The Future of Frontline CLL Treatment Hinges on Chemotherapy-Free Approaches

The standard of care for patients with chronic lymphocytic leukemia (CLL) has drastically shifted over the past decade, expanding from chemotherapy treatments to targeted therapies with agents such as BTK inhibitors and BCL-2 inhibitors like venetoclax (Venclexta), according to Anthony Mato, MD, MSCE.

“In CLL today, as compared with a decade ago, we have some impressive therapies, some impressive classes,” Mato, a hematologic oncologist and director of the CLL Program at Memorial Sloan Kettering Cancer Center, said. “Patients can do quite well with several of [the available] choices.”

However, current frontline treatment methods for CLL rely on patient characteristics and preferences because of the lack of comparative data between approved regimens. As such, many ongoing studies are comparing various combinations of ibrutinib (Imbruvica), venetoclax, obinutuzumab (Gazyva), and acalabrutinib (Calquence) in patients with CLL, aiming to determine the regimens and treatment plans that will provide the best patient outcomes.

In an interview with OncLive^®, Mato discussed current data surrounding BTK inhibitors in CLL, the benefits of targeted therapies in this population, ways to begin addressing unmet needs, and the importance of improved clinical trial designs for varying patient populations.

OncLive^®: What are the takeaways of your presentation from the 26th Annual International Congress on Hematologic Malignancies®, which focused on choosing therapy for newly diagnosed patients with CLL?

Mato: At the conference, I presented the current data that we have available for modern chemotherapy-free approaches in the frontline setting. I largely focused on the choices we have between BTK inhibitors, of which ibrutinib and acalabrutinib are approved, and venetoclax-based time-limited therapy. Leaning into the future, I looked at what’s coming next in terms of novel-novel combinations and studies looking at doublets and triplets.

What are some of the factors that influence treatment decisions for patients with CLL?

Unfortunately, we don’t have head-to-head data of any BTK inhibitors vs venetoclax, or BTK inhibitors vs one another in the frontline setting. [Currently, when prescribing treatments, we] look at the entire picture. Patient preference comes into play significantly, as well as their comorbidities and their molecular genetic profiles. We also consider available data for each of the regimens from the perspective of progression-free survival, overall survival, and adverse effect profiles.

[Coming to a decision requires] a long conversation, given the fact that we don’t have comparative data or [treatment] sequencing data available.

How has the CLL treatment paradigm shifted in recent years with the development of some of these new agents?

[Today’s treatments are] a radical departure from the past. A decade ago, chemotherapy was the standard of care, with the best chemotherapy being [fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) chemotherapy]. However, that was largely limited to patients who were young and fit.

Now, whether you’re young or old, have comorbidities or are in excellent health, have poor- or favorable-risk features of your disease, targeted therapies work quite well, and they essentially level the playing field for most patients. If I have an 85-year-old patient and a 55-year-old patient, the standard of care is the same for both. The targeted therapies, because they’re so well tolerated and active, have really helped address many of the disparities associated with health conditions.

What are some of the biggest unmet needs that remain for this patient population?

[There are 3 main unmet needs in the frontline setting.] The first is head-to-head comparative data. Most of the controls from the most recent trials are not clinically relevant. Oftentimes, we compare a great modern therapy to an old standard of care, and we don’t learn much from that. For instance, a BTK inhibitor such as ibrutinib is compared with chlorambucil, then acalabrutinib is, then venetoclax is, but yet we don’t have direct comparisons.

Secondly, we don’t have any prospective data on sequencing of therapies following frontline treatment. For example, if I start with a BTK inhibitor: What should I do next? There’s not a lot of information about sequencing, especially addressing the value of sequential monotherapies vs novel-novel combination therapies.

Lastly, there are some patient populations, particularly those with 17p deletions or TP53 mutations, who are still at the highest risk for having a poor outcome related to novel targeted therapies. We need studies specifically looking at outcomes in those patient populations, not small subgroup analyses from larger trials.

Are there any ongoing trials that you’re interested in seeing the results of?

One of the most interesting trials that I’m excited to see the results of is the CLL17 trial [NCT04608318], which is comparing ibrutinib vs venetoclax plus obinutuzumab vs ibrutinib plus venetoclax. [In other words, this trial is looking at] continuous therapy vs event-based time-limited therapy vs [a minimal residual disease (MRD)]–driven approach.

There’s also the MAJIC trial [NCT05057494], which is comparing 2 different doublets: venetoclax plus acalabrutinib vs venetoclax plus obinutuzumab. This trial is trying to decide the best doublet using an MRD-driven approach in both arms.

Both are exciting and relevant, ongoing frontline trials, and their results are eagerly anticipated.

[This space needs] trials that are comparative to modern controls. Secondly, we need more information from real-world data, real-world evidence to help fill in the gaps that the trials won’t answer. That information should be incorporated into the [treatment] guidelines that we develop.