scholarly journals Iron storage in liver, bone marrow and splenic Gaucheroma reflects residual disease in type 1 Gaucher disease patients on treatment

2017 ◽  
Vol 179 (4) ◽  
pp. 635-647 ◽  
Author(s):  
Martine Regenboog ◽  
Anneloes E. Bohte ◽  
Erik M. Akkerman ◽  
Jaap Stoker ◽  
Carla E.M. Hollak
Keyword(s):  
Bone Marrow ◽  
Gaucher Disease ◽  
Residual Disease ◽  
Iron Storage ◽  
Type 1 Gaucher Disease

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.

Impact of velaglucerase alfa on bone marrow burden score in adult patients with type 1 Gaucher disease: 7-Year follow-up

2014 ◽  
Vol 53 (1-2) ◽  
pp. 56-60 ◽  
Author(s):  
Deborah Elstein ◽  
Andrew H. Haims ◽  
David Zahrieh ◽  
Gabriel M. Cohn ◽  
Ari Zimran
Keyword(s):  
Bone Marrow ◽  
Gaucher Disease ◽  
Adult Patients ◽  
Type 1 Gaucher Disease

scholarly journals A Prospective Study of Bone Marrow Hematopoietic and Mesenchymal Stem Cells in Type 1 Gaucher Disease Patients

PLoS ONE ◽  
2013 ◽  
Vol 8 (7) ◽  
pp. e69293 ◽  
Author(s):  
Séverine Lecourt ◽  
Enguerran Mouly ◽  
Delphine Freida ◽  
Audrey Cras ◽  
Raphaël Ceccaldi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Prospective Study ◽  
Gaucher Disease ◽  
Type 1 Gaucher Disease ◽  
A Prospective Study

Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 830-835 ◽  
Author(s):  
Maaike de Fost ◽  
Carla E. M. Hollak ◽  
Johanna E. M. Groener ◽  
Johannes M. F. G. Aerts ◽  
Mario Maas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Gaucher Disease ◽  
Bone Marrow Involvement ◽  
Median Dose ◽  
Long Term Outcome ◽  
Enzyme Replacement ◽  
Type 1 Gaucher Disease

AbstractDosing of enzyme replacement therapy (ERT) for Gaucher disease type 1 is still a subject of debate and varies from 15 to 130 U/kg/mo, making a huge economic difference of US $70 000 to US $380 000 (€55 000-300 000) per patient per year. To investigate whether this difference in dosing ultimately translates into a different response, we retrospectively compared long-term outcome of ERT at 2 large European treatment centers, Academic Medical Center, Amsterdam, The Netherlands (n = 49, median dose, 15-30 U/kg/4 wks) and Heinrich-Heine University, Duesseldorf, Germany (n = 57, median dose, 80 U/kg/4 wks). These adult cohorts had a similar genetic background. All follow-up parameters were matched separately at baseline, to avoid bias with respect to disease severity. Improvement in hemoglobin, platelet count, and hepatosplenomegaly was not significantly different between both cohorts, whereas plasma chitotriosidase and bone marrow involvement by magnetic resonance imaging improved more quickly and was more pronounced in the higher-dosed group. Major bone complications rarely occurred in both groups. In conclusion, different dosing regimens of ERT do not affect outcome of hematologic and visceral parameters, but higher dosing leads to accelerated decrease of chitotriosidase and better objective bone response in adult type 1 Gaucher disease.

scholarly journals Impact of Velaglucerase Alfa in the Inflammatory Status of Type 1 Gaucher Disease Patients after One Year on Therapy. A Prospective Multicentre Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4606-4606
Author(s):  
Marcio Andrade-Campos ◽  
Javier Gervas ◽  
Inmaculada García-Jiménez ◽  
Olga Salamero ◽  
Pedro Martinez-Odriozola ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Clinical Practice ◽  
Gaucher Disease ◽  
Cytokine Profile ◽  
Inflammatory Status ◽  
Inflammatory State ◽  
Type 1 Gaucher Disease ◽  
One Year

