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Optimizing BTKi Use Across CLL
Expert Q&A: Optimizing BTK Inhibitor Use Across the CLL/SLL Treatment Landscape

Released: January 21, 2026

Matthew Cortese
Matthew Cortese, MD, MPH
Brian Hill
Brian Hill, MD, PhD
Sameer A. Parikh
Sameer A. Parikh, MBBS
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Key Takeaways
  • Early evidence suggests that treatment with a BTK inhibitor can enhance subsequent outcomes with CAR T-cell therapy when used safely.
  • Pirtobrutinib is now approved for adults with relapsed/refractory CLL/SLL who have been previously treated with a covalent BTK inhibitor regardless of prior BCL2 inhibitor therapy.

Matthew Cortese, MD, MPH, Brian Hill, MD, PhD, and Sameer A. Parikh, MBBS, recently discussed strategies for optimizing disease management and improving outcomes in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) during our live webinar “Aligning Discovery With Clinical Practice: Applying Expert Consensus Guidelines To Improve Patient Outcomes in CLL/SLL”. The following questions were posed by audience members at the live event.

How does a concomitant BTK inhibitor improve the efficacy and toxicity profile of CAR T-cell therapy?
Matthew Cortese, MD, MPH:
A concomitant BTK inhibitor can improve both the efficacy and safety of CAR T-cell therapy when used thoughtfully with patient safety as the primary consideration. CAR T-cell therapy is potentially curative for some patients, so it is important to maximize its outcomes. For many patients, combining CAR T-cell therapy with a BTK inhibitor like ibrutinib is a good strategy. Mechanistically, in addition to BTK, ibrutinib also inhibits inducible T-cell kinase, which can shift T-cell signaling and cytokine profiles in a way that enhances T-cell fitness and function and may improve CAR T-cell activity while mitigating excessive inflammatory responses that contribute to toxicity. However, if a patient has an underlying condition such as uncontrolled hypertension or ventricular arrhythmia, I would not start them on a BTK inhibitor. Achieving disease control and being optimally debulked is the most important strategy for keeping patients on track. Overall, if a patient is eligible for ibrutinib pre leukapheresis, even if only for a couple weeks, I think it is a reasonable strategy, but above all else, we must keep our patients safe.

Sameer A. Parikh, MBBS:
It was originally thought that the observed benefit was unique to ibrutinib because of its broad BTK inhibitory effects. However, a subsequent study investigated pirtobrutinib just prior to CAR T therapy and suggested a trend toward improved survival. Thus, some BTK inhibition in addition to CAR T therapy appears to benefit patients and serve as a promising management strategy, but this study was performed in a small number of patients, so additional evidence is warranted.

How might the new indication for pirtobrutinib after failure on a covalent BTK inhibitor in relapsed/refractory CLL/SLL change your treatment sequencing? In other words, after failure on a covalent BTK inhibitor, would you choose pirtobrutinib or venetoclax-based treatment?
Brian Hill, MD, PhD:
Great question. Pirtobrutinib was first approved for patients with CLL/SLL in the double-refractory setting—after failure on a covalent BTK inhibitor and a BCL2 inhibitor. Now, it can be used in earlier lines of therapy, expanding treatment options for patients with relapsed/refractory CLL/SLL and introducing greater nuances into treatment sequencing decisions. At this point, it is difficult to say what the best approach is. The choice between pirtobrutinib and venetoclax-based therapy should be individualized, but I think it depends on the presence of a BTK mutation. If a patient harbors the C481S mutation, for instance, they will probably respond well to pirtobrutinib; alternatively, if a patient has another mutation or the mechanism of resistance is not known, venetoclax may be a better option. Overall, the expanded indication for pirtobrutinib enhances flexibility in sequencing but also highlights an unmet need for more data.

Matthew Cortese, MD, MPH:
I full agree. I prefer to treat with pirtobrutinib after a covalent BTK inhibitor because it was designed for this scenario, though longer-term follow-up is needed. Additional data should be able to address whether the response times and median time to progression are longer in this earlier-line setting. These data will ultimately help define where pirtobrutinib best fits relative to venetoclax-based regimens.

For patients with hypertension, do you treat with acalabrutinib or zanubrutinib?
Matthew Cortese, MD, MPH:
First, both are very effective drugs. In fact, any of the 3 approved covalent BTK inhibitors (acalabrutinib, zanubrutinib, ibrutinib) are better than chemoimmunotherapy, although based on studies in which acalabrutinib or zanubrutinib were compared to ibrutinib, acalabrutinib and zanubrutinib performed better than ibrutinib in the vast majority of patients. From a cardiovascular standpoint, if a patient has hypertension, particularly if they are on antihypertensive therapy, have effusions, or carry additional cardiovascular risk factors, I prefer acalabrutinib because it may be less likely to worsen the preexisting hypertension. However, I think it is reasonable to treat with zanubrutinib with close monitoring and input from the primary care provider and cardiologist.

One important, discriminating factor between these 2 covalent BTK inhibitors is that acalabrutinib is dosed twice daily, whereas zanubrutinib can be taken twice daily or once daily. For patients who may struggle with adherence, pill fatigue, or complex medication schedules, I recommend zanubrutinib daily. Similarly, when thinking about dose reductions, one should consider that the half-life of zanubrutinib is slightly longer than that of acalabrutinib and has higher BTK occupancy. I think more follow-up data are needed, and I would love to see a head-to-head trial comparing these drugs.

Your Thoughts
What are your current questions related to managing patients with CLL/SLL in the clinic today? Let us know in the comments.

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What is your preferred frontline therapy for your patients with CLL today?

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