The proposed trial will address two clinically important questions for younger patients with newly diagnosed acute myeloid leukemia (AML): the optimal dose of daunorubicin in induction therapy and the necessity of a second induction cycle in patients with a good response after the first induction. The primary endpoint is the rate of good responders. Secondary outcomes will be relapse-free survival, overall survival and minimal residual disease kinetics. Patients will be recruited in about 40 treatment centers of the Study Alliance Leukemia study group over a period of 40 months. The results will be of great clinical relevance: First, the study could facilitate the establishment or confirmation of the optimal daunorubicin dose.
In the first part of the trial, patients will be randomly assigned to receive either 90 mg/m2 or 60 mg/m2 daunorubicin in the first induction cycle in addition to standard dosed cytarabine. Assuming a superiority of 90 mg/m2, 436 patients will be recruited. In the second part of the trial, good responders will be randomized to receive either a second or no further induction cycle. Assuming a non-inferiority of the single induction regarding the rate of complete remissions, a number of 360 patients will be included in the second part. Furthermore, in case of a non-inferiority of single versus double induction in good responders, about half of all younger AML patients could be spared a second induction cycle, leading to a reduction in treatment-related mortality, fewer days spent in hospital and improved quality of life. As a result of the preplanned interim analysis of part I, the sponsor decided to suspend randomization in trial part I and to offer all patients the standard dose of 60 mg/m2 daunorubicin in both induction cycles (part I and II of the trial). Because of this an Amendment was sent to and approved by regulatories and ethics comitee. The inclusion age was raised to 65 years based on the current German treatment guidelines in which patients up to the age of 65 are considered eligible for intensive induction chemotherapy with DA60 \[Onkopedia-Leitlinie 2017\].
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
721
standard induction dose of daunorubicin 60 mg/m2 on days 3-5
single induction cycle versus double induction cycles (only patients with good response after first induction) Allocation is randomized for cytogenetic risk.
Interní klinika LF Masarykovy univerzity a Fakultní nemocnice Brno
Brno, Czechia
Faculty Hospital Hradec Králové, II. Clinic of international medicine
Hradec Králové, Czechia
Fakultní nemocnice Olomouc
Olomouc, Czechia
Fakultní nemocnice Královské Vinohrady
Prague, Czechia
Ústav hematologie a krevní transfuze (ÚHKT)
Prague, Czechia
response rate after first induction
To investigate whether a higher dose of daunorubicin in induction chemotherapy leads to an increase in hematological good responders defined as having \<5% myeloid blasts on day 15 after start of induction therapy.
Time frame: day 15
Rate complete remissions
To investigate whether the rate of complete remissions (CR) after single induction is similar to that after double induction in patients with good response to induction I.
Time frame: day 35 after final induction
rate cytogenetic and molecular complete remissions
To investigate whether a higher dose of daunorubicin in induction chemotherapy will lead to an increase in cytogenetic and molecular complete remissions.
Time frame: day 35
event-free survival (EFS)
To investigate whether a higher dose of daunorubicin will lead to improved event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). To investigate whether EFS, RFS and OS are similar after single versus double induction in patients with good response to induction I.
Time frame: 5 years
relapse-free survival (RFS)
To investigate whether a higher dose of daunorubicin will lead to improved event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). To investigate whether EFS, RFS and OS are similar after single versus double induction in patients with good response to induction I.
Time frame: 5 years
overall survival (OS)
To investigate whether a higher dose of daunorubicin will lead to improved event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). To investigate whether EFS, RFS and OS are similar after single versus double induction in patients with good response to induction I.
Time frame: 5 years
Correlation between Minimal Residual Disease (MRD) and EFS, RFS, OS
To correlate the level of cytogenetic and molecular minimal residual disease after induction treatment with survival outcomes EFS, RFS and OS.
Time frame: day 35
Rate of induction deaths
Rate of induction deaths (until day 60 or beginning of consolidation treatment - whichever occurs first)
Time frame: day 60
Incidence of serious infectious complications
Incidence of serious infectious complications Grades 3-4 (Common Toxicity Criteria for Adverse Effects (CTCAE) V4.0
Time frame: day 35
Sonographic cardiac left ventricular ejection fraction
Sonographic cardiac left ventricular ejection fraction
Time frame: day 35
Serum levels of pro-brain natriuretic peptide (por-BNP) and Troponin-T
Serum levels of pro-BNP and Trop-T
Time frame: day 35
Incidence of CTCAE grade ≥3 cardiac complications
Incidence of CTCAE grade ≥3 cardiac complications
Time frame: day 35
Rate of early deaths
Rate of early deaths (2 weeks)
Time frame: week 2
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Uniklinik RWTH Aachen
Aachen, Germany
Klinikum Altenburger Land GmbH
Altenburg, Germany
Klinikum Augsburg
Augsburg, Germany
Sozialstiftung Bamberg Klinikum am Bruderwald
Bamberg, Germany
Charite Campus Benjamin Franklin
Berlin, Germany
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