Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines

INTRODUCTION — Cancer patients receiving chemotherapy have an increased risk of developing cardiovascular complications, and the risk is even greater if there is a known history of heart disease.

Among the serious complications that have been reported are:

●Arrhythmias

●Heart failure

●Myocardial necrosis causing a dilated cardiomyopathy

●Vasospasm or vasoocclusion resulting in angina or myocardial infarction

●Pericardial disease

●Arterial occlusive events

A wide range of chemotherapy agents have been associated with cardiotoxicity, for which the anthracyclines and related compounds (which may have been administered in childhood) are the most frequently implicated agents [1,2]. However, many other agents, including conventional cytotoxic and molecularly targeted agents, have the potential to cause cardiotoxicity.

The cardiotoxicity of chemotherapy agents other than fluoropyrimidines, anthracyclines, and HER2-targeted therapies will be reviewed here. Most of these data are derived from patients who received these agents as adults rather than children.

The cardiotoxicity of anthracyclines, HER2-targeted therapies, fluoropyrimidines (fluorouracil, capecitabine), molecularly targeted agents that target angiogenesis, and checkpoint inhibitor immunotherapy agents are discussed in more detail separately. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents" and "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management" and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Left ventricular dysfunction and myocardial ischemia' and "Toxicities associated with immune checkpoint inhibitors", section on 'Cardiovascular toxicity'.)

ANTIMETABOLITES

Fludarabine — Fludarabine, a purine antagonist used in hematologic malignancies, has been reported to cause hypotension and chest pain [3]. In addition, the combination of fludarabine and melphalan has been associated with severe cardiac toxicity in at least seven cases when used as the conditioning agent for bone marrow transplantation [4]. The use of either agent alone in high doses has only rarely been associated with cardiac toxicity.

Pentostatin and cladribine — Pentostatin (2'-deoxycoformycin) and cladribine (2-chlorodeoxyadenosine) are additional purine antagonists used in hematologic malignancies. Both have rarely been reported to cause ischemia and heart failure [5,6].

Methotrexate — Although no definite cardiac toxicity has been associated with methotrexate, there are rare reports of syncope, myocardial infarction, and supraventricular and ventricular arrhythmias associated with its use [7-9].

Cytarabine — Multiple cases of pericarditis have been attributed to cytarabine, and this can progress to pericardial effusion and cardiac tamponade [10-12]. Corticosteroid therapy may be beneficial in the treatment of this complication.

MICROTUBULE-TARGETING DRUGS

Vinca alkaloids — Hypertension, myocardial ischemia and infarction, and other vaso-occlusive complications have been reported with the vinca alkaloids. These complications have been reported most commonly with vinblastine, but have also been described with vincristine and vinorelbine [13-20].

Taxanes

●Paclitaxel – Bradycardia and heart block are the most frequently described cardiac effects of paclitaxel, although these usually are asymptomatic [21,22]. The overall incidence of cardiac events in the National Cancer Institute database was low, and routine cardiac monitoring is not required for patients without risk factors [21].

This was illustrated by a phase II series of 140 women with ovarian cancer, in whom transient asymptomatic bradycardia occurred in 29 percent. More serious cardiac toxicity (atrioventricular conduction block, ventricular tachycardia, cardiac ischemia) was seen in 5 percent [22].

Cardiomyopathy is reported when paclitaxel is combined with doxorubicin. Heart failure has developed in up to 20 percent of patients treated with paclitaxel plus doxorubicin [23,24], although an increased incidence of cardiotoxicity was not seen in all studies [25]. The development of heart failure may occur at cumulative doxorubicin doses that are much lower than would be expected with doxorubicin alone [26-28]. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Anthracycline-containing regimens'.)

Nanoparticle albumin-bound paclitaxel (nabpaclitaxel, Abraxane) has the same cardiac toxicity profile as the non-albumin-bound formulation. Asymptomatic electrocardiographic (ECG) changes, including nonspecific changes, sinus bradycardia, and sinus tachycardia, are most common [29]. Rare cases of chest pain, supraventricular tachycardia, and cardiac arrest have been reported.

●Docetaxel – Conduction abnormalities, cardiovascular collapse, and angina have been reported in patients treated with docetaxel [30-33], although there is no convincing evidence that causally links docetaxel to these complications.

Like paclitaxel, docetaxel appears to potentiate the cardiotoxicity of anthracyclines. This was illustrated by a trial in which 50 women with newly diagnosed stage III breast cancer were treated with docetaxel plus doxorubicin [34]. Heart failure developed in 8 percent, with a mean decrease in ejection fraction of 20 percent. The total doxorubicin dose was <400 mg/m² in all of these patients.

Eribulin — Eribulin mesylate, a synthetic analogue of halichondrin B, a substance derived from a marine sponge, inhibits the polymerization of tubulin and microtubules. In an uncontrolled open-label ECG study in 26 patients, corrected QT (QTc) prolongation was observed on day 8 of treatment, with no QTc prolongation seen on day 1 [35]. The US Food and Drug Administration-approved labeling recommends ECG monitoring in patients who have heart failure or bradyarrhythmias, and for those who are receiving other drugs known to prolong the QTc interval (table 1). The drug should be avoided in those with congenital long QT syndrome.

Ixabepilone — Ixabepilone is an epothilone, a class of nontaxane tubulin polymerizing agents. It is approved as monotherapy and in combination with capecitabine for treatment of metastatic breast cancer.

In a trial comparing capecitabine with or without ixabepilone, the frequency of adverse cardiac events (myocardial ischemia, ventricular dysfunction) was higher in the combined arm than with capecitabine alone (1.9 versus 0.3 percent), and supraventricular arrhythmias were seen with combined therapy (0.5 percent) but not with capecitabine alone [36]. Given that cardiotoxicity was not reported in a phase II trial of ixabepilone monotherapy conducted in 126 women with advanced breast cancer [37], it is possible that it is the combination of ixabepilone plus capecitabine that is cardiotoxic. However, the approved manufacturer's labeling for ixabepilone suggests caution in patients with a history of cardiac disease and discontinuation of therapy in patients who develop cardiac ischemia or impaired cardiac function during therapy.

ALKYLATING AGENTS

Cyclophosphamide — Cyclophosphamide (Cy) can cause an acute cardiomyopathy that is associated with high-dose protocols, develops early, and is not related to cumulative dose [38-42]. Cardiotoxicity is a limiting factor for treatment with high-dose Cy, but reduced doses have decreased the incidence of acute complications over recent decades [43].

●High-dose Cy for conditioning – In a series of 811 patients who received Cy total dose >100 mg/kg as conditioning therapy for allogeneic hematopoietic cell transplantation (HCT), 1.5 percent developed fatal heart failure, a median of four days after first administration [44]. The incidence of heart failure was dose-dependent; heart-failure occurred in 8.5, 1.2, and 0 percent of patients who received a total Cy dose of 200, 120, and 100 mg/kg, respectively.

In a single-institution study of 56 patients who had a left ventricular ejection fraction (LVEF) ≤45 percent prior to HCT, with median follow-up of 29 months, 12.5 percent developed grade ≥2 cardiac complications, but there were no deaths from cardiac complications; the rate of cardiac complications was not higher than historical controls who had pre-transplant LVEF ≥50 percent [45].

●Post-transplant Cy – Post-transplantation Cy (PTCy; eg, 50 mg/kg on days +3 and +4) has emerged as an important agent for prophylaxis of graft-versus-host-disease (GVHD) in patients undergoing haploidentical allogeneic HCT. Use of PTCy for GVHD prophylaxis is discussed separately. (See "Prevention of graft-versus-host disease", section on 'Post-transplant cyclophosphamide (PTCy)'.)

In a study of 585 patients undergoing allogeneic HCT with PTCy, the incidence of post-HCT cardiotoxicity (arrhythmias, heart failure, pericardial effusion, and/or myocardial ischemia) was 6.5 percent (38 patients) [46]. Cardiotoxicity rates were slightly higher in those who received PTCy compared with those who did not (7.4 versus 5.8 percent), and the development of cardiotoxicity was associated with worse one-year overall survival and non-relapse mortality. Risk factors for cardiotoxicity after Cy included age >55 years; history of hypertension, arrhythmias, diabetes; and other cardiac comorbidities. The authors developed a cardiac risk score based on the sum of these risk factors that predicted cardiotoxicity at day 100 (4, 4, 8, 13, and 37 percent for those with 0, 1, 2, 3, or 4 risk factor).

