Researchers seeking to optimize the frontline treatment of chronic lymphocytic leukemia (CLL) are evaluating different combinations of currently available agents. Newer combinatorial strategies might be of interest, particularly in previously untreated, higher-risk CLL.

We have the established doublets, such as venetoclax plus obinutuzumab, a regimen that tends to be used more at academic centers than in the community. And then, in terms of doublets that incorporate BTK inhibitors, we can go back several years to the trial that led to the US Food and Drug Administration approval of obinutuzumab plus ibrutinib (ie, the phase 3 iLLUMINATE study). However, that trial did not have a control arm for ibrutinib alone. In the phase 3 ELEVATE-TN trial, there were 3 arms: chlorambucil plus obinutuzumab, acalabrutinib alone, and acalabrutinib plus obinutuzumab; this is really the only frontline trial in which we have a direct comparison of a BTK inhibitor alone and with an antibody.

In ELEVATE-TN, there appeared to be a benefit for the entire population in terms of progression-free survival with acalabrutinib plus obinutuzumab. But when you look at the high-risk patients, namely those with 17p-deleted or TP53-aberrant CLL, there does not appear to be a benefit from adding obinutuzumab to acalabrutinib. If you are going to start with a BTK inhibitor, the question arises: Do you add an antibody or not? I think that this is a complicated question that comes down to whether the suppression of the immune system with obinutuzumab treatment is worth the slight edge in terms of longer progression-free survival in the overall population. Now, if the survival curve with the combination really continues to look better, I think that this might make the question less complicated. However, any potential survival benefit in the combination arm is confounded by the fact that the patients progressing on chlorambucil (and obinutuzumab) were allowed to cross over, but only to the single-agent acalabrutinib arm.

As relates to the newer investigational doublet and triplet therapies that are garnering a lot of interest, there are several of them, including those that are being studied in the phase 3 AMPLIFY trial and the phase 2 BOVen trial. There had also been a fair amount of excitement generated by the phase 2 CAPTIVATE trial, which is evaluating fixed-duration ibrutinib plus venetoclax in patients aged 70 years or younger; however, that combination does not seem to be on the path to regulatory approval in the United States. The ongoing randomized AMPLIFY trial is evaluating the combination of acalabrutinib and venetoclax, with or without obinutuzumab, in patients with previously untreated CLL. There is a high bar to clear for this triplet, because doublet therapies can have a minimal residual disease undetectability rate of 60% to 80%. The ongoing multicenter BOVen trial is evaluating the combination of zanubrutinib, obinutuzumab, and venetoclax in patients with previously untreated CLL or small lymphocytic lymphoma, and this trial is using an undetectable minimal residual disease–driven treatment discontinuation design.

The GAIA (CLL13) trial has been presented several times and is a large, 4-arm, randomized trial done in Europe and conducted in a population that does not have TP53 aberrations. In this trial, they do have a venetoclax-plus-obinutuzumab arm as well as a venetoclax-plus–ibrutinib and obinutuzumab arm, and I would say that, at 3 years, these triplet and doublet arms look pretty similar. Will that be true at 5 years? We do not know.