title: Dose Escalation of Total Marrow Irradiation in High-Risk Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.
abstract: Patients with refractory leukemia or minimal residual disease (MRD) at transplantation are at increased risk of relapse. Augmentation of irradiation, especially to sites of disease (ie, bone marrow) is one potential strategy for overcoming this risk. We studied the feasibility of radiation dose escalation in high-risk patients using total marrow irradiation (TMI) in a phase I dose-escalation trial. Four pediatric and 8 adult patients received conditioning with cyclophosphamide and fludarabine in conjunction with image-guided radiation to the bone marrow at 15 Gy and 18 Gy (in 3-Gy fractions), while maintaining the total body irradiation (TBI) dose to the vital organs (lungs, hearts, eyes, liver, and kidneys) at <13.2 Gy. The biologically effective dose of TMI delivered to the bone marrow was increased by 62% at 15 Gy and by 96% at 18 Gy compared with standard TBI. Although excessive dose-limiting toxicity, defined by graft failure or excessive specific organ toxicity, was not encountered, 3 of 6 patients experienced treatment-related mortality at 18 Gy. Thus, we halted enrollment at this dose level and treated an additional 4 patients at 15 Gy. The 1- year overall survival was 42% (95% confidence interval [CI], 15%-67%) and disease-free survival was 22% (95% CI, 4%-49%). The rate of relapse was 36% (95% CI, 10%-62%), and nonrelapse mortality was 42% (95% CI, 14%-70%). This study shows that TMI dose escalation to 15 Gy is feasible with acceptable toxicity in pediatric and adult patients with high-risk leukemia undergoing umbilical cord blood and sibling donor transplantation.
authors.affiliation: Department of Therapeutic Radiology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Susanta
authors.initials: S
authors.lastname: Hui
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Claudio
authors.initials: C
authors.lastname: Brunstein
authors.affiliation: Department of Therapeutic Radiology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Blood and Marrow Transplant Program, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Todd
authors.initials: T
authors.lastname: DeFor
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Shernan G
authors.initials: SG
authors.lastname: Holtan
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Veronika
authors.initials: V
authors.lastname: Bachanova
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wilke
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Darren
authors.initials: D
authors.lastname: Zuro
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Celalettin
authors.initials: C
authors.lastname: Ustun
authors.affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weisdorf
authors.affiliation: Department of Therapeutic Radiology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Dusenbery
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota. Electronic address: michael.verneris@ucdenver.edu.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Verneris
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018365:Neoplasm, Residual / Q000628:therapy*; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous / Q000379:methods*; D014916:Whole-Body Irradiation / Q000379:methods*; D055815:Young Adult
keywords: BMT; Cord blood; Total marrow irradiation