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

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 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

MPS-1

Hurler 6 yrs old

Scheie 9 yrs old

Continues spectrum Severe mild

-Hepato-splenomegaly -Deaf / blind -Progressive developmental retard. -Cardiovascular / pulm. Failure -PREMATURE DEATH (med. 8yr)

MPS 1: who to transplant? De Ru et al, Orphanet J Rare Diseases 2011

Decision made in multidisciplinary team: -metabolic specialist -transplant physician

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) – 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

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

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)

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)

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

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

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±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)

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 <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)

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?

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 for long term endpoints

How to optimize the transplantation-procedure?

• Carrier donor, mixed chimerism, stem cell source, etc

• Novel therapies: e.g. gene-therapy

• 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

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

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

– London 13

– Paris 7

Hurler patients included

Total: 197

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

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

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=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)

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)

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

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%

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 - -0,03 0,042

> reference 71 -1,09

Exclusion criteria: TBI, endocrinologic abnormalities, GH treatment Statistical analysis: Mean, standard deviation, unpaired t test

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

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)

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!

Eliane Gluckman MD FRCP

Project Leader

Vanderson Rocha MD PhD

Scientific Director

Annalisa Ruggeri, MD Agnès Devergie

MD

Luciana Tucunduva MD

Myriam Pruvost Administrative Assistant Fernanda Volt, MT

Chantal Kenzey Data Manager

EUROCORD TEAM 2013

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