A Global Delphi Consensus Initiative for Early Diagnosis of Gaucher Disease: Key Presenting Signs and Patient Co-Variables in Type 1 Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3676-3676
Author(s):  
David J Kuter ◽  
Sam Salek ◽  
Atul Mehta
Keyword(s):  
Scoring System ◽  
Gaucher Disease ◽  
Research Funding ◽  
Diagnostic Testing ◽  
Likert Scale ◽  
Western Hemisphere ◽  
Free Text ◽  
Early Type ◽  
Major Factors

Abstract Background: Gaucher disease (GD) is associated with a broad spectrum of signs and symptoms, with phenotypes ranging from fatal perinatal to asymptomatic adult forms. Given the heterogeneous presentation and rarity of the disease, misdiagnosis is common and diagnosis is often delayed, which can lead to avoidable morbidities and potentially irreversible tissue damage. Among the three phenotypes of GD, type 1 is the most prevalent in the Western hemisphere. As part of the global Gaucher earlier diagnosis consensus (GED-C) initiative, we report here the signs and patient co-variables that are regarded by expert physicians as most indicative of type 1 GD in its early stages. The overarching goal of the GED-C initiative is to generate a web-based point-scoring system that can be used by clinicians across specialties to facilitate identification of patients who may benefit from diagnostic testing for GD. Methods: In an anonymous iterative Delphi process, a panel of expert physicians was asked to provide free-text answers to a series of open questions, including: "Which unexplained signs and co-variables may be important to consider in early type 1 GD?" An independent facilitator categorized responses from round 1 into themes, which were checked and consolidated by the two non-voting co-chairs of the initiative to generate a set of summary factors. In round 2, panel members independently rated the importance of each factor using a 5-point Likert scale (1 = not important, 5 = extremely important). Factors assigned an importance score of at least 3 by more than 75% of respondents were provisionally classified as major; other factors were classified as minor. In round 3, panel members rated their level of agreement with the provisional classification of factors as major using a 5-point pivoted Likert scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree). Consensus was defined as more than 67% of respondents agreeing or strongly agreeing (a score of ≥ 4) with the classification; if consensus was not reached, factors were classified as minor. Results: In total, 22 physicians with expertise in type 1 GD were recruited to the GED-C panel from 16 countries. Round 1 (100% response, n = 22) yielded 104 phrases, which were grouped into 38 themes, then consolidated as 21 factors. In round 2 (100% response, n = 22), 10 factors were provisionally classified as major. In round 3 (100% response, n = 22), consensus was reached on 9 major factors in early type 1 GD, including 7 presenting signs and 2 patient co-variables. The mean importance scores (round 2) and agreement scores (round 3) awarded to these 9 major factors are given in Table 1. Minor factors included asthenia, bleeding or bruising, dyslipidaemia, fatigue, gallstones, growth retardation, low bone mineral density and a family history of Parkinson disease. Table 1. Mean scores of importance and agreement for 9 major factors in rounds 2 and 3, respectively. Discussion: Definitive diagnostic tests for GD have been available for several years, but patient referral for testing is impeded by several issues, including a general lack of knowledge among clinicians of the signs and co-variables that should arouse a suspicion of GD. The presenting signs and patient co-variables identified by this multidisciplinary consensus initiative will help clinicians to identify those patients who may benefit from diagnostic testing for GD. Several algorithms have been devised with the aim of facilitating GD diagnosis, but these may be perceived as complex by the non-specialist. The next stage of the GED-C initiative will be to use the factors identified here to create a point-scoring system that clinicians of any specialty can use to obtain clear direction regarding the need to test a patient for GD. Acknowledgment: Submitted on behalf of the GED-C panel members and the European Hematology Association Scientific Working Group 'Quality of Life and Symptoms'. Administration of the GED-C initiative was funded by an unrestricted educational grant from Shire. Table 1. Table 1. Disclosures Kuter: Amgen: Consultancy; Eisai: Consultancy; Genzyme: Consultancy; GlaxoSmithKline: Consultancy; ONO: Consultancy; Pfizer: Consultancy; Shionogi: Consultancy; Shire: Consultancy; 3SBios: Consultancy; Bristol-Myers Squibb: Research Funding; Protalix: Research Funding; Rigel: Research Funding. Salek:Agios: Consultancy; Servier: Consultancy; Shire: Consultancy; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Mehta:Actelion: Honoraria, Other: Travel grants, Research Funding; Genzyme: Honoraria, Other: Travel grants, Research Funding; Protalix/Pfizer: Honoraria, Other: Travel grants, Research Funding; Shire: Honoraria, Other: Travel grants, Research Funding.

