Clinical Issues in Gaucher Disease

New research on Gaucher disease and insights into effective disease management are continuously emerging. In this section, we bring you some of the most promising and thought-provoking new ideas in the field. Please check back often to find more of the latest clinical issues in Gaucher disease.

Effect of Enzyme Replacement Therapy with Imiglucerase on BMD in Type 1 Gaucher Disease

Authors: RJ Wenstrup, KA Kacena, P Kaplan, GM Pastores, A Prakash-Cheng, A Zimran, TN Hangartner
Published in: The Journal of Bone and Mineral Research, Volume 22, Number 1, 2007.

ABSTRACT: The effect of ERT with imiglucerase on BMD in type 1 GD was studied using BMD data from the International Collaborative Gaucher Group Gaucher Registry. Data were analyzed for 160 untreated patients and 342 ERT-treated patients. Imiglucerase significantly improves BMD in patients with GD, with 8 years of ERT leading to normal BMD.

Objective:

  • To determine the effect of enzyme replacement therapy (ERT; Cerezyme, imiglucerase) on BMD in type 1 Gaucher disease (GD)

Participants

  • 502 patients with Type 1 GD, enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry for whom lumbar spine BMD measurements were available
  • 160 of those patients were untreated; 342 were treated with ERT
  • Men aged 18–70 years; women aged 18–50 years

Methods

  • BMD data with up to 8 years of follow-up were analyzed for 160 patients who received no ERT and for the 342 patients who were treated with ERT alone
  • BMD was assessed by DXA of the lumbar spine
  • Z scores for patients with GD were compared with a reference population

Results

  • DXA Z scores for patients in the no ERT (untreated) group were significantly below normal
  • The DXA Z scores for patients who received ERT at a dose of 60 U/kg/2 weeks were significantly lower than the reference population at baseline but improved significantly over time
  • A significant dose–response relationship was noted for the ERT group, with the slopes for the three main dosing groups of 15, 30, and 60 U/kg/2 weeks of +0.064, +0.086, and +0.132 Z score units per year, respectively.
  • The BMD of patients treated with ERT increased to -0.12 (60 U/kg/2 weeks), -0.48 (30 U/kg/2 weeks), and -0.66 (15 U/kg/2 weeks)
  • SD of the mean of the reference population after 8 years of ERT, approaching the reference population
  • Estimated risk of osteoporosis of this GD population, if left untreated, ranged from ~10 to 30% in women and 10% to 25% in men

Conclusions: ERT with imiglucerase (Cerezyme) may increase BMD in patients with GD. Response to treatment with imiglucerase is slower for BMD than for hematologic and visceral aspects of GD. A normal (age- and sex-adjusted) BMD should be a therapeutic goal for patients with type 1 GD.

Consequences of diagnostic delays in type 1 Gaucher disease: the need for greater awareness among hematologists-oncologists and an opportunity for early diagnosis and intervention.

Authors: Mistry PK, Sadan S, Yang R, Yee J, Yang M.
Published in: Am J Hematol 2007 Aug;82(8):697-701.

ABSTRACT: "Gaucher disease (GD) is a progressive macrophage lipidosis capable of causing disabling and life-threatening complications. Anecdotal experiences suggest that GD may go undiagnosed for many years, leading to severe complications that are preventable or reversible by enzyme replacement therapy (ERT) with imiglucerase. We conducted surveys of patients and Hematology–Oncology specialists to assess the frequency of diagnostic delays. Additionally, we report a series of patients who suffered diagnostic delays and as a result developed disabilities including potentially life-threatening manifestations of GD. Of 136 patients surveyed, the average time from first appearance of GD symptoms to final diagnosis was 48.7 ± 123.6 months. More than two-thirds were evaluated and managed by a Hematologist–Oncologist (Hem–Onc). A global survey of 406 Hem–Oncs found that only 20% considered GD in the differential diagnosis for all of its classic symptoms (cytopenia, hepatosplenomegaly, bone pain); the diagnosis considered most likely included leukemia, lymphoma, and multiple myeloma. To illustrate actual consequences of diagnostic delays, we describe 14 patients with GD who suffered from symptoms for up to 10 years before correct diagnosis. Diagnostic delays led to complications that are preventable or reversible with ERT (i.e., avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure, liver pathology). Patients homozygous for N370S mutation in this series were vulnerable to diagnostic delays. In conclusion, prolonged diagnostic delays occur in GD and may result in severe disease manifestations. Our findings suggest that physician education will increase the likelihood of prompt detection of GD and improve its management with ERT with imiglucerase when indicated."

