title: Simultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemia.
abstract: BACKGROUND
  Homoharringtonine (HHT) has antileukemic activity in patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML). Combinations of HHT, interferon-alpha (IFN-alpha), and cytarabine (ara-C) have been studied in various CML phases. The objectives of this study were to evaluate the efficacy and toxicity profiles of a combination regimen of simultaneous HHT and IFN-alpha therapy in patients with chronic-phase CML who were not exposed previously to either agent.
  
  
  METHODS
  Forty-seven patients were treated: 37 patients with early chronic-phase CML (2 patients with clonal evolution) and 10 patients with late chronic-phase CML. Their median age was 62 years (range, 23-73 years). HHT was given at a dose of 2.5 mg/m(2) by continuous intravenous infusion over 24 hours daily for 5 days every month, and IFN-alpha was given daily at a target dose of 5 x 10(6) units/m(2) subcutaneously. Response, survival, and treatment toxicity were analyzed.
  
  
  RESULTS
  Overall, the complete hematologic response (CHR) rate was 85%; the cytogenetic response rate was 66%, with major cytogenetic responses (Ph positive in < 35% of metaphases) in 49% of patients and complete cytogenetic responses in 21% of patients. The CHR rate, cytogenetic response rate, and major cytogenetic response rate were 84%, 69%, and 52%, respectively, in patients with early chronic-phase CML. Among the 10 patients with late chronic-phase CML, the CHR rate, cytogenetic response rate, and major cytogenetic response rate were 80%, 50%, and 40%, respectively. Response rates in patients age > 60 years were 84%, 62%, and 49% for CHR, cytogenetic response, and major cytogenetic response. Myelosuppression was frequent but manageable: Anemia with hemoglobin < 8.0 g/dL occurred in 36% of patients, requiring dose adjustments and erythropoietin therapy. Nonhematologic toxicities were mainly fatigue, aches, and gastrointestinal disturbances. Dose reductions with multiple courses were significant and were due to myelosuppression: After 6-24 courses, the median daily IFN-alpha dose was 1 MU/m(2), and the median number of days on HHT per month was 2 days. With a median follow-up of 26 months, the estimated 2-year survival rate was 90% (95% confidence interval, 79-100%).
  
  
  CONCLUSIONS
  The simultaneous combination of HHT and IFN-alpha is safe and effective, but the dose schedules that actually were delivered were significantly lower than the planned dose schedules. With the availability of signal-transduction inhibitor 571 (imatinib mesylate), studies of combination of HHT and IFN-alpha chemotherapy in patients with CML who have disease that fails to respond to imatinib mesylate and of combinations with imatinib mesylate need to be explored.
authors.affiliation: Department of Leukemia and Bioimmunotherapy, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Jianqin
authors.initials: J
authors.lastname: Shan
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Stefan
authors.initials: S
authors.lastname: Faderl
authors.forename: Deborah
authors.initials: D
authors.lastname: Thomas
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Susie
authors.initials: S
authors.lastname: Mallard
authors.forename: Mary
authors.initials: M
authors.lastname: Beth
authors.forename: Charles
authors.initials: C
authors.lastname: Koller
authors.forename: Steve
authors.initials: S
authors.lastname: Kornblau
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Anthony
authors.initials: A
authors.lastname: Murgo
authors.forename: Michael
authors.initials: M
authors.lastname: Keating
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000328:Adult; D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006248:Harringtonines / Q000008:administration & dosage; D000077863:Homoharringtonine; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D006248:Harringtonines; D016898:Interferon-alpha; D000077863:Homoharringtonine