Comparison Between Two Dose Levels of Daunorubicin and Between One vs. Two Induction Cycles for Adult Patients With AML

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 \[Onkopedia-Leitlinie 2017\].

Eligibility Criteria:
Inclusion Criteria:

* Newly diagnosed AML other than acute promyelocytic leukemia (APL) according to WHO criteria, i.e. bone marrow aspirate or biopsy must contain ≥20% blasts of all nucleated cells or differential blood count must contain ≥20% blasts. In acute erythroid leukemia, ≥20% blasts in all non-erythroid bone marrow cells. In AML defined by cytogenetic aberrations, the rate of blasts may be \<20%. Secondary AMLs are eligible for inclusion.
* Age 18- inkl.65 years
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Adequate liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening:

  * Total bilirubin ≤ 1.5 times the upper limit of normal
  * alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 times upper limit of normal
  * Creatinine ≤ 1.5 times upper limit of normalExclusion Criteria:
* Adequate cardiac function, i.e. left ventricular ejection fraction (LVEF) of ≥ 50% as assessed by transthoracic two-dimensional echocardiography ("M Mode") or multiple gated acquisition scan (MUGA scan)
* Signed informed consent
* Women must fulfill at least one of the following criteria in order to be eligible for trial inclusion:

  * Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum follicle stimulating hormone (FSH) \> 40 U/ml)
  * Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy
  * Continuous and correct application of a contraception method with a Pearl Index of \<1% (e.g. implants, depots, oral contraceptives, intrauterine device - IUD).
  * Sexual abstinence
  * Vasectomy of the sexual partner

Exclusion criteria:

* Patients who are not eligible for standard chemotherapy as assessed by the treating physician
* Central nervous system manifestation of AML
* Cardiac disease: i.e. heart failure New York Heart Association (NYHA) III or IV; unstable coronary artery disease (MI more than 6 months prior to study entry is permitted); serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
* Patients undergoing renal dialysis
* Chronic pulmonary disease with clinical relevant hypoxia
* Known HIV or Hepatitis infection
* Uncontrolled active infection
* Medical conditions other than AML with an estimated life expectancy below 6 months
* Previous treatment of AML except hydroxyurea up to 5 days
* Relapsed or primary refractory AML
* Acute promyelocytic leukemia
* Previous anthracycline-containing chemotherapy
* Treatment with any known non-marketed drug substance or experimental therapy within 4 weeks prior to enrollment
* Incapability of understanding purpose and possible consequences of the trial
* Pregnant or breastfeeding women
* Evidence suggesting that the patient is not likely to follow the study protocol (e.g. lacking compliance)