Atezolizumab/avadomide/doxorubicin

Abstract

Cardiotoxicity in the form of myocardial injury and myocarditis: 2 case reports In a case report involving 3 patients, a 73-year-old woman (case 1) and a 48-year-old woman were described, who developed cardiotoxicity in the form of myocardial injury and myocarditis, respectively, during treatment with atezolizumab, avadomide or doxorubicin for diffuse large B cell lymphoma or lung adenocarcinoma [routes, dosages and times to reactions onsets not stated]. Case 1: The 73-year-old woman developed cardiotoxicity in the form of myocardial injury during treatment with avadomide and doxorubicin for diffuse large B cell lymphoma: The woman, who had stage IVB diffuse large B-cell lymphoma, was scheduled to receive chemotherapy with six cycles of doxorubicin (anticipated cumulative dose 280 mg/m2), avadomide [CC-122; immune modulatory therapy] along with concomitant rituximab, cyclophosphamide, vincristine, prednisone and methotrexate. Prechemotherapy evaluation showed a left ventricular (LV) ejection fraction (LVEF), global longitudinal strain (GLS), N-terminal pro–Btype natriuretic peptide (NT-proBNP) levels of of 53%, -15.5% (normal), 864 pg/mL (elevated), respectively. Troponin I was undetectable, and transthoracic echocardiography (TTE) showed grade I diastolic dysfunction. Chest CT scan showed substantial coronary calcifications. Total cholesterol and low density lipoprotein were 250 mg/dL and 133 mg/dL, respectively (hyperlipidaemia). Thus, the hyperlipidaemia, her age, coronary calcification, underlying heart failure (HF) with preserved ejection fraction (HFpEF) along with anticipated high-dose of anthracyclines (>250 mg/m2) were considered as risk factors for cardiotoxicity. Therefore, she started receiving carvedilol, rosuvastatin and aspirin before chemotherapy, and these were continued during chemotherapy. Also, she started receiving furosemide for evidence of volume overload and HF. The planned chemotherapy was started. At 3 months, LVEF was unchanged; however, NT-proBNP was noted to have increased. Also, the troponin I was minimally elevated. These findings indicated congestion and potential injury, which prompted adjustment of carvedilol and furosemide dosing. On completion of 6 months of the chemotherapy, the LVEF had decreased to 45% and NT-proBNP was noted to have improved (795 pg/mL). However, the troponin I was found to be persistently elevated (0.22–0.25 ng/mL) on serial assessment. ECG was unchanged. She started receiving lisinopril to optimise cardiovascular (CV) therapy. She was suspected to have developed myocardial ischaemia, anthracycline-related cardiotoxicity or avadomide-related myocarditis (differential diagnoses). A subsequent cardiac MRI (cMRI) showed a mildly depressed LVEF (43%), with late gadolinium enhancement (LGE) in the right coronary artery territory. These findings suggested prior myocardial infarction. Subsequent left heart catheterisation revealed elevated LV enddiastolic pressure (18mm Hg) and mild, non-obstructive multi-vessel coronary artery disease. The combined findings of elevated troponin and LGE on cMRI consistent with myocardial injury were considered to be probably related to doxorubicin (anthracycline) chemotherapy. Also, avadomide was considered to have contributed the myocardial injury (cardiotoxicity). Twelve months following initiation of doxorubicin-based chemotherapy and with optimal cardioprotective therapy, the LVEF was normal (67%). However, the GLS had not normalised (-11.9%), and NT-proBNP had remained modestly elevated (440 pg/mL), while troponin was undetectable. The LVEF was fully recovered at 1-year post-chemotherapy. Case 2: The 48-year-old woman developed cardiotoxicity in the form of myocarditis during treatment with atezolizumab for lung adenocarcinoma: The woman, who had stage IV lung adenocarcinoma, had been treated over a 4-year period with right lower lobe wedge resection, followed by sequential carboplatin, pemetrexed and radiotherapy, to which a suboptimal response was noted. Therefore, treatment was switched to immunotherapy with atezolizumab. Approximately after 2 months, she developed oedema and dyspnoea. TTE revealed severe global hypokinesis, with abnormal LVEF and GLS. Right ventricular size and function was normal. Also, a small-to-moderate pericardial effusion, without tamponade physiology, was noted. Biomarker testing showed troponin I, NT-proBNP, high-sensitivity CRP (hsCRP) levels of 0.35 ng/mL, 3863 pg/mL and 55.2 mg/dL. An endomyocardial biopsy (EMBx) showed focal, mild cardiomyocyte damage along with mild lymphoplasmacytic inflammation, and these findings were consistent with myocarditis. It was noted that she developed atezolizumab (immunotherapy)-related cardiotoxicity in the form of myocarditis. Therefore, atezolizumab was permanently stopped, and she was then treated with methylprednisolone, followed by a slow taper of prednisone. Due to depressed LVEF, she started receiving carvedilol and sacubitril/valsartan. After 1 month, troponin I was undetectable. The hsCRP and NT-proBNP had decreased to 17.7 mg/dL and 574 pg/mL, respectively. A cMRI revealed a persistently reduced LVEF (21%), without any evidence of LGE. She continued to receive guideline-directed HF therapy, including spironolactone and prednisone, with resolution of the HF symptoms. At a 6-month follow-up TTE showed that the LVEF had increased to 37%, while the GLS had improved.