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CLL Challenges
Key Challenges in Managing Patients With CLL

Released: November 15, 2023

Expiration: November 14, 2024

Danielle M. Brander
Danielle M. Brander, MD
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Key Takeaways
  • Key challenges in managing CLL include individualizing frontline therapy, treating relapsed/refractory disease after both covalent BTK inhibitor–based and venetoclax-based therapy, and managing patients with Richter’s transformation.
  • Join us for a live discussion of these and other issues in CLL management at ASH 2023

There have been many advances in recent years surrounding the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma. Despite these advances, we recognize that there are still key challenges and areas of unmet need in treating our patients. In this commentary, I discuss some of these challenges and how our field is moving toward solutions.

Individualizing Therapy
A challenge in the frontline treatment setting is how to best individualize treatment for CLL. We currently have 2 highly efficacious categories of targeted therapy for frontline treatment: covalent  BTK inhibitors, including second-generation acalabrutinib and zanubrutinib, and venetoclax in combination with obinutuzumab. These treatments are administered differently and have different sets of challenges and toxicities to consider when determining the optimal therapy for an individual patient. In this way, we are challenged to select the best therapy for our patients among very good options. Clinical trials also should be considered for all patients with CLL.

Treatment Following Progression After Covalent BTK Inhibitors and Venetoclax-Based Therapy
Perhaps the greatest unmet need in treating CLL is for patients who relapse after treatment with covalent BTK inhibitors and venetoclax. What is the best treatment in this setting, and how best to sequence therapy? Most of these patients should be encouraged to enroll on clinical trials that look at novel therapeutic strategies, including noncovalent BTK inhibitors, such as pirtobrutinib and nemtabrutinib, other small molecule treatments, or cellular therapies, such as bispecific antibodies or CAR T-cell therapy. Pirtobrutinib, a noncovalent BTK inhibitor in clinical trials for CLL, is not yet approved for patients with CLL. However, it does have an indication in mantle cell lymphoma and is now listed by national guidelines as useful in the second-line or third-line setting in certain circumstances for patients with CLL, specifically, when there is resistance or intolerance to prior covalent BTK inhibitor therapy.

Richter’s Transformation
In the scenario of Richter’s transformation, CLL that transforms or evolves into a more aggressive lymphoma, such as diffuse large B-cell lymphoma, represents a significant treatment challenge. Despite other promising advances in CLL management, the bar really has not been moved much for patients with Richter’s transformation and their overall survival is often less than a year from diagnosis. This remains a condition where novel approaches to treatment beyond standard-of-care chemotherapy are needed. Important studies are looking at the role of novel agent combinations and cellular therapies in treating Richter’s transformation.

Health Maintenance in Patients With CLL
Although we understandably dedicate a considerable amount of our focus to CLL-directed therapy, it is important to consider other key aspects of the health of our patients with CLL. Of note, patients with CLL are generally immunocompromised. This has been recognized more broadly during the COVID-19 pandemic, but most patients with CLL will tell you that well before the pandemic, they have faced challenges with the severity of infection and response to vaccines, for example.

Patients with CLL also can be at risk for other malignancies unrelated to their CLL. Most commonly, these are skin malignancies, but there are certain other secondary malignancies that can arise in our patients. I think we all should empower patients to manage their health and stay up to date with screenings for other secondary malignancies.

Your Thoughts?
What do you see as key challenges in managing your patients with CLL? Please answer the polling question and join the conversation by posting a comment in the discussion section.

Attending ASH?
Join me and my colleagues Brian Hill, MD, PhD, and Deborah Stephens, DO, live in San Diego or via online simulcast as we discuss these and other questions during a CME-certified symposium titled “Applying the Latest Evidence and NCCN Guideline Recommendations in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma” at the 2023 ASH meeting on Friday, December 8.

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Which of the following do you consider most challenging in managing your patients with CLL?

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