A 56-year-old woman had a history of hyperlipidemia, osteoarthritis, gastroesophageal reflux disease, and AML in complete remission. Her home medications were meloxicam and omeprazole; she was allergic to statins and penicillins. Her AML was treated with 7 + 3 induction chemotherapy with cytarabine and daunorubicin, followed by maintenance therapy with azacitidine—stopped ten months before this presentation. She presented to the emergency department with recurrent fevers to 102°F, generalized myalgias, fatigue, pharyngitis, and diffuse bruising. The examination was notable for oropharyngeal exudates, cervical lymphadenopathy, and generalized ecchymosis on all extremities. She was found to have new leukocytosis to 53 K/uL with 86% circulating blasts, acute anemia to 7 g/dL, and new thrombocytopenia to 18 K/uL, concerning for AML recurrence.
Empiric vancomycin and cefepime were started for febrile neutropenia. A broad immunocompromised infectious work-up initially was unremarkable for viral, bacterial, and fungal pathogens. Computed tomography of the chest revealed patchy nodular opacities in the mid to lower lungs with ground glass airspace disease. Eventually, a bronchoscopy was performed. The patient was diagnosed with Serratia marcescens pneumonia and antibiotics were deescalated to levofloxacin for a total antibiotic duration of 14 days.
With additional laboratory studies, she was diagnosed with recurrent AML. Mutational analysis of her peripheral blood revealed new FLT3 internal tandem duplications (FLT3-ITD), a therapeutic target for AML. Before initiating targeted therapy, a baseline cardiac work-up was completed. An electrocardiogram (ECG) was unremarkable (Fig. 1). Transthoracic echocardiogram (TTE) showed a normal left ventricular ejection fraction (LVEF) of 67% and global longitudinal strain of -24% (Fig. 2, Supplemental Movie 1 and 2). Cardiac biomarkers demonstrated a mildly elevated brain natriuretic peptide 195 pg/mL (normal < 100 pg/mL) and undetectable troponin I < 0.11 ng/mL.
The patient underwent cytoreductive therapy with hydroxyurea before transitioning to FLT3 targeted therapy with daily oral gilteritinib monotherapy. Following four doses of gilteritinib, she developed new shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, bilateral lower extremity edema, and 23-pound weight gain. The examination was notable for new jugular venous distension, mild rhonchi, diminished breath sounds at the bilateral lung bases, and 2 + bilateral pitting edema of her lower extremities. Labs were notable for a decreased/improved white blood cell count to 0.87 K/uL with now 20% blasts, hemoglobin to 6.7 g/dL, and platelets to 49 K/uL. Brain natriuretic peptide was elevated to 1,574 pg/mL and troponin I elevated to 0.36 ng/mL. Repeat chest radiography showed new cardiomegaly and worsening bilateral airspace disease compared to 5 days prior (Fig. 1). ECG was unchanged and did not reveal ischemic changes (Fig. 1). Repeat TTE ruled out pericardial effusion but demonstrated newly reduced LVEF to 35–40% from 67%, now with focal septal hypokinesis, new moderate to severe tricuspid regurgitation and elevation of right ventricular systolic pressure to 50 mm Hg (Fig. 2, Supplemental Movie 3 and 4).
Gilteritinib was promptly discontinued after a total of four doses due to concern for acute cardiotoxicity. The patient progressed to acute hypoxic respiratory failure requiring 8 liters of supplemental oxygen and was treated with intravenous diuresis. Ischemic work-up with cardiac catheterization was deemed too high risk due to her active AML with pancytopenia. Cardiac magnetic resonance imaging (MRI) obtained two days after discontinuation of gilteritinib revealed borderline biventricular function with interval improvement in LVEF to 51%. Late-gadolinium enhancement imaging revealed patchy midwall fibrosis involving the septal and lateral walls and elevated T2 signal in the inferoseptum (up to 70 ms; normal < 53 ms) suggestive of myocardial edema or inflammation, findings which were consistent with inflammatory cardiomyopathy (Fig. 3, Supplemental Movie 5). Endomyocardial biopsy was not performed due to the associated procedural risks in this patient with relapsed AML.
Given the timecourse of events with new heart failure developing within days of treatment initiation, improved hematologic disease, and lack of alternative explanations, gilteritinib associated acute systolic heart failure and inflammatory cardiomyopathy was considered the most probable etiology due to the timeline of symptoms. Gilteritinib was withheld, and the patient eventually started guideline-directed medical therapy for non-ischemic cardiomyopathy with metoprolol succinate, lisinopril, and spironolactone once euvolemic. The patient declined rechallenge with gilteritinib. She continued to follow up with the AML transplant team and cardio-oncology team. She received two cycles of azacitidine and venetoclax before achieving morphologic and molecular remission of AML confirmed by bone marrow biopsy. Interval TTE five months later showed improved left ventricular function to 50–55% with mild global hypokinesis and reduced global longitudinal strain at -17.6% (Supplemental Movie 6 and 7). Five months later, follow-up cardiac MRI showed recovered LV function with mild non-ischemic fibrosis and resolution of myocardial edema and inflammation on T2 mapping compared to prior (Fig. 3). Given this resolution of her myocarditis and AML remission, she received an allogeneic stem cell transplant from a matched unrelated donor.