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CLL Treatment
My Thoughts on the Current and Emerging Treatment of CLL/SLL

Released: October 25, 2024

Expiration: October 24, 2025

Alessandra Tedeschi
Alessandra Tedeschi, MD
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Key Takeaways
  • A key challenge in CLL is selecting optimal first-line therapy using patient and disease characteristics beyond genetic factors, such as assessing frailty and comorbidities, as well as incorporating socioeconomic and logistical considerations into treatment decisions.
  • The lack of clear sequencing data creates uncertainty in managing CLL beyond the first line, highlighting the need for prospective studies.
  • New data on combinations with second-generation BTK inhibitors, noncovalent BTK inhibitors, MRD-guided approaches, and novel agents like BTK degraders offer hope for improved outcomes in CLL.

When I first began my practice, chronic lymphocytic leukemia (CLL) treatment involved only chlorambucil and fludarabine. Now, targeted agents have changed the prognosis of CLL and improved outcomes for our patients. For first-line treatment, we can consider either continuous treatment with a Bruton tyrosine kinase (BTK) inhibitor or fixed-duration treatment with a venetoclax-based regimen. Today, the challenges we face for patients with CLL/small lymphocytic leukemia (SLL) are not about the absence of options but rather about selecting the right therapy at the right time for each patient.

Selecting Optimal First-line Treatment: Disease and Patient Considerations
One of the primary challenges in CLL treatment is determining which patients will benefit most from continuous vs fixed-duration therapies. When considering first-line therapy, we traditionally categorize patients according to genetic lesions, such as del(17)p and IGHV (unmutated or mutated) status. In addition to these factors, we should consider patients’ age, frailty, and specific comorbidities. Unfortunately, there is not a specific set of guidelines for determining whether a patient should be considered frail, fit or unfit, or elderly in the setting of CLL, and clinical judgement is necessary.

Different comorbidities may help determine which treatment is optimal for an individual patient. For example, patients with cardiologic comorbidities such as a history of ventricular arrythmias or congestive heart failure should avoid treatment with BTK inhibitors. While patients with renal dysfunction and or high tumor burden with splenomegaly should avoid treatment with venetoclax because of the potential risk for development of tumor lysis syndrome.

Logistical factors are also very important to consider when selecting the optimal treatment for patients. Some of these factors include whether the patient has consistent caregivers and the distance from the patient’s house to the hospital or treatment center. For me, these comorbidities, socioeconomic factors, and patient resilience are the major challenge when recommending first-line treatment.

For elderly patients and those considered unfit for more aggressive treatment, I prefer continuous treatment with a BTK inhibitor regardless of their biological characteristics. It is important to consider that first-line therapy might be the only treatment some of these patients will receive. Healthcare professionals should think about quality of life, and I believe that continuous treatment with a BTK inhibitor gives these patients good quality of life.

Once decided on BTK inhibitor therapy, the question becomes how to choose between acalabrutinib, zanubrutinib, and ibrutinib. In some European countries, ibrutinib is still being used for patients with CLL, possibly due to the ability to adjust the dose of ibrutinib. However, a second-generation BTK inhibitor, either zanubrutinib or acalabrutinib, is preferred over ibrutinib in most cases based on current clinical data and adverse event profiles. My own current preference is zanubrutinib, based on the ALPINE study that showed a superior overall response rate and superior median progression-free survival (PFS) with zanubrutinib vs ibrutinib and less atrial fibrillation or flutter with zanubrutinib. However, acalabrutinib is very well tolerated as well, and the ELEVATE-RR trial showed no difference (noninferiority) in median PFS with acalabrutinib vs ibrutinib in patients with high-risk CLL but higher rates of short- and long-term toxicity with ibrutinib vs acalabrutinib.