Abstract Gaucher disase(GD), the most studied lysosomal rare disorder, is characterized by an inflammatory status involved in the high incidence of complications, immune impairment and comorbidities (infections, bone, pulmonary involvement, gammapathies and parkinsonism). The role of cytokines in this inflammatory state is partially known, and the modifications in this profile in GD patients under enzymatic replacement therapy have not been reported and neither included in clinical trial. Our group has reported some changes on the cytokine profile in patients with severe bone involvement and some inflammatory biomarkers of macrophage activation related to the iron profile. (Gervas 2015, Medrano 2015). However there are not specific studies related to different therapies. Here we are presenting the final outcomes of a multicentre prospective non interventional study to explore the changes in the biomarkers of immune response in a cohort of Spanish type 1 Gaucher disease patients after one year on Velaglucerase alfa therapy. Patients and Methods: A total of 17 type 1 GD from 15 centers, were included in a prospective protocol following these criteria: symptomatic patients of both sexes, aged older than 4 years, naïve or previously treated but without ERT at least one month previous to be included. The study was approval by ethical committees and designed according Helsinki declaration rules; every one patient signed the informed consent and commitment to complete all study. Current recommendation for ERT with Velaglucerase alfa were followed in every centre. The study included hematological parameters, goals of therapy assessment, bone disease assessment were carried out in every visit and bone marrow MRI evaluated by Spanish-MRI score (Roca et al 2004) and densitometry were performed at baseline and in the final visit according the availability in each centre. GD biomarkers (Chitotriosidase, CCL18/PARC), proinflammatory biomarkers (ferritin level, serum protein electrophoresis and gammapathy profile including free light chain analysis) and the following cytokine profile: IL-10, IL-13, IL-4, IL-6, IL-7, Mip1a, Mip1b,TNFa, performed at baseline and 12 months after therapy. Results: General characteristics: 9 males, 8 females, mean age: 37.5 years (9-72). 3 splenectomized patients (17.6%); genotype: 3 N370S homozygous one heterozygous for N370S/L444P and the rest heterozygous for N370S/other. Seven patients (41.2%) have previous history of bone disease complications. All patients received velaglucerase alfa (30U/kg-60U/kg) iv every two weeks for 1 year in every day clinical practice, and achieving an bjective response on goals of disease (hemoglobine, platelets count, spleen reduction and clinically asymptomatic),bone marrow burden decrease and stabilization were registered by MRI in 14 patients, bone mineral density improvement were reported during the year of therapy in those patients. No infusion reactions were reported, neither antibodies against velaglucerase alfa; concerning to biomarkers, a reduction or stabilization of CT activity and CCL/18PARC concentration were significantly reduced (p=0.011; p=0.041 respectively), no modification in the ferritin concentration were registered, no monoclonal gammopathy were found but polyclonal gammopathy were observed in the majority of patients, a tendency of normalization were detected. The cytokine profile showed a decrease in all inflammatory cytokines tested however for Mip1a (p=0.017) and TNFa (p=0.023) a significant reduction were achieved. Table 1 Conclusion: Velaglucerase alfa is a well-tolerated therapy in every day clinical practice, with a positive impact in the immune response with a significant decrease on the inflammatory state reflected through the cytokine reduction and preventing development of bone complications in this cohort independently of previous therapies. Acknowledgments: This work was partially supported by a grant from Shire and FIS: PS12/01219 Table 1. Comparative reduction of cytokines between baseline and 12 months IL10 IL13 IL4 IL6 IL7 Mip 1a Mip 1b TNF a Chi X2 3.415 0.000 2.668 1.606 1.545 8.159 3.308 4.263 grade 2 2 2 2 2 2 2 2 significance 0.181 1.000 0.263 0.448 0.462 0.017 0.191 0.023 A significant decrease on Mip1a (p=0.017) and TNFa (p=0.023) and the end of study Disclosures No relevant conflicts of interest to declare.

scholarly journals Standardization of MRI and Scintigraphic Scores for Assessing the Severity of Bone Marrow Involvement in Adult Patients With Type 1 Gaucher Disease

2016 ◽  
Vol 206 (6) ◽  
pp. 1245-1252 ◽  
Author(s):  
Giuliano Mariani ◽  
Marzio Perri ◽  
Fabrizio Minichilli ◽  
Simona Ortori ◽  
Silvia Linari ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Gaucher Disease ◽  
Bone Marrow Involvement ◽  
Adult Patients ◽  
Type 1 Gaucher Disease
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