Ifosfamide — Ifosfamide has been associated with arrhythmias, ST-T wave changes, and heart failure in a dose-related manner [47,48]. These cardiac complications, when symptomatic, are generally reversible with medical management. Controversy exists whether there is increased cardiotoxicity when ifosfamide is used in combination with anthracyclines [48-52].

Cisplatin — Cardiotoxicity due to cisplatin can be manifested by supraventricular tachycardia, bradycardia, ST-T wave changes, left bundle branch block, acute ischemic events, myocardial infarction, and ischemic cardiomyopathy [53,54]. This toxicity may be related to electrolyte abnormalities secondary to cisplatin-induced nephrotoxicity. (See "Cisplatin nephrotoxicity".)

Cisplatin has also been associated with vascular toxicities that include Raynaud phenomenon, hypertension, and cerebral ischemic events. The increased risk of late cardiovascular toxicity in young men who have been cured of testicular germ cell tumors using cisplatin-based chemotherapy is of particular concern. The long-term consequences of treatment in this group are discussed elsewhere. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Treatment-related complications' and "Treatment-related toxicity in testicular germ cell tumors".)

Busulfan — Busulfan is used at high doses as part of the preparative regimen for bone marrow transplantation. One case of endocardial fibrosis has been reported that was attributed to busulfan [55].

Trabectedin — Trabectedin is a nonclassical alkylating agent that is approved for use in soft tissue sarcomas after progression on an anthracycline. It has been associated with a low rate of cardiac toxicities, including congestive heart failure and rarely, cardiac arrest [56,57]. The median time to development of grade 3 to 4 cardiotoxicity on trabectedin is 5.3 months [58]. A baseline assessment of ejection fraction should be performed using echocardiogram or multigated acquisition (MUGA) prior to initiation of trabectedin and at two- to three-month intervals while treatment is continued. Trabectedin should be held for a decrease in ejection fraction below the lower limit of normal and permanently discontinued for symptomatic cardiomyopathy or for persistent left ventricular dysfunction that does not recover to the lower limit of normal within three weeks.

ANTITUMOR ANTIBIOTICS

Mitomycin — Mitomycin causes DNA alkylation and cross-linking [59]. Heart failure has been observed in patients treated with mitomycin, with the incidence increasing at cumulative doses >30 mg/m² [60]. Cardiotoxicity may be additive when mitomycin is given with anthracyclines [61-63]. Histologically, the damage resembles radiation-induced cardiac injury [64].

Bleomycin — Bleomycin has been associated with several different forms of cardiotoxicity:

●Pericarditis is an uncommon but potentially serious complication associated with bleomycin. In a series of 88 patients with lymphoma receiving bleomycin, pericarditis was observed in two cases [65].

●The acute onset of substernal chest pain has also been reported in less than 3 percent of patients treated with bleomycin [66]. There are no consistent signs or symptoms associated with these events, and long-term cardiac sequelae have not been observed. Treatment is supportive, and discontinuation of the drug is not needed, as further infusions do not usually cause recurrence of the symptoms.

●Coronary artery disease, myocardial ischemia, and myocardial infarction have been observed in young patients during and after treatment with bleomycin-based chemotherapeutic regimens [67-69]. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Treatment-related complications' and "Treatment-related toxicity in testicular germ cell tumors".)

MONOCLONAL ANTIBODIES

Rituximab — Rituximab, a monoclonal antibody against the CD20 antigen on normal and malignant B lymphocytes, is used to treat a variety of malignant and benign hematologic conditions.

Arrhythmias and angina have been reported during less than 1 percent of infusions, and acute infusion-related deaths have been seen in less than 0.1 percent. These deaths appear to be related to an infusion-related complex of hypoxia, pulmonary infiltrates, adult respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock [70-72]. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab'.)

Long-term cardiac toxicity has not been reported with rituximab administration.

Alemtuzumab — Alemtuzumab targets the CD52 antigen that is present on the cell membrane of most T and B lymphocytes. Alemtuzumab is used to treat T-cell prolymphocytic leukemia. (See "Treatment of T cell prolymphocytic leukemia", section on 'Alemtuzumab'.)

Alemtuzumab therapy of patients with T-cell lymphomas (mycosis fungoides, Sézary syndrome) is associated with a significant risk of heart failure and/or arrhythmias. Among eight patients treated at MD Anderson Cancer Center, heart failure developed in three, atrial fibrillation in one, and ventricular tachycardia in one [73]. Two patients previously had been treated with doxorubicin, but no other causes of cardiac toxicity were identified. The mechanism of this toxicity is not known, and all patients had partial or total resolution of symptoms after discontinuing treatment.

TOPOISOMERASE INHIBITORS

Etoposide — Etoposide has been linked to the development of myocardial infarction and vasospastic angina in several case reports [74-76]. Additionally, etoposide is often a part of cisplatin-based regimens that have been associated with acute and delayed cardiac toxicity. (See "Posttreatment follow-up for testicular germ cell tumors", section on 'Treatment-related complications'.)

INTERFERON AND INTERLEUKIN-2 — The toxicities of biologic response modifiers are generally not due to a direct cytotoxic effect of the drugs, but rather reflect alterations of cellular physiology.

●Interferon-alfa – Interferon-alfa (IFNa) is used as an adjuvant in patients with melanoma and to treat advanced melanoma and renal cell carcinoma. The cardiovascular side effects of IFNa include:

•Myocardial ischemia and infarction, which are generally related to a prior history of coronary artery disease. These may be due to increased fever or associated flu-like symptoms that increase myocardial oxygen requirements [77].

•Atrial and ventricular arrhythmias have been reported in up to a 20 percent of cases [78-81], and two cases of sudden death have been reported [77]. It is unclear whether prior heart disease is linked to an increased risk of arrhythmias.

•Prolonged administration of IFNa has been associated with cardiomyopathy, manifested by a depressed ejection fraction and heart failure. The cardiomyopathy was reversible upon cessation of IFNa infusion in some but not all cases [82-85]. The pathogenesis of IFNa-induced cardiomyopathy is unknown.

●Interleukin-2 – Interleukin-2 is primarily used in the treatment of advanced renal cell cancer. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Interleukin 2 and other interleukins'.)

•Virtually all patients receiving high-dose interleukin-2 (IL-2) develop a capillary leak syndrome associated with increased vascular permeability and hypotension. This results in cardiovascular symptoms similar to those of septic shock, with an increased heart rate and cardiac output and a decrease in systemic peripheral resistance. These symptoms are partially responsive to fluid replacement therapy, but patients often require vasopressors as well. These symptoms usually peak approximately four hours after each dose of IL-2 and worsen with further treatment. The decreased systemic vascular resistance may not return to normal for up to six days after IL-2 has been discontinued [86]. It is not known whether the decrease in peripheral vascular resistance is a direct or indirect effect of IL-2.

•IL-2 also is associated with direct myocardial toxicity although the mechanism of this is unclear. In patients with underlying coronary artery disease, ischemia, myocardial infarction, arrhythmias, and death have been reported [87]. Ventricular and supraventricular arrhythmias have been reported to occur in 6 to 21 percent of patients [86,88,89]. This is illustrated by a series of 199 patients in which 6 percent developed arrhythmias, including ventricular tachycardia, and 2.5 percent had elevated creatine kinase (CPK) isoenzyme MB levels [89]. Supraventricular tachycardias were usually responsive to treatment [86].

DIFFERENTIATION AGENTS

All-trans retinoic acid — All-trans retinoic acid (ATRA) is used to treat acute promyelocytic leukemia. Approximately 10 to 15 percent of patients develop the differentiation syndrome (previously called the "retinoic acid syndrome"), which can cause pericardial effusions (including the potential for cardiac tamponade) and myocardial ischemia/infarction. The differentiation syndrome is discussed elsewhere. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'Administration and side effects'.)

Arsenic trioxide — Arsenic trioxide (ATO) is used to treat acute promyelocytic leukemia. Serious adverse events attributed to treatment with ATO include the "differentiation syndrome," similar to that seen with ATRA, and cardiac abnormalities, including prolongation of the corrected QT (QTc) interval. These complications are discussed elsewhere. (See "Initial treatment of acute promyelocytic leukemia in adults", section on 'ATO plus ATRA'.)

