Paediatric Transplantation in Metabolic Disease

Jo Page

November 2011

Introduction

Biology of disease Severity of disease Pre transplant care Post transplant care Manchester Data Summary

Genetic-Inherited Disease-MPS I

Autosomal recessive disorder

Defective gene from each of the parents

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.

Metabolic Disease-MPS I

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

NucleusAbnormal cell

Nucleus

Lysosomes with accumulated

substrate

Normal cell lysosomes

Severity of Disease

Severe Less Severe

a-L-iduronidase deficiency

Hurler

Hurler Scheie

Scheie

50-80 % patients have MPS I H

Spectrum of Phenotypes

MPS I H MPS I H S MPS I S

Mean age at diagnosis 1

Before 1 y

[0,2 y – 7 y]

4 y

[0,2 y – 36 y]

9 y

[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 2

7y

Estimated20 years

Estimated

Adulthood

Each patient is unique and may exhibit a distinct clinical courseDiagnostic delay is common, and partly due to a lack of disease

awareness

How MPS I affects the body

Progressive multi-organ involvement

Brain Eyes Ears, nose and throat Lungs Heart Liver Spleen Joint and bones

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 Hip Dysplasia

Severe vertebral abnormalities

Severe MPS I

Pre Transplant

Enzyme Replacement Therapy given weekly in an attempt 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:

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)

Why HSCT?

• In HSCT donor cells repopulate the blood system and release enzyme which cross-corrects affected cells

• Blood cells cross the brain barrier and secrete enzyme cross-correcting neuronal cells

• 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

• HSCT can reverse many of the somatic manifestations of the disease including:

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• 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

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

Busulfan: IV with PK monitoring, 16 doses over 4 days

Cyclophosphamide: 4 doses

ERT: given longer if specific pre transplant co-morbidities eg cardiac

Serotheraphy: ATG if cord, Alemtuzemab if MUD, None if sibling

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)

6050403020100

1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

HLA 6/6 n= 22 81±8 %

HLA 5/6 n= 66 68±6 %

HLA 4 or 3/6 n= 28 57±9 %

P=0.166050403020100

1,0

,9

,8

,7

,6

,5

,4

,3

,2

,1

0,0

<2.8 x105/kg 60±7 %

>2.8 x105/kg 77±6 %

P=0.046

Post Transplant

Monitor enzyme levels

Monitor chimerism

Monitor urine Gags (Substrate of iduronidase Glycosaminoglycans stored in the urine)

Annual assessment

FOLLOW UP CLINIC FOR POST HSCT CHILDREN

MPS SOCIETY

CLINICAL NURSE SPECIALIST

METABOLICCONSULTANT

ENDOCRINOLOGIST(Over 6yr old)

BMTCONSULTANT (under 6yr old)

PHYSIOTHERAPIST

SPINAL CONSULTANT

POST BMT PATIENT

Post Transplant

Manchester

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

0

1

2

3

4

5

6

7

8

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Year

No

of

pat

ien

ts

no of tx

Outcome

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

All other patients survived

Single limited GvHD (skin)

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 transplantGood cord matchUse of Bu Cy

Thank You !