Late Outcomes of Cord Blood
Transplantation for Patients with Hurler
Syndrome
Jaap J Boelens
June 2013 (11th CB symposium ...
I have no Conflict of Interest to Declare
SCT for Inborn Errors of Metabolism
Since 1980
45%
MPS type 1
15%
Other MPS
15%
X-ALD
10%
MLD
8%
Other
• Worldwide >1100 S...
MPS-1
Hurler
6 yrs old
Scheie
9 yrs old
Continues spectrum Severemild
-Hepato-splenomegaly
-Deaf / blind
-Progressive deve...
MPS 1: who to transplant?
De Ru et al, Orphanet J Rare Diseases 2011
Decision made in
multidisciplinary team:
-metabolic s...
Long term outcome after successful SCT
Girl; 4 years old
NO SCT
Boy; 4 years old
2 years post-SCT
Successful HCT influences Long Term Survival in HS-patients
Moore et al 2008
N=67
N=129
TRM
UK patients 1981-2003
How to Optimize the Outcomes?
1. Outcomes of HSCT for MPS I in Europe (1994-2004): a risk factor
analysis: BMT 2007 (N=146...
EBMT-Protocol/Guideline: HCT in IEM
Jan 2006 (EHA/EBMT Handbook 2008/2012)
Stem cell hierarchy:
1. SIB / MFD (non carrier)...
Safer Transplantation of Hurler Syndrome > 2006
2006-2009: 91% (OS 94%)
1994-2004: 53% (n=146)
Boelens et al; BMT2007
Log ...
How to Optimize the Outcomes? (2)
4. CIBMTR / EBMT / Eurocord / Duke University comparison
study: unrelated donors vs. unr...
Outcomes of Transplantation using a Various
Allogeneic Hematopoietic Stem Cell sources
in Children with Hurlers Syndrome a...
Aim and Methods
Study outcomes of Transplantation using a Various allogeneic
HSC Source in Children with Hurler syndrome a...
Multivariate Cox Regression
“for endpoint EFS”
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...
EFS- by age
< 16,7 months 71±4% n=128
> 16,7 months 55± 4% n=130
P=0.02
P=0.02
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 ...
In Summary: Cell Source Comparison
• EFS was influenced by donor type and HLA:
– Highest EFS after id-SIB and 6/6 uCB-tran...
Urinary GAG excretion (DS/CS-ratio)
Wynn et al. J Pediatr. 2009
Highly Variable Long Term Outcome!
Large differences between Hurler patients post-HSCT
Explanation?
International Hurler Long Term Outcome Study
• Aims
– Natural course of Hurler syndrome post-HSCT
– Identify predictors fo...
• Main endpoints
– Neurodevelopmental outcome (WISC/WAIS/Mullen)
• Other endpoints
– Multi-system outcome
• Growth, orthop...
International Hurler outcome study
• Inclusion criteria
– Hurler patients, allogeneic HSCT 1980 – 2008
– ‘Alive and Engraf...
Mieke Aldenhoven (PhD student):
Visited all (larger) centers
in USA and Europe to
collect data
How to collect these data?
International Hurler outcome study
– Manchester 30
– Dublin 27
– Utrecht 19
– Monza 6
– Minnesota 50
– Duke/UNC 48
– Londo...
Total number = 197 (8 centers)
Variable %
No of HSCT 1 – 2 - 3 151 – 32 – 1
Gender Male 57
Ethnicity Caucasian 92
ERT pre-...
Neurodevelopmental Outcomes (1)
N= 139
(With multiple measurements post-HSCT, 76 pre-
HSCT measurement):
Median DQ 0.83 (0...
Neurodevelopmental Outcomes (2)
• DQ prior to HSCT is a predictor for DQ after HSCT
Cord Compression Surgery According to IDUA level
IDUA < ref: 45% +/-15
IDUA > ref: 2,3% +/-2
FU post-HSCT (months)
P=0,004
Hip Dysplasia and Geno Valgum Surgery
Nonsense-Nonsense: 66% +/-10
Other known: 15% +/-7
Hip Dysplasia Surgery
Genotype
P=...
Carpal Tunnel Surgery According to Age@HCT and IDUA
IDUA < ref: 100%
P=0,020
IDUA > ref: 68% +/-8
CTS Surgery
IDUA level
A...
Progression of Mitral Insufficiency According to
IDUA and Age@HCT
Clinical outcome Variable % Odds ratio p
Mitral insuffic...
Progression of corneal clouding & retinopathy
According to IDUA, Age@HCT and Genotype
Clinical outcome Variable % Odds rat...
Hearing Aids According to IDUA
IDUA < ref: 66% +/-13
IDUA > ref: 34% +/-7
Linear Growth according to IDUA
SDS according to WHO growth references (2009)
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...
International Hurler outcome study
• Inclusion criteria
– Hurler patients, allogeneic HSCT 1980 – 2008
– ‘Alive and Engraf...
In Summary
• HCT significantly influences the long term outcome of patients with Hurler’s
Syndrome but there remains a sig...
In Conclusion
International collaborations has given us insight in predictors for outcomes (short and
long term):
 In (ve...
Eliane Gluckman MD
FRCP
Project Leader
Vanderson Rocha
MD PhD
Scientific Director
Annalisa Ruggeri, MD
Agnès Devergie
MD
L...
Acknowledgements
• University Medical Center Utrecht, the Netherlands: Peter van Hasselt, Mieke Aldenhoven
• University of...
Upcoming SlideShare
Loading in...5
×

Late Outcomes of Cord Blood Transplantation for Patients with Hurler Syndrome

546

Published on

Published in: Health & Medicine, Education
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
546
On Slideshare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
11
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Late Outcomes of Cord Blood Transplantation for Patients with Hurler Syndrome

  1. 1. Late Outcomes of Cord Blood Transplantation for Patients with Hurler Syndrome Jaap J Boelens June 2013 (11th CB symposium San Fransisco)
  2. 2. I have no Conflict of Interest to Declare
  3. 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. 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. 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. 6. Long term outcome after successful SCT Girl; 4 years old NO SCT Boy; 4 years old 2 years post-SCT
  7. 7. Successful HCT influences Long Term Survival in HS-patients Moore et al 2008 N=67 N=129 TRM UK patients 1981-2003
  8. 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. 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. 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. 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. 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. 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. 14. Multivariate Cox Regression “for endpoint EFS”
  15. 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. 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. 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. 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. 19. Urinary GAG excretion (DS/CS-ratio) Wynn et al. J Pediatr. 2009
  20. 20. Highly Variable Long Term Outcome! Large differences between Hurler patients post-HSCT Explanation?
  21. 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. 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. 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. 24. Mieke Aldenhoven (PhD student): Visited all (larger) centers in USA and Europe to collect data How to collect these data?
  25. 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. 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. 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. 28. Neurodevelopmental Outcomes (2) • DQ prior to HSCT is a predictor for DQ after HSCT
  29. 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. 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. 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. 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. 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. 34. Hearing Aids According to IDUA IDUA < ref: 66% +/-13 IDUA > ref: 34% +/-7
  35. 35. Linear Growth according to IDUA SDS according to WHO growth references (2009)
  36. 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. 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. 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. 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. 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. 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
  1. A particular slide catching your eye?

    Clipping is a handy way to collect important slides you want to go back to later.

×