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Late Outcomes of Cord Blood Transplantation for Patients with Hurler Syndrome

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  • 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