The United States Prescribing Information for ATO recommends withholding the drug for a QTc interval >450 msec in men and >460 msec in women. Although the optimal way to calculate the QTc interval in patients receiving chemotherapy drugs that have the potential to alter the QTc interval is debated [90,91], the original trial used the Framingham formula (calculator 1) [92].

PROTEIN KINASE INHIBITORS

Brigatinib — Brigatinib is a tyrosine kinase inhibitor (TKI) used in the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC). It is associated with both hypertension and bradycardia. Blood pressure and heart rate should be monitored regularly during treatment. If patients are symptomatic or have severe hypertension, brigatinib should be withheld, then dose reduced or permanently discontinued.

In a phase II study, hypertension was reported in approximately 20 percent and bradycardia was noted in 7.6 percent of those receiving the recommended dose of brigatinib [93,94].

Cobimetinib, trametinib, and binimetinib — Cobimetinib, trametinib, and binimetinib inhibit mitogen-activated protein kinase (MEK). Cobimetinib and binimetinib are used, in conjunction with a BRAF inhibitor, for the treatment of advanced, metastatic or unresectable, BRAF-mutated melanoma. There is an increased risk for cardiomyopathy in patients receiving dual therapy with either cobimetinib and vemurafenib or binimetinib and encorafenib compared with a single-agent BRAF inhibitor, and baseline left ventricular ejection fraction (LVEF) should be evaluated prior to initiation of these agents, after one month of treatment, and every two to three months thereafter [95,96]. (See 'Vemurafenib and encorafenib' below.)

In clinical trials of trametinib in patients with metastatic melanoma, left ventricular dysfunction has been seen in up to 11 percent of treated patients:

●In a phase II trial in which all 97 patients underwent assessment of LVEF at baseline, at week 4, and every 12 weeks thereafter, three patients (3 percent) developed asymptomatic and reversible grade 3 LVEF reduction [97].

●In a phase III trial comparing trametinib versus chemotherapy with dacarbazine or paclitaxel, 14 of the 211 patients who received at least one dose of trametinib developed cardiac toxicity (7 percent), 11 developed a decreased LVEF, and three had left ventricular dysfunction [98]. Cardiomyopathy resolved in 10 of the 14, but four patients had serious cardiac-related events that were considered to be drug related and led to permanent discontinuation of the study drug [99].

●Across clinical trials of trametinib at the recommended dose, approximately 11 percent of patients developed evidence of cardiomyopathy (a decrease in LVEF below the institutional lower limits of normal with an absolute decrease in LVEF ≥10 percent below baseline), and 5 percent developed a decrease in LVEF below the institutional lower limits of normal with an absolute decrease in LVEF of ≥20 percent below baseline [99].

●In the PHAROS trial, LVEF decline below institutional lower limit of normal, with an absolute decrease in LVEF ≥10 percent, occurred in 11 percent of patients receiving binimetinib and encorafenib. Grade 3 LV dysfunction occurred in 1 percent of patients. Cardiomyopathy resolved in 82 percent of patients receiving the combination [95].

The US Food and Drug Administration (FDA) recommends the following, in regards to management of cardiotoxicity on trametinib or binimetinib [95,96]:

●Assess LVEF before initiation of therapy, at one month after treatment initiation, and then at two- to three-month intervals during treatment.

●Withhold treatment if the absolute LVEF decreases by 10 percent from pretreatment values to less than the institutional lower limit of normal.

●Permanently discontinue for symptomatic heart failure, any absolute decrease in LVEF of >20 percent from baseline that is below the institutional lower limit of normal, and a persistent LVEF decrease of ≥10 percent from baseline that does not resolve within four weeks.

Prolongation of the corrected QT (QTc) interval is reported with binimetinib in combination with encorafenib. (See 'Vemurafenib and encorafenib' below.)

Crizotinib and ceritinib — Crizotinib and ceritinib are orally active inhibitors of the anaplastic lymphoma kinase (ALK); they are both approved for treatment of advanced or metastatic non-small cell lung cancer (NSCLC) if the tumor contains a characteristic EML4-ALK fusion oncogene. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Ceritinib' and "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Crizotinib'.)

Sinus bradycardia is common in patients receiving these agents and can be profound, although it is generally asymptomatic and not associated with other events such as other arrhythmias:

●In two trials evaluating the efficacy of crizotinib for advanced NSCLC, bradycardia was reported in only 12 of 240 patients who were assessable for treatment-related toxicity; all were mild (grade 1 or 2) in severity [100].

●In another report of 42 patients receiving treatment with crizotinib for advanced NSCLC, there was an average decrease of 26 bpm among all patients; 69 percent had at least one episode of sinus bradycardia (heart rate <60 beats per minute [bpm]) [101]. Profound sinus bradycardia (heart rate <50 bpm) developed in 13 (31 percent). None of the patients who developed bradycardia during treatment were symptomatic or had electrocardiographic (ECG) changes such as QTc interval prolongation.

●Less information is available with regard to ceritinib. In one report of 255 patients receiving ceritinib, bradycardia (heart rate <50 bpm) was reported as a new finding in only 1 percent [102].

The United States Prescribing Information for both crizotinib and ceritinib recommends avoiding use in patients who are using other agents known to cause bradycardia (eg, beta-blockers, clonidine, nondihydropyridine calcium channel blockers, digoxin), and that heart rate and blood pressure be monitored regularly during therapy. Dose adjustment guidelines in the setting of symptomatic bradycardia are also provided.

In addition to bradycardia, QTc interval prolongation has been observed with both drugs, although it is uncommon. Three percent of 255 patients treated with ceritinib experienced a QTc interval increase over baseline of 60 msec; in a larger population of 304 patients treated with the drug, only one (<1 percent) developed a QTc interval of >500 msec [102]. The US prescribing information for crizotinib and ceritinib recommends avoiding both drugs in patients with congenital long QT syndrome and that patients with heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking other medications known to prolong the QTc interval (table 1) undergo periodic monitoring with ECGs and assessment of serum electrolytes. Treatment interruption and dose reduction is advised if QTc interval exceeds >500 msec during treatment, with permanent discontinuation if it recurs or is accompanied by an arrhythmia, heart failure, hypotension, shock, syncope, or torsade de pointes.

Given that both drugs are CYP3A4 substrates, they should be used with caution in patients who are receiving other drugs that inhibit CYP3A4 (table 2).

Practice is variable regarding cardiac monitoring during therapy, however, some clinicians perform a baseline ECG for patients starting crizotinib or ceritinib only if they have known history of heart failure or cardiac arrhythmia issues, and check ECGs during therapy if bradycardia (symptomatic or not) develops or if the patient is started on another drug with known side effect of QTc prolongation. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Management of toxicities associated with ALK inhibitors'.)

BTK inhibitors — Ibrutinib, zanubrutinib, acalabrutinib, and pirtobrutinib are orally active inhibitors of the Bruton tyrosine kinase; they are used for a variety of B-cell hematologic malignancies, including chronic lymphocytic leukemia, Waldenström macroglobulinemia, and mantle cell and marginal zone lymphoma. All three drugs have been associated with cardiotoxicity. However, the later-generation BTK inhibitors (zanubrutinib, acalabrutinib, pirtobrutinib) demonstrate greater BTK selectivity and less off-target inhibition than ibrutinib, and this has translated into lower rates of cardiotoxicity. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma" and "Treatment and prognosis of Waldenström macroglobulinemia" and "Treatment of relapsed or refractory mantle cell lymphoma" and "Splenic marginal zone lymphoma".)

●Ibrutinib – Several cardiovascular toxicities have been reported with ibrutinib, including supraventricular arrhythmias, ventricular arrhythmias, heart failure, conduction disorders, hypertension, and sudden death. The following data are available regarding overall risk:

•A review of the World Health Organization's global database of individual case safety reports among 13,572 patients receiving ibrutinib revealed reports of supraventricular arrhythmias in 959 (7 percent), heart failure in 363 (2.7 percent), ventricular arrhythmias in 70 (0.5 percent), cardiac conduction disorders in 50 (0.4 percent), and hypertension in 295 (2.2 percent) [103].

