Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT

Abstract

Objective: Although enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy.

Methods: We evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy.

Results: Seven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1-1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients.

Conclusions: The ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD.

Conflict of interest statement

Competing Interests: SGB, SNP, TTP, CM, KBS, CWR, FL, PC, and ASR have no financial or proprietary interest in the materials presented herein. SMD has received honoraria from Genzyme. DSB reports receiving research and grant support from Genzyme. JAR has received travel support, speaker fees and his department has received unrestricted educational grants from Genzyme. RYW has a material interest in Biomarin Pharmaceuticals, is a member of the Genzyme/Sanofi Aventis North American Board of Advisors for MPS I, and has received research support from Shire plc. He has received travel and lodging support for attendance to scientific meetings from Genzyme/Sanofi Aventis as well as from Shire plc, and is the local study site principal investigator for the Genzyme/Sanofi Aventis Lumizyme phase III extension trial. JC is a member of the Fabry and Gaucher Disease Registry Advisory Board for Genzyme Corporation. He has received honoraria from Genzyme Corporation. PH has received educational grants, travel support to scientific meetings and speaker's honorarium from Genzyme Corporation. PSK reports receiving research and grant support from Genzyme. PSK also receives honoraria and consulting fees from Genzyme and is a member of the Pompe disease and the Gaucher Disease Registry Advisory Boards. Duke University and the inventors of the method of treatment and precursors of the cell lines used to generate the enzyme (rhGAA) used commercially have received royalties pursuant to the University's policy on inventions, patents, and technology transfer. This potential conflict for Duke University has been resolved through monetization. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

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 . ‡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 , . **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 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 .

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.

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).

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.