1) Hematopoietic stem cell transplantation (HSCT) is being explored as a potentially curative treatment for sickle cell disease (SCD) due to the severe complications associated with SCD including stroke, acute chest syndrome, chronic pain, and early mortality. 2) While HSCT can cure SCD by replacing the defective hematopoietic stem cells, current transplant approaches still carry high risks of transplant-related mortality, graft-versus-host disease, and long-term effects on fertility and cognition. 3) Recent efforts aim to reduce the intensity of pre-transplant conditioning to lower toxicity while maintaining graft-versus-host disease prevention. Additional areas of research focus on optim

1. Hematopoietic Stem Cell
Transplantation for Sickle Cell Disease
Disclosures: None
Shalini Shenoy, MD
Professor of Pediatrics
Director, Stem Cell Transplant Program

2. Why discuss HSCT in a treatable disorder?
Quinn et al. Blood 2010Platt et al. NEJM 1994 Fitzhugh et al. Am J Hematol 2010
2007
1975

3. Mean age at death: 33.4 for males and 36.9 for
females (reviewed in 2013)
Lanzkron et al. Pub Health Rep April 2013
The reason ….

4. It is not fun to live with SCD
• Stroke, cerebral vasculopathy – moyamoya disease,
high TCD, poor performance score
(20% recur with overt stroke; 28% with silent strokes;
30% have a third stroke)
• Recurrent acute chest syndrome
• Chronic pain and narcotic dependence
• Osteonecrosis; avascular necrosis; nephropathy;
retinopathy
• Red cell allo-immunization
• Prolonged hospitalization
Scothorn J et al. Pediatr 2002; Hulbert M et al. Blood 2011

5. Transplant is curative (CNS, lung, spleen, kidney)
Can we fulfill this wish list?
• Low TRM, low organ toxicity, High DFS
• Low or NO GVHD (especially chronic)
• Minimal toxicities and late side effects
• Fertility preservation
• Early immune reconstitution
• Low graft rejection
• QOL, QOL, QOL

6. Eapen et al Lancet 2007
Outcomes based on donor selection of unrelated product
6/6 matched UCB
5/6 matched UCB

7. Cord/BM Match Rates
Provided by NMDP, 2011. Used with permission.
*Less than 14% of SCD patients have matched sibling donors!

8. Ruggeri et al BBMT 2011Locatelli et al Blood 2013
URD UCBT - Graft rejection and mortality are the
problem

9. Variables we have to work with
Immunosuppresssion
MMUD-GVHDMUD-GVHDSib-GVHD
Stem cell source
Intensity of Conditioning
Focus: Reducing toxicity of conditioning in UCBT

10. • Hypogonadism (60%), ovarian failure (71%),
sterility
• Neurocognitive – 20% with memory problems,
32% with neuro events, 25% seizures, 10%
cognitive impairment
• Height impaired in pubertal recipient
Myeloablative transplants for SCD
Walters BBMT 2010; Fitzhugh Blood 2008; Eggleston Br J Haematol 2007
“Perhaps less is better” – the case for reducing
intensity of conditioning – alemtuzumab,
fludarabine & melphalan

11. Rationale
• Early host immune suppression (day -21)
• Some continued T cell depletion due to long
half-life of alemtuzumab - ?GVHD benefit
• Early immune reconstitution
• Offset risk for PTLD (T and B cell depletion)
• Early infection risk
• Potentially lower incidence of irreversible
organ damage and late effects

12. Food for thought
(for a prospective transplant consideration with RIC )
• The transplanter’s ability to accept a change of
paradigm from myeloablative conditioning where
most children will recover from early toxicities
• All RICs not equal; one failure is not applicable to all
• Acceptance of “stable long-term mixed chimerism”
for non-malignant disorders
• A change of definition of “acceptable” – in some
situations, graft rejection is perhaps more
acceptable than major transplant related toxicities
• A second transplant is feasible following RIT

13. Based on multi-center experience with SCD HSCT
• # transplanted: 32
• Follow up: 3m - 8 yrs
• Age: 2-18 yrs
• TRM: 5%
• Graft Rejection: 8%
• Gr 2-4 aGVHD: 22% Gr 3-4 aGVHD: 7%
• cGVHD: 15%
Cord arm closed on the BMT CTN SCURT trial for
increased rejection Kamani N et al. BBMT 2012
The SCURT Trial
Reduced intensity trial of unrelated donor transplantation for
severe SCD

14. Bednarski J et al…Tandem 2013

15. Late Effects - > 2 years post
Madden L, et al……2013

16. Fertility

17. The Intensified RIT approach
The URTH trial (Unrelated RIT for thalassemia)
Prednisone – d 28
Calcineurin inhibitor – d 100
A
F
M
T
MTX
TTHU
Extended to:
-mismatched marrow
-cord blood

18. Enhancing outcomes
• Size of cord product: > 4 x 10E7 TNC/Kg
• Renal function, HYPERTENSION, fluid
balance
• Seizure prophylaxis
• Maintain platelet counts – risk of ICH
• Weekly infection surveillance – CMV,
adeno, RSV, paraflu, flu - All
• Bacterial and fungal infection prophylaxis
• Anti-HLA antibodies; non-inherited maternal
ags; cord product CFUs

19. Early experience
• Enrolling on phase I design
• Eligible: 5-6/6 matched cords with target
cell dose
• 13 transplants
• 1 rejection
• 1 death – GVHD
• All non-malignant disorders

20. Additional avenues of research
• Mesenchymal stem cell infusion with UCB
• Ex-vivo expansion of cord products using
proliferative signaling molecules
• Haplo-identical cell infusion with cord
blood transplant following RIC
• “Reduced toxicity” transplants
• Notch-mediated expansion of cord
progenitors for myeloid reconstitution

21. Cellular anti-viral therapy
• Dual antigen specific third party T cells – anti
EBV, CMV, adenovirus ( over 2 weeks)
• No GVHD risk
• Developed from peripheral blood
mononuclear cells
Hanley PJ et al. Cytotherapy 2011

22. Bolanos-Meade et al. Blood 2012
Haploidentical transplants for SCD
14 patients; graft rejection 43%; NO deaths
Cairo et al. NYMC: Haploidentical transplant for severe SCD using CD34
enriched familial product
Freed/Cairo et al. BMT 2012

23. Summary
• Transplantation for SCD is evolving and
improving
• New frontiers in conditioning, optimizing
stem cell source, supportive care, and
GVHD therapy is helping the field advance
• Our definitions of success must now be
based not just on OS/DFS but on short and
long term toxicities and QOL
• The ONLY way of moving the field forward
is developing, cooperating with and
participating in formal trials designed to
improve and track outcomes

24. Acknowledgement
• M. Pulsipher – Utah
• K. Schultz – Vancouver
• D. Wall; K. Chan – San Antonio
• M. Nieder; G.Hale – Tampa
• M. Andreansky – Miami
• S. Chaudhry – Chicago
• M. Bhatia – New York
• R. Adams – Phoenix
• J. Brochstein – New York
• N. Bunin – Philadelphia
• L. Yu – New Orleans
• A. Gilman – Charlotte
• K. Kasow – Chapel Hill
• D. Jacobsohn – Washington DC
• P. Haut – Indianapolis
• J. Dalal – Kansas City
• J. Fort – Miami
• E. Anderson – San Diego
• BMT Team – St. Louis Children’s
Hospital, Washington University
• DSMB for the various trials
• BMT CTN, CIBMTR, SCD CRN,
PBMTC, TCRN
• Participating patients
and their families