10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.
Lübbert, Michael; Wijermans, Pierre W; Kicinski, Michalet al.
2023 • In The Lancet Haematology, 10 (11), p. 879 - e889
[en] [en] BACKGROUND: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes.
METHODS: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m2) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m2) was administered over the first 3 days and cytarabine (200 mg/m2) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants.
FINDINGS: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group.
INTERPRETATION: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics.
FUNDING: Janssen Pharmaceuticals.
Disciplines :
Hematology
Author, co-author :
Lübbert, Michael; Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany. Electronic address: michael.luebbert@uniklinik-freiburg.de
Wijermans, Pierre W; Department of Hematology, Haga Teaching Hospital, The Hague, Netherlands
Kicinski, Michal; The European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
Chantepie, Sylvain; Department of Hematology, Centre Hospitalo-Universitaire de Caen, Caen, France
Van der Velden, Walter J F M; Department of Hematology, Radboud University, Nijmegen, Netherlands
Noppeney, Richard; Klinik für Hämatologie und Stammzelltransplantation, University Hospital Essen, Essen, Germany
Griškevičius, Laimonas; Department of Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius University, Vilnius, Lithuania
Neubauer, Andreas; Department of Internal Medicine, Hematology, Oncology and Immunology, Philipps University Marburg and University Hospital Gießen and Marburg, Campus Marburg, Marburg, Germany
Crysandt, Martina; Department of Hematology, Oncology, Hemostasiology and Stem Cell Transplantation, Medical Clinic IV, University Hospital RWTH Aachen, Aachen, Germany
Vrhovac, Radovan; Department of Haematology, University Hospital Centre Zagreb, Zagreb, Croatia
Luppi, Mario; Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, University of Modena and Reggio Emilia, Azienda Ospedaliera Universitaria, Modena, Italy
Fuhrmann, Stephan; Department of Hematology and Oncology, Helios Hospital Berlin-Buch, Kiel, Germany
Audisio, Ernesta; Department of Haematology, Azienda Ospedaliera Città della Salute e della Scienza di Torino-Ospedale Molinette, Torino, Italy
Legrand, Olivier; Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France
Foà, Robin; Ematologia, Dipartimento di Medicina Traslazionale e di Precisione, Sapienza Università di Roma, Rome, Italy
Gaidano, Gianluca; Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy
van Lammeren-Venema, Danielle; Department of Hematology, Haga Teaching Hospital, The Hague, Netherlands
Posthuma, Eduardus F M; Department of Internal Medicine, Reinier de Graaf Hospital, Delft, Netherlands
Hoogendoorn, Mels; Department of Hematology, Medical Center Leeuwarden, Leeuwarden, Netherlands
Giraut, Anne; The European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
Stevens-Kroef, Marian; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
Jansen, Joop H; Laboratory Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
de Graaf, Aniek O; Laboratory Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
Efficace, Fabio; Italian Group for Adult Hematologic Diseases (GIMEMA), Data Center and Health Outcomes Research Unit, Rome, Italy
Ammatuna, Emanuele; University Medical Center Groningen, Groningen, Netherlands
Vilque, Jean-Pierre; Department of Hematology, Centre Hospitalo-Universitaire de Caen, Caen, France
Wäsch, Ralph; Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany
Becker, Heiko; Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany
Blijlevens, Nicole; Department of Hematology, Radboud University, Nijmegen, Netherlands
Dührsen, Ulrich; Klinik für Hämatologie und Stammzelltransplantation, University Hospital Essen, Essen, Germany
Baron, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique
Suciu, Stefan; The European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
Amadori, Sergio; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
Venditti, Adriano; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
Huls, Gerwin; University Medical Center Groningen, Groningen, Netherlands. Electronic address: g.huls@umcg.nl
EORTC Leukemia Group, GIMEMA, and German MDS Study Group
10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.
KWF - Kankerbestrijding DJCLS - José Carreras Leukämie-Stiftung Janssen Pharmaceuticals DFG - Deutsche Forschungsgemeinschaft
Funding text :
We are grateful to Janssen Pharmaceuticals for supporting this study. This work was also supported by a grant from the Dutch Cancer Society (grant number RUG 11072 to GH) and from the José Carreras Leukemia Foundation (AH06-01 to AN). We thank the investigators who participated in this study and who have not been included among the coauthor list of this publication ( appendix 1 pp 4–5 ). We warmly thank all EORTC Headquarters team members who have not been included among the coauthor list of this publication and who contributed to the study success (Kin-Jip Cheung, Liv Meert, Safaa Ramadan, Delphine Sartori, Maarten Caspers); thanks also to Johanna Thomas for excellent clerical support. MLü acknowledges funding from the German Research Foundation (DFG Lu429/15-2). Finally, we wish to thank the patients and their families for participating in this study, providing their invaluable contribution.We are grateful to Janssen Pharmaceuticals for supporting this study. This work was also supported by a grant from the Dutch Cancer Society (grant number RUG 11072 to GH) and from the José Carreras Leukemia Foundation (AH06-01 to AN). We thank the investigators who participated in this study and who have not been included among the coauthor list of this publication (appendix 1 pp 4–5). We warmly thank all EORTC Headquarters team members who have not been included among the coauthor list of this publication and who contributed to the study success (Kin-Jip Cheung, Liv Meert, Safaa Ramadan, Delphine Sartori, Maarten Caspers); thanks also to Johanna Thomas for excellent clerical support. MLü acknowledges funding from the German Research Foundation (DFG Lu429/15-2). Finally, we wish to thank the patients and their families for participating in this study, providing their invaluable contribution.
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