Dataset Information

Long- and Short-Term Glucosphingosine (lyso-Gb1) Dynamics in Gaucher Patients Undergoing Enzyme Replacement Therapy.

ABSTRACT: Background: Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in the GBA1 gene, leading to β-glucocerebrosidase deficiency and glucosylceramide accumulation. Methods: We analyzed short- and long-term dynamics of lyso-glucosylceramide (lyso-Gb1) in a large cohort of GD patients undergoing enzyme replacement therapy (ERT). Results: Eight-years analysis of lyso-Gb1 revealed statistically insignificant variability in the biomarker across the years and relatively high individual variability in patients' results. GD type 1 (GD1) patients exhibited higher variability compared to GD type 3 (GD3) patients (coefficients of variation: 34% and 23%, respectively; p-value = 0.0003). We also investigated the short-term response of the biomarker to enzyme replacement therapy (ERT), measuring lyso-Gb1 right before and 30 min after treatment administration. We tested 20 GD patients (16 GD1, 4 GD3) and observed a rapid and significant reduction in lyso-Gb1 levels (average decrease of 17%; p-value < 0.0001). This immediate response reaffirms the efficacy of ERT in reducing substrate accumulation in GD patients but, on the other hand, suggests the biomarker's instability between the infusions. Conclusions: These findings underscore lyso-Gb1's potential as a reliable biomarker for monitoring efficacy of treatment. However, individual variability and dry blood spot (DBS) testing limitations urge a further refinement in clinical application. Our study contributes valuable insights into GD patient management, emphasizing the evolving role of biomarkers in personalized medicine.

SUBMITTER: Dubiela P

PROVIDER: S-EPMC11275231 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Long- and Short-Term Glucosphingosine (lyso-Gb1) Dynamics in Gaucher Patients Undergoing Enzyme Replacement Therapy.

Dubiela Pawel P Szymanska-Rozek Paulina P Hasinski Piotr P Lipinski Patryk P Kleinotiene Grazina G Giersz Dorota D Tylki-Szymanska Anna A

Biomolecules 20240712 7

Background: Gaucher disease (GD) is a lysosomal storage disorder caused by mutations in the GBA1 gene, leading to β-glucocerebrosidase deficiency and glucosylceramide accumulation. Methods: We analyzed short- and long-term dynamics of lyso-glucosylceramide (lyso-Gb1) in a large cohort of GD patients undergoing enzyme replacement therapy (ERT). Results: Eight-years analysis of lyso-Gb1 revealed statistically insignificant variability in the biomarker across the years a ...[more]

PMID: 39062556

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Project description:BackgroundPatients with Gaucher disease (GD) require continual monitoring; however, lack of specific disease biomarkers was a significant challenge in the past. Glucosylsphingosine (lyso-Gb1) has been shown to be a reliable, key, specific, and sensitive biomarker for diagnosis, prognosis, and treatment response in clinical studies of patients with GD. We evaluated the change in lyso-Gb1 concentration over time following enzyme replacement therapy in patients with confirmed GD using real-world data from the Gaucher Outcome Survey disease registry.MethodsData for patients aged ≥ 18 years with a confirmed diagnosis of GD and at least two lyso-Gb1 assessments were analyzed retrospectively. Patients were stratified by treatment status at baseline (time of first lyso-Gb1 assessment). Lyso-Gb1 concentrations were measured from dried blood spot (DBS) samples by Centogene AG. Assessments included change in lyso-Gb1 concentration, hemoglobin concentration, platelet counts, and spleen and liver volume from baseline to the last lyso-Gb1 assessment.ResultsOf 2007 patients enrolled in the Gaucher Outcome Survey as of February 25, 2022, 435 met the inclusion criteria and were included in the study: 318 treated ('all treated'; 277 receiving treatment at baseline, 41 treatment naive at baseline), 38 receiving treatment at baseline who stopped treatment before the last lyso-Gb1 assessment, and 79 untreated. Lyso-Gb1 concentrations decreased from baseline to the last lyso-Gb1 assessment for all treated patients (median change - 8.6 ng/mL), and increased for untreated patients (median change 25.0 ng/mL) and those who stopped treatment (median change 19.5 ng/mL). Decreases were greater for all treatment-naive than previously treated patients (median change - 120.5 vs. - 3.3 ng/mL) and for velaglucerase alfa-treated patients vs. the overall treated cohort (-32.6 vs. - 8.6 ng/mL). Small improvements in hemoglobin concentrations, platelet counts, and spleen volume were observed for treated patients but not untreated/stopped treatment cohorts.ConclusionsIn this study, changes in lyso-Gb1 concentrations from DBS were reflective of responses to enzyme replacement therapy initiation or withdrawal in most patients. These findings confirm that the use of DBS samples for routine monitoring of lyso-Gb1 concentrations in patients with GD is feasible in real-world settings and may be useful to assess treatment response.

