Paediatric Transplantation
in Metabolic Disease
Jo Page
November 2011
Introduction
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Biology of disease
Severity of disease
Pre transplant care
Post transplant care
Manchester Data
Summary
Genetic-Inherited Disease-MPS I
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Autosomal recessive disorder
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Defective gene from each of the
parents
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For each pregnancy there is a:
25% chance the child will have
MPS I.
50% chance the child will be a
carrier.
25% chance the child will be
normal.
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Metabolic Disease-MPS I
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MPS I (Hurlers Disease) is a Lysosomal Storage
Disorder. Incidence 1:100 000
Proteins, carbohydrates and fats are broken down in the
lysosomes within all cells by certain enzymes
The enzyme α-L-iduronidase breaks down complex
proteins into simple proteins
In MPS I, the missing enzyme is α-L-iduronidase and it is
found in every cell in the body
Without this enzyme the cell accumulates protein
causing an alteration of cell, tissue and organ function
A LYSOSOMAL STORAGE DISEASE
Normal cell
lysosomes
Nucleus
Abnormal cell
Lysosomes with
accumulated
substrate
Nucleus
Severity of Disease
Severe
Less Severe
a-L-iduronidase deficiency
Hurler
Scheie
Hurler Scheie
50-80 % patients have
MPS I H
Spectrum of Phenotypes
Each patient is unique and may exhibit a distinct clinical course
Diagnostic delay is common, and partly due to a lack of disease
awareness
MPS I H
Mean age at
diagnosis 1
MPS I H S
MPS I S
Before 1 y
[0,2 y – 7 y]
4y
[0,2 y – 36 y]
9y
[2 y – 54 y]
Cognition
Pronounced mental
delay with loss of
acquired skills
No or mild mental delay
Learning disabilities
No impairment
Life
expectancy
Mean age of survival
Estimated
20 years
Estimated
Adulthood
2
7y
How MPS I affects the body
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Progressive multi-organ
involvement
Brain
Eyes
Ears, nose and throat
Lungs
Heart
Liver
Spleen
Joint and bones
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Onset of disease in first 2
years of life
Neurological regression
Corneal clouding
Enlarged tonsils/adenoids
Respiratory/ENT Infections
Valvular heart
disease/Cardiomyopathy
Hepatomegaly/Splenomegaly
Multiple skeletal
deformities/joint stiffness
Hernias
Corneal clouding
Severe vertebral abnormalities
Severe Hip
Dysplasia
Severe MPS I
Pre Transplant
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Enzyme Replacement Therapy given weekly in an attempt
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Donor search
Information for families
Genetic counselling
Recipient baseline investigations: (ENT, Opthalmology,
Cardiology, Physiotherapy, Radiology, Dental, Child
Psychology, Sleep Study, Virology)
Sibling donor Investigations: (HTA, IMA, Virology)
Additional factors (geography, family needs, complex
families)
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to improve/stabilise the child’s medical condition prior to BMT. ERT
is given currently for approx 12 weeks prior and 2-4 weeks post
HSCT:
Why HSCT?
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In HSCT donor cells repopulate the blood system and release enzyme
which cross-corrects affected cells
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Blood cells cross the brain barrier and secrete enzyme cross-correcting
neuronal cells
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Ideally HSCT should be undertaken in children under the age of 2 years
before they have significant neuro-developmental involvement. Children
tend to reach a developmental plateau before beginning to decline
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HSCT can reverse many of the somatic manifestations of the disease
including:
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Obstructive sleep apnoea,
Hepatosplenomegaly, and
Cardiomyopathy (but not valve disease)
Reduce coarse facial features
Importantly appears to stabilise the neurological decline.
Planning
Individual Assessment: Age at diagnosis, Symptoms at diagnosis,
Mutational analysis, Family history.
