title: Phase I evaluation of prolonged-infusion gemcitabine with mitoxantrone for relapsed or refractory acute leukemia.
abstract: OBJECTIVE
  To ascertain the maximum tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with mitoxantrone at 12 mg/m(2) daily for 3 days in the treatment of acute leukemia.
  
  
  METHODS
  Thirty-four patients were enrolled. Stratum I consisted of 26 patients, median age 50 years (range, 25 to 71 years), with relapsed or refractory leukemia. Stratum II contained eight patients, median age 62.5 years (range, 38 to 83 years), who had received fewer than three cycles of myelotoxic therapy for chronic myeloid leukemia or myelodysplasia that had evolved into leukemia. Patients received mitoxantrone at 12 mg/m(2) daily for 3 days. After the first mitoxantrone dose, gemcitabine was provided intravenously at 10 mg/m(2)/min with the duration adjusted by following a continuous reassessment model.
  
  
  RESULTS
  Severe myelosuppression, and stomatitis or esophagitis were the most common hematologic and nonhematologic dose-limiting toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours (7,200 mg/m(2)). The mean steady-state concentration of gemcitabine was 24.72 micromol/L and varied over a fivefold range among patients. Overall response rates in this phase I trial for strata I and II were 42% and 63%, respectively.
  
  
  CONCLUSIONS
  Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m(2)/min for 12 hours with 12 mg/m(2)/d mitoxantrone for 3 days is a tolerable induction regimen and achieves plasma concentrations sufficient for maximal intracellular activation. Stomatitis or esophagitis should be anticipated; however, this regimen may induce significant responses in patients with difficult-to-treat leukemias.
authors.affiliation: Division of Medical Oncology and Transplantation, Duke University Medical Center, Durham, NC 27710, USA. rizzi003@mc.duke.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Rizzieri
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.forename: Gary L
authors.initials: GL
authors.lastname: Rosner
authors.forename: Jon P
authors.initials: JP
authors.lastname: Gockerman
authors.forename: Carlos M
authors.initials: CM
authors.lastname: DeCastro
authors.forename: William P
authors.initials: WP
authors.lastname: Petros
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Laughlin
authors.forename: Patti
authors.initials: P
authors.lastname: Davis
authors.forename: Traci
authors.initials: T
authors.lastname: Foster
authors.forename: Robert
authors.initials: R
authors.lastname: Jacobson
authors.forename: Herbert
authors.initials: H
authors.lastname: Hurwitz
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D007262:Infusions, Intravenous; D007938:Leukemia / Q000188:drug therapy*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D009436:Neural Tube Defects / Q000188:drug therapy; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003841:Deoxycytidine; D008942:Mitoxantrone; D000093542:Gemcitabine