Hematopoietic Stem Cell Transplantation for Sickle Cell Disease

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Hematopoietic Stem Cell Transplantation for Sickle Cell Disease

  1. 1. Hematopoietic Stem Cell Transplantation for Sickle Cell Disease Disclosures: None Shalini Shenoy, MD Professor of Pediatrics Director, Stem Cell Transplant Program
  2. 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. 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. 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. 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. 6. Eapen et al Lancet 2007 Outcomes based on donor selection of unrelated product 6/6 matched UCB 5/6 matched UCB
  7. 7. Cord/BM Match Rates Provided by NMDP, 2011. Used with permission. *Less than 14% of SCD patients have matched sibling donors!
  8. 8. Ruggeri et al BBMT 2011Locatelli et al Blood 2013 URD UCBT - Graft rejection and mortality are the problem
  9. 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. 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. 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. 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. 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. 14. Bednarski J et al…Tandem 2013
  15. 15. Late Effects - > 2 years post Madden L, et al……2013
  16. 16. Fertility
  17. 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. 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. 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. 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. 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. 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. 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. 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

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