1. EWGGD 2012
1882

2. 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 Mistry
Department 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

3. 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.

4. Type 3 Gaucher disease Onset Typical neurological manifestations
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

5. Neuronopathic L444P GBA Mutation – Likely the most common disease mutation world-wide* *

6. 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.

7. 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

8. Methods: 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

9. Statistical Analysis Statistical Analysis
Non-linear mixed effects models
Alpha-level of 0.05 for statistical significance
SAS 9.1 (SAS Institute, Cary, NC) 9

10. Results

11. Patient Characteristics (N=344)
‡Diagnosed prenatally. 11

12. Patient Characteristics
*13 patients are D409H/D409H
70% of disease alleles are L444P and 2.5% D409H 12

13. After 4 years of imiglucerase
L444P Homozygous GD3
Effects of ERT
This is the same individual. This is what we have to think about when we think someone cannot be treated.
At Diagnosis
After 4 years of imiglucerase
Courtesy of Dr Amal El-Beshlawy, University of Cairo

14. Age at first infusion (n=366)

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

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

19. Baseline Hemoglobin: Linear Regression, n=247
Estimate (Standard error)
p-value
Intercept
9.74( 0.52)
<.0001
Covariates
Ever splenectomized
0.10( 0.38)
0.802
Age categories at first infusion
>0 - < 2
referent
>2 - < 10
0.25( 0.38)
0.5056
>10 - < 18
1.45( 0.58)
0.0136
Age categories at diagnosis
>2
0.02( 0.37)
0.9604
Genotype categories
L444P/L444P
L444P/OTHER
0.52( 0.38)
0.1741
OTHER/OTHER
0.68( 0.35)
0.0548

20. Estimate (Standard error)
Baseline Platelet Count: Linear Regression (non-splenectomized patients), n=213
Estimate (Standard error)
p-value
Intercept
151.4(33.55)
<.0001
Covariates
Age categories at first infusion
>0 - < 2
referent
>2 - < 10
-39.3(21.75)
0.0725
>10 - < 18
-40.5(36.88)
0.2739
Age categories at diagnosis
>2
-13.5(22.51)
0.5492
Genotype categories
L444P/L444P
L444P/OTHER
15.14(21.85)
0.4894
OTHER/OTHER
24.95(19.71)
0.2076

21. Baseline Liver Volume (MN): Linear Regression, n=101
Estimate (Standard error)
p-value
Intercept
2.95( 0.40)
<.0001
Covariates
Ever splenectomized
-0.13( 0.29)
0.6689
Age categories at first infusion
>0 - < 2
referent
>2 - < 10
-0.07( 0.26)
0.8048
>10 - < 18
-0.48( 0.48)
0.3217
Age categories at diagnosis
>2
-0.14( 0.25)
0.577
Genotype categories
L444P/L444P
L444P/OTHER
-0.09( 0.31)
0.7684
OTHER/OTHER
-0.61( 0.28)
0.0339

22. Estimate (Standard error)
Baseline Spleen Volume (MN): Linear Regression (non-splenectomized patients), n=101
Estimate (Standard error)
p-value
Intercept
69.81( 7.42)
<.0001
Covariates
Age categories at first infusion
>0 - < 2
referent
>2 - < 10
-1.84( 4.36)
0.6743
>10 - < 18
-3.77(10.51)
0.7213
Age categories at diagnosis
>2
-0.62( 4.33)
0.887
Genotype categories
L444P/L444P
L444P/OTHER
-14.1( 5.05)
0.0068
OTHER/OTHER
-14.4( 4.51)
0.0022

23. Baseline Height Z-Score: Linear Regression, n=215
Estimate (Standard error)
p-value
Intercept
-1.39( 0.48)
0.0045
Covariates
Ever splenectomized
-0.56( 0.34)
0.1023
Age categories at first infusion
>0 - < 2
referent
>2 - < 10
-0.76( 0.36)
0.0363
>10 - < 18
-1.27( 0.57)
0.0266
Age categories at diagnosis
>2
0.23( 0.35)
0.5209
Genotype categories
L444P/L444P
L444P/OTHER
0.83( 0.38)
0.0285
OTHER/OTHER
0.79( 0.32)
0.0155

24. Hemoglobin During Follow-Up
20.00
15.00
10.00
Hemoglobin (g/dL)
5.00
0.00 1 2 3 4 5
Years Following Initiation of Therapy N
235
209
180
159
141
130
Median
9.40
10.40
11.40
11.60
11.80
11.90
Mean
10.35
11.33
11.44
11.66
11.75

25. Platelet Count During Follow-Up
800.00
600.00
Platelet Count (X103/mm3)
400.00
200.00
0.00 1 2 3 4 5
Years Following Initiation of Therapy N
203
181
154
133
115
107
Median
101.0
137.0
195.0
208.0
212.0
203.0
Mean
128.3
159.4
228.8
228.1
218.1
210.6

26. Liver Volume During Follow-Up8 6 4
Liver Volume in Multiples of Normal 2 1 2 3 4 5
Years Following Initiation of Therapy N 85 69 63 54 42 36
Median
2.19
1.72
1.54
1.39
1.28
1.18
Mean
2.35
1.86
1.57
1.43
1.32
1.26

27. Spleen Volume During Follow-Up Among Non-Splenectomized Patients
100 75 50
Spleen Volume in Multiples of Normal 25 1 2 3 4 5
Years Following Initiation of Therapy N 87 70 65 55 45 42
Median
37.49
31.60
24.01
20.73
16.78
14.33
Mean
38.17
29.16
24.46
19.04
16.06
14.46

28. Height Z-Score During Follow-Up
2.5
-2.5
Height Z-Score
-5.0
-7.5
-10.0 1 2 3 4 5
Years Following Initiation of Therapy N
197
174
148
135
120
114
Median
-2.04
-2.40
-2.02
-1.63
-1.60
-1.45
Mean
-2.22
-2.26
-2.01
-1.50
-1.41

29. 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

30. Kaplan-Meier Analysis
100
Upper 95% CL 80
Survival 60
Lower 95% CL
Proportion of Patients Alive 40 20
Number of Patients:
325:
Number of Deaths:
54 (17%) 5 10 15 20
Years Following Initiation of Therapy
Patients at Risk
n = 325
n = 195
n = 90
n = 35
n = 0

31. 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.