Abstract
ObjectiveAlthough enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy.MethodsWe evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy.ResultsSeven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1–1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients.ConclusionsThe ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.
Highlights
Pompe disease (OMIM 232300; acid maltase deficiency, glycogen storage disease type II) is an autosomal recessive deficiency of lysosomal acid alpha-glucosidase (GAA; OMIM 606800) that results in progressive glycogen accumulation [1]
We evaluate the effectiveness of this algorithm by examining clinical outcomes seen in the CN patients treated with Enzyme replacement therapy (ERT)+ITI versus CN patients treated with ERT monotherapy
Seven CN infantile Pompe disease (IPD) patients were identified at six different institutions in three countries
Summary
Pompe disease (OMIM 232300; acid maltase deficiency, glycogen storage disease type II) is an autosomal recessive deficiency of lysosomal acid alpha-glucosidase (GAA; OMIM 606800) that results in progressive glycogen accumulation [1]. Enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA; alglucosidase alfa) has been commercially available since 2006, and has led to improved clinical outcome measures, including prolonged overall and ventilator-free survival in IPD patients [3,4,5,6]. While such improvements have been noted initially for the IPD population as a whole, marked variability and long-term unpredictability in treatment response remains a challenge. Given the rapid disease progression, early diagnosis and treatment are critical, as even slight delays can result in a significantly altered clinical course [6,7]
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