Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor–Associated Myocarditis

Thavendiranathan, Paaladinesh; Zhang, Lili; Zafar, Amna; Drobni, Zsófia; Mahmood, Syed; Cabral, Marcella; Awadalla, Magid; Nohria, Anju; Zlotoff, Daniel A.; Thuny, Franck; Heinzerling, Lucie; Barac, Ana; Sullivan, Ryan J.; Chen, Carol L.; Gupta, Dipti; Kirchberger, Michael C.; Hartmann, Sarah; Weinsaft, Jonathan W.; Gilman, Hannah; Rizvi, Muhammad A.; Kovacina, Bojan; Michel, Caroline; Sahni, Gagan; González‐Mansilla, Ana; Calles, Antonio; Fernández‐Avilés, Francisco; Mahmoudi, Michael; Reynolds, Kerry L.; Ganatra, Sarju; Gavira, Juán José; González, Nahikari Salterain; Castro, Manuel García de Yébenes; Kwong, Raymond Y.; Jerosch‐Herold, Michael; Coelho‐Filho, Otávio R.; Afilalo, Jonathan; Zataraín-Nicolás, Eduardo; Baksi, A John; Wintersperger, Bernd J.; Calvillo‐Argüelles, Oscar; Éderhy, Stéphane; Yang, Eric H.; Lyon, Alexander R.; Fradley, Michael G.; Neilan, Tomas G.

doi:10.1016/j.jacc.2021.01.050

Cited by 107 publications

(70 citation statements)

References 38 publications

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“…Increased T1 values alone were found in 78% of myocarditis cases and had an excellent discriminatory value for subsequent major cardiac events. 17 Myocardial tissue characterization therefore appears as a critical step in the assessment of ICI-related myocarditis: in a series of 35 patients with ICI-related myocarditis, 46% of the patients experienced MACE in the follow-up and the majority of them had normal left ventricle (LV) ejection fraction at admission, highlighting the fact that an initial normal LV function alone cannot exclude the progression toward major cardiac complications. 18 Molecular imaging could be a valuable addition when the diagnosis of ICI-related myocarditis remains possible but not definite myocarditis after a complete cardiac workup, as we previously reported in a patient with refractory, severe ICI-associated myocarditis.…”

Section: Introductionmentioning

confidence: 99%

⁶⁸Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis

Boughdad

Latifyan

Fenwick

et al. 2021

J Immunother Cancer

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BackgroundImmune checkpoint inhibitor (ICI)-related myocarditis is a rare but potentially fatal adverse event that can occur following ICI exposure. Early diagnosis and treatment are key to improve patient outcomes. Somatostatin receptor-based positron emission tomography–CT (PET/CT) showed promising results for the assessment of myocardial inflammation, yet information regarding its value for the diagnosis of ICI-related myocarditis, especially at the early stage, is limited. Thus, we investigated the value of 68Ga-DOTA(0)-Phe(1)-Tyr(3)-octreotide (68Ga-DOTATOC) PET/CT for the early detection and diagnosis of ICI-related myocarditis.MethodsConsecutive patients with clinically suspected ICI-related myocarditis from July 2018 to February 2021 were retrospectively evaluated in this single-center study. All patients underwent imaging for the detection of ICI-related myocarditis using either cardiac magnetic resonance (CMR) imaging or 68Ga-DOTATOC PET/CT. PET/CT images were acquired 90 min after the injection of 2 MBq/kg 68Ga-DOTATOC with pathological myocardial uptake in the left ventricle (LV) suggestive of myocarditis defined using a myocardium-to-background ratio of peak standard uptake value to mean intracavitary LV standard uptake (MBRpeak) value above 1.6. Patients had a full cardiological work-up including ECG, echocardiography, serum cardiac troponin I (cTnI), cardiac troponin T and creatine kinase (CK), CK-MB. Endomyocardial biopsy and inflammatory cytokine markers were also analyzed. The detection rate of ICI-related myocarditis using 68Ga-DOTATOC PET/CT and CMR was assessed.ResultsA total of 11 patients had clinically suspected ICI-related myocarditis; 9 underwent 68Ga -DOTATOC PET/CT. All nine (100%) patients with 68Ga-DOTATOC PET/CT presented with pathological myocardial uptake in the LV that was suggestive of myocarditis (MBRpeak of 3.2±0.8, range 2.2–4.4). Eight patients had CMR imaging and 3/8 (38%) patients had lesions evocative of myocarditis. All PET-positive patients were previously treated with a high dose of steroids and intravenous immunoglobulin prior to PET/CT had elevated serum cTnI except for one patient for whom PET/CT was delayed several days. Interestingly, in 5/6 (83%) patients who presented with concomitant myositis, pathological uptake was seen on whole-body 68Ga-DOTATOC PET/CT images in the skeletal muscles, suggesting an additional advantage of this method to assess the full extent of the disease. In contrast, four patients with CMR imaging had negative findings despite having elevated serum cTnI levels (range 20.5–5896.1 ng/mL), thus defining possible myocarditis. Newly identified immune correlates could provide specific biomarkers for the diagnosis of ICI-related myocarditis. Most tested patients (six of seven patients) had serum increases in the inflammatory cytokine interleukin (IL)-6 and in the chemokines CXCL9, CXCL10, and CXCL13, and the mass cytometry phenotypes of immune cell populations in the blood also showed correlations with myocardial inflammation. Four of five patients with myocarditis exhibited a Th1/Th2 imbalance favoring a pronounced inflammatory Th1, Th1/Th17, and Th17 CD4 memory T-cell response. The high proportion of non-classical monocytes and significantly reduced levels of CD31 in four to five patients was also consistent with an inflammatory disease.ConclusionThe use of 68Ga-DOTATOC PET/CT along with immune correlates is a highly sensitive method to detect ICI-related myocarditis especially in the early stage of myocardial inflammation, as patients with elevated cTnI may present normal CMR imaging results. 68Ga-DOTATOC PET/CT is also useful for detecting concomitant myositis. These results need to be confirmed in a larger population of patients and validated against a histological gold standard if available.

