1882 ewggd 2012. phenotype spectrum of hematological and visceral disease in type 3 gaucher disease...
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1882
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
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
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-value
Intercept 9.74( 0.52) <.0001
Covariates
Ever 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) 0.9604
Genotype 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-value
Intercept 151.4(33.55) <.0001
Covariates
Age categories at first infusion
>0 - < 2 referent referent
>2 - < 10 -39.3(21.75) 0.0725
>10 - < 18 -40.5(36.88) 0.2739
Age categories at diagnosis
>0 - < 2 referent referent
>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
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 referent
>2 - < 10 -0.07( 0.26) 0.8048
>10 - < 18 -0.48( 0.48) 0.3217
Age categories at diagnosis
>0 - < 2 referent referent
>2 -0.14( 0.25) 0.577
Genotype categories
L444P/L444P referent referent
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
Estimate (Standard error) p-value
Intercept 69.81( 7.42) <.0001
Covariates
Age categories at first infusion
>0 - < 2 referent referent
>2 - < 10 -1.84( 4.36) 0.6743
>10 - < 18 -3.77(10.51) 0.7213
Age categories at diagnosis
>0 - < 2 referent referent
>2 -0.62( 4.33) 0.887
Genotype categories
L444P/L444P referent referent
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-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 referent
>2 - < 10 -0.76( 0.36) 0.0363
>10 - < 18 -1.27( 0.57) 0.0266
Age categories at diagnosis
>0 - < 2 referent referent
>2 0.23( 0.35) 0.5209
Genotype 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 Therapy
0 1 2 3 4 50.00
5.00
10.00
15.00
20.00H
emo
glo
bin
(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
Years Following Initiation of Therapy
0 1 2 3 4 5
0.00
200.00
400.00
600.00
800.00
1000.00P
late
let
Co
un
t (X
103
/mm
3)
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
Years Following Initiation of Therapy
0 1 2 3 4 5
0
2
4
6
8L
ive
r V
olu
me
in M
ult
iple
s o
f N
orm
al
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
Years Following Initiation of Therapy
0 1 2 3 4 5
0
25
50
75
100S
ple
en V
olu
me
in M
ult
iple
s o
f N
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
Years Following Initiation of Therapy
0 1 2 3 4 5-10.0
-7.5
-5.0
-2.5
0
2.5H
eig
ht
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 Therapy
0 5 10 15 20
Patients at Risk n = 325 n = 195 n = 90 n = 35 n = 0
0
20
40
60
80
100P
rop
ort
ion
of
Pat
ien
ts A
live 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.