title: Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study.
abstract: OBJECTIVE
  Acadesine has shown in vitro to selectively induce apoptosis in B cells from chronic lymphocytic leukemia (CLL) patients. We conducted a phase I/II open-label clinical study, to determine the safety and tolerability of acadesine given intravenously as a 4-h infusion to CLL patients.
  
  
  METHODS
  Patient population included CLL patients with relapsed/refractory disease who had received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen. Twenty-four patients were included: eighteen in Part I treated at single doses of 50-315 mg/kg, and six in Part II, three with two doses at 210 mg/kg and three with five doses at 210 mg/kg.
  
  
  RESULTS
  A manageable and predictable safety profile was demonstrated for acadesine at single doses between 50 and 210 mg/kg; 210 mg/kg was the maximum tolerated dose (MTD) and optimal biological dose (OBD). Grade ≥2 hyperuricemia occurred commonly but was not clinically significant and resolved with the administration of prophylactic allopurinol. Other adverse events included transient anemia and/or thrombocytopenia (not clinically significant), renal impairment, and transient infusion-related hypotension (clinically significant). Trends of efficacy such as a reduction of peripheral CLL cells and reduction in lymphadenopathy were observed; however, the results were variable due to the small population and the range of doses tested.
  
  
  CONCLUSIONS
  A MTD of 210 mg/kg was established with single acadesine dose. Multiple dose administrations at the OBD were tested with an acceptable safety profile, showing that acadesine might be a valuable agent for the treatment of relapsed/refractory CLL patients.
authors.affiliation: Hematology Department, Cliniques universitaires UCL Saint-Luc, Brussels, Belgium. eric.vandenneste@uclouvain.be
authors.forename: Eric
authors.initials: E
authors.lastname: Van Den Neste
authors.forename: Bruno
authors.initials: B
authors.lastname: Cazin
authors.forename: Ann
authors.initials: A
authors.lastname: Janssens
authors.forename: Eva
authors.initials: E
authors.lastname: González-Barca
authors.forename: María José
authors.initials: MJ
authors.lastname: Terol
authors.forename: Vincent
authors.initials: V
authors.lastname: Levy
authors.forename: Jaime
authors.initials: J
authors.lastname: Pérez de Oteyza
authors.forename: Pierre
authors.initials: P
authors.lastname: Zachee
authors.forename: Andrew
authors.initials: A
authors.lastname: Saunders
authors.forename: Mercè
authors.initials: M
authors.lastname: de Frias
authors.forename: Clara
authors.initials: C
authors.lastname: Campàs
mesh_terms: D000368:Aged; D000620:Aminoimidazole Carboxamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D017567:Karnofsky Performance Status; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008196:Lymph / Q000166:cytology / Q000187:drug effects; D018655:Lymphocyte Count; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012008:Recurrence; D012263:Ribonucleosides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine