Approaches for relapsed CLL after chemotherapy-free frontline regimens

Novel agents, including Bruton's tyrosine kinase inhibitors (BTKi; ibrutinib, acalabrutinib), venetoclax, and phosphatidylinositol 3-kinase inhibitors (PI3Ki; idelalisib, duvelisib), have fundamentally changed the chronic lymphocytic leukemia (CLL) treatment landscape, allowing for a chemotherapy-free paradigm for many. Randomized trials that demonstrated efficacy of these agents in the relapsed/refractory setting rarely included patients with prior novel agent exposure. Herein, we review available data, including single-arm prospective studies and retrospective cohorts, on outcomes for novel agent approaches after novel agent exposure. We examine data for subsequent treatment options in 3 specific scenarios: (1) progression of disease while receiving BTKi, (2) progression of disease after discontinuation of BTKi for intolerance, and (3) after treatment with venetoclax. Data are most robust for venetoclax-based regimens after progression on BTKi. For patients who experience progression of disease after discontinuation of BTKi for intolerance, venetoclax-based regimens and retreatment with BTKi (depending on severity of initial intolerance) are 2 data-driven options. After frontline venetoclax/obinutuzumab, subsequent treatment approaches depend on whether patients experience progression of disease during or after discontinuation of their fixed duration frontline regimen and whether venetoclax/obinutuzumab was discontinued for intolerance. After progression of disease while on venetoclax, we recommend BTKi as second-line therapy. For patients who experience progression after completion or premature discontinuation (because of intolerance) of fixed duration venetoclax/obinutuzumab, either BTKi or retreatment with venetoclax (with aggressive supportive care if prior intolerance) are reasonable considerations. Subsequent lines of therapy in these scenarios include PI3Ki and consideration of cellular therapies. Finally, clinical trial enrollment for interested patients in any line of therapy is recommended.