CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy

Abstract

Purpose: Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross-reactive immunologic material (CRIM)-negative (CN) patients have immune responses with significant clinical decline despite continued ERT. We aimed to characterize immune responses in CN patients with IPD receiving ERT monotherapy.

Methods: A chart review identified 20 CN patients with IPD treated with ERT monotherapy for ≥6 months. Patients were stratified by anti-rhGAA antibody titers: high sustained antibody titers (HSAT; ≥51,200) at least twice; low titers (LT; <6,400) throughout treatment; or sustained intermediate titers (SIT; 6,400-25,600).

Results: Despite early initiation of treatment, the majority (85%) of CN patients developed significant antibody titers, most with HSAT associated with invasive ventilation and death. Nearly all patients with HSAT had at least one nonsense GAA mutation, whereas the LT group exclusively carried splice-site or frameshift mutations. Only one patient in the HSAT group is currently alive after successful immune modulation in the entrenched setting.

Conclusion: Immunological responses are a significant risk in CN IPD; thus induction of immune tolerance in the naive setting should strongly be considered. Further exploration of factors influencing immune responses is required, particularly with the advent of newborn screening for Pompe disease.

Figures

Figure 1. Cohort of infantile Pompe disease patients

† n=1 rescued with an ITI protocol in the entrenched setting after six months on ERT; therefore, data for this patient was included up until the initiation of ITI; n=2 included as ITI regimen was unsuccessful with persistence of antibody titers, IPD, infantile Pompe disease; CN, CRIM, cross reactive immunologic material (CRIM); CN, CRIM-negative; CP, CRIM-positive; ERT, enzyme replacement therapy; ITI, immune tolerance induction

Figure 2. Kaplan-Meier Curves* for (A) overall survival and (B) ventilator-free survival for HSAT, SIT, and LT groups

(A) Overall survival for HSAT, SIT, and LT groups (B) Invasive ventilator-free survival for HSAT, SIT, and LT groups * Patient 10 was successfully rescued using ITI at 86 weeks and was excluded in these calculations HSAT, high sustained antibody titers; LT, low titers; SIT, sustained intermediate titers

Figure 2. Kaplan-Meier Curves* for (A) overall survival and (B) ventilator-free survival for HSAT, SIT, and LT groups

(A) Overall survival for HSAT, SIT, and LT groups (B) Invasive ventilator-free survival for HSAT, SIT, and LT groups * Patient 10 was successfully rescued using ITI at 86 weeks and was excluded in these calculations HSAT, high sustained antibody titers; LT, low titers; SIT, sustained intermediate titers