title: A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing.
abstract: Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 × 10(8)/kg of T cells resulted in consistent engraftment, immune reconstitution, and acceptable rates of GVHD. Cumulative incidences of grade III-IV GVHD, nonrelapse mortality (NRM), and relapse-related mortality were 7.4%, 22.2%, and 29.6%, respectively. With a follow-up of 28-56 months, the 3-year probability of overall survival for the whole cohort is 48% and 75% in patients without disease at HSCT. In the context of CY tolerization, a high, fixed dose of haploidentical T cells was associated with encouraging outcomes, especially in good-risk patients, and can serve as the basis for further exploration and optimization of this 2-step approach. This study is registered at www.clinicaltrials.gov as NCT00429143.
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia, PA, USA. dolores.grosso@jefferson.edu
authors.forename: Dolores
authors.initials: D
authors.lastname: Grosso
authors.forename: Matthew
authors.initials: M
authors.lastname: Carabasi
authors.forename: Joanne
authors.initials: J
authors.lastname: Filicko-O'Hara
authors.forename: Margaret
authors.initials: M
authors.lastname: Kasner
authors.forename: John L
authors.initials: JL
authors.lastname: Wagner
authors.forename: Beth
authors.initials: B
authors.lastname: Colombe
authors.forename: Patricia
authors.initials: P
authors.lastname: Cornett Farley
authors.forename: William
authors.initials: W
authors.lastname: O'Hara
authors.forename: Phyllis
authors.initials: P
authors.lastname: Flomenberg
authors.forename: Maria
authors.initials: M
authors.lastname: Werner-Wasik
authors.forename: Janet
authors.initials: J
authors.lastname: Brunner
authors.forename: Bijoyesh
authors.initials: B
authors.lastname: Mookerjee
authors.forename: Terry
authors.initials: T
authors.lastname: Hyslop
authors.forename: Mark
authors.initials: M
authors.lastname: Weiss
authors.forename: Neal
authors.initials: N
authors.lastname: Flomenberg
mesh_terms: D000328:Adult; D000368:Aged; D002138:Calibration; D002452:Cell Count; D005260:Female; D006086:Graft vs Host Disease / Q000453:epidemiology / Q000209:etiology; D006239:Haplotypes; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods* / Q000592:standards; D006801:Humans; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000009:adverse effects / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000166:cytology*; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D019653:Myeloablative Agonists