Onco-Cardiology: Focus on Cardiac Complications of Hematologic Treatments

Oncological Indication

Anthracyclines are cytostatic antibiotics discovered in the 1960s and encompass several anthracyclines including doxorubicin, epirubicin, idarubicin, daunorubicin, and liposomal encapsulated doxorubicin, used for a broad range of solid tumors, sarcomas, and hematological malignancies.

Cardiotoxicity

Anthracycline-induced cardiotoxicity (AIC) can develop in an acute, subacute, or chronic manner. Injury to the myocyte may begin as early as the initial exposure, with some studies detecting a rise in troponin levels immediately after the first dose is administered. This occurs in less than 1% of patients and manifests as an acute, transient decline in myocardial contractility, which is usually reversible.

The subacute form occurs in 1.6% to 2.1% of patients within the first year after treatment whereas the late-onset chronic form presents at least 1 year after completion of therapy in 1.6% to 5% of patients receiving lower doses. Both the subacute and chronic forms tend not to be reversible.

AIC occurs in a dose-dependent manner, increasing with a cumulative dose. Studies evaluating cumulative probability of doxorubicin-induced heart failure have found rates in the range of 3% to 5% at doses less than 400 mg/m ² , 7% to 26% at 550 mg/m ² , and 18% to 48% at 700 mg/m ² . However, subclinical cardiotoxicity defined by troponin rise, strain imaging, and MRI studies has been shown with doses less than 250 mg/m ² ( Fig. 158.1 ).

Mechanism of Cardiotoxicity

Previously, the most commonly accepted hypothesis for AIC was the generation of reactive oxygen species (ROS) by electron exchange between the anthracycline and oxygen molecules and the formation of complexes with iron that undergo redox cycling and generate oxygen radicals. Although in vivo and in vitro studies confirmed increased ROS production in cardiomyocytes after anthracycline therapy, neither antioxidants nor iron chelation have prevented the development of cardiomyopathy ( Fig. 158.2 ).

More recent studies demonstrate topoisomerase (Top) 2b as the primary mediator of AIC. Top2b is present in all quiescent cells, including cardiomyocytes and is responsible for unwinding deoxyribonucleic acid (DNA) chains during normal DNA replication, transcription, or recombination. Anthracycline inhibition of Top2b results in double-stranded breaks in DNA, production of ROS, and mitochondrial dysfunction which leads to cardiomyocyte apoptosis. Mice models have shown Top2b deletion from the heart protects cardiomyocytes from anthracycline-induced cardiomyopathy, which strongly implicates Top2b as the key mediator of AIC.

Prevention and Treatment

Anthracycline cardiotoxicity should be mitigated without compromising oncological efficacy. The strategies may include dose limitation, altering infusions schedules, use of alternative molecules such as liposomal encapsulated doxorubicin, using less cardiotoxic derivatives (e.g., epirubicin or idarubicin), and cardio-protection using targeted cardioprotective agent (e.g., dexrazoxane) in conjunction with treatment.

Dexrazoxane is the only FDA-approved, targeted, cardioprotective agent for AIC. It changes Top2’s configuration to a closed-clamp form through tight binding to Top2’s ATP-binding sites, thus preventing anthracyclines from binding to the Top2 complex. Even though in some pediatric studies it has shown a relative risk reduction of up to 79% in cardiotoxicity, there have been adult studies suggesting myelosuppression, secondary malignancy, and reduced anthracycline efficacy which has not been validated in any randomized controlled trials. However, currently dexrazoxane is only approved by the FDA for adults needing additional anthracyclines after an initial dose of greater than 300 mg/m ² .

Other cardioprotective agents including beta-blockers, angiotensin-converting enzyme inhibitors (ACEi), and angiotensin receptor blockers (ARBs) have been studied for both primary and secondary prevention in smaller studies. Stringent control of concomitant risk factors such as diabetes, dyslipidemia, hypertension, and avoiding combination cardiotoxic chemo and concomitant radiotherapy to the mediastinum/left chest are other ways to mitigate AIC.

Imatinib

In patients treated with imatinib monotherapy, clinical heart failure is very rare, occurring in 0.5% to 1.7% of patients. Initial studies that used serum B-type natriuretic peptide (BNP) or troponin T levels as a marker of cardiac dysfunction reported no cardiotoxicity with imatinib therapy ; however, some noninvasive imaging studies have demonstrated a decline in the left ventricular ejection fraction with this therapy. Although pathological findings characteristic of toxin-induced myopathy have been demonstrated on biopsy in imatinib-treated patients, studies have failed to correlate with clinical heart failure. Which patients are most susceptible to developing cardiac dysfunction with imatinib therapy and are candidates for appropriate preventative and management interventions is currently unknown.

