Cancer drug class associated with high risk for cardiovascular adverse events
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Key takeaways:
- First-generation BTK inhibitors and preexisting cardiovascular disease linked to higher odds of CVAEs.
- More than half of patients treated with first-generation BTK inhibitors discontinued treatment.
SAN DIEGO — Individuals treated with first-generation Bruton tyrosine kinase inhibitors with preexisting cardiovascular disease had significantly higher odds of developing cardiovascular adverse events, study results showed.
The data — presented at ASH Annual Meeting and Exposition — revealed that patients treated with ibrutinib (Imbruvica, Pharmacyclics/Janssen Biotech) developed more cardiovascular adverse events compared with patients receiving second-generation Bruton tyrosine kinase (BTK) inhibitors, although the difference did not achieve statistical significance, according to researchers.
“Only 50 patients out of the total cohort had preexisting cardiovascular disease, so it was surprising that results were statistically significant for patients with preexisting cardiovascular disease to develop a higher rate of cardiovascular adverse events,” Maria J. Fernandez Turizo, MD, internal medicine resident at Beth Israel Deaconess Medical Center, told Healio. “We knew it would be a little bit higher going in, but we did not expect to see such a significant number.”
Background and methodology
Researchers conducted a retrospective analysis to evaluate and compare the rate of cardiovascular adverse events during BTK inhibitor therapy among individuals with and without preexisting cardiovascular disease; researchers also compared outcomes of patients treated with first- and second-generation BTK inhibitors.
Study participants (n = 180) included patients treated with BTK inhibitors for hematologic malignancies from 2013 to 2022 at Beth Israel Deaconess Medical Center, with exclusion criteria including prior treatment with anthracyclines and BTK inhibitors, prescription of BTK inhibitor therapy without administration, prior BTK inhibitor treatment for graft-vs-host disease and loss to follow-up.
Researchers characterized cardiovascular adverse events as new-onset or worsening atrial fibrillation, new-onset or worsening hypertension, supraventricular or ventricular arrhythmias and sudden cardiac death.
Results, next steps
Among the 180 study participants, 106 (60%) had , 31 (17.2%) had mantle cell lymphoma, 17 (9.4%) had diffuse large B-cell lymphoma and 16 (8.9%) had Waldenström macroglobulinemia. For treatment, 141 patients (78.3%) received ibrutinib, 35 (19.4%) received acalabrutinib (Calquence, AstraZeneca) and four (2.2%) received zanubrutinib (Brukinsa, BeiGene).
Researchers identified cardiovascular disease as a preexisting condition in 49 patients (27.2%), with 21 patients (11.6%) experiencing cardiovascular adverse events while receiving BTK inhibitor therapy.
In total, 11 of 49 patients with preexisting cardiovascular disease developed cardiovascular adverse events compared with 10 of 131 patients without cardiovascular disease (22% vs. 8%; OR = 3.38; 95% CI, 1.3–8.5).
Researchers noted that ORs remained “robust ranging from 3.4 to 4.1” among multiple adjusted logistic regression models, according to researchers.
Patients with preexisting cardiovascular disease exhibited significantly higher odds of developing new or worsening atrial fibrillation (16% vs. 5%; OR = 3.94; 95% CI, 1.3–12). Through subgroup analysis, researchers observed that patients treated with first-generation BTK inhibitors had a higher rate of cardiovascular adverse events than patients treated with second-generation BTK inhibitors (OR = 6.28; 95% CI, 0.8–48.3).
Thirteen patients treated with first-generation therapies (62%) discontinued BTK inhibitor treatment during the study, while eight (38%) continued treatment. Meanwhile, 17 patients (80%) required medical interventions.
“I would love to continue to work on one of the questions that one of the moderators posed after my [ASH] presentation, which was a really good point in that we should investigate if delaying treatment or discontinuing BTK inhibitor therapy will lead to worse outcomes in general — like PFS and OS,” Fernandez Turizo told Healio “So, next steps would be evaluating if a patient that required BTK inhibitor discontinuation did worse than patients who did not.”
Perspective
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Shazia K. Nakhoda, MD
The majority of real-world data evaluating BTK inhibitors comes from patients treated with ibrutinib. These have shown much higher rates of discontinuation for side effects compared with clinical trial data, identifying a major limitation of this class of agent in clinical practice. Since development of ibrutinib, novel BTK inhibitors — including second-generation acalabrutinib and zanubrutinib, as well as the recently approved noncovalent inhibitor pirtobrutinib (Jaypirca, Eli Lilly & Co.) — have all demonstrated improved toxicity profiles compared with ibrutinib, particularly related to cardiac arrythmia risk.
However, these randomized controlled prospective studies comparing ibrutinib with the second-generation BTK inhibitors excluded patients with major cardiovascular disease prior to treatment. Therefore, real-world studies are particularly necessary to better identify the difference in risk for subsequent cardiovascular adverse events (CVAE) in those with baseline cardiac comorbidities.
In this retrospective, single institution evaluation of CVAE risk in patients treated with BTK inhibitors, only patients without any prior line BTK inhibitors or anthracycline therapy were included, to minimize effect of prior treatments. CVAE rate was significantly higher amongst those with baseline cardiovascular disease compared with those without (22% vs. 8%). This result was likely driven by the ibrutinib-treated patients, as they made up 78% of the population, with 19% having received acalabrutinib and only 2% having received zanubrutinib. There was a nonstatistically significant trend toward improved CVAE risk with second-generation BTK inhibitors vs. ibrutinib (3 vs. 14%).
This study confirms that the presence of baseline cardiovascular comorbidities should remain a major consideration prior to BTK inhibitor treatment. However, the small sample size of those having received second-generation BTK inhibitor is a major limitation of the study (n = 49), as these agents are now the preferred treatment modality in routine practice compared with first-generation BTK inhibitor. Clinicians treating [non-Hodgkin lymphoma (NHL)] continue to see a rise in rates of patients eligible for BTK inhibitors with advanced age and major medical comorbidities who would have been excluded from clinical trial assessment.
Additionally, demographic disparities in clinical trial enrollment serves as a major gap in understanding BTK inhibitors effects in patients from underrepresented non-white populations, which carries an independent impact on cardiovascular disease risk. Therefore, a real-world study with a larger sample size is paramount to better understand CVAE risk according to baseline comorbidity and demographic data among those treated with the later generation BTK inhibitors, including combination therapies and, in the future, the noncovalent BTK inhibitors therapies.
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Fernandez Turizo MJ, et al. Abstract 496. Presented at: ASH Annual Meeting and Exhibition; Dec. 9-12, 2023; San Diego.
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