Randomized Phase-III, two-arm, open-label, multi-center study in adult patients with AML and NPM1 mutation.

Before Amendment No. 4 (December 2013):

Primary Efficacy Objective:

• Evaluation of efficacy based on event-free survival (EFS) after induction and consolidation chemotherapy plus all-trans retinoic acid (ATRA) with or without gemtuzumab ozogamicin (GO) in adult patients with acute myeloid leukemia (AML) and mutant nucleophosmin-1 (NPM1)

After Amendment No. 4 (December 2013):

Primary Efficacy Objective:

• Evaluation of efficacy based on overall survival (OS) after induction and consolidation chemotherapy plus all-trans retinoic acid (ATRA) with or without gemtuzumab ozogamicin (GO) in adult patients with acute myeloid leukemia (AML) and mutant nucleophosmin-1 (NPM1)

Inclusion Criteria:

• Patients with confirmed diagnosis of acute myeloid leukemia according to the World Health Organization (WHO) classification.

• Presence of NPM1 mutation as assessed in one of the central AMLSG reference laboratories.

• Age ≥ 18 years. There is no upper age limit.

• No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis if needed for up to 5 days during the diagnostic screening phase.

• Non-pregnant and non-nursing. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to registration.

• Female patients in the reproductive age and male patients must agree to avoid getting pregnant or to father a child while on therapy and within one year after the last dose of chemotherapy.

  • Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control: one highly effective method (e.g., IUD, hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (e.g., latex condom, diaphragm, or cervical cap).
  • "Women of childbearing potential" is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months.
  • Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy.

• Signed written informed consent.

Exclusion Criteria:

• AML with other recurrent genetic changes (according to WHO 2008):

  • AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
  • AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
  • AML with t(15;17)(q22;q12); PML-RARA (or other translocations involving RARA)
  • AML with t(9;11)(p22;q23); MLLT3-MLL (or other translocations involving MLL)
  • AML with t(6;9)(p23;q34); DEK-NUP214
  • AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1.

• Performance status WHO > 2.

• Patients with ejection fraction < 50% by MUGA or ECHO scan within 14 days of day 1.

• Organ insufficiency:

  • creatinine > 1.5x upper normal serum level
  • bilirubin, AST or ALP > 2.5x upper normal serum level, not attributable to AML
  • heart failure NYHA III/IV
  • severe obstructive or restrictive ventilation disorder.

• Uncontrolled infection.

• Severe neurological or psychiatric disorder interfering with ability of giving an informed consent.

• Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.

• Known positive for HIV, active HBV, HCV, or Hepatitis A infection.

• Bleeding disorder independent of leukemia.

• No consent for registration, storage and processing of the individual disease-characteristics and course as well as information of the family physician about study participation.