Combination Treatment Strategies for Patients With Chronic Lymphocytic Leukemia

At the 2026 LL&M Winter Symposium in Amelia Island, Florida, Jacqueline Barrientos, MD,  Mount Sinai Medical Center, Miami, Florida, discusses emerging combination treatment strategies in chronic lymphocytic leukemia (CLL). 

Dr Barrientos highlights the growing role of Bruton's tyrosine kinase (BTK) inhibitor-based doublet and triplet regimens and the evolving use of minimal residual disease (MRD) to guide treatment duration and sequencing.

Transcript: 

My name is Jacqueline Barrientos and I am the chief of hematology malignancies at Mount Sinai Medical Center in Miami Beach. I am delighted to be here participating as a speaker in the L&M Winter Session Symposium.

My talk was about CLL and the combination treatment strategies that are being currently developed in research and in trials. We had prior trials that initially used first generation BTK inhibitor ibrutinib in combination with venetoclax. That regimen is approved outside of the US but not approved in the US. We now have some more data on the use of acalabrutinib in combination with venetoclax and/or zanubrutinib in combination with venetoclax, plus or minus obinutuzumab. Those regimens with the second-generation PTK inhibitors are actually in the NCCN guidelines, even though neither regimen is approved by the FDA yet. We're still waiting to see whether the FDA will feel that the data that they have is strong enough for approval.

We presented the data on the outcomes which are amazing in double to triple therapy. Most of these patients have excellent overall response rate. The time in remission is measured in years and the survival is impressive, including in patients that have traditionally have high-risk markers or prognostic markers such as unmutated IGHV or deletion 17p. I think that the field is moving towards doublets in anyone that can tolerate it, or triplet therapy if there's a patient that has high-risk disease and maybe you need to get them into remission faster.

The role of MRD is changing, and it's changing quite rapidly. As of right now, MRD-driven treatment strategies are not the frontline approach for all. Right now we're still doing fixed-duration treatment strategies. But as we see on the recent data that has been presented, in certain patients that have high-risk disease, the longer the patients that are on these combination treatment strategies, the deeper the response. And with that, they may be able to overcome the known potential for early relapse.

When you look at the data for those patients that did achieve undetectable MRD, they no longer have a very prolonged remission duration. They also have the ability to be rechallenged later on, with these novel drugs in combination and have a response, which is excellent because what it does is you take a drug until you get into an undetectable minimal residual disease, you get off any drug, minimizing the risk for development of clonal selection, minimizes the risk of toxicities, including financial toxicity. Then at the time that you relapse, you may not need therapy immediately, you might just be on active surveillance, and then at the time that you need therapy, be rechallenged again several years later with the same drugs that got you in remission in the first place, and see that you have a good response. 

So, I'm very excited. I think the field is moving so quickly in the last couple of years that I can only expect in the future to get everyone to have a normal lifespan, which we already have shown that is doable when using continuous daily dosing, but ideally it comes at a price of developing some side effects over the years. So ideally, if you can achieve that same remission duration and efficacy in a smaller or shorter period of time, that would be great.

Source: 

Barrientos J. Updates in BTKi + BCL2i combinations. Presented at LL&M Winter Symposium; January 30-February 1, 2026. Amelia Island, Florida.