Cardiac Function in Children and Young Adults Treated with MEK Inhibitors: A Retrospective Cohort Study

Abstract

MEK inhibitors (MEKi) have shown efficacy in pediatric low-grade glioma as well as plexiform neurofibroma. MEKi have been associated with acute cardiac dysfunction in adults. Cardiac consequences in children are unknown. We performed a single center retrospective cohort study evaluating cardiac function by echocardiography (echo) in children and young adults < 21 years receiving MEKi between October 2013 and May 2018. Blinded assessment of left ventricular function by fractional shortening (FS) and ejection fraction (EF) was performed on all available echocardiograms performed before, during, and following therapy, as well as after re-initiation of therapy. Twenty-six patients underwent MEKi therapy with echo follow-up during the study period. Twenty-four of these had complete echo data. Median follow-up was 12 months. Borderline EF (EF 53-57.9%) occurred in 12 (50%) patients; and 3 (12.5%) progressed to abnormal EF (EF < 53%). Cardiac dysfunction, when it occurred, was mild (lowest documented EF was 45%, and lowest FS was 24.4%). EF abnormalities typically fluctuated during therapy, resolved off therapy, and recurred with MEKi re-initiation. No clinical or demographic differences were detected between those who maintained normal cardiac function and those who developed borderline or overt cardiac dysfunction. Symptomatic heart failure did not occur. In this cohort of children and young adults, MEKi use was associated with a high (50%) incidence of borderline or mildly decreased left ventricular function. There was no evidence of permanent cardiac dysfunction. Further evaluation in larger prospective trials is needed.

Keywords: Echocardiography; Low-grade glioma; MEK inhibitor; Pediatrics; Ventricular dysfunction.

Fig. 1. Case examples of patients with borderline or decreased cardiac function.

(a) A 19-year-old female with tectal glioma, undergoing treatment with a single agent MEK inhibitor, experienced asymptomatic decrease in left ventricular function during the first 7 months of treatment. This resolved without dose interruption or modification. Decreased left ventricular function reoccurred two and a half years later; lisinopril was prescribed. (b) A 12-year-old male with BRAF V600E-mutated anaplastic astroblastoma, treated with dual agent MEK and BRAF inhibitors, experienced asymptomatic decrease in left ventricular shortening fraction after one month of therapy. MEKi treatment was interrupted and then resumed at the same dose. BRAF inhibitor was continued without interruption. Grey dotted and dashed lines represent lower limits of normal and lower limits of borderline values, respectively, for both EF and FS. M, MEK inhibitor therapy. EF, left ventricular ejection fraction. FS, left ventricular fractional shortening

Fig. 2. Freedom from borderline and overt cardiac dysfunction.

(a) Kaplan-Meier estimate of freedom from borderline cardiac function at 2 years from MEKi initiation was 38.2% (95% confident interval [CI] 12.9–63.7%) for EF and 60.6% (95% CI 25.5–83.2%) for FS. For this survival analysis, borderline cardiac function was defined as left ventricular FS <29% or EF<58%. Patients with borderline EF at baseline were excluded from borderline EF survival analysis. (b) Kaplan-Meier estimate of freedom from abnormal cardiac function at 2 years was 71.6% (95% CI 26.1–92.0%). Abnormal cardiac function was defined as FS<27% or EF < 53%. Abnormal FS and EF always occurred synchronously in this cohort, thus only a single abnormal-free survival curve is shown.. EF, left ventricular ejection fraction. FS, left ventricular shortening fraction. MEKi, MEK inhibitor.