Key Presenting Signs and Patient Co-Variables in Early Diagnosis of Type 3 Gaucher Disease: A Global Delphi Consensus Initiative

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4886-4886 ◽  
Author(s):  
David J Kuter ◽  
Sam Salek ◽  
Atul Mehta
Keyword(s):  
Early Diagnosis ◽  
Expert Testimony ◽  
Gaucher Disease ◽  
Research Funding ◽  
Diagnostic Testing ◽  
Early Type ◽  
Travel Grant ◽  
Major Factors ◽  
Type 3

Abstract Background: Among the three phenotypes of Gaucher disease (GD), type 1 is the most prevalent in the Western hemisphere, but types 2 and 3 are increasingly seen, and occur with similar prevalence to type 1 in parts of Asia. There is a spectrum of signs and symptoms among these phenotypes, which range from fatal perinatal to asymptomatic adult disease, and this heterogeneity contributes to relatively high levels of misdiagnosis and delays in diagnosis of GD. As part of the global Gaucher earlier diagnosis consensus (GED-C) initiative, we report here the signs and patient co-variables that are regarded by expert physicians as most indicative of type 3 GD in its early stages. The overarching goal of the GED-C initiative was to generate a web-based point-scoring system for use across clinical specialties to facilitate identification of patients who may benefit from diagnostic testing for GD. Methods: In an anonymous, iterative Delphi process, a panel of expert physicians was asked to provide free-text answers to a series of open questions, including: "Which unexplained signs and co-variables may be important to consider in early type 3 GD?" An independent facilitator categorized responses from round 1 into themes, which were checked and consolidated by the two non-voting co-chairs of the initiative to generate a set of summary factors. In round 2, panel members independently rated the importance of each factor using a 5-point Likert scale (1 = not important, 5 = extremely important). Factors that were assigned an importance score of at least 3 by more than 75% of respondents were provisionally classified as major; other factors were classified as minor. In round 3, panel members rated their level of agreement with the provisional classification of factors as major using a 5-point pivoted Likert scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree). Consensus was defined as more than 67% of respondents agreeing or strongly agreeing (a score of ≥ 4) with the classification; if consensus was not reached, factors were classified as minor. Results: In total, 19 physicians with expertise in type 3 GD were recruited to the GED-C panel from 14 countries. Round 1 (100% response, n = 19) yielded 70 phrases, which were grouped into 34 themes, then consolidated as 23 factors. In round 2 (100% response, n = 19), 16 factors were provisionally classified as major. In round 3 (100% response, n = 19), consensus was reached on 10 major factors in early type 3 GD, including 9 presenting signs and 1 patient co-variable. The mean importance scores (round 2) and agreement scores (round 3) awarded to these 10 major factors are given in Table 1. Minor factors included bleeding or bruising, cardiovascular calcification, cognitive deficit, growth retardation, hyperferritinaemia, aged 18 years or younger, Jewish ancestry and a family history of Parkinson disease. Discussion: Definitive diagnostic tests for GD have been available for several years, but patient referral for testing is impeded by several issues, including a lack of knowledge among clinicians of the signs and co-variables that should arouse suspicion of GD. In type 3 GD, the problem is exacerbated by the relative rarity of the phenotype. Presenting signs and patient co-variables identified by this multidisciplinary consensus initiative will help clinicians identify those patients who may benefit from diagnostic testing for GD. Several algorithms have been devised to facilitate GD diagnosis, but non-specialists may perceive these as complex. The GED-C initiative will use the factors identified here to create a point-scoring system that clinicians of any specialty can use to obtain clear direction regarding the need to test a patient for GD. Acknowledgment: Submitted on behalf of the GED-C panel members and the European Hematology Association Scientific Working Group 'Quality of Life and Symptoms'. Administration of the GED-C initiative was funded by an unrestricted educational grant from Shire. Table 1 Mean scores of importance and agreement for 10 major factors in early diagnosis of type 3 Gaucher disease. Table 1. Mean scores of importance and agreement for 10 major factors in early diagnosis of type 3 Gaucher disease. Disclosures Kuter: Eisai: Consultancy; Genzyme: Consultancy; MedImmune: Consultancy; Rigel: Consultancy, Research Funding; CRICO: Other: Paid expert testimony; Pfizer: Consultancy; Protalex: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Consultancy, Paid expert testimony; Bristol-Myers Squibb: Research Funding; ONO: Consultancy; Shionogi: Consultancy; Shire: Consultancy; Syntimmune: Consultancy; 3SBios: Consultancy. Salek:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Shire: Consultancy; Servier: Consultancy; Sanofi: Research Funding; Agios: Consultancy. Mehta:Protalix/Pfizer: Honoraria, Other: travel grant, Research Funding; Genzyme: Honoraria, Other: travel grant, Research Funding; Actelion: Honoraria, Other: travel grant, Research Funding; Shire: Honoraria, Other: travel grant, Research Funding.

