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): a randomised, non-inferiority, phase 3 trial.

Dietrich Wilhelm Beelen, Rudolf Trenschel, Matthias Stelljes, Christoph Groth, Tamás Masszi, Péter Reményi, Eva-Maria Wagner-Drouet, Beate Hauptrock, Peter Dreger, Thomas Luft, Wolfgang Bethge, Wichard Vogel, Fabio Ciceri, Jacopo Peccatori, Friedrich Stölzel, Johannes Schetelig, Christian Junghanß, Christina Grosse-Thie, Mauricette Michallet, Hélène Labussiere-Wallet, Kerstin Schaefer-Eckart, Sabine Dressler, Goetz Ulrich Grigoleit, Stephan Mielke, Christof Scheid, Udo Holtick, Francesca Patriarca, Marta Medeot, Alessandro Rambaldi, Maria Caterina Micò, Dietger Niederwieser, Georg-Nikolaus Franke, Inken Hilgendorf, Nils Rudolf Winkelmann, Domenico Russo, Gérard Socié, Régis Peffault de Latour, Ernst Holler, Daniel Wolff, Bertram Glass, Jochen Casper, Gerald Wulf, Helge Menzel, Nadezda Basara, Maria Bieniaszewska, Gernot Stuhler, Mareike Verbeek, Sandra Grass, Anna Paola Iori, Juergen Finke, Fabio Benedetti, Uwe Pichlmeier, Claudia Hemmelmann, Michael Tribanek, Anja Klein, Heidrun Anke Mylius, Joachim Baumgart, Monika Dzierzak-Mietla, Miroslaw Markiewicz

Journal: The Lancet. Haematology 2020;7(1):e28-e39

PMID: 31606445

Full Text on Elsevier Science View on PubMed

Abstract

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/m 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/m 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.

Address: Department of Bone Marrow Transplantation, West German Cancer Centre, University of Duisburg-Essen, Essen, Germany. Electronic address: [email protected].; Department of Bone Marrow Transplantation, West German Cancer Centre, University of Duisburg-Essen, Essen, Germany.; Department of Medicine A/Haematology and Oncology, University of Muenster, Muenster, Germany.; Third Department of Internal Medicine, Semmelweis University, Budapest, Hungary; St István and St László Hospital of Budapest, Budapest, Hungary.; St István and St László Hospital of Budapest, Budapest, Hungary.; Third Department of Medicine - Haematology, Internal Oncology & Pneumology, Johannes Gutenberg-University Medical Centre, Mainz, Germany.; Department of Medicine V, University of Heidelberg, Heidelberg, Germany.; Department of Haematology & Oncology, Medical Centre University Hospital Tuebingen, Tuebingen, Germany.; Haematology and Bone Marrow Transplantation Unit, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy.; Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.; Department of Haematology, Oncology, and Palliative Care, University Medical Centre, University of Rostock, Rostock, Germany.; Department of Haematology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France.; Clinicum Nuremberg, Paracelsus Medical Private University, Nuremberg, Germany.; University Clinic Wuerzburg, Wuerzburg, Germany.; University Clinic Wuerzburg, Wuerzburg, Germany; Department of Cell Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital and Institute, Stockholm, Sweden.; Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany.; Haematological Clinic, Unit of Cellular Therapy 'Carlo Melzi', University Hospital, Udine, Italy.; Haematology and Bone Marrow Transplant Unit, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, University of Milan, Bergamo, Italy.; University Clinic Leipzig AöR, Leipzig, Germany.; Universitätsklinikum Jena, Klinik für Innere Medizin II, Abteilung für Hämatologie und Onkologie, Jena, Germany.; Unit of Blood Diseases and Stem Cell Transplantation, Department of Clinical and Experimental Sciences, University of Brescia, Azienda Socio Sanitaria Territoriale Spedali Civili Brescia, Brescia, Italy.; Hospital Saint-Louis, Paris, France.; University Medical Centre, University of Regensburg, Department of Internal Medicine 3, Regensburg, Germany.; Asklepios Clinic Hamburg GmbH, Bone Marrow Transplantation, Asklepios Clinic St Georg, Hamburg, Germany; current affiliation: Clinic for Haematology and Stem Cell Transplantation, HELIOS Clinic Berlin-Buch GmbH, Berlin, Germany.; Clinic Oldenburg AöR, Oldenburg, Germany.; University Medicine Goettingen, Georg-August-University, Goettingen, Germany.; Malteser Hospital St Franziskus-Hospital, Flensburg, Germany.; Department of Haematology and Transplantology, Medical University of Gdańsk, Gdansk, Poland.; DKD Helios Clinic, Wiesbaden, Germany.; Clinic right side of the Isar, Technical University Munich, Munich, Germany.; Policlinic Umberto I University La Sapienza, Rome, Italy.; University Clinic Freiburg, Medical Clinic, Freiburg, Germany.; Policlinic GB Rossi (Borgo Rome), Verona, Italy.; medac GmbH, Wedel, Germany.; Department of Haematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland.; Department of Haematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland; Faculty of Medicine, University of Rzeszow, Rzeszow, Poland.

DOI: 10.1016/S2352-3026(19)30157-7

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MeSH Terms: Adult, Aged, Antineoplastic Agents, Busulfan, Disease-Free Survival, Female, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute, Male, Middle Aged, Myelodysplastic Syndromes, Transplantation Conditioning, Vidarabine