title: Pilot study of lonafarnib, a farnesyl transferase inhibitor, in patients with chronic myeloid leukemia in the chronic or accelerated phase that is resistant or refractory to imatinib therapy.
abstract: BACKGROUND
  Lonafarnib (SCH66336) is a nonpeptidomimetic farnesyl transferase inhibitor that has demonstrated significant preclinical activity against chronic myelogenous leukemia (CML) cells and in CML animal models.
  
  
  METHODS
  In the current study, the efficacy of lonafarnib was investigated in patients with CML in the chronic or accelerated phase that was resistant or intolerant to imatinib. Thirteen patients with CML in the chronic (n = 6 patients) or accelerated (n = 7 patients) phase were treated with lonafarnib at a dose of 200 mg orally twice daily. Ten patients had failed therapy with imatinib and 3 patients were intolerant to imatinib. The median age of the patients was 62 years (range, 38-80 yrs) and the median time from the diagnosis of CML to therapy with lonafarnib was 5 years (range, 0.3-13 yrs). In addition to imatinib mesylate, all patients had received prior therapy with interferon-alpha and seven patients had received other treatments. The median duration of therapy with lonafarnib was 8 weeks (range, 2-41 wks).
  
  
  RESULTS
  Two patients responded. One patient in the accelerated phase of CML returned to the chronic phase, a response that lasted for 3 months. Another patient with chronic phase disease had lowering of the leukocyte count without the need for hydroxyurea and normalization of the differential count that lasted for 5 months. The most common adverse event was diarrhea, which was noted in 11 patients (84%) (Grade > or = 3 in 4 patients; 31%; toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Therapy was discontinued in one patient because of diarrhea not responding to dose adjustments.
  
  
  CONCLUSIONS
  Single-agent lonafarnib appears to have clinical activity in a small proportion of patients with CML refractory to imatinib.
authors.affiliation: Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: George
authors.initials: G
authors.lastname: Daley
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Francis
authors.initials: F
authors.lastname: Giles
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Mary
authors.initials: M
authors.lastname: Sugrue
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D010879:Piperazines / Q000627:therapeutic use; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D003986:Dibenzocycloheptenes
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D051231:Farnesyltranstransferase; D000068877:Imatinib Mesylate; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011743:Pyrimidines; C115354:lonafarnib; D003986:Dibenzocycloheptenes