(P 012) ACUTE CARDIAC CHANGES IN PEDIATRIC AND YOUNG ADULT SOLID TUMOR PATIENTS TREATED WITH TYROSINE KINASE INHIBITORS

Objective: Multi-targeted tyrosine kinase inhibitors (MTKIs) are increasingly used for the treatment of pediatric and young adult sarcomas, including in combination with cytotoxic and immune therapies. Cardiac toxicity of MTKI therapy has been described in adults; however, data from pediatrics and young adults is limited. We reviewed our institutional experience with the use of MTKIs in pediatric and young adult solid tumor patients to describe the incidence of cardiac dysfunction and outcomes for patients treated with these therapies.

Methods: We performed a retrospective chart review of patients with solid tumors who were treated at our institution with a MTKI from 2000 - 2021. Patients who did not have an echocardiogram within 60 days prior to starting to within 2 days after starting treatment were excluded. Basic demographic information, diagnosis details, type of MTKI, duration of treatment, and co-morbidities were reviewed. History of cardiotoxic agents, chest radiation, and cardiac dysfunction were obtained. An experienced cardiologist at our institution reviewed the echocardiograms obtained for patients on therapy and up to 6 months off therapy. Ejection fraction (EF), global longitudinal strain (GLS), left ventricular end systolic dimension (LVESd), and left ventricular end diastolic dimension (LVEDd) were quantified. Blood pressure at the time of echocardiogram was recorded. An abnormal ejection fraction was defined as being < 55%. An abnormal GLS was defined as ≥ -17%. Dose modifications were reviewed for the reason of modification. Any cardiac interventions while on therapy were described.

Results: One hundred unique patients were reviewed (43 female, 57 male). The average age was 15.4 years (range 1.7-26.3 years). Most patients had treatment with 2 or more prior therapies.; 63% had prior anthracycline exposure (median 375 mg/m2, range 70-525 mg/m2). Of patients with prior cardiac history available, 20.5% had a pre-existing cardiac condition with left ventricular dysfunction being the most common. Among 69 patients who had an echocardiogram available from two different timepoints, 69.6% developed a decrease in ejection fraction on therapy (change from baseline in those who declined: range –11 to -1%, average -6.4%). Excluding patients who did not have baseline data or who had an abnormal value at baseline, 27.9% (17/61) developed an abnormal ejection fraction on therapy, 9.3% (4/43) an abnormal LVESd, and 8.9% (4/45) an abnormal LVEDd. Among 32 patients who had data available for GLS, 21 (65.6%) developed an abnormal GLS while on therapy. The majority (59.4%) of patients developed elevation of blood pressure or had worsening of already elevated pressures while on therapy (9.8% elevated, 63.4% stage 1, 26.8% stage 2). Twenty-six patients had cardiac medications initiated while on therapy; 2 required a dose reduction due to cardiac dysfunction and another 2 for hypertension. An additional 26 patients had dose reductions for reasons other than cardiac dysfunction or hypertension, with the most common reason for reduction being skin toxicity. Most patients (15/17) who developed an abnormal EF had improvement or normalization of EF later in therapy or after discontinuation of MTKI.

Conclusion: While changes in cardiac function occurred in greater than two thirds of pediatric and young adult patients on MTKIs, discontinuation of therapy or dose reductions due to cardiac toxicity were uncommon. Most patients had improvement in function with medical intervention or discontinuation of MTKI. The high incidence of abnormal GLS likely reflects subclinical myocardial dysfunction; however, the lack of ventricular dilation, along with the significant possibility for functional improvement, points to cardiac energetic dysregulation as the mechanism as opposed to the cardiac myocyte damage seen with anthracyclines. Cardiac function should be monitored closely when using MTKIs. Early intervention in patients who develop changes may allow the patient to remain on therapy.