title: Radiation-free allogeneic conditioning with fludarabine, carmustine, and thiotepa for acute lymphoblastic leukemia and other hematologic malignancies necessitating enhanced central nervous system activity.
abstract: Total body irradiation has been the mainstay of conditioning since the inception of allogeneic hematopoietic cell transplantation, but toxicity often precludes its use. For less-fit patients with acute lymphoblastic leukemia and other hematologic malignancies frequently affecting the central nervous system, we designed a radiation-free regimen with fludarabine (25 mg/m2/day on days -6 to -4), carmustine (400 mg/m2 on day -6), and thiotepa (5 mg/kg twice daily on days -5 and -4), all of which readily penetrate the blood-brain barrier and have potent antileukemic and lymphotoxic activity. Here we present a series of 30 consecutive patients with high-risk or relapsed disease who underwent allogeneic hematopoietic cell transplantation with this protocol. The median patient age was 60 years (range, 42-70 years), and the median follow-up was 968 days (range, 58-1989 days). Graft-versus-host disease prophylaxis consisted of cyclosporine A and alemtuzumab (10-20 mg). At 2 years, overall survival was 52% (95% confidence interval [CI], 34%-71%), event-free survival was 39% (95% CI, 22%-57%), cumulative incidence of relapse/progression was 30% (95% CI, 17%-52%), and treatment-related mortality was 31% (95% CI, 18%-53%). Neurologic toxicity is a concern, especially in older and heavily pretreated patients. Our experience indicates the feasibility of this regimen as an alternative to total body irradiation and a potentially curative option for less-fit patients who need a highly central nervous system-active conditioning.
authors.affiliation: Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Petros
authors.initials: P
authors.lastname: Christopoulos
authors.forename: Hartmut
authors.initials: H
authors.lastname: Bertz
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ihorst
authors.forename: Reinhard
authors.initials: R
authors.lastname: Marks
authors.forename: Ralph
authors.initials: R
authors.lastname: Wäsch
authors.forename: Jürgen
authors.initials: J
authors.lastname: Finke
mesh_terms: D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D002330:Carmustine / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects* / Q000503:physiopathology; D016572:Cyclosporine / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D016019:Survival Analysis; D013852:Thiotepa / Q000627:therapeutic use; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000074323:Alemtuzumab; D016572:Cyclosporine; D013852:Thiotepa; D014740:Vidarabine; C024352:fludarabine; D002330:Carmustine