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Hematopoietic Stem Cell Transplant in
Adults with Sickle Cell Disease: the
changing landscape
Adetola Kassim, M.D.Associate Professor of Medicine
Vanderbilt-Meharry-Matthew Walker
Center of Excellence for Sickle Cell Disease
Vanderbilt University Medical Center
Nashville, Tennessee
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Outline
• Sickle cell disease morbidity
• Hematopoietic stem cell transplant in SCD
– what we have learnt so far
• The challenges in the adult patient
• Transplant approach in the adult patient
• Future directions
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Case
• 51 year old AAM, lawyer, with sickle cell disease
(SCD), Hb SS, h/o recurrent pain episodes, ACS,
depression, DVT, cholecystectomy, chronic fatigue
and poor QOL. Treatment in the past included: hydrea
(1995-2007), decitabine, thalidomide, on chronic
transfusion, presented for transplant consultation
• Other medical problems:
- Transfusional iron overload
- Sickle cell nephropathy
- AVN of the Left femoral head
- Priapism with secondary impotence
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Outcome of sickle cell anemia: A 4-decade
observational study of 1056 patients
• Childhood survival improved from 79% to 89%
• 73% had 1 or more clinically recognized forms of
irreversible organ damage.
• By the fifth decade, 48% had documented irreversible
organ damage.
– ESRD 11.6%
– Sickle cell chronic lung disease 16% (often associated with
pulmonary hypertension)
– Cerebrovascular accident 11%
Powars et. al. Medicine. 84(6):363-376, November 2005.
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1.0
0.9
0.8
0.70 2 4 6 8 10 12 14 16 18
Follow-Up (Years)
Fra
ctio
n S
urv
ivin
g
1983-2006
1983-1990
1973-1975
Improved survival of sickle cell disease
Quinn et al. Blood. 2010 Apr 29;115(17):3447-52
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Age at death for individuals with SCD
from CDC compressed mortality reports
Hassell, K.L. (2010) AJPM, 38, S512–S521.
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Factors associated with survival in a
contemporary adult SCD cohort
OS curves by genotype
Elmariah et al., Am. J. Hematol., 2014 vol. 89(5) pp. 530-5
Survival by pain crises/yr
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Factors associated with survival in a
contemporary adult SCD cohort
Characteristics Hazard ratio P value
Pulmonary hypertension 2.34 0.0036
Leg ulcer 1.66 0.0118
Proteinuria 1.86 0.0014
Cerebrovascular event 1.95 0.0005
Stroke 1.64 0.0335
Seizure 2.54 <0.0001
Pain crisis in past year 1.74 0.0054
Antihypertensive 1.74 0.0168
Short-acting narcotics (daily) 1.55 0.0395
sVCAM-1 2.03 0.0003
Elmariah et al., Am. J. Hematol., 2014 vol. 89(5) pp. 530-5
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Factors associated with survival in a
contemporary adult SCD cohort
OS by organ severity score Other end-points
• Effect of organ severity score
was additive (p < 0.001)
• Median OS - 61years
• HbSS and HbSβ0 - 58 years
• HbSC and HbSβ+ - 66 year
• HU and HbF had no effect on
survival
Elmariah et al., Am. J. Hematol., 2014 vol. 89(5) pp. 530-5
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Let’s look at the impact of sickle
cell disease on a specific organ,
the brain.
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Direct effects of sickle cell disease
on the brain
• Overt stroke
• Silent stroke
• Anemia
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Overt strokes
• Most widely recognized cause of brain injury in SCD
• Occur in 5 – 10% of children with SCD
• Highest incidence of first stroke: ages 2 – 5
• Rate of stroke recurrence is around 70%
• Blood transfusion therapy can decrease recurrence to around 10%
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Stroke free interval versus
sickle cell phenotype
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Hemorrhagic Stroke
• Most common in adults
• Peak incidence between 20 to 29 years of age
• Subarachnoid hemorrhages most common
• The hemorrhagic predominance may reflect
the development of "moya-moya" syndrome
years after an earlier thrombotic stroke
• Angiography reveals the complex filamentous
structure of the moya-moya lesion
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Secondary prevention of
overt strokes
• Therapies for prevention of second strokes:
– Chronic blood transfusion therapy
– Allogeneic stem cell transplant
– Hydroxyurea
– Revascularization
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Summary of treatment of stroke
• Recurrence Rate
– 22% (2.2 per 100 pt yrs) with transfusion (J Pediatr. 2002;140(3):348-54)
– 50% with cessation of transfusions (J Pediatr 1991; 118(3):377-82.)
– 67 % without treatment (Am J Med. 1978;65(3):461-71)
– *Risk higher in first 2 yrs after initial stroke
• Initial treatment should include exchange transfusion(J Pediatr. 2006,149(5):710-2)
• Approximately 45% of the patients that are rigorously
transfused will have progressive disease (overt or silent
strokes) Blood. 2011 Jan 20;117(3):772-9
– Progressive CNS lesions based on progressive vasculopathy
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Event-free interval of new overt or silent cerebral
infarcts in children with SCD while on transfusion
therapy for secondary stroke prevention.
Hulbert et al, 2011
• 11/40 with new SCI
• 7/40 new over strokes
• 45% with progressive
cerebral infarcts, mean
follow-up of 5.2 years
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Given the rate of cerebral infarcts in
children (37% before 18 years of age),
coupled with the high rate of cerebral
hemorrhage in adults, we elected to
introduce as standard of care MRI and
MRA imaging evaluation in adults
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Rationale
• High pre-test probability > 37%
• Detection of either silent cerebral infarcts or
moya moya would significantly alter medical
care
– Cognitive testing
• Alter expectations
– Consideration for blood transfusion therapy or
Hematopoietic stem cell transplant (HSCT)
– Ongoing CNS imaging surveillance
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Preliminary findings of MRI/MRA
result in adult patients with SCD
• Implemented as standard of care in 2011
• n=69 ( predominantly HbSS -57)
• 9% with aneurysms ( ~ 5% in general
population); 6 patients with moya moya
– 6 patients were recommended to have a
neurological procedure
– 2 agreed to the neurosurgical procedure
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Consequence of stroke in SCD
• High recurrence rate (progressive)
• Motor, speech, sensory impairment
• Cognitive impairment
• Excessive iron stores secondary to
transfusions
– Burden of chelation due to transfusion therapy
• Death
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Neurocognitive functioning in a
clinical sample of adult patients with
sickle cell disease (n = 41)
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Clinical Cognitive Assessment Program
• 2.5-hour battery of tests and questionnaires that
measures:
~ General Intelligence (IQ)
~ Memory
~ Executive Function
~ Psychosocial Adjustment
• Goal: to identify signs of impairment and assist
medical team in developing plan of care
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Domain/Test Patient Mean
(SD)
Population Mean
(SD)
p value
IQ (Wechsler Adult
Intelligence Scale-IV)
Full Scale IQ 85.5 (13.9) 100 (15) < .001
Verbal Comprehension Index 89.2 (13.5) 100 (15) < .001
Perceptual Reasoning Index 89.8 (15.8) 100 (15) <.001
Working Memory Index 86.6 (11.7) 100 (15) <.001
Processing Speed Index 85.1 ( 13.7) 100 (15) <.001
Patient scores on cognitive tests
compared to population mean
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Cognitive test scores in patients with
overt strokes vs no overt strokes
Test Overt Stroke No Overt Stroke p value
Full Scale IQ 83.7 (22.9) 85.8 (11.9) Not Significant
Total Memory Recall 30.1 (8.8) 40.5 (11.1) .026
Executive Functioning 5.3 (3.7) 7.7 (2.5) .033
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Relation between cognitive
functioning and employment status
Test Employed/In School Unemployed p value
Full Scale IQ 93.1 (12.6) 78.9 (11.6) .001
Total Memory Recall 41.1 (11.8) 36.8 (10.9) Not Significant
Delayed Memory Recall 43.9 (13.3) 35.5 (12.0) .04
Executive Functioning 8.1 (2.5) 6.7 (3.0) Not Significant
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Given the high rate of CNS
morbidity, and progressive organ
dysfunction, can we abate
progression of the disease?
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Outcome after transplantation for 50 children with advanced, symptomatic SCD
An event is defined as death, graft rejection or recurrence of sickle cell disease
Walters et al. Blood 2000; 95:6
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Late effects evaluation
• 55 long-term survivors >2yrs post-BMT
• Median age 9.4 year (range 3.3-14.0)
• No patient had an additional stroke or SCI
• All patients had abrogation of SCD related
clinical symptoms such as pain and ACS
• Significant gonadal toxicity >females
• Unchanged or improved pulmonary function
Walters et al. BBMT 16:263-272 (2010)
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Outcome of patients with hemoglobinopathies
given either cord blood or BMT from an
HLA-identical sibling: Eurocord-EBMT
Overall survival Other outcomes
• Median age 6yrs and 8yrs
• Median year 2001 vs 1999
for CBT v BMT respectively
• Median follow-up 70 months
• DFS did not differ in both
• GVHD: BMT > CBT
• Graft failure: CBT > BMT
• Outcomes were comparable
Franco Locatelli, et al. Blood, 2013
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Long-term outcome and evaluation of organ
function in Pediatric patients with SCD
following HSCT- St. Judes experience
Matched related donor (n=14) Haploidentical (n=8)
Dallas et. al Biol Blood Marrow Transplant 19 (2013) 820-830
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Late effects: MRD or Haplo
• Indication: stroke, recurrent ACS and VOE
• Median follow-up: 9.0 + 2.3yrs / 7.4 + 2.7yrs
• Greater risk of GVHD in both arms
• Higher risk of graft rejection in Haplo arm
• Beneficial outcomes similar in both arms
- No recurrent stroke or SCI, MRI improved
- Stable NCT with no change in IQ post-HSCT
- Decline in DLCO, renal and cardiac function in
MRD cohort, likely due to conditioning
Dallas et. al Biol Blood Marrow Transplant 19 (2013) 820-830
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Health related quality of life in children with
SCD and thalassemia following HSCT
Kelly et al. Pediatr Blood Cancer. 2012 October ; 59(4): 725–731.
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Benefits and risks of HSCT
Benefits
– Curative in SCD
– Halts and reverses chronic end-organ damage
– Improved overall QOL
Risks– Early and Late regimen related toxicities
– Increased risk of infertility
– Growth disturbance in children
– 5% long term increased risk of secondary cancer
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Hematopoietic stem cell transplant
(HSCT) for SCD by donor type and
overall survivalTransplantation for SCD EBMT-Eurocord
(1986-2013)
CIBMTR
(1986-2012)
Total
Type of donor
HLA identical
CB related and unrelated
Haploidentical donor
Other unrelated donor
611
487
73
34
17
627
430
71
61
65
Overall survival
1 year
2 year
95% + 1%
94% + 1%
96% + 2%
94% + 1%
Eliane Gluckman, ASH 2013
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The challenges
• Severely shortened life span in adults with SCD
(mean age of death 38.2 years 1994- 2004, unchanged
from the early 90s)
• Improved survival into adulthood has uncovered true
natural history of adult SCD with progressive organ
damage with significant morbidity and mortality
• Goal: sustained donor engraftment with minimal
toxicity using novel approaches
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Other concerns
• Need to avoid the high morbidity and
mortality associated with conventional bone
marrow transplantation (BMT)
• What level of hematopoietic chimerism
alleviates both disease related morbidity,
and prevents silent organ damage
• The scarcity of acceptable stem cell donors
• No hard & fast indications for transplant
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Approach to HSCT in the
adult patient …..
“Primum non nocere”
(first do no harm)
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Summary of earlier non-myeloablative
transplant experience2000
Van Besien
2002
Van Besien
2003
Iannone
2002
Schleuning
2008
Krishnamurti
total
Number 2 2 6 1 7 18
Conditioning Flu, Mel,
ATG
Flu, Mel,
campath
Flu, 200
TBI, ATG
Flu, Cy Flu, Bu,
ATG, TLI
Immunosupp Tacro, MTX Tacro or
CSA, MMF
CSA, MMF CSA
Age 40, 56 19, 24 3 to 20 8 6 to 18
Engraftment 2 2 5 1 6
Rejection 0 1 6 0 1 8
Acute GvHD 2 0 1 (Gr 2) 0 1 (Gr 2)
Chronic GvHD 1 0 0 0 1 (limited)
Mixed
chimerism
0 1 6 1 6
Death 2 (GvHD) 0 0 0 0
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In the adult patient with an HLA
identical sibling
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NIH protocol 03-H-0170
non-myeloablative stem cell transplant
Sirolimus (target 10-15 ng/dL)
-7 -6 -5 -4 -3 -2 -1 0
Alemtuzumab
(1 mg/kg total)
TBI300 cGy
Unmanipulated G-CSF
mobilized PBSC
infusion
• Hydroxyurea is continued through day -8
• Red cell exchange to lower HbS ~ 30%
• Platelet transfusion threshold is 50k/uL (to prevent CNS bleeding)
• Taper immunosuppression planned at 1 year post transplant, if CD3 donor chimerism is >50%
-8
Hsieh et al. N Engl J Med 2009;361:2309-17.
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Update on protocol 03-H-0170
Overall survival, 100%
Disease free survival, 87%
30 SCD patients transplanted
22 patients with white cell
engraftment
21 patients with donor red cell engraftment
1 patient with delayed red cell engraftment (anti-donor RBC antibody)
No GvHD
3 patients with rejection
Su
rviv
al
-Median f/up >3 yrs
-Age 17-65yrs
-GCSF primed PBSC
-Graft failure 3/26
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How about the adult SCD patient
without an HLA identical
sibling?
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Haplo-identical Transplant
for Sickle Cell Disease and other
Hemoglobinopathies
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Proof of principle
• Non-myeloablative regimen, suggests that
the procedure can be performed in patients
who are ineligible for myeloablative
alloBMT
• Expands the donor pool for eligible patients
• Immune suppression approach reduces risk
of graft rejection and minimizes GVHD
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Mechanism of tolerance induction by
high dose cytoxan
Leo Luznik, Paul O’Donnell and Ephraim Fuchs, Semin Oncol. 2012
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Conditioning schema
Bolaños-Meade J et al. Blood 2012;120:4285-4291©2012 by American Society of Hematology
-First 2 pts were transplanted w/o ATG
-Sirolimus replaced tacrolimus w/ 11 pt to reduce the
incidence of PRES
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Outcomes data
• 19 patients screened, 17/19 were transplanted (89%)
• 14 -haploidentical; 3 -HLA-matched related donors.
• Eleven patients engrafted durably.
• After median follow-up of 711 days (minimal follow
up 224 days), 10 patients are asymptomatic, and 6
patients are off immunosupression.
• Only 1 patient developed skin-only acute GVHD that
resolved without any therapy.
• No mortality
Bolaños-Meade J et al. Blood 2012;120:4285-4291
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Limitations
• No assessment of whether there was
attenuation of end organ disease,
specifically CNS, lung or kidneys
• Graft failure, 43% in haploidentical pairs,
remains a major obstacle
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Pros and cons of three existing of alloBMT
approaches in patients with SCD
Myeloablative
matched alloBMT
Non-myeloablative
matched alloBMT
Non-myeloablative
mismatched (haplo)
alloBMT
Pros Curative Does not exclude SCD
patients with end-organ
damage
Does not exclude SCD
patients with end-organ
damage
Large experience
Good rates of engraftment
May attenuate end-organ
damage
EFS 85%; OS 97%
More available to adults
with SCD (30%)
TRM < 5%
EFS 79%; OS 95%
Available to most SCD
patients (>50%)
TRM < 5%
EFS 58%; OS 96%
Cons Limited availability ~10% Limited experience Limited experience
Limited to children less
than 16 yrs old
Graft rejection (11– 50%) Graft rejection (40-50%)
TRM 7% Acute and chronic GVHD No GVHD
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International Consortium
• Vanderbilt teamo Haydar Frangoul
o Michael Debaun
o Adetola Kassim
• Johns Hopkins team o Robert Brodsky
o Kenneth Cooke
• UAB team
o Racquel Shelton
• UK Teamo Josu de la Fuente
o Baba Inusa
o Paul Telfer
• French teamo Nathalie Dhedin
o Francoise Bernaudin
o Mariane Demontal
o Mathieu Kuentz
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Update on collaborative effort
• Created both pediatric and adult transplant
consortium for haplo-identical transplant in SCD
• Common entry criteria and protocol
• Signed memorandum of understanding
• To date: 4- patients at VUMC; 3-patients in France
• JHC - 10/12 (83%, all haplos) engrafted with
GCSF mobilized donors; 1 death (TRM 4%) -
?IPD; 1-GVHD (4%).
• Enrollment pending in UAB and UK
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HSCT approach for the adult patient
Adult SCD patient with organ
dysfunction(?severity score or CI)
HLA identical
sibling available
No HLA
identical sibling
Non-myeloablative BM or
PBSC*
Related non-myeloablative
haploidentical BM
Other approaches being evaluated: Unrelated cord blood, expanded cord strategies, MUD
* Using the haploidentical approach with high dose cytoxan
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Case: follow-up
• Patient had no HLA matched sibling
• Underwent a Haplo-BMT from 58yr old sister
• Indication: SCD with multiple comorbidities
• Data D+100: RFLP 100% donor; sorted chimerism
CD3 / CD 33 100% donor; HPLC: nl hemoglobin
• Presently: >D +120 from Haplo-BMT
• Complications: AKI due to sirolimus, and rash
(suppurative folliculitis) - resolved
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Special dedication
“ I never thought that
this could happen in
my lifetime. I still
have lingering issues
from living with SCD
for so long; but no
NEW organ damage or
bone damage will
occur to me because I
am cured”.
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Conclusions
• Haplo-BMT approach has low toxicity, applicable to adults with severe organ damage
• Less than full engraftment sufficient to revert the sickle phenotype– no acute or chronic GvHD
– data suggest operational tolerance to donor blood cells
• Longer follow-up and further accrual to ascertain– stable chimerism off immunosuppression
– reversal of end-organ damage
• Amended protocol to enroll pediatric patients
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Acknowledgements
• Patients and their families
• Michael Debaun, MD
• Robert Brodsky, MD
• Maureen Sanger, PhD
• Nicoll Hannaway, LCSW
• Members of the Vanderbilt-Meharry-
Matthew Walker Center of Excellence for
Sickle Cell Disease