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Gaucher Disease Treatment & Management

  • Author: Ellen Sidransky, MD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Nov 24, 2014
 

Medical Care

Enzyme replacement

Enzyme replacement therapy (ERT) for type 1 Gaucher disease includes imiglucerase (Cerezyme), velaglucerase alfa (VPRIV), and taliglucerase alfa (Elelyso). Historically, most patients received the recombinant enzyme imiglucerase.[7] This preparation is highly effective in reversing the visceral and hematologic manifestations of Gaucher disease. However, skeletal disease is slow to respond, and pulmonary involvement is relatively resistant to the enzyme. Treatment is typically administered once every other week at a high dose, but, in some patients, treatment is administered every week at a medium dose or as many as 3 times per week at low doses. Good responses have been described with all dose regimens, and the issue of the most suitable initial and maintenance dosages remains controversial.

ERT is indicated for patients with type 1 Gaucher disease who exhibit clinical signs and symptoms of the disease, including anemia, thrombocytopenia, skeletal disease, or visceromegaly. Severity and rate of disease progression widely varies, especially in adults, which makes treatment decisions extremely difficult in some patients. Generally, children who present symptomatically, rather than because of family history, may have severe disease manifestations that require early treatment. Presymptomatic treatment with ERT remains controversial because of the lack of prognostic correlation between genotype and disease severity and the high cost of the therapy.

For most patients with Gaucher disease in the United States, treatment with ERT is typically guided by a geneticist or a hematologist. Patients should receive periodic follow-up at a center familiar with Gaucher disease, if possible.

ERT has a remarkable effect on hepatosplenomegaly, with an average overall decrease of 25% in liver and spleen volume after 6 months of therapy. In most patients with anemia, hemoglobin levels rise by 1.5 g/dL during the first 4-6 months of therapy. An additional increase of 1 g/dL is observed in the subsequent 9-18 months in patients with persistent anemia. The platelet count responds more slowly, doubling on average over 1 year. The hematologic status of patients with splenomegaly must be closely monitored, and splenectomy is still occasionally necessary.

Skeletal disease is the slowest to respond, with symptomatic improvement described by some within the first year of treatment, although a much longer period of ERT is required to achieve a radiologic response. Patients with bone crises require pain relief, hydration, and close monitoring. A bone scan is sometimes needed to differentiate between a bone crisis and infection.

Other effects of ERT in children with Gaucher disease include an increased growth velocity, weight gain, increased energy levels, and a correction of both delayed puberty and hypermetabolic state.

The response of patients to ERT widely varies and does not correlate with genotype, disease severity, splenectomy, or age. However, a number of factors, including cirrhosis and portal hypertension, extensive infarction and fibrosis of the spleen, and lung involvement, portend a poor response to therapy.

The symptoms of patients with Gaucher disease who have associated hematologic malignancies respond relatively poorly to ERT. To overcome these difficulties, increased dosage and frequency of enzyme infusions have been attempted. The symptoms of patients with decompensated liver disease do not appear to respond well to ERT, and these patients remain at risk for life-threatening hemorrhage due to variceal bleeding.

No evidence shows that ERT results in neurologic improvement. Although the enzyme affects the visceral involvement in types 2 and 3 disease, the associated brain involvement may persist or progress.

Glucosylceramide synthase inhibitors

Glucosylceramide synthase inhibitors include miglustat (Zavesca) and eliglustat (Cerdelga). Miglustat was approved in 2003 as monotherapy for treatment of adults with mild-to-moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option.

Eliglustat was approved in August 2014 as first-line treatment for the long-term treatment of adults with Gaucher disease type 1. The dose of eliglustat is determined by establishing the patient’s CYP2D6 phenotype (ie, extensive metabolizers [EM], intermediate metabolizers [IM], or poor metabolizers [PM]).

Approval was based on efficacy data from 2 positive phase 3 studies involving 199 patients. One study involved patients new to therapy (trial 1), and the other involved patients switching from approved enzyme replacement therapies (trial 2). Efficacy data from 4 years of the Cerdelga phase 2 study also contributed to the approval. Improvements in study participants were observed in spleen size, platelet levels, hemoglobin levels, and liver volume, and noninferiority to enzyme replacement therapy (imiglucerase) was established in trial 2.[8, 9]

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Surgical Care

Partial and total splenectomy was once advocated in the treatment of patients with Gaucher disease. However, with the availability of ERT, this procedure is no longer necessary in most patients.

In addition, patients with Gaucher disease may require hip replacements or other orthopedic procedures to treat skeletal disease. This is best undertaken after the patient has undergone several months of ERT.

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Consultations

Consultations with the following specialists are indicated:

  • Medical geneticist
  • Hematologist
  • Orthopedist
  • Neurologist
  • Neuro-ophthalmologist
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Diet

No dietary manipulation has been found to affect disease progression.

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Activity

Patients with massive splenomegaly or severe thrombocytopenia should avoid contact sports and any other activities that place them at risk for splenic rupture or bleeding.

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Contributor Information and Disclosures
Author

Ellen Sidransky, MD Senior Investigator, Chief, Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, NIH

Ellen Sidransky, MD is a member of the following medical societies: American Society of Human Genetics, International Parkinson and Movement Disorder Society, Society for Pediatric Research, Society for Inherited Metabolic Disorders

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD Chief Medical Officer, Acer Therapeutics; Clinical Professor, University of Wisconsin School of Medicine and Public Health

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Acer Therapeutics; Retrophin; Raptor Pharma; Veritas Genetics; Censa Pharma<br/>Received income in an amount equal to or greater than $250 from: Acer Therapeutics; Retrophin; Raptor Pharma; Censa Pharma.

Acknowledgements

The author acknosledges the assistance of Mary E. LaMarca, who co-authored the initial version of this chapter prior to her death in 2010.

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Autosomal recessive inheritance pattern.
 
 
 
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