yields strong outcomes.

The panel also discusses the importance of evaluating disease tempo and biology at relapse. Rapid progression or aggressive symptoms may prompt an urgent switch to a BTKi, whereas more indolent relapse creates time for venetoclax ramp-up. Molecular profiling, including TP53 disruption and evolving resistance mechanisms, can inform sequencing, although real-world practice often prioritizes clinical urgency.

Safety remains a critical consideration: cardiovascular risks may steer clinicians away from certain BTKis, whereas tumor lysis syndrome risk guides venetoclax use. The conversation also touches on venetoclax retreatment evidence, laying the groundwork for deeper later-segment discussion. Treatment decisions after first relapse rely on a combination of prior therapy, patient factors, disease behavior, and emerging evidence regarding cross-resistance and sequencing.