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Gaucher Disease Overview and Therapeutic GoalsHedayati Asl A.Mahak Cancer Childrens Hospital Stem Cell Transplantation Department

Dear chairmen and dear colleagues,Thank you for this great opportunity to be here with you and present you about Gaucher disease.I hope you are all fine. Im Amir Hedayati, Hematologist & Oncologist at Mahak Hospital.In this presentation, I will briefly give you a report of my patient with hepato-splenomegaly.

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Patient history and symptomsA 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.

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Physical examinationMild abdominal distention began developing about two months before admission, progressed gradually Physical examination and abdominal ultrasonographic study confirmed hepatosplenomegaly.

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Differential DiagnosisAnatomical abnormalitiesCongestionInfectionHematologic disordersInfiltrative processes What would be the likely diagnosis for this patient?

In this slide we can focus on the differential diagnosis, Considering the broad categories of disease that present with hepatosplenomegaly:Anatomical abnormalities, Congestion, Infection, Hematologic disorders, Infiltrative processes.

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Bone marrow aspiration was done: Foamy infiltrative cells

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

hematologic disorders could explain organomegaly, several of these including: chronic hemolytic anemia, disorders associated withextramedullary hematopoiesis, myeloproliferative disorders, and sickle-cell disease) were ruled out. In this slide, you can see a sample of morphologic features of foam cell

So, we evaluate her BMA and liver patholgy

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1th differential diagnosis

Hepato-splenomegaly due to Lipid Storage Disease Compatible with Gauchers Disease

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Complementary Work-upsCENTOGENE Gmbh Germany

-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 plasmaNorm(0-145)

Complementary Work-ups results which had been done in CENTOGENE Gmbh laboratory in germany were:

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TreatmentGlucocerebrosidase (Cerezyme)

A specific enzyme replacement therapy for Gaucher Disease is availableChildren 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.

We treat her with Cerezyme since 2007, which is continuing by now.As we know:Glucocerebrosidase

Four years after diagnosis, she had an attack of severe right elbow pain, that she was unable to move it. She had a similar episode of bone pain about a year before this attack, which was resolved spontaneously. and about five years after diagnosis she had frequent episodes of epistaxis due to thrombocytopenia and splenomegaly. So, she underwent splenectomy at 2011. We increased Cerezyme dosage after splenectomy.

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Children at high risk for complicationsSymptomatic disease including:manifestations of abdominal or bone painfatigue exertional limitations weakness cachexia growth failureevidence 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

Are those with ....

these patients should9

Today.....She is 8 yrs oldWeight 21 kgHeight 120 cmLab Test:WBC 12000Hb 13.3Hct 38.6Plt 454000SGOT 78SGPT 53

Photo with permission

The man behind the disease

Phillipe Charles Ernest Gaucher18541918His MD thesis entitled De lepithelioma primitif de la ra te; hypertrophie idiopathique de la ra te sans leucemie. 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: OverviewThe most common lysosomal storage diseaseIncidence: approximately 1 in 40,000 for non-Jewish populationsCaused by a deficiency of the enzyme glucocerebrosidaseThe glycolipid glucocerebroside accumulates in lysosomes of macrophagesLipid-filled Gaucher cells displace normal cells inBone marrowSpleenLiverLungsCNS*

Gaucher Disease: OverviewGaucher disease is the most common form of the sphingolipidoses and is inherited in an autosomal recessive manner.Due to a deficiency of the enzyme glucocerebrosidase, the glycolipid glucocerebroside accumulates in lysosomes of monocyte-macrophage cell types.Lipid-filled Gaucher cells displace normal cells in the bone marrow, spleen, liver, lungs, and, in neuronopathic subtypes, the brain and central nervous system.Gauchers disease results from deficient activity of Lysosomal Hydrolase, - Glucocerebrosidase. Theenzyme defect results in accumulation of undegraded glycolipid in the form of Glucosyl ceramide in thecells of reticuloendothelial system. This progressive accumulation results in infiltration of bonemarrow, hepatosplenomegaly and skeletal complications.

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Gaucher Disease: Clinical Signs and Symptoms

Pulmonary involvementProgressive neurologic symptoms*HepatosplenomegalySkeletal involvementThrombocytopeniaand anemia

* In neuronopathic subtypes only.

Gaucher Disease: Clinical Signs and SymptomsExcess accumulation of glucosylceramide in macrophages leads to hepatosplenomegaly, thrombocytopenia and anemia, skeletal involvement, and less commonly, pulmonary involvement.The visceral manifestations are common to all variants of Gaucher disease, but progressive neurologic symptoms are characteristic of neuronopathic type 2 and type 3 Gaucher disease.

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Clinical featuresType-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 Gauchers disease is gaucher cells in the reticuloendothelial system, particularly in the bone marrow. These cells have a typical appearance, they are 20-100m in diameter, wrinkled looking due to the presence of intracytoplasmic inclusion bodies.The presence of these cells is highly diagnostic of Gauchers disease.

There are three clinical sub types depending upon the presence of, absence of or progression of neurological complications.The patients present with easy bruising due to thrombocytopenia, chronic fatigue due to anemia, hepatomegaly with or without impaired liver functions. Progressive enlargement of spleen is there which can become massive. 14

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.

Now more in details:

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Laboratory DiagnosisEnzyme 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

The following studies are indicated in gaucher disease:

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StudiesUltrasonography 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 Gauchers cells is diagnostic.Liver biopsy Liver biopsy is occasionally performed to assess unexplained hepatomegaly.

Here we have the details of the studies for help diagnosis.19

Assessing Disease Severity

DomainAssessmentDisease Severity Score Index0123Skeletal DomainBMIabsent/minimalmildintermediatesevereMineral componentabsent/minimalmildintermediatesevereOsteonecrosisnonemedullary infarctionosteonecrosisprosthesisFractureabsent+Hematological DomainHemoglobin> 12 g/dL (male)> 11.5 g/dL (female)1012 g/dL89.9 g/dL< 8 g/dL*(*) or need for blood transfusionWBC count> 4 x 109/L2.54 x 109/L< 2.5 x 109/L< 1.9 x 109/LPlatelet count> 150 x 109/L101150 x 109/L60100 x 109/L< 60 x 109/LBleeding time< 8 min> 8 minBiomarker DomainChitotriosidase< 600 nmol/mL x h6004,000nmol/mL x h4,00115,000 nmol/mL x h> 15,000 nmol/mL x hCCL 18< 72 ng/mL72236 ng/mL2371,000 ng/mL> 1,000 ng/mLVisceral DomainSpleenno MR/US lesionsno splenectomyvolume < 5 Nvolumebetween 59 Nsplenectomy volume between 1015 NMR/US lesions volume > 15 NLiverno hepatic disease volume < 1.25 Nvolume between 1.252.5 Nvolume > 2.5 Nhepatic diseaseLung DomainPulmonary hypertensionabsentmoderatesevereRespiratory failureabsentmoderatesevereNeurological Domainno signs/symptomsperipheral neuropathyParkinsons disease/ParkinsonismTotal

20Assessing Disease Severity

ReferenceDi Rocco M, Giona F, Carubbi F, et al. Haematologica. 2008;93(8):12111218.

Treatment1) 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 GoalsAreas targeted for treatment goal developmentVisceral organsLiver volumeSpleen volumeHematologicalAnemiaThrombocytopeniaPulmonaryInterstitial lung diseasePulmonary vascular diseaseTime frames that are described are based on past experience with alglucerase/imigluceraseThese goals may be useful as benchmarks when evaluating treatment regimens

Therapeutic GoalsDeveloped by a group of physicians from around the world with clinical expertise in treating Gaucher patients (ICGG).Areas targeted for treatment goal development areVisceral organs: Liver volume and spleen volumeHematological: Anemia and thrombocytopeniaPulmonary: Interstitial lung disease and pulmonary vascular diseaseSkeletal pathology: Bone pain/bone crisis, osteonecrosis and subchondral joint collapse, and bone mineral densityGrowth (pediatric population): Growth patterns/pubertyFunctional health and well-being: Normal daily activities

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Therapeutic Goals: HepatosplenomegalyHepatomegaly*Splenomegaly*Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):414.PatientsGoalAll patientsReduce liver volume to 11.5 times normal and maintainAll patientsReduce liver volume by 2030%Reduce liver volume by 3040%

PatientsGoalAll patientsReduce spleen volume to 2 to 8 times normal and maintainAll patientsReduce spleen volume by 3050%Reduce spleen volume by 5060%All patientsAlleviate symptoms due to splenomegaly: abdominal distension, early satiety, new splenic infarctionEliminate hypersplenism

*Please note regular assessments will be conducted.

23Therapeutic Goals: Hepatosplenomegaly

Therapeutic Goals: Anemia*PatientsGoalAdult female patients and childrenHb 11.0 g/dLMale patients > 12 yearsHb 12.0 g/dLAll patientsEliminate blood transfusionReduce fatigueMaintain improved Hb levels

Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):414.

*Please note regular assessments will be conducted.

24Therapeutic Goals: Anemia

Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):414.PatientsGoalAll patientsSufficient platelets to reduce bleedingSplenectomized patients Normalization of platelet countsIntact 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.

25Therapeutic Goals: Thrombocytopenia

Therapeutic Goals: Pulmonary Involvement*Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):414.PatientsGoalPatients with overt, symptomatic pulmonary involvement**Reverse hepatopulmonary syndrome and dependency on oxygenAmeliorate pulmonary hypertensionImprove functional status and quality of lifePrevent rapid deterioration of pulmonary disease and sudden deathAll patientsPrevent 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.

26Therapeutic Goals: Pulmonary Involvement

Therapeutic Goals: Bone Disease* Pastores GM, et al. Semin Hematol. 2004;41(4 suppl 5):414.PatientsGoalAll patients Lessen or eliminate bone painPrevent bone crisesPrevent osteonecrosis and subchondral joint collapsePediatric patients

Improve BMDAttain normal or ideal peak skeletal massIncrease cortical and trabecular BMDImprove BMDIncrease trabecular BMD

Adult patients

*Please note regular assessments will be conducted.35 years

27Therapeutic Goals: Bone Disease

Pediatric Growth and Functional Health and Well-beingPediatric GrowthPatientsGoalPediatric patients Normalize growth such that patient achieves a normal height according to population standardsPediatric patientsAchieve normal onset of puberty

Functional Health and Well-beingPatients GoalAll patients Improve or restore physical function for carrying out normal daily activities and fulfilling functional rolesAll patientsImprove scores from baseline of a validated quality-of-life instrument

28Therapeutic Goals: Pediatric Growth and Functional Health and Well-being

PrognosisMany 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.

So in conclusion

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