What`s new in Sickle Cell Disease

What’s new in Sickle Cell Disease
ASH 2015
Orlando
A.Ferster and L. Dedeken
Survival in SCD: Data from a Well-Ressourced,
National Health System Setting
K. Garner (UK)
 712 adults observed over 10 years
 5268 pt-years Median observation per pts : 8 y
 42 deaths at a median age of 42
 Age at « entry »??? 34 years?
Survival in SCD: Data from a Well-Ressourced,
National Health System Setting
K. Garner (UK)
N= 450, 33 deaths
Demographics
Laboratory
Admissions
Hazard ratio
P value
α thal
1,342
0,411
Sex (F)
0,674
0,261
Total bilirubine
1,006
<0,000001
Ferritine >1000µg/L
2,51
0,016
LDH UI/L
1,002
0,038
WBC x 10e9/L
1,181
0,012
Hb g/L
0,979
0,073
Reticulocytes x 10e9/L
1,002
0,285
Mean / year
1,374
<0,001
High admission rate
(>0.5/year)
3,131
0,001
Survival in SCD: Data from a Well-Ressourced,
National Health System Setting
K. Garner (UK)
Risk of death:
• 2.5-fold if ferritin is high (>1000ug/L),
• 6% for every extra 10 µmol/L total bilirubin,
• 20% for every extra 100 IU/L LDH
• 18% for every extra 1 x109/L WBC (all steady state values).
• Hospitalization rates : X 37% for every admission accrued in an
individual's mean admission/year statistic; high versus low :
HR over 3-fold /low admission rates.
Survival in SCD: Data from a Well-Ressourced,
National Health System Setting
K. Garner (UK)
Estimated median
survival of 67
years for
HbSS/Sβ0 and 82
years for HbSC
Belgian data on survival
469 patients
5110 patient-years
Median age at last FU: 14,5 y
0,23 deaths/ 100 patient-years
Ischemic Stroke in Children and Young Adults with SCD
in the post STOP Era
Janet Kwiatkowski
Long term follow-up of the STOP1/2→ 2 trials
• Higher stroke risk if velocities > 200 cm/sec at TCD
• Prevention of stroke by chronic transfusion
After exit: Follow-up according to local practice
3539 subjects → 2850 follow-up data
12 pts with stroke during STOP 1/2 excluded → data on 2838
• Mean age at start post STOP: 10.5 y
• Median duration FU: 9.1 y
Ischemic Stroke in Children and Young Adults with SCD
in the post STOP Era
Janet Kwiatkowski
69 1st ischemic stroke (0.27 / 100 pt-years) - mean age of 14.4 y
• 25 abnormal TCD prior stroke → 15 CRCT
• 44 pts had no abnormal TCD
 29 (44%) never rescreened (7 older than 16 y)
 5 (11%) had normal TCD < 1 y before stroke
 Other normal TCD >>> 1 y before stroke
Conclusion
 Lower stroke rate than reported before
 39% stroke associated with failure to rescreen according
current guidelines
 11% in low risk TCD patients
TCD with Transfusion Changing to HU (TWITCH): Hydroxyurea as an
alternative to transfusion for primary stroke prevention in children
with SCD
R. Ware
Multicenter randomized trial comparing 24-months of
standard treatment (TF) to alternative treatment (HU)
in children with SCA and abnormal TCD velocities noninferiority trial design
Inclusion criteria:

At least 12 months of transfusions

Absence of stroke or severe vasculopathy

Normal TCD at RDZ
TCD with Transfusion Changing to HU (TWITCH): Hydroxyurea as an
alternative to transfusion for primary stroke prevention in children
with SCD
R. Ware
Primary endpoint: 24-month TCD velocity obtained from a linear mixed
model, controlling for baseline (enrollment) values, with a non-inferiority margin of 15
cm/sec
• Transfusion arm: HbS <30% + Chelation according to LIC
identified by R2 MRI FerriScan®
• Hydroxyurea arm included an overlap period with
transfusions until MTD+ phlebotomy to reduce iron overload
Transfusion
OR
TCD velocities obtained every 12 weeks
Transfusion
HU until MTD
TCD with Transfusion Changing to HU (TWITCH): Hydroxyurea as an
alternative to transfusion for primary stroke prevention in children
with SCD
R. Ware
• 159 children were enrolled (38 failed: severe
vasculopathy on brain MRA or inadequate TCD exams)
→ 121 children randomized
61 to transfusions
60 to hydroxyurea
• Enrollment maximum TCD velocities: 145 ± 21 versus 145
± 26 cm/sec
• Hydroxyurea arm: MTD after 7 ± 2 months at an average
dose of 27 mg/kg/day
TCD with Transfusion Changing to HU (TWITCH): Hydroxyurea as an
alternative to transfusion for primary stroke prevention in children
with SCD
R. Ware
The final TCD velocities
• TF arm: 143 ± 1.6
• HU arm: 138 ± 1.6 cm/sec
29 new neurological events
• no strokes but 6 transient ischemic attacks (3 in each arm).
