Advancements in CLL: CAR T, BTK Inhibitors and Personalized Medicine

Cyrus M. Khan, MD

Over recent years, targeted agents like Bruton tyrosine kinase (BTK) inhibitors, including ibrutinib (Imbruvica), acalabrutinib (Calquence), zanubrutinib (Brukinsa), and the newer pirtobrutinib (Jaypirca), have transformed the chronic lymphocytic leukemia (CLL) treatment landscape by offering new and effective options, even for patients who progress on standard therapies.

CLL management has moved away from chemotherapy, with 2 major options now: BTK inhibitors or BCL-2 inhibitors like venetoclax (Venclexta), which are often combined with immunotherapy for a finite treatment duration.

Personalized medicine like mutation testing and minimal residual disease (MRD) testing also have a growing role in this space as experts are looking to further tailor treatment and monitor disease progression for their patients with CLL.

While a cure is still needed, Cyrus M. Khan, MD, envisions ongoing research in bispecifics and MRD-based decision-making to further enhance individualized CLL care.

“We still need a cure—that is the biggest goal…I am excited about the potential of bispecific T-cell engagers and how they might fit into the treatment paradigm for CLL,” Khan, hematologist in the Division of Hematology and Cellular Therapy at West Penn Hospital of Allegheny Health Network, told Targeted Oncology^TM, in an interview. “MRD testing holds promise for helping us make more informed decisions in clinical practice, guiding us on when to monitor, when to treat, and when to hold off on treatment.

In the interview, Khan further discussed recent advancements in CLL treatment.

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Targeted Oncology: What are the most significant recent advancements in CLL treatment that you believe will impact patient care?

Khan: We have had many advancements over the last few years in nonchemotherapeutic interventions. There have been numerous targeted agents approved, as well as significant developments in immunotherapy. The newest advancement has been the approval of [chimeric antigen receptor (CAR)] T-cell therapy for patients with CLL, which represents the most substantial recent progress.

In addition, BTK inhibitors have been available for quite some time and have proven very effective in treatment. Examples include ibrutinib, zanubrutinib, and acalabrutinib. However, until recently, we did not have a solution for patients who progressed on these BTK inhibitors. Now, there is a new drug called pirtobrutinib, which works for patients who progress on any of these 3 BTK inhibitors, allowing patients to continue with an oral treatment option.

Previously, there was also no robust cellular therapy option for patients who progressed on all the standard oral treatments and immunotherapies. Now, fortunately, we have CAR T-cell therapy available for these patients as well, and it has proven effective. This is a significant advancement for patients with CLL.

In recent years, how have treatment paradigms for CLL changed, particularly regarding frontline therapy options?

Over the last 10 years, we have seen significant changes. In the past, for younger, fit patients, we typically chose chemotherapy—most commonly the FCR regimen, a combination of fludarabine, cyclophosphamide, and rituximab [Rituxan]. However, due to its toxicity, we were always looking for alternatives. For older patients, we used bendamustine with rituximab, or for even older patients, single-agent chlorambucil—all chemotherapies but generally less effective than targeted treatments. Any chemotherapy, of course, comes with [adverse] effects and can increase the long-term risk of secondary cancers.

Now, we have transitioned to being entirely chemotherapy free. Most of our frontline treatments are nonchemotherapy drugs, with 2 major options. One option is starting with a BTK inhibitor; any of the options I mentioned previously, such as acalabrutinib, ibrutinib, or zanubrutinib, can be used, although second-generation inhibitors like acalabrutinib and zanubrutinib are often preferred over first-generation ones. These treatments are very effective, but patients do need to continue them for life, as they cannot be stopped until the disease progresses. Acalabrutinib can also be combined with immunotherapy, specifically obinutuzumab [Gazyva], an anti-CD20 antibody similar to rituximab but a newer version. When combined, the [intravenous (IV)] therapy lasts 6 months while the acalabrutinib continues.

The other major option is a BCL-2 inhibitor, specifically venetoclax, which we also combine with obinutuzumab. Here, the IV therapy continues for 6 months, and venetoclax is given for only 1 year. This regimen is an effective immunotherapy and targeted treatment combination with a defined treatment duration, so it does not have to be lifelong.

There are pros and cons to both of these options, and both are excellent choices. Physicians work closely with patients to determine the best treatment for each [patient]. Additionally, there are ongoing combination trials that investigate using BTK inhibitors with venetoclax, with or without immunotherapy, in time-limited regimens. This approach could shape how frontline treatment evolves in the future.

Are there any combinations that have emerged or any that have clinical implications so far?

One combination that could be approved in the future is venetoclax with acalabrutinib, with or without obinutuzumab. This might become a frontline therapy option down the line. However, it raises the question of what the best treatment option would be for patients who progress after receiving both of these agents in combination. This is something we will need to consider as we move forward.

