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Genet Med. 2019 Apr;21(4):887-895. doi: 10.1038/s41436-018-0270-7. Epub 2018 Sep 14.

An immune tolerance approach using transient low-dose methotrexate in the ERT-naïve setting of patients treated with a therapeutic protein: experience in infantile-onset Pompe disease.

Author information

1
Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, USA.
2
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
3
Department of Pediatrics, New York Medical College, Valhalla, NY, USA.
4
Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, CA, USA.
5
Department of Pediatrics, University of Nebraska Medical Center, Nebraska Medical Center Omaha, Omaha, NE, USA.
6
Department of Neurology, University of Arizona, Tucson, AZ, USA.
7
Munroe-Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, USA.
8
Quest Diagnostics and Children's National Health System, Washington, DC, USA.
9
Amrita Institute of Medical Sciences & Research Centre, Kochi, Kerala, India.
10
All India Institute of Medical Sciences, New Delhi, India.
11
University of California, San Diego, CA, USA.
12
Department of Pediatrics, Ochsner Health System, New Orleans, LA, USA.
13
Medical Genetics Institute, Shaare Zedek Medical Center and the Hebrew University School of Medicine, Jerusalem, Israel.
14
Sanofi Genzyme, Framingham, MA, USA.
15
Division of Medical Genetics, Department of Pediatrics, Duke University Health System, Durham, NC, USA. priya.kishnani@duke.edu.

Abstract

PURPOSE:

To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid α-glucosidase (rhGAA), in treatment-naïve cross-reactive immunologic material (CRIM)-positive infantile-onset Pompe disease (IOPD) patients.

METHODS:

Newly diagnosed IOPD patients received subcutaneous or oral 0.4 mg/kg TLD-MTX for 3 cycles (3 doses/cycle) with the first 3 rhGAA infusions. Anti-rhGAA IgG titers, classified as high-sustained (HSAT; ≥51,200, ≥2 times after 6 months), sustained intermediate (SIT; ≥12,800 and <51,200 within 12 months), or low (LT; ≤6400 within 12 months), were compared with those of 37 CRIM-positive IOPD historic comparators receiving rhGAA alone.

RESULTS:

Fourteen IOPD TLD-MTX recipients at the median age of 3.8 months (range, 0.7-13.5 months) had a median last titer of 150 (range, 0-51,200) at median rhGAA duration ~83 weeks (range, 36-122 weeks). One IOPD patient (7.1%) developed titers in the SIT range and one patient (7.1%) developed titers in the HSAT range. Twelve of the 14 patients (85.7%) that received TLD-MTX remained LT, versus 5/37 HSAT (peak 51,200-409,600), 7/37 SIT (12,800-51,000), and 23/37 LT (200-12,800) among comparators.

CONCLUSION:

Results of TLD-MTX coinitiated with rhGAA are encouraging and merit a larger longitudinal study.

KEYWORDS:

Pompe disease; alglucosidase alfa; antidrug antibodies; methotrexate; prophylactic immune tolerance induction

PMID:
30214072
PMCID:
PMC6417984
DOI:
10.1038/s41436-018-0270-7
[Indexed for MEDLINE]
Free PMC Article

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