Epidemiology And Risk Factors

Acute myelocytic leukemia (AML) is a clonal expansion of any one of several nonlymphoid hematopoietic progenitors that retain the capacity of self-renewal, but are severely limited in their ability to differentiate into functional mature cells. These various progenitors include cells of granulocytic, monocyte/macrophage, erythroid, and megakaryocytic lineage.

Leukemia is not a common malignancy relative to many other forms of cancer, comprising 3% of all new cancers in males and less than 2% in females. Deaths from leukemia comprised 4.3% of all cancer deaths in males in 2006 and 3.3% in females. In 2006, it was estimated there were 11,930 new cases of AML, representing 34% of all forms of leukemia. An estimated 9040 deaths due to AML occurred in 2006—40.6% of deaths from all leukemias. Both the incidence and the number of deaths are slightly greater in males versus females.1 Surveillance, epidemiology, and end-results (SEER) data over a 25-year period from 1973 to 1998 show that the incidence rates by age groups have been stable, other than a slight increase in the age group above or equal to 65 years old.2 As per the SEER data (1996-2000), 86% of acute leukemia in adults (>20 years old) is AML.

Although there are several well-recognized risk factors for the development of AML, little is known about the etiology of most cases. Like most malignancies, there is no recognized factor common to most cases of AML. While there is little reason to assume that adult and childhood leukemia do not have a common etiology, differences in tumor biology and outcomes suggest that these disorders are significantly different. Proven or possible risk factors for AML can be categorized as genetic, environmental, and therapy-related. At this time, the proven risk factors include only radiation, benzene exposure, and chemotherapeutic agents.3-9

Studies of leukemia in identical twins have shed considerable light on the pathogenesis of this disease. While concordance rates for monochorionic, monozy-gotic twin childhood leukemia is less than 25%, concordance in infants (< 1-year old) is nearly 100%.10-15 This implies that events occurring in utero are sufficient for the rapid development of acute leukemia and that clonal progeny spread from the initially affected fetus to the other fetus via shared placental circulation. Yet, in older twin children the discordance rate is 90%, indicating the prenatal event is insufficient for leuke-mogenesis and a second postnatal event is required, probably involving genes regulating a proliferation or survival function. In adult twins there is no evidence of concordance.16

Familial acute leukemia outside of a recognized medical syndrome is rare, but there are documented familial clusters of specific subtypes of AML.1718 There are also a number of medical syndromes in which AML is a component feature, including Down syndrome, Bloom syndrome, Fanconi anemia, neurofibromatosis I, ataxia-telangiectasia, Schwachman syndrome, and dyskaratosis congenita.19-25 Many of these disorders have been associated with both AML and acute lym-phocytic leukemia (Table 1.1).

Table 1.1 Conditions associated with an increased incidence of AML

Genetic

Identical twin with leukemia Familial leukemia Down syndrome Bloom syndrome Fanconi anemia Neurofibromatosis I Schwachman syndrome Dyskrytosis congenital Ataxia-telangiectasia Acquired hematologic diseases Chronic myelocytic leukemia Myelofibrosis

Essential thrombocythemia Polycythemia rubra vera Aplastic anemia Paroxysmal noctural hemoglobinuria

The effects of acute high-dose exposure from the nuclear explosions at Hiroshima and Nagasaki as well as the nuclear accident at Chernobyl demonstrate the leukemogenic potential of ionizing radiation.326 Follow-up of the atomic bomb survivors through 1990 identified 249 leukemic deaths, with 53.7% attributable to radiation exposure. In this population, there is an excess relative risk of leukemia (ERR) per sievert of 4.62 compared with an ERR of 0.40 for other cancers.27 The risk appears to be greatest at 5-10 years after exposure.28 Evaluation of the specific types of leukemia in the life span study (LSS) of atomic bomb survivors showed the highest ERR for acute lymphocytic leukemia (Table 1.2), although those exposed to gamma irradiation at Nagasaki more commonly had AML.28'29 Leukemogenic risks for lower doses of ionizing radiation are less clear, and are complicated by the need to distinguish acute versus protracted low-dose exposure. Table 1.3 outlines the levels of exposure to radiation in routine daily activity compared to the episodes of more acute exposure. Among the cohort in the LSS study with exposure of 5-100 mSv (mean for entire study 200 mSv), there is a statistically significant increased incidence of solid organ cancer compared to the population exposed to less than 5 mSv.30 Chronic low-dose exposure studies in workers in nuclear plants have found an increased risk of leukemia, although these studies have some limitations and are not all statistically significant.31 A greater than expected risk of AML has been reported in the use of low doses of radiation for benign medical conditions, such as menor-rhagia, ankylosing spondylitis, rheumatoid arthritis, tinea capitis, and peptic ulcer disease.32-36 Exposure to the chronic low dose a-particles of thorium dioxide in Thorotrast has been associated with an increased incidence of the acute erythroleukemia subtype of AML.37 However, there is no evidence that diagnostic X-rays are causally related to leukemia.38 39 The contribution of nonionizing radiation to the development of leukemia is unclear, as there have been conflicting results and criticism of the methodologies in some studies. At this time, there is no evidence of a major contribution of either occupational or residential electromagnetic field exposure resulting in an increased incidence of leukemia.40-42 Cosmic radiation exposure has been shown to increase slightly the risk of AML in commercial jet pilots.4344

Among environmental factors associated with an increased risk of leukemia, benzene has been studied extensively. Occupational benzene exposure in the leather, petrochemical, rubber, and printing industries has been linked to an excess incidence of leukemia.8 45 46 Ethylene oxide, butadiene, and styrene are industrial chemicals that have been associated with leukemia, but studies have been somewhat inconsistent or inconclusive in establishing a direct link.47-51 Pesticide use has been suggested as a possible explanation for the increased risk of dying from leukemia among farmers and other agricultural workers.52 However, other case-control and cohort studies have

Environmental Radiation Ionizing Nonionizing Chemicals Benzene Pesticides Smoking

Therapy related Alkylating agents Topoisomerase II Inhibitors DNA intercalating agents

Table 1.2 Leukemia incidence by cell type and corresponding model-based risk estimates for LSS cohort or atomic bomb survivors

Excess absolute risk

Leukemia Number Excess relative Attributable (cases per 104 person subtype of cases risk per Sv risk (%) years at 1 Sv)

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