1. Late Outcomes of Cord Blood
Transplantation for Patients with Hurler
Syndrome
Jaap J Boelens
June 2013 (11th CB symposium San Fransisco)

2. I have no Conflict of Interest to Declare

3. SCT for Inborn Errors of Metabolism
Since 1980
45%
MPS type 1
15%
Other MPS
15%
X-ALD
10%
MLD
8%
Other
• Worldwide >1100 SCTs for Inborn Errors of Metabolism (IEM)
• Mucopolysaccharidoses, type
– I - Hurler
– III - Sanfilippo
– VI - Maroteaux-Lamy
– VII - Sly
• Leukodystrophies
– X-ALD, MLD, GLD
• Other
– α-mannosidosis, etc

4. MPS-1
Hurler
6 yrs old
Scheie
9 yrs old
Continues spectrum Severemild
-Hepato-splenomegaly
-Deaf / blind
-Progressive developmental retard.
-Cardiovascular / pulm. Failure
-PREMATURE DEATH (med. 8yr)

5. MPS 1: who to transplant?
De Ru et al, Orphanet J Rare Diseases 2011
Decision made in
multidisciplinary team:
-metabolic specialist
-transplant physician

6. Long term outcome after successful SCT
Girl; 4 years old
NO SCT
Boy; 4 years old
2 years post-SCT

7. Successful HCT influences Long Term Survival in HS-patients
Moore et al 2008
N=67
N=129
TRM
UK patients 1981-2003

8. How to Optimize the Outcomes?
1. Outcomes of HSCT for MPS I in Europe (1994-2004): a risk factor
analysis: BMT 2007 (N=146)
– Predictors graft-failure: T-cell depletion, RIC
– Predictor higher EFS: Busulfan with “therapeutic drug monitoring”
2. SCT in combination with Enzyme Replacement Therapy in patients with
Hurler syndrome: BMT 2006
– No impact, but poor performing patients became eligible for BMT
3. Outcomes of Cord blood transplantation for Hurler syndrome: an
EUROCORD / DUKE Collaborative study: BBMT 2009 (n=93)
– Predictor higher EFS: BuCy, interval Dx-CBT < 4.5mths, 6/6 CBU

9. EBMT-Protocol/Guideline: HCT in IEM
Jan 2006 (EHA/EBMT Handbook 2008/2012)
Stem cell hierarchy:
1. SIB / MFD (non carrier)
2. UD (10/10)* or UCB (6/6)
3. UCB (5/6)
4. UCB (4/6) or mismatched-UD (non-TCD)
5. UCB (3/6) or HAPLO
Conditioning: Bu(+TDM) / Cy (serotherapy for UD/UCB)
FluBu (2012)
Note: UD (10/10) may be bypassed on institutional preference or time

10. Safer Transplantation of Hurler Syndrome > 2006
2006-2009: 91% (OS 94%)
1994-2004: 53% (n=146)
Boelens et al; BMT2007
Log rank <0,0001
Event-free survival
Cord blood (36/45)

11. How to Optimize the Outcomes? (2)
4. CIBMTR / EBMT / Eurocord / Duke University comparison
study: unrelated donors vs. unrelated cord blood vs.
matched sibling donors: Prepublication Blood 2013 (n=258)
5. (Transatlantic) Long Term Outcome of Hurler Syndrome
Patients after successful Stem Cell Transplantation: in
analyses phase (n=197)
Larger Transplant Centers only (9)

12. Outcomes of Transplantation using a Various
Allogeneic Hematopoietic Stem Cell sources
in Children with Hurlers Syndrome after
Myelo-ablative Conditioning Regimen
Jaap Jan Boelens
UMC Utrecht, the Netherlands
A study on behalf of Eurocord, IEWP- EBMT, CIBMTR, University of Minnesota
and Duke University

13. Aim and Methods
Study outcomes of Transplantation using a Various allogeneic
HSC Source in Children with Hurler syndrome after myelo-
ablative conditioning
• Main endpoints:
1) Event Free Survival (EFS: alive and engrafted >10%D)
2) Overall Survival (OS)
• Other endpoints:
1) Neutrophils recovery
2) GvHD
3) Full donor chimerism (≥95%) and enzyme levels

14. Multivariate Cox Regression
“for endpoint EFS”

15. 15
EFS by type of donor and HLA (n=258)
Cell Source Comparison (CIBMTR, EBMT, EUROCORD, Duke)
MSD, 81±6% (n=37)
5/6 CB, 68±6% (n=66)
MMUD, 41±6% (n=58)
6/6 CB, 81±9% (n=22)
4/6 CB, 57±10% (n=28)
MUD, 66±7% (n=47)