•In a multi-institutional series of 562 consecutive patients treated with ibrutinib for B-cell malignancies, 78 percent of ibrutinib users developed new or worsened hypertension during therapy, and the development of hypertension was associated with a twofold higher risk of other major adverse cardiovascular events [104]. Atrial fibrillation was the most common cardiovascular complication, occurring in 13 percent; this was followed by new heart failure (3.7 percent), myocardial infarction (MI, 1.4 percent), and ventricular arrhythmias or sudden cardiac death (1.1 percent).

•Another population-based cohort study of 778 pairs of ibrutinib-treated and unexposed patients with chronic lymphocytic leukemia revealed a higher three-year incidence of atrial fibrillation (23 versus 12 percent) and heart failure (7.7 versus 3.6 percent) with ibrutinib, but no increase in risk of acute MI [105].

•Data are also available from a safety analysis of four randomized trials of ibrutinib for B-cell malignancies (756 patients receiving ibrutinib); cardiac disorders developed in 15 percent, the most common of which was atrial fibrillation (6 percent), which was grade 3 or 4 in 3 percent [106]. The greatest risk was during the first three months of therapy.

According to the updated United States Prescribing Information for ibrutinib, these events have occurred particularly in patients with cardiac risk factors, including hypertension, diabetes mellitus, acute infection, and a previous history of cardiac arrhythmias. Specific dose reduction guidelines are provided for patients who develop grade 2 cardiac failure (table 3) or a symptomatic cardiac arrhythmia for which urgent intervention is needed (ie, grade 3) during therapy.

●Zanubrutinib – Although less cardiotoxic than ibrutinib, zanubrutinib has also been associated with atrial flutter and atrial fibrillation (approximately 3 to 4 percent), and hypertension (12 percent all grade, 3 percent grade 3 or 4) [107]. According to the United States Prescribing Information for zanubrutinib, patients with cardiac risk factors, hypertension, and acute infection may be at increased risk. Grade ≥3 ventricular arrhythmias have been reported in 0.2 percent of patients [107].

●Acalabrutinib – Across clinical trials of acalabrutinib, atrial fibrillation/flutter was reported in 4 percent of patients overall, and was grade 3 in 1.1 percent [108]. According to the United States Prescribing Information for acalabrutinib, patients with cardiac risk factors, hypertension, and acute infection may be at increased risk.

Risk for ventricular arrhythmias also appears to be elevated in patients treated with acalabrutinib. In a series of 290 consecutive patients treated with acalabrutinib over a six-year period, the overall risk was low (eight cases of incident ventricular arrhythmias [ventricular fibrillation, ventricular tachycardia, or symptomatic premature ventricular contractions] and one sudden death, 3 percent), this represented an eightfold higher relative risk for ventricular arrhythmias relative to similar aged non-BTK inhibitor treated individuals [109].

●Pirtobrutinib – In a clinical trial in 583 patients treated with pirtobrutinib, atrial fibrillation or flutter were reported in 2.7 percent of patients [110], with grade 3 or 4 atrial fibrillation or flutter noted in 1 percent. Patients with cardiac risk factors (eg, hypertension or previous arrhythmia) may be at higher risk.

Agents targeting BCR::ABL1

●Imatinib – Imatinib, a small-molecule inhibitor of BCR::ABL1, KIT, PDGFR, and the SRC family of tyrosine kinases, is used to treat Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML), which is characterized by the BCR::ABL1 fusion protein, which functions as a tyrosine kinase, and gastrointestinal stromal tumors (GIST), which are characterized by mutations in KIT or PDGFR genes. Adverse cardiac events in patients receiving imatinib are likely mediated by inhibition of ABL1 [111,112].

Despite an early report of heart failure in patients treated with imatinib for Ph+ CML [111], subsequent reports indicate <2 percent incidence of clinically significant heart failure in CML clinical trial settings [113]. Patients receiving imatinib for treatment of GIST have not been reported to have an increased risk for heart failure or left ventricular dysfunction [114-116]. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Side effects and their management' and "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Imatinib'.)

However, the cardiac consequences of long-term imatinib therapy remain unknown. Importantly, none of these reports were based on studies in which cardiac function was prospectively monitored. Assessment was based primarily on adverse event reports, which may not reflect the true incidence of cardiac disease. In the only study to prospectively assess left ventricular function in 59 patients with CML who were treated with imatinib, there was no evidence of deterioration over the initial 12 months [117]. In the lone prospective study in which patients receiving imatinib for GIST were monitored with serum levels of brain natriuretic peptide (BNP), 2 of 55 patients followed over a three-month period had substantial increases in BNP (4 percent), suggesting the possibility of subclinical heart failure [118].

Additional information from well-designed prospective studies with objective cardiac monitoring is needed to determine the incidence and clinical significance of heart failure attributable to imatinib, both in patients with CML and GIST. Until then, some have suggested that patients receiving imatinib for either CML or GIST be thought of as stage A heart failure patients (ie, at risk for heart failure), but without structural heart disease or symptoms [116,119].

Some have suggested that patients receiving these drugs be treated as "stage A" heart failure patients (ie, at risk for heart failure), but without structural heart disease or symptoms [119]. Year 2013 guidelines for management of stage A heart failure from the AHA suggest that it may be reasonable to evaluate those who are receiving potentially cardiotoxic agents such as imatinib for left ventricular dysfunction [120].

However, obtaining a baseline assessment of LVEF in all patients receiving imatinib (particularly for GIST where it is not even clear that there is a risk of cardiotoxicity) is not supported by compelling data. In our view, patients receiving imatinib should be monitored for signs and symptoms of heart failure, and clinicians should have a low threshold for formal assessment of left ventricular dysfunction.

Guidelines for management of imatinib toxicity from the National Comprehensive Cancer Network (NCCN) suggest only that patients with cardiac disease or risk factors for heart failure who are receiving imatinib be monitored carefully, and that any patient with signs or symptoms consistent with heart failure be evaluated and treated [121].

We agree with these guidelines, and do not obtain a baseline assessment of LVEF prior to starting imatinib.

●Nilotinib, dasatinib, and bosutinib – Nilotinib, dasatinib, and bosutinib are three second-generation multitargeted TKIs that are used for the treatment of Ph+ CML; all target the ATP binding site of BCR::ABL1, while nilotinib also targets KIT and PDGFR; dasatinib targets KIT, PDGFR, and the SRC family of kinases; and bosutinib targets the SRC family of tyrosine kinases.

Cardiac effects have been described with each of these agents:

•All three drugs have been associated with QT prolongation [91,122,123]. Abnormalities in potassium and magnesium levels must be corrected prior to drug initiation, other drugs that may affect the QTc interval should be avoided, caution should be used in patients at risk for QT interval prolongation, and serial ECGs should be followed. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Initial treatment of chronic myeloid leukemia in chronic phase", section on 'Other toxicity'.)

The optimal way to calculate the QTc interval in patients receiving chemotherapy drugs that have the potential to alter the QTc interval is debated [90,91]; the United States Prescribing Information for any of the three drugs does not specify which correction formula to use (calculator 1). Use of the Framingham formula has been suggested by one group [90].

•Although a definite causal relationship has not been established, dasatinib has also been associated with chest pain, pericardial effusion, ventricular dysfunction, and heart failure [124]. The United States Prescribing Information states that 1.6 percent of 258 patients taking dasatinib developed cardiomyopathy, heart failure, diastolic dysfunction, fatal myocardial infarction, and/or left ventricular dysfunction [124].

•Although clinical heart failure is not described, fluid retention occurs with bosutinib and may manifest as pericardial effusion or pulmonary edema [125]. (See "Cardiotoxicity of trastuzumab and other HER2-targeted agents", section on 'Lapatinib'.)

●Ponatinib – Ponatinib is a third generation BCR::ABL1 TKI with activity against CML with a T3151 mutation; it is approved for treatment of patients with CML or acute lymphoblastic leukemia who are resistant or unable to tolerate another TKI. Although the antitumor efficacy appears due to its inhibition of the tyrosine kinase BCR::ABL1, ponatinib also blocks several other receptor tyrosine kinases such as the VEGF receptor 2. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Ponatinib'.)

