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Immune Checkpoint Inhibitor-Associated Myocarditis: A New Challenge for Cardiologists
Canadian Journal of Cardiology 34 (2018) 92.e1e92.e3 www.onlinecjc.ca
Case Report
Immune Checkpoint Inhibitor-Associated Myocarditis: A New Challenge for Cardiologists Mauro Frigeri, MD,a Philippe Meyer, MD,b Carlo Banfi, MD, PhD,c Raphaël Giraud, MD, PhD,d Anne-Lise Hachulla, MD,e David Spoerl, MD,f Alex Friedlaender, MD,a Angela Pugliesi-Rinaldi, MD,a and Pierre-Yves Dietrich, MDa a
Department of Oncology, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland b
c
d e f
Division of Cardiology, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
Division of Cardiovascular Surgery, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland Intensive Care Service, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
Department of Radiology, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
Division of Clinical Immunology and Allergology, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
ABSTRACT
RESUM E
The ever-increasing use of immune checkpoint inhibitors in cancer is leading to a high incidence of autoimmune side effects. This report discusses an autoimmune fulminant myocarditis in an elderly patient with metastatic pulmonary adenocarcinoma in whom the most advanced invasive heart failure therapies were used successfully. She was treated with nivolumab. This case illustrates a severe cardiovascular complication of immunotherapy and highlights to cardiologists the importance of aggressive treatments in patients with metastatic cancers whose prognosis has improved dramatically.
L’utilisation sans cesse croissante des inhibiteurs des points de contrôle immunitaire dans le cancer entraîne beaucoup d’effets seconsent rapport porte sur une daires de type auto-immun. Le pre e myocardite fulminante auto-immune chez une patiente âge sentant un ade nocarcinome pulmonaire me tastatique chez qui la pre plupart des traitements invasifs novateurs contre l’insuffisance carussi. Elle a e te traite e par nivolumab. Ce cas illustre une diaque ont re rapie et montre complication cardiovasculaire grave de l’immunothe nergiques chez les aux cardiologues l’importance des traitements e tastatiques dont le pronostic s’est patients ayant des cancers me rablement ame liore . conside
Immunotherapy with immune checkpoint inhibitors is increasingly used as a standard treatment for multiple cancers. Autoimmune myocarditis is a rare but dramatic side effect of this novel type of therapy. We present herein a patient who was successfully treated for a severe autoimmune myocarditis secondary to the immune checkpoint inhibitor nivolumab.
nivolumab, an immune checkpoint inhibitor (ICI), for recurrent metastatic pulmonary adenocarcinoma. Seven months earlier, her left ventricular ejection fraction (LVEF) was normal. At presentation, she exhibited signs of heart failure (HF), including bibasilar pulmonary rales and lower limb edema. N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin levels were elevated at 32,447 ng/L and 2674 ng/L, respectively. Transthoracic echocardiography revealed a normal-sized left ventricle with severely reduced LVEF, at 15%, and multiple apical thrombi. The patient rapidly experienced cardiogenic shock and was transferred to the intensive care unit, where her LVEF dropped to < 10% and her cardiac index was 1.3 L/min/m2 despite large doses of inotropic drugs. Venoarterial extracorporeal membrane oxygenation (ECMO) was instituted and an intra-aortic balloon pump (IABP) was inserted for inadequate LV decompression. Angiography ruled out coronary artery disease (Videos 1 ; view videos online). Viral antibody titers were and 2
Case Report A 76-year-old woman without a history of cardiovascular disease was admitted for rapidly progressive dyspnea. She was in complete remission after 7 biweekly administrations of the antieprogrammed cell death protein 1 (PD-1) antibody Received for publication March 6, 2017. Accepted September 26, 2017. Corresponding author: Dr Mauro Frigeri, Rue Gabrielle-Perret-Gentil 4 CH-1211 Genève 14, Switzerland. Tel.: þ41 79 553 24 08; fax: þ41 22 372 98 86. E-mail: [email protected] See page 92.e2 for disclosure information.
