Q&A with Dr. Nicole Lamanna: The Latest Advances in CLL Treatment and Research

What’s new—and what’s next—in chronic lymphocytic leukemia (CLL)? Columbia oncologist Nicole Lamanna, MD, shares updates on emerging therapies and research. 

CLL treatment has changed significantly over the last decade. What are the latest developments?

Yes, it’s really been a paradigm shift from chemotherapy, moving towards targeted treatment approaches using new classes of inhibitors and other agents. We’ve made major strides with targeted therapies, but it’s important to remember that these treatments are not curative – patients often relapse. That’s why ongoing research is so important. Right now, there are three main classes of FDA-approved targeted therapies: covalent BTK inhibitors, BCL-2 inhibitors like venetoclax, and non-covalent BTK inhibitors like pirtobrutinib, which was just FDA-approved in late 2023. 

As clinicians and researchers, we work to understand how and when we use these drugs—particularly in time-limited combinations that can help patients achieve remission without staying on therapy indefinitely. 

Why is combination therapy such a big focus in CLL research? 

Most patients today may initially be treated with a daily BTK inhibitor like acalabrutinib or zanubrutinib until it stops working (i.e., they develop resistance and the cancer progresses), or if they have unmanageable side effects. This is a very effective therapy for many patients and is certainly convenient as a daily oral medication. The problem with chronic BTK inhibitor therapy is that once resistance occurs, you can’t typically go back to that therapy, so we have to move on to yet another therapy. We are constantly working to combat this eventual treatment resistance – and one way we can try to do that is to limit the amount of time patients take a certain drug to achieve remission, so they don’t develop resistance. That way we can go back to that therapy later if needed. 

If their cancer progresses, at that point, treatment is often changed to a time-limited course of venetoclax (a BCL2 inhibitor and an oral medicaiton) with rituximab or obinutuzumab (an anti-CD20 monoclonal antibody and given intravenously).  

We’re also exploring all-oral combinations—like BTK and BCL-2 inhibitors—without the need for the intravenous monoclonal antibody therapy.  This will be a gamechanger in terms of patient convenience and quality of life and could help with resistance since most of these combination therapies are also being given in a time-limited fashion. We anticipate the first BTK-BCL-2 combination to be FDA approved in the near future.  

At Columbia, we’re a site for the CELESTIAL study, which is testing a next-generation BCL-2 inhibitor, sonrotoclax, in combination with zanubrutinib. The goal is to develop an even safer, more effective oral regimen that doesn't require intravenous infusions or indefinite use. 

What’s exciting about pirtobrutinib (pirto), the newer non-covalent BTK inhibitor?

Pirtobrutinib is another oral therapy and especially promising because it works even after patients develop resistance to a covalent BTK inhibitor like acalabrutinib or zanubrutinib. It also works in patients who have relapsed after venetoclax. It’s very well tolerated by many patients and there are several studies looking at this therapy in earlier lines of treatment. We’re also studying whether time-limited courses of pirtobrutinib can provide deep remissions without long-term use. 

We have trials here at Columbia evaluating pirtobrutinib alone and in combination with other agents—looking not just at efficacy but also whether we can minimize side effects and resistance. 

CAR T-cell therapy was just approved for CLL in March 2024. What does that mean for patients?

It means another potential option for therapy. CAR T therapy took longer to be approved in CLL because of initial concerns regarding toxicity and because we have other effective treatment options. The side effect profile of CART therapy has also become more manageable given that this type of therapy has now been used for quite some time in a variety of other disease types. For certain CLL patients—especially those with high-risk or multiply relapsed disease—it can offer durable responses. It won’t be for everyone, but it’s another important tool in our toolkit. 

We’re part of national trials that helped pave the way for CAR T approval in CLL, and we continue to offer it to eligible patients at Columbia through our cell therapy and transplant program. 

Are there any other novel therapies that you’re watching closely?

Yes, bispecific antibodies like epcoritamab and others are generating a lot of interest. While some of these therapies are currently approved for large B-cell lymphoma and follicular lymphoma, they are showing promising activity in CLL as well. These drugs help the immune system directly target cancer cells by binding to both the T-cells and the B-cells, thereby activating the T-cells to directly kill the malignant B-cells. They’re currently in clinical trials as single agents and in combination with other therapies, including in patients with aggressive, transformed CLL.  

Another exciting new class of agents in development are BTK degraders. Unlike traditional BTK inhibitors, which block BTK activity, these degraders eliminate the BTK protein entirely, offering a promising solution to overcome the resistance mutations that can develop with BTK inhibitors. These are still in early clinical trials, and the potential is exciting. 

What’s next in CLL research? 

We’re focused on understanding resistance mechanisms and identifying better biomarkers to guide treatment decisions. At Columbia, we’re leading a number of investigator-initiated trials and collecting patient samples for in-depth genomic and molecular studies. This translational work is crucial—it helps us figure out why certain treatments stop working and how we can intervene earlier or more effectively. It helps us keep pushing the science forward. For patients at Columbia, it also means access to cutting-edge therapies through clinical trials, often before they’re widely available. 

The future of CLL treatment lies not only in better drugs but in using what we already have in new combinations—and hopefully getting patients to deep remissions without indefinite therapy.