International Collaborative Gaucher Group Research Articles

Plain language summary of a study looking at the long-term benefits of enzyme replacement therapy in children and teenagers with Gaucher disease type 3

What is this study about? Gaucher disease is a rare genetic condition. There are three types of Gaucher disease: type 1, type 2, and type 3 (GD3). Symptoms of GD3 include problems with the brain and spinal cord, bones, blood, enlarged liver and spleen, and slow growth. Symptoms have a great impact on the quality of life of people with GD3 and are known to cause loss of life in childhood. In Gaucher disease, people have two non-working copies of a gene called GBA, which tells the body how to make an enzyme called beta-glucosidase (which breaks down excess fats called sphingolipids). In Gaucher disease, people do not make enough beta-glucosidase enzyme, meaning sphingolipids build up inside cells, affecting many organs and systems of the body. Enzyme replacement therapy (ERT) is a treatment for Gaucher disease. Previous studies looking at ERT showed that treatment can greatly improve most symptoms and quality of life in people with Gaucher disease. How ERT may help people with GD3 is only available in small studies. What was the aim of this study? Researchers looked at long-term changes in the blood, spleen, liver, and growth in children and teenagers living with GD3 and how long they survived once they had started an ERT called imiglucerase. Researchers used data from a large global database called the International Collaborative Gaucher Group (ICGG) Gaucher Registry. The aim was to investigate if imiglucerase could improve long-term symptoms and prevent early loss of life. What were the results of this study? Low red blood cell counts (causing a condition called anaemia), low platelet (specialised blood cells that stop bleeding and bruising) counts, enlarged liver and spleen, and slow growth were the most common symptoms in people with GD3 before treatment. People with GD3 who had received imiglucerase had improved symptoms after 5 years of treatment. They also had a greater chance of living longer, with 92% of people alive after 5 years of treatment. These results show that the ERT imiglucerase helps to improve blood, spleen, liver, and growth symptoms, and most importantly that it is a life-prolonging treatment.

Pregnancy outcomes in imiglucerase-treated patients with Gaucher disease: Real-world data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry Pregnancy Sub-Registry

Pregnancy outcomes in imiglucerase-treated patients with Gaucher disease: Real-world data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry Pregnancy Sub-Registry

Bone involvement outcomes in Spanish patients with Gaucher disease type 1 treated with eliglustat: Sub-study International Collaborative Gaucher Group (ICGG)

Bone involvement outcomes in Spanish patients with Gaucher disease type 1 treated with eliglustat: Sub-study International Collaborative Gaucher Group (ICGG)

Updated Analysis of a Prospective, Multicenter, Observational Study on the Prevalence of Type 1 Gaucher Disease in Patients with Multiple Myeloma

Introduction. Type I Gaucher disease (GD1) has been associated with increased cancer risk in the International Collaborative Gaucher Group (ICGG) Registry. Particularly, it is well recognized that the risk for multiple myeloma (MM) in affected individuals may be about 9 times higher than expected in the general US populations (Rosenbloom et al, 2022). Pathogenetic relationship between GD1 and MM is still unclear. It was hypothesized that accumulation of glucosylceramide in the macrophages leads to their activation and chronic immune stimulation favouring polyclonal gammopathies. In this scenario plasma cell clone selection could be promoted and subsequent MGUS/MM could derive from it. Diagnosis of GD1 is often inaccurate or delayed since symptoms and signs of disease are nonspecific or underhand. We designed a prospective study to investigate the prevalence of GD1 in a large MM patient population to provide substantial evidences to consider GD1 in the pathogenesis and management of MM. Patients and Methods. This is an observational, prospective, cross-sectional, multicentre study. Twenty-five Italian hematologic centers participated in this study. Due to the lack of data on the effective prevalence of GD1 in MM, the sample size has been determined considering clinically relevant a prevalence of the condition > 0.5% for defining as “high risk” the selected population. Considering an alpha error of 5% and a statistical power of 95%, approximately 1000 patients should beenrolled.. All MM patients are screened by Dried Blood Spots (DBS) sampling technique, that was centralized at the Istituto per la Ricerca e l'Innovazione Biomedica CNR-Palermo. All patients with a positive DBS test undergo genetic test to confirm the diagnosis of GD1. Primary end-point of the study is the prevalence of DBS test positivity in MM patients, which measures glucocerebrosidase activity in peripheral blood leukocytes (normal range 0.2-2.5 nMol/h/m). If the observed prevalence had been significantly higher than predicted, we would have tried to identify the population at higher potential risk of associated GD1. Results. We enrolled 902 patients with a median age of 68 years (range 37-90), 60% of which were male. No patients were Jews, 2 were Asian and 10 were Black, all others were Caucasian. Newly diagnosed and relapsed-refractory MM were 65% and 35%, respectively, whereas SMM and MM were 15% and 85%, respectively. Monoclonal component was IgG in 60%, IgA in 25%, light chain in 15%. Median Ferritin was 310 ng/ml (range 17-1236) and median Alkaline Phosphatase was 75 U/L (range 29-355). Descriptive data of DBS test, enzymatic activity and genetic tests are reported in the Table. In summary, DBS test was found positive in 12/902 (1.33%). Genetic test confirms GBA gene mutations, single heterozygous in 11 patients and double heterozygous in 1 patient. N370S and L444P loci accounted for 50% of GBA gene mutations found. Double-heterozygous patient started replacement therapy for GD1 with imiglucerase. Conclusions. After the enrolment of more than three quarter of the planned patients, the prevalence of DBS test positivity was higher than 0.5% (1.3%). Genetic test confirmed involvement of GBA genes, all but one in heterozygosity fashion. This study allowed to identify one patient with MM and GD1 requiring therapy for both diseases at the same time. The results of this study support further investigations on the implication of the GD1 in the pathogenesis and management of MM. More data on MM patient subgroups at higher risk of associated GD1 may be provided.

Prevalence of Type 1 Gaucher Disease in Patients with Multiple Myeloma: Updated Interim Analysis of a Prospective, Multicentre, Observational Study

Introduction. Type I Gaucher disease (GD1) is an autosomal recessive lysosomal storage disease, caused by deficiency of the enzyme glucocerebrosidase, that degrades glycosphingolipids, resulting in a storage of them with/without enlargement of vital organs and complex bone involvement. GD1 is characterized by its extreme heterogeneity including asymptomatic or more severe presentations. In GD1, aberrant macrophage activation and immune dysregulation are associated with increased cancer risk, particularly Multiple Myeloma (MM), whose risk was estimated at almost 37-fold compared to the general population [Mistry, Crit Rev Oncog 2013]. Recent studies even described biological implications of sphingolipid metabolism alterations in the regulation of MM development and its progression from the pre-malignant stage, discussed the roles of sphingolipids in MM migration and adhesion, survival, proliferation, angiogenesis and invasion [Petrusca, Front Oncol. 2022]. The International Collaborative Gaucher Group (ICGG) Registry comprising 2742 eligible patients [Rosenbloom BE et al, 2005] found there was a 5.9-fold (95% CI 2.8-10.8) increased risk of Multiple Myeloma (MM) in patients with GD1. However, this risk was likely underestimated in this study because the younger age distribution of the study population and incomplete ascertainment because the ICGG is an observational registry to track responses to treatment. Despite the association between GD1 and cancer, specifically MM, is well-documented there's not enough data on the association of cancer with GBA mutation carriers. Moreover, data describing the prevalence of GD1 in MM patients are lacking. So, we prospectively investigated the prevalence of GD1 in a large population of patients affected by MM, also collecting the prevalence of GBA mutation carriers in the same population. Methods. This is an observational, prospective, cross-sectional, multicentre study. The primary objective was to determine the prevalence of Dried Blood Spots (DBS) test positivity in a large prospective MM population. Patients with DBS test positivity were then purposed for genetic test to confirm the diagnosis GD1. The DBS test will be centralized at the Istituto per la Ricerca e l'Innovazione Biomedica CNR-Palermo. Considering that no effective prevalence data of GD1 in patients with MM are available, the sample size has been determined considering clinically relevant a prevalence > 0.5% for defining as "high risk” the selected population. To test this hypothesis (alpha 5%, beta 5% errors), we will enrol approximately 1000 patients. Results. At the present data cut-off, 454 patients have been enrolled, so far. Median age was 67 years (range 37-90 years) and 56% of patients were male. No patients was of Jew ethnicity, one was Asian and one was black, Caucasian the remaining. Fifty-five percent had newly diagnosed MM while 45% had relapsed-refractory MM. Ten percent of patients had smouldering MM and 60% of all patients enrolled had prior diagnosis of MGUS. Monoclonal component was IgG in 56%, IgA in 24%, light chain in 10%. Median Ferritin was 325 ng/ml (range 17-1236 ng/ml) and median Alkaline Phosphatase was 83 U/L (range 29-355 U/L). At July data cut-off, we identified 6 patients with low glucocerebrosidase enzyme activity by DBS screening (< 4 nM/h/ml). Among them, 5 had heterozygous mutation in GBA gene (enzymatic activity 2.7, 3.4, 3.9, 2.5 and 3.5 nM/h/ml) whereas one was double heterozygous (enzymatic activity 2.0 nM/h/ml). This patient had Lyso Gb1 high level (14.6 ng/ml) and than he started eliglustat for GD1 in conjunction with therapy for MM. Considering only this patient as DBS positive the prevalence was 1/454 (0.22%), so far. Conclusions. Despite the trial enrolment is just in the first third of the whole planned sample size, our preliminary data showed an interesting prevalence of DBS test positivity. Data updates are needed to define the real incidence of DBS test positivity in MM and the relationship of GD1 and plasma cell disorders. Acknowledgment. This study is supported by Sanofi Genzyme

Long-term bone outcomes in Italian patients with Gaucher disease type 1 or type 3 treated with imiglucerase: A sub-study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

BackgroundGaucher disease (GD) is a lysosomal storage disorder. We evaluated the “real-world” effectiveness of first-line imiglucerase on long-term bone outcomes in Italian patients in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. MethodsPatients treated with imiglucerase for ≥2 years and with bone assessments at baseline and during follow-up were selected. Data on bone pain, bone crises, marrow infiltration, avascular necrosis, infarction, lytic lesions, Erlenmeyer flask deformity, bone fractures, mineral density, and imiglucerase dosage were evaluated. ResultsData on bone manifestations were available for 73 of 229 patients (31.9 %). Bone crises frequency decreased significantly from baseline to the most recent follow-up (p < 0.001), with some improvement observed in bone pain prevalence. Bone pain and bone crises prevalence decreased significantly from baseline at 2 to <4 and 4 to <6 years (all p < 0.05). A low median (25th, 75th percentile) baseline imiglucerase dosage was identified in patients reporting bone pain or bone crises (15.0 [13.7, 30.0] and 22.8 [17.5, 36.0] U/kg once every 2 weeks, respectively). ConclusionOur study suggests that the management of GD in Italy, with regards to imiglucerase dosage, is suboptimal and confirms the need for clinicians to monitor and correctly treat bone disease according to best practice guidelines.

Baseline characteristics of 32 patients with Gaucher disease who were treated with imiglucerase: South African data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

