TY - JOUR
T1 - Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L)
T2 - a randomised, non-inferiority, phase 3 trial
AU - Beelen, Dietrich Wilhelm
AU - Trenschel, Rudolf
AU - Stelljes, Matthias
AU - Groth, Christoph
AU - Masszi, Tamás
AU - Reményi, Péter
AU - Wagner-Drouet, Eva Maria
AU - Hauptrock, Beate
AU - Dreger, Peter
AU - Luft, Thomas
AU - Bethge, Wolfgang
AU - Vogel, Wichard
AU - Ciceri, Fabio
AU - Peccatori, Jacopo
AU - Stölzel, Friedrich
AU - Schetelig, Johannes
AU - Junghanß, Christian
AU - Grosse-Thie, Christina
AU - Michallet, Mauricette
AU - Labussiere-Wallet, Hélène
AU - Schaefer-Eckart, Kerstin
AU - Dressler, Sabine
AU - Grigoleit, Goetz Ulrich
AU - Mielke, Stephan
AU - Scheid, Christof
AU - Holtick, Udo
AU - Patriarca, Francesca
AU - Medeot, Marta
AU - Rambaldi, Alessandro
AU - Micò, Maria Caterina
AU - Niederwieser, Dietger
AU - Franke, Georg Nikolaus
AU - Hilgendorf, Inken
AU - Winkelmann, Nils Rudolf
AU - Russo, Domenico
AU - Socié, Gérard
AU - Peffault de Latour, Régis
AU - Holler, Ernst
AU - Wolff, Daniel
AU - Glass, Bertram
AU - Casper, Jochen
AU - Wulf, Gerald
AU - Menzel, Helge
AU - Basara, Nadezda
AU - Bieniaszewska, Maria
AU - Stuhler, Gernot
AU - Verbeek, Mareike
AU - Grass, Sandra
AU - Iori, Anna Paola
AU - Finke, Juergen
AU - Benedetti, Fabio
AU - Pichlmeier, Uwe
AU - Hemmelmann, Claudia
AU - Tribanek, Michael
AU - Klein, Anja
AU - Mylius, Heidrun Anke
AU - Baumgart, Joachim
AU - Dzierzak-Mietla, Monika
AU - Markiewicz, Miroslaw
N1 - Funding Information:
DWB received honoraria for consultation, a grant for study patient documentation, speaker fees, and travel support from medac GmbH, during the conduct of the study. UP, CH, MT, AK, HAM, and JB are employees of medac GmbH. JB has licensed an employee's invention (PCT/EP00/10871) to medac GmbH. WB received personal fees from medac GmbH, Neovii, Miltenyi Biotech, and Jazz Pharma, outside the submitted work. AR received personal fees from Amgen, Pfizer, and Novartis, outside the submitted work. EH received personal fees from Novartis, MaatPharma, and Apceth, outside the submitted work. PD reports grants from medac GmbH, outside the submitted work. TM received support for advisory board membership from AbbVie, Bristol-Myers Squibb, Janssen-Cilag, Novartis, Pfizer, Takeda, Novartis, Merck, Sharp & Dohme, and Pfizer, outside the submitted work. FS received travel support from medac GmbH and Neovii; personal fees from Janssen and Jazz Pharma; and grants from Astellas, outside the submitted work. UH received non-financial support from medac GmbH, outside the submitted work. FP reports honoraria from Celgene, Janssen, and Jazz; and travel grants from medac GmbH and Neovii, outside the submitted work. DN received grants from Novartis and non-financial support from Amgen, outside the submitted work. IH reports grants and non-financial support from medac GmbH and Novartis. DW obtained grants and personal fees from medac GmbH, and personal fees from Neovii, outside the submitted work. BG reports fees for study documentation from medac GmbH; personal fees and non-financial support from Jazz and Roche; non-financial support from Celgene; and grants, personal fees, and non-financial support from Riemser, outside the submitted work. JC received grants and personal fees from medac GmbH, outside the submitted work. JF reports grants from Novartis and medac GmbH; and grants, personal fees, and other support from Neovii and Riemser, outside the submitted work. SM received non-financial support from European Society for Blood and Marrow Transplantation/European Hematology Association, International Academy for Clinical Hematology, Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie, and International Society Cell & Gene Therapy; and personal fees and non-financial support from Celgene, Miltenyi, Kiadis, Bellicum, and Jazz Pharma. RT, MS, CG, PR, BH, TL, WV, FC, JP, JS, CJ, CG-T, MMi, HL-W, KSE, SD, GUG, CS, MMe, MCM, GNF, NRW, DR, GS, RPL, GW, NB, MB, GS, MV, SG, API, FB, MDM, MMa, HM, and UP declare no competing interests.
Publisher Copyright:
© 2020 Elsevier Ltd
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/1
Y1 - 2020/1
N2 - Background: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. Methods: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18–70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 treosulfan daily applied as a 2-h infusion for 3 days (days –4 to –2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days –4 and –3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days –6 to –2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008–002356–18) and ClinicalTrials.gov (NCT00822393). Findings: Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8–23·6) for patients treated with treosulfan and 17·4 months (6·3–23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0–70·9) in the treosulfan group and 50·4% (42·8–57·5) in the busulfan group (HR 0·65 [95% CI 0·47–0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. Interpretation: Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan–fludarabine regimen suggest its potential to become a standard preparative regimen in this population. Funding: medac GmbH.
AB - Background: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. Methods: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18–70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 treosulfan daily applied as a 2-h infusion for 3 days (days –4 to –2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days –4 and –3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days –6 to –2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008–002356–18) and ClinicalTrials.gov (NCT00822393). Findings: Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8–23·6) for patients treated with treosulfan and 17·4 months (6·3–23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0–70·9) in the treosulfan group and 50·4% (42·8–57·5) in the busulfan group (HR 0·65 [95% CI 0·47–0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. Interpretation: Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan–fludarabine regimen suggest its potential to become a standard preparative regimen in this population. Funding: medac GmbH.
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U2 - 10.1016/S2352-3026(19)30157-7
DO - 10.1016/S2352-3026(19)30157-7
M3 - Article
C2 - 31606445
AN - SCOPUS:85076714955
VL - 7
SP - e28-e39
JO - The Lancet Haematology
JF - The Lancet Haematology
SN - 2352-3026
IS - 1
ER -