https://doi.org/10.1016/j.cjca.2017.09.025 0828-282X/Ó 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
92.e2
negative. Endomyocardial biopsy was not performed because of the shock-induced coagulopathy and anticoagulation required by ECMO. The most likely diagnosis was autoimmune myocarditis secondary to nivolumab, although other rare causes of acute HF, such as hypersensitivity myocarditis, could not be excluded. Methylprednisolone 5 mg/kg/d was started on day 4. Plasmapheresis was performed and immunoglobulin G 1 g/kg was administered. On day 6, the patient received infliximab 5 mg/kg with clinical and biological improvement (NT-proBNP level, 4849 ng/L; LVEF, 20%). ECMO, IABP, and inotropic support were weaned on days 12, 12, and 14, respectively. The patient was transferred to the ward on day 19. A second infusion of infliximab was administered on day 27 because of worsening HF, with increased NT-proBNP levels at 8869 ng/L. On day 25, cardiac magnetic resonance imaging revealed a diffuse delayed myocardial contrast enhancement compatible with an autoimmune myocarditis (Fig. 1), LVEF was 23%. A third infusion of infliximab was administered on day 39. Standard pharmacologic therapy for HF with reduced LVEF was initiated, and the patient was discharged on day 60. At 5 months, an internal cardioverterdefibrillator with cardiac resynchronization therapy was implanted because of sudden complete atrioventricular block, with the LVEF remaining at 30%. The further clinical course was uneventful.
Figure 1. (A-C) Delayed contrast-enhanced T1 images 10 minutes after injection of gadoterate meglumine show a diffuse and patchy subepicardial enhancement extending to the mesocardium and subendocardium (arrows), which is atypical for viral myocarditis or an infarct. Two apical thrombi are also seen (arrowheads in C). (D) T2weighted image shows a diffuse and patchy edema (arrows). T1 mapping reveals an increased relaxation time of 1231 ms and an extracellular volume of 49%.
Canadian Journal of Cardiology Volume 34 2018
Figure 2. CD8þ T cell recognizes the tumour antigen (asterisk) through its T-cell receptor (TCR). The tumour cell overexpresses programmed cell death protein ligand 1 (PD-L1) and inhibits the CD8þ T cell through programmed cell death protein 1 (PD-1) interaction, preventing its death. The antiePD-1 antibody blocks the PD-1/PD-L1 interaction, restoring the killing properties of CD8þ T cells. CD, cluster of differentiation; HLA, human leukocyte antigen.
Discussion Immunotherapy with ICIs is an effective emerging treatment. In the tumour microenvironment and draining lymph nodes, inhibitory checkpoint molecules, such as PD ligand 1, are overexpressed, keeping immune responses in check by preventing CD8þ T-cellemediated killing of cancer cells. ICIs are antibodies that inactivate inhibitory checkpoint molecules, thus reactivating cytotoxic CD8þ T cells (Fig. 2). Unfortunately, the benefits of ICIs can be offset by severe immune-related adverse events (irAEs). Occurring in 0.06% to 0.27% of patients,1 myocarditis is a rare but serious irAE that can result in refractory cardiogenic shock, chronic HF, and conduction disorders. The mechanism of this cardiotoxicity is likely related to the role of PD-1 in cardiomyocyte protection against autoimmune attacks, because PD-1edeficient mice develop dilated cardiomyopathy.2 As shown for other irAEs,3 rapid diagnosis appears critical to downsize the immune attack using steroid therapy. Use of other immunosuppressive agents, like those targeting tumour necrosis factor, may be required if symptoms do not promptly respond to steroids.4 Finally, shorter ICI therapies may be attempted to reduce irAEs without affecting patient outcomes compared with long-term administration.5 In conclusion, this case not only illustrates a severe cardiovascular complication of ICI but also shows that aggressive management should now be considered even for patients with metastatic cancers, because their survival has dramatically improved with novel therapies. Disclosures The authors have no conflicts of interest to disclose. References 1. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375: 1749-55.
Frigeri et al. A New Kind of Autoimmune Myocarditis 2. Tarrio ML, Grabie N, Bu DX, et al. PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J Immunol 2012;188:4876-84. 3. Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 2016;13:473-86. 4. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(suppl 4):iv119-42.
92.e3
5. Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 2017;35:785-92.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at https://doi.org/10. 1016/j.cjca.2017.09.025.
Case Report
Immune Checkpoint Inhibitor-Associated Myocarditis: A New Challenge for Cardiologists Mauro Frigeri, MD,a Philippe Meyer, MD,b Carlo Banfi, MD, PhD,c Raphaël Giraud, MD, PhD,d Anne-Lise Hachulla, MD,e David Spoerl, MD,f Alex Friedlaender, MD,a Angela Pugliesi-Rinaldi, MD,a and Pierre-Yves Dietrich, MDa a
Department of Oncology, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland b
c
d e f
Division of Cardiology, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
Division of Cardiovascular Surgery, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland Intensive Care Service, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
Department of Radiology, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
Division of Clinical Immunology and Allergology, Geneva University Hospitals and Medical Faculty, Geneva, Switzerland
ABSTRACT
RESUM E
The ever-increasing use of immune checkpoint inhibitors in cancer is leading to a high incidence of autoimmune side effects. This report discusses an autoimmune fulminant myocarditis in an elderly patient with metastatic pulmonary adenocarcinoma in whom the most advanced invasive heart failure therapies were used successfully. She was treated with nivolumab. This case illustrates a severe cardiovascular complication of immunotherapy and highlights to cardiologists the importance of aggressive treatments in patients with metastatic cancers whose prognosis has improved dramatically.
L’utilisation sans cesse croissante des inhibiteurs des points de contrôle immunitaire dans le cancer entraîne beaucoup d’effets seconsent rapport porte sur une daires de type auto-immun. Le pre e myocardite fulminante auto-immune chez une patiente âge sentant un ade nocarcinome pulmonaire me tastatique chez qui la pre plupart des traitements invasifs novateurs contre l’insuffisance carussi. Elle a e te traite e par nivolumab. Ce cas illustre une diaque ont re rapie et montre complication cardiovasculaire grave de l’immunothe nergiques chez les aux cardiologues l’importance des traitements e tastatiques dont le pronostic s’est patients ayant des cancers me rablement ame liore . conside
Immunotherapy with immune checkpoint inhibitors is increasingly used as a standard treatment for multiple cancers. Autoimmune myocarditis is a rare but dramatic side effect of this novel type of therapy. We present herein a patient who was successfully treated for a severe autoimmune myocarditis secondary to the immune checkpoint inhibitor nivolumab.
nivolumab, an immune checkpoint inhibitor (ICI), for recurrent metastatic pulmonary adenocarcinoma. Seven months earlier, her left ventricular ejection fraction (LVEF) was normal. At presentation, she exhibited signs of heart failure (HF), including bibasilar pulmonary rales and lower limb edema. N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin levels were elevated at 32,447 ng/L and 2674 ng/L, respectively. Transthoracic echocardiography revealed a normal-sized left ventricle with severely reduced LVEF, at 15%, and multiple apical thrombi. The patient rapidly experienced cardiogenic shock and was transferred to the intensive care unit, where her LVEF dropped to < 10% and her cardiac index was 1.3 L/min/m2 despite large doses of inotropic drugs. Venoarterial extracorporeal membrane oxygenation (ECMO) was instituted and an intra-aortic balloon pump (IABP) was inserted for inadequate LV decompression. Angiography ruled out coronary artery disease (Videos 1 ; view videos online). Viral antibody titers were and 2
Case Report A 76-year-old woman without a history of cardiovascular disease was admitted for rapidly progressive dyspnea. She was in complete remission after 7 biweekly administrations of the antieprogrammed cell death protein 1 (PD-1) antibody Received for publication March 6, 2017. Accepted September 26, 2017. Corresponding author: Dr Mauro Frigeri, Rue Gabrielle-Perret-Gentil 4 CH-1211 Genève 14, Switzerland. Tel.: þ41 79 553 24 08; fax: þ41 22 372 98 86. E-mail: [email protected] See page 92.e2 for disclosure information.
https://doi.org/10.1016/j.cjca.2017.09.025 0828-282X/Ó 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
92.e2
negative. Endomyocardial biopsy was not performed because of the shock-induced coagulopathy and anticoagulation required by ECMO. The most likely diagnosis was autoimmune myocarditis secondary to nivolumab, although other rare causes of acute HF, such as hypersensitivity myocarditis, could not be excluded. Methylprednisolone 5 mg/kg/d was started on day 4. Plasmapheresis was performed and immunoglobulin G 1 g/kg was administered. On day 6, the patient received infliximab 5 mg/kg with clinical and biological improvement (NT-proBNP level, 4849 ng/L; LVEF, 20%). ECMO, IABP, and inotropic support were weaned on days 12, 12, and 14, respectively. The patient was transferred to the ward on day 19. A second infusion of infliximab was administered on day 27 because of worsening HF, with increased NT-proBNP levels at 8869 ng/L. On day 25, cardiac magnetic resonance imaging revealed a diffuse delayed myocardial contrast enhancement compatible with an autoimmune myocarditis (Fig. 1), LVEF was 23%. A third infusion of infliximab was administered on day 39. Standard pharmacologic therapy for HF with reduced LVEF was initiated, and the patient was discharged on day 60. At 5 months, an internal cardioverterdefibrillator with cardiac resynchronization therapy was implanted because of sudden complete atrioventricular block, with the LVEF remaining at 30%. The further clinical course was uneventful.
Figure 1. (A-C) Delayed contrast-enhanced T1 images 10 minutes after injection of gadoterate meglumine show a diffuse and patchy subepicardial enhancement extending to the mesocardium and subendocardium (arrows), which is atypical for viral myocarditis or an infarct. Two apical thrombi are also seen (arrowheads in C). (D) T2weighted image shows a diffuse and patchy edema (arrows). T1 mapping reveals an increased relaxation time of 1231 ms and an extracellular volume of 49%.
Canadian Journal of Cardiology Volume 34 2018
Figure 2. CD8þ T cell recognizes the tumour antigen (asterisk) through its T-cell receptor (TCR). The tumour cell overexpresses programmed cell death protein ligand 1 (PD-L1) and inhibits the CD8þ T cell through programmed cell death protein 1 (PD-1) interaction, preventing its death. The antiePD-1 antibody blocks the PD-1/PD-L1 interaction, restoring the killing properties of CD8þ T cells. CD, cluster of differentiation; HLA, human leukocyte antigen.
Discussion Immunotherapy with ICIs is an effective emerging treatment. In the tumour microenvironment and draining lymph nodes, inhibitory checkpoint molecules, such as PD ligand 1, are overexpressed, keeping immune responses in check by preventing CD8þ T-cellemediated killing of cancer cells. ICIs are antibodies that inactivate inhibitory checkpoint molecules, thus reactivating cytotoxic CD8þ T cells (Fig. 2). Unfortunately, the benefits of ICIs can be offset by severe immune-related adverse events (irAEs). Occurring in 0.06% to 0.27% of patients,1 myocarditis is a rare but serious irAE that can result in refractory cardiogenic shock, chronic HF, and conduction disorders. The mechanism of this cardiotoxicity is likely related to the role of PD-1 in cardiomyocyte protection against autoimmune attacks, because PD-1edeficient mice develop dilated cardiomyopathy.2 As shown for other irAEs,3 rapid diagnosis appears critical to downsize the immune attack using steroid therapy. Use of other immunosuppressive agents, like those targeting tumour necrosis factor, may be required if symptoms do not promptly respond to steroids.4 Finally, shorter ICI therapies may be attempted to reduce irAEs without affecting patient outcomes compared with long-term administration.5 In conclusion, this case not only illustrates a severe cardiovascular complication of ICI but also shows that aggressive management should now be considered even for patients with metastatic cancers, because their survival has dramatically improved with novel therapies. Disclosures The authors have no conflicts of interest to disclose. References 1. Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375: 1749-55.
Frigeri et al. A New Kind of Autoimmune Myocarditis 2. Tarrio ML, Grabie N, Bu DX, et al. PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis. J Immunol 2012;188:4876-84. 3. Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 2016;13:473-86. 4. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(suppl 4):iv119-42.
92.e3
5. Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol 2017;35:785-92.
Supplementary Material To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at https://doi.org/10. 1016/j.cjca.2017.09.025.