A Trial to Establish the Feasibility of Combining Either the Tyrosine Kinase Inhibitor AC220,CXCR4 Inhibitor Plerixafor or HSP90 Inhibitor Ganetespib With Chemotherapy in Older Patients With Acute Myeloid Leukaemia and High Risk Myelodysplastic Syndrome. (AML18 Pilot)

Inclusion Criteria:

• They have one of the forms of acute myeloid leukaemia, except Acute Promyelocytic Leukaemia or CML in blast crisis 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).
• Serum creatinine ≤ 1.5 × ULN (upper limit of normal)
• White cell count of <30 x 109/L at diagnosis (for Plerixafor option only). If WCC is >30 x 109/l patients in the Plerixafor pilot should have the WCC reduced to <30 x 109/L using Hydroxycarbamide to avoid the risk of hyperleucocytosis
• Serum potassium, magnesium, and calcium levels should be at least within institutional normal limits, and every effort should be made to keep potassium at institutional normal limits, and every effort should be made to keep potassium concentrations above 4.0 mEq/dL, and serum calcium at normal concentration.
• Total serum bilirubin ≤ 1.5 × ULN (upper limit of normal) and serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤ 2.5 × ULN
• 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).
• Over 60 years of age
• Provided written informed consent

Exclusion Criteria:

• 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 are not eligible for the AC220 option if they have:

• Uncontrolled or significant cardiovascular disease, including :
• A myocardial infarction within 12 months
• Uncontrolled angina within 6 months
• Current or history of congestive heart failure New York Heart Association (NYHA) class 3 or 4, unless an echocardiogram (ECHO) or Multiple Gated Acquisition Scan (MUGA) performed either within 1 month prior to study screening or during screening results in a left ventricular ejection fraction (LVEF) that is ≥ 45% (or institutional lower limit of normal value).
• Diagnosed or suspected congenital long QT syndrome. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes [TdP]); any history of arrhythmia will be discussed with the Sponsor's Medical Monitor prior to patient's entry into the study.
• Prolonged QTcF interval on pre-entry ECG (≥450 ms) - this will be the average of 3 readings within a 2 hour period.
• Any history of second or third degree heart block (may be eligible if the patient currently has a pacemaker).
• Heart rate < 50/minute on pre-entry ECG
• Uncontrolled hypertension
• Obligate need for a cardiac pacemaker
• Complete left bundle branch block
• Atrial fibrillation