Although rare, severe CHF and left ventricular dysfunction have been reported during imatinib treatment, especially in patients with risk factors or comorbidities. In the IRIS trial, this was observed in 0.7% of patients.^1,2,20 Cardiotoxicity associated with high-dose imatinib was not reported during the START-R study.¹⁶ In smaller studies of high-dose imatinib, existing CHF was exacerbated in one study (6% of patients), and was related to mortality in another (4% of patients).^21,22

In a large review of patients enrolled in imatinib clinical studies (n=1,276), 1.8% of patients had symptoms suggestive of systolic heart failure. Most had risk factors for cardiac failure. In total, 0.6% of patients had cardiac events attributed to imatinib treatment. The authors concluded that CHF is rare during imatinib treatment.²³ A similar incidence of CHF (1%) was reported in a nine-year retrospective review at a single institution.²⁴ Reports of smaller studies also confirm that cardiac failure is a rare feature of imatinib therapy.^25,26

The mechanism underlying imatinib-induced cardiac failure is currently unclear. In an in vitro study, physiological concentrations of imatinib significantly and adversely affected mitochondrial membrane potential, apoptosis, cell viability, and cellular ultrastructure.²⁷ This cardiotoxic effect may be linked to inhibition of BCR-ABL. Imatinib was reported to cause stress-induced and dose-dependent mitochondrial changes in murine ventricular myocytes, which was reduced by re-engineering the imatinib molecule such that BCR-ABL inhibition was hampered.^28,29 Nonetheless, the re-engineered molecule may have had altered activities besides reduced BCR-ABL inhibition.

A second cardiac AE associated with imatinib therapy is fluid retention manifesting as pericardial effusion. Grade 3–4 fluid retention reactions, which included pericardial effusions, were reported in 2% of patients in the IRIS study and in 6% of all other CML clinical studies.²⁰ Frank pericarditis has been observed in <0.1% of patients receiving imatinib (all indications).²⁰ Other cardiac AEs include tachycardia, hypertension, hypotension, flushing, and peripheral coldness, were each reported in 0.1–1.0% of patients.²⁰

Precautions and general guidelines for dose adjustment for cardiac AEs associated with imatinib treatment are included in the prescribing information and have been summarized in Table 2. CML patients with existing cardiac disease or cardiac risk factors should be monitored and treated accordingly.^20,23 Patients should also be weighed regularly and monitored for signs and symptoms of fluid retention. Unexpected weight gain should be investigated carefully, and treated appropriately.^20,30 Significant fluid retention (local or general) can usually be managed by interrupting imatinib treatment and using diuretics or other supportive care.²⁰ In severe cases of fluid retention, imatinib should be withheld until this is resolved.

Table 2

Agent	Dose modification	Precautions
Imatinib20	On the emergence of a severe event, withhold until the event has resolved. Resume at an appropriate dose, depending on initial severity of event.	Carefully monitor any patient with or at risk of cardiac failure.All patients with signs or symptoms of cardiac failure should be evaluated and treated.
Dasatinib13	On the emergence of a severe event, withhold until the event has resolved or improved. Resume at an appropriate dose, depending on initial severity of event.	Administer with caution to patients with or at risk of QTc prolongation: those with hypokalemia, hypomagnesemia, or congenital long QT syndrome; or taking medicines known to prolong QT, including anti-arrhythmic drugs, and cumulative high-dose anthracycline therapy Correct hypokalemia or hypomagnesemia prior to administration.
Nilotinib18	QTc >480 ms: 1) withhold therapy, correct serum potassium and magnesium levels if below normal, and review concomitant medication; 2) resume at prior dose in <2 weeks if QTc returns to <450 ms and <20 ms of baseline; 3) reduce dose to 400 mg/day if QTc 450–480 ms after 2 weeks; 4) discontinue if QTc returns to >480 ms after dose reduction; 5) repeat ECG assessment approx. 7 days after any dose adjustment.	Do not administer to patients with long QT syndrome. Do not administer drugs known to prolong QT, and strong CYP3A4 inhibitors. Correct hypokalemia or hypomagnesemia prior to administration, and periodically monitor serum electrolyte levels during therapy. Perform ECGs at baseline, 7 days after treatment starts, periodically as indicated clinically, and after any dose adjustment.

