Cardio-Oncology Corner

Cardiac arrhythmias: An emerging issue with anticancer drugs

There has been much focus in cardio-oncology on cardiomyopathic and vascular effects of oncology therapies. Less appreciated are arrhythmogenic sequalae of traditional and newer cancer drugs. Arrhythmias can occur with or without any underlying cardiomyopathy. Moreover, all types of arrhythmias are encountered.

Many pharmaceutical agents interact with cardiac ion channels, resulting in prolongation of the QT interval, which is associated with torsades de pointes. This has been the case for several oncologic drugs. Therefore, platforms have been instituted to assess QT prolongation during preclinical as well as in clinical development of each new therapy.

Joe-Elie Salem

Several new cancer drugs currently carry a black box warning for QT prolongation by the FDA: vandetanib (Caprelsa, Genzyme), nilotinib (Tasigna, Novartis), panobinostat (Farydak, Novartis) and arsenic trioxide (Trisenox, Cephalon). Vandetanib and nilotinib are kinase inhibitors and have been approved for medullary thyroid cancer and chronic myeloid leukemia, respectively. Panobinostat is a histone deacetylase inhibitor, used in combination with other therapies for multiple myeloma, whereas arsenic trioxide is used for leukemia treatment.

When a considerable QTc prolongation occurs with these drugs, it will be important to reassess the patient, possibly stopping and switching to alternative anticancer drugs. Avoiding use of other concomitant QT-prolonging drugs (antibiotics, antiemetics, morphine derivatives) and correcting for additive risk factors frequently present in patients with cancer such as hypokalemia, hypocalcemia and hypothyroidism might help prevent further QT prolongation and, potentially, torsades de pointes.

It is important to note that a number of other cancer therapies, especially kinase inhibitors, carry warning language in the FDA labeling and will need QT monitoring (see Table). For example, ribociclib (Kisqali, Novartis) is a recently approved kinase inhibitor (CDK4/6 inhibitor) for breast cancer. The FDA label recommends monitoring QT at baseline and during the first two cycles of therapy.

Sex hormones act as growth factors on nuclear receptors and can promote cancer of sex-specific organs such as prostate in men and breast or endometrium in women. Hormone-modulating therapies have been effective in these cancers. Sex hormones are also major determinants of ventricular repolarization. Testosterone in men shortens and estradiol in women prolongs ventricular repolarization. For this reason, anti-androgenic therapy, used in prostate cancer, has been associated with QT prolongation of 10 milliseconds to 20 milliseconds depending on the specific therapy used. QT prolongation, seen in early clinical trials for luteinizing hormone agonists (leuprolide, goserelin [Zoladex, AstraZeneca]) and antagonists (degarelix [Firmagon, Ferring]), have prompted FDA warnings for these therapies. Furthermore, toremifene (Fareston, Kyowa Kirin) is a selective estrogen receptor modulator used in breast cancer and carries an FDA black box warning for QT prolongation.

Novel cancer drugs can cause other types of arrhythmias. Ibrutinib (Imbruvica, Pharmacyclics/Janssen) is a Bruton’s tyrosine kinase inhibitor and is highly effective to treat chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom’s macroglobulinemia. Atrial fibrillation can occur in up to 20% of patients on ibrutinib. More recently, ventricular arrhythmia also has been reported with this drug. Currently, no data exist regarding best treatment strategies for ibrutinib-associated AF. Ibrutinib is also associated with increased bleeding risk, adding another level of complexity to anticoagulation decisions for patients who have AF.

Javid J. Moslehi

Immune checkpoint inhibitors harness the immune system to destroy cancer cells with several therapies having been approved for many cancer indications. Immune checkpoint inhibitors target several key immune inhibitory molecules, including programmed death 1 (PD-1 and its ligand PD-L1) immune checkpoints. Five such drugs have been approved (pembrolizumab [Keytruda, Merck], nivolumab [Opdivo, Bristol-Myers Squibb], avelumab [Bavencio, Pfizer], atezolizumab [Tecentriq, Genentech], durvalumab [Imfinzi, AstraZeneca]), with many more such drugs awaiting approval. Myocarditis has been reported in a small subset of patients treated with checkpoint inhibitors. Interestingly, a key clinical presentation of checkpoint inhibitor-associated myocarditis includes heart block and ventricular arrhythmias. For this reason, cardiologists should be aware that a patient developing new-onset arrhythmias or conduction blocks in a context of immune checkpoint inhibitors administration may have myocarditis. Because of the fulminant nature of this new clinical syndrome, patients should be diagnosed quickly and be referred to a tertiary care center.