scholarly journals A Global Delphi Consensus Initiative for Early Diagnosis of Gaucher Disease: Barriers, Their Resolution and the Impact on Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4885-4885
Author(s):  
David J Kuter ◽  
Sam Salek ◽  
Atul Mehta
Keyword(s):  
Clinical Practice ◽  
Early Diagnosis ◽  
Expert Testimony ◽  
Gaucher Disease ◽  
Research Funding ◽  
Likert Scale ◽  
Free Text ◽  
Heterogeneous Nature ◽  
Travel Grant ◽  
The Impact

Abstract Background: Diagnosis of Gaucher disease (GD) can be difficult and diagnostic delays are common in both adult and paediatric patients. This may in part be attributable to the heterogeneous nature of early presenting signs and symptoms in GD, which may result in patients consulting various specialists before a diagnosis is reached. As part of this global Gaucher earlier diagnosis consensus (GED-C) initiative, a panel of expert physicians was asked to determine the most important barriers to diagnosis of GD. The panel was also asked about the impact of the initiative if its primary objective of facilitating earlier diagnosis was realized. Methods: In round 1 of an anonymous, multi-stage, iterative Delphi process, the panel provided free-text answers to a series of open questions, including: "In your experience, what are the greatest barriers to diagnosis in patients with early GD?" and "Assuming that this initiative achieves its goal, what difference could it make to clinical practice?" An independent facilitator grouped the responses to these questions by theme, and these were checked and consolidated as summary statements by the two non-voting co-chairs of the GED-C initiative. In round 2, panel members independently rated the importance of each statement using a 5-point Likert scale (1 = not important, 5 = extremely important). Statements awarded an importance score of at least 3 by more than 75% of respondents were reissued in round 3, in which panel members rated their level of agreement with each statement using a 5-point pivoted Likert scale (1 = strongly disagree; 3 = neither agree nor disagree; 5 = strongly agree). Consensus was defined as more than 67% of respondents agreeing or strongly agreeing (a score of ≥ 4) with a statement. Results: In total, 22 experts from 16 countries were recruited to the GED-C panel. Round 1 (100% response, n = 22) yielded 47 phrases relating to barriers to diagnosis, and 30 relating to the impact of the initiative on clinical practice, which were consolidated as 9 statements describing barriers to diagnosis, and 8 summarizing the initiative's impact. In round 2 (100% response, n = 22) and round 3 (100% response, n = 22), 6 barrier statements and all 8 impact statements met the stipulated importance criteria, and consensus was then reached for all 6 barrier statements and for 7 impact statements (Table). Discussion: This initiative highlights that, as well as the heterogeneous nature of GD, clinicians' lack of awareness of GD and poor knowledge of important presenting signs probably contribute to incorrect or delayed diagnoses. The GED-C initiative aims to resolve this by providing clinicians with simple guidance regarding important factors in GD, thereby improving disease awareness and facilitating early diagnosis. This may improve understanding of the natural history of GD, patient management, and potentially patients' long-term outcomes. Acknowledgment: Submitted on behalf of the GED-C panel members and the European Hematology Association Scientific Working Group 'Quality of Life and Symptoms'. Administration of the GED-C initiative was funded by an unrestricted educational grant from Shire. Table Table. Disclosures Kuter: Bristol-Myers Squibb: Research Funding; ONO: Consultancy; Protalex: Research Funding; Eisai: Consultancy; Shionogi: Consultancy; 3SBios: Consultancy; Syntimmune: Consultancy; MedImmune: Consultancy; CRICO: Other: Paid expert testimony; Amgen: Consultancy, Paid expert testimony; Pfizer: Consultancy; Rigel: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Shire: Consultancy; Genzyme: Consultancy. Salek:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Shire: Consultancy; Servier: Consultancy; Sanofi: Research Funding; Agios: Consultancy. Mehta:Protalix/Pfizer: Honoraria, Other: travel grant, Research Funding; Genzyme: Honoraria, Other: travel grant, Research Funding; Actelion: Honoraria, Other: travel grant, Research Funding; Shire: Honoraria, Other: travel grant, Research Funding.

