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CLL Therapy Today: Answers to Your Latest Questions From the Experts

Released: July 09, 2025

James Davis
James Davis, PharmD, BCOP
Victoria Nachar
Victoria Nachar, PharmD, BCOP
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Key Takeaways
  • Acalabrutinib plus venetoclax with or without obinutuzumab is a new fixed-duration initial therapy option for patients with chronic lymphocytic leukemia (CLL).
  • Pirtobrutinib is generally a well-tolerated treatment option in patients with CLL after previous covalent Bruton tyrosine kinase inhibitors (BTKi) and/or BCL-2 inhibitor–based therapy.
  • Routine check-ins by pharmacists have been shown to reduce the incidence of severe adverse events and improve adherence to BTKi and BCL-2 inhibitor therapy in patients with CLL.

At a recent live webinar hosted by ProCE in partnership with Clinical Care Options, Victoria Nachar, PharmD, BCOP, and James Davis, PharmD, BCOP, fielded a number of important questions submitted by the audience of healthcare professionals who manage patients with chronic lymphocytic leukemia (CLL). This commentary captures their responses to a handful of the most practice-relevant inquiries related to the use of covalent (ibrutinib, acalabrutinib, zanubrutinib) and noncovalent (pirtobrutinib) Bruton tyrosine kinase inhibitors (BTKi) and venetoclax-based regimens. These agents remain the cornerstone of CLL therapy in 2025.

What factors guide the selection of time-limited frontline therapy in CLL, particularly with the recent incorporation of acalabrutinib plus venetoclax with or without obinutuzumab (AV/AVO) into guidelines and approval by the European Union?

Victoria Nachar, PharmD, BCOP:
This is such an important question, especially now that we have 2 fixed-duration regimens available. Venetoclax plus obinutuzumab (VO) (evaluated in the CLL14 trial) has long been our go-to treatment for time-limited frontline therapy, and now AV—based on the AMPLIFY trial—adds a convenient all-oral option. Although obinutuzumab adds depth of response, its infusion requirements can be a logistical burden for many patients. The AV combination (without obinutuzumab) was shown to significantly improve progression-free survival compared with chemoimmunotherapy and offers simplicity. We should note that undetectable measurable residual disease (uMRD) rates were higher with the VO regimen in the CLL14 trial, which may explain the longer time-off therapy observed in that trial. Long-term data for AV are still pending, and the lower uMRD rates reported from the AMPLIFY trial raise questions about durability. For patients with high-risk cytogenetics like del(17p) or TP53 mutations, I would still prefer continuous BTKi monotherapy because of the superior progression-free survival outcomes.

How would you manage a patient who relapses after receiving AVO?

Victoria Nachar, PharmD, BCOP:
It really depends on the timing of the relapse. If it is a late relapse—typically defined as beyond 2 years—there is rationale to consider reusing a venetoclax-based approach or switching to a single-agent BTKi. If it is an early relapse, especially within 1 year, we would avoid repeating the same therapy. In such cases, pirtobrutinib becomes a key option, especially if the patient has already been exposed to both a covalent BTKi and venetoclax.

James Davis, PharmD, BCOP:
I agree. This is where sequencing becomes complex. We do not yet have prospective data on what to do for patients following disease progression on or after AV or AVO. For patients relapsing after receiving all 3 agents as their initial therapy, we are now forced to consider newer options like noncovalent BTKi or to refer these patients to clinical trials. Pirtobrutinib stands out in this setting because of its activity in patients with BTK C481 mutations, which confer resistance to covalent BTKi. Beyond that, we may need to consider CAR T-cell therapy or even stem cell transplantation for appropriate patients.

What is your clinical experience with adverse events associated with pirtobrutinib?

James Davis, PharmD, BCOP:
In the BRUIN trial, pirtobrutinib demonstrated a generally favorable safety profile. The most common adverse events included respiratory infections, bruising, rash, and arthralgias. In my practice, patients tend to tolerate it quite well—certainly better than ibrutinib. Atrial fibrillation and hypertension are less common and milder than what we see with earlier-generation BTKi. The bruising is often just a cosmetic issue, and the infections are typically low grade and manageable with outpatient oral antibiotics if needed. It is quickly becoming a preferred option for patients progressing after prior covalent BTKi exposure.

Is atrial fibrillation (AFib) with BTKi limited to patients with preexisting cardiovascular disease?

Victoria Nachar, PharmD, BCOP:
Not at all. Although patients with a history of cardiovascular disease or preexisting AFib are at greater risk, AFib can develop in anyone receiving a BTKi. That said, newer agents like acalabrutinib, zanubrutinib, and pirtobrutinib carry a lower risk of cardiovascular toxicities compared with ibrutinib. For patients who develop AFib, we usually manage the arrhythmia with β-blockers being preferred as they avoid drug–drug interactions rather than discontinuing the BTKi. The only time we discontinue the BTKi is if we are unable to control the arrhythmia after medical management. If anticoagulation is needed, we favor a direct oral anticoagulant over warfarin and monitor closely for bleeding but do not automatically stop therapy.

Do you have a preferred BTKi or dosing strategy for patients with severe neutropenia?

Victoria Nachar, PharmD, BCOP:
In our experience, neutropenia is often disease related, especially in patients with packed bone marrow. Starting therapy helps relieve the cytopenias in many cases. We typically continue full-dose BTKi unless the patient is receiving concurrent antifungal prophylaxis that requires dose adjustment. In terms of agent selection, we do not have strong preferences purely based on neutropenia, but we do assess the broader clinical context. If this is neutropenia that occurs after starting a BTKi, then we usually only hold or make dose adjustments if the neutropenia is severe or prolonged.

James Davis, PharmD, BCOP:
I agree. Most cases of neutropenia improve with effective therapy. We might delay obinutuzumab or venetoclax if the neutropenia is prolonged, but we rarely use antifungal prophylaxis unless the patient is immunosuppressed from other factors like steroids or CAR T-cell therapy. It is very much a patient-specific decision.

How can pharmacists help optimize adverse effect management and improve adherence in CLL?

Victoria Nachar, PharmD, BCOP:
Pharmacists have a huge role here. We routinely check in with patients within the first 2 weeks of starting therapy and again at 1 month. Many adverse events like headache, myalgia, or diarrhea are manageable if addressed early. Patient education on holding BTKi before procedures, monitoring blood pressure, and managing mild adverse effects with over-the-counter medicines is crucial. This allows patients to remain adherent and avoid unnecessary discontinuations.

James Davis, PharmD, BCOP:
I love data that support this. One study showed that pharmacist-led interventions through monthly check-ins, adherence tracking, and managing drug–drug interactions reduced grade ≥3 adverse events and improved adherence. This is not just good care; it is cost effective. Fixed-duration regimens may reduce long-term costs, but only if patients can adhere to them and manage toxicity well. Pharmacists are essential to making that happen.

Your Thoughts
What are your ongoing challenges in the care of your patients with CLL? Has your practice adopted fixed-duration therapy with AV/AVO as a treatment option for patients with previously untreated CLL? Answer the poll and leave a comment below to join the conversation.

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Has your practice incorporated the regimen of AV/AVO into the care of patients with previously untreated CLL?

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