Jean-Hugues Dalle 4th EBMT training course for

Jean‐Hugues Dalle
4th EBMT training course for pediatricians and
pediatric nurses on HSCT in children and
adolescents: interactive educational EBMT PDs
course.
Bucarest, May 2013
Rationnal
y Thalassemia:
y Hemoglobin disorder
y Most common monigenetic disorder:
y
≈5% of the world population with globin gene variant
80 million people with β Thalassemia
y 30‐60 000 births a year with major thalassemia
y Initially from (sub) tropic area
y Now worldwide
y
Beta‐thalassemia
Always severe
phenotype
From http://www.patient.org.in/blood/thalassemias.htm
Erythroïd hyperplasia
(BM and extraBM)
Hemolytic anemia
Ineffective
erythropoiesis
Iron overload
± Hepatitis C
Chronic transfusions
Multiple organ
damages:
Heart, Liver,
Endocrine deficiencies
y < 50% of patients still remain alive after 35 year of
age
85‐96
1.00
80‐84
75‐79
Survival Probability
0.75
70‐74
65‐69
0.50
60‐64
0.25
Log‐rank test: p<0.0001
0.00
0
5
10
15
20
25
30
Age (years)
35
40
45
50
Borgna 2010
y To avoid early death:
y Chronic transfusion Î Substitutive therapy
y
HSCT from full‐matched compatible donor
Î Only curative therapy
y
Multi‐disciplinary and long‐life follow‐up
Balance
y Curative therapy
Transfusion program + Iron
chelation
y Subtitutive therapy
y Risk of death during
procedure
y Risk of viral infections
(hepatitis C +++)
y Risk of GvHD
y Risk of allo‐immunisation
y Risk of long‐term
sequelaes
y Risk of toxicity
HSCT
Renal failure
y BM failure (‐)
y Cost +++
y
The problem of the costs
Medical
therapy
Direct costs in Italy
(transfusion +
chelation with DFO)
€ =14,916 /year
HSCT
Acute Leukemia. Euro € = 94,350 (CV 40%)
Study. Median value
Gene
therapy
Manipulated stem cell
???????
Scalone L et al.
Curr Med Res
Opin
2008;24:1905–17
Orsi C et al Bone
Marrow Transplant
2007; 40: 643-9
Personal
information
Factors that must be considered for individual
decision making about HSCT for thalassemia.
Angelucci E Hematology 2010;2010:456‐462
1981 : First HSCT for thalassemia
y Seattle group
y 14 month old girl
y HLA identical sister
y Successful outcome
y Pesaro group
y 16 year‐old heavely transfused thalassemia patient
y HLA identical brother
y Rejection
First report and results
Lucarelli et coll., NEJM 1990
y 222 patients < 17 years of age
y OS: 82%
y EFS: 75%
y Multivariate analysis for 116 pts
y Highly homogeneous patient group and therapy
y Bu14 + Cy200
y GvHD prophylaxis:
y
y
CSA + MP
± ATG
Pesaro score
Class 1
Class 2
Class 3
Chelation
Regular
Regular/
Irregular
Irregular
Hepatomegaly
> 2 cm
No
No/Yes
Yes
Liver Fibrosis
(biopsy)
No
No/Yes
Yes
OS
94%
80%
61%
EFS
94%
77%
53%
Recurrence
0%
9%
16%
Risk
Factors
Risk
Classes
HSCT from related donors for
Class 1 & Class 2 patients under 17y.o.
About 515 classes 1‐2 patients under 17 years of age
In order to decrease the rate of rejection: + Thiotepa for patients less than 4 years
and short course MTX
Lucarelli & Gaziev, Blood Reviews 2008
HSCT from related donors for
Class 3 patients under 17y.o.
y Bu14 + Cy200: high TRM
y Bu14 + Cy 120 to 160:
y Better overall survival (53 to79%)
y Higher rejection rate (7 to 30%)
y Protocol 26 from 1997
y Azathioprine 3mg/kg/d from D‐45
y Hydroxyurea 30mg/k/d from D‐45
y Hypertransfusion regimen (Hb>14g/dl) + continuous
chelation
y Growth factors twice weekly
y Fludarabine 20mg/m²/d from D‐17 to D‐13
y Bu14 + Cy 160
About 73 class 3 patients under 17 y.o
Lucarelli & Gaziev, Blood Reviews 2008
HSCT from related donors for
adult patients (Gaziev et al, Ann NY Acd Sc 2005)
y Modified protocol 26: Cy 90
HSCT results from 10/10 MUD
in very genetically stable population
All patients, n=68
HSCT results from 10/10 MUD
in very genetically stable population
Class 1‐2 patients
Class 3 patients
Table 2. HSCT in Thalassemia (2003 ‐2013)
Author and year
#
OS
TFS
TRM
1
Galambrun C et al 2013
108
15 years : 86.8%
15 years
69.4%
15 years
12%
2
Yesilipek MA et al. 2012
245
1 year : 85%
3
Li C. et al. 2012
82
3 years: 91%
1 year
7.75%
3 years 8%
4
Choudhary D. et al.. 2013
28
78.5%
1 year
68%
3 years
87%
71.4%
5
Bernardo ME et al. 2012
60
5 years: 93%
7%
6
Sabloff M et al. 2011
179
5 years: Intermediate risk :91%
High risk 64%
5 years
84%
5 years Intermediate risk :88%,
High risk: 62%
7
Ghavamzadeh A. et al 2008
183
2 years: PBSCs 83% BM 89%
2 years PBSCs 76% BM 76%
1 year PBSC 14% BM9%
8
Iravani M. et al. 2010
52
4.1 years: 80%
4.1 years: 65%
4.1 years 7/52
9
Irfan M. et al 2008
56
5 years: BM: 73% PBSCs: 65%
5 years BM: 67% PBSCs: 55%
100 days: 10/56
10
Kabbara N et al. 2008
259
6 years: 95%
6 years: 86%
4%
11
Ullah K. Et al. 2008
48
6 years: 79%
6 years: 75%
20.8%
12
Di Bartolomeo P. et al2008
115
20 years: 89.2%
20 years: 85.7%
13
Gaziev J. et al 2005
107
12 years: 66%
12 years: 62%
1 year
8.7%
37%
14
Lawson SE et al. 2003
55
8 years : 94.5%
8 years :81.8%
5,4%
15
Gaziev J 2010
68
3 years: 91%
3 years: 87%
100 days 3%
21.4%
Intermediate risk:5/75
High risk 23/64
Article reporting series of patients partially or fully already reported have been excluded.
Sickle Cell Disease
• S/S > S‐βThal > S/C
• Very wide phenotype,
including into a same
family
From http://biologycorner.com
Epidemiology
y In North America:
y
About 8% of African‐American people carry sickle
cell gene (1/400)
y In Sub‐Saharian Africa
y
10% to 30% of people have Sickle cell trait or disease
because of protective effect against malaria in
endemic regions that leads to positive selection for
the gene mutation.
y In France
y
y
1/3360 live births (≈380/y)
1/950 live births in Paris and sub‐urban area (250 à
270/y)
Challenge
Sickle Cell Disease
Low early mortality but high morbidity risk
Wide phenotype
Stem cell transplantation
Alternative treatments
y Only curative therapy
y Transfusion program
y Toxicity risks (GVHD,
y Viral infections
gonadic failure) but offers
hope of cure and better
quality of life
y Donor availability
y Allo‐immunization
y Cost
y Hydroxyurea
y Toxicity
y Compliance
y (availability)
y Cost
>25‐year experience with
SCT for SCD patients
y Two first reports
one SCD leukemic patient successfully transplanted
in US
y 5 SCD patients successfully engrafted in Belgium
y
Related Myeloablative Stem Cell
Transplantation
to Cure Sickle Cell Anemia: Update of French
Results
Françoise Bernaudin et al, for the SFGM-TC
ASH Orlando December 2010
y Our first experience, reported in Blood 2007,
included 87 consecutive severe SCA‐ patients
transplanted in France between 1988 and Dec‐2004
y the introduction of rabbit anti‐thymocyte globulin
(ATG) in the conditioning regimen in 2000 allowed a
significant reduction of the rejection rate from 22.6%
to 3%
y Global results were similar to worldwide experience
Transplantation procedure
y HbS < 30%
y Myelo‐ablative Conditioning Regimen
y BU‐CY (1988‐1992)
y
4/12 unstable chimerism, rejection
y BU‐CY‐rabbit ATG (Thymoglobulin 20 mg/kg)
y
y
y
Busulfan Day‐10 to –7
y Oral 485 mg/m2 (>= 16 mg/kg)
y Intravenous > 2001
CY 200 mg/kg ( 50 mg/kg/d x 4: day –5 to –2)
Rabbit ATG 20 mg/kg (5 mg/kg x 4 day –6 to –3)
Transplantation procedure (2)
y GVHD prophylaxis (6‐9 months)
y CSA‐MTX for BMT and CSA alone for CBT
y Seizure prevention
y Clonazepam during conditioning and CSA therapy
y Hemoglobin maintained 9‐11g/dl
y Platelet count > 50,000/mm3
y Arterial hypertension strictly controlled
y Magnesium deficiency promptly corrected
y After 2002, CSA replaced by MMF in case of GVHD
requiring steroids
Consecutive Geno‐identical myeloablative SCT for
SCD (n=161)
y SFGM‐TC data in
Promise
y Follow‐Up stopped on
21 March 2010
y Conditioning Regimen:
BU‐CY
without ATG n= 17
y with ATG n=144
y
y BM n=121, CB n=21
Indications (n=144)
y
Cerebral vasculopathy
y
y
y
y
y
y
y
y
y
y
89
Overt Strokes
TIA
Stenoses +/‐ silent strokes
Abnormal TCD
Silent stokes ± anemia, cogn.deficit
Erythroid polyalloimmunisation
≥ 3 VOC/yr ± ACS
Osteonecrosis
1 ALL, 1 AML
TRJV > 2.5 m/sec
39
3
20
9
18
4
41
7
2
1
Events (n=9)
y Non‐engraftment (n=2)
y Rejections (n=1) at 3.2 years post‐transplant
y Deaths (n=6)
y Sepsis during aplasia (n=1)
y Hemorrhagic stroke (n=1) at day32 in a patient with severe
Moya‐Moya syndrome
y Extensive GVHD (n=4)
y
death at 2, 4 12, 30 months post‐transplant
y
y
obliterans bronchiolitis (n=2)
Aspergillosis, CMV, adenovirus…..
100
90
Survival at 5 years: 95% (SE: 2%)
Survival probability (%)
80
70
60
50
40
30
20
10
0
0
2
Number at risk
143
87
4
6
8
10
12
14
16
18
20
2
1
1
1
Years post-Transplant
59
34
26
11
8
100
90
Rejection probability (%)
80
70
60
50
40
30
20
Rejection at 5 years : 2.8% (SE: 1.7%)
10
0
0
2
Number at risk
142
85
4
6
8
10
12
14
16
18
20
2
1
1
1
Years post-Transplant
57
32
25
11
8
100
Event-free Survival probability (%)
90
80 Event‐free (Disease‐free) Survival at 5 years 92.2% (SE: 2.6%)
Event‐free (Disease‐free) Survival at 5 years 92.2% (SE: 2.6%)
70
60
50
40
30
20
10
0
0
2
Number at risk
142
85
4
6
8
10
12
14
16
18
20
2
1
1
1
Years post-Transplant
57
32
25
11
8
EFS at 5y: 95.8% (SE 2.5%)
EFS at 5y: 95.8% (SE 2.5%)
Event-Free Survival probability (%)
100
90
Log Rank:
Rank: p=0.0001
p=0.0001
Log
80
70
EFS
EFS at
at 55 y:
y: 73.9%
73.9% (SE
(SE 9.2%)
9.2%)
60
Year of Transplant
0= < 2000
1= > 2000
50
40
30
20
10
0
0
2
Number at risk
Group: 0
23
17
Group: 1
119
68
4
6
8
10
12
14
16
18
20
Years post-Transplant
17
15
15
11
8
2
1
1
1
40
17
10
0
0
0
0
0
0
Event-Free Survival probability (%)
100
90
80
EFS
EFS at
at 55 years:
years: 90.2%
90.2% (SE
(SE 6.6%)
6.6%) vs
vs 92.4%
92.4% (SE
(SE 2.9%)
2.9%)
Log Rank: p=0.53 NS
70
60
Cell Source
Cord Blood
BM or PBC
50
40
30
20
10
0
0
2
Number at risk
Group: cord blood
19
14
Group: other
123
71
4
6
8
10
12
14
16
18
20
Years post-Transplant
11
5
4
0
0
0
0
0
0
46
27
21
11
8
2
1
1
1
100
Event-Free Survival probability (%)
90
80
70
60
Age at Transplant
< 16 years (n=132)
> 16 years (=12)
50
40
30
20
10
0
0
1
2
3
4
5
6
Years post-Transplant
7
8
9
10
Umbilical Cord Blood Transplantation for Children
with Thalassemia and Sickle Cell Disease
Annalisa Ruggeri et al for the Eurocord Registry, CIBMTR and the New York Blood Center.
BBMT 2012
Copyright © American Society for Blood and Marrow Transplantation Terms and Conditions
Unrelated volunteer donor
y SCD patients :
y < 1% of full‐matched unrelated availability
y On‐going multicenter trial in US
y Thalassemia:
y MUD from Sardegna for Thal‐patient from Sardegna ≠
different combination
Haplo‐identical HSCT
y Bolanos‐Meade et al, Blood 2012
y 17 patients
y 14 haplo‐id donor
y 3 SC patients?
No death
Reduced toxicity / Reduced intensity
conditioningr regimen
y Flu‐based conditioning regimen (Cy substitution)
y Threo‐based conditioning regimen (Bu substitution)
y Main concern: rejection / engraftment failure,
including secondary engraftment
Clinical Trial: Gene Transfer of the β87 lenti‐vector into a Hb E‐β‐
thalassemia patient promotes transfusion independence
Cavazzana‐Calvo,Nature2010
Expert meeting report on
Hematopoietic stem cell transplantation in thalassemia major and sickle
cell disease:
Indications and Management Recommendations from the EBMT.
Emanuele Angelucci, Susanne Matthes‐Leodolter, Ayad
Achmed, Donatella Baronciani, Françoise Bernaudin,
Sonia Bonanomi, Maria Domenica Cappellini, Jean‐
Hugues Dalle, Paolo Di Bartolomeo, Cristina Díaz de
Heredia, Roswitha Dickerhoff, Claudio Giardini, Eliane
Gluckman, Naynesh Karmani, Milen Minkov, Franco
Locatelli, Vanderson Rocha, Jan Smiers, Isabelle Thuret,
Isaac Yaniv, Marina Cavazzana‐Calvo, Christina Peters
Recommendations for Thalassemia
y
Young patients with TM with an available HLA identical
sibling should be offered HSCT as soon as possible before
development of iron overload and iron‐related tissue
damage.
y HLA genoidentical CB and BM are equally effective stem
cell sources provided the CB unit has an adequate number
of nucleated cells (i.e. greater than 3.5x107/kg)
y HSCT from an HLA mismatched family member in TM
should still be considered an experimental approach to be
conducted only in the context of well‐designed controlled
trials.
y If a well‐matched unrelated‐donor is available, allogeneic
HSCT is a suitable option for a child with life‐long control
of iron overload and absence of iron‐related tissue
complications.
Recommendations for Thalassemia
y
The unrelated volunteer must be selected using high‐
resolution molecular typing for both HLA class I and II loci
and according to stringent criteria of compatibility with the
recipient.
y UCBT in thalassemia is an option to be considered a
promising approach if the CB unit is HLA matched and
contains an appropriate cell number.
y This type of transplantation should be performed in the
context of a well‐ controlled clinical trial in centers with
specific UCBT programs.
y An ablative conditioning regimen (without radiation)
should always be used for standard transplantation.
Recommendations for Thalassemia
y
y
y
y
y
Reduced‐toxicity regimens are under investigation and
may be used in the context of clinical trials.
Use of fludarabine instead of cyclophosphamide can
reduce the risk of undue extramedullary toxicity.
Any prospective attempt to induce stable mixed
chimerism should be considered experimental.
The combination of cyclosporine and short course
methotrexate represents the gold standard for GvHD for
HSCT from MSD.
Whether mono‐ or polyclonal antibodies like ATG or
alemtuzumab could contribute to better GVHD‐
prevention in the context of MSD HSCT. For GVHD
prevention in the UD‐HSCT setting antibodies are
common praxis.
Recommendations for Sickle cell disease
y Young patients with symptomatic SCD requiring
intensification treatment such as Hydroxyurea or
transfusion program who have a HLA‐matched sibling
donor should be transplanted as early as possible,
preferably at pre‐school age
y Unmanipulated bone marrow or umbilical cord blood
(whenever available) from matched related donors
are the recommended stem cell sources and therefore
the cryopreservation of sibling umbilical cord blood
should be encouraged and performed routinely.
Recommendations for Sickle cell
disease (2)
y SCT from unrelated marrow or cord blood donors
should only be considered in the context of well‐
designed controlled trials.
Recommendations for Sickle cell disease (3)
y The gold standard for conditioning in patients with
SCD is busulfan, cyclophosphamide and ATG.
y The promising disease‐ and GvHD‐free survival rates
reported in some small studies following RIC should
be validated by larger prospective trials.
Recommendations for Sickle cell disease (4)
y The use of ATG and post‐transplantation cyclosporine
A plus MTX is the gold standard for patients with
SCD following myeloablative conditioning.
y RIC regimens and the use of Campath‐1H instead of
ATG should be evaluated in prospective trials.
Acknwoledgments
y Georgio Dini
y Christina Peters
y Inge Hirsh
y Constantin Arion
y Anita Colita