Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants

Abstract

Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy. Patients synthesize a non-functional form of GAA or are unable to form native enzyme. Enzyme replacement therapy with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe patients but may be less effective in cross-reactive immunologic material (CRIM)-negative patients. We retrospectively analyzed the influence of CRIM status on outcome in 21 CRIM-positive and 11 CRIM-negative infantile Pompe patients receiving rhGAA. Patients were from the clinical setting and from clinical trials of rhGAA, were 6 months of age, were not invasively ventilated, and were treated with IV rhGAA at a cumulative or total dose of 20 or 40 mg/kg/2 weeks. Outcome measures included survival, invasive ventilator-free survival, cardiac status, gross motor development, development of antibodies to rhGAA, and levels of urinary Glc(4). Following 52 weeks of treatment, 6/11 (54.5%) CRIM-negative and 1/21 (4.8%) CRIM-positive patients were deceased or invasively ventilated (p<0.0001). By age 27.1 months, all CRIM-negative patients and 4/21 (19.0%) CRIM-positive patients were deceased or invasively ventilated. Cardiac function and gross motor development improved significantly more in the CRIM-positive group. IgG antibodies to rhGAA developed earlier and serotiters were higher and more sustained in the CRIM-negative group. CRIM-negative status predicted reduced overall survival and invasive ventilator-free survival and poorer clinical outcomes in infants with Pompe disease treated with rhGAA. The effect of CRIM status on outcome appears to be mediated by antibody responses to the exogenous protein.

Trial registration: ClinicalTrials.gov NCT00025896 NCT00053573 NCT00059280 NCT00074919 NCT00125879.

Fig. 1

Representative gel showing CRIM-positive and CRIM-negative samples run on the gel with known positive and negative control samples.

Fig. 2

Kaplan–Meier curve of ventilator-free survival of the CRIM-negative (n = 11) and CRIM-positive (n = 21) patients.

Fig. 3

Fig. 3A. Left ventricular mass index (LVMI) at baseline and after 24 and 52 weeks of rhGAA treatment in CRIM-positive and CRIM-negative patients (labeled as 1 and 0 on X-axis, respectively). Fig. 3B. Alberta Infant Motor Scale (AIMS) scores at baseline and after 26 and 52 weeks of rhGAA treatment in CRIM-positive and CRIM-negative patients (Labeled as 1 and 0 on the x-axis, respectively). Fig. 3C. Urine Glc₄ levels at baseline and after 26 and 52 weeks of rhGAA treatment in CRIM-positive and CRIM-negative patients (Labeled as 1 and 0 on the x-axis, respectively).

Fig. 3

Fig. 3A. Left ventricular mass index (LVMI) at baseline and after 24 and 52 weeks of rhGAA treatment in CRIM-positive and CRIM-negative patients (labeled as 1 and 0 on X-axis, respectively). Fig. 3B. Alberta Infant Motor Scale (AIMS) scores at baseline and after 26 and 52 weeks of rhGAA treatment in CRIM-positive and CRIM-negative patients (Labeled as 1 and 0 on the x-axis, respectively). Fig. 3C. Urine Glc₄ levels at baseline and after 26 and 52 weeks of rhGAA treatment in CRIM-positive and CRIM-negative patients (Labeled as 1 and 0 on the x-axis, respectively).

Fig. 3

Fig. 3A. Left ventricular mass index (LVMI) at baseline and after 24 and 52 weeks of rhGAA treatment in CRIM-positive and CRIM-negative patients (labeled as 1 and 0 on X-axis, respectively). Fig. 3B. Alberta Infant Motor Scale (AIMS) scores at baseline and after 26 and 52 weeks of rhGAA treatment in CRIM-positive and CRIM-negative patients (Labeled as 1 and 0 on the x-axis, respectively). Fig. 3C. Urine Glc₄ levels at baseline and after 26 and 52 weeks of rhGAA treatment in CRIM-positive and CRIM-negative patients (Labeled as 1 and 0 on the x-axis, respectively).