scholarly journals Not All Patients with Mild Phenotype of Gaucher Disease (GD) Need Disease Specific Treatment As Reflected By Patients Reported Outcomes Measures

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4712-4712
Author(s):  
Shoshana Revel-Vilk ◽  
Tama Dinur ◽  
Majdolen Istaiti ◽  
Dafna Frydman ◽  
Michal Becker-Cohen ◽  
...  
Keyword(s):  
Functional Status ◽  
Gaucher Disease ◽  
Research Funding ◽  
Financial Burden ◽  
Specific Therapy ◽  
Specific Patient ◽  
Mild Phenotype ◽  
Patient Reported ◽  
Disease Specific

The introduction of disease specific therapy for patients with type 1 Gaucher disease (GD) was a revolution in the management of patients, but not without significant cost to the patient and to society. The management of mildly effected patients is still debated, and reviews about GD as well as chapters in textbooks fail to emphasize the fact that some patients may remain untreated for many years without any GD-related complications. Patient reported outcome measures (PROMs) were developed as a way to ascertain patients' views of their symptoms, their functional status, and their health-related quality-of-life (HRQoL). In this study, we evaluated the responses to a GD -specific PROM of untreated patients with GD1 and compared them to patients on GD-specific therapy. Methods: A PROM survey was developed for GD including 15 questions; six Point Verbal Response Scale regarding the last month and nine Visual Analogue Scales (VAS) from 0-10 regarding the last week (Elstein D, et al. Molecular Genetics and Metabolism 2019;126:S52). The PROM survey was proven to be accurate in encompassing disease-specific patient concerns. A Hebrew translated version of the GD-PROM was sent via mobile phone survey to 400 adult patients with type 1 GD followed in our Gaucher Unit. Clinical data and treatment status were extracted from the clinical charts. T-test and Mann-Whitney U test were used to compare normally and non-normally distributed data in independent samples, respectively. IBM SPSS version 25 was used for analysis. Results were considered to be statistically significant when two-tailed P-values were ≤0.01. Results: A total of 181 patients responded (45% response rate) of whom 65 (36%) were followed for at least 5 years in our unit without receiving GD specific therapy, i.e. enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT). The median (range) age of patients, 49 (20-91) years, was not significantly different between treated and untreated patients. The percentage of patients with the N370S/N370S genotype was significantly higher in untreated patients [55/65 (85%)] compared to treated patients [67/116 (57%)]. Significantly more treated patients reported that GD had restricted their education/job (38, 34%) and fun activities (29,25%) compared to untreated patients, (4, 6.5%) and (2, 3%), respectively. Compared to untreated patients, treated patients were more worried to be an emotional burden on others [27 (23%) vs. 3 (5%)], of being financial burden on others [57 (50%) vs. 16 (25%)] and more concerned regarding the risk of bone disease [82 (74%) vs. 26 (40%)], and the risk of Parkinson disease [72 (64%) vs. 27 (42%)]. Treated patients had a significantly higher score on VAS for questions on swollen abdomen, fatigue, physical weakness, severity of bone pain and worry regarding the future over the past week compared to untreated patients (Table 1). Patients concern regarding the risk for cancer (32%) and VAS score for a question on depression were similar between groups. Conclusion:The GD-specific PROM survey shows that asymptomatic or mildly affected untreated patients with GD1 have good functional status and HRQoL, supporting our practice that not all patients with GD1 require disease-specific therapy. Still, we advise a periodic (annual or bi-annual) follow-up, preferably at a referral center. Inclusion of GD-specific PROMs in the periodic assessments is important for better understanding patients' perspectives. It is important to note that mildly affected and asymptomatic patients are mainly found among Ashkenazi Jews and from this aspect our cohort reflects patients' populations in Israel, USA, UK, etc. but less relevant to non-Jewish and particularly to Asian cohorts. With the expected increase in early diagnosis via parental and/or newborn screening the understanding that not all subjects diagnosed with GD needs disease-specific therapy is all the more important. Despite the expected differences between the more severely affected treated patients and the by definition milder untreated ones, still a high percentage of the treated patients show good HRQoL parameters, reflecting the overall success of ERT/SRT. Larger cohorts and further analysis will evaluate potential predictors for differences in PROMs within the treatment group. Disclosures Revel-Vilk: Sanofi: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Prevail therapeutics: Honoraria, Other: Travel, Research Funding. Zimran:Prevail Therapeutics: Consultancy; TAKEDA: Honoraria; Centogene: Other: research grant; Targeted Cell Therapies: Consultancy; Pfize: Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding; Bio-events: Honoraria.

Correlating liver stiffness with disease severity scoring system (DS3) values in Gaucher disease type 1 (GD1) patients

2018 ◽  
Vol 123 (3) ◽  
pp. 357-363 ◽  
Author(s):  
Suraj D. Serai ◽  
Anjani P. Naidu ◽  
T. Andrew Burrow ◽  
Carlos E. Prada ◽  
Stavra Xanthakos ◽  
...  
Keyword(s):  
Disease Severity ◽  
Scoring System ◽  
Gaucher Disease ◽  
Liver Stiffness ◽  
Disease Type ◽  
Severity Scoring ◽  
Gaucher Disease Type 1

scholarly journals Bone Marrow Involvement in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long Term Enzyme Replacement Therapy (median 18 years)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4862-4862
Author(s):  
Shoshana Revel-Vilk ◽  
Jeffrey Szer ◽  
Michal Becker Cohen ◽  
Ari Zimran
Keyword(s):  
Bone Marrow ◽  
Gaucher Disease ◽  
Research Funding ◽  
Low Dose ◽  
Bone Marrow Involvement ◽  
Bone Marrow Infiltration ◽  
Enzyme Replacement ◽  
Fat Fraction ◽  
Type 1 Gaucher Disease

Bone complications are the most dramatic and life-impairing outcomes of type 1 Gaucher disease (GD1), a common lysosomal storage disorder. Bone marrow infiltration by Gaucher cells substantially decreases the bone marrow fat fraction (FF), and the extent of this reduction correlates with the overall severity of skeletal manifestations in this disorder. Previous studies have demonstrated that the degree of infiltration can best be estimated by magnetic imaging resonance (MRI)-based quantitative chemical shift imaging (QCSI) and that the fat fraction (FF) score so derived can predict the risk of clinically important bone events. The aim of this study was to evaluate bone marrow involvement in GD1 patients who had received enzyme replacement therapy (ERT) for at least 5 years. Methods: Patients from SZMC Gaucher unit, ≥ 18 years, who were treated with ERT for ≥ 5 years, with a stable dose in the previous 6 months, were recruited. Patients taking another experimental drug, with past exposure to taliglucerase-alfa, presence of any medical, emotional, behavioral or psychological condition were excluded. Energy x-ray absorptiometry (DEXA) was performed at SZMC and the QSCI was performed at the Academic Medical Center in Amsterdam, Netherlands as previously described [Mass et al, Am J Radiol 2002:179:961-965]. A QCSI score of <0.30 was indicative of bone at risk. This investigator initiated clinical trial was approved IRB at SZMC and AMC and sponsored by Pfizer. Study number registration- MOH-2017-04-000351. Results: Thirty patients (13 females) at a median (range) age of 46 (19-71) years consented to participate in this study and to perform the QCSI test. GBA mutations of study patients included N370S homozygote (n=12), N370S compound heterozygote (n=17), and T431 homozygote (n=1). The median (range) duration of ERT was 18 (5-26) years. Thirteen patients were receiving imiglucerase as the primary ERT [median (range) duration, 19 (9-26) years], five patients were receiving velaglucerase alfa [median (range) duration, 11 ( 5-12) years], and 12 patients converted from imiglucerase to velaglucerase alfa [median (range) duration, 7 (6-10) years]. The majority of patients received low-dose regimen, i.e. 15 Units/kg/2 weeks (Table 1). The median (range) T score for lumbar spine from DEXA scans, available for 26 of 30 patients, was −1.3 (−2.8-0.0). The median (range) QCSI score was 0.42 (0.24-0.66). Seven patients, 23% (95% confidence interval 10%-42%), had abnormal QCSI FF scores (<0.30). Abnormal QSCI score was more common in female compared to male (Table 1) (p=0.025). Only one of these was menopausal. No differences were found in age, gender, genotype, history of splenectomy, duration and type of ERT and GD-related parameters between those with QSCI score of bone at risk to those with normal score (Table 1). In summary, these findings demonstrate that, despite prolonged treatment with imiglucerase and/or velalgucerase alfa, 23% of patients still had QCSI scores indicative of an inadequate response in bones. Nevertheless, most patients with prolonged low-dose ERT maintain a normal QCSI, indicative of a positive bone status. The higher prevalence of women in the cohort with low FF is not related to menopausal phase and remains unexplained. As no other patient-related nor GD-related parameter predicted abnormal bone marrow infiltration, a more widely available, quantitative measure of bone marrow infiltration is required for the assessment of response in bones to ERT for patients with GD1. The second phase of this study will evaluate the impact of a switch to a third ERT in those patients from this study with QCSI scores of <0.30. These patients will be offered treatment with taliglucerase alfa at equivalent doses and subsequent reassessment of any impact on clinical symptoms and QCSI scores evaluated. Disclosures Revel-Vilk: Takeda: Honoraria, Other: Travel, Research Funding; Prevail therapeutics: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding. Szer:Alexion: Honoraria, Other: Travel, Research Funding; Amgen: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Prevail Therapeutics: Honoraria, Other: Travel, Research Funding. Zimran:Centogene: Other: research grant; Shire: Consultancy, Honoraria, Research Funding; TAKEDA: Honoraria; Pfize: Honoraria, Research Funding; Bio-events: Honoraria; Targeted Cell Therapies: Consultancy; Prevail Therapeutics: Consultancy.

