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EWGGD 2012

Phenotype Spectrum of Hematological and Visceral Disease in Type 3 Gaucher Disease –

Genotype Correlations and Response to Imiglucerase Therapy in 325 Patients from the ICGG Registry

Pramod MistryDepartment of Pediatrics and Medicine.

Yale University School of Medicine, New Haven, CT, USA

On behalf of :

Edwin H. Kolodny1, Anna Tylki-Szymanska2, Nadia Belmatoug3, Juan F. Cabello4, Ashok Vellodi5, J. Alexander Cole6, Amal El-Beshlawy7, Gregory Grabowski8

1New York University School of Medicine, New York, USA; 2Children’s Memorial Health Institute, Warsaw, Poland; 3Centre de Référence des Maladies Lysosomales Assistance Publique-Hôpitaux de Paris Service de Médecine Interne Hôpital, Beaujon, France; 4Laboratorio de Genetica y Enfermedades Metabolicas. INTA, Universidad,de Chile, Santiago, Chile; 5Great Ormond Street Childrens' Hospital NHS Trust, London, UK; 6Biostatistics/Epidemiology, Genzyme, a Sanofi company, Cambridge, MA, USA; 7Pediatric Hospital of Cairo University, Cairo, Egypt; 8Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Background

In Gaucher disease, the phenotype spectrum and response to imiglucerase therapy have been characterized in detail for the non-neuronopathic Type 1 Gaucher disease in many large studies.

Fewer analyses have focused on long-term outcomes in Type 3 Gaucher disease.

Type 3 Gaucher disease

Onset Before 2 years or later Types 3a, 3b and 3c

Typical neurological manifestations Oculomotor apraxia Supranuclear ophthalmoplegia Extrapyramidal features Myoclonic or generalized seizures Cerebellar ataxia Developmental delay

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Neuronopathic L444P GBA Mutation – Likely the most common disease mutation

world-wide

International Collaborative Gaucher Group (ICGG)Gaucher Registry

An observational database of phenotype, genotype and treatment status of patients with Gaucher disease

Supported by Genzyme Sanofi, governed by international physician experts in Gaucher disease.

The largest database of GD with >6,000 GD patients from 60 countries.

Objectives and Analysis Plan

What are the correlates of baseline hematological, growth, and visceral organ status in GD3?

Set of multivariate regressions to characterize baseline status as a function of covariates

What are the predictors of hematological, growth, and visceral organ outcomes in GD3?

Second set of multivariate regressions to characterize outcomes as a function of covariates

Methods: Study Population

Study Population All patients <18 years of age at the start of therapy Enrolled in the ICGG Gaucher Registry as of July 2010 Diagnosis of type 3 Gaucher disease Subsets of patients with baseline data

Anemia Thrombocytopenia Splenomegaly Hepatomegaly Height z-score ≤-1

Statistical Analysis

Statistical Analysis Non-linear mixed effects models Alpha-level of 0.05 for statistical significance SAS 9.1 (SAS Institute, Cary, NC)

Results

Patient Characteristics (N=344)

Male 166 (49.7) Female 168 (50.3)

0‡ to <6y 291 (89.8) 6 to <12y 24 (7.4) 12 to <18y 9 (2.8)

65.8 (58.26)

0 to <6y 270 (80.8) 6 to <12y 44 (13.2) 12 to <18y 20 (6.0)

Age at First Infusion, n(%)

Gender, n(%)

Age at Diagnosis, n(%)

Treatment dose, mean±SD, U/kg per 2 wk

‡Diagnosed prenatally.

Patient Characteristics

Latin America 30 (9.0) Europe 98 (29.3) Middle East 114 (34.1) Asia, Pacific 30 (9.0) USA 54 (16.2) Canada 8 (2.4)Genotype, n(%) n=260 L444P/L444P 164 (63.1) L444P/OTHER 41 (15.8) OTHER/OTHER 55 (21.1)

Geographic Distribution, n(%)

*13 patients are D409H/D409H

70% of disease alleles are L444P and 2.5% D409H

Effects of ERT

At Diagnosis

L444P Homozygous GD3

After 4 years of imiglucerase

Courtesy of Dr Amal El-Beshlawy, University of Cairo

Age at first infusion (n=366)

Scatter plot of age at first infusion x baseline hemoglobin (g/dl) (n=283)

Scatter plot of age at first infusion x baseline platelet count (x103/mm3) (n=287)

Baseline Hemoglobin: Linear Regression, n=247

Estimate (Standard error) p-valueIntercept 9.74( 0.52) <.0001

CovariatesEver splenectomized 0.10( 0.38) 0.802

Age categories at first infusion

>0 - < 2 referent referent >2 - < 10 0.25( 0.38) 0.5056 >10 - < 18 1.45( 0.58) 0.0136

