Catherine C. Coombs, MD: There are very few patients for whom I would add an anti-CD20 agent to the BTK [Bruton tyrosine kinase] inhibitor if it’s a BTK-based treatment. The reason is based on the results of several clinical trials. In the context of venetoclax, I often add a CD20 inhibitor because the pivotal trials demonstrating a superiority of venetoclax-based regimen were paired with a CD20 agent. We don’t have randomized comparisons of venetoclax by itself to venetoclax with the CD20. Typically, I add a CD20 to venetoclax-based regimens, but I do not do so with BTK-based regimens. The exception to that is if there is a separate indication for an anti-CD20 agent, which primarily would be a patient with CLL [chronic lymphocytic leukemia] and an active autoimmune hemolysis or autoimmune cytopenia that would have a separate indication for the anti-CD20.

E1912 was a pivotal trial that demonstrated the superiority of an ibrutinib-containing regimen to the prior gold standard therapy of FCR: fludarabine, cyclophosphamide, and rituximab. The standard arm was compared with the investigational arm, which is ibrutinib plus rituximab, because at the time of the study design it was not clear whether rituximab had an added benefit to ibrutinib.

The study was a 2:1 randomization and the ibrutinib-rituximab arm demonstrated superiority both from a progression-free survival [PFS] and an overall survival [OS] standpoint. However, 2 other studies did compare ibrutinib-rituximab with ibrutinib by itself, which is my main reasoning for not adding rituximab to the majority of patients. The first trial that demonstrated no added benefit from a PFS or OS standpoint with the addition of rituximab to ibrutinib was the Alliance trial published by Jennifer Woyach, et al, in 2018. That was a 3-arm study, and both ibrutinib-containing regimens—the ibrutinib monotherapy and the ibrutinib-rituximab regimens—were superior to bendamustine-rituximab in older adults with CLL. However, there is no difference in the patients who received ibrutinib by itself vs the patients receiving ibrutinib with rituximab.

A randomized phase 2 trial published by Jan Burger, et al, in Blood, 2019 was mostly relapsed-refractory CLL patients, though there were some up-front CLL patients who had the same findings. It demonstrated no added benefit either from a PFS or OS standpoint when adding rituximab to ibrutinib.

ELEVATE-TN is a recent phase 3 trial that compared 3 different regimens: acalabrutinib monotherapy, acalabrutinib with obinutuzumab, and a previously accepted standard-of-care regimen chlorambucil with obinutuzumab. This study demonstrated the superiority of the acalabrutinib-containing regimens compared with the prior standard of care, chlorambucil with obinutuzumab.

There was a post-talk analysis to this study that seems to suggest a potential benefit of adding obinutuzumab to acalabrutinib, but the added benefit is modest at best. At this time I do not add obinutuzumab to my patients getting acalabrutinib because the benefit is pretty modest, and it does add toxicity. The main toxicities that seem to be exaggerated in the acalabrutinib-obinutuzumab–treated patients, compared with the acalabrutinib-only–treated patients, were an increased risk of infusion-related reactions and an increased risk for infections. It’s not clear that the benefit of adding that drug is worth the potential cost, both financially and with respect to toxicity.

Transcript Edited for Clarity