• 1 child (TF arm) withdrawn after developing TCD velocities
>240 cm/sec.
• Exit brain MRI/MRA: no new parenchymal abnormalities but 1
(TF arm) developed new vasculopathy
TCD with Transfusion Changing to HU (TWITCH): Hydroxyurea as an
alternative to transfusion for primary stroke prevention in children
with SCD
R. Ware
• Sickle cell related SAE more common in the HU arm
• Iron overload improved more in the Hydroxyurea arm
Conclusion: In TWiTCH trial (abnormal TCD velocities but no
severe MRA vasculopathy), HU at MTD was non-inferior and
possibly superior to CT for maintaining TCD velocities.
Hydroxyurea may represent an effective alternative to indefinite
transfusions for the prevention of primary stroke in this high risk
population.
Long term follow-up of children with sickle cell anemia treated
for abnormal transcranial Doppler velocities
Françoise Bernaudin, Suzanne Verlhac, Cécile Arnaud et al, Blood 2016
Long-term follow-up of SCA-children from the newborn-CHIC-Créteil-cohort at
risk by TCD and placed on chronic transfusions
Patients with
• normalized-velocities and no persistent stenosis → hydroxyurea
• trimestrial Doppler
• transfusions re-started immediately if reversion to abnormal-velocities
• patients with a genoidentical donor underwent transplantation.
Abnormal-TCD (TAMMV≥200cm/sec): 92 SCA-children
 mean age of 3.7 years (range:1.3-8.3) - mean follow-up of 6.1 years,
 no stroke occurred post-transfusion
 normalization of velocities (TAMMV<170cm/sec) in 83.5%
 stenosis (27.5% of patients) associated with non-TCD-normalization
Long term follow-up of children with sickle cell anemia treated
for abnormal transcranial Doppler velocities
Françoise Bernaudin, Suzanne Verlhac, Cécile Arnaud et al, Blood 2016
Switch from transfusions to hydroxyurea
• 45 patients
• Mean follow-up of 3.4 years.
• Reversion, predicted by baseline reticulocyte count
≥400x109/L in 13/45 (28.9%) at the mean age of 7.1 y
Transfusions can be stopped in a subset of patients switched to
HU with trimestrial TCDoppler follow-up and immediately restarting transfusions in case of reversion
Long term follow-up of children with sickle cell anemia treated
for abnormal transcranial Doppler velocities
Françoise Bernaudin, Suzanne Verlhac, Cécile Arnaud et al, Blood 2016
Kaplan-Meier estimates of the
probability of abnormal-TCDI
reversion on Hydroxyurea:
A. in the 46 patients with
normalized velocities treated by
hydroxyurea
B. depending on the baseline
reticulocyte count < or ≥
400x109/L recorded before age 3
Progressive Loss of Brain Volume in Children with SCA:
A report from the SIT Trial Cohort
• Silent cerebral Infarct Transfusion (SIT) Trial
– Multicenter
– To determine the efficacy of blood transfusion therapy for
prevention of recurrent silent cerebral infarcts with SCA
– N = 196, 5-14y, ≥ 1 SI lesion (no stroke)
• Randomization : Blood transfusion vs. Observation (36 months)
– De Baun, NEJM 2014
Regular transfusion reduced the incidence of recurrence of cerebral
infarct in children?
