Addressing Cardiovascular Toxicities with BTK Inhibitors for the Treatment of CLL

For patients with B-cell malignancies, Bruton tyrosine kinase (BTK) inhibitors can be an effective treatment option. However, some BTK inhibitors carry the risk of cardiovascular toxicities.

According to investigators of a pooled analysis of the ACE-CL-001 [NCT02029443], ACE-CL-007 [ELEVATE-TN, NCT02475681], ACE-CL-309 [ASCEND, NCT02970318], and 15-H-0016 [NCT02337829] clinical trials, the BTK inhibitor, ibrutinib (Imbruvica) has demonstrated an increased incidence of cardiovascular toxicity.

The analysis looked at acalabrutinib (Calquence), a next-generation, potent, highly selective covalent BTK inhibitor approved from chronic lymphocytic leukemia (CLL) as an alternative. A total, 762 patients with CLL were included. Overall, 46% were treatment-naïve, 54% were relapsed/refractory, and the median age was 67 years old. Led by Jennifer R. Brown, et al, the investigators sought to determine the incidence of cardiovascular toxicities in patients treated with acalabrutinib.

Results showed that cardiac adverse events (AEs) were reported in 17% of patients, the most common being atrial fibrillation (4%), atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). The median time to onset was 521 days. Overall, only 0.9% discontinued treatment due to cardiac AEs.

Overall, cardiac AEs were infrequent in patients with CLL who received acalabrutinib. The findings led to a phase 3 randomized ACE-CL-006 study of acalabrutinib versus ibrutinib (NCT02477696). 

In an interview with Targeted Oncology, Jennifer R. Brown, MD, PhD, a medical oncologist, director of the Chronic Lymphocytic Leukemia Center at the Dana-Farber Cancer Institute and professor of Medicine at the Harvard School of Medicine, discusses the chance of cardiovascular toxicities with BTK inhibitors and the safety of acalabrutinib.

TARGETED ONCOLOGY: Are cardiovascular toxicities a class effect of BTK inhibitors?

BROWN: I think we're still determining for certain the answer to that question. Currently, I think that they're significantly enriched with ibrutinib compared to at least the next-generation covalent inhibitors that we're most familiar with, like acalabrutinib and zanubrutinib (Brunkinsa). For acalabrutinib, we don't have any head-to-head comparative data yet. We have, for example, the study that we report during ASH 2020 with about 700 CLL patients who over 2-years had about a 4% rate of atrial fibrillation, which definitely appears to compare favorably to some of the ibrutinib data out there. But it's not directly comparative data. Zanubrutinib showed a marked decrease in atrial fibrillation head-to-head against ibrutinib in a Waldenstrom macroglobulinemia study. There are also ongoing studies in CLL, and that's certainly consistent with my clinical experience of the next-generation BTK inhibitors.

TARGETED ONCOLOGY: What is traditionally done in practice to mitigate cardiovascular toxicities?

BROWN: We mostly do surveillance. In my practice, I've actually switched more toward the next-generation BTK inhibitors for everyone. But, I think particularly if you have an older patient, or one who has a lot of underlying cardiovascular comorbidities, it's sensible to choose a next-generation inhibitor. We don't have any great knowledge of risk factors. When we did a pooled analysis of the ibrutinib studies looking at atrial fibrillation, the primary risk factors were increasing age and receiving ibrutinib. So, that's not so helpful. A prior history of atrial fibrillation was the other risk factor, which again, is not so helpful. But, you could use those to steer you toward the next -generation inhibitor.

In the absence of clear predictors, it's more surveillance. For example, I think oncologists have become much more aware of paying attention to the blood pressure of their patients on BTK inhibitors. We now know that hypertension is an extremely common AE, at least of ibrutinib. So, we're monitoring that very closely. Similarly, if a patient complains of palpitations you probably get them a monitor to find out if they're having atrial fibrillation.

TARGETED ONCOLOGY: Then turning specifically to this analysis, what methods were used in the evaluate the 4 trials ?

BROWN: The 4 trials included the phase 1 study, the 2 randomized trials ELEVATE and ASCEND, and a study specific for patients with deletion 17p. The median follow-up was 26 months, and it was a retrospective analysis of the reported AEs with the acalabrutinib arms. There was no comparison, for example, to the control arms with the randomized trials at this point. There were over 700 patients and 17% of the patients did develop some cardiovascular toxicity. Only 5% had grade 3 cardiovascular toxcitiy and the most common was atrial fibrillation in 4% of the patients. That was actually followed by palpitations and tachycardia, which are not exactly events as we know, their symptoms of the disease.

TARGETED ONCOLOGY: Was there anything about the analysis that surprised you?

BROWN: I was expecting to find relatively favorable cardiac profile for acalabrutinib based on my clinical experience. I certainly think atrial fibrillation is less. Hypertension is still an open question. It's still hard to tell from this analysis, just because of the relatively short follow-up. It's a 3-, 4-, and 5-year follow-up that we see the very high rates of hypertension with ibrutinib. We don't have that follow-up from most of the acalabrutinib studies yet.

TARGETED ONCOLOGY: What impact could these finding have on practice patterns?

BROWN: I think the data supports what many of us have observed in the clinic, that it appears that cardiovascular AEs are reduced with next-generation BTK inhibition. I've shifted my practice toward favoring acalabrutinib. You would certainly consider that very strongly in patients with known cardiac risk factors. We're obviously waiting on the head-to-head data comparing acalabrutinib to ibrutinib some patients with CLL.

TARGETED ONCOLOGY: Apart from that head-to-head trial, are there any next steps for this research that have yet to be explored?

BROWN: I think as we get more randomized data, we can do a meta-analysis of the randomized trials comparing the acalabrutinib containing arms to the control arms, and that would include both chemotherapy, immunotherapy, and ibrutinib. I'd be interested in doing that. My group is also pursuing a deeper dive into the mechanisms of cardiac toxicity in collaboration with Javid J. Moslehi, MD at Vanderbilt University Medical Center who is a cardiac oncologist. What we're trying to do is use cardiac MRI as well as cardiac monitoring and blood pressure monitoring in asymptomatic patients to assess the overall rates of undetected asymptomatic events as well as symptomatic events. Also, we want to see if we can identify what may be going on structurally.

_REFERENCE:

_{1.Brown J, Byrd J, Ghia P, et al. Pooled analysis of cardiovascular events from clinical trials evaluating acalabrutinib monotherapy in patients with chronic lymphocytic leukemia (CLL). Blood. 2020; 136 (suppl 1): 52–54. doi: https://doi.org/10.1182/blood-2020-134797}