A favorable outcome in an infantile-onset Pompe patient with cross reactive immunological material (CRIM) negative disease with high dose enzyme replacement therapy and adjusted immunomodulation

Shiri Curelaru, Ankit K Desai, Daniel Fink, Yoav Zehavi, Priya S Kishnani, Ronen Spiegel, Shiri Curelaru, Ankit K Desai, Daniel Fink, Yoav Zehavi, Priya S Kishnani, Ronen Spiegel

Abstract

Infantile onset Pompe disease (IOPD) is a rare devastating disease that presents in early infancy with rapidly progressive hypertrophic cardiomyopathy, severe generalized myopathy and death within the first year of life. The emergence of enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has improved the natural course of IOPD with a significant impact on cardiomyopathy but has a more limited effect on the progression of myopathy and consequently the later deterioration of the disease. Possible reasons for reduced ERT efficacy include insufficient enzyme, partial targeting of skeletal muscle and the development of IgG rhGAA antibodies especially in patients who are cross-reactive immunological material (CRIM) negative. We report a CRIM-negative IOPD female patient who started treatment upon diagnosis at 4.5 months with ERT at 20 mg/kg every other week and a course of combined immunomodulation with rituximab, methotrexate and IVIG according to the published Duke protocol and increased ERT within a month to 40 mg/kg/week. Despite initial good clinical response to ERT and immunomodulation, monthly monitoring identified a gradual increase of serum antibody titers to rhGAA necessitating a second course of immunomodulation with bortezomib and maintenance rituximab and methotrexate. A gradual reduction in frequency of immunotherapy was instituted and over a period of 14 months was discontinued. Serum anti-rhGAA antibody titers remained negative for 5 months since cessation of immunomodulation and the patient is now immune tolerant with recovery of CD19. At the age of 30 months the patient is walking independently and has normal cardiac function and anatomy. We recommend initiating ERT at 40 mg/kg/week in CRIM-negative IOPD patients, concomitant with immunomodulation and monthly monitoring of serum anti-rhGAA IgG titers upon confirmation of the diagnosis.

Keywords: Cross reactive immunological material (CRIM); Enzyme replacement therapy; GAA gene; Immunomodulation; Infantile-onset Pompe disease.

Conflict of interest statement

AKD has received grant support from Sanofi Genzyme and the Lysosomal Disease Network. PSK has received research/grant support from Sanofi Genzyme and Amicus Therapeutics. PSK has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, JCR Pharmaceutical and Asklepios Biopharmaceutical, Inc. (AskBio). PSK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics, and Baebies. PSK has equity in Asklepios Biopharmaceutical, Inc. (AskBio), which is developing gene therapy for Pompe disease and Maze Therapeutics, which is developing small molecule in Pompe disease. YZ has received travel reimbursement from Sanofi Genzyme, RS has received travel reimbursement and speaker payments from Sanofi Genzyme.

© 2022 The Authors.

Figures

Fig. 1
Fig. 1
Immunomodulation protocol, anti rhGAA titer, cardiac mass and biomarker evolution over time. A. The course of left ventricular mass index (LVMI), B. The course of serum CK and urinary Glc4 in relation to ERT and immunomodulation treatment. C. Serum anti rhGAA antibody titers and detailed immunomodulation treatment according to patient's age. s.c = subcutaneous, R = rituximab, M = methotrexate, B = bortezomib. Glc4 = urinary glucose tetrasaccharide. *4 weekly doses of rituximab starting on the day before the first dose of ERT. **methotrexate given for three consecutive days (dose) starting on the day of first ERT and continuing with two additional doses at two weeks and four weeks after the first injection.
Fig. 2
Fig. 2
Immunomodulation protocol with bortezomib, rituximab, methotrexate and IVIG and maintenance therapy thereafter.

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