Nilotinib can cause QT prolongation and sudden death and carries a black box warning for these side effects.¹⁸ Nilotinib prolongs the QT interval in a concentration-dependent manner, and the common AEs occurred in 1–10% of all patients in clinical trials.¹⁸ In a study in healthy volunteers, nilotinib was associated with a maximum mean QT interval increase of 18 ms (adjusted for placebo).¹⁸ In imatinib-resistant patients with CML, nilotinib caused a maximum mean QT change of 10 ms from baseline; QT increase >60 ms and QT >500 ms associated with nilotinib were reported in 2.1% and <1% of patients, respectively. Sudden deaths were reported in 0.6% of patients in a clinical study, and at a similar frequency in an expanded access study. The early occurrences of some of these deaths relative to the start of nilotinib treatment suggest that ventricular repolarization may have contributed to their occurrence.¹⁸

Another common cardiac AE associated with nilotinib therapy is myocardial ischemia. In the pivotal phase II study, it was reported in 7% (21/321) of patients with CP CML receiving nilotinib as second-line treatment.³¹ Uncommon cardiac events (0.1–1% of all patients in clinical trials) include cardiac failure, angina pectoris, atrial fibrillation, pericardial effusion, coronary artery disease, cardiomegaly, cardiac murmur, and bradycardia. Rare events (of uncertain frequency) include myocardial infarction, ventricular dysfunction, pericarditis, cardiac flutter, and extrasystoles.¹⁸

The mechanisms underlying these AEs are still unclear. In a manner similar to imatinib, nilotinib was found to decrease the cellular viability of rat cardiomyocytes cultured in vitro, although the integrity of the mitochondrial membrane potential was unaffected.²⁷ However, nilotinib has also been found to inhibit human ether-a-go-go related gene (hERG) potassium currents with an IC50 of 0.66 μM. This concentration is approximately one-tenth the expected Cmax for this compound, well within therapeutic levels. This mechanism is likely to underlie nilotinib-induced QT prolongation. Inhibition of hERG channels is established as a cause of QT prolongation for a number of compounds, and is a significant barrier in the development of new drugs.³² Indeed, the phase II development of the aurora kinase inhibitor MK-0457 (VX-680) was recently suspended, pending a full analysis of all efficacy and safety data. The decision was based on preliminary safety data, in which QT prolongation was observed in one patient.³³

The potential for QT prolongation and sudden death associated with nilotinib, although rare, necessitates vigilant monitoring. In particular, ECGs should be performed at baseline, seven days after initiation of treatment, periodically throughout therapy, and following dose adjustments. Electrolyte levels should be monitored periodically throughout therapy. Nilotinib is contraindicated for patients with hypokalemia, hypomagenesmia or long QT syndrome.¹⁸ The nilotinib prescribing information recommends dose adjustments for QT prolongation, presented in Table 2.

The events of dasatinib-induced QT prolongation are rare although a warning for such a possible event is given. In single-arm studies of dasatinib, nine patients (1%) had QT prolongation reported as an AE.¹³ The mean QT interval increased by 3–6 ms (Fridericia's method); this increase was not clinically relevant.³⁴ In total, <1% of patients had a QT increase to >500 ms. In contrast with nilotinib, the IC50 for dasatinib for the inhibition of hERG currents (14.3 μM) is 100 times the expected Cmax for this drug.²⁷ This may explain why QT prolongation is more clinically prominent for nilotinib than it is for dasatinib.

Common cardiac AEs (observed in 1 – <10% of all patients in clinical trials) include arrhythmia and palpitations. Severe pericardial effusions have been reported in 1% of all patients in all clinical studies, and the prescribing information for dasatinib includes a warning for this toxicity.¹³ Severe CHF has also been reported in 1% of all patients.¹³ In single-arm studies, CHF or ventricular dysfunction occurred in 4% (20/911) of patients.³⁴ However, in the dose optimization study, dasatinib 100 mg once daily was not associated with any incidence of severe CHF or pericardial effusion in any patient; both AEs were reported in patients receiving the 70 mg twice daily dose (all grades, 4%; grade 3–4, 3%).¹⁷

Both pericardial effusions and cardiac failure associated with dasatinib therapy may be caused by similar mechanisms to those associated with imatinib treatment, although, in contrast with imatinib, dasatinib has not been found to significantly affect mitochondrial membrane potential, apoptosis, cell viability, or cellular ultrastructure at physiological concentrations.²⁷

Uncommon cardiac AEs associated with dasatinib include angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia, and myocardial infarction (reported in 0.1 – <1% of patients). Rare events (reported in <0.1% of patients) include myocarditis and acute coronary syndrome.¹³

Dasatinib should be administered with caution to any patient at risk of cardiac problems (especially prolongation of the QT interval). Patients with pre-existing congenital long QT syndrome or those receiving anti-arrhythmic medicine should be monitored closely.¹³ Patients with hypokalemia or hypomagnesemia should have these conditions corrected prior to receiving dasatinib. As several anti-neoplastic agents, including the anthracyclines, are associated with cardiotoxicity, the treatment history of a patient should also be taken into consideration before commencing any therapy. Fluid retention events can typically be managed by supportive measures. Dose interruption is also indicated (Table 2).¹³