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Experts Discuss CLL
Experts Discuss Cases and Questions in Contemporary CLL Treatment

Released: July 13, 2026

Catherine C. Coombs
Catherine C. Coombs, MD
Nitin Jain
Nitin Jain, MD
Nicole Lamanna
Nicole Lamanna, MD
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Key Takeaways
  • Risk-adapted, individualized treatment planning remains central to CLL management, with disease biology, comorbidities, treatment logistics, and personal preferences guiding the selection and sequencing of frontline and subsequent therapies.
  • Frontline treatment selection should be individualized according to genomic risk, patient characteristics, and treatment goals, balancing fixed-duration and continuous targeted therapy approaches while incorporating shared decision-making to align treatment with patient preferences.
  • Management of relapsed/refractory CLL now incorporates newer agents such as pirtobrutinib and CAR T-cell therapy, underscoring the importance of thoughtful sequencing and timely referral to specialized centers when appropriate.

In this commentary derived from a live symposium at ASCO 2026, Catherine C. Coombs, MD; Nitin Jain, MD; and Nicole Lamanna, MD, discuss current treatment paradigms for patients with chronic lymphocytic leukemia (CLL) and answer healthcare professionals' questions on this topic, with a focus on cases in previously untreated and relapsed/refractory disease.

Patient Cases: Previously Untreated CLL
Nicole Lamanna, MD: Let’s look at management of a few case patients with previously untreated CLL. The first is a 63-year-old man with newly diagnosed CLL. Upon biomarker testing, we see that his CLL is negative for deletion(17p) (by FISH), and TP53 wild-type (by PCR) and mutated for IGHV. Overall, this is a favorable risk patient. He has a past medical history notable for hypertension and diabetes, and he does have indications for therapy because he is symptomatic with cytopenias. He expresses a preference to receive a fixed-duration, pill-only regimen, if possible, because he is busy with his career as a truck driver.

The recommendation by each of the panelists for this activity would be venetoclax plus acalabrutinib, based on patient preferences and data from the phase III AMPLIFY study. The patient expressed an interest in an all-oral regimen, which would suggest that fixed-duration venetoclax plus acalabrutinib or a continuous BTK inhibitor (such as acalabrutinib or zanubrutinib) would be optimal.  However, the patient is relatively young and has favorable risk features, so a time-limited approach might be better for him.

Now, let’s look at the case of a 76-year-old woman with previously untreated CLL. She was diagnosed with CLL 2 years ago. Initially, she was followed with watchful waiting, but now she has developed progressive disease and requires treatment. Upon biomarker testing, her CLL has unmutated IGHV and deletion(17p). This is a much higher-risk patient than the previous patient. Her comorbidities are significant for controlled hypertension and chronic kidney disease (CKD) with a GFR of 40, and her ECOG performance status is 1. Of importance, she lives an hour away from the treatment center and is the primary caregiver for her 80-year-old husband. 

Catherine C. Coombs, MD: For this case, we had a consensus among panelists in that we would all recommend continuous oral BTK inhibitor therapy with either acalabrutinib or zanubrutinib. 

Nitin Jain, MD: For me, the key factors informing treatment for this patient are that she lives some distance from her treatment center and that she has CLL with unmutated IGHV and del(17p). Those are high-risk genomics. The best prospective frontline data for patients with this form of high-risk disease are with continuous BTK inhibitors such as acalabrutinib or zanubrutinib. Of note, the patient also has CKD, with a GFR of 40. This is not an absolute contraindication to use a venetoclax-based regimen, but impaired renal function can increase the risk of tumor lysis syndrome with these regimens. Overall, with high-risk characteristics, CKD, and her distance from the treatment center, continuous oral BTK inhibitor therapy with either acalabrutinib or zanubrutinib would be my choice.

When might you consider adding obinutuzumab to a BTK inhibitor–containing regimen?
Catherine C. Coombs, MD: Although covalent BTK inhibitors are highly effective for CLL, there are occasional situations where I consider combining obinutuzumab with these agents to accelerate disease control. One common scenario is a patient presenting with autoimmune cytopenias that have not responded adequately to prior therapies. In those cases, I need to treat both the autoimmune complication and the underlying CLL, and adding obinutuzumab can help achieve more rapid disease control. I also consider this approach for patients with bulky lymphadenopathy or significant cytopenias who require a faster clinical response. BTK inhibitors work well, but their responses can take time to develop, so incorporating obinutuzumab may hasten improvement in carefully selected patients.

What is the role of MRD in CLL treatment?
Nitin Jain, MD: Measurable residual disease (MRD) has become an important prognostic tool in CLL, particularly for patients receiving fixed-duration therapy. For patients treated with continuous BTK inhibitor therapy, MRD assessment has relatively little clinical utility because most patients remain MRD positive despite long-term disease control. However, for time-limited regimens such as venetoclax plus obinutuzumab or acalabrutinib plus venetoclax, MRD status at the end of treatment has consistently predicted long-term progression-free survival across multiple studies.

