title: A prospective dose-finding trial using a modified continual reassessment method for optimization of fludarabine plus melphalan conditioning for marrow transplantation from unrelated donors in patients with hematopoietic malignancies.
abstract: BACKGROUND
  Because of the less graft-facilitating effect by bone marrow (BM), we need to assess a dosage of conditioning more accurately particularly in combination with reduced-intensity conditioning. Thus we examined that modified continual reassessment method (mCRM) is applicable for deciding appropriate conditioning of allogeneic BM transplantation.
  
  
  METHODS
  The conditioning regimen consisted of i.v. fludarabine (125 mg/m2) plus an examination dose of i.v. melphalan. The primary endpoint was a donor-type T-cell chimerism at day 28 with successful engraftment defined as >90% donor cells. Five patients per dose level were planned to be accrued and chimerism data were used to determine the next dose.
  
  
  RESULTS
  Seventeen patients were enrolled at doses between 130 and 160 mg/m2. The dose was changed from 160 to 130 mg/m(2) (second level) after five full-donor chimerisms. With one patient of 0% chimera in the second level, the dose was increased to 135 mg/m2 (third level). Following five full-donor chimerisms in the third level, the study was complete as projected.
  
  
  CONCLUSIONS
  mCRM was shown to be a relevant method for dose-finding of conditioning regimen. The melphalan dose of 135 mg/m2 was determined as the recommended phase II dose to induce initial full-donor chimerism.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Japan. tseit@med.nagoya-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Terakura
authors.forename: Y
authors.initials: Y
authors.lastname: Atsuta
authors.forename: M
authors.initials: M
authors.lastname: Sawa
authors.forename: H
authors.initials: H
authors.lastname: Ohashi
authors.forename: T
authors.initials: T
authors.lastname: Kato
authors.forename: S
authors.initials: S
authors.lastname: Nishiwaki
authors.forename: N
authors.initials: N
authors.lastname: Imahashi
authors.forename: T
authors.initials: T
authors.lastname: Yasuda
authors.forename: M
authors.initials: M
authors.lastname: Murata
authors.forename: K
authors.initials: K
authors.lastname: Miyamura
authors.forename: R
authors.initials: R
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Naoe
authors.forename: T
authors.initials: T
authors.lastname: Ito
authors.forename: Y
authors.initials: Y
authors.lastname: Morishita
mesh_terms: D000328:Adult; D016026:Bone Marrow Transplantation; D046528:Chimerism / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019337:Hematologic Neoplasms / Q000601:surgery*; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage*; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000187:drug effects; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D019653:Myeloablative Agonists; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan