Multimodality Imaging of Acute Myocarditis in Cytokine Release Syndrome (CRS) Following CAR-T Therapy

Chimeric antigen receptor T-cell therapy is a novel immunotherapy with promising results for patients with advanced malignancies (1). Cytokine Release Syndrome is an adverse effect of this therapy, associated with multi-organ, including cardiovascular complications (1). We describe a case of CAR-T cell associated cardiotoxicity and the associated multimodality imaging findings. Chimeric antigen receptor T-cell therapy is a novel immunotherapy with promising results for patients with advanced malignancies (1). Cytokine Release Syndrome is an adverse effect of this therapy, associated with multi-organ, including cardiovascular complications (1). We describe a case of CAR-T cell associated cardiotoxicity and the associated multimodality imaging findings. A 74-year-old woman known for hypertension, hypothyroidism, psoriasis, fibromyalgia and internal jugular vein thrombosis was admitted for Chimeric antigen receptor T-cell (CAR-T) therapy due to relapsed/refractory diffuse large B-cell lymphoma (DLBCL), which was diagnosed 14 months ago, when she presented with flank pain and fatigue. Laboratory evaluation at that time was notable for anemia and thrombocytopenia. An initial abdominal CT scan revealed multiple enlarged, conglomerated intrabdominal lymph nodes. Subsequent 18F-fluorodeoxyglucose (FDG)–positron-emission tomography (PET) / CT showed diffusely enlarged, FDG-avid lymph nodes in the abdomen and thorax. A surgical lymph node biopsy confirmed the diagnosis of diffuse large B cell lymphoma. She received 5 courses of R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and prednisone) treatment, which was completed 7 months prior to her current admission with no significant complication. A follow up PET/CT scan done 5 months prior the current admission showed disease progression. A repeated biopsy from cervical lymph nodes confirmed a relapse of DLBCL (CD20 +, CD 10 -). A bone marrow biopsy showed no sign of lymphoma. Considering her refractory/relapsed DLBCL, the decision was made to administer CAR-T cell therapy. Her baseline cardiac workup done 6 months after having received 5 courses of R-CHOP, but prior to starting CAR-T cell therapy, demonstrated a normal left ventricular ejection fraction of 62% with no regional wall motion abnormality. Baseline inflammatory markers were elevated with a C-reactive protein (CRP) of 22.6 (0-5.00 mg/L) and a ferritin level of 707 (11.0-306.0 ug/L), reflecting a baseline inflammatory state. There were no clinical signs of infections nor other concurrent systemic processes, and the patient received 4 doses of COVID 19 vaccination, the 4th dose being 15 months prior to her CAR-T cell therapy, therefore her baseline inflammatory profile was attributed to her underlying malignancy. She underwent lympho-depletion with fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) for 3 days, starting 5 days prior to CAR-T cell infusion, and subsequently received an infusion of Yescarta (axicabtagene ciloleucel) CAR-T cells. Her baseline complete blood count prior to receiving CAR-T cell therapy were as follows: WBC: 500 (4500-11,0000), Hgb: 75g/L (120-160), Platelet 94,0000 (140,0000-450,0000). On day 1 post CAR-T cell infusion, she developed low grade cytokine release syndrome (CRS) according to American Society for Transplantation and Cellular Therapy Grading System for CRS (1Lee D.W. Santomasso B.D. Locke F.L. Ghobadi A. Turtle C.J. Brudno J.N. et al.ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells.Biology of Blood and Marrow Transplantation. 2019 Apr; 25: 625-638Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), characterized by fatigue, low grade fever (38.5 degree) and palpitations. She denied chest pain and shortness of breath. Resting ECG confirmed sinus tachycardia with a heart rate of 124 beats/min. On day 5 post CAR-T cell infusion, she continued to be febrile and showed signs of respiratory distress, had mild hypoxia and significant tachycardia up to 160 beats/min consistent with grade 2 CRS. Chest radiograph revealed pulmonary edema. Lab tests revealed mild anemia with a hemoglobin of 93g/L (120-160g/L), thrombocytopenia with a platelet count of 93 (140-450 10ˆ9/L), and a WBC count of 4.9 (4.5-11 10ˆ9/L), elevated CRP 113 mg/L (0-5.00 mg/L), ferritin 3473ug/L (11.0-306.0 ug/L), NT-proBNP 11259pg/mL (<125pg/mL), and Hs troponin I 2291ng/L (<12.0 ng/L) raising the suspicion of an inflammatory process with myocardial involvement. She received nasal oxygen and was empirically started on broad spectrum antimicrobial therapy once blood cultures were obtained. She received intravenous diuretic therapy and was transferred to the Intensive Care Unit for further monitoring. A transthoracic echocardiogram was done on ICU admission, which showed severely reduced left ventricular ejection fraction of 25-30%, an abnormal global peak longitudinal strain at -11.4%, and regional wall motion abnormalities most notable for akinesia of the mid inferoseptal segment, severe hypokinesia of the mid and apical inferior and anteroseptal segments, and mild-moderate hypokinesia of the other segments (Fig 1). CAR-T cell induced cardiotoxicity was suspected in view of temporal correlation of CAR-T cell therapy administration and clinical deterioration. There were no signs of systemic infection and lab work was not suggestive of tumor lysis syndrome. As per hospital guidelines for the management of CAR-T cell associated toxicity, she received immunosuppressive therapy with both tocilizumab (an anti IL-6 antibody) and corticosteroids, with subsequent clinical improvement with no signs or laboratory parameters to suggest cardiogenic shock and had down trending Hs troponin I levels from 2291ng/L to 38.8ng/L. She was weaned off supplemental oxygen with diuretics alone and did not require further escalation of therapy with inotropes. Given the high clinical suspicion for CAR-T-induced cardiotoxicity, on day+14 post CAR T therapy, Cardiac magnetic resonance imaging (CMR)(Fig 2) was performed to evaluate myocardial injury and revealed mild global hypokinesia, diffuse myocardial edema as elevated T2-values and increased myocardial signal intensity onT2-map and T2-weighted STIR images, nonischemic myocardial injury in form of diffusely prolonged T1-relaxtaion times on T1- map , subepicardial/mid-myocardial late enhancement involving mid to distal anterior/inferolateral segments adjacent to a tiny pocket of pericardial fluid on late gadolinium enhancement (LGE) images. LV systolic function was significantly improved compared to the last echocardiography (59% vs 25%). CAR-T therapy has emerged as a promising biologic therapy for refractory/relapse hematologic malignancy. Cytokine release syndrome (CRS) is the most common adverse event following CAR-T cell therapy, with an incidence rate of 85-93%. Among these cases, 0-46% manifest a severe or life-treating form(1Lee D.W. Santomasso B.D. Locke F.L. Ghobadi A. Turtle C.J. Brudno J.N. et al.ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells.Biology of Blood and Marrow Transplantation. 2019 Apr; 25: 625-638Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,2Ghosh A.K. Chen D.H. Guha A. Mackenzie S. Walker J.M. Roddie C. CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity?.JACC CardioOncol. 2020 Mar; 2: 97-109Crossref PubMed Google Scholar).Retrospective studies have shown that 10-20% of patients with high-grade CRS post CAR T-cell therapy (grade 3 and 4) experience cardiovascular complications, including cardiomyopathy, heart failure, new-onset arrhythmias, and myocardial infarction(2Ghosh A.K. Chen D.H. Guha A. Mackenzie S. Walker J.M. Roddie C. CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity?.JACC CardioOncol. 2020 Mar; 2: 97-109Crossref PubMed Google Scholar). Acute myocardial injury in the context of cytokine release syndrome (CRS) shares similarities with sepsis-related cardiomyopathy and is thought to be likely mediated by IL-6, a cytokine elevated during infectious and inflammatory processes(3Martin L. Derwall M. Al Zoubi S. Zechendorf E. Reuter D.A. Thiemermann C. et al.The Septic Heart: Current Understanding of Molecular Mechanisms and Clinical Implications.Chest. 2019 Feb; 155: 427-437Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). We acknowledge that CAR-T cell induced myocarditis might be a challenging diagnosis to make, in view of other potential confounders such as other cardiotoxic agents. In our case, our patient was 7 months post doxorubicin therapy with a normal transthoracic echo prior to initiating CAR-T cell therapy, making doxorubicin cardiotoxicity less likely. Cyclophosphamide cardiotoxicity was also considered in the differential diagnosis, as it was administered for 3 days, starting 5 days prior to CAR-T cell therapy. While there are a few case reports of cyclophosphamide induced cardiotoxicity, such cases typically have a poor prognosis due to the direct damage to endothelial capillaries, leading to the leakage of proteins and erythrocytes and the development of hemorrhagic pericarditis, interstitial hemorrhage, and coronary microthrombi. According to these studies, echocardiographic findings in cyclophosphamide-related cardiotoxicity have shown significant pericardial effusion and marked myocardial thickening (4Katayama M. Imai Y. Hashimoto H. Kurata M. Nagai K. Tamita K. et al.Fulminant fatal cardiotoxicity following cyclophosphamide therapy.J Cardiol. 2009 Oct; 54: 330-334Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) which our case did not illustrate. Additionally, the timing of symptoms is more consistent with cytokine release syndrome. Nonetheless, the potential for a synergistic cardiotoxic effect between cyclophosphamide and CAR-T cell therapy cannot be entirely ruled out without autopsy. Another potential cause for cardiomyopathy in our patient could be sepsis-related or septic cardiomyopathy. This condition is characterized by reversible myocardial dysfunction triggered by an immune response to an infection(3Martin L. Derwall M. Al Zoubi S. Zechendorf E. Reuter D.A. Thiemermann C. et al.The Septic Heart: Current Understanding of Molecular Mechanisms and Clinical Implications.Chest. 2019 Feb; 155: 427-437Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). While there is no standard definition for septic cardiomyopathy, It is generally described as cardiac dysfunction that is unrelated to ischemia with one or more of the following criteria (I) a temporary reduction in left ventricular ejection fraction to less than 50%,(II) left ventricular dilation under normal or low filling pressure; (III) right ventricular dysfunction and/or left ventricular dysfunction with a poor response to fluid infusion (3Martin L. Derwall M. Al Zoubi S. Zechendorf E. Reuter D.A. Thiemermann C. et al.The Septic Heart: Current Understanding of Molecular Mechanisms and Clinical Implications.Chest. 2019 Feb; 155: 427-437Abstract Full Text Full Text PDF PubMed Scopus (200) Google Scholar). Recent research by Muehlberg et al. has shown that myocardial edema using myocardial T2-mapping, is a common finding in patients with septic cardiomyopathy, similar to acute myocarditis(5Muehlberg F. Blaszczyk E. Will K. Wilczek S. Brederlau J. Schulz-Menger J. Characterization of critically ill patients with septic shock and sepsis-associated cardiomyopathy using cardiovascular MRI.ESC Heart Fail. 2022 Aug; 9: 2147-2156Crossref Scopus (5) Google Scholar). Their findings suggests that the reversibility of cardiac dysfunction and the lack of subepicardial fibrosis on Cardiac Magnetic Resonance (CMR) imaging can serve as distinguishing factors between septic cardiomyopathy and myocarditis. In our patient, the clinical improvement and the trend towards normalization of troponin levels with tocilizumab treatment, associated with the presence of non-ischemic myocardial late enhancement on LGE CMR sequences, are indicative of a pattern consistent with acute myocarditis induced by CAR-T Cell Therapy. Transthoracic echocardiogram is often one of the first line imaging modalities used to evaluate baseline cardiac function and serves as a useful tool to follow up cardiac function during the course of potentially cardiotoxic therapies. Worsening cardiomyopathy in the setting of cardiotoxic treatment has been described as a drop in LVEF of more than 10% from baseline to less than 50%(6Ganatra S. Redd R. Hayek S.S. Parikh R. Azam T. Yanik G.A. et al.Chimeric Antigen Receptor T-Cell Therapy–Associated Cardiomyopathy in Patients With Refractory or Relapsed Non-Hodgkin Lymphoma.Circulation. 2020 Oct 27; 142: 1687-1690Crossref PubMed Scopus (0) Google Scholar). Left ventricular global longitudinal strain (GLS) is emerging as an earlier method of detecting subclinical myocardial dysfunction. It has been particularly helpful in identifying individuals with an LVEF of 50-59% who develop subclinical LV dysfunction in the setting of cardiotoxic meds, described as a GLS more positive than -16%(7Liu J.E. Barac A. Thavendiranathan P. Scherrer -Crosbie Marielle Strain Imaging in Cardio-Oncology.JACC: CardioOncology. 2020 Dec; 2: 677-689Crossref Scopus (65) Google Scholar). Importantly, similar subclinical dysfunction can be present in the setting of chemotherapy induced myocarditis however current strain-based techniques are unable to differentiate one from the other. In consequence, if there is a clinical suspicion for myocarditis (including but not limited to: regional strain dysfunction in the basal inferior and inferolateral segments, markedly elevated troponin and elevated inflammatory markers), additional imaging with a CMR is often needed. Our patient demonstrated both of these findings on her echocardiogram – she had a >10% drop in LVEF from 62% to 25-30% and had an abnormal GLS of -11.4% in addition to elevated inflammatory markers and troponins. CMR has been established as the non-invasive gold standard for detecting myocardial injuries across a wide range of cardiotoxic causes. CMR assess both cardiac function and tissue characterization, including myocardial edema that is accompanied with acute myocardial injury. CMR can help identify evidence of active myocardial inflammation by using the parametric cardiac modalities, such as T1 and T2 mapping (2Ghosh A.K. Chen D.H. Guha A. Mackenzie S. Walker J.M. Roddie C. CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity?.JACC CardioOncol. 2020 Mar; 2: 97-109Crossref PubMed Google Scholar). In this patient, the CMR shows widespread myocardial edema, as well as combined subepicardial and mid-myocardial pattern of LGE with smooth enhancement of the pericardium, which may be secondary to the CRS. The previous case report utilized CMR to identify CAR-T cell associated myocardial damage in patients with cardiac lymphomatous involvement or pre-existing cardiomyopathy. The pattern and type of late myocardial enhancement was corresponding to the prior cardiac lymphomatous involvement, suggesting past scarring. However, our case describes MRI findings in a patient with no baseline cardiac abnormalities. CMR has been recommended to follow up patients with suspected cardiac involvement post CAR-T cell therapy, particularly those presenting with sustained sinus tachycardia, hypotension, elevated troponin, impaired left ventricular function (LV ejection fraction <50% or decreased >10%), right ventricular dysfunction, and arrhythmias(2Ghosh A.K. Chen D.H. Guha A. Mackenzie S. Walker J.M. Roddie C. CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity?.JACC CardioOncol. 2020 Mar; 2: 97-109Crossref PubMed Google Scholar) . In conclusion, we recommend the use of multimodality imaging with transthoracic echocardiogram and cardiac MRI during the initial evaluation and for subsequent monitoring of patients with suspected CAR-T cell therapy. •A diagnosis of CAR-T cell therapy mediated Cytokine Release Syndrome and associated Cardiotoxicity should be considered in individuals who develop clinical signs/symptoms of heart failure while receiving this potentially life saving therapy.•Multimodality imaging, with the use of transthoracic echocardiogram and cardiac MRI, is recommended for further evaluation when there are concerns of CAR-T cell mediated cardiotoxicity. Video 1: Parasternal long axis view (echocardiogram): Parasternal long axis view showing severe hypokinesia of the mid anteroseptal segment, moderate hypokinesia of the basal anteroseptal and mid inferolateral segments, and mild hypokinesia of the basal inferolateral segment. Video 2: Parasternal short axis view (echocardiogram): Parasternal short axis view showing akinetic mid inferoseptal segment, severely hypokinetic mid inferior and mid anteroseptal segments, moderately hypokinetic mid anterior and mid inferolateral segments, and mildly hypokinetic mid anterolateral segment. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJkYTBhNmQ5OTgzODQxNTdhMjFhODJlYmMwMjFlNWQzNiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNzEzNDQzNTYxfQ.PGK9Q8U8nCnJvp1UsQuyGcj3MtO8Bx6fQwoJsytLqfUTP3csld-9wsyDF05LqGykc-36FIa27kCw3_fE4Xav1NBSkYJeWt9hiPif9JpZn77ZcNpQC6_ZQNoUj2Ol-F9RBElIELyovJGSb6RhLueUyfe_3F8v_rU5dPs_BSRAyxdOt_SLp6jLog7Yya029MU_jAXxLy47-nv3nCCQfpNZhQtoExZ5GPzOsascq5vE9db6DX9RWQzsNXlSBtTngjYQuV0w8-c_D939Ss6ys9qZNJLUyr8jA1pFBUSs9-gsapo-n76oBUdsmBHg-VyubEKY03uBhMSjnBD6H2RS9s0T2Q Download .mp4 (0.29 MB) Help with .mp4 files eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiIyZTU1MmRlN2Q4ZTE3ODJlMTE4Njk5NmQyNjFjN2E4YSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNzEzNDQzNTYxfQ.pw0BUs2n-mFTldWAb6bH4f8eHGOjxguIePMn9vGkedDZSoxg4Agc0873yhftuJsDmVq4zO8fZEbPyPVrfxR6oHtf24VLqdVydvT6yVB0ua1od0zXVykmFMp8LtGpuzoQ2dYXLwHWOozoDB-T_1Hzqmg0Kip2yRhn_KiuSV-xoyPIwhN-HhvV7-YfHyvM3KrqDlLM0PqlAFlfh1eKwLVPOb5krdmvYaumWdbw9lfzvrKhTB9gXFejPoKsAaVzz6UxcSKjBtT1BbDfq4VBFf9HMEk974yxuSIMfrHl0j6wEVbKB3ON5ekLEfnN-U9iHe7jSXpxa6jjbllZ7xw_pZvdvQ Download .mp4 (0.31 MB) Help with .mp4 files

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