Abstract 4134417: Cardiotoxicity Conundrum: Distinguishing Immune Checkpoint Inhibitor Myocarditis from Fluorouracil Cardiotoxicity in Concurrent Therapy

Case Description: The patient is a 37-year-old male with metastatic gastroesophageal junction adenocarcinoma presenting with chest pain and dyspnea two days after initiation of leucovorin, fluorouracil, oxaliplatin (FOLFOX), and nivolumab therapy. He was tachycardic and hypotensive with elevated cardiac biomarkers and globally reduced left ventricular systolic function. Suspecting immune checkpoint inhibitor (ICI) myocarditis versus fluorouracil (5-FU) cardiotoxicity, he was treated simultaneously for both. After starting high-dose steroids and before uridine triacetate, he had improved symptoms, cardiac function, biomarkers, and invasive hemodynamics. Though his endomyocardial biopsy did not show inflammatory cell infiltrates, his CMR demonstrated increased T1 and T2 relaxation times consistent with myocarditis. Testing revealed normal dihydropyrimidine dehydrogenase (DPD) activity. He completed uridine triacetate and was discharged on a steroid taper. At follow-up, he remained clinically stable, tolerating oxaliplatin and docetaxel (FLOT) initiation and nivolumab rechallenge without 5-FU. Discussion: This case is challenging as the presentation does not conclusively identify a causative agent. The patient’s symptom severity suggests ICI myocarditis, while the early onset points to 5-FU cardiotoxicity. His quick recovery of cardiac function after medication cessation suggests 5-FU-associated Takotsubo cardiomyopathy. His improvement after steroids raises concern for an adverse immunologic response as in ICI myocarditis or idiosyncratic reactions to oxaliplatin with 5-FU. This patient received ICI therapy and chemotherapy, increasing his risk for cardiac immune-related adverse events. His protracted 5-FU infusion increased his risk for 5-FU cardiotoxicity, but his normal DPD activity mitigates this risk. Although his biopsy was negative, it cannot exclude ICI myocarditis. By the IC-OS 2021 consensus, he meets the criteria for ICI myocarditis presenting 48 hours after nivolumab exposure with cardiogenic shock, elevated cardiac biomarkers, decline in cardiac function, and CMR with elevated T1 and T2 relaxation times. Yet, his biomarkers remained normal with nivolumab rechallenge, arguing against ICI myocarditis and suggesting 5-FU as the culprit. Early recognition and differentiation of the culprit in concurrent therapies impact management and future treatment options. Rechallenge carries risk and requires interdisciplinary collaboration to ensure patient safety.