title: Salvage therapy in refractory acute myeloid leukemia: prediction of outcome based on analysis of prognostic factors.
abstract: Acute myeloid leukemia (AML) non-responsive to initial chemotherapy is generally of poor prognosis. High-dose cytarabine (HD-AraC) has been proposed as salvage therapy in combination with amsacrine. The aim of the current study was first to assess the toxicity and the efficacy of such a combination therapy, and secondly to determine prognostic factors allowing to predict whom patients could benefit of such a treatment. Out of 91, 45 patients referred to our institution have been treated by HD-AraC (3 g/m(2)/12h from day 1 to 4) combined with amsacrine (90 mg/m(2) per day from day 5 to 7) as a salvage regimen. Forty-five of the 91 patients (49%, 95% confidence interval (CI): 39-60%) achieved complete remission (CR). Thirty-five patients were refractory to the salvage therapy and 11 patients died from toxicity during aplasia. Median disease-free survival (DFS) was 11.5 months (95% CI: 6-16 months). After CR achievement, 26 patients received consolidation therapy according to the protocol in which they were included. Nineteen patients with an HLA-identical sibling donor underwent allogeneic bone marrow transplantation. At time of analysis, 27 of the 45 patients (60%) who achieved CR have relapsed. Median overall survival (OS) was 7.5 months (95% CI: 6-15 months). There was 12 long survivors (13%). In univariate analysis, initial karyotype was the main prognostic factor as well as in terms of CR achievement (P=0.002) than in terms of DFS (P=0.01) or OS (P=0.009). CR achievement was negatively influenced by higher WHO performance status index (P=0.006), higher LDH level (P=0.02), and higher CD34 expression by leukemic cells (P=0.03) at diagnosis, and presence of circulating blasts (P=0.001), platelet count <80 x 10(9)/l (P=0.0001), and polymorphonuclear (PMN) percentage <30% (P=0.01) at time of starting salvage therapy. DFS was negatively influenced by secondary AML (P=0.01), weight loss > or =5% (P=0.03), and higher white blood cell (WBC) count (P=0.03) at time of diagnosis. Age over 60 years (P=0.002), prior history of toxic exposure (P=0.01), higher CD34 expression (P=0.02), weight loss > or =5% (P=0.006), and WHO performance status index > or =2 (P=0.01) at diagnosis, and platelet count <80 x 10(9)/l (P=0.02) at time of salvage therapy were the main prognostic factors associated with shorter OS. In multivariate analysis, karyotype grouping at diagnosis (P=0.006) and blood count before salvage therapy (P=0.001) were of prognostic value for CR achievement. Karyotype remained of prognostic value for DFS and OS (P=0.007 and <0.0001, respectively).We conclude that HD-AraC combined with amsacrine was as a useful salvage regimen in AML non-responding to a first intensive course of chemotherapy. Using objective parameters of proven significance (karyotypic grouping and blood count before salvage), we devised a prognostic system of immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices. Patients with favorable risk cytogenetics and those with intermediate risk cytogenetics and favorable blood count (PMN > or =30%, no circulating blasts, and platelet count > or =80 x 10(9)/l) before salvage therapy had a similar outcome than those achieving CR after only one course of chemotherapy. All other patients displayed a poor outcome. This suggests their orientation at an earlier time to alternate therapeutic programs based on investigational drugs.
authors.affiliation: Service d'Hématologie Clinique, Hôpital Edouard Herriot, 69437 Lyon Cedex 03, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tavernier
authors.forename: Quoc-Hung
authors.initials: QH
authors.lastname: Le
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elhamri
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000677:Amsacrine / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000633:toxicity; D001772:Blood Cell Count; D003561:Cytarabine / Q000008:administration & dosage; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011446:Prospective Studies; D012074:Remission Induction; D012189:Retrospective Studies; D012307:Risk Factors; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000677:Amsacrine; D003561:Cytarabine