title: Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia.
abstract: OBJECTIVE
  Expression of Bcl-2 protein is associated with chemotherapy resistance and decreased survival in chronic lymphocytic leukemia (CLL). We evaluated whether oblimersen would improve response to chemotherapy in patients with relapsed or refractory CLL.
  
  
  METHODS
  Patients had received at least one prior fludarabine-containing regimen and were stratified on the basis of prior fludarabine response, number of prior regimens, and duration of response to last prior therapy. Patients were randomly assigned to 28-day cycles of fludarabine 25 mg/m2/d plus cyclophosphamide 250 mg/m2/d administered intravenously for 3 days with or without oblimersen 3 mg/kg/d as a 7-day continuous intravenous infusion (beginning 4 days before chemotherapy) for up to six cycles. The primary end point was the proportion of patients who achieved complete response (CR) or nodular partial response (nPR).
  
  
  RESULTS
  Of 241 patients randomly assigned, CR/nPR was achieved in 20 (17%) of 120 patients in the oblimersen group and eight (7%) of 121 patients in the chemotherapy-only group (P = .025). Achievement of CR/nPR was correlated with both an extended time to progression and survival (P < .0001). In patients who remained sensitive to fludarabine, oblimersen was associated with a four-fold increase in the CR/nPR rate and a significant survival benefit (P = .05). Oblimersen was frequently associated with thrombocytopenia and, rarely, tumor lysis syndrome and cytokine release reactions; the incidence of opportunistic infections and second malignancies was similar in both groups.
  
  
  CONCLUSIONS
  The addition of oblimersen to fludarabine plus cyclophosphamide significantly increases the CR/nPR rate in patients with relapsed or refractory CLL (particularly fludarabine-sensitive patients), as well as response duration among patients who achieve CR/nPR.
authors.affiliation: Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;, USA. sobrien@mdanderson.org
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Boyd
authors.forename: Loree M
authors.initials: LM
authors.lastname: Larratt
authors.forename: Aleksander
authors.initials: A
authors.lastname: Skotnicki
authors.forename: Benjamin
authors.initials: B
authors.lastname: Koziner
authors.forename: Asher A
authors.initials: AA
authors.lastname: Chanan-Khan
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.forename: R Gregory
authors.initials: RG
authors.lastname: Bociek
authors.forename: Steve
authors.initials: S
authors.lastname: Pavletic
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D019254:Genes, bcl-2; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D016016:Proportional Hazards Models; D012008:Recurrence; D013873:Thionucleotides / Q000008:administration & dosage; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; C408162:oblimersen; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine