Acute Myelogenous Leukaemia

Acute myelogenous leukaemia is the result of a malignant transformation of a single stem or primitive multipotential marrow haematopoietic cell, converting it to a leukaemic stem cell. The transformation process involves the acquisition of driver and cooperating mutations in relevant proto-oncogenes. The neoplastic transformation imparts a growth and survival advantage to the cell clone that emerges. Leukaemic cells fill the haematopoietic cords of marrow. The functional result of this alteration is to impair normal blood cell production in the marrow, leading to a profound decrease in normal red cells (anaemia), white cells (leukopaenia) and platelets or thrombocytes (thrombocytopaenia) in the blood. The disease is rapidly progressive, unless treated promptly. Therapy usually consists of at least two drugs, cytosine arabinoside and an anthracycline antibiotic (e.g. daunorubicin), except in the case of acute promyelocytic leukaemia for which all-trans-retinoic acid and, often, arsenic trioxide are used. The response of the disease to treatment is dependent on several factors but the two most compelling are the age of the patient at diagnosis and the cytogenetic and genetic features of the cells; older age and unfavourable chromosomal karyotypes or gene mutations decrease the proportion of long-term remissions or cures. Key Concepts Cancer of any type is the result of a series of gene mutations in a single tissue cell. Acute myelogenous leukaemia, like all cancers, originates in a single tissue cell, in this case a primitive haematopoietic cell. The risk of acute myelogenous leukaemia can be increased by the inheritance of predisposition genes that are unapparent (non-syndromic familial cases) or apparent as manifest by syndromic cases, such as Fanconi anaemia or familial platelet syndrome. Leukaemic cells accumulate because they have a proliferative and survival advantage compared to normal cells. It is estimated that approximately 1 trillion leukaemic cells are present at diagnosis. Very small proportions of these cells are leukaemic stem cells, which sustain leukaemic haematopoiesis. Acute myelogenous leukaemia stem cells have multipotential haematopoietic lineage potential. Thus, they can differentiate into leukaemic precursor cells of all haematopoietic lineages. The predominance of one or two leads to the phenotypic classification of acute myelogenous leukaemia (e.g. erythroid, monocytic, myelomonocytic or megakaryocytic leukaemia). The accumulation of leukaemic cells in the marrow suppresses normal blood cell development and may disrupt the normal stem cell niche. Chemotherapy is predicated on the coexistence of normal polyclonal haematopoietic stem cells and leukaemic stem cells in the marrow. Reduction of the leukaemic cell population by at least three logs by chemotherapy can, in many cases, result in the release of inhibition of normal stem cells and a return of normal haematopoiesis for a variable period of time (i.e. a remission). Development of effective consolidation or continuation therapy to reduce further the tumour population and to eliminate leukaemic stem cells is under intense study. Intensive therapy can be curative in younger patients and in those with favourable genetic abnormalities [e.g. t(15;17)]. Allogeneic haematopoietic stem cell transplantation can be curative. Keywords: acute leukaemia; anaemia; chemotherapy; cytogenetics; leukopaenia; marrow; mutation; myelodysplasia; stem cell transplantation; thrombocytopaenia