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Section: Introductionmentioning

confidence: 99%

⁶⁸Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis

Boughdad

Latifyan

Fenwick

et al. 2021

J Immunother Cancer

View full text Add to dashboard Cite

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“…Gold standard de nitive diagnosis with endomyocardial biopsy was deferred due to its associated procedural risks and low likelihood of altering management. Yet, given the increasing recognition of the potential induction of myocardial injury seen with several targeted or immunomodulatory therapies, cardiac MRI was promptly obtained [3]. Due to a lack of alternative explanations, acute systolic heart failure due to gilteritinib therapy was determined to be the most probable cause.…”

Section: Discussionmentioning

confidence: 99%

Acute Cardiotoxicity after Initiation of the Novel Tyrosine Kinase Inhibitor Gilteritinib for Acute Myeloid Leukemia

Kim

Fowler

Campbell

et al. 2021

Preprint

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Background: Gilteritinib is a novel FMS-like tyrosine kinase 3 inhibitor recently approved by the United States Food and Drug Administration in 2018 for relapsed or refractory acute myeloid leukemia. However, gilteritinib may be associated with underrecognized cardiotoxicities.Case Presentation: This case describes a patient with a history significant for hyperlipidemia who was diagnosed with relapsed acute myeloid leukemia. After four doses of gilteritinib monotherapy, she abruptly developed acute systolic heart failure with global hypokinesis and septal wall motion abnormalities. Two days after discontinuation, cardiac magnetic resonance imaging showed partial recovery of her left ventricular ejection fraction as well as myocardial edema and non-ischemic fibrosis suggestive of inflammatory cardiomyopathy. She underwent intravenous diuresis and eventually started guideline-directed heart failure therapy. Follow-up cardiac magnetic resonance imaging five months later showed improved ejection fraction with mild non-ischemic fibrosis and resolution of myocardial edema and inflammation. She later received an allogeneic stem cell transplant from a matched unrelated donor. Conclusions: Gilteritinib may be associated with early cardiotoxicities, including non-ischemic cardiomyopathy and myocarditis. Cardiac magnetic resonance imaging can be an important modality to help differentiate or diagnose early cardiotoxicities associated with novel targeted therapies.

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“…8,9) The use of CMR also provides a significant value for the diagnosis of immune checkpoint inhibitorsrelated myocarditis, although the absence of LGE or abnormal native T1 or T2 values in patients with a clinical suspicion cannot exclude the diagnosis of myocarditis. [18][19][20] Echocardiography continues to be the primary imaging modality, but its performance for the detection of subclinical CTRCD is inferior to that of CMR. 21) The choice of imaging modality in clinical practice is generally determined on the basis of availability and cost.…”

Section: Discussionmentioning

confidence: 99%

Detection of Profound Myocardial Damage by Cardiac MRI in a Patient with Severe Cardiotoxicity Induced by Anti-HER2 Therapy

et al. 2021

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Anti-HER2 therapy has greatly improved the long-term prognosis of patients with HER2-positive breast cancer. Meanwhile, by interfering with the protective effects of neuregulin-1/HER2 signaling on stressed cardiomyocytes, anti-HER2 therapy occasionally induces reversible cancer therapeutics-related cardiac dysfunction (CTRCD). Cardiac magnetic resonance (CMR) parametric mapping or myocardial feature-tracking, in combination with late gadolinium enhancement (LGE) imaging, has the potential to detect changes in the myocardium in anti-HER2 therapy-related cardiac dysfunction. Here we report a breast cancer patient who experienced lifethreatening CTRCD after treatment with trastuzumab plus pertuzumab. This case showed multiple transmural LGE-positive myocardial lesions in CMR imaging and high native T1 and T2 values in CMR parametric mapping, which was apparently more extensive than those observed in most patients with anti-HER2 therapy-related cardiac dysfunction. Consistent with profound myocardial damage indicated by CMR, her cardiac function was not fully restored despite intensive care and cardioprotective drug therapy. These findings suggest the potential usefulness of LGE imaging and parametric mapping by CMR for the assessment of myocardial injury to determine the clinical severity of anti-HER2 therapy-related cardiac dysfunction.

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Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor–Associated Myocarditis

Cited by 107 publications

References 38 publications

⁶⁸Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis

⁶⁸Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis

Acute Cardiotoxicity after Initiation of the Novel Tyrosine Kinase Inhibitor Gilteritinib for Acute Myeloid Leukemia

Detection of Profound Myocardial Damage by Cardiac MRI in a Patient with Severe Cardiotoxicity Induced by Anti-HER2 Therapy

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Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor–Associated Myocarditis

Cited by 107 publications

References 38 publications

68Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis

68Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis

Acute Cardiotoxicity after Initiation of the Novel Tyrosine Kinase Inhibitor Gilteritinib for Acute Myeloid Leukemia

Detection of Profound Myocardial Damage by Cardiac MRI in a Patient with Severe Cardiotoxicity Induced by Anti-HER2 Therapy

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⁶⁸Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis

⁶⁸Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis