Existing Options for Second-Line Treatment of Patients with R/R CLL

A comprehensive review of existing second-line treatment options for patients with R/R CLL.

Catherine Coombs, MD, MS: We have a lot of different treatment options for second-line therapy in CLL [chronic lymphocytic leukemia]. I’d say we can divide this into a couple of different classes. The first is covalent BTK [Bruton tyrosine kinase] inhibitors. The 2 FDA-approved options in April 2022 are ibrutinib and acalabrutinib. I would say the most important study to consider when selecting between these 2 agents is the ELEVATE-RR trial, which compared acalabrutinib with ibrutinib. What it shows is that these agents are very similarly efficacious. They both have a median progression-free survival [PFS] of 48.4 months with a hazard ratio of 1.0. This was a noninferiority study. However, there were a number of key secondary end points. What we learned from this trial is that acalabrutinib overall appears to have better tolerability when it comes to atrial fibrillation, where they saw all-grade atrial fibrillation at 9% compared to ibrutinib, 16%, and also lower rates of hypertension. The drugs work pretty equally well in my view, but acalabrutinib is likely the better-tolerated drug based upon this very important study.

We also have some data looking at acalabrutinib compared to some other comparators. The ASCEND trial looked at it in comparison to idelalisib with rituximab and BR [bendamustine and rituximab]. We saw that acalabrutinib was superior to that investigator’s choice regimen. That to me provides further evidence to support what I had already said, which is that I favor a BTK inhibitor over a PI3K inhibitor, and also over chemoimmunotherapy.

Another second-line option is venetoclax. The MURANO trial was a very well conducted trial comparing venetoclax and rituximab to bendamustine and rituximab. This showed that Ven-R [venetoclax and rituximab] was significantly better with respect to PFS and OS [overall survival] compared to bendamustine and rituximab. I don’t think that necessarily applies well to this patient, given that he got venetoclax in the frontline setting. But I think we’ll explore later in this discussion the data that we do and do not yet have for venetoclax retreatment. However, I always consider venetoclax in patients who got chemotherapy in the frontline setting, based upon the results of the MURANO trial. I also consider venetoclax in the second-line setting for patients who got BTK inhibitors in the frontline setting. I certainly also consider venetoclax retreatment, but that was not the subject of the MURANO study for the patients who got venetoclax for the first go-round.

Transcript edited for clarity.

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