NOVEL IMMUNOTHERAPIES (CAR-T, BiTE)

Background and Treatment

Mrs. JB is a 48-year-old Caucasian female. She was initially diagnosed with metastatic melanoma in 2014, with involvement of the anal skin. She underwent surgical resection along with radiation therapy to the tumor bed. She experienced relapsed disease in 2016, and received neoadjuvant chemotherapy including cisplatin, vinblastine, and dacarbazine.

On 1/27/2017, Mrs. JB underwent surgery including robotic-assisted lower anterior resection with diverting ileostomy, with a subsequent ileostomy reversal performed in 4/2017. Next, she underwent radiofrequency ablation treatment on 7/23/2018. She then proceeded with immunotherapy including ipilimumab and nivolumab x 4 cycles from 7/2018 through 10/2018. She also underwent radioembolizations in 2/2019. Mrs. JB received nab-paclitaxel therapy x 4 cycles from 2/2019 through 4/2019. Next, she received pembrolizumab from 8/2019 through 10/2019. 

Mrs. JB was noted to have progression of disease and was enrolled in a clinical trial, where she received NKTR-262 including bempegaldesleukin plus nivolumab. She then proceeded with additional radiation therapy including a total of 560 cGy from 12/7/2020 through 12/10/2020. Next, she was admitted for additional cancer therapy including CARTOX MAGE-A4c1032T. Mrs. JB’s hospital course was complicated by cytokine release syndrome (CRS), for which she was treated with tocilizumab. She experienced multiple organ complications, including a unilateral lower extremity macular rash, lobar pneumonia, hypotension, adrenal insufficiency, and elevated cardiac troponin T with the following trend: peak 421, 328, 373, 380, with eventual downward trend to 133. She was also noted to have an abnormal EKG with diffuse T-wave inversions noted.

A cardiology consultation was obtained, and a recommendation was made to proceed with a RHC/LHC with endomyocardial biopsy. The endomyocardial pathology showed biopsy-proven myocarditis. All of Mrs. JB’s complications were thought to be directly secondary to CAR-T therapy.

See below for results from Mrs. JB’s diagnostic studies.

Discussion

Cardiovascular toxicity related to CAR-T therapy is considered rare; however, when it is encountered, it can have dangerous consequences. Specifically, these patients can experience cardiac dysfunction that is secondary to the CRS, and CRS progresses rapidly. Up to 10% of patients receiving CAR-T can experience cardiomyopathy in the context of CRS. There can be associated vascular leakage with peripheral and pulmonary edema, and cancer patients can experience multi-organ failure.

As emphasized in previous discussions, it is imperative to review the cardiovascular risk profile for each individual patient (see Table 1). Patients with multiple cardiovascular risks portend increased risk for cardiovascular sequelae when subjected to CAR-T cell therapy that induces CRS. As these complications are potentially lethal, aggressive cardiovascular workup and management is warranted. Be mindful of these important tips as outlined by the (ACC) American College of Cardiology noted in December 2020.

Key Points

• Cytokine release syndrome (CRS)-related major adverse cardiac events include arrhythmias, cardiomyopathy, heart failure, and death.
• Myocardial injury as evident by troponin elevation is common and associated with subsequent adverse cardiovascular (CV) events.
• Signs and symptoms of high-grade CRS should trigger further cardiac evaluation with electrocardiogram, troponin, brain natriuretic peptide, and echocardiogram.
• Early administration of tocilizumab after the onset of CRS may be associated with lower rate of CV events.

Mrs. JB’s Diagnostic Studies

EKG
From 12/24/2020:
Sinus tachycardia with rate 103, diffuse TWI, low voltage noted, QTcF 414 ms.

ECHOCARDIOGRAM
From 12/21/2020:
Normal left ventricular size and systolic function.
LV ejection fraction (LVEF) is in the range of 60% (calculated by method of discs).
The right ventricle is grossly normal size.
The right ventricular systolic function is normal.
Small pericardial effusion.
Left Ventricle:
Normal left ventricular size and systolic function. Microbubble enhanced LVEF using the bi-plane method of disks method is 60% to 65% .LVEF is in the range of 60% (calculated by method of discs). No regional wall motion abnormalities noted.

LEFT/RIGHT CARDIAC CATH WITH ENDOMYOCARDIAL BIOPSY
From 12/22/2020:
Due to thrombocytopenia, additional time was required for obtaining access and
catheter exchanges that has increased the complexity of our procedure.
Minimal coronary artery disease.
Normal coronary angiography; there was no evidence of significant coronary artery disease.
No aortic valve stenosis.
The left ventricular ejection fraction was > 65%.
Right atrium mean pressure: 6.
Pulmonary wedge mean pressure: 3.
Appropriate Use Criteria for Right and Left Heart Cath (AUC Indication 93/Appropriate)
Cardiomyopathies / Known or suspected cardiomyopathy with or without heart failure.

CARDIAC MRI
From 12/22/2020:

Cardiac chambers: Normal.

Myocardium:
Thickness: Normal.
Perfusion: Normal.
Edema: While DIR sequence is degraded by motion, there are questionable areas of increased signal concerning for edema.
Delayed enhancement: Questionable subtle area of enhancement mid inferior wall, series 2300 image 8. Native T2 levels in the septal and lateral walls borderline 50-60, increased inferior wall 100.

LV wall motion: No areas of hypokinesis, dyskinesis, or akinesis are identified. Left ventricular function grossly normal.

Valves:
Aortic valve: Normal.
Mitral valve: Normal.
Pulmonic valve: Normal.
Tricuspid valve: Normal.

Large vessels:
Aorta: 27 mm.
Pulmonary trunk:  26 mm.

Pericardium: Small to moderate pericardial effusion, increased.

Extracardiac:
Trace left and moderate right pleural effusions, stable on the left, increased on the right. Consolidative changes in the right lung and adenopathy better demonstrated CT. Left chest wall port present. Subcutaneous nodular density right chest wall measuring 20 mm series 5 image 20, similar to CT.

ENDOMYOCARDIAL PATHOLOGY REPORT
From 12/22/2020:
Diagnosis:
Myocardium, RV:
 - Focal areas of interstitial inflammation with associated cardiomyocyte damage.
 - Focal perivascular fibrosis and interstitial edema. 

Resources

Afzal, A., Farooque, U., Gillies, E., & Hassell, L. (2020). T-cell therapy-mediated myocarditis secondary to cytokine release syndrome. Cureus, 12, e10022. https://doi.org/10.7759/cureus.10022

Ganatra, S., Redd, R., Hayek, S. S., Parikh, R., Azam, T., Yanik, G. A.,…Nohria, A. (2020). Chimeric antigen receptor T-cell therapy–associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma. Circulation, 142, 1687–1690. https://doi.org/10.1161/CIRCULATIONAHA.120.048100

Mahmood, S. S., & Liu, J. E. (2020). CV complications of CAR T-cell therapy. American College of Cardiology. Expert Analysis.