title: Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: final induction results of Cancer and Leukemia Group B Study 9621.
abstract: OBJECTIVE
  P-glycoprotein (Pgp) is strongly inhibited by PSC-833. A chemotherapy dose-escalation study was performed with PSC-833 in patients younger than 60 years with untreated acute myeloid leukemia. Clinical rather than pharmacokinetic end points were used to develop two induction therapies containing drugs susceptible to Pgp-mediated efflux and associated with comparable toxicities at the maximum-tolerated doses.
  
  
  METHODS
  A total of 410 patients were enrolled. Fifteen induction regimens containing variable doses of daunorubicin (DNR) and etoposide (ETOP) and fixed doses of cytarabine were evaluated with (ADEP) or without (ADE) a fixed dose of PSC-833.
  
  
  RESULTS
  Doses selected for phase III testing were DNR 90 mg/m(2) and ETOP 100 mg/m(2) in ADE, and DNR and ETOP each 40 mg/m(2) in ADEP. Intolerable mucosal toxicity occurred at higher doses of ADEP. Although the design of this study precludes direct comparisons, there was an apparent advantage for receiving ADEP with respect to disease-free and overall survival in patients < or = 45 years old, despite the significantly lower doses of DNR and ETOP given in ADEP compared with ADE.
  
  
  CONCLUSIONS
  A large clinical data set was used to develop induction regimens containing two drugs susceptible to Pgp-mediated efflux, with and without an inhibitor of Pgp function. The chosen doses have comparable antileukemia activity and toxicity, making them suitable for use in a phase III comparative study of induction chemotherapy for patients with acute myeloid leukemia younger than 60 years. That trial will also clarify whether patients < or = 45 years old are especially likely to benefit from Pgp inhibition during induction therapy.
authors.affiliation: Don Monti Division of Oncology and Division of Hematology, Department of Medicine, North Shore University Hospital, New York University School of Medicine, NY 11030, USA. kolitz@nshs.edu
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.forename: Stephen L
authors.initials: SL
authors.lastname: George
authors.forename: Richard K
authors.initials: RK
authors.lastname: Dodge
authors.forename: David D
authors.initials: DD
authors.lastname: Hurd
authors.forename: Bayard L
authors.initials: BL
authors.lastname: Powell
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.forename: Enrique
authors.initials: E
authors.lastname: Velez-Garcia
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Shea
authors.forename: Eva
authors.initials: E
authors.lastname: Hoke
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: James W
authors.initials: JW
authors.lastname: Vardiman
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D003524:Cyclosporins / Q000008:administration & dosage / Q000009:adverse effects; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D003630:Daunorubicin / Q000008:administration & dosage / Q000009:adverse effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D003524:Cyclosporins; D003561:Cytarabine; D005047:Etoposide; C070272:valspodar; D003630:Daunorubicin