Real-World Evidence Supports Switch to Next-Generation BTK Inhibitor for CLL: A Q&A With Margaret Krackeler, MD

When Kaiser Permanente Northern California transitioned its patients with chronic lymphocytic leukemia (CLL) from ibrutinib (Imbruvica; Pharmacyclics LLC and Janssen Biotech) to zanubrutinib (Brukinsa; BeOne), the health system generated the largest real-world cohort examining this practice change. In a study of 281 patients published in Cancer Medicine, researchers found that 79% remained on zanubrutinib at last follow-up, with notably fewer treatment-limiting and cardiac adverse events (AEs) compared with ibrutinib—outcomes that validated the systemwide formulary switch and offer insights for other health systems navigating similar transitions.¹

Margaret Krackeler, MD, a hematologist-oncologist at Kaiser Permanente Northern California and lead author of the study, discusses how real-world data captured the nuances clinical trials often miss: patients with preexisting cardiac comorbidities, those on anticoagulation therapy, and even some who had progressed on ibrutinib but showed encouraging tolerability and persistence on zanubrutinib. In this interview with The American Journal of Managed Care^® (AJMC^®), she shares lessons on implementing evidence-based formulary changes, the role of Bruton tyrosine kinase (BTK) inhibitor sequencing in everyday practice, and why real-world research is becoming essential for understanding long-term outcomes in chronic hematologic malignancies.

This interview was lightly edited for clarity.

AJMC: This study captures a systemwide transition from ibrutinib to zanubrutinib in a real-world community oncology setting. What outcomes most strongly validated this practice change once it was implemented at scale?

Krackeler: In a real-world practice change from ibrutinib to zanubrutinib at Kaiser Permanente in Northern California, I would say the most compelling outcomes that validated the switch were the improved tolerability and persistence with zanubrutinib compared with ibrutinib. In our study, patients switching to zanubrutinib had fewer treatment-limiting AEs, as well as cardiac AEs, and most of them, 79% of these patients, did remain on zanubrutinib at the last follow-up without any treatment-related deaths. I would say that these outcomes, supported by our real-world data, really suggest that the switch led to better real-world safety and effective use of zanubrutinib after this practice change at Kaiser Permanente in Northern California.

AJMC: Most patients who switched from ibrutinib, including some who previously progressed, remained on zanubrutinib. What does this tell us about BTK inhibitor sequencing in everyday practice?

Krackeler: Most of our patients who switched from ibrutinib remained on zanubrutinib. As I stated earlier, 79% of the patients remained at the end of our follow-up, and we did see good tolerability on that medication. Looking at the patients who specifically had AEs on ibrutinib, 17% of those patients ended up having a recurrence of those AEs while on zanubrutinib, but there were low rates of treatment discontinuation of zanubrutinib with those AEs.

I do think that our real-world data support the use of switching to a different BTK inhibitor like zanubrutinib if the first generation or a different BTK inhibitor is not tolerated. There was a small cohort of patients where we found that they were switched to zanubrutinib due to progression on ibrutinib, and that was done at the discretion of the treating provider. However, a lot more research is needed to see if that is a standard practice or something that should be adopted. More information is really needed to see if that is effective. Our small population of patients were still on zanubrutinib, even after progression of ibrutinib, but there's really not enough data to really comment on if that sequencing is appropriate for that indication.

AJMC: Zanubrutinib showed fewer treatment-limiting and cardiac events despite similar overall AE rates. How should this influence treatment decisions, especially for older patients or those with cardiac risk?

Krackeler: Zanubrutinib did demonstrate similar overall rates of AEs compared with other BTK inhibitors, and our real-world data did show that there were lower rates of treatment-limiting AEs, so those that led to discontinuation as well as cardiac events within the group. I would say this is especially relevant for older patients, because we want to ensure that they are able to tolerate the medication long term, so that they continue to have good disease control, even as their risk increases with age and, additionally, with cardiac comorbidities.

In our cohort, there were 25% of patients who had preexisting cardiac comorbidities, and 39% of the patients in our cohort were on some anticoagulation or antiplatelet agent prior to the BTK inhibitor initiation. We see that, despite that, our cohort had great tolerability and low rates of cardiac AEs. I do think that for these higher cardiac risk patients and older patients, zanubrutinib is a good option to consider so that you can help with their disease but also reduce the risk of complications that might impact their quality of life moving forward.

AJMC: High-risk patients appeared to do well on zanubrutinib in this cohort. What signals stood out to you, and where should clinicians be careful in interpreting these real-world data?

Krackeler: For high-risk patients in our cohort, we did see that there was good tolerability, and they did primarily remain on standard treatment at the end of follow-up. For us, we interpret that as it was effective during our treatment period. But I would say that the population was really limited and small in our cohort, and while reviewing the patients, we saw that there was a lack of cytogenetic data for a lot of the patients. We acknowledge that that's a limitation in our study and in real-world data collection; therefore, I really think that there is some hesitancy to interpret these data as saying BTK inhibitors are the option for high-risk patients. However, recent data have shown favorable outcomes of BTK inhibitor use in high-cytogenetic-risk patients. They also similarly had small sample sizes, however, so I do think there's additional research needed for this specific population to see truly how BTK inhibitors are going to be effective or tolerated.

AJMC: From a health system perspective, what lessons does this experience offer about implementing formulary or practice changes when new data emerge?

Krackeler: With this practice change, it was really valuable to see the collaboration between the pharmacy team, our providers, and the patients to ensure a successful transition. And I do believe that what we've learned is that this method can be used to help implement quick practice changes based on evidence here at our system. I do believe that our research on real-world evidence is particularly valuable in informing these decisions as well, since it reflects outcomes that directly impact utilization and adherence but also focuses on the patient outcomes and how they are tolerating the treatment decisions that we make for them. Therefore, I really hope that more real-world research can be done in this field of oncology, particularly for these chronic diseases that require long-term therapy.

AJMC: What role do real-world data play in advancing the understanding of the latest oncology therapies?

Krackeler: Our study really shows the value in real-world data. This was the largest cohort at the time of real-world analysis for patients with CLL on zanubrutinib, and it was 281 patients in the system of Kaiser Permanente in Northern California. However, if we could get even more patients and larger cohorts, then we could really speak to the real-world experience of patients and learn a lot more about the tolerability and efficacy of these medications outside of just clinical trials. I do hope that this study helps contribute to this field of real-world research that I think a lot of our oncology field is moving toward as well.

Reference

Krackeler ML, Chee BH, Orchanian AK, et al. Real-world treatment patterns and outcomes of zanubrutinib in chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL). Cancer Med. Published online October 25, 2025. doi:10.1002/cam4.71300