Therapeutic Goals

Because Type 1 Gaucher disease is variable, a patient-centered, goal-oriented approach is critical for achieving optimal outcomes. Yet, the procedures for establishing an individualized disease management plan can be similar for all Gaucher disease patients. The International Collaborative Gaucher Group (ICGG) has published a series of recommended therapeutic goals for Gaucher disease.1 The findings are summarized below.

Liver Volume

Goal: < 1.5 x normal
(normal = 2.5% body weight)

Goal Time frame
1-2 years 20%-30% decrease
3-5 years 30%-40% decrease

Bone Disease

Patients Goal Time frame
All patients Lessen or eliminate bone pain
Prevent bone crises
Years 1 to 2
Adults Improve and normalize BMD 8+ years

Hemoglobin Concentration

Patients Goal Time frame
Adult Females and children > 11.0 g/dL 1-2 years
Male > 12 years > 12.0 g/dL 1-2 years

Platelet Concentration

Patients Platelet count Time frame
All Sufficient platelets to reduce bleeding Year 1
Splenectomized Normalization of platelet counts Year 1
Intact spleen
Moderate thrombocytopenia
(>60,000 - < 120,000/mm3)
Low-normal platelet counts Year 2
Intact spleen
Severe thrombocytopenia
(<60,000/mm3)
Continued increases but no normalization Year 2

Spleen volume

Goal Time frame
30% decrease Year 1
50% decrease 2-5 years

Comprehensive Assessment

The first step in setting therapeutic goals is an initial comprehensive assessment of all potential disease manifestations: anemia, thrombocytopenia, hepatomegaly, splenomegaly, skeletal pathology, growth retardation in pediatric patients, pulmonary involvement, functional health and well-being, and a thorough physical examination. The information obtained should then be used to establish therapeutic goals for all disease compartments. The recommended primary assessments are:

Overall clinical assessment Complete patient and family history, preferably including pedigree
Comprehensive physical examination (annual)
Quality of Life (annual); patient-reported using SF-36
Blood tests Hemoglobin
Platelet count
Biochemical markers (chitotriosidase, ACE, or TRAP)
Additional blood tests (based on age and clinical status) WBC, PT, and PTT
Iron, iron binding capacity, ferritin, vitamin B12
AST and/or ALT; alkaline phosphatase, calcium, phosphorous, albumin, total protein, total and direct bilirubin
Serum immunoelectrophoresis
Hepatitis profile
Bone MRI (coronal; T1 and T2 weighted) of the entire femora
DXA lumbar spine and femoral neck
X-ray (AP view of the entire femora) and lateral view of the spine
Visceral Volume and structure of spleen and liver by MRI or CT (or ultrasound)
Contiguous transaxial 10mm thick sections for sum of region of interest
Pulmonary ECG, chest X-ray and Doppler echo for right ventricular systolic pressure
Other Beta-glucosidase and mutation analysis
Antibody sample

Other parameters that should be monitored:

  • Physical examination results should improve
  • Stabilize or decrease serial measurements of the biomarkers chitotriosidase, TRAP, or ACE
  • Quality of Life (QoL)
    • Improve or restore physical function for normal daily activities
    • Improve scores on validated QoL instrument within 2 to 3 years or less

Ongoing Monitoring

According to data from the Gaucher Registry, most patients are able to achieve these therapeutic goals with the proper dosing. The highest success rates have been seen in bone crises, liver volume, and hemoglobin.2

One-hundred and ninety-five Type 1 Gaucher disease patients enrolled in the Gaucher Registry were evaluated for achievement of published therapeutic goals. After 48 months of treatment with Cerezyme, the proportion of patients who met all six therapeutic goals increased from 2.1% at first infusion to 41.5% at 4 years; ≥5 goals from 12.8% to 76.9%; ≥4 goals from 37.4% to 92.8%; ≥3 goals from 70.8% to 99.0%; and ≥2 goals from 95.4% to 99.5%. All patients met at least one goal at first infusion and after 4 years of treatment. The proportion of patients meeting specific therapeutic goals increased for all parameters between first infusion and 4 years of therapy: platelet count (24.6%–79.5%), spleen volume (25.6%–78.5%), liver volume (45.6%– 90.8%), bone pain (62.6–70.3%), hemoglobin (68.2–91.8%), and bone crises (91.8–99.0%). On average, patients who received higher doses of imiglucerase achieved a greater number of therapeutic goals.

It is recommended that patients who are unable to maintain their therapeutic goals on a lower dose should return to the therapeutic dosing that enabled them to achieve their goals. Routine or comprehensive monitoring is recommended.

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).

References

  1. Pastores GM, Weinreb NJ, Aerts H, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol 2004:41(suppl 5);4-14.
  2. Weinreb N, Taylor J, et al. A benchmark analysis of the achievement of therapeutic goals for type 1 Gaucher disease patients treated with imiglucerase. Am J Hematol. 2008;83(12):890–895.
Within 4 years of initiating Cerezyme therapy, 93% of patients in the Gaucher Registry met at least 4 of 6 therapeutic goals.*
* Weinreb N et al. A benchmark analysis of the achievement of therapeutic goals for type 1 Gaucher disease patients treated with imiglucerase. Am J Hematol. 2008;83(12):890–895.