Table 1. Overview of safety and efficacy of immunomodulation approaches.
| Publication | Regimen* | Cohort size (No. patients) | CRIM status | Median IgG antibody titers (range) | No. patients with B cell recovery | No. immune tolerant patients | No. patients alive at time of publication | Conclusion and limitations | |
|---|---|---|---|---|---|---|---|---|---|
| Peak IgG antibody titer | IgG antibody titer at study end | ||||||||
| Prophylactic immunomodulation approaches | |||||||||
| Messinger et al. 2012, Banugaria et al. 2013, Kazi et al. 2017 | A | 19 | 19 CN | 200 (0–51,200) | 200 (0–25,600) | 15 | 16 | 14 | • Short 5-week course was able to achieve long-term tolerance in 69% (13/19) of CRIM-negative patients |
| • Additional 16% (3/19) patients were immune tolerized with an additional round of immunomodulation | |||||||||
| Broomfield et al. 2016 | B | 9 | 8 CN; 1 CP | 0 (0–12,800) | 0 | 8 | 8 | 6 | • 88% (7/8) CRIM-negative IPD did not seroconvert and were immune tolerant to ERT |
| Poelman et al. 2017 | C | 3 | 1 CN; 2 CP | 200,000 (6,250–800,000) | N/A | 3 | 1 | 3 | • Prevented antibody formation during B cell suppression |
| • Failed to induce immune tolerance in 66% (2/3) patients | |||||||||
| • Duration and dosage was different from the regimen previously shown to be successful in achieving immune tolerance | |||||||||
| Elder et al. 2013 | D, E, F | 5 | 4 CN; 1 CP | N/A | N/A | 2 | 1 | 4 | • 80% (4/5) patients did not develop antibodies. |
| • Regimen required delay in ERT by at least 3 weeks for initial immunomodulation | |||||||||
| • Regimen required long-term immune suppression (maintenance rituximab) | |||||||||
| Kazi et al. 2018 | G | 14 | 13 CP; 1 CN | 3,200 (50–102,400) | 150 (0–51,200) | Not assessed | 12 | 12 | • Immune tolerance achieved in 86% (12/14) of IPD patients |
| • Long-term follow-up on a larger cohort is needed to assess safety, and to verify whether tolerance to ERT is maintained | |||||||||
| Therapeutic immunomodulation approaches | |||||||||
| Mendelsohn et al. 2009 | H | 1 | 1 CN | 1,600 | 0 | N/A | 1 | 1 | • Achieved immune tolerance |
| • Patient had low antibody titers at time of immune modulation | |||||||||
| Messinger et al. 2012 | I | 2 | 2 CN | 7,200 (1,600–12,800) | 0 | 2 | 2 | 2 | • Successful in inducing immune tolerance in both patients |
| • Required longer duration of immunosuppression | |||||||||
| Markic et al. 2010; Markic et al. 2013 |
J | 1 | 1 CP | 6,400 | 0 | 1 | 1 | 1 | • IgG antibody titers were reduced and IARs were resolved |
| • Resolution of IARs cannot be solely attributed to immunomodulation | |||||||||
| Peak IgG antibody titer | IgG antibody titer at study end | ||||||||
| Rohbarch et al. 2010 | K | 1 | 1 CN | 400 | 400 | N/A | 1 | 1 | • IARs resolved and patient maintained low IgG titers throughout the treatment |
| • It remains unclear how omalizumab affects IgG antibody development, or if the patient would have maintained low titers even without omalizumab | |||||||||
| Deodato et al. 2014 | L | 1 | 1 CN | 25,600 | 100 | 1 | 1 | 1 | • Immune tolerance was achieved |
| • In another reported case plasma exchange was not successful in eliminating high antibodies | |||||||||
| • Efficacy of plasma exchange requires further verification | |||||||||
| Banugaria et al. 2013; Kazi et al. 2016 | M, N, O | 3 | 1 CN; 2 CP | 204,800 (204,800–819,200) | 800 (100–1,600) | 3 | 3 | 3 | • Achieved immune tolerance |
| • Required more than one cycle of immunomodulation to achieve long-term immunomodulation | |||||||||
| Rairikar et al. 2017 | P | 1 | 1 CN | 204,800 | 12,800 | Not assessed | 0 | 1 | • Reduced IgG antibodies but did not induce immune tolerance |
