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Long-term outcomes with agalsidase alfa enzyme replacement therapy: Analysis using deconstructed composite events
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
performed including sensitivity, precision, linearity, and specificity. GALC enzyme activity was linear over the range 0.093-1.60 μmol/L/hr with a limit of detection and quantification of 0.24 μmol/L/hr. We also present similar analytical characterization data for ASM. doi:10.1016/j.ymgme.2015.12.190
33 Leukocyte cystine as a biomarker to monitor cystinosis Bruce A. Barshop, Ilya Gertsman, Jon A. Gangoiti, UCSD, La Jolla, CA, United States For years, assay of intracellular cystine in mixed leukocytes has been the standard method for both diagnosis of cystinosis, and for monitoring therapy. More favorable outcome was associated, by retrospective outcome analysis of creatinine, with mean concentrations of b1.0 nmol cystine (expressed as “half-cystine”) per mg protein in mixed leukocyte preparations. Analysis of cystine in granulocytes, rather than in mixed leukocytes, has been shown to be a more sensitive measure which is also able to better distinguish heterozygotes. We have developed methods to prepare granulocytes in samples of whole blood and have demonstrated consistent values with specific shipment conditions, and whereas cystine determinations were shown to be stable in mixed leukocyte preparations only when prepared at the point of care, this allows more access to testing for patients who live near small local laboratories. However, the results of granulocyte cystine determinations are higher when normalized to protein, due to the unpredictable contributions of other cell types’ protein and cystine in mixed leukocyte preparations. There leads to uncertainty about what constitutes a target therapeutic range, since the granulocyte cystine content may be considerably N1.0 nmol/mg protein in a sample from a well-treated patient. We have looked into correlation of granulocyte and mixed leukocyte cystine, related to the differential leukocyte count. We have isolated other cell types isolated immunomagnetically (lymphocytes, monocytes, etc.) and found that they have appreciable amounts of cystine accumulation in cystinosis. Elucidation of the relative levels of cystine accumulation among leukocyte classes will allow establishment of rational therapeutic targets for monitoring cystinosis. doi:10.1016/j.ymgme.2015.12.191
34 Long-term outcomes with agalsidase alfa enzyme replacement therapy: Analysis using deconstructed composite events Michael Becka, Derralynn Hughesb, Christoph Kampmanna, Svetlana Bizjajevac, Guillem Pintos-Morelld, Uma Ramaswamib, Michael Weste, Roberto Giuglianif, aUniversity Medical Center, Mainz, Germany, b Royal Free London NHS Foundation Trust, University College of London, London, United Kingdom, cShire, Zug, Switzerland, dUniversity Hospital “Germans Trias i Pujol”, Badalona, Universitat Autònoma de Barcelona, Badalona, Spain, eDalhousie University, Halifax, NS, Canada, fMedical Genetics Service HCPA/Department of Genetics UFRGS and INAGEMP, Porto Alegre, Brazil Previously, 5-year morbidity outcomes in patients from the Fabry Outcome Survey (FOS; sponsored by Shire) receiving agalsidase alfa enzyme replacement therapy (ERT; 0.2 mg/kg every 2 weeks) were examined as age at first clinical composite event (Beck et al. 2015 Mol Genet Metab Rep 3;21-27). Currently, an additional retrospective analysis of FOS data from children and adults was performed to
S25
examine 5-year composite morbidity endpoints separately for cerebrovascular (including cerebrovascular accident, stroke, or transient ischemic attack), cardiac (including myocardial infarction or other serious cardiac events indicative of coronary artery disease, heart failure, valvular disease, or arrhythmia), and renal (including renal transplant, dialysis, or ≥33% increase from baseline in serum creatinine) events. Among 677 patients overall (360 male, 317 female), the mean (standard deviation) age at first symptom was 19.0 (17.2) years and mean (standard deviation) age at diagnosis was 32.7 (18.6) years. The number and proportion of patients with at least one cerebrovascular event was 40 (11.1%) male and 59 (18.6%) female; with at least one cardiac event was 151 (41.9%) male and 148 (46.7%) female; and with at least one renal event was 49 (13.6%) male and 14 (4.4%) female. The Kaplan-Meier point estimate for median age (in years) at first cerebrovascular event was 70.9 in females and 71.2 overall; at first cardiac event it was 50.6 in males, 59.9 in females, and 55.4 overall. Kaplan-Meier median age of first renal events for both sexes was not estimable because of the small number of events. Cardiac events occurred at younger ages than cerebrovascular or renal events, cerebrovascular events were more frequent in females than males, and male patients were more likely to experience cardiac and renal events at a younger age than female patients. This work was funded by Shire. doi:10.1016/j.ymgme.2015.12.192
35 The French Gaucher Disease Registry: Clinical characteristics, complications and treatment of 616 patients Jerome Stirnemanna, Dalil Hamrounb, Monia Bengherbiac, Karima Yousfic, Juliette Bergerd, Anais Brassiere, Christine Broissande, Catherine Caillaude, Fabrice Camouf, Florence Dalbiesg, Dries Dobbelaereh, Roseline Froissarti, Bernard Grosboisj, Vanessa Leguy-Seguink, Thierry Levadel, Agathe Masseaum, Christian Rosen, Christine Serratricea, Vassili Valayannopoulose, Bruno Fantinc, Marc Bergerd, Thierry Billette de Villemeuro, Nadia Belmatougc, aGeneva University Hospital, Geneva, Switzerland, bCHRU de Montpellier, Montpellier, France, cHôpital Beaujon, Clichy, France, dCHU Estaing, Clermont-Ferrand, France, eHôpital NeckerEnfants Malades, Paris, France, fCHU Haut Levêque, Pessac, France, gCHRU MORVAN, BREST, France, hHôpital Jeanne de Flandre, Lille, France, iGH est, Lyon, France, jCHU de Rennes, Rennes, France, kCHU Bocage Central, DIJON, France, lCHU de Rangueil, Toulouse, France, mCHU Hôtel Dieu, Nantes, France, nHôpital St Vincent de Paul, Lille, France, oHôpital Trousseau, Paris, France Objectives: To describe the epidemiological, clinical and biological features, complications and treatments of Gaucher disease (GD) patients in France in 2015. Methods: All patients with known GD, living in France, with ≥1 consultations (1980-2015), were included in the French GD Registry. Data are expressed as medians (range) for continuous variables and numbers (%) for categorical variables. Results: Among the 616 registry patients, 114 died. 502 patients were alive in september 2015. 261 (52 %) were females; 434 (86.0%) had type 1, 1 (0.2%) type 2, 17 (3.3%) type 3, 37 (6.9%) perinatallethal type and 50 had an unknown phenotype. Median ages at first GD symptoms and diagnosis, respectively, were 15 (0-77) and 22 (084) years for all types. The first symptom diagnosing GD was splenomegaly and/or thrombocytopenia (38 % and 26 %, respectively). Bone-marrow aspiration and/or biopsy yielded the diagnosis for 55 % of the patients, with enzyme deficiency confirming GD for all patients. Birth incidence rate was estimated at 1/50,000 and prevalence at 1/136,000. Major clinical complications were bone
performed including sensitivity, precision, linearity, and specificity. GALC enzyme activity was linear over the range 0.093-1.60 μmol/L/hr with a limit of detection and quantification of 0.24 μmol/L/hr. We also present similar analytical characterization data for ASM. doi:10.1016/j.ymgme.2015.12.190
33 Leukocyte cystine as a biomarker to monitor cystinosis Bruce A. Barshop, Ilya Gertsman, Jon A. Gangoiti, UCSD, La Jolla, CA, United States For years, assay of intracellular cystine in mixed leukocytes has been the standard method for both diagnosis of cystinosis, and for monitoring therapy. More favorable outcome was associated, by retrospective outcome analysis of creatinine, with mean concentrations of b1.0 nmol cystine (expressed as “half-cystine”) per mg protein in mixed leukocyte preparations. Analysis of cystine in granulocytes, rather than in mixed leukocytes, has been shown to be a more sensitive measure which is also able to better distinguish heterozygotes. We have developed methods to prepare granulocytes in samples of whole blood and have demonstrated consistent values with specific shipment conditions, and whereas cystine determinations were shown to be stable in mixed leukocyte preparations only when prepared at the point of care, this allows more access to testing for patients who live near small local laboratories. However, the results of granulocyte cystine determinations are higher when normalized to protein, due to the unpredictable contributions of other cell types’ protein and cystine in mixed leukocyte preparations. There leads to uncertainty about what constitutes a target therapeutic range, since the granulocyte cystine content may be considerably N1.0 nmol/mg protein in a sample from a well-treated patient. We have looked into correlation of granulocyte and mixed leukocyte cystine, related to the differential leukocyte count. We have isolated other cell types isolated immunomagnetically (lymphocytes, monocytes, etc.) and found that they have appreciable amounts of cystine accumulation in cystinosis. Elucidation of the relative levels of cystine accumulation among leukocyte classes will allow establishment of rational therapeutic targets for monitoring cystinosis. doi:10.1016/j.ymgme.2015.12.191
