title: 4-hydroperoxycyclophosphamide--purged peripheral blood stem cells for autologous transplantation in patients with acute myeloid leukemia.
abstract: We have performed a phase I dose escalation of 4-Hydroperoxycyclophosphamide (4HC) purging of autologous peripheral blood progenitor cells (PBPCs) to improve the outcome of autologous transplantation for patients with myeloid leukemia. Peripheral blood stem cells were mobilized after cytosine arabinoside of 2 g/m(2) every 12 hours x 8 doses with etoposide of 40 mg/kg total dose infused over 4 days, followed by growth factor support. The preparative regimen included Busulfan of 1 mg/kg orally every 6 hours x 16 doses, followed by etoposide of 60 mg/kg x 1 day (the patient with chronic myeloid leukemia received cyclophosphamide of 60 mg/kg/d x 2 days in lieu of etoposide). PBPCs purged with 4HC were infused following this induction. Toxicities included grade 3 or 4 skin rashes, stomatitis/mucositis, and delay in time to hematopoietic recovery. The maximum tolerated dose of 4HC used to purge PBPCs in this trial was 20 microg/mL, which resulted in an average of 18 days for white blood cells and 28 days for platelet recovery. With a median follow-up of 2.25 years in surviving patients, the 3-year disease free survival rate is 44% and the overall survival rate is 89%. These data suggest that autologous PBPCs are more sensitive than marrow purged with 4HC, tolerating less intense purging, although a survival advantage may still be seen and should be assessed in larger studies. Approaches to minimize stomatitis and protect normal stem cells from the toxicity of 4HC may improve the tolerance and efficacy of this approach.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. rizz003@mc.duke.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Rizzieri
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Talbot
authors.forename: Gwynn D
authors.initials: GD
authors.lastname: Long
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Christina
authors.initials: C
authors.lastname: Gasparetto
authors.forename: Clayton S
authors.initials: CS
authors.lastname: Smith
authors.forename: Michael O
authors.initials: MO
authors.lastname: Colvin
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.forename: Ashley
authors.initials: A
authors.lastname: Morris
authors.forename: Richard
authors.initials: R
authors.lastname: Dodge
authors.forename: Jennifer
authors.initials: J
authors.lastname: Loftis
authors.forename: Barbara
authors.initials: B
authors.lastname: Waters-Pick
authors.forename: Melissa
authors.initials: M
authors.lastname: Reese
authors.forename: Helen
authors.initials: H
authors.lastname: Carawan
authors.forename: Liang Piu
authors.initials: LP
authors.lastname: Koh
authors.forename: Nelson J
authors.initials: NJ
authors.lastname: Chao
mesh_terms: D000208:Acute Disease; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000633:toxicity*; D005260:Female; D006410:Hematopoiesis; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D006801:Humans; D007951:Leukemia, Myeloid / Q000401:mortality / Q000628:therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating / Q000187:drug effects*; D036102:Peripheral Blood Stem Cell Transplantation / Q000379:methods* / Q000401:mortality; D012074:Remission Induction / Q000379:methods; D016019:Survival Analysis; D014182:Transplantation, Autologous
chemical_list: D003520:Cyclophosphamide; C011272:perfosfamide