| Owens et al. 2018 | Q, R | 2 | 1 CN; 1 CP | 460,800 (102,400–819,200) | 115,200 (25,600–204,800) | N/A | 0 | 0 | • Did not induce immune tolerance |
| • Could be due to delay in initiation of immunomodulation and/or disease progression | |||||||||
| Poelman et al. 2019 | S | 3 | 2 CN; 1 CP | 156,250 | 31,250 | 3 | 0 | 3 | • Not successful in eliminating IgG antibodies |
| • Combination differed from previously published protocol in terms of dosing, duration and use of rapamycin in place of MTX** | |||||||||
*Immunomodulation administration details: A. RTX (375 mg/m2) ×4 weekly doses initiated at ERT week 0, MTX (0.4 mg/kg) ×3 doses every other week (9–17 doses total) initiated at week 0, IVIG (0.5g/kg) initiated at week 0; B. RTX 1-4 doses, MTX 10–18 doses; C. RTX (375 mg/m2) immediately followed by MTX (1 mg/kg) ×4 weekly doses each, both drugs initiated at week 0, IVIG (400 mg/kg); D. Induction RTX (750 mg/m2) ×2 doses 10–14 days apart initiated at week 0, daily sirolimus (0.6–1 mg/m2/day) initiated AFTER induction RTX, monthly IVIG (500–1,000 mg/kg), maintenance RTX (375 mg/m2) every 12 weeks; E. Induction RTX (375 mg/m2) ×3 weekly doses initiated at week 0, daily sirolimus (0.6–1 mg/m2/day) initiated AFTER induction RTX , monthly IVIG (500–1,000 mg/kg), maintenance RTX (375 mg/m2) every 12 weeks; F. Induction RTX (750 mg/m2) ×2 doses 10–14 days apart initiated at week 0, daily sirolimus (0.6–1 mg/m2/day) initiated AFTER induction RTX, monthly IVIG (500–1,000 mg/kg), maintenance RTX (375 mg/m2) every 12 weeks; G. MTX (0.4 mg/kg) for 3 cycles (3 doses/cycle) initiated with first 3 ERT infusions; H. Induction RTX (375 mg/m2) ×4 weekly doses, followed by maintenance RTX every 4–12 weeks, MTX (0.5 mg/kg) weekly initiated at week 7, IVIG (500 mg/kg) every 4 weeks; I. Induction RTX (375 mg/m2) ×4 weekly doses, followed by maintenance RTX every 4 weeks, MTX (0.5 mg/kg) weekly given enterally, IVIG (0.5 g/kg) every 4 weeks; J. Induction RTX (375 mg/m2) ×4 weekly doses, followed by maintenance RTX (4 doses, every 5–12 weeks), MTX (0.5 mg/kg) weekly initiated at week 5, IVIG (500 mg/kg) every 4 weeks; K. Omalizumab initiated at 4 months on ERT and continued for >1 year; L. Plasma exchange ×3 sessions 2 months after ERT discontinued, followed by RTX (375 mg/m2) ×1 dose, then IVIG (dose unknown) ×4 doses; M. Bortezomib (1.3 mg/m2) for 3 cycles (4 doses/cycle), RTX (375 mg/m2) ×4 weekly doses initiated after second cycle of BTZ, followed by monthly maintenance RTX and biweekly MTX (15 mg/m2). Monthly IVIG (400–500 mg/kg); N. Bortezomib (1.3 mg/m2) for 3 cycles (4 doses/cycle), RTX (375 mg/m2) ×4 weekly doses initiated after first cycle of BTZ, followed by monthly maintenance RTX and biweekly MTX (15 mg/m2). Monthly IVIG (400–500 mg/kg); O. Bortezomib (1.3 mg/m2) for 6 cycles (4 doses/cycle), monthly maintenance RTX (375 mg/m2) thereafter with the exception of RTX ×4 weekly doses following first and third cycles of BTZ, biweekly MTX (15 mg/m2) initiated after first cycle BTZ. Monthly IVIG (400–500 mg/kg); P. Weekly IVIG (1g/kg) for 20 weeks; Q. RTX ×4 weekly doses, followed by weekly MTX and monthly IVIG, then BTZ ×4 weekly doses; R. Weekly MTX and monthly IVIG, followed by RTX and BTZ ×4 weekly doses each; S. RTX (375 mg/m2) ×3 weekly doses, BTZ (1.3 mg/m2) twice a week ×6 doses, monthly IVIG (first dose 1.0 g/kg, subsequent doses 0.5 g/kg), all initiated simultaneously. Rapamycin (10–20 kg, 1.0–1.5 mg/day; 20–30 kg, 1.5–2.0 mg/day); double dose on first day of rapamycin. CRIM, cross-reactive immunologic material; CP, CRIM-positive; CN, CRIM-negative; MTX, methotrexate; RTX, rituximab; BTZ, bortezomib; IVIG, intravenous immunoglobulin; IPD, infantile Pompe disease; ERT, enzyme replacement therapy; IgG, immunoglobulin G; N/A, not available; IARs, infusion associated reactions.