Abstract 4396: Clinical Response to Recombinant Acid α-Glucosidase is Predicted by Cardiac Outcome Measures in Children with Pompe Disease

Abstract

Background : Pompe disease is an autosomal-recessive glycogen storage disease due to deficiency of acid α-glucosidase (GAA). Clinical findings in infantile onset disease are due to glycogen accumulation leading to hypertrophic cardiomyopathy, skeletal myopathy, respiratory failure and death. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA; Myozyme®) has been shown to prolong survival in infants. We assessed the hypothesis that myocardial response to rhGAA predicts clinical outcome in Pompe. Methods: Echos during one year of ERT were reviewed from patients enrolled in open label trials of rhGAA (n=38). A standardized echo protocol was used at specific time points (wks 0, 4, 8, 12, 26, 38, 52). A central reader made measurements off-line, blinded to study information. Variables including LV mass, volumes, and ejection fraction (EF) were determined. Clinical outcomes at study-end were analyzed in 2 groups: Group A, alive and free of assisted ventilation (AV) or Group B, died or requiring AV. Z-scores were calculated for all echo variables and median z-scores between outcome groups at wk 0 and wk 52 were compared using median scores tests. Non-linear random effects models were used to examine changes over time. Results: Mean age at first infusion = 10.9±9.8 months (range 1.2 – 43.1). At study onset, 7/38 received AV. At study end, mean time to last infusion = 115±44 weeks with 16/38 in Group A and 22/38 in Group B. For Group A vs. Group B, median z-scores at week 0 for LV mass = 6.11 vs. 7.41, mass to volume ratio (MVR) = 4.5 vs. 8.8, and EF = 0.8 for both groups; p≥ 0.12 for each measure. Median z-scores for the same outcome groups, respectively, at week 52 for LV mass = 0.57 vs. 3.41 (p=0.06), for MVR = 0.48 vs. 3.54 (p=0.001) and EF = −0.6 in both groups. In the subgroup not requiring AV at study onset (n=31), MVR is higher at all times in Group B (p≤ 0.03). Conclusion: rhGAA therapy can prolong life in young patients with Pompe, improving outcome compared to an untreated natural history cohort. Even with ERT, there is significant morbidity and mortality. Diminished myocardial response with persistence of significant LV hypertrophy predicts progression to poor clinical outcomes. These and other predictors are required to fully understand response to ERT in Pompe disease.