Ponatinib is associated with more cardiovascular toxicity than the prior generations of BCR::ABL1 TKIs. Cardiac toxicities include heart failure, ischemic heart disease due to arterial occlusive events, cardiac arrhythmias, QTc prolongation, and peripheral vascular events, both arterial and venous. Cardiovascular toxicity led to the drug being withdrawn from the market in 2013, but given the lack of alternative effective treatment option for CML resistant to other TKIs, it was reintroduced with added safety measures regarding cardiovascular risk. Since then, a newly approved agent, asciminib (discussed below) is available and should be considered for treatment of patients with BCR::ABL1 T3151 who have high-risk for cardiovascular adverse events.

The cardiovascular risks associated with ponatinib can be summarized as follows:

•Arterial occlusive events (AOEs) – In the first analysis of the PACE trial the incidence of cardiovascular, cerebrovascular, and peripheral arterial vascular adverse events in patients treated with ponatinib were 7.1, 3.6, and 4.9 percent, respectively [126]. Of the 5 percent of patients who had a serious cardiovascular event, 55 percent had a history of ischemic disease at study enrollment, and 95 percent had one or more risk factors (hypertension, diabetes, hypercholesterolemia, or obesity) with or without a history of ischemic disease, nonischemic cardiac disease, or venous thromboembolism.

In a later analysis of the trial with five-year follow-up, the cumulative incidence of any AOE was 26 percent, and vascular occlusive events appeared more frequently during the first and second year of treatment (14.5 and 14.1 percent, respectively) than afterward (10.5 percent during the third year, 7.2 percent thereafter) [127]. Post hoc analysis suggested that these events might be dose dependent.

However, this could not be confirmed in the OPTIC study, which directly compared three daily doses of ponatinib (45 mg [standard], 30 mg, and 15 mg) in 283 adults with refractory CML [128]. For patients who were initially assigned to 45 or 30 mg daily, the dose was reduced to 15 mg daily upon clinical response. The primary end point (response at 12 months) was achieved by more patients who received the initial 45 mg dose (44 versus 29 and 23 percent with 30 and 15 mg doses), but independently confirmed grade ≥3 AOEs were not more frequent with the higher initial dose (occurring in 5, 5, and 3 percent of those treated initially 45, 30, and 15 mg daily dose groups, respectively). The authors concluded that the optimal risk/benefit outcomes occurred with the 45 mg starting dose, which was reduced to 15 mg daily upon achievement of a response.

The United States Prescribing Information for ponatinib recommends an assessment for whether the benefits of ponatinib are expected to exceed the cardiovascular risks prior to initiating therapy. They also suggest monitoring for evidence of AOEs during ponatinib therapy and provide guidance for dose modification based on recurrence/symptom severity. They also recommend that clinicians "consider" benefit-risk to guide a decision to restart the drug.

One such tool that may be beneficial to ascertain the risk for AOEs with ponatinib is a risk chart (table 4) that includes the Systematic COronary Risk Evaluation (SCORE) categories predicting 10-year cardiovascular mortality based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels, as defined in the 2016 European guidelines on cardiovascular disease prevention in clinical practice [129-131]. Those patients with high to very high SCORE levels (ie, ≥10 percent) seem to be at the greatest risk of AOEs with ponatinib.

•Heart failure – Potentially fatal heart failure has been reported with ponatinib:

-In the OPTIC study described above, of the 94 patients initially treated with 45 mg daily, heart failure developed in 12 percent, and was severe in 1.1 percent [128].

-In the PACE trial, heart failure occurred in 9 percent of the 449 patients; 7 percent were ≥grade 3 [126].

The United States Prescribing Information for ponatinib recommends monitoring patients closely for signs and symptoms of heart failure, and provides recommendations for dose modification based on severity.

•Cardiac arrhythmias

-Of the 94 patients who received a starting dose of 45 mg daily in the OPTIC trial, cardiac arrhythmias developed in 15 percent; 4.3 percent experienced grade 3 or 4 cardiac arrhythmias (which included atrial fibrillation, cardiorespiratory arrest, supraventricular asystoles, and syncope) [128].

-In the PACE trial, cardiac arrhythmias developed in 20 percent of the 449 patients; 7 percent experienced grade 3 or 4 arrhythmias. Atrial fibrillation was the most frequent (8 percent, 3.3 percent grade 3 or 4), but ventricular arrhythmias occurred in 3.4 percent (with only one event being grade 3 or 4). Other grade 3 or 4 arrhythmia events included syncope, tachycardia (including ventricular tachycardia) and bradycardia, QTc interval prolongation, atrial flutter, complete AV block, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction.

The United States Prescribing Information recommends closely monitoring for signs and symptoms suggestive of a slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations, dizziness), and provides recommendations for dose modifications based on severity.

•Mechanisms – Underlying mechanisms for cardiotoxicity associated with ponatinib are not completely understood. Ponatinib may exert its cardiotoxic effects by inhibition of growth signaling pathways that are known to regulate cardiomyocyte survival and maintain cardiac homeostasis [132]. Off-target actions on platelet activation and/or endothelial cell function through targeting of VEGF receptors or drug-induced thrombotic microangiopathy may also contribute to the development of AOEs [133-135]. (See "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Cancer therapies'.)

•Prevention and management – The US Food and Drug Administration and the European Medicine Agency recommend that the cardiovascular profile of patients who are candidates for ponatinib should be carefully evaluated. For patients deemed to carry a high risk of cardiovascular events, other life-saving therapeutic options should be considered. When alternative options are not available, treatment with ponatinib is indicated but requires that hematologists and cardiologists collaborate and identify modalities of surveillance and risk mitigation in the best interest of the patient.

Several guidelines regarding the identification, prevention, and management of cardiovascular adverse events in CML patients on ponatinib are published [129,136-140]. Algorithmic approaches to cardiovascular screening of patients undergoing therapy with potentially cardiotoxic TKIs have been proposed [129].

●Asciminib – Asciminib is also used for treatment of Ph+ CML refractory to ≥2 prior treatments or Ph+ CML with a T315I mutation; it targets BCR::ABL1, but by a different mechanism than the other four drugs described above. Asciminib is a first-in-class STAMP (Specifically Targeting the ABL1 Myristoyl Pocket) inhibitor with the potential to overcome resistance or intolerance to other approved TKIs. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy".)

Cardiovascular toxicity (including ischemic cardiac, central nervous system, and arterial thromboembolic conditions ) and heart failure occurred in 46 (13 percent) and 8 (2.2 percent) of 356 patients receiving the drug, respectively, and fatalities were reported [141]. Arrhythmias, including prolongation of the QTc interval, occurred in 23 patients (7 percent). Mostly, cardiovascular toxicity has occurred in patients with preexisting risk factors, and/or prior exposure to multiple TKIs.

The United States Prescribing Information for asciminib recommends monitoring patients with a history of cardiovascular risk factors for cardiovascular signs and symptoms, and contains specific recommendation for dose modification for grade 3 or higher nonhematologic adverse reactions. There are no specific guidelines for monitoring serial ECGs during therapy.

Osimertinib and mobocertinib — Osimertinib is a third-generation oral EGFR TKI that is active in non-small cell lung cancers harboring the EGFR T790M mutation. Decreases in LVEF of ≥10 percent from baseline to a level <50 percent were observed in 3 to 5 percent of patients treated on two trials [142,143] and in 3.9 percent of patients in a pooled population [144] However, most events were asymptomatic and resolved without treatment of the event or discontinuation of osimertinib. Although causality remains uncertain, cardiac monitoring is advised with assessment of LVEF at baseline and every three months on treatment [145]. Additionally, patients with predisposition towards or history of QTc prolongation or those taking medications known to cause QTc prolongation should have monitoring of ECG and electrolytes while on osimertinib [145].

Mobocertinib is a third-generation oral EGFR TKI that is active in non-small cell lung cancers harboring the EGFR exon 20 insertion mutation. As with osimertinib, both reduced ejection fraction and prolongation of the QTc interval are reported with this agent:

●In the pooled safety population of 250 patients treated with this agent who had electrocardiograms during treatment, 1.2 percent had a QTc interval >500 msec, and 11 percent had a change-from-baseline QTc interval >60 msec. One patient developed grade 4 torsades de pointes.

●Cardiac toxicity (decreased ejection fraction, cardiomyopathy, and heart failure) may be fatal. In this same pooled safety population, heart failure occurred in seven (2.7 percent), three cases were grade 3 or 4, and there was one fatality.

