complex cytogenetics, which carries a worse prognosis than de novo AML. Pharmacology Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function oxidase enzymes (cytochrome P450 system) in the liver to active metabolites. The main active metabolite is 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is then oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxycyclophosphamide. A small proportion of aldophosphamide freely diffuses into cells, where it is decomposed into two compounds, phosphoramide mustard and acrolein. The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, are assumed to cross the placenta and are known to be present in breast milk. It is specifically in the oxazaphosphorine group of medications. Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction. Drugs altering hepatic microsomal enzyme activity (e.g., alcohol, barbiturates, rifampicin, or phenytoin) may result in accelerated metabolism of cyclophosphamide into its active metabolites, increasing both pharmacologic and toxic effects of the drug; alternatively, drugs that inhibit hepatic microsomal enzymes (e.g. corticosteroids, tricyclic antidepressants, or allopurinol) result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects. Cyclophosphamide reduces plasma pseudocholinesterase activity and may result in prolonged neuromuscular blockade when administered concurrently with succinylcholine. Tricyclic antidepressants and other anticholinergic agents can result in delayed bladder emptying and prolonged bladder exposure to acrolein. Mechanism of action The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis. Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting aldophosphamide to carboxycyclophosphamide that does not give rise to the toxic metabolites phosphoramide mustard and acrolein. This is because carboxycyclophosphamide cannot undergo β-elimination (the carboxylate acts as an electron-donating group, nullifying the potential for transformation), preventing nitrogen mustard activation and subsequent alkylation. Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include: Elimination of T regulatory cells (CD4+CD25+ T cells) in naive