Impact of Imiglucerase Supply Shortage on Clinical and Laboratory Parameters in Norrbottnian Patients with Gaucher Disease Type 3

Maciej Machaczka 0 1 2 3 4 5 Cecilia Ka mpe Bjo rkvall 0 1 2 3 4 5 Joanna Wieremiejczyk 0 1 2 3 4 5 Martin Paucar Arce 0 1 2 3 4 5 Kristina Myhr-Eriksson 0 1 2 3 4 5 Monika Klimkowska 0 1 2 3 4 5 Hans Ha gglund 0 1 2 3 4 5 Per Svenningsson 0 1 2 3 4 5 0 C. Kampe Bjorkvall J. Wieremiejczyk K. Myhr-Eriksson Department of Medicine, Sunderby Regional Hospital of Norrbotten County , Lulea, Sweden 1 M. Machaczka (&) H. Hagglund Hematology Center Karolinska and Department of Medicine at Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge , M54, Stockholm, Sweden 2 M. Machaczka Medical Faculty, University of Rzeszow , 35-959 Rzeszow, Poland 3 M. Klimkowska Department of Clinical Pathology and Cytology, Karolinska University Hospital Huddinge , Stockholm, Sweden 4 M. Paucar Arce P. Svenningsson Department of Clinical Neuroscience, Karolinska Institutet , Stockholm, Sweden 5 M. Paucar Arce P. Svenningsson Department of Neurology, Karolinska University Hospital Huddinge , Stockholm, Sweden A viral contamination of the production plant producing imiglucerase (CerezymeTM) resulted in an unpredicted worldwide shortage of global supplies during 2009-2010. The aim of the study was to describe the effects of dose reduction of enzyme replacement therapy (ERT) in adults with Norrbottnian form of Gaucher disease type 3 (N-GD3). There were ten adults with N-GD3 treated with imiglucerase in the county of Norrbotten in June 2009. Analyzed variables included plasma chitotriosidase activity and concentration of CCL18/PARC, whole blood hemoglobin concentration (Hb) and platelet count (PLT), as well M. Machaczka and C. Kampe Bjorkvall contributed equally to this manuscript. - Gaucher disease is a pan-ethnic lysosomal storage disorder which belongs to the so-called ultra rare diseases affecting less than 20 individuals/million inhabitants (or \1 persons/ 50,000 inhabitants). It is caused by a deficient activity of the lysosomal enzyme glucocerebrosidase (GBA), resulting from autosomal recessive mutations in the GBA1 gene (1q21) (Machaczka 2013; Zimran 2011). Decreased GBA activity leads to accumulation of glucosylceramide in monocytes-macrophages throughout the body, and in severe disease forms leads to neurodegenerative changes in the central nervous system (Erikson et al. 1997; Machaczka et al. 2011). There are three major clinical subtypes of Gaucher disease, distinguished by the presence of neurologic symptoms and the dynamics of their development: an acute neuronopathic form (type 2), a chronic neuronopathic form (type 3), and a non-neuronopathic form (type 1) (Machaczka 2013; Zimran 2011). Thrombocytopenia, anemia, splenomegaly, hepatomegaly, and bone manifestations are the most typical signs of Gaucher disease type 1 (GD1), which is the most prevalent form of Gaucher disease (Machaczka et al. 2012b; Zimran 2011). Besides the aforementioned symptoms, the presence of central nervous system disease is a hallmark of Gaucher disease type 2 and 3 (GD2 and GD3) (Erikson et al. 1997). Although the neuronopathic forms are the rarest variants of Gaucher disease, an endemic cohort of Swedish patients with chronic neuronopathic Gaucher disease lives in Northern Sweden in the county of Norrbotten, an area of approximately 100,000 square km, which is inhabited by approximately 250,000 people. This unique form of Gaucher disease, belonging to the subtype 3B of Gaucher disease, is called the Norrbottnian form of Gaucher disease (N-GD3) (Dreborg et al. 1980). In Sweden, N-GD3 consists of approximately 40 % of all known cases of Gaucher disease. Since the early 1990s, enzyme replacement therapy (ERT) with macrophage-targeted recombinant GBA is the standard of care in moderate to severe Gaucher disease (Erikson et al. 2006; Machaczka et al. 2012a; Zimran 2011). Until 2009, imiglucerase (CerezymeTM, Genzyme Corporation, Cambridge, MA, USA) was the only ERT available for treatment of patients with Gaucher disease in the European Union (Hollak et al. 2010). In June 2009, the Genzyme Corporation announced a vesivirus 2117 contamination of the production plant, which led to a worldwide supply shortage of CerezymeTM over 1 year. This resulted in an unintentional discontinuation of treatment for many hundreds of patients with milder forms of Gaucher disease (GD1) and a significant dose reduction for those with moderate and severe forms of Gaucher disease (GD1 and GD3) (Deroma et al. 2013; Giraldo et al. 2011; Goldblatt et al. 2011; Zimran et al. 2011). The aim of this retrospective analysis is to describe the effects of the imiglucerase shortage in adults with N-GD3 to increase the knowledge of therapy effects on type 3 Gaucher disease. To our knowledge, this is the only study describing what happened to patients with GD3 during the ERT shortage. Materials and Methods There were 15 patients with N-GD3 in the county of Norrbotten in June 2009. Twelve of them were adults aged 2158 years and followed at the Department of Medicine, Sunderby Regional Hospital of Norrbotten County in Lulea, Sweden. Ten of the 12 patients (four females and six males) were treated with imiglucerase in June 2009. Two of the twelve patients successfully underwent matchedrelated allogeneic bone marrow transplantation as children and thus do not require ERT (Ringden et al. 1995). One man died in November 2009 due to esophageal cancer. The remaining nine patients were suitable for this long-term impact study, analyzing changes in clinical and laboratory parameters of Gaucher disease due to the unintended dose reduction of imiglucerase (CerezymeTM). Patient characteristics are presented in Table 1, including a retrospective assessment using the modified severity scoring tool for neuronopathic Gaucher disease according to Davies et al. (2011). The patient files were reviewed for the collection of relevant clinical data. Patients provided their informed consent. Analyzed variables included results of clinical examination and Gaucher disease biomarkers: plasma chitotriosidase activity (control range \40 nkat/L) and plasma concentration of chemokine (CC motif) ligand 18/pulmonary and activation-regulated chemokine (CCL18/PARC; control range \100 lg/L). Furthermore, Table 1 Characteristics of adults with the Norrbottnian form of Gaucher disease in June 2009 Total number of patients 12 Men 6 (50 %) Women 6 (50 %) Median age (range) (years) 42 (2158) Number of splenectomized patients 11 (92 %) Partial splenectomy 2/11 Median age at the time of splenectomy (range) 7 (120) (years) Number of patients with bone disease 12/12 (100 %) Number of patients with diagnosed epilepsy 7/12 (58 %) Number of patients on ERT in June 2009 10/12 (83 %) Median duration of ERT in June 2009 (range) (years) 17 (817) mSST of patients included in the study (n = 9) mean mSST 10 median mSTT (range) 9 (123.5) values of the whole blood hemoglobin concentration (Hb; control range: 117153 g/L), and whole blood platelet count (PLT; control range 165 (...truncated)