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CLL 1L Therapy
Key Considerations in Selecting Frontline Therapy for Patients With CLL/SLL

Released: April 24, 2024

Expiration: April 23, 2025

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Key Takeaways
  • The second-generation BTK inhibitors acalabrutinib and zanubrutinib and the BCL-2 inhibitor‒based combination of venetoclax plus obinutuzumab are highly effective in treating CLL as frontline options and should be considered for the vast majority of patients, where available.
  • Key factors in selecting between regimen classes include the presence or absence of high-risk CLL features (eg, 17p deletion or TP53 mutation), patient preference for continuous oral therapy vs time-limited IV therapy, and the presence of specific patient comorbidities, including significant cardiac conditions and renal dysfunction.

In this commentary, Nicole Lamanna, MD, provides a contemporary overview of frontline therapy for patients with chronic lymphocytic leukemia (CLL) and discusses key factors she considers in her practice when recommending a course of treatment.

Selecting Between BTK and BCL-2 Inhibitor Therapy
In the frontline setting, we currently have 2 main choices for patients with CLL: continuous BTK inhibitor therapy with acalabrutinib or zanubrutinib or time-limited therapy with the BCL-2 inhibitor venetoclax plus obinutuzumab. We have been very fortunate to have these targeted therapies approved, allowing us to move away from traditional chemoimmunotherapy (eg, FCR, BR) for patients with CLL. These therapies are outstanding options for patients with CLL in terms of progression-free survival and overall survival advantages over previous standards of care. Many patients could choose either therapy and do very well; however, there are a few factors that I consider when recommending these therapies to my patients.

High-Risk CLL
When selecting between frontline therapy options, one of the key factors I consider and discuss with patients is whether they have high-risk disease—specifically, a 17p deletion or TP53 mutation. For these patients, I generally recommend chronic continuous therapy with a BTK inhibitor, such as acalabrutinib or zanubrutinib. While ibrutinib also is approved for patients with CLL, given some of the head-to-head data with ibrutinib vs acalabrutinib and ibrutinib vs zanubrutinib in the relapsed CLL setting, the second-generation BTK inhibitors are associated with fewer cardiac adverse events vs ibrutinib. However, if you only have access to ibrutinib due to geographic location or other factors, such as insurance choice, ibrutinib can be utilized as well for these patients. When considering time-limited venetoclax plus obinutuzumab for CLL with a 17p deletion or TP53 mutation, progression-free survival appears shorter than that observed with continuous BTK inhibitor‒based therapy, although there are no head-to-head trials with long-term data yet (stay tuned!).

Patient Preferences
Outside of high-risk features, patient preferences regarding chronic continuous therapy with a BTK inhibitor vs time-limited therapy with venetoclax plus obinutuzumab are very important. It is essential to discuss goals of therapy with your patients. Do they want to take a pill every day? It can be easier to be on BTK inhibitor therapy in terms of the ease of administration, and you do not have to monitor very closely in terms of tumor lysis, which is a caveat with the venetoclax plus obinutuzumab regimen. So, if a patient is traveling a lot or otherwise busy and does not want to have to be in and out of the clinic for several months, as is required with venetoclax plus obinutuzumab, then a BTK inhibitor might be preferred.

There are other patients who do not want to take a pill every day and would prefer a time-limited therapy with venetoclax plus obinutuzumab, as per CLL14, for 1 year. After this, they can be monitored for several years, just as they were before they required treatment. I generally preface this conversation by saying that for the first 2-3 months you are on therapy, you are going to be coming into the lab/clinic office frequently for monitoring and blood work. If a patient has bulky lymphadenopathy or a markedly elevated white blood cell count, they might have to be admitted for the first part of their treatment to be monitored for tumor lysis syndrome, but then the remainder of treatment is in the outpatient setting. Treatment is not difficult, but requires commitment on the part of the patient to come to the clinic weekly to have labs and tumor lysis monitoring. There is also an appeal with time-limited therapy that any adverse events a patient experiences with treatment will be finite in duration due to the nature of the regimen.

Comorbidities
Other factors to consider are the presence of a comorbid condition that might preclude use of a specific therapy, which is relatively uncommon. However, for example, if a patient has considerable brittle cardiac issues or poorly controlled hypertension despite treatment, then I may recommend venetoclax-based therapy vs a continuous BTK inhibitor based on adverse cardiac events observed with BTK inhibitors. Conversely, if a patient has poor renal insufficiency and bulky disease (putting them at a higher risk for tumor lysis syndrome), and I am very concerned about trying to give them venetoclax as an outpatient and they do not want to be admitted to receive early treatment as an inpatient, then I may recommend a BTK inhibitor. These are 2 more extreme situations where comorbidities may play a role, and these are generally uncommon, but they are important to keep in mind when recommending therapy.

Your Thoughts?
What do you consider when selecting frontline therapy for patients with CLL? Join the discussion by posting a comment, and be sure to check back on this page often for additional CLL education, including an updated online treatment decision support tool for CLL, additional commentaries, and expert text discussions of key topics in the management of patients with CLL.

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Which of the following is typically the most important factor you consider when recommending frontline therapy for patients with CLL?

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