title: T cell-depleted partial matched unrelated donor transplant for advanced myeloid malignancy: KIR ligand mismatch and outcome.
abstract: To evaluate the applicability of high-dose conditioning, CD34 selection, and enhanced natural killer (NK) cell alloreactivity reported as promising after haploidentical transplantation, we tested the same strategy for patients with advanced/high-risk myeloid leukemia lacking either related or well-matched unrelated donors (URD). In a prospective multicenter clinical trial using pretransplantation conditioning of thiotepa (5 mg/kg/day × 2), fludarabine (40 mg/mg/M(2)/day × 5), and total body radiation (800 cGy) plus thymoglobulin (2.5 mg/kg/day × 2), as well as a CD34 selected filgrastim stimulated peripheral blood graft from a partial matched URD, we treated 24 patients. The patients (median age 40 [range: 22-61]) were mismatched at 1-3 of 10 HLA loci with their donors; all were mismatched at HLA-C. Thirty-seven percent were ethnic or racial minorities. Twenty-one of 24 engrafted promptly with 1 primary graft failure and 2 early deaths. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) (34%, 95% confidence interval [CI], 14-54%), chronic GVHD (20%, 95% CI, 2%-38%), and relapse (26%, 95% CI, 8%-84%) were unaffected by KIR ligand donor:recipient mismatch (n = 5) versus KIR ligand match (n = 19). Only 3 (12%) had grade III-IV GVHD. Nonrelapse occurred in 17% (95% CI, 30%-31%) by 100 days and in 35% (95% CI, 15%-55%) by 1 year. Two-year survival and leukemia-free survival were each 40% (95% CI, 21%-59%) and was similar in KIR ligand matched or mismatched patients. Infections, mostly in the first 2 months, were frequent, and were the cause of death in 5 patients (35% of deaths). T cell recovery and NK cell proliferation and functional maturation were not altered by KIR ligand match or mismatch status. For these high-risk patients, this high intensity regimen and T depleted approach yielded satisfactory outcomes, but logistical difficulties in arranging URD grafts for patients with high-risk, unstable leukemia limited accrual. Improvements in peritransplantation disease control and additional measures to augment the allogeneic graft-versus-leukemia effect are still required.
authors.affiliation: University of Minnesota, Minneapolis, Minneapolis, MN 55455, USA. weisd001@umn.edu
authors.forename: Daniel
authors.initials: D
authors.lastname: Weisdorf
authors.forename: Sarah
authors.initials: S
authors.lastname: Cooley
authors.forename: Steven
authors.initials: S
authors.lastname: Devine
authors.forename: Todd A
authors.initials: TA
authors.lastname: Fehniger
authors.forename: John
authors.initials: J
authors.lastname: DiPersio
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
authors.forename: David
authors.initials: D
authors.lastname: Porter
authors.forename: Sherif
authors.initials: S
authors.lastname: Farag
authors.forename: William
authors.initials: W
authors.lastname: Drobyski
authors.forename: Todd
authors.initials: T
authors.lastname: Defor
authors.forename: Michael
authors.initials: M
authors.lastname: Haagenson
authors.forename: Julie
authors.initials: J
authors.lastname: Curtsinger
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Miller
mesh_terms: D000328:Adult; D018952:Antigens, CD34 / Q000276:immunology; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D018572:Disease-Free Survival; D005006:Ethnicity; D006086:Graft vs Host Disease / Q000517:prevention & control*; D015236:HLA-C Antigens / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology; D007951:Leukemia, Myeloid / Q000208:ethnology / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008212:Lymphocyte Depletion; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D011446:Prospective Studies; D054340:Receptors, KIR / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013852:Thiotepa / Q000008:administration & dosage; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D061349:Unrelated Donors; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014916:Whole-Body Irradiation
chemical_list: D018952:Antigens, CD34; D000961:Antilymphocyte Serum; D000970:Antineoplastic Agents; D015236:HLA-C Antigens; D054340:Receptors, KIR; D013852:Thiotepa; C512542:thymoglobulin; D014740:Vidarabine; C024352:fludarabine