Progressive Loss of Brain Volume in Children with SCA
A report from the SIT Trial Cohort
• Brain imaging review to determine longitudinal
percentage brain volume change (MRI)
– Multivariate analysis to identify predictors of brain volume
change
– N = 169
N = 169
Brain Volume Entrance
Brain Volume Exit
Changes
1237,6 cm³
1194,7 cm³
-2,7%
Brain Volume Male
Brain Volume Female
1290,6 cm³
1166,6 cm³
Brain Volume Change Male
Brain Volume Change Female
-2,6%
-2,8%
P < 0,001
P = 0,75
Gray matter
White matter
Transplantation and gene
therapy
Hematopoietic Stem Cell Transplantation
from an HLA identical sibling for Sickle Cell Disease:
an International Survey on behalf of Eurocord-Monacord,
EBMT Pediatric Disease WP and CIBMTR
Barbara Cappelli, Francoise Bernaudin, Myriam Labopin, Annalisa Ruggeri, Fernanda Volt,
Belinda Pinto Simoes, Alina Ferster, Sophie Dupont, Josu de la Fuente, Mark C. Walters,
Susanne Matthes, Marco Zecca, Franco Locatelli, Mary Eapen and Eliane Gluckman.
International Observatory on Sickle Cell Disease
Centre Scientifique de Monaco
Hopital Saint Louis, Paris
1000 HLA identical sibling SCD transplants
from 88 centers in 23 countries
Transplant period: 1986-2013
1
7 6 1 8 63
14 9
52 2
9 6 18 7
1
17
49
55
439
99
237
CIBMTR, 439
France, 237
Belgium, 99
Italy, 55
UK, 49
Spain, 17
Germany, 14
Austria, 9
Sweden, 9
The Netherlands, 7
Switzerland, 6
Turkey, 6
Denmark, 1
Greece, 1
Brazil, 18
Saudi arabia, 8
Iran, 7
South africa, 6
Israel, 5
Nigeria, 3
Canada, 2
Jordan, 2
Russia, 1
USA, N=439
EBMT
European
countries
N=513
EBMT
Non European
countries
N=48
Patients Characteristics at transplant
Patients characteristics
N (% evaluable patients)
Median follow up in months (range)
45 ( 1-325)
Median age at HSCT in years (range)
9 (1 -54)
Age group
Children (<16 years)
846 (85 %)
Adults (>16 years)
154 (15 %)
Median weight / kg (range)
Year of transplant
Hemoglobin genotype
27 (8-96)
<1991
17 (2%)
>= 1991 and <=1999
158 (16%)
>=2000 and <=2006
291 (29%)
>=2007
Hb S/S
Hb S/b0
Other
534 (53%)
94%
4%
3%
Indication for HSCT
(only EBMT patients n=561)
One or more complications for each patient
% of the evaluable patients
Recurrent vaso-occlusive crises
77%
Stroke or CNS event
48%
Recurrent chest syndrome
32%
Elevated Cerebral Arterial Velocity
13%
Osteonecrosis of multiple joints
12%
Red-cell alloimmunization
11%
Growth impairment
7%
Cardiac insufficiency
6%
Sickle nephropathy
5%
Priapism
2%
Retinopathy
2%
Gonadal dysfunction
2%
Other
10%
Conditioning Regimen
MAC n=873, 87%
RIC n=127, 13%
Bu+Cy+Flu; 2
Flu+Mel; 3
Bu+Flu+Thio; 16
Flu+Mel +/-Thio; 15
TBI+Flu; 12
TBI+Flu+ Mel; 4
TBI+Campath; 4
Bu+Cy+Flu; 3
Bu+Flu; 63
Bu+Cy; 719
Bu+Flu+Thio; 3
Bu+Flu; 19
RIC; 127
Flu+Cy; 48
Unknown ; 16
TBI based; 26
Treo+Flu+/-Thio; 27
In vivo T-cell depletion=70%
Anti-Thymocyte globulin
(n=630)
Alemtuzumab
(n=76)
Unknown ; 19
Results – Engraftment
CI of neutrophil engraftment was 98%
60-day PMN
Engraftment
p < 0.001
BM, n=838 PB, n=73
98%
95%
[97-99]
[84-98]
CB, n=89
97%
[89-99]
Median time for PMN engraftment was
19 days:
- BM= 18 days
- PB = 15 days
- CB = 27 days
CI of platelet engraftment was 98%,
median time 25 days.
