title: Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity.
abstract: OBJECTIVE
  Pharmacologic downregulation of Bcl-2, an antiapoptotic protein overexpressed in cancer, might increase chemosensitivity in acute myeloid leukemia (AML). Herein, we investigated the feasibility of this approach in untreated elderly AML patients by administering oblimersen sodium (G3139), an 18-mer phosphorothioate antisense to Bcl-2, during induction and consolidation treatments.
  
  
  METHODS
  Untreated patients with primary or secondary AML (stratified to cohort 1 or 2, respectively) who were > or = 60 years received induction with G3139, cytarabine, and daunorubicin at one of two different dose levels (45 and 60 mg/m2) and, on achievement of complete remission (CR), consolidation with G3139 and high-dose cytarabine. An enzyme-linked immunosorbent assay (ELISA)-based assay was used to measure plasma and intracellular concentrations (IC) of G3139. Bcl-2 mRNA and protein levels were quantified by real-time reverse transcriptase polymerase chain reaction and ELISA, respectively, in bone marrow samples collected before induction treatment and after 72 hours of G3139 infusion, prior to initiation of chemotherapy.
  
  
  RESULTS
  Of the 29 treated patients, 14 achieved CR. With a median follow-up of 12.6 months, seven patients had relapsed. Side effects of this combination were similar to those expected with chemotherapy alone and were not dose limiting at both dose levels. After 72-hour G3139 infusion, Bcl-2/ABL mRNA copies were decreased compared with baseline (P = .03) in CR patients and increased in nonresponders (NRs; P = .05). Changes in Bcl-2 protein showed a similar trend. Although plasma pharmacokinetics did not correlate with disease response, the median IC of the antisense was higher in the CR patients compared with NRs (17.0 v 4.4 pmol/mg protein, respectively; P = .05).
  
  
  CONCLUSIONS
  G3139 can be administered safely in combination with intensive chemotherapy, and the degree of Bcl-2 downmodulation may correlate with response to therapy.
authors.affiliation: Division of Hematology-Oncology, The Comprehensive Cancer Center, The Ohio State University, 433A Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210, USA. marcucci-1@medctr.osu.edu
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
authors.forename: Guowei
authors.initials: G
authors.lastname: Dai
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Klisovic
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Marko I
authors.initials: MI
authors.lastname: Klisovic
authors.forename: William
authors.initials: W
authors.lastname: Blum
authors.forename: Cheryl
authors.initials: C
authors.lastname: Kefauver
authors.forename: Dorie A
authors.initials: DA
authors.lastname: Sher
authors.forename: Margaret
authors.initials: M
authors.lastname: Green
authors.forename: Mollie
authors.initials: M
authors.lastname: Moran
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.forename: Steven
authors.initials: S
authors.lastname: Novick
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.forename: James A
authors.initials: JA
authors.lastname: Zwiebel
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Chan
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001682:Biological Availability; D003630:Daunorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics; D011336:Probability; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000378:metabolism; D012074:Remission Induction; D018570:Risk Assessment; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D013873:Thionucleotides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D013873:Thionucleotides; C408162:oblimersen; D003630:Daunorubicin