The FDA recommends assessment of left ventricular ejection fraction, QTc interval, and electrolyte levels at baseline, and periodically during treatment; QTc should be assessed more frequently in patients with severe renal impairment [145]. Electrolyte abnormalities should be corrected prior to initiating treatment. Concomitant treatment with drugs that are known to prolong the QTc interval or that are strong or moderate CYP3A inhibitors (table 2) should be avoided during treatment. There are also provisions for withholding, reducing the dose, or permanently discontinuing mobocertinib based on the severity of the QTc prolongation or heart failure during therapy.

Quizartinib — Quizartinib is a kinase inhibitor approved for use in adults with newly diagnosed acute myeloid leukemia that is FLT3 internal tandem duplication-positive, in combination with cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy [146].

Quizartinib has been associated with QT prolongation, Torsades de Pointes, and cardiac arrest. As such, the United States Prescribing Information recommends monitoring electrocardiograms and levels of serum electrolytes [146]. In a clinical trial, QTc prolongation occurred in 14 percent with quizartinib compared with 4 percent with placebo; grade 3 or 4 QT prolongation occurred in 3 and 1.1 percent, respectively.

Ribociclib — Ribociclib is one several kinase inhibitors that inhibit the cyclin-dependent kinase (CDK) 4/6 pathway. Ribociclib is approved for use in the treatment of hormone-positive, advanced or metastatic breast cancer. Prolongation of the QTc interval has been observed in patients receiving ribociclib. Typically, QTc prolongation occurred within the first four weeks of initiating drug therapy and was reversible with dose interruption.

As a result, the United States Prescribing Information for ribociclib recommends that serum electrolytes be monitored prior to initiation and before each of the first six cycles. Abnormalities should be corrected prior to starting treatment. Additionally, an ECG is recommended prior to initiating therapy. Treatment should only be started if the QTc is <450 msec. Although the optimal way to calculate the QTc interval in patients receiving chemotherapy drugs that have the potential to alter the QTc interval is debated [90,91], the United States Prescribing Information specifically recommends use of the Fridericia formula (calculator 1) for this drug.

An ECG should be repeated at day 14 of cycle 1, at initiation of the second cycle, and thereafter as clinically indicated. QTc intervals >480 msec require dose interruption. Specific management recommendations are outlined in the United States Prescribing Information for ribociclib.

Ripretinib — Ripretinib is a kinase inhibitor of KIT and PDGFRA that is approved as a fourth-line agent for treatment of advanced gastrointestinal stromal tumors; in vitro, it also inhibits VEGFR2. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Ripretinib'.)

The following data are available regarding cardiotoxicity:

●In the phase III INVICTUS trial, cardiac failure occurred in 1.2 percent of the 85 patients who received ripretinib; of the 77 who had a baseline and at least one postbaseline echocardiogram, grade 3 decreased ejection fraction (table 5) developed in 2.6 percent [147].

●In a pooled safety population of 351 patients, cardiac dysfunction (heart failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) occurred in 1.7 percent, and the adverse reactions were grade 3 in 1.1 percent [148]. Of the patients who had a baseline and at least one post-treatment echocardiogram, grade 3 decreased ejection fraction (table 5) occurred in 3.4 percent.

Whether these reflect inhibition of VEGFR2, KIT, PDGFRA, or a combination of these targets remains unclear. Several other antiangiogenic TKIs are associated with left ventricular dysfunction. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Specific VEGFR tyrosine kinase inhibitors'.)

The United States Prescribing Information for ripretinib recommends a baseline echocardiogram or multigated acquisition (MUGA) scan prior to initiation of therapy and as clinically indicated afterwards; ripretinib should be discontinued in those who develop grade ≥3 left ventricular diastolic dysfunction on treatment. There are no data on safety of this drug in those with a baseline ejection fraction <50 percent.

Selpercatinib — Selpercatinib is a kinase inhibitor approved to treat non-small cell lung cancer, medullary thyroid cancer, and other types of thyroid cancers that have an alteration (mutation or fusion) in the specific rearranged during transfection gene (RET). (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'RET rearrangements' and "Medullary thyroid cancer: Systemic therapy and immunotherapy", section on 'Selpercatinib'.)

Selpercatinib can cause concentration-dependent prolongation in the corrected QT interval (QTc). In clinical trials, an increase in the QTc interval to >500 ms was measured in 6 percent of patients, and an increase in the QTc interval of at least 60 ms over baseline was measured in 15 percent of patients [149]. The United States Prescribing Information recommends that clinicians assess QT interval, electrolytes, and thyroid-stimulating hormone (TSH) at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea, and that hypokalemia, hypomagnesemia, and hypocalcemia be corrected prior to initiating and during treatment.

The QT interval should be monitored more frequently when selpercatinib is administered concomitant with strong and moderate CYP3A inhibitors (table 2) or other drugs known to prolong QTc interval (table 1).

Sorafenib and sunitinib — Sorafenib and sunitinib are orally active multi-targeted TKIs that are used for the treatment of metastatic renal cell carcinoma. In addition, sorafenib is used in the treatment of advanced hepatocellular cancer, and sunitinib is used for imatinib-refractory gastrointestinal stromal tumors (GIST) and for advanced pancreatic neuroendocrine tumors. (See "Antiangiogenic and molecularly targeted therapy for advanced or metastatic clear cell renal carcinoma" and "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'Sunitinib' and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Sunitinib' and "Systemic treatment for advanced hepatocellular carcinoma", section on 'Sorafenib'.)

In clinical trials, both drugs have been associated with a small but definite risk of hypertension and cardiotoxicity.

However, a major problem with defining the precise rate of cardiotoxicity associated with both drugs (and its reversibility) is that phase III trials have not pursued cardiac endpoints, and the identification of cardiac side effects with both drugs has predominantly been based on the occurrence of clinical symptoms. Further detailed prospective study of cardiotoxicity of these agents is needed. This subject is addressed in detail elsewhere. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Left ventricular dysfunction and myocardial ischemia'.)

In addition to declines in LVEF and clinical heart failure, reported ECG changes have included changes in rhythm, conduction disturbance, change in axis or QRS amplitude, ST or T wave changes, and QTc prolongation with sunitinib. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Prolongation of the QTc interval and cardiac arrhythmias'.)

Vandetanib — Vandetanib is an orally active multi-targeted TKI that inhibits epidermal growth factor reception (EGFR), vascular endothelial growth factor (VEGF), rearranged during transfection (RET), protein tyrosine kinase 6 (BRK), TIE2, EPH kinase receptors, and SRC kinase receptors, selectively blocking intracellular signaling, angiogenesis, and cellular proliferation. It is used mainly for treatment of medullary thyroid cancer. In clinical trials, vandetanib has been associated with prolongation of the QTc interval, torsades de pointes, and sudden death. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Specific VEGFR tyrosine kinase inhibitors'.)

Because of the risk of cardiotoxicity, the United States Prescribing Information includes a black box warning to correct hypocalcemia, hypokalemia, and/or hypomagnesemia prior to drug administration. In addition, given the long half-life of the drug (19 days), ECGs are recommended to monitor the QT interval at baseline, at two to four weeks, 8 to 12 weeks after starting treatment, and every three months thereafter. Monitoring of serum potassium, calcium, and magnesium levels as well as TSH is recommended on the same schedule. Concurrent administration of drugs known to prolong the QTc interval should be avoided (table 1). Largely because of the cardiovascular risk, vandetanib is only available through a restricted distribution program (the Vandetanib Risk Evaluation and Mitigation Strategy [REMS] Program). (See "Medullary thyroid cancer: Systemic therapy and immunotherapy", section on 'Vandetanib'.)

Vemurafenib and encorafenib — Vemurafenib and encorafenib are orally available inhibitors of some mutated forms of BRAF that are approved for treatment of metastatic melanoma with a V600E BRAF mutation. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Dabrafenib plus trametinib' and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Toxicities of BRAF and MEK inhibitors'.)

Both drugs have been associated with prolongation of the QTc interval. The United States Prescribing Information for vemurafenib recommends that the drug not be given to patients with congenital long QTc syndrome or to those who are receiving other drugs that prolong the QT interval (table 1). Furthermore, it is recommended that ECGs and electrolytes be monitored before treatment and after dose modification. For patients starting therapy with vemurafenib, ECGs are recommended at day 15, monthly during the first three months of treatment, every three months thereafter, and more often as clinically indicated. If the QTc interval exceeds 500 msec, treatment should be temporarily interrupted, and electrolyte abnormalities should be sought and corrected.

