Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy

Heinzerling, Lucie; Ott, Patrick A.; Hodi, F. Stephen; Husain, Aliya N.; Tajmir-Riahi, Azadeh; Tawbi, Hussein; Pauschinger, Matthias; Gajewski, Thomas F.; Lipson, Evan J.; Luke, Jason J.

doi:10.1186/s40425-016-0152-y

Tab. 1 Patients’ characteristics, overview of cardiologic side effects and outcome

From: Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy

Pat-ID	Age (y)	Gender (m/f)	Type of pathology (cardiomyopathy, heart block, etc.)	Occured in week xxx after initiation of checkpoint inhibitor therapy	Signs and symptoms	Treatment of side effect	Outcome of side effect (resolved/permanent changes/other)	Other immune-related AEs	Ipilimumab (number of doses and dosage)	Nivolumab or Pembrolizumab (number of doses and dosage)	Clinical response (CR, PR, MR, SD, PD)	Survival in months from time of distant metastases
1	72	M	myocarditis and cardiomyopathy	week 22	Clinical findings: edema, ascites, pleural effusion, dyspnea	diuresis, steroids (1 mg/kg), life vest	good regression of symptoms under steroid therapy; slight permanent decrease in EF	thyroiditis, hypophysitis	Ipilimumab 3 mg/kg x 4	Nivolumab 1 mg/kg x 4 followed by 3 mg/kg x 6	PR	22
					ECHO: EF from 50 % down to 15 % und up again to 40 %; dilatation of heart
					Stress MRI: DCM, EF 15-23 %, no signs for ischemia
					Cardiac catheterization: no signs for ischemia
					Endomyocardial biopsy: interstitial inflammation mainly with lymphocytes and interstitial fibrosis
2	68	M	cardiomyophathy	week 12	Clinical findings: dyspnea, edema	diuresis	resolved	none	Ipilimumab 3 mg/kg x 4	no	PD	40+
					Echo: decrease of EF to 46 %; mild LV dysfunction; increased pulmonary pressures with moderate tricuspid regurgitation
					Endomyocardial biopsy: Myocyte hypertrophy, interstitial and perivascular fibrosis, mild focal subendocardial myocyte vacuolization. Focal fibrous endocardial thickening.
					Transmission electron microscopy: mild perinuclear accumulation of lysosomes, consistent with lipofuscin pigment deposition; increase of cytoplasmic glycogen and the number of mitochondria, without anomalous forms.
					Cardiac catheterization: no evidence of coronary artery disease, however, measurements of his right heart pressures suggested an RA pressure of 16, RV pressure of 67/10, wedge of 23 and PA pressures of 68/39
3	61	M	myocardial fibrosis	week 4	Clinical findings: no cardiologic symptoms	steroids (2 mg/kg), intensive care unit	fatal; massive autoimmune side effects could not be overcome	autoimmune hepatitis	Ipilimumab 3 mg/kg x 2	no	died of side effects	3
3	61	M	myocardial fibrosis	week 4	Endomyocardial biopsy: myocardial fibrosis identified at autopsy	steroids (2 mg/kg), intensive care unit		autoimmune hepatitis	Ipilimumab 3 mg/kg x 2	no	died of side effects	3
4	81	M	heart failure	week 22	Clinical findings: dyspnea	diuresis	permanent decrease in EF	colitis, hypophysitis	Ipilimumab 3 mg/kg x 3	no	PR	22+
4	81	M	heart failure	week 22	ECHO: moderately-to-severely reduced left ventricular EF at 35 %; mildly dilated left ventricle; global hypokinesis with regional variation; akinetic basal inferior and inferoseptal segments	diuresis	permanent decrease in EF	colitis, hypophysitis	Ipilimumab 3 mg/kg x 3	no	PR	22+
5	23	M	myocarditis/CHF	week 31	Clinical findings: cardiogenic shock requiring dopamine and dobutamine gtt	High dose steroids 2 mg/kg methylprednisolone per day converted to 80 mg prednisone/d with taper over 1 month, ACEi and beta blocker	resolved to baseline (NYHA C1)	uveitis	Ipilimumab 3 mg/kg x 4	no	SD	31
					Endomyocardial biopsy: T cell infiltration without eosinophilia
					ECHO: drop of EF to 20 %
					Cardiac MRI: left ventricular dilation and moderate LV systolic dysfunction (LVEF 34 %); right ventricular dilation and moderate RV systolic dysfunction (RVEF 33 %); increased T2 signal in the mid-inferolateral wall, suggestive of underlying myocardial edema supportive of myocarditis.
6	64	M	myocarditis	week 5	Clinical findings: fatigue, seizures, abdominal pain	dopamine and fentanyl	fatal	none	Ipilimumab 10 mg/kg x 2	no	NA	died of side effects
					Cardiac catheterization and electrocardiogram: normal
					evidence of myocarditis and LV hypertrophy upon autopsy
7	88	M	cardiac arrest	week 20	Clinical findings: collapse with cardiac arrest during shopping without any prodromi	AED with defibrillation, intensice care unit, catecholamines, steroids (125 mg i.v./d)	resolved	none	no	Pembrolizumab 2 mg/kg x 9	PR	8+
					ECHO: akinesis of the apex
					Cardiac catheterization and electrocardiogram: coronary artery disease with no culprit stenosis, reduced LV function; similar to taktsubo cardiomyopathy
8	80	M	myocarditis	week 5	Clinical findings: dyspnea, edema, arrhythmias	steroids (10 mg dexamethasone + 4 mg every 4 h), intensive care unit	fatal	autoimmune hepatitis	Ipilimumab 3 mg/kg x 2	no	PR	died of side effects
					EKG: atrial fibrillation, right bundle-branch block
					Nuclear stress test: no stress-induced ischemia
					ECHO: drop of EF to 31 %, hypokinesis
					Endomyocardial biopsy: Multinucleated giant cells, lymphocytes, eosinophils

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