Background. Gaucher disease (GD) is a rare inherited autosomal recessive metabolic disorder with a prevalence in the general population of ~1 per 100 000. To optimise the recognition, diagnosis and management of patients with GD in South Africa (SA), it is important to have an understanding of local patterns of presentation of the disease. Objectives. To describe the baseline pretreatment characteristics of the SA cohort of patients enrolled into the International Collaborative Gaucher Group (ICGG) Gaucher Registry whowere treated with imiglucerase (Cerezyme; Sanofi Genzyme). Methods. The ICGG Gaucher Registry is an observational, longitudinal, international database that tracks the clinical, demographic, genetic, biochemical and therapeutic characteristics of patients with GD globally, irrespective of disease severity, treatment status or treatment choice. The study population included all SA patients reported in the ICGG Gaucher Registry as of 1 May 2020. Results. The registry included 49 SA GD patients, of whom 32 received imiglucerase as first primary GD therapy. All the patients had GD type 1, 59.4% were female, and mean and median ages at diagnosis were 14.7 and 9.8 years, respectively. The most common genotype was N370S/N370S (37.5%). At treatment initiation, 30.0% of patients had been splenectomised. Among patients for whom data were available, anaemia was present in one-third of non-splenectomised patients and 12.5% of those with splenectomy, and moderate or severe thrombocytopenia was reported in two-thirds of non-splenectomised patients. Bone pain was present in 30.8% and 57.1% of non- splenectomised and splenectomised patients, respectively. No bone crises were reported, and data relating to other bone complications were available for only ≤3 patients. Conclusions. Haematological findings and bone pain in this group are similar to those in the global ICGG Gaucher Registry cohort. Lack of baseline data for other bone complications limits interpretation in that regard. Clinicians who treat patients with GD are encouraged to submit accurate, complete and up-to-date information so that comprehensive data for the subset of SA GD patients can be maintained to improve recognition and diagnosis, and guide appropriate and effective use of treatment for SA patients.

The International Collaborative Gaucher Group GRAF (Gaucher Risk Assessment for Fracture) score: a composite risk score for assessing adult fracture risk in imiglucerase-treated Gaucher disease type 1 patients

BackgroundFractures in Gaucher disease type 1 (GD1) patients cause significant morbidity. Fracture risk may be decreased by enzyme replacement therapy (ERT) but not eliminated. When considering initiation of treatment, it is useful to know to what extent fixed patient-specific factors determine risk for future fractures beyond standard risk factors that change with time and treatment, such as decreased bone mineral density. We developed a tool called the GRAF score (Gaucher Risk Assessment for Fracture) that applies 5 widely available characteristics (sex, age at treatment initiation [ATI], time interval between diagnosis and treatment initiation, splenectomy status, history of pre-treatment bone crisis) and provides a practical method to assess future fracture risk when imiglucerase ERT is initiated.MethodsInclusion criteria: GD1 patients in the International Collaborative Gaucher Group Gaucher Registry as of September 2019 initially treated with alglucerase/imiglucerase; known splenectomy status; at least one skeletal assessment on treatment (3216 of 6422 patients). Data were analyzed by ATI group (< 18, ≥ 18 to < 50, or ≥ 50 years of age) using Cox proportional hazards regression with all 5 risk factors included in the multivariable model. A composite risk score was calculated by summing the contribution of each parameter weighted by the strength of its association (regression coefficient) with fracture risk.ResultsPatients were followed from the date of treatment initiation (or age 18 years for patients if treatment started earlier) to the date of first adult fracture (n = 288 first fracture endpoints), death, or end of follow-up. The GRAF score for each ATI group was associated with a 2.7-fold increased risk of adult fracture for each one-point increase (p < 0.02 for < 18 ATI, p < 0.0001 for ≥ 18 to < 50 ATI and ≥ 50 ATI).ConclusionsThe GRAF score is a tool to be used with bone density and other modifiable, non-GD-specific risk factors (e.g. smoking, alcohol intake, frailty) to inform physicians and previously untreated GD1 patients about risk for a future fracture after starting imiglucerase regardless of whether there is an eventual switch to an alternative ERT or to substrate reduction therapy. GRAF can also help predict the extent that fracture risk increases if initiation of treatment is further delayed.

Hematologic malignancies and monoclonal gammopathy of undetermined significance in Gaucher disease type 1 patients in the International Collaborative Gaucher Group Gaucher Registry

Hematologic malignancies and monoclonal gammopathy of undetermined significance in Gaucher disease type 1 patients in the International Collaborative Gaucher Group Gaucher Registry

Transformation in pre-treatment presentations of Gaucher disease during the first two decades of imiglucerase enzyme replacement therapy: a report from the International Collaborative Gaucher Group Gaucher Registry

Transformation in pre-treatment presentations of Gaucher disease during the first two decades of imiglucerase enzyme replacement therapy: a report from the International Collaborative Gaucher Group Gaucher Registry

The history and accomplishments of the ICGG Gaucher registry.

The history and accomplishments of the ICGG Gaucher registry.

Foreword.

The International Collaborative Gaucher Group (ICGG) Gaucher Registry (clinicaltrials.gov NCT00358943) is the largest observational study of patients and Gaucher disease in the world. As a recipient of data from the Registry, the National Gaucher Foundation (NGF) has been able to see firsthand the benefits it provides to the medical community, researchers, patients, and physicians. Through the Registry, patients and physicians have been brought closer together; patients have been able to play a greater role in their health and physicians, after learning how potentially life-saving information could be shared with others, have become more eager to participate in and add patient data to the Registry. An important outcome is that, as a prototype, the Registry showed physicians that data can be used effectively to better understand disease and establish a standard of care. In the past, there had been many disagreements and differences of opinion about the management of Gaucher disease, but the Registry has enabled sharing of “best practice” and the development of more uniform treatment and care programs, which have ultimately improved patients’ lives. Without Registry data, for example, we would not have learned how quickly the skeleton and other organs are adversely affected by Gaucher disease, and this has created a greater sense of urgency regarding diagnosis and treatment. For more than 20 years, through its participating physicians and dedicated staff, the Registry has successfully implemented its mission to increase the understanding of the intricacies of Gaucher disease and to improve the lives of those living with this often debilitating and sometimes fatal disease. The European Gaucher Alliance (EGA) congratulates Genzyme, a Sanofi company, on the establishment of the ICGG Gaucher Registry more than 20 years ago and on the contribution the Registry has made to the Gaucher community over the last two decades. The forethought in the establishment of the Registry was creative and has allowed those with access to its data to take a long view of disease progression and the impact of therapy. The Gaucher Registry has been an invaluable resource in enhancing knowledge and understanding of the manifestations and progression of Gaucher disease amongst the whole Gaucher community, which has undoubtedly resulted in improved clinical management. Information from the Registry has also been an invaluable tool in educating clinicians new to the field of Gaucher disease. The ICGG Neurological Outcomes Subregistry was introduced in recognition of the complexities faced by this group of patients needing specific data collection and has helped to identify unmet needs and the necessity for additional monitoring in patient care. The further development and enhancement of Registry data collection over the years has offered the Gaucher community a resource for increasing the understanding and management of Gaucher disease, for supporting areas of unmet needs by stimulating research, and for fuelling the publication of peer-reviewed papers that are available globally to those involved in treating patients. The impact of the Registry is felt by Gaucher patients every day and, on behalf of Gaucher patients, the EGA wishes to express its thanks to all who have been involved with the ICGG Gaucher Registry throughout the years. The authors acknowledge Genzyme, a Sanofi company, for supporting this publication with an unrestricted grant. The opinions expressed in this article are those of the authors and do not necessarily reflect those of Genzyme.

Afterword.

Some two decades have passed since the introduction of the first effective, specific therapy for an intracellular enzyme deficiency state, Gaucher disease, and this therapy provided a positive transformation of the lives of people suffering from this devastating disease. As is evident from the contributions in this supplement, much more has been learned than just the ability to alleviate many of the Gaucher disease manifestations in afflicted individuals. Fundamental to progress in learning more about Gaucher disease has been the compilation and analysis of Gaucher disease manifestations, their natural progression, their response to specific therapies, and the emergence of comorbidities. This knowledge can only be derived from datasets of sufficient size to allow rigorous analyses. The International Collaborative Gaucher Group (ICGG) Gaucher Registry (clinicaltrials.gov NCT00358943), with its independent oversight, continues to provide detailed and expanding datasets to facilitate such analyses and encourage investigators to ask penetrating, patient-relevant questions. As Grabowski et al. point out in their contribution to this supplement, ICGG Gaucher Registry analyses have radically changed the perception of Gaucher disease type 1 from a late-onset indolent disorder to a disease that has onset during the pediatric years in >50% of patients with the disease (i.e., a progressive disease of childhood and adolescence). This is true even in patients with the “mild N370S/N370S genotype,” indicating the need to abandon such subjective attributions to genotypes. As highlighted by Mistry et al. in the first review of this supplement, long-term, progressive morbidity of untreated or late-treated adults with Gaucher disease type 1 is now well-delineated and an essential part of the decision-making process around treatment options. Also, as reviewed by Charrow et al., sufficient data are now becoming available from the ICGG Gaucher Registry to track treatment outcomes over the long-term, and identify the limits of enzyme replacement therapies (ERTs). Certainly, these outcomes provide comparison standards for other new therapeutic approaches. Critically important has been the emerging recognition of comorbidities in Gaucher disease type 1, including malignancies and Parkinson's/Lewy body disease, which Cox et al. review in their contribution to this supplement. Clearly, further studies/analyses will elucidate the expected ethnic and demographic variations in Gaucher disease type 1 so that therapeutic interventions can not only be tailored to the individual, but also to his/her specific ethnic predilections to ensure greater personalized treatment programs and enhanced outcomes. Of additional significance to the field of lysosomal storage diseases (LSDs), the ICGG Gaucher Registry is a prototype for the other LSD registries, analyses, and directions. These other registries are now becoming sufficiently mature to contribute, similarly to the ICGG Gaucher Registry, to enhanced and data-driven improvements in patient care. In this way, the ICGG Gaucher Registry, similar to ERT for Gaucher disease type 1, has been transformative for patients and for the field of LSDs and their treatments. The author thanks Laura Croal, PhD (medical communications manager for Gaucher disease, Genzyme Global Medical Affairs), Pam Pickering of Conscience Creative, and Cheryl Lathrop for editorial assistance, which was funded by Genzyme, a Sanofi company. This publication was supported by an unrestricted grant from Genzyme, a Sanofi company. The opinions expressed in this article are those of the author and do not necessarily reflect those of Genzyme.

Gaucher disease and comorbidities: B-cell malignancy and parkinsonism.

Data emerging from the International Collaborative Gaucher Group (ICGG) Gaucher Registry together with other contemporary clinical surveys have revealed a close association between Gaucher disease and non-Hodgkin's B-cell lymphoma and myeloma and Gaucher disease and Parkinson's disease. Several possible explanations for increased B-cell proliferation and neoplasia in Gaucher disease have been proposed, including the possible influence of sphingosine (derived from the extra lysosomal metabolism of glucosylceramide), gene modifiers, splenectomy and immune system deregulation induced by cytokines, chemokines, and hydrolases released from Gaucher cells. Parkinson's disease is frequently seen in the otherwise-healthy relatives of Gaucher disease patients leading to the finding that GBA mutations represent a genetic risk factor for Parkinson's disease. The mechanism of the association between GBA mutations and Parkinson's disease has yet to be elucidated but the pathogenesis appears distinct from that of Gaucher disease. Several pathogenic pathways have been proposed including lysosomal and/or mitochondrial dysfunction. The effect of Gaucher disease specific therapies on the incidence of cancer or Parkinson's disease are not clear and will likely be evaluated in future ICGG Gaucher Registry studies.

Understanding the natural history of Gaucher disease.

Gaucher disease is a rare and extraordinarily heterogeneous inborn error of metabolism that exhibits diverse manifestations, a broad range of age of onset of symptoms, and a wide clinical spectrum of disease severity, from lethal disease during infancy to first age of onset of symptoms in octogenarians. Before the advent of the International Collaborative Gaucher Group (ICGG) Gaucher Registry, the understanding of the natural history and phenotypic range of Gaucher disease was based on isolated case reports and small case series. Limited data hindered understanding of the full spectrum of the disease leading to some early misconceptions about Gaucher disease, notably, that nonneuronopathic (type 1) disease was a disease of adults only. The global scope of the ICGG Gaucher Registry, with its vast body of longitudinal data, has enabled a real appreciation of both the phenotypic spectrum of Gaucher disease and its natural history. This body of evidence represents the foundation for accurate assessment of the response to specific therapies for Gaucher disease and to the development of standard-of-care to monitor disease activity. Here, we outline the key developments in delineating the natural history of this highly complex disease and role of the ICGG Gaucher Registry in this effort.

Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry.

