title: Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial.
abstract: BACKGROUND
  The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients.
  
  
  METHODS
  We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957.
  
  
  RESULTS
  Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Gray's test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event).
  
  
  CONCLUSIONS
  In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients.
  
  
  BACKGROUND
  Agenzia Italiana del Farmaco.
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. Electronic address: arambaldi@hpg23.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rambaldi
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Grassi
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Masciulli
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Boschini
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Maria Caterina
authors.initials: MC
authors.lastname: Micò
authors.affiliation: Bone Marrow Transplant Unit, University of Torino, Turin, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Busca
authors.affiliation: Bone Marrow Transplant Unit, University of Torino, Turin, Italy.
authors.forename: Benedetto
authors.initials: B
authors.lastname: Bruno
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Ospedale Centrale di Bolzano, Bolzano, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Cavattoni
authors.affiliation: Bone Marrow Transplant Center, Ospedale Spirito Santo, Pescara, Italy.
authors.forename: Stella
authors.initials: S
authors.lastname: Santarone
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Ospedale San Bortolo, Vicenza, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Raimondi
authors.affiliation: Hematology, Azienda Ospedali Riuniti, Ancona, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Montanari
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda Policlinico-Vittorio Emanuele, Catania, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Milone
authors.affiliation: Unit of Hematology, Policlinico Universitario A Gemelli, Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Chiusolo
authors.affiliation: Department of Emergency and Organ Transplantation, Section of Hematology with Transplantation, Medical School, University of Bari, Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Pastore
authors.affiliation: Department of Hematology, Bone Marrow Transplant Unit, University of Firenze, Florence, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guidi
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliero Universitaria Ospedale Santa Maria della Misericordia di Udine, Udine, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Patriarca
authors.affiliation: Hematology, AOU Federico II, Naples, Italy.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Risitano
authors.affiliation: Hematology-Bone Marrow Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Saporiti
authors.affiliation: Hematology, AO SS Antonio e Biagio e C Arrigo, Alessandria, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pini
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda ospedaliera San Gerardo, Monza, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Terruzzi
authors.affiliation: Hematology Division-Stem Cell Transplant Unit, Policlinico Tor Vergata, Rome, Italy.
authors.forename: William
authors.initials: W
authors.lastname: Arcese
authors.affiliation: Department of Oncology, UOSA Transplant and Cellular Therapy Center, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Marotta
authors.affiliation: Hematology and Bone Marrow Transplant Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Angelo Michele
authors.initials: AM
authors.lastname: Carella
authors.affiliation: Division of Hematology Bone Marrow Transplant & CBB, Chaim Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.affiliation: Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Russo
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS Istituto Nazionale Tumori and University of Milano, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Corradini
authors.affiliation: Department of Hematology Oncology, IRCCS Fondazione Policlinico San Matteo & University of Pavia, Pavia, Italy.
authors.forename: Emilio Paolo
authors.initials: EP
authors.lastname: Alessandrino
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Giovanni Fernando
authors.initials: GF
authors.lastname: Torelli
authors.affiliation: Bone Marrow Transplant Unit, AOR Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Scimè
authors.affiliation: Hematology, Azienda Ospedaliera S Croce e Carle, Cuneo, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Mordini
authors.affiliation: Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Oldani
authors.affiliation: Fondazione Mario Negri Sud, Santa Maria Imbaro, Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Marfisi
authors.affiliation: Department of Hematology and Oncology, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bacigalupo
authors.affiliation: Department of Hematology, Bone Marrow Transplant Unit, University of Firenze, Florence, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosi
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002066:Busulfan / Q000008:administration & dosage*; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine