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.

Autor:	Lübbert M; 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 PW; Department of Hematology, Haga Teaching Hospital, The Hague, Netherlands., Kicinski M; The European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium., Chantepie S; Department of Hematology, Centre Hospitalo-Universitaire de Caen, Caen, France., Van der Velden WJFM; Department of Hematology, Radboud University, Nijmegen, Netherlands., Noppeney R; Klinik für Hämatologie und Stammzelltransplantation, University Hospital Essen, Essen, Germany., Griškevičius L; Department of Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius University, Vilnius, Lithuania., Neubauer A; Department of Internal Medicine, Hematology, Oncology and Immunology, Philipps University Marburg and University Hospital Gießen and Marburg, Campus Marburg, Marburg, Germany., Crysandt M; Department of Hematology, Oncology, Hemostasiology and Stem Cell Transplantation, Medical Clinic IV, University Hospital RWTH Aachen, Aachen, Germany., Vrhovac R; Department of Haematology, University Hospital Centre Zagreb, Zagreb, Croatia., Luppi M; Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto, University of Modena and Reggio Emilia, Azienda Ospedaliera Universitaria, Modena, Italy., Fuhrmann S; Department of Hematology and Oncology, Helios Hospital Berlin-Buch, Kiel, Germany., Audisio E; Department of Haematology, Azienda Ospedaliera Città della Salute e della Scienza di Torino-Ospedale Molinette, Torino, Italy., Candoni A; Clinica Ematologica Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy., Legrand O; Service d'Hématologie Clinique et de Thérapie cellulaire, Hôpital Saint Antoine, APHP, Paris, France., Foà R; Ematologia, Dipartimento di Medicina Traslazionale e di Precisione, Sapienza Università di Roma, Rome, Italy., Gaidano G; Division of Hematology, Department of Translational Medicine, Università del Piemonte Orientale and Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy., van Lammeren-Venema D; Department of Hematology, Haga Teaching Hospital, The Hague, Netherlands., Posthuma EFM; Department of Internal Medicine, Reinier de Graaf Hospital, Delft, Netherlands., Hoogendoorn M; Department of Hematology, Medical Center Leeuwarden, Leeuwarden, Netherlands., Giraut A; The European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium., Stevens-Kroef M; Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands., Jansen JH; Laboratory Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands., de Graaf AO; Laboratory Hematology, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands., Efficace F; Italian Group for Adult Hematologic Diseases (GIMEMA), Data Center and Health Outcomes Research Unit, Rome, Italy., Ammatuna E; University Medical Center Groningen, Groningen, Netherlands., Vilque JP; Department of Hematology, Centre Hospitalo-Universitaire de Caen, Caen, France., Wäsch R; Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany., Becker H; Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany., Blijlevens N; Department of Hematology, Radboud University, Nijmegen, Netherlands., Dührsen U; Klinik für Hämatologie und Stammzelltransplantation, University Hospital Essen, Essen, Germany., Baron F; GIGA-I3 and Centre Hospitalier Universitaire, University of Liège, Liège, Belgium., Suciu S; The European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium., Amadori S; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy., Venditti A; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy., Huls G; University Medical Center Groningen, Groningen, Netherlands. Electronic address: g.huls@umcg.nl.
Jazyk:	angličtina
Zdroj:	The Lancet. Haematology [Lancet Haematol] 2023 Nov; Vol. 10 (11), pp. e879-e889.
DOI:	10.1016/S2352-3026(23)00273-9
Abstrakt:	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/m 2 ) 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/m 2 ) was administered over the first 3 days and cytarabine (200 mg/m 2 ) 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. Competing Interests: Declaration of interests MLü received research support to his institution from Janssen and European Organisation for Research and Treatment of Cancer (EORTC); is on the advisory boards for AbbVie, Astex, Janssen-Cilag, Otsuka, and Syros; and is currently working in an ongoing trial with a study drug provided by Cheplapharm. MK received research funding from Merck, Bristol Myers Squibb (BMS), Pierre Fabre, Janssen, and Immunocore. SF received personal funding by BMS and Celgene. AG received a grant for study conduct, and drug supply for Dacogen from Janssen Pharma Educational. JHJ received support for molecular analysis from Janssen and EORTC. FE received personal funding from AbbVie, Incyte, Janssen, Novartis, and Syros. RW received consulting fees from Amgen, BMS, Celgene, Janssen, Kite, Gilead, Novartis, Pfizer, and Sanofi; payment from AbbVie, Amgen, BMS, Celgene, Janssen, Kite, Gilead, Pfizer, and Sanofi; and support for attending meetings or travel from Janssen. HB is secretary of EORTC Leukemia Group; received research funding by the German Jose Carreras Leukemia Foundation and German Research Foundation; and honoraria from AbbVie, BMS, Celgene, Merck, Novartis, and Servier. UD received personal honoraria for participation in a data safety monitoring board from Avencell Europe and data safety monitoring board for an acute myeloid leukaemia CAR-T cell trial from Avencell Europe. FB received payments to his institution from Incyte Biosciences, Takeda, ExCellThera, and MaaT Pharma. SS received funding to his institution from Janssen Pharmaceuticals. All other authors declare no competing interests. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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