title: Dose escalation of total marrow irradiation with concurrent chemotherapy in patients with advanced acute leukemia undergoing allogeneic hematopoietic cell transplantation.
abstract: OBJECTIVE
  We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) at 16 Gy without chemotherapy or TMI at 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This article reports results of a study of TMI combined with higher intensity chemotherapy regimens in 2 phase I trials in patients with advanced acute myelogenous leukemia or acute lymphoblastic leukemia (AML/ALL) who would do poorly on standard intent-to-cure HCT regimens.
  
  
  METHODS
  Trial 1 consisted of TMI on Days -10 to -6, etoposide (VP16) on Day -5 (60 mg/kg), and cyclophosphamide (CY) on Day -3 (100 mg/kg). TMI dose was 12 (n=3 patients), 13.5 (n=3 patients), and 15 (n=6 patients) Gy at 1.5 Gy twice daily. Trial 2 consisted of busulfan (BU) on Days -12 to -8 (800 μM min), TMI on Days -8 to -4, and VP16 on Day -3 (30 mg/kg). TMI dose was 12 (n=18) and 13.5 (n=2) Gy at 1.5 Gy twice daily.
  
  
  RESULTS
  Trial 1 had 12 patients with a median age of 33 years. Six patients had induction failures (IF), and 6 had first relapses (1RL), 9 with leukemia blast involvement of bone marrow ranging from 10%-98%, 5 with circulating blasts (24%-85%), and 2 with chloromas. No dose-limiting toxicities were observed. Eleven patients achieved complete remission at Day 30. With a median follow-up of 14.75 months, 5 patients remained in complete remission from 13.5-37.7 months. Trial 2 had 20 patients with a median age of 41 years. Thirteen patients had IF, and 5 had 1RL, 2 in second relapse, 19 with marrow blasts (3%-100%) and 13 with peripheral blasts (6%-63%). Grade 4 dose-limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials.
  
  
  CONCLUSIONS
  TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to dose-limiting toxicities. Future efforts will focus on whether further dose escalation with CY/VP16 is safe, with the goal of improving disease control in this high-risk population.
authors.affiliation: Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California 91010, USA. jwong@coh.org
authors.forename: Jeffrey Y C
authors.initials: JY
authors.lastname: Wong
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Joseph
authors.initials: J
authors.lastname: Rosenthal
authors.forename: An
authors.initials: A
authors.lastname: Liu
authors.forename: Timothy
authors.initials: T
authors.lastname: Schultheiss
authors.forename: Eric
authors.initials: E
authors.lastname: Radany
authors.forename: Joycelynne
authors.initials: J
authors.lastname: Palmer
authors.forename: Anthony
authors.initials: A
authors.lastname: Stein
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001853:Bone Marrow / Q000528:radiation effects*; D002066:Busulfan / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy / Q000009:adverse effects / Q000379:methods; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000628:therapy*; D008099:Liver / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D058958:Organs at Risk / Q000528:radiation effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000401:mortality / Q000628:therapy*; D011879:Radiotherapy Dosage; D012008:Recurrence; D013280:Stomatitis / Q000209:etiology; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation / Q000009:adverse effects / Q000379:methods*; D055815:Young Adult
chemical_list: D005047:Etoposide; D003520:Cyclophosphamide; D002066:Busulfan