The United States Prescribing Information for encorafenib does not provide a specific recommendation about how often to monitor ECGs during therapy but recommends the following for managing prolongations in QTc during therapy:

●Corrected QT by Fridericia/Framingham (QTcF) >500 msec, and ≤60 msec increase from baseline – Withhold encorafenib until the QTcF is ≤500 msec, then resume at a reduced dose. If there is more than one recurrence, permanently discontinue encorafenib.

●QTcF >500 msec, and >60 msec increase from baseline – Permanently discontinue encorafenib.

The optimal way to calculate the QTc interval in patients receiving chemotherapy drugs that have the potential to alter the QTc interval is debated [90,91,150]. The United States Prescribing Information is ambiguous, using the term "QTcF" for encorafenib, which is undefined and could refer to the Framingham or Fridericia correction (calculator 1). (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management", section on 'ECG findings'.)

Use of binimetinib with encorafenib is discussed above. (See 'Cobimetinib, trametinib, and binimetinib' above.)

MISCELLANEOUS AGENTS

Diethylstilbestrol — Diethylstilbestrol (DES) is a synthetic estrogen that was used to treat advanced prostate cancer and breast cancer. Multiple studies demonstrated an increased risk of cardiovascular death in patients treated with DES. This agent is no longer commercially available in the United States. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)

LHRH agonist/antagonist — Increasingly more attention is being given to the potential cardiovascular toxicities associated with long-term androgen deprivation using luteinizing hormone releasing hormone (LHRH) agonists and antagonists and antiandrogen therapies. To date, conflicting data exist regarding cardiovascular toxicity of manipulation of the androgen axis. This subject is discussed elsewhere. (See "Side effects of androgen deprivation therapy", section on 'Potential cardiovascular harm'.)

Serotonin antagonists — Although usually well tolerated, the serotonin receptor antagonists often used during chemotherapy as antiemetics have some potential for cardiac effects, notably corrected QT (QTc) prolongation [151]. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Cardiac issues'.)

Clinical trials in healthy subjects and patients undergoing chemotherapy have demonstrated transient asymptomatic electrocardiographic (ECG) changes (increases in PR interval, QRS complex duration, and QTc interval) following administration of ondansetron, granisetron, or dolasetron [152-157]; chest pain has been attributed to ondansetron [158]. Since almost all of these studies excluded patients with preexisting cardiac disease, the clinical significance of these events in such patients, particularly those receiving cardiac medications, is unknown.

Proteasome inhibitors — Bortezomib and carfilzomib are proteasome inhibitors that are used for the treatment of multiple myeloma.

In clinical trials of carfilzomib, a second-generation proteasome inhibitor, new onset or worsening of preexisting heart failure with decreased left ventricular function or myocardial ischemia has been reported in approximately 7 percent of patients, and deaths due to cardiac arrest have occurred within one day of drug administration [159]. In addition, pulmonary arterial hypertension has been reported in 2 percent of patients treated with carfilzomib.

In a phase II trial of 266 patients treated with carfilzomib monotherapy for relapsed myeloma, 10 experienced heart failure (3.8 percent), 4 had a cardiac arrest (1.5 percent), and 2 had a myocardial infarction during the study (0.8 percent) [160]. The risk did not appear to be cumulative, at least through 12 cycles of therapy. However, the magnitude of the attributable risk, risk factors, and natural history, including reversibility, of carfilzomib-related cardiac toxicity remain incompletely characterized. Recommended dose modification based upon cardiac toxicity is available in the US prescribing information.

Cardiotoxicity might represent a class effect, as heart failure events (acute pulmonary edema, cardiac failure, cardiogenic shock) have also been described in patients treated with bortezomib, a first-generation proteasome inhibitor [161]. However, causality remains unclear, and the risk seems lower than with carfilzomib:

●In a phase III trial comparing bortezomib versus dexamethasone for relapsed myeloma, the incidence of treatment-emergent cardiac disorders during treatment with bortezomib or dexamethasone was 15 and 13 percent, respectively; seven patients receiving bortezomib (2 percent) and eight patients receiving dexamethasone (2 percent) developed heart failure during the study [162]. There were eight deaths thought to be possibly related to study drug; four in the bortezomib group (including three from cardiac causes and one from respiratory failure), and four in the dexamethasone group (three from sepsis and one from sudden death of unknown cause).

●In the multicenter PROTECT (Prospective Observation of Cardiac Safety with Proteasome Inhibitor) trial, conducted in patients treated for relapsed multiple myeloma, cardiovascular adverse events occurred in 51 percent of the 65 patients treated with carfilzomib and 17 percent of the 30 patients treated with bortezomib [161]. In both groups, 86 percent of the cardiovascular adverse events occurred within the first three months. Interestingly, elevated levels of natriuretic peptides (BNP or N-terminal proBNP) occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of adverse cardiovascular events (odds ratio 36). Validation of this finding is needed before assay of natriuretic peptides can be incorporated into the routine management of patients receiving carfilzomib.

As with carfilzomib, cardiac dysfunction does not appear to be cumulative [163].

Abnormalities appear to be largely reversible with prompt cessation of therapy and initiation of traditional heart failure treatment [164].

Histone deacetylase inhibitors — The reversible acetylation of histones, a family of nuclear proteins that interact with DNA, is an important mechanism by which gene expression is regulated. Removal of acetyl groups by histone deacetylase (HDAC) stabilizes the interaction between DNA and histones, repressing transcription. Inhibitors of HDAC re-acetylate histones, thereby reactivating transcription of dormant tumor-suppressor genes.

Two HDAC inhibitors (vorinostat [suberoylanilide hydroxamic acid, SAHA] and romidepsin [depsipeptide]) are approved in the United States for the treatment of cutaneous T-cell lymphoma. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Romidepsin'.)

Both drugs have been associated with transient ECG changes (including prolongation of the QTc interval (waveform 1) and ST segment and T wave changes) in some but not all studies [165-167]. Supraventricular and ventricular arrhythmias including nonsustained ventricular tachycardia are rare in patients receiving romidepsin, and evidence of acute or cumulative cardiac damage has not been seen [165].

Routine ECG monitoring is not recommended for either drug in the US prescribing information. However, both drugs should be used with caution in patients with significant heart disease, congenital long QT syndrome, and those who are receiving other drugs that prolong the QTc interval (table 1) or inhibit CYP3A4, which is the principal enzyme responsible for the metabolism of romidepsin and vorinostat (table 2) [168]. In addition, serum potassium and magnesium levels should be in the normal range before drug administration since hypokalemia and hypomagnesemia predispose to arrhythmias.

PREVENTION

In contrast to anthracycline and anthracycline-like agents, efforts at prevention with molecularly targeted agents are in their infancy. (See "Risk and prevention of anthracycline cardiotoxicity".)

There are several reasons for this:

●Molecularly targeted agents are generally newer drugs with less clinical experience with their toxicity or toxicity management than with anthracyclines. Furthermore, patients at the highest risk for developing such cardiac toxicity are often excluded from clinical trials evaluating efficacy and safety of mechanistically new anti-neoplastic agents. As a result, unexpected toxicities often become more evident in post-registry databases.

●Despite the critical need to increase our mechanistic understanding of physiologic and pathophysiologic cellular mechanisms in order to design rational "targeted" anticancer therapy, the clinical correlates of basic science discoveries are in most cases too vague or unexplained to provide information about expected side effects and how to prevent them with rational drug design. In most cases, we simply do not know if cardiovascular toxicity results from a direct effect of the drug on the intended molecular target, or if it represents an "off-target" effect [169].

●To further complicate the development of generally applicable therapeutic approaches, evidence suggests that cardiovascular toxicity may not only occur during the course of treatment and worsen with higher cumulative doses, but it may resolve despite continued treatment, or may develop years after therapy is completed in some patients. We are also just beginning to understand how genetic predisposition may affect an individual's risk and clinical pattern of cardiovascular toxicity. Additional fundamental, clinical, and epidemiologic research is required to resolve these questions around the use of each of the existing classes of anticancer drugs and those that will become available in the future.

Despite these limitations, some general principles apply for minimizing the development of cardiovascular toxicity across all classes of anticancer agents, including the molecularly targeted agents.