Study of the natural history of Gaucher disease has revealed marked phenotypic variation. Correlations to genotypes could provide insight into individual susceptibility to varying disease severity, which may impact whole-life medical care, reproductive decisions, and therapeutic choices for affected families. Importantly, pre-symptomatic or prospective interventions or the use of therapies with significant risk require accurate risk-benefit analyses based on the prognosis for individual patients. The body of international data held within the International Collaborative Gaucher Group (ICGG) Gaucher Registry provides an unprecedented opportunity to characterize the phenotypes of Gaucher disease types 1 and 3 and to appreciate demographic and ethnic factors that may influence phenotypes. The diversity of GBA gene mutations from patients with Gaucher disease represented in the ICGG Gaucher Registry database and in the literature provides the basis for initial genotype/phenotype correlations, the outcomes of which are summarized here.

Predictors of fracture in treated Gaucher disease patients

Skeletal complications, particularly fracture, can be one of the most debilitating consequences of Gaucher disease (GD). Understanding the risk factors for fracture and the relationship to timing of initiation of treatment is important for successful evaluation and management of patients. The International Collaborative Gaucher Group (ICGG) Gaucher Registry is a multinational, observational study (sponsored by Genzyme, a Sanofi company, Cambridge, MA) that captures clinical outcomes in both treated and untreated GD patients. Descriptive statistics and an adjusted logistic regression model were used to evaluate demographics and risk factors in patients enrolled in the ICGG Registry with GD type 1who had experienced a fracture. A total of 4047 patients with GD type 1 in the ICGG Registry who had received imiglucerase had sufficient bone and splenectomy data for analyses. Of these, 46% were male, the median age of diagnosis was 15 years of age, and 336 patients (8%) had experienced a fracture during treatment. Splenectomized patients were nearly twice as likely to have a fracture compared to those who were not (OR 1.930; p = b0.0001). The presence of bone pain or bone crisis (acute pain requiring immobilization, narcotics, and accompanied by periosteal elevation, elevated WBC count, fever and/or debilitation of N3 days) was a predictor of fracture, even if reported considerably prior to the fracture itself. Patients with bone pain were 2.5 times more likely to have a fracture (OR 2.683; p = b0.0001); those with bone crises were nearly twice as likely (OR 1.739; p = b0.0004). Additionally, early treatment decreased fracture risk. Patients who did not begin treatment until after the age of 25 were 30% (OR 1.373; p = 0.0132) more likely to have a fracture. The 3711 patients who did not have a fracture were diagnosed (median age: 14 years) and treated (median age: 27 years) younger than the 336 with a fracture who were diagnosed (median age: 17.5 years) and treated (median age: 37 years) later. Understanding risk factors, symptoms, and treatment patterns is important to avoid potential fractures. Splenectomy, bone pain, and bone crisis substantially elevate risk of fractures in patients on therapy, and should be considered early warning signs. Younger age at treatment initiation lowers the risk of fracture, suggesting that developing bone pathologymay be interrupted when early treatment is provided.

ZFN-mediated genome editing of albumin “safe harbor” in vivo results in supraphysiological levels of human IDS, IDUA and GBA in mice

Skeletal complications, particularly fracture, can be one of the most debilitating consequences of Gaucher disease (GD). Understanding the risk factors for fracture and the relationship to timing of initiation of treatment is important for successful evaluation and management of patients. The International Collaborative Gaucher Group (ICGG) Gaucher Registry is a multinational, observational study (sponsored by Genzyme, a Sanofi company, Cambridge, MA) that captures clinical outcomes in both treated and untreated GD patients. Descriptive statistics and an adjusted logistic regression model were used to evaluate demographics and risk factors in patients enrolled in the ICGG Registry with GD type 1who had experienced a fracture. A total of 4047 patients with GD type 1 in the ICGG Registry who had received imiglucerase had sufficient bone and splenectomy data for analyses. Of these, 46% were male, the median age of diagnosis was 15 years of age, and 336 patients (8%) had experienced a fracture during treatment. Splenectomized patients were nearly twice as likely to have a fracture compared to those who were not (OR 1.930; p = b0.0001). The presence of bone pain or bone crisis (acute pain requiring immobilization, narcotics, and accompanied by periosteal elevation, elevated WBC count, fever and/or debilitation of N3 days) was a predictor of fracture, even if reported considerably prior to the fracture itself. Patients with bone pain were 2.5 times more likely to have a fracture (OR 2.683; p = b0.0001); those with bone crises were nearly twice as likely (OR 1.739; p = b0.0004). Additionally, early treatment decreased fracture risk. Patients who did not begin treatment until after the age of 25 were 30% (OR 1.373; p = 0.0132) more likely to have a fracture. The 3711 patients who did not have a fracture were diagnosed (median age: 14 years) and treated (median age: 27 years) younger than the 336 with a fracture who were diagnosed (median age: 17.5 years) and treated (median age: 37 years) later. Understanding risk factors, symptoms, and treatment patterns is important to avoid potential fractures. Splenectomy, bone pain, and bone crisis substantially elevate risk of fractures in patients on therapy, and should be considered early warning signs. Younger age at treatment initiation lowers the risk of fracture, suggesting that developing bone pathologymay be interrupted when early treatment is provided.