16. EFS- by age
< 16,7 months 71±4% n=128
> 16,7 months 55± 4% n=130
P=0.02
P=0.02

17. Full Donor Chimerism (>95%)
UCB UD TCD-UD idSIB
Full donor chimerism
(%)
92 74 47 70
Mixed 50- 95% donor 7 17 26 20
Mixed <50% donor <1 9 26 10
Normal enzyme level
(%)
98 66 50 66
Cord blood significantly associated with higher full donor
chimerism & normal enzyme levels (p< 0.01)

18. In Summary: Cell Source Comparison
• EFS was influenced by donor type and HLA:
– Highest EFS after id-SIB and 6/6 uCB-transplantation
• 10/10 MUD or 5/6 uCB
• Lower EFS: 4/6 uCB
• Worst EFS: mismatch MUD
• EFS was also influenced by:
– Younger age (<16.7mths)
• Almost all CB recipients had full-donor chimerism associated with normal
enzymes
– (May) impact longer term outcomes?

19. Urinary GAG excretion (DS/CS-ratio)
Wynn et al. J Pediatr. 2009

20. Highly Variable Long Term Outcome!
Large differences between Hurler patients post-HSCT
Explanation?

21. International Hurler Long Term Outcome Study
• Aims
– Natural course of Hurler syndrome post-HSCT
– Identify predictors for long term endpoints
 How to optimize the transplantation-procedure?
• Carrier donor, mixed chimerism, stem cell source, etc
• Novel therapies: e.g. gene-therapy

22. • Main endpoints
– Neurodevelopmental outcome (WISC/WAIS/Mullen)
• Other endpoints
– Multi-system outcome
• Growth, orthopedic, cardiac, respiratory, ophthalmologic,
audiologic, etc
– Quality of life (CHQ) / Processes of care (MPOC)
Endpoints of the International Hurler outcome study

23. International Hurler outcome study
• Inclusion criteria
– Hurler patients, allogeneic HSCT 1980 – 2008
– ‘Alive and Engrafted’ (≥10% donor chimerism)
– Follow-up ≥3 years post-HSCT
• Statistical analyses
– Cox proportional-hazards regression models
• Kaplan-Meier curves
– Logistic Regression: events without clear “time to event”
• Multivariate analyses: variables selected with p< 0.05

24. Mieke Aldenhoven (PhD student):
Visited all (larger) centers
in USA and Europe to
collect data
How to collect these data?

25. International Hurler outcome study
– Manchester 30
– Dublin 27
– Utrecht 19
– Monza 6
– Minnesota 50
– Duke/UNC 48
– London 13
– Paris 7
Hurler patients included
Total: 197

26. Total number = 197 (8 centers)
Variable %
No of HSCT 1 – 2 - 3 151 – 32 – 1
Gender Male 57
Ethnicity Caucasian 92
ERT pre-HSCT Yes 23
Donor – Source BM/PBSC 64
CB 36
Donor – Relationship SIB 29
Other familial 6
Unrelated 65
Donor – Carriership Carrier 21
Chimerism Full donor (>95%) 72
IDUA level Normal (>ref) 75
Variable Median Range
Year last HSCT 2001 1985-2008
Age at last HSCT (mths) 16 2-80
Age at diagnosis (mths) 9 0-49
FU post last HSCT (mths) 88 36-258
Patient Characteristics

27. Neurodevelopmental Outcomes (1)
N= 139
(With multiple measurements post-HSCT, 76 pre-
HSCT measurement):
Median DQ 0.83 (0.25 – 1.40)
Predictors DQ post-HSCT:
1) Pre-HSCT DQ (for those with pre-HSCT
testing): p<0.01
2) Age at HSCT: p<0.01
Maria Escolar, Pittburgh University

28. Neurodevelopmental Outcomes (2)
• DQ prior to HSCT is a predictor for DQ after HSCT

29. Cord Compression Surgery According to IDUA level
IDUA < ref: 45% +/-15
IDUA > ref: 2,3% +/-2
FU post-HSCT (months)
P=0,004

30. Hip Dysplasia and Geno Valgum Surgery
Nonsense-Nonsense: 66% +/-10
Other known: 15% +/-7
Hip Dysplasia Surgery
Genotype
P=0,002
FU post-HSCT (months)
IDUA < ref: 88% +/-10
P=0,004
IDUA > ref: 65% +/-8
Genu Valgum Surgery
IDUA level
FU post-HSCT (months)

31. Carpal Tunnel Surgery According to Age@HCT and IDUA
IDUA < ref: 100%
P=0,020
IDUA > ref: 68% +/-8
CTS Surgery
IDUA level
Age < median: 65% +/-10
Age > median: 91% +/-8
P=0,000
CTS Surgery
Age at HSCT
FU post-HSCT (months) FU post-HSCT (months)

32. Progression of Mitral Insufficiency According to
IDUA and Age@HCT
Clinical outcome Variable % Odds ratio p
Mitral insufficiency – Progression IDUA: < ref 55% 3.149 0.044
38% IDUA: > ref 11%
Age at HSCT: < median 15%
Age at HSCT: > median 52% 2.792 0.023
IDUA ref: local reference, Median Age at HSCT: 16 months

33. Progression of corneal clouding & retinopathy
According to IDUA, Age@HCT and Genotype
Clinical outcome Variable % Odds ratio p
Corneal clouding – Progression IDUA: < ref 53% 4.880 0,015
29% IDUA: > ref 10%
Age at HSCT: < med 9%
Age at HSCT: > med 44% 7,125 0.007
Retinopathy – Presence Genotype: nonsense 25% 5.365 0.038
19% Genotype: other 9%
IDUA: < ref 4%
IDUA: > ref 32% 19,292 0,008
Corneal transplantation: 6%

34. Hearing Aids According to IDUA
IDUA < ref: 66% +/-13
IDUA > ref: 34% +/-7

35. Linear Growth according to IDUA
SDS according to WHO growth references (2009)

36. Linear Growth at 60 Mths according to IDUA
Variable % Mean SDS t 95%-CI p
IDUA level < reference 29 -1,93 -2,17 -2,17 - -0,03 0,042
> reference 71 -1,09
Exclusion criteria: TBI, endocrinologic abnormalities, GH treatment
Statistical analysis: Mean, standard deviation, unpaired t test

37. International Hurler outcome study
• Inclusion criteria
– Hurler patients, allogeneic HSCT 1980 – 2008
– ‘Alive and Engrafted’ (≥10% donor chimerism)
– Follow-up ≥3 years post-HSCT
• Statistical analyses
– Cox proportional-hazards regression models
• Kaplan-Meier curves
– Logistic Regression: events without clear “time to event”
• Multivariate analyses: variables selected with p< 0.05

38. In Summary
• HCT significantly influences the long term outcome of patients with Hurler’s
Syndrome but there remains a significant “Residual Disease Burden”
• Various long term endpoints were influenced by:
– IDUA level (Stem Cell Source) after HSCT
– Genotype
– “Age at HSCT”
• Strategies to influence long term outcome
– Earlier transplant (neonatal screening)
– Unrelated donor transplants (higher enzyme levels)
– Novel strategies to increase enzyme levels (e.g. Gene therapy)

39. In Conclusion
International collaborations has given us insight in predictors for outcomes (short and
long term):
 In (very) rare disease the collaboration is essential
Multi-disciplinary follow up (+ registration) is essential:
 Further improve outcomes / Novel therapies
Better / Optimal collaboration / infrastructure is of utmost importance to run
prospective studies!

40. Eliane Gluckman MD
FRCP
Project Leader
Vanderson Rocha
MD PhD
Scientific Director
Annalisa Ruggeri, MD
Agnès Devergie
MD
Luciana Tucunduva
MD
Myriam Pruvost
Administrative AssistantFernanda Volt, MT
Chantal Kenzey
Data Manager
EUROCORD TEAM
2013

41. Acknowledgements
• University Medical Center Utrecht, the Netherlands: Peter van Hasselt, Mieke Aldenhoven
• University of Pittsburgh, USA: Maria Escolar, Michele Poe
• Royal Manchester Children’s Hospital, UK: Rob Wynn, Ed Wraith, Jean Mercer
• Our lady’s Hospital for Sick Children, UK: Anne O’Meara
• Ospedale San Gerardo, Monza, Italy: Antillio Rovelli
• Great Ormond Street Hospital, UK; Paul Veys
• University of Minnesota, USA: Paul Orchard, Elsa Shapiro, Teresa Kivisto
• Duke University, USA: Joanne Kurtzberg, Vinod Prasad
• All other participating transplantation centers