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Treatment decision making in CLL SLL
FAQs: Expert Perspectives on Treatment Decision-making for Patients with CLL/SLL Based on the Latest Evidence

Released: July 16, 2025

Expiration: January 15, 2026

Brad Kahl
Brad Kahl, MD
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Key Takeaways
  • Choosing between indefinite BTK inhibitor therapy and time-limited venetoclax plus obinutuzumab for patients with previously untreated chronic lymphocytic leukemia/small lymphocytic leukemia should involve a consideration of patient preferences, age/frailty, and other individualized factors.
  • Treatment with venetoclax plus obinutuzumab in a rural community center setting may require initial treatment at a larger academic center for optimal management of infusion reactions and tumor lysis syndrome.

How do you approach choosing between time-limited vs indefinite therapy for your patients with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) in need of initial treatment?
I tend to favor time-limited treatment with venetoclax plus obinutuzumab for my patients with treatment-naive CLL/SLL whenever possible. However, I always offer my patients the option of BTK inhibitor therapy, which is given indefinitely until disease progression and/or intolerance. Some patients prefer the simplicity and convenience of taking a pill, and for those patients, I will recommend BTK inhibitor therapy. Also, if patients are older, perhaps in their 80s, I am less enthusiastic about obinutuzumab infusions, venetoclax ramp-up monitoring, or the need to make frequent visits to the clinic for treatment. For such patients, I would likely recommend indefinite therapy with a BTK inhibitor.

How do you approach the selection of the next-line of therapy for a patient with CLL/SLL who has developed resistance to a covalent BTK inhibitor?
If I have a patient on a covalent BTK inhibitor—either acalabrutinib or zanubrutinib—and I see that the patient is developing progressive disease, my next line of therapy is pirtobrutinib or a venetoclax-based therapy. If the patient has not been previously exposed to venetoclax, I would lean more in the direction of recommending a venetoclax-based treatment and save pirtobrutinib for later on should the disease become double refractory to a covalent BTK inhibitor and venetoclax.

However, for patients with treatment resistance to either acalabrutinib or zanubrutinib, it would be reasonable to consider pirtobrutinib as the next line of therapy if they wish to avoid the hassle factor of initiating venetoclax. The response rates for pirtobrutinib in patients after the failure of a covalent BTK inhibitor is >70%. Given that most patients will respond to pirtobrutinib, BTK mutational testing is not essential. We do not have comparative data to guide the next optimal treatment choice for pirtobrutinib vs venetoclax after the emergence of treatment resistance to first-line treatment with a covalent BTK inhibitor.

How do you tailor treatment for elderly and/or frail patients with CLL/SLL?
In general, I try to avoid the use of obinutuzumab or rituximab for elderly and/or frail patients because these 2 anti-CD20 monoclonal antibodies increase the risk of infections. Sometimes less treatment can be as effective, and better tolerated; so, I try to keep my treatment approach as simple as possible.

For this patient population, I typically recommend a BTK inhibitor monotherapy; specifically, acalabrutinib or zanubrutinib. Because acalabrutinib and zanubrutinib are oral agents without the need for frequent monitoring, patients do not need to travel to the clinic more than once a month to start treatment. I typically see patients monthly for the first 6 months to monitor the response and react to any adverse effects. After I have treated the patient for approximately 6 months, I will usually cut back on the frequency of the clinic visits to every 3 months for checkups. This approach is convenient for patients and is not disruptive to their lifestyle. Acalabrutinib and zanubrutinib appear to slightly increase the risk of infection. If an infection such as influenza or COVID-19 does occur, my approach is to hold the BTK inhibitor until symptoms resolve.

Overall, a very important practice is a discussion with the patient regarding treatment goals and preferences before decisions are made.

For a patient with CLL/SLL, what are the differences between receiving treatment at large academic cancer centers and rural community practice centers?
For a patient for whom the plan is to treat with venetoclax and obinutuzumab, I think the academic centers are more used to managing infusion reactions to obinutuzumab and more familiar with the monitoring requirements for tumor lysis syndrome associated with venetoclax. So the large academic cancer centers may be more comfortable with administering venetoclax/obinutuzumab and the monitoring that goes with the regimen.

If a rural community center is not fully equipped to manage severe reactions to obinutuzumab or deal with venetoclax-associated tumor lysis syndrome in a timely manner, an option may be to initiate treatment with venetoclax/obinutuzumab in a larger academic cancer center. After the initial high-risk treatment period has passed (Week 5), treatment with venetoclax/obinutuzumab may continue at the community center. 

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