Project description:BackgroundGaucher disease (GD) is an autosomal recessive disease caused by GBA1 mutations resulting in glucosylceramide accumulation in macrophages. GD is characterized by hepatosplenomegaly, anemia, thrombocytopenia, bone complications, and neurological complications. Glucosylsphingosine (lyso-Gb1), a deacylated form of glucosylceramide, has been identified as a promising biomarker for the diagnosis and treatment response in GD. The aim of this study was to examine the relationship between plasma lyso-Gb1 and therapeutic goals for GD (improvements in hepatomegaly, splenomegaly, anemia, thrombocytopenia, bone pain, and bone crisis), as well as disease type and GBA1 mutation type, in Japanese patients with GD receiving velaglucerase alfa, an enzyme replacement therapy (ERT). Furthermore, this study compared the plasma lyso-Gb1 concentration observed in Japanese patients included in this study with that observed in a previous non-Japanese clinical study.ResultsThis non-interventional, open-label, multicenter observational cohort study (October 2020 to March 2021) included a total of 20 patients (of any age) with GD (type 1: n = 8; type 2: n = 9; type 3: n = 3) treated with velaglucerase alfa for ≥ 3 months. Median (minimum-maximum) duration of velaglucerase alfa treatment was 49.5 (3-107) months. A total of 14 (70.0%) patients achieved all therapeutic goals (i.e., 100% achievement; improvements in hepatomegaly, splenomegaly, anemia, thrombocytopenia, bone pain, and bone crisis). Overall, median (minimum-maximum) lyso-Gb1 concentration was 24.3 (2.1-150) ng/mL. Although not statistically significant, numerically lower plasma lyso-Gb1 concentrations were observed in patients with 100% achievement compared with those without; no statistically significant difference in plasma lyso-Gb1 concentration was observed between patients with different disease type or mutation type. Furthermore, lyso-Gb1 concentrations observed in Japanese patients were numerically lower than that observed in a previous study of non-Japanese patients with GD receiving ERT.ConclusionsIn this study, high achievement rates of therapeutic goals with low lyso-Gb1 concentration were observed, demonstrating a correlation between therapeutic goals and lower plasma lyso-Gb1 concentration in Japanese patients with GD treated with velaglucerase alfa. This study further suggests that plasma lyso-Gb1 concentration may be a useful biomarker for treatment response in patients with GD.

Project description:ObjectiveTo evaluate the cost-effectiveness of enzyme replacement therapy (ERT) compared to standard medical care without ERT in the Dutch cohort of patients with type 1 Gaucher disease (GD I).DesignCost-effectiveness analysis was performed using a life-time state-transition model of the disease's natural course. Transition probabilities, effectiveness data and costs were derived from retrospective data and prospective follow-up of the Dutch study cohort.SettingThe tertiary referral center for Gaucher disease in the Netherlands.ParticipantsThe Dutch cohort of patients with GD I.InterventionERT versus standard medical care without ERT in symptomatic patients.Main outcome measuresYears free of end organ damage (YFEOD) (splenectomy, bone complication, malignancy, multiple complications), quality adjusted life years (QALY), and costs.ResultsOver an 85 year lifetime, an untreated GD I patient will generate 48.9 YFEOD and 55.86 QALYs. Starting ERT in a symptomatic patient increases the YFEOD by 12.8 years, while the number of QALYs gained increases by 6.27. The average yearly ERT medication costs range between € 124,000 and € 258,000 per patient. The lifetime costs of ERT starting in the symptomatic stage are € 5,716,473 against € 171,780 without ERT, a difference of € 5,544,693. Consequently, the extra costs per additional YFEOD or per additional QALY are € 434,416 and € 884,994 respectively. After discounting effects by 1.5% and costs by 4% and under a reasonable scenario of ERT unit cost reduction by 25%, these incremental cost-effectiveness ratios could decrease to € 149,857 and € 324,812 respectively.DiscussionERT is a highly potential drug for GD I with substantial health gains. The conservatively estimated incremental cost-effectiveness ratios are substantially lower than for Pompe and Fabry disease. We suggest that the high effectiveness has contributed importantly to acceptance of reimbursement of ERT for GD I. The present study may further support discussions on acceptable price limits for ultra-orphan products.

Dataset Information

Long- and Short-Term Glucosphingosine (lyso-Gb1) Dynamics in Gaucher Patients Undergoing Enzyme Replacement Therapy.

Publications

Long- and Short-Term Glucosphingosine (lyso-Gb1) Dynamics in Gaucher Patients Undergoing Enzyme Replacement Therapy.

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