●In general, the risk of cardiovascular toxicity and the need for treatment gradually increase if patients do not receive primary and secondary prevention measures (figure 1) [169].

•Primary prevention to reduce cardiovascular risk may be achieved by measures "that rest on common sense" [102]. Management of pre-existing comorbidities (hypertension, systolic or diastolic cardiac dysfunction, arrhythmias, metabolic disorders) should reasonably be optimized and a healthy lifestyle encouraged (cessation of smoking, weight reduction towards ideal, increased exercise) both before and after cancer therapy is begun.

•There is evidence that administration of certain cardiac agents (eg, beta-blockers and angiotensin converting enzyme [ACE] inhibitors) to patients without cardiac risk factors may be beneficial. As an example, ACE inhibitors have been shown to improve outcomes and slow disease progression in patients with left ventricular systolic dysfunction due to a variety of causes. However, the role of ACE inhibitors in the treatment of patients with chemotherapy-induced cardiotoxicity is less clear. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity", section on 'Management of systolic dysfunction' and "Primary pharmacologic therapy for heart failure with reduced ejection fraction".)

A separate question relates to the potential protective effect of ACE inhibitors for preventing the development of left ventricular dysfunction in response to chemotherapy in patients who are at risk. Patients with elevations in serum cardiac troponin levels in response to chemotherapy may be at an increased risk for developing impaired left ventricular dysfunction.

The potential protective effect of ACE inhibitors in patients with elevated serum cardiac troponin following chemotherapy was evaluated in a randomized trial; the high-dose chemotherapy regimen included a variety of anthracycline-containing and non-anthracycline-containing agents [170]. From a total population of 473 cancer patients, 114 with an elevated troponin T were randomly assigned to one year of treatment with the ACE inhibitor enalapril (2.5 mg daily, titrated to a maximum of 20 mg daily), or to no enalapril. After one year, patients assigned to no treatment had a significant reduction in left ventricular ejection fraction (LVEF), while those in the ACE inhibitor group did not (LVEF at 12 months 48 versus 62 percent). In addition, the primary endpoint, an absolute reduction in LVEF of 10 percent or more, was reached in 43 percent of the untreated patients, but in none of the patients treated with enalapril.

Secondary prevention measures such as the use of ACE inhibitors require that patients be monitored during and after cancer therapy and managed when toxicity signals appear. Potentially useful biomarkers for cardiotoxicity include elevation in cardiac markers (brain natriuretic peptide [BNP] or troponin) and the development of systolic or diastolic dysfunction on tests such as echocardiography. Unfortunately, there are no universally applicable imaging modalities or markers to reliably predict the risk of developing post-treatment cardiovascular toxicity, and routine serial testing with these modalities cannot be recommended for all patients in the absence of clinical indications. (See "Risk and prevention of anthracycline cardiotoxicity", section on 'Preventive management of anthracycline therapy'.)

MONITORING DURING AND AFTER THERAPY — In contrast to anthracyclines and HER2-targeted treatments, there are few guidelines as to optimal monitoring for cardiovascular disease in patients receiving any of the potentially cardiotoxic agents discussed above [171-174]. In the absence of specific guidelines for cardiac monitoring for a potentially cardiotoxic agent, evaluation and monitoring of left ventricular ejection fraction (LVEF) or other biomarkers should be considered on a case-by-case basis. The toxicity profile, patient, and disease characteristics should be considered when making this decision. Typically, LVEF monitoring parameters recommended in the United States Prescribing Information for individual agents should be followed. Patients with underlying cardiovascular disease and those developing cardiovascular signs or symptoms during treatment may need more frequent follow-up testing, although guidelines have not specifically addressed this point.

An important point is that when treatment is palliative but potentially life prolonging, the benefits of therapy often outweigh the risks of LV dysfunction. In this situation, many clinicians evaluate for LV dysfunction only upon the development of symptoms. Conversely, when the goal of therapy is cure or long-term remission, a more aggressive schedule of monitoring for LV dysfunction may be advisable.

When starting an agent that may cause or worsen hypertension, serial blood pressure monitoring should be performed and maintained while on the particular drug. Proposed guidelines regarding intervention for treatment-related hypertension are provided in the table (table 6).

Monitoring may also be important for cancer survivors. Survivors tend to develop more comorbidities and reduce their overall levels of physical activity, which may cause subclinical cardiovascular toxicity to become manifest later in life (concept of "multiple hit hypothesis" for risk of cardiovascular disease [175]). Hence, it is not surprising that outcomes may be better when cancer survivors who have been treated with potentially cardiotoxic drugs are referred to centers with expertise in long-term surveillance and risk-based medical care [176]. (See "Cancer survivorship: Cardiovascular and respiratory issues" and "Treatment of alcohol use and smoking for cancer survivors".)

SUMMARY AND RECOMMENDATIONS

●Chemotherapy and cardiovascular complications

•Cancer patients receiving chemotherapy have an increased risk of developing cardiovascular complications, and the risk is even greater if there is a known history of cardiovascular disease.

•Anthracycline and anthracycline-like agents, agents that target the human epidermal growth factor receptor 2 (HER2), such as trastuzumab, and fluoropyrimidines are the most frequent anticancer agents associated with cardiac toxicity. Cardiotoxicity associated with these agents is discussed separately. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity" and "Cardiotoxicity of trastuzumab and other HER2-targeted agents" and "Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management".)

•However, many other agents, including conventional cytotoxic and molecularly targeted agents, have the potential to cause cardiotoxicity.

●Specific risks – Among the serious complications that have been reported with agents other than anthracyclines, HER2-targeted therapies, and fluoropyrimidines are:

•Arrhythmias (eg, histone deacetylase inhibitors, nilotinib, asciminib. ponatinib, vandetanib, crizotinib, vemurafenib, taxanes).

•Myocardial necrosis causing a dilated cardiomyopathy and clinical heart failure (eg, sunitinib and other multitargeted tyrosine kinase inhibitors [TKIs] that target the vascular endothelial growth factor [VEGF], alemtuzumab, imatinib, trametinib, taxanes [in combination with anthracyclines]).

•Prolongation of the correct QT (QTc) interval, which can occur with many agents, including eribulin, arsenic trioxide, crizotinib, osimertinib and mobocertinib, selpercatinib, vandetanib, BRAF inhibitors, histone deacetylase inhibitors, and TKIs that target BCR::ABL1.

•Pericarditis (eg, cytarabine, bleomycin).

•Pericardial effusions (eg, all-trans retinoic acid).

•Heart failure, myocardial ischemia, and cardiac arrest (proteasome inhibitors, antiangiogenic therapies, osimertinib and mobocertinib, interferon, interleukin-2 [IL-2], and asciminib).

•Arterial occlusive events (eg, ponatinib). (See 'Agents targeting BCR::ABL1' above.)

•Fluid retention, which may be manifest as a pericardial or pleural effusion (bosutinib, IL-2).

●Prevention and monitoring

•For all patients receiving potentially cardiotoxic therapies, primary prevention to reduce cardiovascular risk should be emphasized. Management of preexisting hypertension, systolic or diastolic cardiac dysfunction, arrhythmias, and metabolic/electrolyte disorders should be optimized and a healthy lifestyle encouraged (cessation of smoking, weight reduction towards ideal, increased exercise) prior to and during therapy. (See 'Prevention' above.)

When starting an agent that may cause or worsen hypertension (eg, antiangiogenic agents), serial blood pressure monitoring should be performed during therapy. Proposed guidelines for treatment-related hypertension are provided (table 6).

•In contrast to anthracyclines, there are no specific guidelines for cardiac monitoring during therapy with a potentially cardiotoxic agent. Evaluation and monitoring of left ventricular ejection fraction (LVEF) or other biomarkers should be considered on a case-by-case basis, taking into account the toxicity profile, patient, and disease characteristics. (See 'Monitoring during and after therapy' above.)

LVEF monitoring parameters recommended in the United States Prescribing Information for individual agents should be followed. Patients with underlying cardiovascular disease and those developing cardiovascular signs or symptoms during treatment may need more frequent follow-up testing.

When treatment is palliative but potentially life prolonging, and benefits of therapy outweigh the risks of LV dysfunction, LV dysfunction can be evaluated only upon the development of symptoms. When the goal of therapy is cure or long-term remission, a more aggressive schedule of monitoring for LV dysfunction may be advisable.