Recurrent Reactions to Enzyme Replacement Therapy in Infantile‐Onset Pompe Disease: A Case of Immunologic Barriers to Drug Tolerance

Infantile-Onset Pompe Disease (IOPD) is a rapidly progressive lysosomal disorder caused by acid alpha-glucosidase (GAA) deficiency with universal mortality if untreated. Enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase (rhGAA) is lifesaving; however, the development of IgG anti-drug antibodies (ADAs), especially in cross-reactive immunologic material (CRIM)-negative patients, can adversely affect ERT efficacy and safety, including an increased risk of infusion-associated reactions (IARs). We describe a patient with CRIM-negative IOPD who developed clinical decline and severe IARs associated with high IgG ADA titers that warranted several rounds of immune tolerance induction (ITI) and a desensitization protocol. Following a clinical diagnosis, ERT with alglucosidase alfa (40 mg/kg/week) with concomitant prophylactic ITI consisting of a short course of rituximab, methotrexate, and intravenous immunoglobulin were initiated at age 6.25 months. Despite early clinical improvement, ADA titers first rose to 12,800 at 12 months and rose to 25,600 at 17 months, prompting a second ITI regimen consisting of rituximab, methotrexate, intravenous immunoglobulin, and bortezomib to target plasma cells. Between ages 34 and 40 months (28-34 months on ERT), she developed recurrent infusion reactions resembling anaphylaxis to previously tolerated ERT with peak ADA titers of 25,600 at 41 months. An additional bortezomib-based ITI protocol with desensitization was administered due to persistence of high-sustained antibody titers (HSATs). Subsequently, the patient was able to tolerate ERT, and she has since continued clinical improvement with declining ADA titers to 1600 at 52 months. Immune modulation is now being tapered. This case highlights the immunological challenges of ERT in CRIM-negative IOPD patients and how multidisciplinary immunosuppression strategies can maintain lifesaving therapies.