Phase III Randomized Study of Amonafide (AS1413) and Cytarabine Versus Daunorubicin and Cytarabine in Patients With Secondary Acute Myeloid Leukemia (AML)- the ACCEDE Study

Inclusion Criteria: * Diagnosis of AML according to WHO diagnostic criteria (at least 20% blasts in the peripheral blood or bone marrow), with FAB classification other than M3 (Acute Promyelocytic Leukemia), documented by bone marrow aspiration and biopsy performed within 14 days prior to administration of 1st dose of remission induction chemotherapy; * Either: Known and documented exposure to specific leukemogenic therapy of a specified nature for a non-myeloid condition; OR Documented diagnosis of MDS according to WHO criteria for at least 3 months prior to study entry, with prior bone marrow aspirate, biopsy and peripheral blood smear documenting MDS available to be submitted for subsequent central pathology review. * Age 18 years or older; * Eastern Cooperative Oncology Group (ECOG) performance score =\< 2; * Fertile sexually active patients (men and women) must use an effective method of contraception which must be continued throughout the study. * Women of childbearing potential must have a negative serum pregnancy test. * Left Ventricular Ejection Fraction (LVEF) \>= 50%, as determined by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO) within 14 days prior to administration of 1st dose of remission induction chemotherapy; * Adequate renal function as evidenced by the following laboratory test, obtained within 10 days prior to administration of 1st dose of remission induction chemotherapy: Serum creatinine =\< 1.5 x ULN; * Adequate hepatic function as evidenced by the following laboratory tests, obtained within 10 days prior to administration of 1st dose of remission induction chemotherapy (unless attributed to hepatic involvement with AML): Total serum bilirubin =\< 1.5 x ULN;Serum AST and ALT =\< 1.5 x ULN; * Ability of the patient to participate fully in all aspects of this clinical trial; * Written Informed Consent and HIPAA authorization (USA sites only) must be obtained and documented. Exclusion Criteria: * Histologic diagnosis of FAB M3 Acute Promyelocytic Leukemia; * Clinically active CNS leukemia; * Prior induction therapy for AML; * Known HIV positive; * Known active hepatitis B or C, or any other active liver disease; * Patients with parenchymal abnormality on screening chest x-ray must have no evidence of pulmonary infection on chest tomography (CT) prior to starting remission induction therapy. * Any major surgery or radiation therapy within 4 weeks prior to study entry; * Prior cytotoxic chemotherapy for MDS within 4 weeks prior to study entry (patients with rapidly rising blast count may be enrolled within 4 weeks of prior cytotoxic chemotherapy with waiver from the Medical Monitor); * Persistent chronic non-hematologic toxicity (other than alopecia) greater than grade 1 from prior therapy for MDS; * Serious concomitant illnesses (for example, pulmonary infiltrate, unstable angina or myocardial infarction or stroke within 3 months prior to study entry, congestive heart failure AHA class 2 or greater, uncontrolled hypertension, uncontrolled diabetes, actively bleeding gastric ulcer, etc.), which in the investigator's opinion would not make the patient a good candidate for the trial; * Pregnant or breast feeding; * History of clinically significant allergic reactions attributed to compounds of similar chemical or biological composition to amonafide, cytarabine or daunorubicin; * Prior enrollment in this trial; * Any other known condition (e.g., familial, sociological, or geographical) or behavior (including substance dependence or abuse, psychological or psychiatric illness), which in the investigator's opinion would make the patient a poor candidate for the trial.