title: Risk factors for outcome in refractory acute myeloid leukemia patients treated with a combination of fludarabine, cytarabine, and amsacrine followed by a reduced-intensity conditioning and allogeneic stem cell transplantation.
abstract: BACKGROUND
  Hematopoietic stem cell transplantation (HCT) is considered a standard treatment for high-risk acute myeloid leukemia (AML) in first or second complete remission (CR). Unfortunately, not all patients achieve complete remission prior to HCT. We sought to establish predictive factors for survival after HCT for refractory AML after FLAMSA-RIC.
  
  
  METHODS
  We analyzed the outcome of 44 consecutive patients aged between 21 and 65 years transplanted at the University Hospitals of Jena and Leipzig for refractory AML between 2006 and January 2013. Conditioning for HCT was performed with chemotherapy consisting of fludarabine, cytarabine, and amsacrine followed by total body irradiation or busulfan combined with cyclophosphamide. Antithymocyte globulin was given when transplanting from unrelated donors (FLAMSA-RIC).
  
  
  RESULTS
  Estimated overall survival (OS) and event-free survival (EFS) at 3 years after a median follow-up of 34 (range 6-71) months were 15 and 12 %, respectively. Causes of death were relapse in 66 %, infection in 11 %, and graft-versus-host disease (GvHD) in 7 % of all patients. Twenty-five from 42 evaluable patients (60 %) achieved CR 4 weeks after HCT, while eight patients had partial remission (PR), and nine patients had stable disease (SD). Another six patients with PR and SD achieved CR (overall CR rate 74 %) from 4 weeks to day 90 after HCT following reduction in immunosuppression. The strongest favorable factors in univariate analysis for OS, EFS, and RI were ≥98 % total donor chimerism 2-4 weeks after HCT and <3 lines of pretreatment prior to HCT. In addition, better OS was detected in patients with <20 % bone marrow blasts alone (32 vs. 5 % at 3 years) and in combination with <3 lines of pretreatment (38 vs. 4 % at 3 years). Only a trend for better EFS and lower RI was observed in patients with limited chronic GvHD. In addition, a lower RI was seen in patients with <5 % blasts 4 weeks after HCT. Multivariate analysis revealed that ≥98 % donor chimerism 2-4 weeks after HCT for OS, EFS, and RI and <3 lines of pretreatment for OS and EFS are the strongest predictors for better outcome.
  
  
  CONCLUSIONS
  FLAMSA-RIC shows long-term survival in refractory AML patients. Factors for favorable outcome are <20 % bone marrow blasts prior to HCT, <3 lines of pretreatment and complete donor chimerism after HCT.
authors.affiliation: Abteilung für Hämatologie, Internistische Onkologie, Universitätsklinikum Leipzig, 04103, Leipzig, Germany. christian.pfrepper@ediacon.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Pfrepper
authors.affiliation: Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Klink
authors.affiliation: Abteilung für Hämatologie, Internistische Onkologie, Universitätsklinikum Leipzig, 04103, Leipzig, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Behre
authors.affiliation: Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schenk
authors.affiliation: Abteilung für Hämatologie, Internistische Onkologie, Universitätsklinikum Leipzig, 04103, Leipzig, Germany.
authors.forename: Georg-Nikolaus
authors.initials: GN
authors.lastname: Franke
authors.affiliation: Abteilung für Hämatologie, Internistische Onkologie, Universitätsklinikum Leipzig, 04103, Leipzig, Germany.
authors.forename: Madlen
authors.initials: M
authors.lastname: Jentzsch
authors.affiliation: Abteilung für Hämatologie, Internistische Onkologie, Universitätsklinikum Leipzig, 04103, Leipzig, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schwind
authors.affiliation: Abteilung für Hämatologie, Internistische Onkologie, Universitätsklinikum Leipzig, 04103, Leipzig, Germany.
authors.forename: Haifa-Kathrin
authors.initials: HK
authors.lastname: Al-Ali
authors.affiliation: Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.affiliation: Abteilung für Hämatologie, Internistische Onkologie, Universitätsklinikum Leipzig, 04103, Leipzig, Germany.
authors.forename: Dietger
authors.initials: D
authors.lastname: Niederwieser
authors.affiliation: Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.|4. Medizinische Klinik (Hämatologie, internistische Onkologie und Hämostaseologie), HELIOS-Klinikum Erfurt, Erfurt, Germany.
authors.forename: Herbert Gottfried
authors.initials: HG
authors.lastname: Sayer
mesh_terms: D000328:Adult; D000368:Aged; D000677:Amsacrine / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000401:mortality*; D018380:Hematopoietic Stem Cell Transplantation / Q000401:mortality*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D009367:Neoplasm Staging; D011379:Prognosis; D012074:Remission Induction; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D055815:Young Adult
chemical_list: D000677:Amsacrine; D003561:Cytarabine; D014740:Vidarabine; C024352:fludarabine
keywords: Allogeneic stem cell transplantation; DLI; FLAMSA-RIC; Reduced-intensity conditioning; Refractory acute myeloid leukemia; Risk factors after allogeneic HCT, donor lymphocytic infusions