Management of Atrial Fibrillation in Patients With CLL on BTK Inhibitors

In April 2023, a 66-year-old woman with CLL returns for re-evaluation after a second dose reduction of ibrutinib for atrial fibrillation. She has already been started on 50 mg of metoprolol and 5 mg of apixaban twice daily for the emergent atrial fibrillation (AF) on ibrutinib therapy. She has been on frontline ibrutinib for her CLL since spring of 2018. Prognostic workup at the time demonstrated no abnormalities via FISH, mutated IGHV, and somatic mutation testing for TP53 was negative. At this time her laboratory evaluation demonstrated continued response to therapy including normal WBC count, hemoglobin, and platelet count. LDH remains within normal limits. There is no palpable adenopathy or splenomegaly on exam and she denies any B symptoms such as drenching night sweats, fevers, significant fatigue, or unintentional weight loss. Since last visit, she was once again evaluated in the local emergency room for palpitations and found to be in AF with rapid ventricular response. The cardiologist who evaluated her is now recommending she consider undergoing an ablation. She wonders how much the ibrutinib may be contributing and what her best next steps should be.

Discussion and Next Steps

You discuss with the patient that there are several options available. First, she is currently in a complete clinical remission, which could be further confirmed by additional testing such as CT scans and a bone marrow biopsy. You share with her that one option would be simply to discontinue the ibrutinib and re-enter into observation with watchful waiting; individuals who discontinued ibrutinib in the frontline setting due to toxicity have a median PFS of approximately 2 years.¹ Alternatively, she could consider switching to a newer generation BTK inhibitor such as acalabrutinib or zanubrutinib. You share with her that AF has been reported with both acalabrutinib and zanubrutinib as well, less with zanubrutinib than with acalabrutinib or ibrutinib, though duration of follow-up on these studies varies. A third option for her would be to switch to a time-limited venetoclax-based regimen.

Each of the currently approved BTK inhibitors in CLL has been associated with a risk for atrial fibrillation to varying degrees. In ELEVATE-RR, the head-to-head study of ibrutinib vs. acalabrutinib in the setting of relapsed CLL, ibrutinib demonstrated increased rated of all-grade AF compared with acalabrutinib (15.6% vs. 9%, respectively). Reported grade ≥ 3 AF was slightly higher with acalabrutinib compared with ibrutinib (4.5% vs. 3.4%, respectively).² In the ALPINE trial, which compared ibrutinib to zanubrutinib in the setting of relapsed CLL, zanbrutinib demonstrated lower rates of both all-grade AF (4.6% vs. 12.3%) and grade ≥ 3 AF (1.9% vs. 3.7%) compared to ibrutinib.³ 

A recent update on long-term outcomes from the E1912 trial comparing the combination of ibrutinib plus rituximab to traditional chemoimmunotherapy with FCR reported, after a median follow up of 5.8 years, a 12% incidence of any-grade AF and 4.5% incidence of grade ≥ 3 AF in patients who received ibrutinib plus rituximab. Researchers noted that patients who had a clinical response to ibrutinib but eventually discontinued due to an adverse event still had a window of time in which disease remained stable despite additional therapy, which varied based on length of exposure to ibrutinib. Patients who received ibrutinib for < 1 year before discontinuation had a median PFS of 19.3 months; patients who stayed on therapy for 1-2 years before ibrutinib discontinuation had a median PFS of 30.3 months, and patients with > 2 years of ibrutinib therapy prior to discontinuation demonstrated a median PFS of 25.0 months, respectively (p = 0.47).¹ Importantly, patients with del17p by FISH were excluded from this trial so this data would not apply to patients with this abnormality.

The last option for this patient would be switching to a time-limited venetoclax-based regimen. Venetoclax is an oral BCL2 inhibitor that is typically combined with a monoclonal anti-CD20 antibody. In the frontline setting, venetoclax is given for 1 year of therapy, whereas in the relapsed setting, it is given for 2 years. Due to the risk for tumor lysis syndrome (TLS), venetoclax does require a 5-week dose escalation including laboratory monitoring and occasionally hospitalization; need for hospitalization and  frequency of lab monitoring is determined based on the patient’s risk factors for TLS including absolute lymphocyte count (ALC) and size of their largest lymph node.⁴

After reviewing all of the options, the patient prefers to discontinue ibrutinib and proceed with observation and watchful waiting. You place orders to see her back in 3 months for follow-up and counsel her on signs and symptoms of disease progression for which to monitor for in the meantime.

References

1. Shanafelt TD, Wang XV, Hanson CA, et al. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022;140:112-120.
2. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39:3441-3452.
3. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388:319-32.
4. Venclexta product information. Accessed March 24, 2023. https://www.venclextahcp.com/cll.html?c=gdc-175d720b5d7&gclid=Cj0KCQjwlPWgBhDHARIsAH2xdNde8yUJGsNI39x4h_qNLP5O8dLHOFxR3vg0-bWkfVKDyDblImgcGtgaAvtoEALw_wcB&gclsrc=aw.ds