Sustained immune tolerance induction in enzyme replacement therapy-treated CRIM-negative patients with infantile Pompe disease

Abstract

Background: Cross-reactive immunological material-negative (CRIM-negative) infantile Pompe disease (IPD) patients develop an immune response against enzyme replacement therapy (ERT) with alglucosidase alfa that nullifies ERT efficacy. Prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and IVIG successfully prevents development of deleterious rhGAA IgG antibodies; however, safety, likelihood of success, and long-term efficacy of ITI in a larger cohort remain unknown.

Methods: Clinical data were analyzed for 19 CRIM-negative IPD patients who received ITI with rituximab, methotrexate, and IVIG in the ERT-naive setting (ERT+ITI) and compared to a historical cohort of 10 CRIM-negative IPD patients on ERT monotherapy.

Results: ITI was safely tolerated, although infections were reported in 4 patients. Fourteen (74%) ERT+ITI patients were alive, with a median age of 44.2 months at their final assessment. The eldest survivor was 103.9 months old, with 100.2 months of follow-up after initiation of ERT+ITI. Death (n = 5) occurred at a median age of 29.2 months and was unrelated to the administration of ITI. Fifteen patients either did not seroconvert (n = 8) or maintained low titers (n = 7; defined as titers of ≤6,400 throughout the course of ERT) following ERT+ITI. Only one patient developed high and sustained antibody titers (defined as titers of ≥51,200 at or beyond 6 months on ERT). Left ventricular mass index (LVMI) decreased from a median of 248.5 g/m2 at baseline to 76.8 g/m2 at a median time from ERT+ITI initiation to 59 weeks. ERT+ITI significantly improved overall survival (P = 0.001), eliminated/reduced antibodies at values of ≤6,400 at week 52 on ERT (P = 0.0004), and improved LVMI at week 52 on ERT (P = 0.02) when compared with ERT monotherapy.

Conclusion: Evidence from this international cohort of CRIM-negative IPD patients further supports the safety, feasibility, and efficacy of ITI in the prevention of immune responses to ERT.

Trial registration: Clinicaltrials.gov NCT01665326.

Funding: This research was supported in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network, and by a grant from Genzyme, a Sanofi company.

Keywords: Genetics; Immunology.

Conflict of interest statement

Conflict of interest: P.S. Kishnani reports receiving research and grant support, honoraria, and consulting fees from Genzyme and is a member of the Pompe Disease and the Gaucher Disease Registry Advisory Boards.

Figures

Figure 1. Kaplan-Meier curve for overall survival of CRIM-negative IPD patients treated with ERT+ITI versus those treated with ERT monotherapy.

A significant difference in terms of overall survival (P = 0.001) was seen between the CRIM-negative ERT+ITI and the ERT monotherapy group. Death occurred in 5 patients in the ERT+ITI group at a median age of 29.2 months (range 15.0–56.9 months). There was a statistically significant difference (P = 0.03) when comparing age at ERT+ITI initiation, with the living patients starting ERT+ITI earlier, at a median age of 2.8 months, versus deceased patients, at a median age of 3.9 months. Survival data of patients with CRIM-negative IPD treated with ERT+ITI were analyzed using the Kaplan-Meier method, with 2-tailed P values generated using the log-rank test (43).

Figure 2. Comparison of longitudinal IgG antibody titers in CRIM-negative IPD patients treated with ERT+ITI tolerized, ERT+ITI nontolerized, or ERT monotherapy.

High and sustained rhGAA IgG antibody titers (HSAT) defined as titers of ≥51,200 at or beyond 6 months on ERT (shown by a horizontal dashed line). ERT+ITI tolerized (n = 15); nontolerized (n = 4); ERT monotherapy (n = 8). CN, CRIM-negative.

Figure 3. Comparison of longitudinal LVMI in CRIM-negative IPD patients treated with ERT+ITI versus those treated with ERT monotherapy.

Left ventricular mass index (LVMI) continued to decline over time in the ERT+ITI cohort, while increasing after an initial period of reduction in the ERT monotherapy cohort. The upper limit of normal LVMI is 64 g/m2 (represented by a horizontal dashed line). LVMI values were compared using Wilcoxon/Kruskal-Wallis rank-sum test. CN, CRIM-negative.