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Experts Answer HCP Questions on CLL Therapy

Released: October 27, 2025

Solomon A. Graf
Solomon A. Graf, MD
Sameer A. Parikh
Sameer A. Parikh, MBBS
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Key Takeaways
  • The choice between frontline therapy with a fixed-duration venetoclax-based regimen or continuous covalent BTK inhibitor is dependent on patient preferences, comorbid conditions, and disease characteristics, including high-risk mutations
  • The noncovalent BTK inhibitor pirtobrutinib or CAR T-cell therapy lisocabtagene maraleucel may be considered for patients with “dual-refractory” CLL

Treatment paradigms for chronic lymphocytic leukemia (CLL) continue to evolve, with several recent FDA approvals and numerous novel treatment strategies in late-phase clinical development. In this commentary, expert faculty discuss questions from healthcare professionals who attended live educational webinars from April to September 2025 on the management of patients with CLL, including treatment selection and sequencing, managing “double refractory” CLL, and emerging therapies.

How do you talk to patients about tradeoffs between fixed-duration therapy and continuous therapy?
Sameer A. Parikh, MBBS: At present, covalent BTK inhibitors are recommended as continuous therapy. I tell my patients that this is a pill that must be taken every day. Treatment can be associated with nuisance side effects, the risk of bleeding, the risk of atrial fibrillation, a rash, hypertension, and possible financial toxicity as well.

Venetoclax-based therapy is generally of a fixed duration. With these regimens, there is a higher upfront effort required because the patient will need to be seen or come to the clinic at least once a week for the first 9 weeks as you go through the ramp-up protocol. However, in the frontline venetoclax plus obinutuzumab setting, you are done with the treatment in a year.

In general, I prefer fixed-duration therapy, if possible, because this treatment works very well and gives us the flexibility of potentially reusing the same drugs later should a patient have progression of disease after a longer time off therapy. However, there are unique situations, like if a patient does not want to come into the infusion therapy center, or if a patient has TP53 mutation. In these cases, continuous BTK inhibitor–based therapy is the preferred treatment option.

How do you choose treatment based on patient preferences when a patient has limited support or has trouble traveling?
Sameer A. Parikh, MBBS: In this patient population, I typically choose a single-agent BTK inhibitor as first-line therapy because that is typically the easiest treatment to deliver and is well tolerated. After treatment has started, I will either do a toxicity check with the help of a nurse or do a video or phone visit within a couple of weeks to make sure that the patient is doing okay. Then I try and see the patient once every 3-6 months while they are on active therapy. 

How do you sequence therapy in patients with “dual-refractory” CLL (refractory disease following both covalent BTK inhibitor and venetoclax-based therapies)?
Sameer A. Parikh, MBBS: At present, the National Comprehensive Cancer Network guidelines recommend treatment with the noncovalent BTK inhibitor pirtobrutinib or CAR T-cell therapy lisocabtagene maraleucel as our 2 FDA-approved treatment options. I will work to get patients with dual-refractory CLL on these preferred regimens.

Let’s discuss noncovalent BTK inhibitors for a moment. These are slightly different molecules compared with the covalent BTK inhibitors and include pirtobrutinib and nemtabrutinib, the latter of which is not FDA approved as of October 2025. Covalent BTK inhibitors bind to the cysteine 481 site of BTK, whereas the noncovalent BTK inhibitors do not bind to that site. One of the most common mechanisms of resistance to covalent BTK inhibitors is the development of a BTK cysteine 481S mutation that then does not allow effective binding of covalent BTK inhibitors to that site. Noncovalent BTK inhibitors are effective in patients that have disease progression on covalent BTK inhibitors, and therefore pirtobrutinib and nemtabrutinib really are important molecules as we see more patients with resistance to covalent BTK inhibitors. It is generally easier to switch to pirtobrutinib as we wait to make arrangements (including insurance authorization) for eventually treating with lisocabtagene maraleucel.

Solomon A. Graf, MD: I use pirtobrutinib preferentially as a third-line option in dual-refractory CLL.

What is your threshold to refer a patient for CAR T-cell therapy?
Sameer A. Parikh, MBBS: Typically, if a patient has received a covalent BTK inhibitor and has received venetoclax plus obinutuzumab, I start thinking about CAR T-cell therapy evaluation. In practical terms, it is hard to refer a patient for CAR T-cell therapy evaluation if they are responding well to venetoclax-based therapy, but I will at least mention that in my discussion with the patient. When they begin third-line therapy or beyond (eg, with pirtobrutinib after a covalent BTK inhibitor and venetoclax-based therapy), I would consider referral for CAR T-cell therapy evaluation.

Solomon A. Graf, MD: This is becoming increasingly relevant as we are seeing more and more patients with dual-refractory CLL. In general, my practice is to think about referring for CAR T-cell therapy evaluation when I am starting pirtobrutinib. If patients are younger and relatively fit and have access to CAR T-cell therapy, then that is absolutely something that I am going to try to initiate.

How do you monitor for and manage resistance mutations such as BTK C481S and PLCG2 in the relapsed CLL setting?
Solomon A. Graf, MD: I do not do this testing routinely in my practice because, at this time, the results do not affect management decisions. That might change in the future once we know a little bit more about the differential efficacy of these, for instance, with noncovalent BTK inhibitors like pirtobrutinib and nemtabrutinib.

How often do you repeat biomarker testing for TP53 mutation or IGHV status at relapse?
Solomon A. Graf, MD: IGHV status does not change over time and even through lines of therapy. It is generally fixed at the time of diagnosis and you can expect that it will remain constant over the course of the illness. However, TP53 mutations can be acquired. Therefore, it is valuable to recheck both next-generation sequencing for TP53, as well as the FISH testing for new chromosomal abnormalities, at least at each time you are going to start a new line of therapy. This may not necessarily impact your management, but it might impact your ability to prognosticate. That can be helpful.

How do you monitor and manage BTK inhibitor–related atrial fibrillation?
Sameer A. Parikh, MBBS: In general, I will partner with my cardio-oncology colleagues to evaluate the patient’s atrial fibrillation. In general, the threshold to stop a covalent BTK inhibitor depends on how far along the patient is on therapy and what sort of response they have had. Additionally, it is also important to understand the severity of atrial fibrillation. In some patients, you can reduce the dose of the covalent BTK inhibitor and continue with careful monitoring, particularly as it relates to concomitant antiplatelet or anticoagulant therapy and the risk of bleeding.  Nowadays, we have the opportunity to either go to a venetoclax-containing regimen or a noncovalent BTK inhibitor like pirtobrutinib, which has been associated with a relatively low incidence of atrial fibrillation. Having said that, I will always ask myself, does the patient really need to continue any therapy or not? For example, in the E1912 study, which was a frontline study that compared ibrutinib plus rituximab with fludarabine/cyclophosphamide/rituximab in patients who needed to stop ibrutinib because of toxicity and not progression of disease, the median time to next treatment after stopping ibrutinib was approximately 2 years, suggesting that not everyone who stops treatment because of toxicity needs to continue with any CLL-directed therapy. That is an important thing to remember.

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In your current practice, for which patients with CLL requiring treatment do you consider pirtobrutinib? (Please select all that apply)

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