Anthracyclines are associated with an increased risk of cardiovascular adverse events. Anthracyclines may cause irreversible cardiomyopathy because of oxidative damage to myocytes, although other mechanisms have also been proposed. The cardiotoxicity of anthracyclines most commonly manifests as late congestive heart failure. Leukemia survivors treated with anthracyclines are also at increased risk for arrhythmia, pericarditis, myocarditis, and myocardial infarction. QT prolongation, which is detectable on an electrocardiograph, and increased risk of aortic stiffness have also been reported. Cardiotoxic effects may occur years after the treatment is completed, although one study reported that the median onset of left ventricular dysfunction was 4 months after completion of treatment with anthracyclines (Cardinale et al. 2010).

Cardiotoxicity in anthracyclines is strongly correlated with the cumulative dose. The cumulative dose of doxorubicin resulting in a 3–5% likelihood of congestive heart failure was reported to be 400 mg/m², and the dose resulting in a 7–26% likelihood of congestive heart failure was 550 mg/m² (Swain et al. 2003; Bird and Swain 2008). Also, patients receiving more than a 360–400 mg/m² cumulative dose of anthracyclines had the highest risk of cardiac mortality (Mertens et al. 2008; Tukenova et al. 2010). Thus, cumulative doses of doxorubicin are generally best limited to 450–500 mg/m². However, sensitivity to anthracyclines varies among patients, and no dose is considered to be safe. Several known risk factors predict cardiotoxic effects in patients treated with less than the recommended cumulative dose of anthracyclines. These include age older than 65 years; history of coronary artery disease, hypertension, or other heart disease; and cardiac irradiation (Steinherz et al. 1991; Swain et al. 2003; Hershman et al. 2008).

In addition to limiting cumulative doses of anthracyclines, several approaches have been investigated to reduce the risk of cardiotoxic effects. For example, in one study, fewer cardiotoxic effects were reported in patients receiving prolonged infusions of anthracyclines (6 hours or more) than in patients receiving bolus infusions of anthracyclines, with no differences between the patient groups in terms of response rates, remission rates, or survival durations (Smith et al. 2010). In the Department of Leukemia at MD Anderson, we currently employ 24-hour continuous infusion of doxorubicin in patients with ALL. More prolonged infusion protocol (48-hour continuous infusion) is used in patients with impaired cardiac function, as assessed by echocardiography.

The use of a liposomal formulation of doxorubicin or daunorubicin has been found to be associated with a significantly lower risk of cardiotoxic effects than the conventional formulation (Smith et al. 2010). Dexrazoxane, an EDTA-like chelator, was also reported to prevent anthracycline-induced damage in cardiac tissue. However, dexrazoxane may also interfere with the efficacy of anthracyclines, although the evidence is not concrete. At this point, dexrazoxane is not generally recommended for adult patients with leukemia who were treated with a doxorubicin-based regimen. Careful management of risk factors such as hypertension or hyperlipidemia is also important for preventing cardiotoxic effects.

Cardiac function assessment is highly recommended before, during, and after potentially cardiotoxic chemotherapy, although the optimal monitoring method and schedule have not yet been determined. Most commonly, left ventricular function is assessed on an echocardiogram or ventriculogram (multiple-gated acquisition scan). In the Department of Leukemia at MD Anderson, we generally obtain an echocardiogram or ventriculogram prior to treatment and repeat assessment as necessary on the basis of the clinical picture and the patient’s risk factors. Cardiac troponins and B-type natriuretic peptide have also been investigated as potential biomarkers for monitoring anthracycline-related cardiomyopathy. These biomarkers may help with early detection of cardiotoxic effects; however, the data remain limited, and further validation is needed.

A small but worrisome risk of toxic effects in the cardiovascular system associated with some TKIs has also been reported. Cardiotoxic effects induced by TKIs are generally reversible when the suspected agent is discontinued. Hence, the cardiotoxicity of TKIs is most worrisome in patients who require chronic therapy for their disease, such as patients with CML.

The cardiotoxicity of imatinib has been debated. Severe congestive heart failure in patients treated with imatinib was first reported in 2006 (Kerkela et al. 2006). Reticulum stress and cell death in cardiomyocytes, likely induced by Abl inhibition, was suggested as the cause of the congestive heart failure in this study. However, in subsequent studies, congestive heart failure was observed in only 0.5–1.7% of patients, and most of them had comorbidities predisposing them to cardiac dysfunction (Atallah et al. 2007; Hatfield et al. 2007). Current available evidence suggests that cardiotoxic effects induced by imatinib are uncommon, occurring mostly in susceptible patients with predisposing factors. Close monitoring of patients with risk factors and symptoms suggestive of cardiac dysfunction is advisable.

Although data are limited, toxic effects in the cardiovascular system induced by other TKIs, including dasatinib, nilotinib, and ponatinib, have also been reported. Dasatinib is a TKI against Bcr-Abl, platelet-derived growth factor receptors a and b, c-Kit, and Src family kinases. Dasatinib is currently indicated for treatment of CML and Philadelphia chromosome–positive ALL. In one report, the incidence of congestive heart failure in patients treated with dasatinib was 2–4% (Yeh and Bickford 2009). Increased risks of QT prolongation, pericardial effusion, and pulmonary artery hypertension with dasatinib have also been reported. Nilotinib inhibits kinase activity of Bcr-Abl, c-Kit, and platelet-derived growth factor receptors a and b. In addition to QT prolongation, peripheral artery disease and other arteriopathy was observed in 6.15% of patients treated with nilotinib in one retrospective report (Le Coutre et al. 2011). Ponatinib was approved by the US Food and Drug Administration for the treatment of CML resistant or intolerant to first-line TKI therapy in 2012, with the inclusion of a boxed warning of potential arterial thrombosis and liver toxicity. Ponatinib is unique because of its potential activity in patients who harbor the T315I BCR-ABL mutation. Symptomatic bradyarrhythmia; supraventricular tachyarrhythmia, most predominantly atrial fibrillation; and serious heart failure were also observed in 1–5% of patients treated with ponatinib. Further observation is warranted to determine the cardiotoxicity of new kinase inhibitors.

Chemotherapy and radiation therapy can be associated with secondary myelodysplastic syndrome and leukemia, as well as solid tumors. Among chemotherapeutic agents, alkylating agents and topoisomerase II inhibitors are most frequently associated with secondary myelodysplastic syndrome or AML. Alkylating agents such as cyclophosphamide and chlorambucil, as well as radiation therapy, may cause secondary myelodysplastic syndrome or AML with a latency of 5–7 years. Typically the patient presents with myelodysplasia, and cytogenetic study often shows complex abnormalities, including deletion of chromosome 5 or 7. Secondary AML associated with topoisomerase II inhibitors generally has a latency of 1–3 years and presents as overt leukemia. The most common cytogenetic abnormalities observed with secondary AML involve 11q26 or 21q22 abnormalities.