TY - JOUR
T1 - Sustained immune tolerance induction in enzyme replacement therapy–treated CRIM-negative patients with infantile Pompe disease
AU - Kazi, Zoheb B.
AU - Desai, Ankit K.
AU - Berrier, Kathryn L.
AU - Bradley Troxler, R.
AU - Wang, Raymond Y.
AU - Abdul-Rahman, Omar A.
AU - Tanpaiboon, Pranoot
AU - Mendelsohn, Nancy J.
AU - Herskovitz, Eli
AU - Kronn, David
AU - Inbar-Feigenberg, Michal
AU - Ward-Melver, Catherine
AU - Polan, Michelle
AU - Gupta, Punita
AU - Rosenberg, Amy S.
AU - Kishnani, Priya S.
N1 - Funding Information:
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.
Funding Information:
This research was supported by a grant from Genzyme, a Sanofi company (Cambridge, Massachusetts, USA), and supported in part by the Lysosomal Disease Network, a part of NIH Rare Diseases Clinical Research Network. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network, an initiative of the Office of Rare Diseases Research, and National Center for Advancing Translational Sciences. This consortium is funded through a collaboration between National Center for Advancing Translational Sciences, National Institute of Neurological Disorders and Stroke, and National Institute of Diabetes and Digestive and Kidney Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank the patients who participated in this study and their families. We thank Deeksha Bali, Catherine Rehder, and Jian Dai for providing the GAA variant data and CRIM status analysis on these patients. We also thank the local clinical care teams, including M. Valerie Marrero-Stein, Matthew Stein, Kathleen Crosby, Jennifer Q. Cook, Lorien King, Michelle Mecija, Holly Zimmerman, Lisa Read, Ashley Boerst, Geetha Puthenveetil, and David Buchbinder for their contributions toward patient care, facilitating the consent process, and assistance with data gathering.
Publisher Copyright:
© 2017 American Society for Clinical Investigation. All rights reserved.
PY - 2017/8/17
Y1 - 2017/8/17
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI.INSIGHT.94328
DO - 10.1172/JCI.INSIGHT.94328
M3 - Article
C2 - 28814660
AN - SCOPUS:85041312127
SN - 2379-3708
VL - 2
JO - JCI insight
JF - JCI insight
IS - 16
M1 - e94328
ER -