GAUCHER DISEASE OVERVIEW AND THERAPEUTIC GOALS

Hedayati Asl A.Mahak Cancer Children’s Hospital

Stem Cell Transplantation Department

Patient history and symptoms

A nine-months-old girl, Iran-born that her parent had familial marriage was admitted to the hospital with hepato-splenomegaly and abdominal pain (2007)

The patient had generally been in good health

during infancy, with no previous hospitalizations and no history of serious illness or disease in her family.

Physical examination

Mild abdominal distention began developing about two months before admission, progressed gradually

Physical examination and abdominal

ultrasonographic study confirmed hepatosplenomegaly.

Differential Diagnosis Anatomical abnormalities Congestion Infection Hematologic disorders Infiltrative processes

What would be the likely diagnosis for this patient?

Bone marrow aspiration was done: Foamy infiltrative cells

Liver biopsy result was wrinkled looking cells No confluent necrosis In portal tracts there were short fibrous septa

1th differential diagnosis

Hepato-splenomegaly due to Lipid Storage Disease Compatible with

Gaucher’s Disease

Complementary Work-upsCENTOGENE Gmbh Germany

ß-Glucosidase enzyme activity in the prepared leucocytes was severely reduced:1.1 nmol MU/mg protein Norm (6.5-18.9)

Chitotriosidase level: 12.713 nmol MU/mg plasma Norm(0-145)

TreatmentGlucocerebrosidase (Cerezyme®)

A specific enzyme replacement therapy for Gaucher Disease is available

Children and Adults: 30-60 units/kg every 2 weeks

Range in dosage: 2.5 units/kg 3 times/week to 60 units/kg once weekly to every 4 weeks.

Initial dose should be based on disease severity and rate of progression.

Children at high risk for complications Symptomatic disease including: manifestations of abdominal or bone pain fatigue exertional limitations weakness cachexia growth failure evidence of skeletal involvement platelet count ≤ 60,000 mm3 documented abnormal bleeding episode Hgb ≥ 2.0 g/dL below lower limit for age and sex impaired quality of life should receive an initial dose of 60 units/kg; failure to respond to treatment within 6 months indicates the need for a higher

dosage

Today.....

She is 8 yrs old Weight 21 kg Height 120 cm Lab Test:

WBC 12000 Hb 13.3 Hct 38.6 Plt 454000 SGOT 78 SGPT 53

Photo with permission

The man behind the disease

Phillipe Charles Ernest Gaucher 1854–1918

His MD thesis entitled “De l’e´pithe´lioma primitif de la raˆ te; hypertrophie idiopathique de la raˆ te sans leuce´mie”. He described primary and idiopathic hypertrophy of the spleen in a young woman, which he attributed to a primary tumour of the spleen with infiltration of the normal parenchyma by large, amorphous nucleated cells.

Gaucher Disease: Overview

The most common lysosomal storage disease Incidence: approximately 1 in 40,000 for non-Jewish

populations Caused by a deficiency of the enzyme glucocerebrosidase The glycolipid glucocerebroside accumulates in lysosomes

of macrophages Lipid-filled Gaucher cells displace normal cells in

Bone marrow Spleen Liver Lungs CNS*

Gaucher Disease: Clinical Signs and Symptoms

Pulmonary involvement

Progressive neurologic symptoms*

Hepatosplenomegaly

Skeletal involvement

Thrombocytopeniaand anemia

* In neuronopathic subtypes only.

Clinical features Type-1- It accounts for 99 % of cases. The age of onset is variable, from early childhood to

lateadulthood. Clinical bone involvement is apparent which is manifested

in the form of bone pains, or pathological fractures. The hall-mark of Gaucher’s disease is gaucher cells in the

reticuloendothelial system, particularly in the bone marrow. These cells have a typical appearance, they are 20-100μm

in diameter, wrinkled looking due to the presence of intracytoplasmic inclusion bodies.

The presence of these cells is highly diagnostic of Gaucher’s disease.

Type 2- Is less common, It is characterized by neurodegeneration,

extreme visceral involvement and death within 2 years of life.

The death is due to respiratory compromise.

Type 3- Is intermediate in presentation to type 1 and 2.

Neurological involvement is there but occurs later in life with decreased severity as compared to Type 2.

Laboratory Diagnosis Enzyme activity testing: Diagnosis can be confirmed

through measurement of Glucocerebrosidase activity in peripheral blood leukocytes. A finding of less than 15% of mean normal activity is diagnostic.

Genotype testing: Molecular diagnosis can be helpful, especially in Ashkenazi patients, in whom 6 GBA mutations account for most disease alleles.

CBC count: Obtain CBC count and differential to assess the degree of cytopenia.

Liver function enzyme testing: Minor elevations of liver enzyme levels are common

Studies Ultrasonography of the abdomen can reveal the extent of

organomegaly. MRI is more accurate than ultrasonography in determining

organ size. Hip MRI may be useful in revealing early avascular necrosis. MRI may be useful in delineating the degree of marrow infiltration and evaluating spinal involvement.

Radiography Skeletal radiography can be used to detect and evaluate skeletal manifestations of Gaucher disease. Perform chest radiography to evaluate pulmonary manifestations.

Bone marrow examination for the presence of Gaucher’s cells is diagnostic.

Liver biopsy – Liver biopsy is occasionally performed to assess unexplained hepatomegaly.