Results - acute and chronic GvHD
CI of aGvHD was 14.4%
CI of cGvHD was 13.3%
BM, n=838 PB, n=73
100days
15.1%
8.6%
aGvHD II-IV [12.7-17.6] [3.5-16.6]
p = 0.26
CB, n=89
12.5%
[6.6-20.4]
3 years
cGvHD
BM, n=838 PB, n=73
14.1%
11.5%
[11.7-16.9]
[5-21]
p = 0.17
CB, n=89
7.9%
[3.2-15.6]
Event Free Survival
(alive with engraftment)
3-years Event Free Survival was 90%
p < 0.001
3Y EFS
BM, n=838
90% +/-1
PB, n=73
78% +/-5
CB, n=89
97% +/-2
Overall Survival
3Y Overall Survival was 94%
p < 0.001
3 year OS
BM, n=838
94% [93-96]
PB, n=73
CB, n=89
80% [71-90] 99% [97-100]
Multivariate analysis
EFS and OS
EFS
OS
95% CI
Signif. Exp(B) Lower Upper
95% CI
Signif. Exp(B) Lower Upper
Age at Tx
<0.001 1.07
1.04
1.10
Age at Tx
<0.001 1.10
1.07
1.14
Year Tx ≥2000
0.363 0.88
0.67
1.16
Year Tx ≥2000
0.014 0.66
0.47
0.92
PBSC vs BM
0.048 2.03 1.007
4.08
PBSC vs BM
0.004 3.43
1.49
7.88
CB vs BM
0.347 0.57 0.174
1.85
CB vs BM**
RIC vs MAC
0.111 0.55 0.268
1.15
RIC vs MAC
0.456 1.55
0.49
4.95
2.20
In vivo T-cell dpl 0.733 1.15
0.52
2.56
In vivo T-cell dpl 0.503 1.22
0.68
NA
NA
**Only 1 death
Younger age at HSCT and the use of BM or CB were independently associated
both with a better EFS and a better OS.
Neither the use of ATG nor the myeloablation (RIC vs MAC) impacted on EFS in
multivariate analysis.
Results - Graft Failure and Death
• 71 (7%) patients had autologous reconstitution (45 late graft
failure)
• 31 (3%) patients underwent a second HSCT
• 67 (7%) patients died (50 after BM, 16 after PBSC, 1 after CB)
Causes of Death
n=67
Transplant related
Infection
14
Toxicity
12
GVHD
9
Unknown
24
Recurrence or disease persistence
Secondary malignancy
Unknown
59
3
2
3
Conclusion
7% failure
7% deaths
• Excellent 3-year overall and disease-free
survival
• Limited transplant related toxicity despite the use of
MAC regimens
• Novel strategies needed for lowering graft failure and
GVHD
• These data should increase awareness for early
referral for HSCT for patients with severe SCD
Gene therapy for hemoglobinopathies
1. Isolation of patient
CD34+ stem cells
(PBSC harvest / Marrow
harvest)
2. Stem Cells Transduced Ex
Vivo with a Lentiviral Beta
AT87Q-Globin Vector)
4. (Partial)
correction of the
gene defect with
therapeutic Hb
production and
clinical
improvement
Thal
SCD
3. Autograft with cell product
after myeloablation (Bu IV)
Outcomes of Gene Therapy for Severe Sickle Disease and BetaThalassemia Major Via Transplantation of Autologous
Hematopoietic Stem Cells Transduced Ex Vivo with a Lentiviral
Beta AT87Q-Globin Vector
Age
Sex
Day of
neutrophil
engraftment
Day of last
RBC
transfusion
FU
(months)
Hb at last visit (Hb
therapeutic)
+88
9M
11,4 (5,5)
Subject with severe SCD
13/ M
+37
Subjects with β Thalassemia Major
18/ F
+13
+10
18 M
10,7 (7,8)
16/ M
+15
+12
15 M
12,8 (9,7)
19/ M
+28
+15
1M
9,2 (?)
Update of Results from the Northstar Study (HGB-204): A Phase 1/2
Study of Gene Therapy for Beta-Thalassemia Major Via
Transplantation of Autologous Hematopoietic Stem Cells Transduced
Ex-Vivo with a Lentiviral Beta AT87Q-Globin Vector (LentiGlobin
BB305 Drug Product)
M. Walters
• 10 subjects with transfusion-dependent β-thalassemia (β0/β0 [n=5],
β0/βE [n=3], β0/β+ [n=1], and 1 heterozygous β0 genotype) have
been infused with drug product.
• Median age: 26 years (range: 18 to 35 years)
• Median of 7.9 x 106 CD34+ cells/kg with median vector copy
number of 0.8 (range: 0.3 to 1.5 copies/diploid genome).
• Median time to engraftment was Day +17 (range +13 to +29) for
neutrophils and Day +30 (range: +17 to +35) for platelets.
• No ≥ Grade 3 drug-product-related adverse events have been
observed
Update of Results from the Northstar Study (HGB-204): A Phase 1/2
Study of Gene Therapy for Beta-Thalassemia Major Via
Transplantation of Autologous Hematopoietic Stem Cells Transduced
Ex-Vivo with a Lentiviral Beta AT87Q-Globin Vector (LentiGlobin
BB305 Drug Product)
M. Walters
• Detectable vector-derived HbAT87Q : median of 5.4 g/dL (range: 2.4
to 8.9 g/dL) ≥ 3 months post-infusion in 10
• 7 subjects monitored > 6 months: median of 5.2 g/dL (range: 1.9 to
8.2 g/dL) of HbAT87Q with total Hb ranging from 8.5 to 11.1 g/dL
• 1 β0/β0 subject remains transfusion dependent
• all 4 non-β0/β0 subjects have been RBC transfusion-free for ≥ 90
days (median 287 days of TF independence, range 171 to 396 days).
Conclusion: LentiGlobin derived HbAT87Qis detectable in all subjects
leading to transfusion independence or reduction in transfusion needs.
Promising modality for the treatment of patients with β-TM
French Drepagreffe Trial: Cognitive performance and
Neuroimaging at enrollment and after 12 months
F.Bernaudin
Comparing the outcome of cerebral vasculopathy following transfusion
program (TP) or transplantation (HSCT)
Inclusion criteria:
• children with SCA (SS/Sb0)
• younger than 15 years
• history of abnormal cerebral arterial velocities (TAMMX ≥ 200
cm/sec) and placed on long-term TP
• with at least one non-SCA sibling, and with parents accepting HLAtyping and HSCT if a genoidentical donor was available.
The 2 arms (TP/HSCT) were defined by the random-availability of
a genoidentical donor
67 patients included
7 previous history of stroke
French Drepagreffe Trial: Cognitive performance and
Neuroimaging at enrollment and after 12 months
F.Bernaudin
• 32 HSCT
• 35 TP
• At enrollment and 12 months post-enrollment: blood
screening, Doppler, and cerebral MRI/MRA + cognitive
performance testing (done in parallel in the non-SCA sibs)
Preliminary findings:
• Safety of HSCT
• Velocities significantly lower post-HSCT than under TP
(p<0.001), and were normalized in a greater number of
patients (p=0.003).
French Drepagreffe Trial: Cognitive performance and
Neuroimaging at enrollment and after 12 months
F.Bernaudin
Conclusion (1)
– HSCT ↓↓more significantly the cerebral velocities at
M12 and in a higher proportion of patients than TP
– Patients with a history of abnormal TCD: significantly
lower cognitive performances than their siblings, even
in the absence of stroke history
– No significant difference between the 2 arms for the
outcomes of SI and stenosis at M0 and M12
French Drepagreffe Trial: Cognitive performance and
Neuroimaging at enrollment and after 12 months
F.Bernaudin
Conclusion (2)
– The fact that cognitive performances were improved
in the TP compared to the HSCT arm might be
explained by the stress of the HSCT procedure and the
lack of schooling during this period
– Despite the higher ability of HSCT to decrease
velocities at M12 compared to TP, a longer follow-up
required to demonstrate its effect on stenosis and
cognitive performances; patients will be reassessed at
3 years post-HSCT