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217 Single Versus Double Induction with “7+3” Containing 60 Versus 90 Mg Daunorubicin for Newly Diagnosed AML: Results from the Randomized Controlled SAL Dauno-Double TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: New Approaches to Combination Chemotherapy and Venetoclax Plus Hypomethylating Agent Therapy in AML
Hematology Disease Topics & Pathways:
adult, Clinical Practice (Health Services and Quality), Combination therapy, Therapies, therapy sequence, Study Population, Human
Saturday, December 10, 2022: 2:00 PM

Christoph Röllig, MD, MSC1*, Björn Steffen, MD2*, Christoph Schliemann, MD3*, Jan-Henrik Mikesch, PD, MD3*, Nael Alakel, MD4*, Regina Herbst, MD5*, Mathias Haenel, MD6*, Richard Noppeney, MD7*, Maher Hanoun, MD, PhD8*, Martin Kaufmann, MD9, Zdenek Racil, MD10*, Kerstin Schäfer-Eckart11*, Tim Sauer, MD12*, Andreas Neubauer, MD13, Claudia D. Baldus, MD14*, Jolana Mertova15*, Edgar Jost16*, Dirk Niemann, MD17*, Jan Novak18*, Stefan W. Krause, MD19*, Sebastian Scholl, MD20*, Andreas Hochhaus21, Gerhard Held, Professor Dr22*, Tomáš Szotkowski, MD, PhD23*, Christoph Schmid, MD24*, Andreas Rank, MD25*, Lars Fransecky, MD26*, Michael Kramer, MSc27*, Frank Fiebig28*, Annett Haake28*, Friedrich Stoelzel, MD29, Johannes Schetelig, MD, MSc30, Jan Moritz Middeke, MD29*, Uwe Platzbecker, MD31*, Christian Thiede, MD27, Carsten Müller-Tidow, MD12*, Wolfgang E. Berdel, MD32, Hubert Serve, MD2, Gerhard Ehninger, MD33, Jiří Mayer, MD34 and Martin Bornhaeuser, MD35

1Universitätsklinikum Carl Gustav Carus, Dresden, Germany
2Department of Medicine II, Hematology/Oncology, Goethe University Hospital, Frankfurt, Germany
3Department of Hematology, Oncolog and Pneumology, University of Münster, Münster, Germany
4University Hospital TU Dresden, Germany, Dresden, Germany
5Klinikum Chemnitz, Chemnitz, DEU
6Medizinische Klinik III, Klinikum Chemnitz, Chemnitz, Germany
7Department of Hematology and Stem Cell Transplantation, University Hospital of Essen, Essen, Germany
8Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
9Medical Centre, Robert-Bosch-Hospital,, Stuttgart, Germany
10Masaryk University Hospital Brno, Brno, CZE
11Department of Internal Medicine V, Nuremberg Hospital North, Paracelsus Medical University, Nuremberg, Germany
12Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
13Klinik für Innere Medizin, Schwerpunkt Hämatologie, Onkologie und Immunologie, Philipps University, Marburg, Germany
14Department of Internal Medicine II, University Hospital Schleswig-Holstein, Kiel, Kiel, Germany
15UHKT, Prague, Czech Republic
16University Hospital Aachen, Germany, Aachen, Germany
17Department of Hematology/Oncology and Palliative Medicine, Ev. Stift St. Martin, Koblenz, Germany
18University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles U, Prague, CZE
19University Hospital Erlangen, Germany, Erlangen, Germany
20University Hospital Jena, Jena, Germany
21Department of Internal Medicine 2, Hematology and Oncology, Jena University Hospital, Jena, Germany
22Department of Internal Medicine I, Westpfalz-Klinikum, Kaiserslautern, Germany
23Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
24Department of Haematology and Oncology, University Hospital and Medical Faculty Augsburg, Augsburg, Germany
25Klinikum Augsburg, Augsburg, DEU
26Department of Internal Medicine II, University Hospital Schleswig-Holstein, Kiel, Germany
27Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany
28Universitätsklinikum Dresden, Dresden, Germany
29Department of Internal Medicine I, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany
30Department of Internal Medicine I, TU Dresden, Dresden, Saxony, Germany
31Department for Hematology, Cell Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany
32Department of Medicine A, Hematology and Oncology, University Hospital Muenster, Muenster, Germany
33Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany
34Department of Internal Medicine Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic
35Universitatsklinikum Cad GustavCarus an der Technischen Universltat Dresden, Dresden, Ferscherstrabo 74, Germany


A combination of cytarabine plus anthracycline according to the 7+3 schedule is the standard treatment backbone of fit newly diagnosed AML patients (pts). A daunorubicin dose of 90 mg/m2 is superior to 45 mg/m2, whereas little difference seems to be between 60 mg/m2 and 90 mg/m2. Double induction is commonly performed in younger pts in order to maximize dose intensity upfront. However, for pts with a good early response after first induction, there is no prospective randomized evidence on the necessity or value of a second induction cycle (IC).


To provide randomized evidence for two fundamental questions in standard induction: First, is 60 mg/m2 really sufficient for induction or is 90 mg/m2 more efficacious? Second, can good responders after the first 7+3 induction be spared a second IC?