The more difficult question is whether MRD is currently actionable. Although ongoing phase III studies, including MAJIC, may eventually answer that question, we are not yet routinely changing treatment based on MRD status alone. In my own practice, I typically assess MRD at the completion of fixed-duration therapy because it provides valuable prognostic information, even if it does not yet alter management.

How do you work with your patients to involve them and engage them in treatment decisions?
Catherine C. Coombs, MD: One of the advantages of caring for patients with CLL is that we usually have time to make thoughtful treatment decisions. Unlike acute leukemia, treatment rarely needs to begin immediately, allowing discussions to evolve over several visits. As I recognize signs of disease progression, I begin introducing the concepts of continuous vs time-limited therapy well before treatment becomes necessary. Those conversations continue over months as patients consider how different treatment strategies align with their priorities and lifestyle.

One lesson I've learned is that patients frequently surprise us. Younger patients may choose continuous BTK inhibitor therapy because it interferes less with work or family responsibilities, whereas older patients may prefer fixed-duration therapy. Rather than assuming what patients will value, I think our role is to provide education, present the available options, and allow enough time for patients to make informed decisions that fit their individual goals.

Nitin Jain, MD: My approach is very similar. Treatment decisions are rarely finalized during a single clinic visit. Instead, I introduce all appropriate options and explain how factors such as lymph node burden, renal function, cardiovascular history, and treatment logistics may make 1 strategy more appealing than another. Ultimately, the decision belongs to the patient, and giving them time to consider those options often leads to more thoughtful, individualized treatment choices.

What do you recommend for patients with CLL refractory to both a covalent BTK inhibitor and BCL-2 inhibitor–based therapy?
Nitin Jain, MD: To address this, let’s look at a case. The patient is a 64-year-old male with CLL with unmutated IGHV, deletion 11q by FISH, and no TP53 mutation or del(17p). The patient received ibrutinib plus rituximab as a frontline therapy from 2016 until 2020; however, experienced disease progression while on ibrutinib. The patient then received venetoclax plus rituximab starting in 2020, with continuous venetoclax after stopping rituximab. Now the patient is experiencing disease progression and needs treatment. Repeat biomarker testing continues to show TP53 mutation–negative disease; however, a BTK C481S mutation is detected. What do we now recommend for this patient?

In many cases, a patient like this would have received time-limited venetoclax plus rituximab, as in the MURANO study. If that were the case, and the patient had progressed sometime later, retreatment with venetoclax-based therapy could be considered. However, this patient continued venetoclax until progression, so that would not be an optimal choice here.

Among the panelists, the noncovalent BTK inhibitor pirtobrutinib and CAR T-cell therapy lisocabtagene maraleucel, or liso-cel, were discussed. 

Nicole Lamanna, MD: Pirtobrutinib would be an excellent choice for a patient with CLL that is double refractory to a covalent BTK inhibitor and BCL-2 inhibitor–based therapy, based on data from the BRUIN trials. We also know that pirtobrutinib is effective in patients with CLL with a BTK C481S mutation. However, disease relapse will eventually occur, so it is important to think about treatment sequencing. Outside of clinical trials, it would be appropriate to have the patient evaluated for CAR T-cell therapy while treating with pirtobrutinib.

Nitin Jain, MD: I agree. Pirtobrutinib has the advantage of being an oral therapy, so you can start a patient on this right away, especially if the patient needs immediate debulking. With liso-cel, for many treatment centers, the patient must be referred to an authorized center where they can be evaluated and potentially treated, which can take some time.

When do you refer patients for CAR T-cell therapy?
Nitin Jain, MD: Let’s build off of our previous case and discuss this further. I generally begin discussing CAR T-cell therapy after patients have received both a covalent BTK inhibitor and a venetoclax-based regimen. These double-exposed patients represent the population most appropriate for referral to a CAR T-cell therapy center. At the same time, pirtobrutinib has become an important therapeutic option, creating questions about the optimal sequencing of therapy. In many cases, I initiate pirtobrutinib while simultaneously beginning discussions about CAR T-cell therapy so that patients have access to both strategies as their disease evolves.

Catherine C. Coombs, MD: I agree that CAR T-cell therapy should generally be reserved for patients who are truly refractory to both BTK inhibitor- and venetoclax-based treatment, rather than those who simply discontinued therapy because of intolerance. Whenever reasonable, I also consider retreatment strategies before proceeding to CAR T-cell therapy. Increasingly, I view pirtobrutinib as an effective bridge to CAR T-cell therapy because it provides excellent disease debulking before lymphocyte collection. Although complete responses are uncommon, reducing tumor burden before CAR T-cell therapy appears clinically advantageous and may contribute to improved outcomes. For younger, fit patients, this sequencing strategy offers the potential for longer-term disease control, whereas for older or more frail patients, continued treatment with pirtobrutinib alone may represent the most appropriate approach as the therapeutic landscape continues to evolve.

Your Thoughts
With recent clinical trial data and guideline changes to treatment paradigms for CLL, how are you managing patients in the frontline setting? How are you sequencing therapy? Join the discussion by leaving a comment or responding to the polling question.

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In my current practice, I feel confident in selecting frontline therapy for previously untreated CLL and sequencing therapy for relapsed/refractory disease.

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