Engage: A Phase 3, Randomized, Double-blind, Placebo-controlled, Multi-center Study To Investigate The Efficacy and Safety Of Eliglustat In Adults With Gaucher Disease Type 1: 9 Month Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2275-2275 ◽  
Author(s):  
Suma Shankar ◽  
Elena Lukina ◽  
Dominick J Amato ◽  
Majed Dasouki ◽  
Seymour Packman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Gaucher Disease ◽  
Research Funding ◽  
Liver Volume ◽  
Disease Type ◽  
Spleen Volume ◽  
Advisory Committees ◽  
Gaucher Disease Type 1

Abstract Background Gaucher disease type 1 is one of the most common lysosomal storage disorders. Deficiency of the lysosomal enzyme acid-β-glucosidase leads to accumulation of glucosylceramide (GL-1) in the spleen, liver, and bone marrow. Enzyme replacement therapy has been the mainstay of therapy for the last 20 years. Substrate reduction therapy is another treatment approach that inhibits GL-1 synthase and ultimately restores the balance between synthesis and degradation of the substrate. Eliglustat is a novel oral substrate reduction therapy that is currently in development for the treatment of Gaucher disease type 1. ENGAGE (NCT00891202) is a randomized, double-blind, placebo-controlled, Phase 3 trial sponsored by Genzyme, a Sanofi company investigating the efficacy and safety of eliglustat in untreated adults with Gaucher disease type 1. Method Forty patients (mean age: 31.8 years; 20 males) with splenomegaly and thrombocytopenia and/or anemia were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg BID depending on plasma levels) or placebo for 9 months. The primary efficacy endpoint was percent change in spleen volume (multiples of normal). Other efficacy measures included hemoglobin, liver volume, and platelets. Bone endpoints included bone marrow burden (BMB) scores and bone mineral density changes (DXA). Quality of life assessments included the Gaucher Disease Severity Scoring System (DS3). Safety monitoring included adverse event reporting, and lab and electrocardiogram evaluations. Results In patients receiving eliglustat vs. placebo, mean spleen volume decreased (-28% vs. +2%, P<0.0001), mean hemoglobin increased (0.69 vs. -0.54 g/dL, P<0.0006), liver volume decreased (-5.20% vs. +1.44%, P<0.0072), and platelets increased (+32% vs. -9.06%, P<0.0001). Significant improvements (eliglustat vs. placebo) were observed for total (-1.1 vs. 0.0, p=0.002), spine (-0.6 vs. 0.1, p=0.002), and femur (-0.5 vs. 0.0, p=0.026) BMB scores. Although patients with symptomatic bone disease were excluded, absolute change in total spine DXA Z-scores approached significance (least square mean treatment difference=0.2, p=0.06). Burden of disease, as measured by the Gaucher DS3, was significantly reduced following treatment with eliglustat vs. placebo (least square mean treatment difference=-0.3, p=0.0452). No patients discontinued due to an adverse event, all of which were classified as mild to moderate, and 39/40 patients transitioned into the ongoing open-label trial. Arthralgia and nasopharyngitis occurred in >10% of eliglustat vs. placebo patients. Conclusion ENGAGE met its primary and secondary efficacy endpoints. Significant effects on bone marrow and a trend toward BMD improvement in spine were observed. Eliglustat treatment was effective and well-tolerated in untreated adults with Gaucher disease type 1. Disclosures: Shankar: Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Lukina:Genzyme, a Sanofi company: Consultancy, Honoraria, Speakers Bureau. Amato:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Packman:Genzyme, a Sanofi company: Consultancy, Research Funding. Pastores:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Balwani:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Mistry:Genzyme, a Sanofi company: Consultancy, Honoraria, Research Funding. Ross:Genzyme, a Sanofi company: Employment. Marulkar:Genzyme, a Sanofi company: Employment. Peterschmitt:Genzyme, a Sanofi company: Employment.

