Familial Haploidentical (FHI) T-Cell Depleted (TCD) Transplantation in High-Risk Sickle Cell Disease (IND 14359) (2012)

Stem cell transplantation has been highly successful for poor-risk SCD but only 14-18% of patients have an HLA-matched unaffected sibling (Bhatia/Walters, BMT, 2008). Alternate allogeneic donors include unrelated adult donors and unrelated cord blood donors (Cairo et al., BBMT, 2008). Due to patient demographics matched unrelated adult donors are limited in the registries and results of unrelated UCB transplants have been dismal to date. (Bhatia/Cairo et al., ASBMT, 2010 and CTN 0601) FHI TCD AlloSCT is an alternative that could greatly improve outcomes in these patients. A recent phase II trial in high-risk leukemia patients utilized CliniMACS (Miltenyi Biotec) one step CD34+ selection, and demonstrated a median recovery of CD34+ cells of 79%, median T-cell depletion of 4.5log, 94/101 patients engrafted with aGVHD in only 8/100 patients. (Aversa et al.,JCO, 2005) Minimal-intensity conditioning followed by FHI TCD in high risk thalassemia patients achieved engraftment in 16/22 patients without aGVHD and 90% OS. (Sodani et al., Blood, 2010) This study seeks to employ a similar approach in high-risk SCD patients. Patients 2-20.99 years of age and who meet SCURT eligibility without an 8/8 HLA matched unrelated donor will be enrolled. Patients will receive hydroxyurea (60mg/kg/day) and azathioprine (3mg/kg/day) from days-59 to -11. Fludarabine (30mg/m2) will be given for 6 days (day -17 to -13), busulfan (4mg/kg/day) for 4 days (day -12 to -9) and cyclophosphamide for 4 days (day -7 to -4), thiotepa (10mg/kg, day -8), R-ATG (day -5 to -2), TLI (500cGy) followed by FHI T-cell depleted AlloSCT. GVHD prophylaxis will consist of tacrolimus. HPC, Apheresis-CD34-enriched cells will be collected by the CliniMACS (FDA IND 14359) with a target dose of 10.0 x 106 CD34+ cells/kg containing 2.0 x 105 CD3+ T cells/kg. We have developed a FHI TCD Consortium of five clinical sites, four processing centers, and cores in donor chimerism, anti-HLA antibodies, immunology, cell processing, biostatistics, neuroimaging, neurocognition, quality of life, pulmonary function, pulmonary vascular, radiation, and a patient advocacy group (www.haploscdconsortium.org) (Table 1). We seek to develop a unique opportunity for high-risk SCD patients to be cured of this debilitating disease, potentially improving organ function, quality of life, and neurocognition while providing a universal allogeneic donor source for many more at-risk SCD patients.Table 1Organizational Schema of ConsortiumClinical Sites/PIsExternal DSMCScientific Advisory CommitteeCoresNYMC:Mitchell S. Cairo, MDMichael Nieder, MD All Children's HospitalGuido Lucarelli, MD University of Tor VergataDonor Chimerism: LeeAnn Baxter-Lowe, PhD (UCSF)CHRCO:Mark Walters, MDRussell E. Ware, MD, PhD Baylor College of MedicineAdrian P. Gee, PhD Baylor College of MedicineHealth Related Quality of Life: Susan Parsons, MD (Tufts)MCW: Julie-An Talano, MDRupert Handgretinger, MD Eberhard Karls Universität TübingenGeorge Buchanan, MD UT SouthwesternNeurocognition: Elizabeth Kera, PhD (NYMC)CUMC: Monica Bhatia, MDDaniel Heitjan, PhD UPennNeuroimaging: Robert McKinstry, MD, PhD (WashU)Wash U: Shalini Shenoy, MDPulmonary Function: Allen Dozor, MD (NYMC)Cell Processing CorePulmonary Vascular Core: Deborah Friedman, MD (NYMC) Rajamma Mathew, MBBS (NYMC)MCW: Carolyn Keever-Taylor, PhD; WashU: Brenda Grossman, MD; CUMC: Joseph Schwartz,MD; Progenitor Cell Therapy: Robert Preti, PhDImmunology: NYMC: Mitchell S. Cairo, MD; MCW: James Verbsky, MD, PhD, Jack Gorski, PhD, and Carolyn Keever-Taylor, PhDRadiation Therapy: R. Chitti, MD (NYMC) Open table in a new tab