Another promising future therapy is bispecific T-cell engagers, particularly epcoritamab-bysp [Epkinly]. There is an ongoing trial in CLL, and while epcoritamab is already approved for relapsed or refractory diffuse large B-cell lymphoma and follicular lymphoma, the current trials suggest it could be effective for patients with refractory CLL. This could add another option for relapsed patients. As we know, CLL is not a curable disease, so these patients will unfortunately continue to relapse, meaning there is always a need for newer and better options in the relapsed setting.

How is the concept of personalized medicine being integrated into CLL management?

Gradually, one of the future goals will be to conduct whole genome sequencing on these patients to identify specific mutations and then select treatments based on those findings. For instance, patients on first- and second-generation BTK inhibitors may progress due to various mutations that make them resistant to their current treatments. One key mutation is called the C481S mutation, which occurs on the BTK site. We test for this mutation if a patient is not responding or is progressing. If it is present, pirtobrutinib can be effective, as it works for patients with this specific mutation, while other BTK inhibitors do not. This is one example of a personalized treatment approach.

Another approach is MRD testing. Although not yet standard practice, MRD testing could be valuable for patients on finite-duration treatments. Current trials are assessing patients’ MRD status at the end of their treatment. The idea is that if MRD is positive, those patients may benefit from additional consolidation or maintenance therapy to further reduce their disease, rather than stopping treatment entirely. As more data become available, this MRD-based approach could help us personalize treatment even further for each patient.

How have updates to clinical guidelines influenced your approach to treating CLL?

Whether in frontline treatment or in the relapsed/refractory setting, treatment choices are generally guideline-based, including guidance on how and what to test for in patients. One key aspect is selecting the appropriate targeted agents for the first- and second-line settings, whether that is a venetoclax-based approach or a BTK-based approach.

Another significant shift has been the preference for second-generation BTK inhibitors over ibrutinib due to their better safety profile. Over time, we have observed that second-generation inhibitors tend to have fewer cardiac [adverse] effects, fewer bleeding events, and overall improved tolerability.

What are your recommendations for monitoring patients on CLL therapies, particularly regarding long-term follow-up?

One of the primary concerns with CLL is managing disease-related issues, but secondary cancers are also a frequent complication. Patients with CLL are at higher risk for secondary cancers, particularly skin cancer, so regular dermatology visits are essential. They also need to keep up with their primary care physician for cancer screenings, including routine colonoscopies, prostate exams, and, if they are smokers, lung cancer screenings. This aspect of care is sometimes undervalued but is critical for [patients with] CLL.

Another important focus is monitoring for infections, which are common, especially in the relapsed setting. We typically assess their immune system by checking [immunoglobulin G (IgG)] levels, and if they have recurrent infections, we consider [IV immunoglobulin] replacement therapy.

Lastly, it is important to monitor their disease status and treat only as needed. This means avoiding overtreatment when it is unnecessary, but also ensuring they receive treatment if they become cytopenic or symptomatic.

What advice do you have when educating patients about their treatment options and the importance of adherence in managing CLL?

One key part of the discussion is presenting all treatment options, particularly comparing BTK inhibitors with venetoclax-based treatments, outlining the pros and cons of each. For instance, with a BTK inhibitor, I explain that it is very easy to start: patients take it daily at home, there is no need for infusions, and it does not require frequent blood work. The downside, however, is that it is a lifelong treatment, which some patients prefer to avoid, and it may have [adverse] effects that are not suitable for everyone. For example, if a patient has cardiac arrhythmia, heart issues, or poorly controlled blood pressure, a BTK inhibitor might not be the best choice.

Venetoclax, on the other hand, is a time-limited treatment, which can be appealing, but it does have logistical challenges. It requires frequent blood work and monitoring, especially early on, to watch for tumor lysis syndrome. After the initial phase, it becomes easier to manage. The benefit, though, is that treatment lasts about a year, and after that, patients may remain off therapy for many years.

Either of these options could be the best approach for a specific patient, depending on their comorbidities. Sometimes both options are equally effective, so it is important to have an in-depth discussion with the patient to determine which best aligns with their lifestyle.

Adherence to the chosen treatment is critical. Poor adherence can lead to the development of resistance, and patients who do not adhere may not achieve the same outcomes as those who follow their treatment consistently.

What do you see as the key areas for future research or development in CLL?

We still need a cure—that is the biggest goal. Secondly, I am excited about the potential of bispecific T-cell engagers and how they might fit into the treatment paradigm for CLL. Third, MRD testing holds promise for helping us make more informed decisions in clinical practice, guiding us on when to monitor, when to treat, and when to hold off on treatment.