Objective:

  • To determine the experiences with diagnosis and management and to evaluate the extent of diagnostic delays in patients with Type 1 Gaucher disease
  • To examine the length of diagnostic delays and their consequences in individual patients

Participants

  • 98 patients in the US, 38 patients in Australia and New Zealand; both groups were naïve to ERT
  • Males comprised 51% of patients in both populations
  • 406 Hem–Oncs: 136 from the U.S., 50 each from Argentina, Brazil, Canada, Japan and Spain, and 20 from Australia
  • Physicians were in practice for a mean of 16 years

Methods

  • A questionnaire-based survey of patients with GD
  • A second survey was conducted to assess Hematology–Oncology specialists’ (Hem–Oncs) awareness of GD
  • A case series was taken from a large Gaucher treatment center.
  • Patient characteristics were examined in this series to identify risk factors that increase vulnerability to diagnostic delays
  • Screening was conducted in a community-based Hem–Onc practice to determine if an opportunity exists in this setting for early detection and intervention of patients with type 1 GD

Results

  • Anecdotal experiences suggest that a delay in the diagnosis of GD and its treatment may lead to serious complications of the disease

Conclusions: Gaucher patients are vulnerable to diagnostic delays, which may result in severe complications attributable to their disease. Physician education is needed to increase early detection and, when needed, treatment of patients with GD. Hem–Oncs have a unique opportunity to provide early diagnosis and optimal management of this treatable disorder.

Indication & Usage

Cerezyme® (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of Type 1 Gaucher disease that results in one or more of the following conditions:

  1. anemia
  2. thrombocytopenia
  3. bone disease
  4. hepatomegaly or splenomegaly

Important Safety Information

Approximately 15% of patients have developed IgG antibodies to Cerezyme during the first year of therapy. Approximately 46% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity, and these patients have a higher risk of hypersensitivity. It is suggested that patients be monitored periodically for IgG antibody formation during the first year of treatment.

Hypersensitivity has also been observed in patients without detectable IgG antibodies. Symptoms suggestive of hypersensitivity have been noted in approximately 6.6% of all patients, and anaphylactoid reactions in less than 1%. Treatment with Cerezyme should be approached with caution in patients who have exhibited hypersensitivity symptoms such as pruritus, flushing, urticarial, angioedema, chest discomfort, dyspnea, coughing, cyanosis, and hypotension. Pre-treatment with antihistamines and/or corticosteroids and a reduced rate of infusion may allow continued treatment in most patients.

In less than 1% of patients, pulmonary hypertension and pneumonia have been observed during treatment with Cerezyme. These are known complications of Gaucher disease regardless of treatment. Patients with respiratory symptoms in the absence of fever should be evaluated for the presence of pulmonary hypertension.

Approximately 13.8% of patients have experienced adverse events related to treatment with Cerezyme. Some of these are injection site reactions such as discomfort, pruritus, burning, swelling or sterile abscess at the site at the site of venipuncture. Additional adverse reactions that have been reported include nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia. Transient peripheral edema has also been reported for this therapeutic class of drug.

To report suspected adverse reactions, contact Genzyme at 800-745-4447, option 2 or FDA at 800-FDA-1088 or http://www.fda.gov/Safety/MedWatch

Please see Full Prescribing Information (PDF).

Treatment with Cerezyme for Type 1 Gaucher disease was observed in Registry data to reduce bone pain, bone crisis and improve bone mineral density.