DaunoDouble was a two-part, two-arm open-label multicenter prospective randomized phase III trial. Pts 18-65 years with newly diagnosed AML, normal cardiac and organ function received a first IC with seven days of cytarabine plus three days of daunorubicin (“7+3”) with a 1:1 stratified randomization for 60 versus (vs) 90 mg/m2 (Dauno60 vs Dauno90). Response assessment in bone marrow was evaluated by cytology on day 15. A blast count <5% was defined as good response, which was the primary endpoint of this first randomization step.

Good responders were randomized to receive a second IC (arm D) or no second IC (arm S). In arm D, the second IC contained 60 mg/m2 after Dauno60 and 45 mg/m2 after Dauno90. Primary endpoint of the second randomization was CR/CRi after completion of induction. We assumed non-inferiority of single induction in terms of CR/CRi rate, based on a margin of 7.5%.


Between 2014 and 2022, 864 pts were enrolled and received the first IC with 7+3. Median age was 52 years, 88% had de novo AML. Favorable, intermediate and adverse risk (ELN 2017) was present in 37%, 46% and 17% of pts, respectively. No significant imbalances were observed between the two treatment arms except for a higher NPM1 mutant rate in the Dauno90 arm (32.4% vs 41.7%, p=0.034).

A pre-planned interim analysis after the first randomization of 218 pts revealed a statistically and clinically non-significant difference of 42% vs 49% good responders after first induction with 60 vs 90 mg/m2 daunorubicin (p=0.341). Based on this result, the first randomization step was suspended and all consecutive pts received 60 mg/m2 in induction I. At the end of enrollment, 707 and 157 pts have received 60 or 90 mg/m2, with a corresponding proportion of good early responders of 44.4% vs 47.8% (p=0.930) and a CR rate of 89.6% vs 88.5% after the end of induction (p=0.691). After a median follow-up of 43.6 months, 3-y RFS after Dauno60 vs Dauno90 was 53.8% vs 50.1% (p=0.561) and 3-y OS 65.2% vs 58.3% (p=0.196). During first induction, 57% of pts in Dauno60 and 58% in Dauno90 experienced an AE ≥ grade 3 (p=0.877); mortality in induction I was 2.3% and 4.7%, respectively (p=0.109).

After IC I, a marrow blast clearance below 5% on day 15 was achieved in 389 pts (45%), providing eligibility for the second randomization. Of these pts, 189 were randomized into arm S and 187 into arm D (ITT population). CR/CRi rates at the end of induction were 85.2% after single induction and 85.6% after double induction, resulting in a CR difference of 0.4% (p for non-inferiority test 0.0269). The CR/CRi rates in 326 pre-defined per-protocol pts (PP) were 86.8% vs 91.5%, resulting in a CR difference of 4.7% (p=0.205). Until the end of induction, 58% of pts in the S arm and 65% of pts in the D arm experienced an AE ≥ grade 3 (p=0.195). Early mortality 60 days after induction start was 0.6% in both arms.

After a median follow-up time of 43.6 months, 3-y RFS after single vs double induction was 51% vs 60%, which was non-significant in the ITT population (HR 1.35; p=0.074) and borderline significant in the PP population (HR 1.43; 0=0.05), but not significant in multivariable analyses. OS after 3 years was identical with 77% vs 75% after single or double induction in the ITT (HR 1.02; p= 0.914) and 77% vs 76% in the PP population (HR 1.12; p=0.628).


The use of 90 mg daunorubicin in the context of classical 7+3 induction did not lead to higher remission rates or longer survival than 60 mg. In pts with a good early response after first induction, a second induction had only limited impact on RFS. Double induction did not lead to an overall survival benefit in pts with a good early response first 7+3 induction.

Disclosures: Röllig: BMS: Consultancy, Honoraria; Amgen: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Servier: Consultancy; Jazz: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria. Steffen: Jazz Pharmaceuticals: Other: Travel/Congress Participation Support; AbbVie: Other: Travel/Congress Participation Support. Schliemann: Jazz: Consultancy, Research Funding; Boehringer-Ingelheim: Research Funding; Astrazeneca: Consultancy; Astellas: Consultancy; Abbvie: Consultancy, Other: travel grants; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Other: travel grants; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Alakel: Pfizer: Consultancy, Honoraria. Haenel: Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; JAZZ: Consultancy, Honoraria. Sauer: Pfizer: Honoraria; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Ridgeline Discoveries: Membership on an entity's Board of Directors or advisory committees. Jost: Jazz: Honoraria; BMS Celgene: Honoraria. Krause: Art-tempi: Honoraria; Kosmas: Honoraria; Abbvie: Other: Expenses. Hochhaus: Incyte: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding. Schmid: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Research Funding; Abbvie: Research Funding. Fransecky: Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau. Schetelig: BeiGene: Honoraria; BMS: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria; Abbvie: Honoraria; DKMS: Current Employment; TU Dresden, Medical Department I: Current Employment. Middeke: Abbvie: Membership on an entity's Board of Directors or advisory committees. Thiede: Kronos Bio, Inc.: Honoraria; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AgenDix GmbH: Current Employment, Current equity holder in private company.

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