B-Cell depletion and immunomodulation before initiation of enzyme replacement therapy blocks the immune response to acid alpha-glucosidase in infantile-onset Pompe disease

Abstract

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.

Keywords: Ab; Acid alpha-glucosidase; Antibody; CRIM; Cross-reactive immunologic material; ERT; Enzyme replacement therapy; GAA; IV; IVIG; Intravenous; Intravenous immunoglobulin; LVMI; Left ventricular mass index.

Conflict of interest statement

The authors have no disclosures and no competing financial interests.

Copyright © 2013 Mosby, Inc. All rights reserved.

Figures

Figure 1

A. Representative CRIM Western Blot for normal control, CRIM-positive (Subject E) and CRIM-negative (Subject C) patients with Pompe disease. B. Integrated Intensity of CRIM-positive Subject E vs. normal control C. Integrated Intensity of CRIM negative Subject C vs. normal control.

Figure 2

Enumeration of Peripheral Blood CD3-positive T cells and CD19/CD20-positive B cells by Flow Cytometry in Subjects with Infantile Pompe Disease on Immunosuppression Over Time.

Figure 3

Anti-GAA Antibody Titers in Subjects with Infantile Pompe Disease receiving pre-ERT Immunomodulation. A) CRIM-negative Subject A treated with induction rituximab only, followed by ERT and daily mycophenolate. B) CRIM-negative subjects B, C, D, E treated with induction and maintenance rituximab, daily sirolimus and ERT. Rituximab, Rapamycin and Myozyme were discontinued for Subject B at ~13 months post initiation of treatment. C) Sequence of treatment events for immunomodulation and ERT.