Vascular toxicity is rare with imatinib treatment; in fact, it may actually have beneficial roles on the vasculature, having shown attenuation of in-stent restenosis and diabetes-associated atherosclerosis in mouse models. Interestingly, in a large retrospective cohort, patients with CML on imatinib treatment had lower rates of peripheral vascular events compared with those treated initially with placebo. These favorable effects also extend to the pulmonary vasculature, where pre-clinical data suggesting reversal of pulmonary arterial hypertension (PAH).

Dasatinib

Dasatinib frequently causes pulmonary hypertension (PAH), the incidence varying from 0.45% to 12.1% in different series. One-third of these cases have irreversible PAH that persists even on discontinuation of the drug. The mechanism of dasatinib-associated PAH remains unclear.

A French PAH registry reported a series of 9 dasatinib-associated PAH cases, the median time between initiation of dasatinib therapy and PAH diagnosis being 8 to 48 months. At diagnosis, most patients had severe clinical, functional, and hemodynamic impairment with minimal acute vasodilator response, suggesting that isolated acute vasoconstriction is not the main mechanism of dasatinib-induced PAH, which seems to be a delayed and sometimes irreversible phenomenon.

Interestingly, dasatinib is associated with a higher incidence of pleural effusion, from 14% to 35%. The mechanisms underlying development of pleural effusion are probably immune-mediated.

Nilotinib

QT prolongation and vascular events are the main CV adverse events seen with nilotinib. Nilotinib prolongs the QT interval more commonly than other tyrosine kinase inhibitors with an incidence of 1% to 10%. The mechanism behind this action potential delay is an inhibition of phosphoinositide-3-kinase due to “on-target” effects of nilotinib.

A baseline ECG should be obtained in all patients prior to starting TKI’s such as nilotinib. Electrolyte abnormalities must be corrected and drug-drug interactions that influence QTc interval (antibiotics, antiemetic, antipsychotic or antidepressant drugs) must be evaluated prior to beginning treatment. ECGs should be repeated a few days after initiation/modification of anticancer therapy. Strict monitoring and repletion of magnesium and electrolyte levels are warranted when using this agent and a corrected QT of greater than 480 ms is an indication to hold therapy or ΔQTc greater than 60 ms during monitoring.

Vascular events have been reported in up to 6.15% of patients who received nilotinib, including severe peripheral atherosclerosis needing angioplasty and limb amputation. In fact, a prospective study of 129 patients with CML screened for peripheral vascular disease (PVD) with ankle-brachial index (ABI) during therapy demonstrated PVD in 26% of patients treated with first-line nilotinib, and 35.7% with second-line nilotinib—far higher than previously reported.

Nilotinib also affects coronary arteries causing vasospasm, direct antiangiogenic, and pro-atherogenic effects on endothelial cells, procoagulant effects, and acceleration of atherosclerotic processes in the coronary and peripheral vasculature. Therefore, it is necessary to have rigorous metabolic control, modification of cardiovascular risk factors, and is to get baseline screening for CAD with stress testing and PVD with ABI in high-risk patients.

Besides VEGF inhibition, an accelerated metabolic dysregulation may be involved in accelerated vascular atherosclerosis, since nilotinib may cause increases in glucose, total cholesterol and LDL, insulin resistance, and compensatory hyperinsulinemia. Nilotinib treatment is also associated with hypothyroidism, which can affect lipid and glucose metabolism, which are all risk factors for developing atherosclerosis.

Ponatinib

Ponatinib is highly effective in CML patients who are resistant to other TKIs. However, in a study with a median follow-up of 27.9 months, serious arterial thrombotic events occurred in 19% of ponatinib-treated patients, including CV events (10%), cerebrovascular events (7%), and peripheral vascular events (7%), with some patients having greater than 1 event. In addition, 5% of patients experienced VTE and at least five patients died from vascular events (VE) thought to be due to ponatinib. Other studies have shown a high incidence of HTN in up to 26% of patients treated with ponatinib. Subsequently, ponatinib now has a black box warning about increased risk of arterial and venous occlusive events which occur earlier and more frequently than even nilotinib.

The underlying mechanisms of ponatinib-induced VE are largely unknown. Ponatinib inhibits numerous tyrosine kinases such as SRC, FGFR, PDGFR, and VEGFR1–3 which result in nitrous oxide depletion, platelet aggregation, endothelial dysfunction, and vasospasm that eventually lead to a high incidence of vascular events.

Controlling risk factors such as diabetes and hypertension, use of ACE-inhibitors, statins, aspirin, and screening for PVD are thereby essential in prevention and treatment of ponatinib and nilotinib induced cardiotoxicities.