In addition to our current decision on whether to recommend a BTK inhibitor or a venetoclax-based regimen, the phase III GLOW trial reported superior PFS with ibrutinib plus venetoclax compared with chlorambucil/obinutuzumab as first-line treatment in older patients with CLL. The ongoing phase III CLL17 study is comparing ibrutinib monotherapy with either fixed-duration venetoclax/obinutuzumab or ibrutinib/venetoclax and should provide some answers on the best approach for first-line therapy. I hope it will inform which population will benefit from one treatment strategy over the other.

Considerations for Second-line Therapy and Beyond
Perhaps the biggest gap we currently have is the lack of evidence supporting optimal treatment sequencing with BTK inhibitors and venetoclax-based therapy. Most of the randomized trials with these agents were conducted with patients who received previous immunochemotherapy and were then enrolled to receive treatment with a BTK inhibitor or venetoclax-based therapy as salvage. With a lack of randomized data, we have to rely on real-world, retrospective studies, which could result in strong data bias and make it difficult for healthcare professionals to have evidence-based treatment decisions on initiation and sequencing of different available therapies.

Now we also have the noncovalent BTK inhibitor, pirtobrutinib, and the CAR T-cell therapy, lisocabtagene maraleucel, available for patients with relapsed/refractory CLL. There is a lack of data on how to sequence these newer agents and whether pirtobrutinib should be used after progression on a covalent BTK inhibitor or after both a covalent BTK inhibitor and a BCL-2 inhibitor regimen. Based on the BRUIN study showing better PFS in patients treated with a covalent BTK inhibitor who have not yet received venetoclax, my preferred sequence is a covalent BTK inhibitor, pirtobrutinib, a venetoclax-based regimen, and then CAR T-cell therapy.

My Thoughts on Next Steps in the Evolution of CLL/SLL Treatment
Minimal residual disease (MRD) has become an area of intense interest, with the potential to guide treatment duration and improve outcomes in CLL. MRD-guided strategies offer the promise of personalizing therapy, allowing us to balance the depth of response with the risks of prolonged exposure to treatment-related toxicities. Yet, implementing MRD-guided approaches in practice is not without challenges.

Standardizing MRD assessment across laboratories remains a hurdle, and the kinetics of MRD clearance differ between patients with mutated vs unmutated IGHV status. While the results from trials like the FLAIR study suggest that adjusting therapy based on MRD status can prolong PFS, we need more data to truly understand how to apply this approach across diverse patient populations. Until then, questions about the optimal length of fixed-duration therapy remain unanswered, especially as we balance the benefits of prolonged therapy against the risk of resistance.

In the future, it may also be possible to enhance efficacy by delivering a second-generation BTK inhibitor in combination with venetoclax or even a new BCL-2 inhibitor therapy like sonrotoclax. The use of triplet therapy, in which an anti-CD20 monoclonal antibody is added to a BTK inhibitor plus a BCL-2 inhibitor, is another possibility through which to better achieve undetectable MRD, albeit potentially at the expense of an increase of toxicity. Nevertheless, studies are lacking, and most have been directed at small numbers of young patient populations. The emergence of new agents like the BTK degraders may also be an exciting avenue to explore for improving outcomes in both first-line and relapsed settings.

From the biological perspective, there remains a need to investigate the causes of resistance to each of the various targeted agents that we use to treat our patients today. Mutation of BTK and BCL2 may confer resistance, but mutation is likely not the only factor. For example, T-cell function should also be considered.

The landscape of CLL treatment has evolved significantly, bringing new opportunities and challenges for clinicians. As we navigate this complexity, a focus on patient-centered care, thoughtful sequencing, and the integration of emerging data will be essential. While gaps in knowledge remain, the ongoing research into sequencing, MRD-guided approaches, and novel agents offers hope for continued improvement in patient outcomes.

Your Thoughts?
How do you approach treatment selection and sequencing for CLL in your practice? Have you encountered challenges in assessing frailty or implementing MRD-guided strategies? Share your experiences and perspectives—let’s continue the conversation about optimizing CLL care together by answering the polling question and posting a comment below.

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In your current practice, what is your preferred initial therapy for your patients with CLL?

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