title: Selective depletion of alloreactive donor lymphocytes: a novel method to reduce the severity of graft-versus-host disease in older patients undergoing matched sibling donor stem cell transplantation.
abstract: We have selectively depleted host-reactive donor T cells from peripheral blood stem cell (PBSC) transplant allografts ex vivo using an anti-CD25 immunotoxin. We report a clinical trial to decrease graft-versus-host disease (GVHD) in elderly patients receiving selectively depleted PBSC transplants from HLA-identical sibling donors. Sixteen patients (median age, 65 years [range, 51-73 years]), with advanced hematologic malignancies underwent transplantation following reduced-intensity conditioning with fludarabine and either cyclophosphamide (n = 5), melphalan (n = 5), or busulfan (n = 6). Cyclosporine was used as sole GVHD prophylaxis. The allograft contained a median of 4.5 x 10(6) CD34 cells/kg (range, 3.4-7.3 x 10(6) CD34 cells/kg) and 1.0 x 10(8)/kg (range, 0.2-1.5 x 10(8)/kg) selectively depleted T cells. Fifteen patients achieved sustained engraftment. The helper T-lymphocyte precursor (HTLp) frequency assay demonstrated successful (mean, 5-fold) depletion of host-reactive donor T cells, with conservation of third-party response in 9 of 11 cases tested. Actuarial rates of acute GVHD were 46% +/- 13% for grades II to IV and 12% +/- 8% for grades III to IV. These results suggest that allodepletion of donor cells ex vivo is clinically feasible in older patients and may reduce the rate of severe acute GVHD. Further studies with selectively depleted transplants to evaluate graft-versus-leukemia (GVL) and survival are warranted.
authors.affiliation: Stem Cell Allogeneic Transplantation Section, Hematology Branch, NHLBI, NIH Bldg 10, Hatfield CRC, Rm 3-5320, 10 Center Dr, MSC 1202, Bethesda, MD 20892-1202, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Solomon
authors.forename: Stephan
authors.initials: S
authors.lastname: Mielke
authors.forename: Bipin N
authors.initials: BN
authors.lastname: Savani
authors.forename: Aldemar
authors.initials: A
authors.lastname: Montero
authors.forename: Laura
authors.initials: L
authors.lastname: Wisch
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
authors.forename: Nancy
authors.initials: N
authors.lastname: Hensel
authors.forename: John
authors.initials: J
authors.lastname: Schindler
authors.forename: Victor
authors.initials: V
authors.lastname: Ghetie
authors.forename: Susan F
authors.initials: SF
authors.lastname: Leitman
authors.forename: Thao
authors.initials: T
authors.lastname: Mai
authors.forename: Charles S
authors.initials: CS
authors.lastname: Carter
authors.forename: Roger
authors.initials: R
authors.lastname: Kurlander
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Read
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Vitetta
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
mesh_terms: D000368:Aged; D002469:Cell Separation / Q000379:methods*; D005260:Female; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000150:complications / Q000628:therapy; D006648:Histocompatibility; D006801:Humans; D015994:Incidence; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D012008:Recurrence; D035781:Siblings; D018183:Transplantation Chimera; D014184:Transplantation, Homologous