Figure 1.
An algorithm for the management of cross-reactive immunologic material (CRIM)-negative (CN) infantile Pompe disease patients.
*Institutional review board (IRB) approved study (NCT01665326; www.clinicaltrials.gov) for rapid determination of CRIM status and long-term follow-up of response to treatment and ITI in Pompe disease. †CN status determination from an established CRIM negative mutation database, which allows prediction of CN status in more than 90% cases [15]. ‡ITI regimen is shown in Figure 2. §Based on the literature antibody titers sustained at ≥6,400 results in a suboptimal therapeutic response to ERT. For that reason, 6,400 was used a cutoff for further intervention [9], [19]. **Based on the half-life of rituximab, CD19% recovery is typically noted around 5 months. ††The decision to repeat the same ITI regimen (figure 3) or to administer ITI with a plasma-cell-targeting agent [20] should be based on multiple factors including, but not limited to, patients clinical status, CD19% and Fcγ receptor polymorphism. ‡‡ITI regimen with plasma cell targeting agent such as bortezomib has been described previously [20].
Figure 2.
Representative Western gel blot showing CRIM negative status of four patients (lanes 3–6).
Lane 1- protein magic marker; lane 8 -CRIM negative control cell line; lane 10 - normal human fibroblast (NHF) control; Lanes 2, 7 and 9 - left empty. 20 ug of skin fibroblast cell protein extract was loaded for each patient lane and 2.5 ug protein was loaded for NHF. Western blot was probed with anti-GAA antibody and ß-Actin was used as a protein loading control.
Figure 3.
ITI treatment regimen which includes rituximab, methotrexate and intravenous immunoglobulin (IVIG).
This short course of ITI regimen (5 weeks) needs to be started together with the first dose of ERT. IVIG is administered on a monthly basis for a period of 5–6 months.
Table 1.
Details of patient demographics, genotype and immune tolerance induction (ITI) regimen.
Figure 4.
Comparison of median left ventricular mass index (LVMI) values seen over time in CRIM-negative (CN) ERT monotherapy (n = 11) versus CN ERT+ITI (n = 7) treated patients.
The upper limit of normal LVMI is 64 g/m2 (represented by a horizontal dashed line).
Table 2.
Clinical parameters.
Table 3.
Laboratory and safety parameters.
Figure 5.
Kaplan-Meier survival curve showing comparison of ventilator-free survival CRIM-negative (CN) ERT monotherapy (n = 11) versus CN ERT+ITI (n = 7) treated patients.
*Three patients in the CN ERT+ITI group began the study invasively ventilated, became ventilator-free with treatment, and are currently still alive and ventilator-free. In contrast, all CN patients in ERT monotherapy treated group were invasive ventilator-free at baseline. This observation suggests that in some cases ERT+ITI can even reverse ventilator dependence in CN Pompe patients.
Figure 6.
Comparison of anti-rhGAA IgG antibody titers seen over time in CRIM-negative (CN) treated with ERT monotherapy (n = 8) versus CN ERT+ITI (n = 7) treated patients.