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