Age categories at diagnosis

>0 - < 2 referent referent >2 0.02( 0.37) 0.9604Genotype categories L444P/L444P referent referent L444P/OTHER 0.52( 0.38) 0.1741 OTHER/OTHER 0.68( 0.35) 0.0548

Baseline Platelet Count: Linear Regression (non-splenectomized patients), n=213

Estimate (Standard error) p-valueIntercept 151.4(33.55) <.0001

Covariates


>0 - < 2 referent referent

>2 - < 10 -39.3(21.75) 0.0725

>10 - < 18 -40.5(36.88) 0.2739



>2 -13.5(22.51) 0.5492

Genotype categories

L444P/L444P referent referent

L444P/OTHER 15.14(21.85) 0.4894

OTHER/OTHER 24.95(19.71) 0.2076

Baseline Liver Volume (MN): Linear Regression, n=101


CovariatesEver splenectomized -0.13( 0.29) 0.6689



>2 - < 10 -0.07( 0.26) 0.8048

>10 - < 18 -0.48( 0.48) 0.3217



>2 -0.14( 0.25) 0.577

Genotype categories


L444P/OTHER -0.09( 0.31) 0.7684

OTHER/OTHER -0.61( 0.28) 0.0339

Baseline Spleen Volume (MN): Linear Regression (non-splenectomized patients), n=101


Covariates



>2 - < 10 -1.84( 4.36) 0.6743

>10 - < 18 -3.77(10.51) 0.7213



>2 -0.62( 4.33) 0.887

Genotype categories


L444P/OTHER -14.1( 5.05) 0.0068

OTHER/OTHER -14.4( 4.51) 0.0022

Baseline Height Z-Score: Linear Regression, n=215

Estimate (Standard error) p-valueIntercept -1.39( 0.48) 0.0045

CovariatesEver splenectomized -0.56( 0.34) 0.1023


>0 - < 2 referent referent >2 - < 10 -0.76( 0.36) 0.0363 >10 - < 18 -1.27( 0.57) 0.0266


>0 - < 2 referent referent >2 0.23( 0.35) 0.5209Genotype categories L444P/L444P referent referent L444P/OTHER 0.83( 0.38) 0.0285 OTHER/OTHER 0.79( 0.32) 0.0155

Hemoglobin During Follow-Up

N 235 209 180 159 141 130Median 9.40 10.40 11.40 11.60 11.80 11.90Mean 9.40 10.35 11.33 11.44 11.66 11.75

Years Following Initiation of Therapy0 1 2 3 4 5

0.00

5.00

10.00

15.00

20.00H

emog

lobi

n (g

/dL)

Platelet Count During Follow-Up

N 203 181 154 133 115 107Median 101.0 137.0 195.0 208.0 212.0 203.0Mean 128.3 159.4 228.8 228.1 218.1 210.6


0.00

200.00

400.00

600.00

800.00

1000.00Pl

atel

et C

ount

(X10

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Liver Volume During Follow-Up

N 85 69 63 54 42 36Median 2.19 1.72 1.54 1.39 1.28 1.18Mean 2.35 1.86 1.57 1.43 1.32 1.26


0

2

4

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8Li

ver V

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e in

Mul

tiple

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Nor

mal

Spleen Volume During Follow-Up Among Non-Splenectomized Patients

N 87 70 65 55 45 42Median 37.49 31.60 24.01 20.73 16.78 14.33Mean 38.17 29.16 24.46 19.04 16.06 14.46


0

25

50

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Vol

ume

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ultip

les

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orm

al

Height Z-Score During Follow-Up

N 197 174 148 135 120 114Median -2.04 -2.40 -2.02 -1.63 -1.60 -1.45Mean -2.22 -2.26 -2.01 -1.63 -1.50 -1.41


-10.0

-7.5

-5.0

-2.5

0

2.5H

eigh

t Z-S

core

Cause of Death

54 out of 325 (17%) patients died and had reported causes of death.

The most frequently cited causes of death were: Progressive neurological disease Infections Cardiac complications Malignancy

Kaplan-Meier Analysis

Years Following Initiation of Therapy0 5 10 15 20

Patients at Risk n = 325 n = 195 n = 90 n = 35 n = 0

0

20

40

60

80

100Pr

opor

tion

of P

atie

nts

Aliv

e

Survival

Lower 95% CL

Upper 95% CL

Number of Patients:

Number of Deaths:

325:

54 (17%)

Conclusions

There is early onset of prominent visceral and hematologic disease in patients with GD3 before the age of 6 years. Moreover, these patients exhibit striking growth failure.

These effects are rapidly reversed by alglucerase/ imiglucerase treatment, with improvement within 5 years of treatment.

This cohort represents the largest cohort of children with type 3 Gaucher disease ever described to delineate the phenotypic spectrum and its response to alglucerase/ imiglucerase therapy.

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