34 Long-term outcomes with agalsidase alfa enzyme replacement therapy: Analysis using deconstructed composite events Michael Becka, Derralynn Hughesb, Christoph Kampmanna, Svetlana Bizjajevac, Guillem Pintos-Morelld, Uma Ramaswamib, Michael Weste, Roberto Giuglianif, aUniversity Medical Center, Mainz, Germany, b Royal Free London NHS Foundation Trust, University College of London, London, United Kingdom, cShire, Zug, Switzerland, dUniversity Hospital “Germans Trias i Pujol”, Badalona, Universitat Autònoma de Barcelona, Badalona, Spain, eDalhousie University, Halifax, NS, Canada, fMedical Genetics Service HCPA/Department of Genetics UFRGS and INAGEMP, Porto Alegre, Brazil Previously, 5-year morbidity outcomes in patients from the Fabry Outcome Survey (FOS; sponsored by Shire) receiving agalsidase alfa enzyme replacement therapy (ERT; 0.2 mg/kg every 2 weeks) were examined as age at first clinical composite event (Beck et al. 2015 Mol Genet Metab Rep 3;21-27). Currently, an additional retrospective analysis of FOS data from children and adults was performed to
S25
examine 5-year composite morbidity endpoints separately for cerebrovascular (including cerebrovascular accident, stroke, or transient ischemic attack), cardiac (including myocardial infarction or other serious cardiac events indicative of coronary artery disease, heart failure, valvular disease, or arrhythmia), and renal (including renal transplant, dialysis, or ≥33% increase from baseline in serum creatinine) events. Among 677 patients overall (360 male, 317 female), the mean (standard deviation) age at first symptom was 19.0 (17.2) years and mean (standard deviation) age at diagnosis was 32.7 (18.6) years. The number and proportion of patients with at least one cerebrovascular event was 40 (11.1%) male and 59 (18.6%) female; with at least one cardiac event was 151 (41.9%) male and 148 (46.7%) female; and with at least one renal event was 49 (13.6%) male and 14 (4.4%) female. The Kaplan-Meier point estimate for median age (in years) at first cerebrovascular event was 70.9 in females and 71.2 overall; at first cardiac event it was 50.6 in males, 59.9 in females, and 55.4 overall. Kaplan-Meier median age of first renal events for both sexes was not estimable because of the small number of events. Cardiac events occurred at younger ages than cerebrovascular or renal events, cerebrovascular events were more frequent in females than males, and male patients were more likely to experience cardiac and renal events at a younger age than female patients. This work was funded by Shire. doi:10.1016/j.ymgme.2015.12.192
35 The French Gaucher Disease Registry: Clinical characteristics, complications and treatment of 616 patients Jerome Stirnemanna, Dalil Hamrounb, Monia Bengherbiac, Karima Yousfic, Juliette Bergerd, Anais Brassiere, Christine Broissande, Catherine Caillaude, Fabrice Camouf, Florence Dalbiesg, Dries Dobbelaereh, Roseline Froissarti, Bernard Grosboisj, Vanessa Leguy-Seguink, Thierry Levadel, Agathe Masseaum, Christian Rosen, Christine Serratricea, Vassili Valayannopoulose, Bruno Fantinc, Marc Bergerd, Thierry Billette de Villemeuro, Nadia Belmatougc, aGeneva University Hospital, Geneva, Switzerland, bCHRU de Montpellier, Montpellier, France, cHôpital Beaujon, Clichy, France, dCHU Estaing, Clermont-Ferrand, France, eHôpital NeckerEnfants Malades, Paris, France, fCHU Haut Levêque, Pessac, France, gCHRU MORVAN, BREST, France, hHôpital Jeanne de Flandre, Lille, France, iGH est, Lyon, France, jCHU de Rennes, Rennes, France, kCHU Bocage Central, DIJON, France, lCHU de Rangueil, Toulouse, France, mCHU Hôtel Dieu, Nantes, France, nHôpital St Vincent de Paul, Lille, France, oHôpital Trousseau, Paris, France Objectives: To describe the epidemiological, clinical and biological features, complications and treatments of Gaucher disease (GD) patients in France in 2015. Methods: All patients with known GD, living in France, with ≥1 consultations (1980-2015), were included in the French GD Registry. Data are expressed as medians (range) for continuous variables and numbers (%) for categorical variables. Results: Among the 616 registry patients, 114 died. 502 patients were alive in september 2015. 261 (52 %) were females; 434 (86.0%) had type 1, 1 (0.2%) type 2, 17 (3.3%) type 3, 37 (6.9%) perinatallethal type and 50 had an unknown phenotype. Median ages at first GD symptoms and diagnosis, respectively, were 15 (0-77) and 22 (084) years for all types. The first symptom diagnosing GD was splenomegaly and/or thrombocytopenia (38 % and 26 %, respectively). Bone-marrow aspiration and/or biopsy yielded the diagnosis for 55 % of the patients, with enzyme deficiency confirming GD for all patients. Birth incidence rate was estimated at 1/50,000 and prevalence at 1/136,000. Major clinical complications were bone