Hematopoietic Stem Cell Transplantation for Sickle Cell Disease
Disclosures: None
Shalini Shenoy, MD Professor of Pediatrics
Director, Stem Cell Transplant Program
Why discuss HSCT in a treatable disorder?
Quinn et al. Blood 2010 Platt et al. NEJM 1994 Fitzhugh et al. Am J Hematol 2010
2007
1975
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 ….
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
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
Eapen et al Lancet 2007
Outcomes based on donor selection of unrelated product
6/6 matched UCB
5/6 matched UCB
Cord/BM Match Rates
Provided by NMDP, 2011. Used with permission.
*Less than 14% of SCD patients have matched sibling donors!
Ruggeri et al BBMT 2011 Locatelli et al Blood 2013
URD UCBT - Graft rejection and mortality are the problem
Variables we have to work with
Immunosuppresssion
MMUD-GVHD MUD-GVHD Sib-GVHD
Stem cell source
Intensity of Conditioning
Focus: Reducing toxicity of conditioning in UCBT
• 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
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
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
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
Bednarski J et al…Tandem 2013
Late Effects - > 2 years post
Madden L, et al……2013
Fertility
The Intensified RIT approach The URTH trial (Unrelated RIT for thalassemia)
Prednisone – d 28
Calcineurin inhibitor – d 100
A F
M
T MTX
TT HU
Extended to: -mismatched marrow -cord blood
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
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
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
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
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
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
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