Figure 1
Trends in anti–recombinant human alglucosidase alfa (anti-rhGAA) IgG antibody titers and left-ventricular mass index (LVMI; (a and b) or urine Glc4 (c) over time are shown by a solid black line and a dashed gray line, respectively (the upper limit of normal LVMI is 65 g/m2;39 control range of urine Glc4 for age >3 years is 3 mmol/mol of creatinine). (a) In patient 1, following unsuccessful immunomodulation with two doses of cyclophosphamide (250 mg/m2 i.v.) and four weekly doses of rituximab (375 mg/m2 per dose i.v.) during weeks 86 to 95, monotherapy with bortezomib (Velcade) was initiated. Bortezomib was administered twice weekly (1.3 mg/m2 of body surface area i.v.) according to a standard dosing regimen (days 1, 4, 8, and 11; equivalent to one cycle of bortezomib)29 during weeks 99 and 100 (cycle 1), weeks 110 and 111 (cycle 2), and weeks 127 and 128 (cycle 3) of enzyme replacement therapy (ERT). Monthly intravenous immunoglobulin (IVIG) was administered at the start of the first cycle of bortezomib. Following a second cycle of bortezomib with continued ERT, a total of four weekly doses of i.v. rituximab (375 mg/m2 per dose) were administered in addition to biweekly methotrexate (15 mg/m2) orally. Rituximab was thereafter administered on a monthly basis. (b) In patient 2, following unsuccessful immunomodulation with rituximab (375 mg/m2, i.v.) and methotrexate (15 mg/m2 s.c.), bortezomib was administered as described in patient 1. Following the first cycle of bortezomib, a total of four weekly doses of rituximab (375 mg/m2 per dose, i.v.) were administered in addition to biweekly methotrexate (15 mg/m2, s.c.). Rituximab was thereafter administered on a monthly basis. Monthly IVIG was administered as described for patient 1. (c) In patient 3, bortezomib was administered as described for patient 1. Six such cycles were administered between weeks 88 and 153. Rituximab was administered (375 mg/m2 per dose, i.v.) approximately every month except after the first and third cycle of bortezomib, at which time a total of four weekly doses were administered after the last bortezomib injection. Methotrexate and IVIG were administered as described in patients 1 and 2.