Assessing Disease SeverityDomain Assessment Disease Severity Score Index

0 1 2 3

Skeletal Domain BMI absent/minimal mild intermediate severe

Mineral component absent/minimal mild intermediate severe

Osteonecrosis none medullary infarction

osteonecrosis prosthesis

Fracture absent +

Hematological Domain Hemoglobin > 12 g/dL (male)> 11.5 g/dL (female) 10–12 g/dL 8–9.9 g/dL

< 8 g/dL*(*) or need for blood transfusion

WBC count > 4 x 109/L 2.5–4 x 109/L < 2.5 x 109/L < 1.9 x 109/L

Platelet count > 150 x 109/L 101–150 x 109/L 60–100 x 109/L < 60 x 109/L

Bleeding time < 8 min > 8 min

Biomarker Domain Chitotriosidase < 600 nmol/mL x h 600–4,000nmol/mL x h

4,001–15,000 nmol/mL x h

> 15,000 nmol/mL x h

CCL 18 < 72 ng/mL 72–236 ng/mL 237–1,000 ng/mL > 1,000 ng/mL

Visceral Domain Spleen no MR/US lesionsno splenectomyvolume < 5 N

volumebetween 5–9 N

splenectomy volume between 10–15 N

MR/US lesions volume > 15 N

Liver no hepatic disease volume < 1.25 N

volume between 1.25–2.5 N

volume > 2.5 N hepatic disease

Lung Domain Pulmonary hypertension

absent moderate severe

Respiratory failure absent moderate severe

Neurological Domain no signs/symptoms peripheral neuropathy

Parkinson’s disease/Parkinsonism

Total

Treatment 1) Enzyme replacement therapy (ERT) by recombinant -

Glucocerebrosidase is currently done. 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.

2) 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.

3) Bone marrow transplant is also helpful. 4) Gene replacement is the permanent cure.

Therapeutic Goals Areas targeted for treatment goal development

Visceral organs Liver volume Spleen volume

Hematological Anemia Thrombocytopenia

Pulmonary Interstitial lung disease Pulmonary vascular disease

Time frames that are described are based on past experience with alglucerase/imiglucerase

These goals may be useful as benchmarks when evaluating treatment regimens

Therapeutic Goals: Hepatosplenomegaly

Hepatomegaly*

Splenomegaly*

Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.

Patients Goal

All patients Reduce liver volume to 1–1.5 times normal and maintain

All patients Reduce liver volume by 20–30%

Reduce liver volume by 30–40%

Patients Goal

All patients Reduce spleen volume to ≤ 2 to 8 times normal and maintain

All patients Reduce spleen volume by 30–50% Reduce spleen volume by 50–60%

All patients Alleviate symptoms due to splenomegaly: abdominal distension, early satiety, new splenic infarction

Eliminate hypersplenism

*Please note regular assessments will be conducted.

Therapeutic Goals: Anemia*

Patients GoalAdult female patients and children

Hb ≥ 11.0 g/dL

Male patients > 12 years

Hb ≥ 12.0 g/dL

All patients Eliminate blood transfusion

Reduce fatigue

Maintain improved Hb levels

Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.

*Please note regular assessments will be conducted.

Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.

Patients GoalAll patients Sufficient platelets to reduce bleeding

Splenectomized patients Normalization of platelet counts

Intact spleenModerate thrombocytopenia (> 60,000–< 120,000/mm3)Severe thrombocytopenia (< 60,000/mm3)

Low-normal platelet counts

Continued increases but no normalization

Therapeutic Goals: Thrombocytopenia*

*Please note regular assessments will be conducted.

Therapeutic Goals: Pulmonary Involvement*

Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.

Patients GoalPatients with overt, symptomatic pulmonary involvement**

Reverse hepatopulmonary syndrome and dependency on oxygen

Ameliorate pulmonary hypertension Improve functional status and quality of life Prevent rapid deterioration of pulmonary disease

and sudden death

All patients Prevent pulmonary disease by timely initiation of treatment and avoidance of splenectomy

** Most patients in this group have had spleen removed.

*Please note regular assessments will be conducted.

Therapeutic Goals: Bone Disease*

Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):4–14.

Patients GoalAll patients Lessen or eliminate bone

pain Prevent bone crises Prevent osteonecrosis

and subchondral joint collapse

Pediatric patients Improve BMD Attain normal or ideal

peak skeletal mass Increase cortical and

trabecular BMD Improve BMD

Increase trabecular BMD

Adult patients

*Please note regular assessments will be conducted.

3–5 years

Pediatric Growth and Functional Health and Well-being

Pediatric Growth

Patients GoalPediatric patients Normalize growth such that patient

achieves a normal height according to population standards

Pediatric patients Achieve normal onset of puberty

Functional Health and Well-being

Patients GoalAll patients Improve or restore physical

function for carrying out normal daily activities and fulfilling functional roles

All patients Improve scores from baseline of a validated quality-of-life instrument

Prognosis Many individuals with Gaucher disease have few

manifestations and a normal life expectancy without any intervention.

The prognosis for symptomatic patients with type 1 or type 3 Gaucher disease who receive treatment is very good, with a decrease in organomegaly and an eventual rise in hemoglobin levels and platelet counts.

Skeletal disease is slow to respond to ERT and widely varies.

Some patients describe symptomatic improvement within the first year of treatment, although a much longer period of ERT is required to achieve a radiologic response.