Patients with type 1 Gaucher disease in South Florida, USA: demographics, genotypes, disease severity and treatment outcomes

BackgroundGaucher disease, an autosomal recessive condition due to deficiency of lysosomal glucocerebrosidase, is a multisystemic disease, with variable age of onset, severity and progression. It is classified into subtypes delineated by the absence (type 1) or presence (type 2 and 3) of primary nervous system involvement.The ethnically diverse, largely immigrant population in South Florida has a spectrum of Gaucher disease phenotypes, creating a challenge for optimization of disease management and an opportunity to explore treatment patterns.MethodsNinety-three records from patients with Gaucher type I in South Florida were retrieved from the International Collaborative Gaucher Group (ICGG) Registry. Individual genotypes were correlated with severity scores and success at achieving published therapeutic goals for haemoglobin concentration, platelet count, spleen volume, liver volume and amelioration of bone pain and bone crises.ResultsThe majority of patients were diagnosed during the fifth decade of life. Almost two-thirds were homozygous for the N370S mutation, reflecting the large Ashkenazi Jewish population in South Florida. The majority received imiglucerase (62.8%) at various intervals. 24.5% of patients underwent splenectomy before starting enzyme replacement therapy. After a median 12 treatment years, South Florida patients matched or exceeded the ICCG 4 year therapeutic goal achievement for platelet count (85.4% vs. 79.6% success), spleen volume (93.3% vs. 78.0% success), liver volume (93.4% vs. 90.6% success), and bone crises (100% vs. 99% success). Nevertheless, fewer patients with intact spleens had sustained achievement of all 6 therapeutic goals (30.4% versus 41.4%) and only 40% of the splenectomy patients sustained achievement of 5/5 possible goals. 54.7% of the intact spleen patients continued to have bone pain vs. 29.8% in ICCG. Significantly, only 37% of the ICGG patient cohort had bone pain prior to initiation of treatment compared to 73.4% of the South Florida patients (moderate or severe pain in 59.6%).ConclusionsDemographic characteristics are a significant determinant of the differences in response to treatment observed in South Florida Gaucher patients compared to those described in the international population enrolled in the ICGG Gaucher Registry. Individual genotypes and ethnic background are important considerations for optimizing patient care for Gaucher disease.

GAUCHER’S DISEASE

The article gives data on epidemiology, pathogenesis, modern classification and the main clinical manifestations of Gaucher’s disease in children; it also gives criteria of differential diagnostics with other diseases. The article shows that the only effective method of treating Gaucher’s disease is pathogenic enzyme-substitutive therapy which arrests the main clinical manifestations of the disease improving life quality of patients without pronounced side effects. Imiglucerase is used for such treatment; it causes hydrolysis of glucocerebroside into glucose and ceramide (regular metabolism of membrane lipids). Imiglucerase is indicated for long-term enzyme-substitutive therapy in patients with confirmed Gaucher’s disease (types 1 and 3). It is recommended to monitor condition of patients in the setting of therapy in compliance with the requirements of the International Collaborative Gaucher Group. The article cites the main mistakes of diagnostics and management of such patients and ungrounded prescriptions when treating this disease.