148. A validated disease severity scoring system for gaucher disease type 1

2009 ◽  
Vol 96 (2) ◽  
pp. S45
Author(s):  
Neal Weinreb ◽  
Maria Cappellini ◽  
Timothy Cox ◽  
Edward Giannini ◽  
Gregory Grabowski ◽  
...  
Keyword(s):  
Disease Severity ◽  
Scoring System ◽  
Gaucher Disease ◽  
Disease Type ◽  
Severity Scoring ◽  
Gaucher Disease Type 1

scholarly journals Preliminary Results of a Prospective Observational Study to Assess the Prevalence of Gaucher Disease in an Adult Population Affected By MGUS

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4868-4868
Author(s):  
Gaetano Giuffrida ◽  
Concetta Conticello ◽  
Daniela Nicolosi ◽  
Valeria Calafiore ◽  
Alessandra Romano ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Observational Study ◽  
Early Onset ◽  
Gaucher Disease ◽  
Research Funding ◽  
Confirmatory Test ◽  
Type I ◽  
Italian Population ◽  
Preliminary Results

INTRODUCTION: Gaucher disease (GD) is a rare, autosomal recessive genetic disorder. It is due to a deficiency of the lysosomal enzyme, glucocerebrosidase, which leads to an accumulation of its substrate, glucosylceramide, in tissue macrophage with damage to hematological, visceral, and skeletal organ systems. Although GD has a continuous spectrum of severity, it is traditionally classified into three forms: type 1 (chronic; lacking early onset neuronopathy), type 2 (acute; with early onset neuronopathy),and type 3 (chronic; with early onsetneuronopathy). Type 1GD accounts for more than 90% all GD patients. Its prevalence world-wide is 1 in 50,000-100,000 but it is as high as ~1 in 850 in individuals of Ashkenazi heritage. Type 1 GD is frequently associated to monoclonal gammopathies; despite the emergence of theories advanced to explain these observations, the cause remains unknown. OBJECTIVE: Aim of the ongoing observational study is to determine the prevalence of unrecognized type I GD in a selected Italian population with MGUS. MATERIALS AND METHODS: From January 2018, dried blood spots (DBS) sample from patients with laboratory evidence of MGUS coming from five hematology units of Sicily and Calabria were collected and tested for the acid β-glucosidase enzyme activity. The study was approved by the local institutional review board. All patients provided informed consent for the prospective collection of their data. In case of DBS positive result, a confirmatory test was carried over and, if GD was confirmed, the patient was referred to one of the Regional Reference Centers for Metabolic Disease, as for current clinical practice in Italy. RESULTS: To date, 308 patients with MGUS were enrolled; acid β-glucosidase enzyme activity was low in 22 patients (7%). Sequence analysis of GBA gene was performed in these selected patients, but we have found only 4 patients with heterozygous mutation in the GBA1 gene, 1 homozygous(c.1226A>G -N370S) and 1 compound heterozygous (c.1226A>G -N370S and c.1448T>C -L444P); the last 2 patients had signs of GD (hepato-splenomegaly and mild thrombocytopenia). CONCLUSIONS: Type 1 GD remains a rare lysosomal storage disorder but preliminary results of our observational study show that it should be considered in the diagnostic framework of patients with MGUS, particularly when other GD symptoms are present. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Di Raimondo:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding.

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