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

Kazi, Zoheb B.; Desai, Ankit K.; Troxler, R. Bradley; Kronn, David; Packman, Seymour; Sabbadini, Marta; Rizzo, William B.; Scherer, Katalin; Abdul-Rahman, Omar; Tanpaiboon, Pranoot; Nampoothiri, Sheela; Gupta, Neerja; Feigenbaum, Annette; Niyazov, Dmitriy M.; Sherry, Langston; Segel, Reeval; McVie-Wylie, Alison; Sung, Crystal; Joseph, Alexandra M.; Richards, Susan; Kishnani, Priya S.

Purpose: To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid a-glucosidase (rhGAA), in treatment-naive 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 similar to 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.

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