Alessandro Rambaldi1, Anna Grassi2, Arianna Masciulli3, Cristina Boschini2, Maria Caterina Micò2, Alessandro Busca4, Benedetto Bruno4, Irene Cavattoni5, Stella Santarone6, Roberto Raimondi7, Mauro Montanari8, Giuseppe Milone9, Patrizia Chiusolo10, Domenico Pastore11, Stefano Guidi12, Francesca Patriarca13, Antonio M Risitano14, Giorgia Saporiti15, Massimo Pini16, Elisabetta Terruzzi17, William Arcese18, Giuseppe Marotta19, Angelo Michele Carella20, Arnon Nagler21, Domenico Russo22, Paolo Corradini23, Emilio Paolo Alessandrino24, Giovanni Fernando Torelli25, Rosanna Scimè26, Nicola Mordini27, Elena Oldani2, Rosa Maria Marfisi3, Andrea Bacigalupo28, Alberto Bosi12. 1. Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. Electronic address: arambaldi@hpg23.it. 2. Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. 3. Fondazione Mario Negri Sud, Santa Maria Imbaro, Italy. 4. Bone Marrow Transplant Unit, University of Torino, Turin, Italy. 5. Hematology and Bone Marrow Transplant Unit, Ospedale Centrale di Bolzano, Bolzano, Italy. 6. Bone Marrow Transplant Center, Ospedale Spirito Santo, Pescara, Italy. 7. Hematology and Bone Marrow Transplant Unit, Ospedale San Bortolo, Vicenza, Italy. 8. Hematology, Azienda Ospedali Riuniti, Ancona, Italy. 9. Hematology and Bone Marrow Transplant Unit, Azienda Policlinico-Vittorio Emanuele, Catania, Italy. 10. Unit of Hematology, Policlinico Universitario A Gemelli, Rome, Italy. 11. Department of Emergency and Organ Transplantation, Section of Hematology with Transplantation, Medical School, University of Bari, Bari, Italy. 12. Department of Hematology, Bone Marrow Transplant Unit, University of Firenze, Florence, Italy. 13. Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliero Universitaria Ospedale Santa Maria della Misericordia di Udine, Udine, Italy. 14. Hematology, AOU Federico II, Naples, Italy. 15. Hematology-Bone Marrow Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy. 16. Hematology, AO SS Antonio e Biagio e C Arrigo, Alessandria, Italy. 17. Hematology and Bone Marrow Transplant Unit, Azienda ospedaliera San Gerardo, Monza, Italy. 18. Hematology Division-Stem Cell Transplant Unit, Policlinico Tor Vergata, Rome, Italy. 19. Department of Oncology, UOSA Transplant and Cellular Therapy Center, Azienda Ospedaliera Universitaria Senese, Siena, Italy. 20. Hematology and Bone Marrow Transplant Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. 21. Division of Hematology Bone Marrow Transplant & CBB, Chaim Sheba Medical Center, Tel Hashomer, Israel. 22. Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili of Brescia, Brescia, Italy. 23. Hematology and Bone Marrow Transplant Unit, Fondazione IRCCS Istituto Nazionale Tumori and University of Milano, Milan, Italy. 24. Department of Hematology Oncology, IRCCS Fondazione Policlinico San Matteo & University of Pavia, Pavia, Italy. 25. Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy. 26. Bone Marrow Transplant Unit, AOR Villa Sofia-Cervello, Palermo, Italy. 27. Hematology, Azienda Ospedaliera S Croce e Carle, Cuneo, Italy. 28. Department of Hematology and Oncology, IRCCS AOU San Martino-IST, Genoa, Italy.
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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Agenzia Italiana del Farmaco.
RCT Entities:
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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Agenzia Italiana del Farmaco.
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