Time-Limited, Targeted, Tailored: The Future of Frontline CLL Treatment

Selecting the right frontline therapy for chronic lymphocytic leukemia (CLL) is less a fixed formula and more a shifting landscape, where age is just one landmark among many on the path to personalized care.

At the Pan Pacific Leukemia Conference held July 15-19, 2025, in Lahaina, HI, this topic commenced the CLL session during which Nitin Jain, MD, professor of Medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, gave a presentation on optimal treatment for older patients. His presentation followed one by R. Gregory Bociek, MD, MSc, professor, UNMC Division of Oncology & Hematology Non-Hodgkin Lymphoma, Hodgkin Disease, Chronic Lymphocytic Leukemia, who presented on optimal treatment for young patients with CLL.

Following his presentation, Dr. Jain sat for an interview with Blood Cancers Today to unpack the details of his presentation and discuss the evolving practice of treating older patients with CLL in the upfront setting. 

Blood Cancers Today: The optimal upfront treatment for CLL is a moving target. What is the most recent information you can share on deciding which treatment to give?

For patients with CLL, the treatment has remarkably changed in the last decade or so. And these days, we’re only using targeted therapies such as BTK inhibitors, PCL2 inhibitors, and CD20 antibodies. And we have completely moved away from chemoimmunotherapy. So, in the discussion at the meeting, I think one of the points was which therapies to select for patients with CLL. We are increasingly deciding therapies based on not just the age of the patient, but more importantly, their commodities, and genomic risk for the CLL, including things like IGHV and deletion 17p mutation.

We also focus on organ function, for example, if they have kidney problems or they have heart issues, atrial fibrillation, and anticoagulation. All these therapies we have for CLL are quite effective, and it comes down to a discussion with the patient about their preferences because there’s a big difference in strategy with CLL. Some therapies are given orally once daily for a long time. Basically, the recommendation would take it forever, and other strategies are a bit more involved. These would likely involve two drugs or three drugs, but those therapies are generally given for one to two years. So, it depends on the intent of the patient as well as how much time they want to spend in the hospital, including monitoring visits and travel to the center for therapy.

The good thing is that all the therapies, whether you talk about a BTK inhibitor alone, whether you talk about BTK plus BCL2, or BTK/BCL2 plus CD20 antibodies, all these are very effective therapies for patients with CLL.

What are the key differences in treatment of older patients and younger patients in the upfront setting?

The age distinction is kind of merging in the context of CLL because, in some sense, older versus younger patients was more relevant when we were treating with chemotherapy. With chemotherapy, you don’t want to give intensive chemotherapy to older patients of 65 years of age and up. But now that we’re using more target therapies, which are non-chemotherapies, I think this distinction between younger and older patients has become less clear, where the same therapies are being used across the board.

Some of the doublet and triplet therapies, which are more involved because they involve frequent visits to the hospital, have some more side effects, like neutropenia. That is something which may be more desirable or more appropriate for patients on the younger side. And when I say younger side, I mean less than 70 to 75 years of age. On the flip side, patients who are certainly in the older category, someone who is above 80 years old, may be okay with just taking a pill every day or twice a day, such as with a BTK inhibitor, and not to be bothered by frequent visits to the clinic for tumor lysis monitoring and whatnot.

So, this distinction of younger versus older patients is kind of merging a bit. But yes, there are a few differences, especially with older patients above 75 years old, where you could rely more on continuous BTK inhibitor therapy if that’s what the patient desires versus two or three drugs together for a time-limited approach.

 What were the key points from your presentation at the 2025 Pan Pacific Leukemia Conference?

The key points here from my presentation are that the frontline therapy of CLL is continuing to evolve and that we are increasingly using time-limited approaches for patients with CLL. Again, those will be approaches generally limited to maybe patients who are less than 75-80 years of age, but age is just one criterion. You have to look at the patient overall, their performance status, cardiac functions, and comorbidities.

We had some recent clinical trial data from the European Hematology Association Congress from a trial called FLAIR, which was done for patients in their 60s, so not very old patients in the context of CLL. But nonetheless, that trial showed that if you use two drugs together, namely ibrutinib plus venetoclax for two to six years of therapy, that led to better progression-free and overall survival compared to one drug, namely ibrutinib.

Given continuously. So that and other trials are, I think, really making a point that there is something to be said about using time-limited approaches if a patient can tolerate it. I would say most patients with CLL can tolerate it unless they have a single cardiac comorbidity or renal dysfunction.

What are the main clinical trials or real-world studies helping to guide your treatment choices today?

In the context of CLL, several randomized clinical trials in the frontline setting have been conducted and reported. One of the main ones, more recently, was the FLAIR trial, which I mentioned, which showed that a combination of ibrutinib plus venetoclax was superior to the ibrutinib monotherapy.

But then there are other clinical trials in the field. For example, we have a trial called the GLOW trial, which showed that a combination of ibrutinib plus venetoclax was better in terms of both progression-free and overall survival compared to a historical control, chlorambucil plus obinutuzumab.

Then, there are several other ongoing trials, such as the CLL13 and CLL14 trials, and some trials with continuous BTK inhibitors with ibrutinib, acalabrutinib, and zanubrutinib, all of which have been reported in the last five years or so. All these trials have come to the conclusion that certainly we should move away from chemotherapy, and we should be doing targeted therapy for our patients.

Also, there are several ongoing randomized clinical trials that have not yet been reported, but we’re expecting some data in the next one to two years or so. I think these trials will further help streamline or identify the right mix of treatment regimen for patients with CLL.

What advice do you have for your peers on approaching upfront CLL treatment in patients who are elderly and possibly frail?

Patients who are elderly and frail think this is a group of patients where you will have to first look at what other comorbidities they have besides being frail. For example, you probably will not be thinking of doublets and triplets for patients with certain comorbidities. You may be thinking of just monotherapies because they are frail. In that context, a BTK inhibitor monotherapy such as acalabrutinib or zanubrutinib given continuously, daily, may be an appropriate strategy.

However, if a patient has single cardiac comorbidities, they have atrial fibrillation, and is on anticoagulation, one could argue that maybe a venetoclax-based therapy such as venetoclax plus obinutuzumab may be a safer approach. Similarly, for patients who are frail and on the older side, I think there are these occasional patients where the goal is just for some count control and some symptom control, even as drugs such as single-agent rituximab or single-agent obinutuzumab could be considered.

But I will say most patients these days are receiving an appropriate single-agent BTK inhibitor if they’re older and frail, and these second-generation BTK inhibitors are very well tolerated.

What are some unanswered questions you hope to see clarified in future studies?

 I think there are several unanswered questions. One, I think we still believe the treatments have been fantastic. I think the question for time-neutral approaches has been how long to continue treatment.

Most of the trials have looked at one year of therapy. Now, some trials are looking at what is called MRD-guided therapy, where you look at the response by MRD at one year and two years, and depending on that, you can extend treatment, and some of those trials are ongoing. So, think that remains an unanswered question.

The second is whether you need a doublet versus a triplet, especially in younger patients. Which patient groups should we rely on doublets or triplets? That is still evolving, and for patients who have 17P deletion or TP53 mutation, which are high-risk patients, the recommendation for them will be to use a single-agent BTK inhibitor. However, could you use doublets and triplets in a time-limited approach for these patients, allowing the option of retreatment if they were to progress down the line? Again, some trials are looking into this now.