title: Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (non-Hodgkin's) lymphoma.
abstract: OBJECTIVE
  Preclinical studies suggested that bryostatin 1 might potentiate the therapeutic effects of fludarabine in the treatment of hematologic malignancies. We undertook a phase I study to identify appropriate schedules and doses of bryostatin 1 and fludarabine to be used in phase II studies.
  
  
  METHODS
  Patients with chronic lymphocytic leukemia (CLL) or indolent lymphoma received fludarabine daily for 5 days and a single dose of bryostatin 1 via a 24-hour continuous infusion either before or after the fludarabine course. Doses were escalated in successive patients until recommended phase II doses for each sequence were identified on the basis of dose-limiting toxic events.
  
  
  RESULTS
  Bryostatin 1 can be administered safely and tolerably with full dose fludarabine (25 mg/m(2)/d x 5). The recommended bryostatin 1 phase II dose is 50 microg/m(2) for both sequences, bryostatin 1 --> fludarabine and fludarabine --> bryostatin 1. The combination is active against both CLL and indolent lymphomas with responses seen in patients who had been previously treated with fludarabine. Correlative studies do not support the hypothesis that bryostatin 1 potentiates fludarabine activity through down-regulation of protein kinase C in target cells.
  
  
  CONCLUSIONS
  Bryostatin 1 can be administered with full dose fludarabine, and the combination is moderately active in patients with persistent disease following prior treatment. In view of the activity of monoclonal antibodies such as the anti-CD20 monoclonal antibody rituximab in the treatment of CLL and indolent lymphomas, the concept of combining bryostatin 1 and fludarabine with rituximab warrants future consideration.
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA 23298, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Roberts
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: Smith
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Feldman
authors.forename: Louise
authors.initials: L
authors.lastname: Cragg
authors.forename: Michael M
authors.initials: MM
authors.lastname: Millenson
authors.forename: Gail J
authors.initials: GJ
authors.lastname: Roboz
authors.forename: Connie
authors.initials: C
authors.lastname: Honeycutt
authors.forename: Rose
authors.initials: R
authors.lastname: Thune
authors.forename: Kristin
authors.initials: K
authors.lastname: Padavic-Shaller
authors.forename: W Hans
authors.initials: WH
authors.lastname: Carter
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D054713:Bryostatins; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018942:Macrolides / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D015996:Survival Rate; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D054713:Bryostatins; D018942:Macrolides; C046785:bryostatin 1; D014740:Vidarabine; C024352:fludarabine