SOHO State of the Art Updates and Next Questions: BTK inhibitors combined with chemoimmunotherapy in CLL, the best of both worlds?

Chemoimmunotherapy (CIT) remains a standard-of-care in many regions for first line (1L) therapy of CLL. In fit patients, fludarabine, cyclophosphamide, and rituximab (FCR) has the advantage of achieving undetectable measurable residual disease (MRD) with time-limited treatment and prolonged treatment-free remissions with a plateau on the PFS curve, but have several limitations, most notably the inferior PFS and survival outcomes for patients with unmutated IGHV compared to ibrutinib + rituximab seen in the E1912 study and a risk for long-term toxicities such as therapy-related myeloid neoplasms. Given the nonoverlapping toxicity profile with CIT and its efficacy in patients with high risk genomics, ibrutinib is a potentially useful agent to combine with CIT, with the aim of achieving deep and durable remissions, with time-limited treatment. Three recent phase 2 studies have combined ibrutinib with chemoimmunotherapy, utilizing different approaches in terms of patient selection, sequencing and duration of therapy and choice of monoclonal antibody. These studies all demonstrated favorable toxicity profiles and higher rates of undetectable MRD than with any other previously utilized 1L regimen. This review will focus on this novel treatment approach in CLL.