1. Paediatric Transplantation in Metabolic Disease Jo Page November 2011

2. Introduction Biology of disease Severity of disease Pre transplant care Post transplant care Manchester Data Summary

3. 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.

4. 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

5. A LYSOSOMAL STORAGE DISEASE Nucleus Abnormal cell Nucleus Lysosomes with accumulated substrate Normal cell lysosomes

6. Severity of Disease Severe Less Severe a-L-iduronidase deficiency Hurler Hurler Scheie Scheie 50-80 % patients have MPS I H

7. Spectrum of Phenotypes MPS I HMPS I H SMPS 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] CognitionPronounced mental delay with loss of acquired skills No or mild mental delay Learning disabilities No impairment Life expectancy Mean age of survival 2 7y Estimated 20 years Estimated Adulthood Each patient is unique and may exhibit a distinct clinical course Diagnostic delay is common, and partly due to a lack of disease awareness

8. 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

9. Corneal clouding Severe Hip Dysplasia Severe vertebral abnormalities

10. Severe MPS I

11. 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)

12. 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.

13. 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

14. 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

15. EFS after UCBT by number of HLA disparities and CD34+ at collection (n=116) HLA 6/6 n= 22 81±8 % HLA 5/6 n= 66 68±6 % HLA 4 or 3/6 n= 28 57±9 % P=0.16 <2.8 x10 5 /kg 60±7 % >2.8 x10 5 /kg 77±6 % P=0.046

16. Post Transplant Monitor enzyme levels Monitor chimerism Monitor urine Gags (Substrate of iduronidase Glycosaminoglycans stored in the urine) Annual assessment

18. FOLLOW UP CLINIC FOR POST HSCT CHILDREN POST BMT PATIENT SPINAL CONSULTANT PHYSIOTHERAPIST BMT CONSULTANT (under 6yr old) ENDOCRINOLOGIST (Over 6yr old) METABOLIC CONSULTANT CLINICAL NURSE SPECIALIST MPS SOCIETY

19. Post Transplant

20. 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)

22. 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

23. Manchester’s Survival

24. 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

25. 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

26. Thank You !