Disclosures: Salem and Moslehi report no relevant financial disclosures.

There has been much focus in cardio-oncology on cardiomyopathic and vascular effects of oncology therapies. Less appreciated are arrhythmogenic sequalae of traditional and newer cancer drugs. Arrhythmias can occur with or without any underlying cardiomyopathy. Moreover, all types of arrhythmias are encountered.

Many pharmaceutical agents interact with cardiac ion channels, resulting in prolongation of the QT interval, which is associated with torsades de pointes. This has been the case for several oncologic drugs. Therefore, platforms have been instituted to assess QT prolongation during preclinical as well as in clinical development of each new therapy.

Joe-Elie Salem

Several new cancer drugs currently carry a black box warning for QT prolongation by the FDA: vandetanib (Caprelsa, Genzyme), nilotinib (Tasigna, Novartis), panobinostat (Farydak, Novartis) and arsenic trioxide (Trisenox, Cephalon). Vandetanib and nilotinib are kinase inhibitors and have been approved for medullary thyroid cancer and chronic myeloid leukemia, respectively. Panobinostat is a histone deacetylase inhibitor, used in combination with other therapies for multiple myeloma, whereas arsenic trioxide is used for leukemia treatment.

When a considerable QTc prolongation occurs with these drugs, it will be important to reassess the patient, possibly stopping and switching to alternative anticancer drugs. Avoiding use of other concomitant QT-prolonging drugs (antibiotics, antiemetics, morphine derivatives) and correcting for additive risk factors frequently present in patients with cancer such as hypokalemia, hypocalcemia and hypothyroidism might help prevent further QT prolongation and, potentially, torsades de pointes.

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It is important to note that a number of other cancer therapies, especially kinase inhibitors, carry warning language in the FDA labeling and will need QT monitoring (see Table). For example, ribociclib (Kisqali, Novartis) is a recently approved kinase inhibitor (CDK4/6 inhibitor) for breast cancer. The FDA label recommends monitoring QT at baseline and during the first two cycles of therapy.

Sex hormones act as growth factors on nuclear receptors and can promote cancer of sex-specific organs such as prostate in men and breast or endometrium in women. Hormone-modulating therapies have been effective in these cancers. Sex hormones are also major determinants of ventricular repolarization. Testosterone in men shortens and estradiol in women prolongs ventricular repolarization. For this reason, anti-androgenic therapy, used in prostate cancer, has been associated with QT prolongation of 10 milliseconds to 20 milliseconds depending on the specific therapy used. QT prolongation, seen in early clinical trials for luteinizing hormone agonists (leuprolide, goserelin [Zoladex, AstraZeneca]) and antagonists (degarelix [Firmagon, Ferring]), have prompted FDA warnings for these therapies. Furthermore, toremifene (Fareston, Kyowa Kirin) is a selective estrogen receptor modulator used in breast cancer and carries an FDA black box warning for QT prolongation.

Novel cancer drugs can cause other types of arrhythmias. Ibrutinib (Imbruvica, Pharmacyclics/Janssen) is a Bruton’s tyrosine kinase inhibitor and is highly effective to treat chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom’s macroglobulinemia. Atrial fibrillation can occur in up to 20% of patients on ibrutinib. More recently, ventricular arrhythmia also has been reported with this drug. Currently, no data exist regarding best treatment strategies for ibrutinib-associated AF. Ibrutinib is also associated with increased bleeding risk, adding another level of complexity to anticoagulation decisions for patients who have AF.

Javid J. Moslehi

Immune checkpoint inhibitors harness the immune system to destroy cancer cells with several therapies having been approved for many cancer indications. Immune checkpoint inhibitors target several key immune inhibitory molecules, including programmed death 1 (PD-1 and its ligand PD-L1) immune checkpoints. Five such drugs have been approved (pembrolizumab [Keytruda, Merck], nivolumab [Opdivo, Bristol-Myers Squibb], avelumab [Bavencio, Pfizer], atezolizumab [Tecentriq, Genentech], durvalumab [Imfinzi, AstraZeneca]), with many more such drugs awaiting approval. Myocarditis has been reported in a small subset of patients treated with checkpoint inhibitors. Interestingly, a key clinical presentation of checkpoint inhibitor-associated myocarditis includes heart block and ventricular arrhythmias. For this reason, cardiologists should be aware that a patient developing new-onset arrhythmias or conduction blocks in a context of immune checkpoint inhibitors administration may have myocarditis. Because of the fulminant nature of this new clinical syndrome, patients should be diagnosed quickly and be referred to a tertiary care center.

Disclosures: Salem and Moslehi report no relevant financial disclosures.