B-Cell Depletion and Immunomodulation before Initiation of Enzyme Replacement Therapy Blocks the Immune Response to Acid Alpha-Glucosidase in Infantile-Onset Pompe Disease

• Published in: The Journal of pediatrics Vol. 163; no. 3; pp. 847 - 854.e1
• Main Authors: Elder, Melissa E., MD, PhD, Nayak, Sushrusha, PhD, Collins, Shelley W., MD, Lawson, Lee Ann, MSN, Kelley, Jeffry S., BS, Herzog, Roland W., PhD, Modica, Renee F., MD, Lew, Judy, MD, Lawrence, Robert M., MD, Byrne, Barry J., MD, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2013; Mosby, Inc
• Subjects: adverse effects; alanine transaminase; alkaline phosphatase; alpha-glucosidase; alpha-Glucosidases - immunology; alpha-Glucosidases - therapeutic use; antibodies; Antibodies, Monoclonal, Murine-Derived - therapeutic use; Antigens, CD - blood; aspartate transaminase; Autoantibodies - blood; B-lymphocytes; B-Lymphocytes - metabolism; Biomarkers - blood; C-reactive protein; creatine; creatine kinase; Drug Administration Schedule; Drug Therapy, Combination; Enzyme Replacement Therapy; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; gamma-glutamyltransferase; Glycogen Storage Disease Type II - drug therapy; Glycogen Storage Disease Type II - enzymology; Glycogen Storage Disease Type II - immunology; Humans; immune response; Immunoglobulin G - blood; immunoglobulins; Immunoglobulins, Intravenous - therapeutic use; immunomodulation; Immunosuppressive Agents - therapeutic use; Infant; infants; intravenous injection; Male; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - therapeutic use; natriuretic peptides; Pediatrics; Rituximab; Sirolimus - therapeutic use; therapeutics; Treatment Outcome; Ab; Antibody; Intravenous; LVMI; ERT; GAA; Acid alpha-glucosidase; Intravenous immunoglobulin; IVIG; Left ventricular mass index; CRIM; IV; Cross-reactive immunologic material; Enzyme replacement therapy
• ISSN: 0022-3476; 1097-6833
• DOI: 10.1016/j.jpeds.2013.03.002

Objective To evaluate whether B-cell depletion before enzyme replacement therapy (ERT) initiation can block acid alpha-glucosidase (GAA) antibody responses and improve clinical outcomes. Study design Six subjects with Pompe disease (including 4 cross-reacting immunologic material–negative infants) aged 2-8 months received rituximab and sirolimus or mycophenolate before ERT. Four subjects continued to receive sirolimus, rituximab every 12 weeks, and intravenous immunoglobulin monthly for the duration of ERT. Sirolimus trough levels, IgG, CD3, CD4, CD8, CD19, CD20, N-terminal pro-brain natriuretic peptide, creatine kinase, creatine kinase-MB, C-reactive protein, platelets, alkaline phosphatase, gamma-glutamyl transferase, aspartate aminotransferase, and alanine aminotransferase were measured regularly. Results Immunomodulation achieved B-cell depletion without adverse effects. After 17-36 months of rituximab, sirolimus and ERT, all subjects lacked antibodies against GAA, 4 continued to gain motor milestones, yet 2 progressed to require invasive ventilation. The absence of infusion-associated reactions allowed the use of accelerated infusion rates. Conclusion B-cell depletion and T-cell immunomodulation in infants naïve to ERT was accomplished safely and eliminated immune responses against GAA, thereby optimizing clinical outcome; however, this approach did not necessarily influence sustained independent ventilation. Importantly, study outcomes support the initiation of immunomodulation before starting ERT, because the study regimen allowed for prompt initiation of treatment.