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      Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment

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          Abstract

          Objective

          We studied the effect of long-term alglucerase/imiglucerase (Ceredase®/Cerezyme®, Genzyme, a Sanofi company, Cambridge, MA, USA) treatment on hematological, visceral, and bone manifestations of Gaucher disease type 1 (GD1).

          Methods

          The International Collaborative Gaucher Group (ICGG) Gaucher Registry identified GD1 patients treated with alglucerase/imiglucerase who had dose and clinical data at first infusion and after 10 years of follow-up. Data for hemoglobin, platelet count, organ volumes, bone pain, and bone crisis were analyzed. Tests of the null hypothesis (no change from first infusion to 10 years) were performed using t tests for within-patient absolute change in continuous measurements and McNemar/chi-square tests for change in distributions using categorical values. An alpha level of 0.05 designated statistical significance.

          Results

          As of October 2011, 557 nonsplenectomized and 200 splenectomized patients met the inclusion criteria. The majority of GD1 patients had at least one N370S allele. Compared with nonsplenectomized patients at first infusion, splenectomized patients had lower percentages of anemia (26.0 % vs. 42.8 %) and thrombocytopenia (14.2 % vs. 76.3 %), similar percentages of moderate or severe hepatomegaly (81.2 % vs. 80.0 %), and higher percentages of bone pain (88.9 % vs. 52.4 %) and bone crises (38.3 % vs. 16.0 %). After 10 years, both groups showed significant ( p < 0.05) improvements in mean hemoglobin levels, platelet count, liver, and spleen (nonsplenectomized) volumes, and bone crises. Initial dosing in both groups ranged from <15 U/kg to ≤90 U/kg every 2 weeks. After 10 years, the majority was receiving 15 to ≤45 U/kg every 2 weeks.

          Conclusion

          Ten years of imiglucerase treatment results in sustainable improvements in all GD1 parameters.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s10545-012-9528-4) contains supplementary material, which is available to authorized users.

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          Most cited references27

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          Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease.

          N Barton, R O Brady, J Dambrosia … (1991)
          Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease. The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed. Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.
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            The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease.

            Rod Scott, Edwin Kolodny, B. Rosenbloom … (2000)
            The Gaucher Registry, the largest database of patients with Gaucher disease (GD) worldwide, was initiated to better delineate the progressive nature of the disorder and determine optimal therapy. This report describes the demographic and clinical characteristics of 1698 patients with GD before they received enzyme replacement therapy. Physicians worldwide who treat patients with GD were invited to submit prospective and retrospective data for an ongoing registry, using standardized data collection forms, for central processing and review. Most patients were from the United States (45%) and Israel (17%), but patients are from 38 countries. Most (94%) had type 1 GD, fewer than 1% had type 2, and 5% had type 3. Mutant allele frequency data, available for 45% of patients, showed the most common alleles to be N370S (53%), L444P (18%), 84GG (7%), and IVS2+1 (2%). Twenty-five percent of L444P homozygotes (13 of 52 patients) had type 1 GD phenotype. Mean age at diagnosis in patients with the N370S/N370S genotype was 27.2 years (SD, 19.7 years); in L444P/L444P patients, 2. 3 years (SD, 3.2 years). Histories of bone pain and radiological bone disease were reported by 63% and 94% of patients, respectively; both were more likely in asplenic patients than in patients with spleens. Mean spleen and liver volumes were 19.8 and 2.0 multiples of normal, respectively. Anemia and thrombocytopenia were present in 64% and 56%, respectively. Thrombocytopenia was present in 13% of asplenic patients. The Gaucher Registry permits a comprehensive understanding of the clinical spectrum of GD because of the uniquely large sample size. The Registry will be useful in evaluating the effects of specific therapies in GD and the possible influences of environment, ethnicity, and genotype on the natural history of the disorder.
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              Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry.

              Neal J. Weinreb, Joel Charrow, Hans Andersson … (2002)
              Gaucher disease is the first lysosomal storage disorder to be treated with macrophage-targeted enzyme replacement therapy. Previous studies in relatively small numbers of patients demonstrated short-term efficacy of this treatment. This study describes the effects of 2 to 5 years of treatment on specific manifestations of type 1 Gaucher disease. Physicians reported data from 1028 patients to the Gaucher Registry. Assessment of response included serial measurements of hemoglobin concentration, platelet count, liver and spleen volumes, and the occurrence of bone pain and bone crises. Among anemic patients, hemoglobin concentration increased to normal or near normal within 6 to 12 months, with a sustained response through 5 years. In thrombocytopenic patients with intact spleens, the most rapid response occurred during the first 2 years, with slower improvement thereafter. The likelihood of achieving a normal platelet count decreased with increasing severity of baseline thrombocytopenia. In patients who had undergone splenectomy, platelet counts returned to normal within 6 to 12 months. Hepatomegaly decreased by 30% to 40% during follow-up; splenomegaly decreased 50% to 60%, but rarely to volumes below five times normal size. In patients with pretreatment bone pain or bone crises, 52% (67/128) were pain free after 2 years and 94% (48/51) reported no additional crises. Enzyme replacement therapy prevents progressive manifestations of Gaucher disease, and ameliorates Gaucher disease-associated anemia, thrombocytopenia, organomegaly, bone pain, and bone crises.
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                Author and article information

                Contributors
                : +1-954-7551904 , +1-954-7551910 , boneal@winning.com
                Journal
                Journal ID (nlm-ta): J Inherit Metab Dis
                Journal ID (iso-abbrev): J. Inherit. Metab. Dis
                Title: Journal of Inherited Metabolic Disease
                Publisher: Springer Netherlands (Dordrecht )
                ISSN (Print): 0141-8955
                ISSN (Electronic): 1573-2665
                Publication date (Electronic): 14 September 2012
                Publication date PMC-release: 14 September 2012
                Publication date (Print): 2013
                Volume: 36
                Pages: 543-553
                Affiliations
                [ ]University Research Foundation for Lysosomal Storage Diseases, Inc, Northwest Oncology Hematology Associates PA, 8170 Royal Palm Boulevard, Coral Springs, FL 33065 USA
                [ ]Genetic Services & Familial Cancer Program of Western Australia, School of Pediatrics and Child Health, University of Western Australia, Perth, WA Australia
                [ ]Universidad Central de Venezuela, Caracas, Venezuela
                [ ]Division of Genetics, Birth Defects and Metabolism, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL USA
                [ ]Genzyme, a Sanofi company, Cambridge, MA USA
                [ ]Instituto de Medicina Integral Professor Fernando Figueira, Recife, Pernambuco Brazil
                [ ]Klinik für Innere Medizin, St. Franziskus-Hospital, Cologne, Germany
                [ ]Department of Internal Medicine, Division of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
                Author notes

                Communicated by: Gregory M. Pastores

                Article
                Publisher ID: 9528
                DOI: 10.1007/s10545-012-9528-4
                PMC ID: 3648688
                PubMed ID: 22976765
                SO-VID: a556cf21-ec6b-492f-bf39-fcbea19ab183
                Copyright © © The Author(s) 2012
                History
                Date received : 14 March 2012
                Date revision received : 27 July 2012
                Date accepted : 30 July 2012
                Categories
                Subject: Original Article
                Custom metadata
                issue-copyright-statement © SSIEM and Springer Science+Business Media Dordrecht 2013

                ScienceOpen disciplines: Internal medicine
                Data availability:
                ScienceOpen disciplines: Internal medicine

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