Trial to Test the Effects of Adding 1 of 2 New Treatment Agents to Commonly Used Chemotherapy Combinations

Inclusion Criteria Patients are eligible for the AML18 trial if: * They have one of the forms of acute myeloid leukaemia, except Acute Promyelocytic Leukaemia as defined by the WHO Classification (Appendix A) this can be any type of de novo or secondary AML - or high risk Myelodysplastic Syndrome, defined as greater than 10% marrow blasts (RAEB-2). (NB patients with prior MDS (\>10% blasts, RAEB2) have received azacitidine are not eligible for the trial, but patients with \<10% who have failed a hypomethylating agent and developed AML may enter the trial). * Patients should normally be over the age of 60, but patients under this age are eligible if they are not considered eligible for the MRC AML19 trial please contact the trial team for further information. * Patients entering the Vosaroxin/Decitabine arm must be over the age of 60 and have known adverse risk cytogenetics. * They have given written informed consent. * Serum creatinine ≤ 1.5 × ULN (upper limit of normal) * Sexually mature males must agree to use an adequate and medically accepted method of contraception throughout the study if their sexual partners are women of child bearing potential (WOCBP). Men should be advised to not father a child while receiving trial treatment. Similarly women must agree to adequate contraceptive measures and avoid becoming pregnant while on protocol treatment. In both males and females these measures must be in place for at least 3 months following completion of Decitabine and at least 6 months after the last administration of Cladribine. The time period following treatment with Decitabine where it is safe to become pregnant is unknown. In the event of pregnancy at any point during the trial, the IMPs should be immediately stopped and the Trial Team should be contacted and pregnancy reporting procedures followed. * ECOG Performance Status of 0-2 Exclusion criteria Patients are not eligible for the AML18 trial if: * They have previously received cytotoxic chemotherapy for AML \[Hydroxycarbamide, or similar low-dose therapy, to control the white count prior to initiation of intensive therapy, is not an exclusion\] * They are in blast transformation of chronic myeloid leukaemia (CML) * They have a concurrent active malignancy excluding basal cell carcinoma * They are pregnant or lactating * They have Acute Promyelocytic Leukaemia * Known infection with human immunodeficiency virus (HIV) * Patients with prior cumulative anthracycline exposure (from prior treatment of a non AML cancer) of greater than 300 mg/m2 daunorubicin (or equivalent). * History of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (CVA/TIA) within 3 months before entry Specific exclusion criteria for the Mylotarg Arm * Pre-existing liver impairment with known cirrhosis * Total bilirubin \> 1.5 x the upper limit of normal (ULN) * Aspartate aminotransferase (AST) \> 2.5 x ULN * Alanine aminotransferase (ALT) \> 2.5 x ULN Specific exclusion criteria for the Vosaroxin/Decitabine Entry * Total bilirubin \> 1.5 x the upper limit of normal (ULN), * Aspartate aminotransferase (AST) \> 2.5 x ULN * Alanine aminotransferase (ALT) \> 2.5 x ULN * Left ventricular ejection fraction (LVEF) \< 40% by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)\] Specific exclusion criteria for CPX-351 treatment * Hypersensitivity to cytarabine, daunorubicin or liposomal products * History of Wilson's disease or other copper-metabolism disorder Specific exclusion criteria for Cladribine • Patient's serum creatinine must be within the local ULN to enter the randomisation. Patients for whom this is not the case can be randomised between the remaining options. In addition patients are not eligible for the AC220 randomisation if they have: Cardiovascular System Exclusion Criteria: Known serious cardiac illness or medical conditions, including but not limited to: I. Clinically unstable cardiac disease, including unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, active myocardial ischemia, or indwelling temporary pacemaker II. Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a Class Ia antiarrhythmic drug (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of other antiarrhythmic drugs is permitted. III. Use of medications that have been linked to the occurrence of torsades de pointes (see Appendix for the list of such medications) IV. Second- or third-degree atrioventricular (AV) block unless treated with a permanent pacemaker V. Complete left bundle branch block (LBBB) VI. History of long QT Syndrome or a family member with this condition VII. Serum potassium, magnesium, and calcium levels not outside the laboratory's reference range VIII. QTc \>450 ms (average of triplicate ECG recordings); a consistent method of QTc calculation must be used for each patient's QTc measurements. QTcF (Fridericia's formula) is preferred. Please see the trial website for QTcF calculator.