Novel therapies have become an increasingly important part of the treatment armamentarium for chronic lymphocytic leukemia (CLL), and several combination regimens are currently under investigation. Our expert panel discusses US Food and Drug Administration (FDA)–approved treatments and potential future therapeutic options for patients with CLL.

Being able to say, “I’m done with treatment,” after completing a fixed-duration regimen is an important goal for many of our patients. Currently, in the United States, the only FDA-approved, fixed-duration combination therapy in the frontline setting is venetoclax plus obinutuzumab. However, there is a subset of patients with del(17p) in whom we do not expect to see durable progression-free survival (PFS) with this treatment; in these patients, continuous BTK inhibitor–based treatment remains the most appropriate initial frontline treatment strategy.

Over the past decade, there have been attempts to develop an all-oral, fixed-duration combination treatment strategy in the frontline setting. Excellent responses have been observed with the combination of ibrutinib plus venetoclax, with many patients achieving undetectable measurable residual disease (uMRD). This regimen is approved by the European Medicines Agency (EMA) but not the FDA. Other doublet regimens are now being tested, particularly acalabrutinib plus venetoclax and zanubrutinib plus sonrotoclax. These combinations are not FDA approved, and the data with them are premature, but I am really looking forward to their potential future use in the clinic.

With respect to triplet therapies, there currently are not enough head-to-head comparison studies with longer-term follow-up available to help us determine whether a triplet is necessary. The exception is the GAIA/CLL13 trial, which compared the combination of venetoclax, obinutuzumab, and ibrutinib with venetoclax plus obinutuzumab, venetoclax plus rituximab, and chemoimmunotherapy. There was a numerically higher PFS with the triplet regimen compared with venetoclax plus obinutuzumab, but it was not statistically different. At the current time, I do not think that we should be using triplets in routine practice because they are not FDA approved and there may be a risk of excess toxicity. For now, I am most excited about the doublets with covalent BTK inhibitors and a Bcl-2 inhibitor in the frontline setting.

I agree with Dr Parikh. It is not obvious to me that one regimen is better than the next, and I tend to prefer a 2-drug regimen over a 3-drug regimen until we know more. I think that the potential combinations of a covalent BTK inhibitor with venetoclax or another Bcl-2 inhibitor are quite exciting. The notion of having all-oral regimens is also appealing to patients. By having a lead-in with the BTK inhibitor, you can often reduce the risk of tumor lysis syndrome, making that regimen easier. However, I would say that I still commonly use venetoclax plus obinutuzumab as my go-to doublet regimen in the frontline setting.

The other layer of complexity here, however, is determining the proper end point. Should we only be stopping treatment if a patient has uMRD? Should we be making different choices in different patient populations, such as those with high-risk cytogenetics, del(17p), or bulky disease? Do some patients require longer-term therapy? Today, we really do not know. I am tempted to continue a BTK inhibitor in someone who still is MRD positive after 1 year of treatment, especially in patients who have del(17p) or other genetic abnormalities.

I think that we will have to wait until we have more outcome data to know the answers to these questions. Just because a patient progresses a little bit earlier does not necessarily mean that the long-term outcome is better for them if they continue therapy. At this point, I would generally use a 2-drug regimen for the vast majority of my patients. There is always the option to end therapy after 1 year.

Dr Flinn pointed something out that is really important, and that is the duration that the drugs are used. Especially with the covalent BTK inhibitor–plus-venetoclax regimens. I often see 1 or both drugs continued based on detectable MRD without proof that it is necessary or that it leads to better outcomes. I think that this also makes it difficult to interpret differences across trials.

The CAPTIVATE study reported interesting data indicating that a lower percentage of patients with mutated IGHV achieve uMRD. However, their rate of uMRD remained stable through the follow-up period. The study also indicated that a higher fraction of people with IGHV-unmutated disease become uMRD, but that rate drops over time and people’s CLL returns to being detectable in the blood. If we treated based on MRD, patients with IGHV-unmutated disease would get much more treatment, despite this group of patients having good PFS when therapy was stopped. So, MRD may not be a good surrogate end point if we do not take mutational status into account.

It is unclear that the addition of an anti-CD20 antibody to a BTK inhibitor and venetoclax to form a triplet therapy is necessary. With the exception of adding obinutuzumab to acalabrutinib, anti-CD20 antibodies have not facilitated a substantial improvement in BTK inhibitor efficacy. Therefore, I would not expect that triplet therapies would result in a massive improvement over doublets, although we do not yet have the data to say that for sure.