Cancer Therapy–Related Arrhythmias

Anthracyclines

Anthracyclines such as doxorubicin, daunorubicin, epirubicin, and idarubicin are chemotherapeutic agents commonly used in the treatment of acute leukemias, lymphomas, breast cancers, and various solid tumors. Although the most common cardiotoxicity is the development of cardiomyopathy and heart failure, anthracycline-induced arrhythmias are also a frequent complication. One study demonstrated an incidence of AF of 10.3% in patients who underwent doxorubicin-containing chemotherapy who did not have other cardiovascular pathology. Furthermore, another study determined that the incidence of AF was 56.6% in patients who received an implantable cardioverter-defibrillator (ICD) because of an anthracycline-induced cardiomyopathy. Those results were also notably similar to other nonischemic cardiomyopathy etiologies.

The mechanism of anthracycline cardiomyopathy is unclear, but it was previously believed that anthracyclines disrupted redox cycling, which resulted in DNA damage because of reactive oxygen species (ROS) production. More recent evidence suggests that the cardiotoxicity is because of effects on topoisomerase 2, although it is likely that other mediators are involved as well. Furthermore, the mechanisms of anthracycline-induced arrhythmias are also unclear but are most likely secondary to impaired intracellular signaling, damage from free radicals and other toxins, and/or direct myocardial injury.

Alkylating Agents and Stem Cell Transplantation

Alkylating agents such as cyclophosphamide, melphalan, and busulfan are a class of cytotoxic chemotherapeutic agents that disrupt the DNA double helix and are used to treat a variety of solid organ and hematologic malignancies. These agents are also common components of stem cell transplant (SCT) preconditioning regimens. Cyclophosphamide, a common agent used in SCT preconditioning regimens, has been associated with chemotherapy-induced arrhythmias. In one review of patients pretreated with cyclophosphamide before SCT, 11% of the patients developed arrhythmias, although only 2% developed AF. Melphalan is another common alkylating agent used in SCT preconditioning regimens and is frequently associated with cancer treatment-induced arrhythmias. In one series studying various chemotherapeutic treatments used in SCT, about 5% of the patients developed atrial arrhythmias, most of which were AF. Furthermore, the same study found that melphalan was the most arrhythmogenic agent and that 11% of the patients developed atrial arrhythmias. More specifically, 8% of patients treated with melphalan developed AF or atrial flutter (AFL). Busulfan is another alkylating agent used in SCT preconditioning regimens. One study found that 6.4% of patients with non-Hodgkin lymphoma (NHL) undergoing autologous SCT with busulfan and cyclophosphamide developed AF.

Hematopoietic SCT (HSCT) itself is a risk factor for the development of various types of arrhythmias independent of the specific preconditioning chemotherapy regimens. A systemic review and meta-analysis estimated the overall incidence for all types of arrhythmias in patients who underwent HSCT to be 7.2%. In another study where multiple myeloma patients underwent autologous SCT, the incidence of AF was reported to be as high as 27%. In addition to the alkylating agents themselves, renal failure and hypertension are also notable risk factors for the development of AF after transplant. Moreover, the development of atrial arrhythmias during SCT portends a worse prognosis with increased mortality, hospital length of stay, and intensive care unit (ICU) admissions compared with patients without arrhythmias at any time.

Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (TKI) are a class of multitargeted therapies that inhibit cancer cell proliferation by targeting the abnormal cancer cell signaling pathways, which are typically altered by mutated or overactive protein kinases. These agents treat a wide variety of solid and liquid tumors including non–small cell lung cancer (NSCLC), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), mantel cell lymphoma (MCL), and Waldenstrom macroglobulinemia (WM). Cardiotoxicities associated with TKIs are broad and include cardiomyopathies, heart failure, acute coronary syndromes, and arrhythmias, including AF. TKIs associated with an increased incidence of AF include ibrutinib, sorafenib, and ponatinib. A phase II trial of sorafenib in combination with 5-fluorouracil demonstrated an incidence of AF in more than 5% of patients. In the Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) phase III trial, ponatinib was associated with an AF incidence of 2%, whereas none of the patients treated with imatinib developed AF.

Although multiple tyrosine kinase inhibitors have been associated with the development atrial arrhythmias, ibrutinib has been most associated with AF. Ibrutinib is a Bruton tyrosine kinase inhibitor (BTKi) that inhibits B-cell development and immunoglobulin synthesis by blocking the Bruton tyrosine kinase (BTK) signaling pathway. AF rates in patients treated with ibrutinib range from 4% to 16%, and ibrutinib itself has been identified as an independent risk factor for AF. In the final analysis from the phase III RESONATE study, the incidence rate of AF was determined to be 12%. Notable risk factors for the development of AF while undergoing treatment with ibrutinib include history of AF, an elevated Framingham Heart Study (FHS) AF risk score, and left atrial enlargement. ^, Furthermore, in a large study of cardiovascular adverse drug reactions (CV-ADRs) associated with ibrutinib, exposure to this agent was associated with increased rate mortality; more importantly, supraventricular arrhythmias were associated with a 10% fatality. The mechanisms of proarrhythmia for ibrutinib are not clearly established but may include off-target effects from inhibition of other kinases. In addition, other hypotheses include the inhibition of PI3K-Akt pathway, enhanced atrial fibrosis, and abnormal sarcoplasmic reticulum calcium release. ^, Lastly, acalabrutinib is a highly selective BTK inhibitor that is becoming a more popular choice for treating CLL and SLL. In one study, patients undergoing treatment with acalabrutinib had an AF incidence rate of 7%.

Platinum Agents

Cisplatin, carboplatin, and oxaliplatin are platinum-based compounds used in the treatment of multiple cancers, including NSCLC, head and neck squamous cell carcinomas, and advanced bladder cancers. One literature review found that when cisplatin was given with 5-fluorouracil (5-FU), the incidence rate of AF was 4% to 6.5%. Moreover, when cisplatin was administered intrapericardially, incidence rates of AF were found to be as elevated as 15.2% to 32%.