Slides - Ida Bianco and Ezio Silvestroni Memorial

Transcription

Haematopoietic stem cell
transplantation in sickle cell anaemia
Christiane Vermylen, MD, PhD
Rome, November 2013
1
Cliniques universitaires Saint-Luc – Christiane Vermylen
Long term therapies in Sickel Cell Anaemia
•Hydroxyurea
•Chronic red blood cell transfusions
•Haematopoietic stem cell transplantation
•… Gene therapy
2
History of Stem Cell Transplantation for Sickel Cell Anaemia
1st report in 1984 by Johnson concerned
a child with SCA and AML
In 1986, 1st stem cell transplantation
done for SCA
Since then, more than 300 patients
transplanted for SCA
Challenge : to find the right balance
between good results and low toxicity
Johnson FL et al New Engl J Med 1984; 311:780-3
Vermylen C et al Lancet 1988;1:1427-8
3
Source:
Stem cell transplantation
Benefits
Risks
prolonged lifespan
freedom of pain and anemia
better quality of life
fewer hospitalisations
GVHD
infertility
delayed immune reconstitution
death
4
Debate about indications and timing
All children with Sickle cell Anaemia or selected patients?
Early, before chronic organ damage?
Later, after symptoms and chronic organ damage have occured?
5
Indications to perform allogeneic SCT in Sickle Cell Anaemia
F. Locatelli Pediatr Blood cancer 2012; 59:372-6
Established indications
Previous history of stroke
CNS event lasting more than 24
hours
More than 3 episodes per year
of acute chest syndrome
More than 3 episodes per year
of VOC
Red cell alloimmunization
Avascular necrosis affecting
multiple joints
Sickle cell nephropathy
Still debated indications
Abnormal transcranial Doppler
6
Siblings
Geno-identical HSCT in children and adults
Alternative sources of stem cells
Non myeloablative conditioning regimen
Alternative sources of donors
Unrelated
Haplo-identical
7
Source:
8
Source:
Myeloablative HSCT for children and young adults with
SCA and matched related donors
Reference
Number of patients
Age (range)
Alive without SCA (%)
Bernaudin, 2007
87
2-22
92
Panepinto, 2007
67
2-27
82
Brachet, 2004
24
2-14
79
Walters, 2001
59
3-16
85
Vermylen, 1998
50
1-11
90
Hsieh M et al, Blood;2011:118:1197-1207
9
Our experience in Brussels (one center)
59 patients with SCA, 60 SCT
Age 1 -29 (median 6y)
BM : 51, CB : 7, BM + CB : 2
BuCy +/_ TLI : 58
Flu/Mel/Campath : 1
Alive and cured : 56
EFS : 94,2%
Death : 3
cGVHD and AML
CMV and
aspergillosis
Encephalitis and
poliomavirus
10
Source:
Myeloablative therapy in 15 young adults
Kuentz M et al Blood 2011;118:4491-2
11
12
Source:
Cord blood vs BM transplantations in hemoglobinopathies
Myeloabalative therapy
Bone Marrow
Cord Blood
N=389
Thal major : 259
SCA : 130 (33%)
N = 96
Thal major : 66
SCA : 30 (31%)
Locatelli F et al. Blood 2013, May 21
13
Locatelli F et al. Blood 2013, May 21
14
GRAFT
SCD
GVHD
Clinical issue
TRM
Multi-organ damage
Infertility
15
16
Source:
Non-Myeloablative conditioning regimen and sibling donors
Iannone 2003
Krishnamurti 2008
Hsieh 2009
Matthes 2013
N
7 (6 SCA, 1 β thal)
7
10
8
Age
3-20 (median 9)
< 18
16-45
2-24 (median 9)
Stem cell
source
BM 6, PBSC 1
BM
BM
BM 7, CB 1
Treatment
TBI 200 cGy,
Flu 150 mg/m2,
CsA and MMF or
Tacro
Bu 8 mg/kg,
Flu 175 mg/m2,
ATG, TLI 500
CsA, MMF
TBI 300,
Alemtuzumab 1
mg/kg,
Sirolimus
Flu 160, Mel 140,
Thiotepa 10mg/kg
or TLI 200, ATG or
Alemtuzumab
1mg/kg
CsA and MMF
Alive
7/7
7/7
10/10
8/8
Cured
0/7
6/7
9/10
8/8
Events
1 did not engraft
(2nd SCT)
6 Recurrences of
disease
1 recurrence
1 recurrence
DLI was given in 3
Iannone R et al. Biol Blood Marrow Transplant 2003;9:519-28
Krishnamurti L et al. Biol Blood Marrow Transplant 2008;14:1270-8
Hsieh MM N Engl J Med 2009;36:2309-17
Matthes-Martin et al Eur J Haematol 2013;90:308-12
17
Van Besien 2000
Jacobsohn 2004
N
2 (very sick patients)
1
Age
40 and 56
22
Stem cell
source
PBSC
PBSC
Treatment
Flu 120 mg/m2
Mel 140 mg/m2
ATG
Tacrolimus, MTX
Flu 180
Bu 6,4 mg/kg IV
ATG
CsA, MMF
Alive
0
0
Cured
0
0
Events
2 deaths due to GVHD and
infection
Died of GVHD
Van Besien K et al Bone marrow transplantaiton 2000;26:445-9
Jacobsohn D et al Lancet 2004;36:156-62
18
Conclusions
Non-myeloablative needs to be better defined
BM and CB should be preferred to PBSC
Alemtuzumab : long duration of action, further depletion of alloreactive T
cells during donor engraftment and immune reconstitution
Sirolimus : influences regulatory T cells to promote tolerance
19
Matched unrelated
Haplo-identical donors
20
Source:
Alternative sources of donor
Why?
Absence of HLA-matched sibling donor
African ancestry reduces the chances to find a suitable matched unrelated
donor
How?
Matched unrelated CB?
Haplo-identical HSCT?
21
Matched unrelated cord blood
Kamani 2012
(SCURT trial, phase II)
Radhakrishnan 2013
N
8
8
Age
7-16 (median 13)
1-10 (median 3,6)
Stem cell source
Unrelated CB (5/6 or 6/6)
Unrelated CB (5/6 or 6/6)
Treatment
Flu 150 mg/m2
Mel 140 mg/m2
Alemtuzumab
CsA or Tacro, MMF
Flu 150 mg/m2
Bu 16 mg/kg
Alemtuzumab
Tacro, MMF
Alive
7/8
5/8
Cured
2/8
4/8
Events
5 autologous recoveries
1 died of GVHD
4 failed to engraft
3 died of infections
Kamani N et al. Biol Blood Marrow Transplant 2012;18:1265-72
Radhakrishnan K et al. Biol Blood Marrow Transplant 2013;19:676-7
22
Haplo-identical stem cell transplantation
Bolanos-Meade 2012
Dallas 2013
N
14
8 with previous CVA
Age
15-46 (median 30)
4-17 (median 9)
Stem cell source
BM
CD34+ selected cells on day 0
CD3+ depleted cells on day 1
Treatment
Flu
Cyclophosphamide
ATG
TBI
Tacro or sirolimus, MMF
Post transplant 50 mg/kg on days 3
and 4
3 patients
Flu 150
Thiotepa 10
Bu
ATG
MoAB OKT3
Alive
14/14
6/8
Cured
8/14
3/8
Events
6 failed to engraft
3 autologous recovery
2 died of GVHD
The more CD3, the more toxicity
5 patients
Hydrea and Azat
Thiotepa 10
Bu
Cyclophosph
MoAB OKT3
MMF
Bolanos-Meade J. et al. Blood 2012;120:4285-91
Dallas MH et al. Biol Blood Marrow Transplant 2013;19:820-30
23
Conclusions
Sibling donor
Best sources of stem cells : bone marrow and CB
Non myeloablative conditioning regimen needs to be better defined
but gives promising results and reduced toxicity
Alemtuzumab and sirolimus
Matched unrelated CB : poor results, especially for adults
Haplo-identical stem cell transplantation
post-transplantation cyclophosphamide may be more effective than
T cell depletion in preventing GVHD
Brodsky R et al Bone marrow transplant 2008;42:523-27
24
Thank you for
your attention
25
Conclusions
SUPPORTIVE CARE
STEM CELL TRANSPLANTATION
Progressive organ damage
Possibility of cure
Chronic illness of adulthood
Disappearance of symptoms
Improvement in organ function
GVHD? Sterility?
Better conditioning regimens
26
When should we propose SCT : Is early better?
Time of SCT
According to guidelines
Earlier
N° of patients (F/M)
36 (18/18)
14 (9/5)
Age (years), median (range)
8,6 (1,7-23)
2 (0,9-15)
N° RBC transfusions
>3
<3
Survival (%)
34/36 (94)
14/14 (100)
Deaths
Absence of engraftment
Recurrence of SCA
Mixed chimerism (>30%
recipient cells)
Total events (%)
2
3
1
3
0
0
1
0
9 (25)
1 (7)
Acute GVHD gr I-II
Acute GVHD gr III-IV
Chronic GVHD limited
Chronic GVHD extensive
14
1
5
3
5
0
2
0
P value
0,0016
< 0,001
Vermylen C et al. Bone marrow transplantation 1998:22:1-6
27
Nonmyeloablative HSCT in children and young adults with SCA from
matched related donors
7 patients
RESULTS
Aged 3 to 20 (median 9)
0/7 engrafted
Matched BM
1/7 died
TBI 200 cGy, Fludarabine 150 mg/m2
6/7 disease recurred when the immune
suppression was tapered.
CsA or Tacrolimus and MMF
Iannone R et al. Biol Blood Marrow Transplant 2003;9:519-28
28
Nonmyeloablative HSCT in patients < 18 yr with high-risk SCA from
matched related donors
RESULTS
7 patients
7/7 alive
Aged< 18
6/7 engrafted
Matched BM
5/7mixed chimerism
Bu 8mg/kg, Fludarabine 175 mg/m2,
equine ATG 130 mg/kg, TLI 500 cGy,
Follow-up : 2-8,5 yr after SCT.
Krishnamurti L et al. Biol Blood Marrow Transplant 2008;14:1270-8
29
Nonmyeloablative HSCT in adults with SCA, from matched related
donors
10 patients
RESULTS
Aged 16 to 45 years
10/10 alive
Matched BM
9/10 alive without SCA at 3 years after
SCT
TBI 300 cGy, Alemtuzumab 1 mg/kg
Sirolimus (6-12 months)
Alemtuzumab : better tolerance, longer duration
of action, further deletion of alloreactive T
cells during donor engraftment and immune
reconstitution
Sirolimus : influences regulatory T cells to
promote tolerance
30
Sickle cell unrelated donor transplant trial (SCURT trial) : phase II
8 children with severe SCA
RESULTS
Aged 7 to 16 y (median 13)
3/8 engrafted
Unrelated CB transplantation (5/6 or
6/6)
5/8 autologous recovery
1/8 died of chronic GVHD
Alemtuzumab, fludarabine and
Melphalan
SCURT trial was suspended
CsA or Tacrolimus and MMF
Kamani N et al. Biol Blood Marrow Transplant 2012;18:1265-72
31
8 children with severe SCA
RESULTS
Aged 1 to 10 y (median 3,6)
4/8 engrafted
Unrelated CB transplantation (5/6 or
6/6)
4/8 failed to engraft
3/8 died of infection
Alemtuzumab (54 mg/m2), fludarabine
(180 mg/m2) and Busulfan (15-16
mg/m2)
‒ CMV pneumonitis on day 84
‒ Adenovirus on day 128
‒ CMV and later Candida parapsilosis
Tacrolimus and MMF
Radhakrishnan K et al. Biol Blood Marrow Transplant 2013;19:676-7
32
Haplo-identical : more cells available, non myeloablative regimen
14 patients with severe SCA
RESULTS
Aged 15 – 46 y (median 30)
8/14 engrafted
14 haplo BM
6/14 failed to engraft
ATG rabbit 4,5 mg/kg, fludarabine (150
mg/m2), Cyclophosphamide (29 mg/kg)
and TBI 2 Gy
No death, no toxicity
Tacrolimus or sirolimus, MMF and
posttransplantation high dose
Cyclophosphamide (50 mg/kg/d on day
3 and 4)
3 PRES syndrome, recovered fully
1 aGVHD gr I, no chronic GVHD
Bolanos-Meade J. et al. Blood 2012;120:4285-91
33
Haplo-identical. St Jude’s experience
8 patients with severe SCA, all with CVA
RESULTS
Median Age : 9 + 5 years
PBSC CD34+ selected on day 0, CD3
depleted product on day 1
First 3 patients : fludarabine (150-200
mg/m2), Thiotepa (10 mg/kg), targeted
Busulfan (900 ng/ml for 4 days), rabbit
ATG (10 mg/kg for 3 days) and OKT3 (0,1
mg/kg over days +1 to +20)
Next 5 patients : Hydroxyurea and
azathioprim 3 months before SCT,
followed by targeted Busulfan (900
ng/ml for 4 days), Thiotepa (10 mg/kg),
Cyclophosphamide (200 mg/kg) and
OKT3 (0,1 mg/kg on days -10 to +17)
MMF
6/8 alive
3/8 sustained engraftment
3/8 graft failure and SCD recurrence
2 deaths due to chronic GVHD
High doses of CD3+ T cells>increased
mortality
Conclusion : post-transplantation
cyclophosphamide may be more
effective than T cell depletion in
preventing GVHD.
Dallas MH et al. Biol Blood Marrow Transplant 2013;19:820-30
34

Slides - Ida Bianco and Ezio Silvestroni Memorial

Transcription

Similar documents

Reading Beetween the lines r3

brochure

heroes final program

A gene complex controlling segmentation in Drosophila

CBC BLUE LitErary SEriES radio-Canada série littéraire

In The News - Clear Passage Therapies

thelastsummeroftherich_pressbook

HBF Textiles Releases New Collaboration with Leading

E` ancora proponibile il Trapianto di Cellule Staminali Allogeniche?