Integrating Real-World Evidence and Clinical Trial Data in CLL Management

In this interview, Matthew S. Davids, MD, MMSc, discusses the role of real-world evidence in chronic lymphocytic leukemia (CLL) management, treatment considerations for high-risk and comorbid patients, strategies for therapy discontinuation, and advancements in combination regimens and novel therapies.

Please state your name, title, and any relevant clinical experience you'd like to share.

Matthew S. Davids, MD, MMSc: I'm Dr Matthew Davids, the clinical research director for the Division of Lymphoma at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School in Boston. I've been a CLL physician-scientist researcher for about 15 years. I care of patients with CLL, run clinical trials, and lead a research lab focused on the biology of chronic lymphocytic leukemia (CLL).

Can you discuss the importance of real-world evidence in understanding treatment efficacy and safety for CLL, particularly outside of clinical trials?

Dr Davids: An important point to highlight in CLL specifically is that this disease tends to affect older individuals. The median age at diagnosis is 70, so many patients requiring CLL treatment are in their mid to late 70s or older. Clinical trials often recruit younger, fitter patients. This is true across all cancers, but particularly in CLL, it is important to also have real-world evidence to support findings from clinical trials to give us some additional confidence that the findings will apply to the more typical CLL patient population that's seen in the community setting.

We had a trial directly comparing ibrutinib to acalabrutinib in CLL—the ELEVATE-RR trial—which showed that ibrutinib and acalabrutinib were similar in terms of efficacy, but that the safety profile was better with acalabrutinib. Recently, there was a study of about 700 or so patients with CLL from the Flatiron Health Database that looked at discontinuation rates of these drugs in real-world settings. Similar to the trial, it showed lower rates of discontinuation due to toxicities or progression with acalabrutinib compared to ibrutinib. That was a really nice validation of what was seen in the clinical trial and gave us gives us more confidence that that those data sets are similar. I do think that that's really important.

How do specific patient subpopulations, such as those with high-risk cytogenetics or comorbidities and CLL, shape your treatment approach?

Dr Davids: This is a big question. High-risk cytogenetics influence whether to use a continuous or time-limited treatment. For the highest-risk patients—those with TP53 aberration—we typically recommend continuous treatment with a BTK inhibitor. In contrast, for patients who do not have high-risk cytogenetics, we could think about using a time limited regimen such as venetoclax-obinutuzumab, and expect to see a durable response even with just the 1 year of treatment.

Comorbidities also play a major role. For example, BTK inhibitors carry cardiovascular risks. For a patient with significant cardiovascular comorbidities, particularly those on systemic anticoagulation, I may opt for a venetoclax-based regimen without a BTK inhibitor. On the other hand, for a patient with significant kidney disease, where tumor lysis syndrome risk is a concern, I might favor a BTK inhibitor. These real-world comorbiditie significantly impact therapy selection.

What are the key considerations or strategies when discontinuing therapy in CLL patients, particularly with newer targeted agents?

Dr Davids: There are 2 scenarios here. For patients on continuous treatment with a BTK inhibitor, the idea is to treat until time of progression or unacceptable toxicity. Ideally, these patients are on treatment for many years. However, if a patient develops significant toxicity and has to discontinue that drug, you don't necessarily need to move on to a new line of therapy right away. I usually discontinue treatment in those patients and say, "Let's go back on observation for a period of time."

Many patients will go a couple of years before needing a different treatment. An exception to that might be a patient who relatively recently started treatment. Let's say in the first month, they develop a toxicity with a drug; that patient is likely going to need to switch to a different treatment right away. It depends on how long they've been on treatment, the quality of their response, and the nature of the toxicity. Did they discontinue a BTK inhibitor because they were experiencing some joint aches? In that case, I might try a different covalent BTK inhibitor. Did they discontinue a BTK inhibitor because they experienced a nearly fatal central nervous system bleed? That is probably not a patient I would rechallenge with a BTK inhibitor; instead, I would move to a different targeted agent.

In the setting of time-limited therapies, discontinuation can occur for 2 reasons. One is time-limited therapy with a fixed duration. With venetoclax-obinutuzumab, it's a 1-year treatment, and all patients stop at the end of 1 year, regardless of their response. Alternatively, we could do a minimal residual disease (MRD)-guided strategy, where the length of therapy depends on when the patient achieves undetectable MRD. Right now, in routine clinical practice, we are mostly using the first approach of fixed-duration therapies. However, as the field continues to evolve, I think it is likely we'll be using MRD-guided therapy soon.

How do you view the role of combination therapies in CLL management, and what considerations are important when designing such regimens?

Dr Davids: In order to have a time-limited regimen, it seems pretty clear that combination therapy is necessary in CLL. When designing such a regimen, I would say you'd want to utilize the drugs that combine very well together based on a scientific preclinical perspective.

It is also critical to use the minimum number of drugs to achieve the best response, because we know that with each drug that added, we add additional toxicities, cost, and inconvenience. Right now in CLL, the backbone of our combination regimens is venetoclax, and we build on that either with CD20 antibodies, BTK inhibitors, or both in triplet-based regimens. It's good to have several different types of regimens because we have many different types of patients. We are learning more and more about which combinations are optimal for which patient types.

What recent advancements in CLL research do you find most promising, and how might these influence the treatment landscape in the next few years?

Dr Davids: We have been pretty ambitious in CLL in terms of targeting every line of therapy through clinical trials. One major advance very recently is focusing on the frontline setting for our very first treatment regimen. I am particularly excited about the development of acalabrutinib-venetoclax (AV)-based combinations.

There were a couple of big readouts recently. One was the AMPLIFY study presented at ASH, which compared AV as a doublet to acalabrutinib, venetoclax, and obinutuzumab (AVO) as a triplet, with a chemoimmunotherapy control arm. This study was designed as a registrational trial, which will hopefully lead to US Food and Drug Administration (FDA) approval of AV and possibly AVO sometime this year. That would be our first BTK-BCL2 doublet, an oral time-limited regimen.

The triplet therapy also demonstrated excellent progression-free survival (PFS) in that study. I'll also highlight that the AMPLIFY study excluded patients with high-risk CLL. Additionally, at ASH, I presented our study from Dan- Farber, a phase 2 study of the AVO triplet focused on patients with high genetic-risk CLL with TP53 aberrations. We just published our results in Journal of Clinical Oncology and found excellent efficacy with this AVO triplet in the high genetic-risk population. Together, these 2 studies support the potential use of AVO across the whole range of patients receiving frontline CLL treatment.

On the other side of the spectrum, for patients who have become refractory to our existing therapies, we have seen promising new data readouts from the recent ASH meeting. One example is the BTK degrader drugs, which target BTK in a novel way and have shown very high overall response rates, even in patients who are refractory to all other treatments. Another example is bispecific antibodies, particularly epcoritamab, where data in CLL suggest that nearly 40% of patients can achieve a complete response, even in the highly relapsed setting, with single-agent epcoritamab.

I'm excited to see how this drug is explored in earlier lines of therapy and in cytoreduced patients, where we may observe even better efficacy and a more favorable safety profile.