title: Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels.
abstract: Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n = 6) or viral pneumonia (n = 1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m(2)), and antithymocyte globulin was associated with excessive organ toxicity.
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis,MN 55455, USA. tolar003@umn.edu
authors.forename: Jakub
authors.initials: J
authors.lastname: Tolar
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
authors.forename: Sally
authors.initials: S
authors.lastname: Arai
authors.forename: Mitchell
authors.initials: M
authors.lastname: Horwitz
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: John M
authors.initials: JM
authors.lastname: McCarty
authors.forename: Roberta H
authors.initials: RH
authors.lastname: Adams
authors.forename: Marian
authors.initials: M
authors.lastname: Ewell
authors.forename: Eric S
authors.initials: ES
authors.lastname: Leifer
authors.forename: Iris D
authors.initials: ID
authors.lastname: Gersten
authors.forename: Shelly L
authors.initials: SL
authors.lastname: Carter
authors.forename: Mary M
authors.initials: MM
authors.lastname: Horowitz
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Nakamura
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pulsipher
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Difronzo
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Confer
authors.forename: Mary
authors.initials: M
authors.lastname: Eapen
authors.forename: Paolo
authors.initials: P
authors.lastname: Anderlini
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000401:mortality / Q000628:therapy*; D000961:Antilymphocyte Serum / Q000008:administration & dosage / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D016026:Bone Marrow Transplantation; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects*; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D019172:Transplantation Conditioning; D061349:Unrelated Donors; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D014916:Whole-Body Irradiation / Q000009:adverse effects
chemical_list: D000961:Antilymphocyte Serum; D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine