title: Nonmyeloablative hematopoietic cell transplantation. Replacing high-dose cytotoxic therapy by the graft-versus-tumor effect.
abstract: Conventional allografting produces considerable regimen-related toxicities that generally limit this treatment to patients younger than 55 years and in otherwise good medical condition. T cell-mediated graft-versus-tumor (GVT) effects are known to play an important role in the elimination of malignant disease after allotransplants. A minimally myelosuppressive regimen that relies on immunosuppression for allogeneic engraftment was developed to reduce toxicities while optimizing GVT effects. Pre-transplant total-body irradiation (200 cGy) followed by post-transplant immunosuppression with cyclosporine (CSP) and mycophenolate mofetil (MMF) permitted human leukocyte antigen (HLA)-matched sibling donor hematopoietic cell engraftment in 82% of patients (n = 55) without prior high-dose therapy. The addition of fludarabine (90 mg/m2) facilitated engraftment in all 28 subsequent patients. Overall, fatal progression of underlying disease occurred in 20% of patients after transplant. Non-relapse mortality occurred in 11% of patients. Toxicities were low. Grade 2-4 acute graft-versus-host disease (GVHD) associated with primary engraftment developed in 47% of patients, and was readily controlled in all but two patients. Donor lymphocyte infusions (DLI) were not very effective at converting a low degree of mixed donor/host chimerism to full donor chimerism; however, the addition of fludarabine reduced the need for DLI. With a median follow-up of 244 days, 68% of patients were alive, with 42% of patients in complete remission, including molecular remissions. Remissions occurred gradually over periods of weeks to a year. If long-term efficacy is demonstrated, such a strategy would expand treatment options for patients who would otherwise be excluded from conventional allografting.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., D1-100, P.O. Box 19024, Seattle, Washington 98109-1024, USA. lfeinste@fhcrc.org
authors.forename: L
authors.initials: L
authors.lastname: Feinstein
authors.forename: B
authors.initials: B
authors.lastname: Sandmaier
authors.forename: D
authors.initials: D
authors.lastname: Maloney
authors.forename: P A
authors.initials: PA
authors.lastname: McSweeney
authors.forename: M
authors.initials: M
authors.lastname: Maris
authors.forename: C
authors.initials: C
authors.lastname: Flowers
authors.forename: J
authors.initials: J
authors.lastname: Radich
authors.forename: M T
authors.initials: MT
authors.lastname: Little
authors.forename: R A
authors.initials: RA
authors.lastname: Nash
authors.forename: T
authors.initials: T
authors.lastname: Chauncey
authors.forename: A
authors.initials: A
authors.lastname: Woolfrey
authors.forename: G
authors.initials: G
authors.lastname: Georges
authors.forename: H P
authors.initials: HP
authors.lastname: Kiem
authors.forename: J M
authors.initials: JM
authors.lastname: Zaucha
authors.forename: K G
authors.initials: KG
authors.lastname: Blume
authors.forename: J
authors.initials: J
authors.lastname: Shizuru
authors.forename: D
authors.initials: D
authors.lastname: Niederwieser
authors.forename: R
authors.initials: R
authors.lastname: Storb
mesh_terms: D000328:Adult; D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D016572:Cyclosporine / Q000627:therapeutic use; D018450:Disease Progression; D004285:Dogs; D005544:Forecasting; D006082:Graft Enhancement, Immunologic / Q000009:adverse effects / Q000379:methods; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000209:etiology; D020350:Graft vs Tumor Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D017710:Lymphocyte Transfusion; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D009369:Neoplasms / Q000628:therapy; D011241:Prednisone / Q000627:therapeutic use; D011828:Radiation Chimera; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use; D014916:Whole-Body Irradiation
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D014740:Vidarabine; D009173:Mycophenolic Acid; C024352:fludarabine; D011241:Prednisone; D008727:Methotrexate