Benefits of Prophylactic Short-Course Immune Tolerance Induction in Patients With Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in an Expanded Cohort.

Ankit K Desai,John W Sleasman,Amy S Rosenberg,Carolyn H Baloh,Priya S Kishnani

doi:10.3389/fimmu.2020.01727

Abstract

Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26–39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1–11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients (n = 33) at a median time of 17 weeks range (11–55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an inadequate response to the Pneumococcal vaccine (n = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population.

Highlights

Lysosomal storage disorders (LSDs) are a group of inherited metabolic disorders caused by disease-associated variants in genes encoding catabolic enzymes active in the lysosome
There is no cure for LSDs, the development of enzyme replacement therapy (ERT) aimed at replacing the deficient lysosomal enzymes and reducing the toxic substrate accumulation has greatly improved the course for several LSDs including Gaucher disease, Fabry disease, Pompe disease, Mucopolysaccharidoses (MPS) I, II, IVA, VI, and VII, and Wolman disease, with additional therapeutic proteins in development (4, 5)
The negative impact of high and sustained anti-rhGAA IgG antibody titers to treatment response has been evident since the first clinical trial of alglucosidase alfa (46)

Summary

Introduction

Lysosomal storage disorders (LSDs) are a group of inherited metabolic disorders caused by disease-associated variants in genes encoding catabolic enzymes active in the lysosome. Despite the success of ERTs in improving outcomes for patients with LSDs, the development of antidrug antibodies (ADA) against the therapeutic protein remains a challenge that impacts both the safety and efficacy of the treatment (6). In 2006, the FDA approved alglucosidase alfa (recombinant human acid alfa-glucosidase, rhGAA) for treatment of Pompe disease, an autosomal recessive LSD caused by disease-associated variants in the GAA gene resulting in deficiency of acid-alpha glucosidase (GAA), predominantly affecting skeletal, smooth, and cardiac muscle (7, 8). Classic IPD is the most severe end of the disease spectrum, with patients presenting with severe cardiomyopathy in the first few days to weeks of life and rarely surviving beyond 2 years of age without treatment (9). The availability of ERT with alglucosidase alfa has changed the natural course of Pompe disease, significantly prolonging survival and improving long-term clinical outcomes. Published literature has demonstrated that long-term IPD survivors often have residual physical impairments including muscle weakness, hypernasal speech, dysphagia with a risk of aspiration, ptosis, and risk of arrhythmias (12)

Objectives

Methods

Results

Conclusion