Donor availability
Risk of therapy
•
short term mortality risk
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long term morbidity risk
Risk of no therapy i.e. risk of underlying disease
Multiple therapies (ERT + HSCT). ERT alone does not cross brain barrier
and can develop antibodies
Transplantation
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Donor Hierachy:
Sibling (unaffected)
Mud cord rather than Mud adult if equivalent match
6/6 cord> 10/10 Mud>5/6 cord>9/10 Mud>4/6 cord
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Busulfan: IV with PK monitoring, 16 doses over 4 days
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Cyclophosphamide: 4 doses
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ERT: given longer if specific pre transplant co-morbidities eg cardiac
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Serotheraphy: ATG if cord, Alemtuzemab if MUD, None if sibling
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GCSF prophylaxis: Ciclosporin/Prednisolone if cord, Ciclosporin / MMF if MUD
PBSC or Ciclosporin alone if MUD marrow, Ciclosporin/short Methotrxate if sibling
EFS after UCBT by number of HLA disparities and CD34+ at collection (n=116)
1,0
1,0
,9
HLA 6/6 n= 22
81±8 %
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>2.8 x105/kg
,8
HLA 5/6 n= 66
,7
68±6 %
,6
,7
<2.8 x105/kg
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HLA 4 or 3/6 n= 28
,5
57±9 %
,4
,3
,3
,2
,2
,1
,1
P=0.16
0
10
20
30
40
50
60
60±7 %
,5
,4
0,0
77±6 %
P=0.046
0,0
0
10
20
30
40
50
60
Post Transplant
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Monitor enzyme levels
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Monitor chimerism
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Monitor urine Gags (Substrate of iduronidase
Glycosaminoglycans stored in the urine)
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Annual assessment
FOLLOW UP CLINIC FOR POST HSCT CHILDREN
SPINAL
CONSULTANT
PHYSIOTHERAPIST
MPS SOCIETY
POST BMT PATIENT
BMT
CONSULTANT
(under 6yr old)
CLINICAL NURSE
SPECIALIST
METABOLIC
CONSULTANT
ENDOCRINOLOGIST
(Over 6yr old)
Post Transplant
Manchester
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2 main centres in UK
From September 2004: 33 patients receiving 35
grafts
Median age at ERT 9 months (3-19 months)
Median age at HSCT 14 months (2-22 months)
Oral Busulfan N=7, IV Busulfan N=26
Family donors N=10 (5 MSD, 4 PBSC, 1 9/10)
Unrelated donors N=23 (18 cord, one received 2, 3
MUD)
Transplants for MPS I
8
7
No of patients
6
5
4
no of tx
3
2
1
0
2000
2001
2002
2003
2004
2005
Year
2006
2007
2008
2009
2010
Outcome
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2 primary graft failure
1 Rescued with immediate second cord after RIC (RIP 12 months
Adeno)
1 later successful MUD after “autologous” back up given on ICU
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All other patients survived
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Single limited GvHD (skin)
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All cord fully engrafted and maintain full donor chimerism, others
acceptable with adequate enzyme level
Manchester’s Survival
Summary
MPS I is a complex and rare disorder that is treatable (but not curable) by HSCT-the disease is
stabilised at time of transplant (higher level of donor enzyme is thought to be more effective
in improving organ function)
The treatment choice is dependent upon factors at diagnosis.
Clinical data from MPSI HSCT in Manchester (transplant outcome) show improved results that
are also in accordance with European data from EBMT Registry
Aim of both HSCT and ERT is to prevent further damage caused by the disease (limitation in
bone/joint abnormalities)
Enzyme Delivery is the future of HSCT by raising awareness of disease and newborn
screening
All patients will have long term follow up and assessments to achieve the best outcome and
quality of life
Publications
“Outcomes of HSCT for Hurler Syndrome in Europe: a risk factor analysis
for graft failure” BMT, 2007, 40, 225-33
Reduced conditioning, T cell depletion and no Bu pK
monitoring leads to increased risk of graft failure
“Risk Factor analysis of outcomes after unrelated cord
transplantation in patients with Hurler Syndrome”. BBMT, 2009, 15,
618-25
Early transplant
Good cord match
Use of Bu Cy
Thank You !