Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study

Lukina, Elena; Watman, Nora; Arreguin, Elsa Ávila; Dragosky, Marta; Iastrebner, Marcelo; Rosenbaum, Hanna; Phillips, Mici; Pastores, Gregory M.; Kamath, Ravi S.; Rosenthal, Daniel I.; Kaper, Mathilde; Singh, Tarunraj; Puga, Ana Cristina; Peterschmitt, Michel

doi:10.1182/blood-2010-06-293902

Cited by 147 publications

(88 citation statements)

References 12 publications

(14 reference statements)

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“…(36) Eliglustat, a more potent and specific inhibitor of glucosylceramide synthase that is currently in clinical trials for GD1, was reported to increase lumbar spine bone mineral density after 1 and 2 years of treatment, with major gains in DXA scores in osteopenic and osteoporotic patients. (37,38) The signature complication of GD1 in the skeleton is the occurrence of AVN, which is clinically devastating when it involves the cortical bone. As with fractures, we did not find any association of AVN with the severity of visceral disease or with biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

Khan

Hangartner

Weinreb³

et al. 2012

Journal of Bone and Mineral Research

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We hypothesized that overall disease activity or the severity of involvement of individual disease compartments, as measured by clinical and surrogate markers, predict the risk of avascular osteonecrosis (AVN) or fractures in type 1 Gaucher disease (GD1). We applied our risk‐set matched case‐control method to identify four patient groups within the International Collaborative Gaucher Group (ICGG) Gaucher Registry based on the presence and absence of AVN and fractures. Characteristics of GD1 were examined by comparing the distributions of each risk factor in cases versus matched controls using conditional logistic regression to calculate adjusted odds ratios (OR). Potential risk factors included hematological and visceral parameters, GD1 biomarkers, white blood cells, GBA1 genotype, and spine and femur dual‐energy X‐ray absorptiometry (DXA) Z‐scores. In the total population of 5894 ICGG Gaucher Registry patients, 544 experienced at least one episode of AVN; 2008 reported no history of AVN. Clinical and surrogate markers of disease activity were similar in patients with and without AVN; patients with AVN were 1.6 times more likely to be anemic compared to matched controls (OR = 1.59; 95% confidence interval [CI], 1.06–2.38, p < 0.05). For fractures, 319 patients suffered fractures and 1233 had no prior history of fractures. Clinical and surrogate markers of disease in patients with and without fractures were similar, except for mean lumbar spine DXA Z‐scores. Among patients with fractures, 49.3% had DXA Z‐scores ≤ −1 compared to 31.0% in the control group. Compared to controls with Z‐scores > −1.0, GD1 patients exhibiting Z‐scores ≤ −1 had an OR of 5.55 (95% CI, 1.81–17.02, p < 0.01) for fracture. In GD1, after controlling for gender, year of birth, treatment status, and splenectomy status, we identified new risk factors for AVN and fractures. Concurrent anemia was associated with an increased risk for AVN. Low bone mineral density of the lumbar spine was a strong risk factor for fractures of the spine and femur in GD1. © 2012 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

Khan

Hangartner

Weinreb³

et al. 2012

Journal of Bone and Mineral Research

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“…1,2 Global prevalence of the disease is 1:50 000, but among Ashkenazi Jews prevalence is 50 times greater than in the general population. 3 The involvement of the maxillomandibular complex in GD is probably more common than realized, considering that the vast majority of patients recover asymptomatically.…”

Section: Introductionmentioning

confidence: 99%

Dentomaxillofacial manifestations of Gaucher's disease: preliminary clinical and radiographic findings

Nobre

Ribeiro²,

Alves-Júnior³

et al. 2012

Dentomaxillofacial Radiology

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Objectives: A wide variety of manifestations is presented in patients with Gaucher's disease (GD), including bone, haematology and visceral disturbances. This study was conducted to ascertain the main maxillofacial abnormalities by means of clinical survey, panoramic and cone beam CT (CBCT); to compare the patient's group with an age-sex matched control group; and to correlate clinical and radiological data. Methods: Ten patients previously diagnosed with GD were submitted to clinical and radiological surveys (CBCT and panoramic radiographs). The examination consisted of anamnesis, extra-and intraoral examinations and analyses of each patient's records. Imaging data were collected from the point of view of 3 observers, and the results compared with a healthy group (20 individuals) by means of statistical analysis (Fisher's exact test). Results: Gaucher patients had significantly more manifestations than otherwise healthy carriers. The most prevalent findings were enlarged marrow spaces, generalized osteopenia and effacement of jaw structures (mandibular canal, lamina dura and mental foramen). Here we describe a case in which thickening of the maxillary sinus mucosa was observed on CBCT rather than opacification of the sinus as seen on panoramic radiographs. Pathological fractures, root resorption and delay on tooth eruption were not observed. Conclusions: A poor relationship could be observed between clinical and radiological data. Patients showed important bone manifestations, which require careful diagnostic and surgical planning whenever necessary. Although panoramic radiographs have shown significant differences, CBCT is more effective in pointing out differences between patients and a control group, thus showing it as an important tool for evaluation of Gaucher patients.

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“…The development of an alternative small-molecule compound for oral substrate reduction therapy, eliglustat tartrate, by Genzyme is also exciting. The compound seems to be safe and well tolerated 18 , and a 2-year follow-up of a Phase II trial indicated major improvements in haematological, visceral and skeletal manifestations in adult patients with type 1 Gaucher's disease, on a par with ERT 19 . moreover, as ERT is not able to prevent or treat neurological abnormalities in severely affected patients because the enzymes are unable to pass the blood-brain barrier, such compounds could provide a much needed treatment option for these patients.…”

Section: Indicationsmentioning

confidence: 99%

Velaglucerase alfa

Aerts¹,

Yasothan²,

Kirkpatrick³

2010

Nat Rev Drug Discov

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Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study

Cited by 147 publications

References 12 publications

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

Dentomaxillofacial manifestations of Gaucher's disease: preliminary clinical and radiographic findings

Velaglucerase alfa

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