Acute Myeloid Leukemia (AML) is a fast-growing cancer of the blood and bone marrow, where the body’s myeloid stem cells fail to mature into healthy white blood cells, red blood cells, and platelets. The disease involves the rapid production of abnormal, immature white blood cells called myeloblasts, which accumulate in the bone marrow and crowd out the normal blood-forming cells. This uncontrolled proliferation leads to a deficiency in healthy blood cells, resulting in symptoms like fatigue, bleeding, and increased infection risk. Understanding the risk factors for AML requires distinguishing between two concepts. Etiological risk factors are external or pre-existing conditions that increase an individual’s likelihood of acquiring AML. Prognostic risk factors are molecular and cellular characteristics used by physicians to determine the disease’s aggressiveness and the best course of therapy.
Factors That Increase Susceptibility to AML
The likelihood of an individual developing AML is primarily influenced by advancing age, which is the single most significant etiological risk factor. The median age at diagnosis is approximately 68, with the incidence rising steeply after the age of 60. This age-related increase is thought to be linked to the accumulation of somatic mutations in blood stem cells over a lifetime.
Environmental and occupational exposures also contribute to etiological risk. Chronic exposure to benzene, an organic solvent found in gasoline and industrial products, is a well-established risk factor for AML. Similarly, high-dose ionizing radiation exposure, such as that experienced by atomic bomb survivors or following certain industrial accidents, significantly increases the risk.
A distinct category of risk is therapy-related AML (t-AML), which arises as a complication of previous cancer treatments. This secondary leukemia typically develops several years after a patient receives chemotherapy or radiation therapy for an unrelated cancer.
A smaller proportion of cases are linked to inherited genetic syndromes that predispose individuals to bone marrow failure or a higher cancer risk. Conditions like Down syndrome, Fanconi anemia, and Bloom syndrome are examples of constitutional disorders associated with an elevated lifetime risk of AML. These syndromes involve defects in DNA repair or chromosome stability.
Pre-Leukemic Conditions That Increase Risk
For many patients, AML does not arise spontaneously but evolves from a pre-existing hematologic disorder, creating a high-risk state that requires close observation. Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms (MPNs) are the two primary groups of conditions that frequently transform into secondary AML. These are collectively known as myeloid neoplasms, characterized by abnormal production and maturation of blood cells.
Myelodysplastic Syndromes (MDS)
MDS are clonal disorders of hematopoietic stem cells marked by ineffective blood cell production and a risk of transformation to AML. The rate of transformation varies widely depending on the specific subtype and the patient’s risk score, but approximately 30% to 40% of all MDS cases will progress to AML. This progression is typically driven by the acquisition of new, high-risk genetic mutations, such as those affecting the RUNX1 or TP53 genes, which accelerate the disease process.
Myeloproliferative Neoplasms (MPNs)
MPNs, including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), also carry a risk of transformation to AML. The risk is highest in PMF, with up to 20% of patients progressing to AML. PV and ET have lower, yet still significant, 10-year transformation rates of approximately 5% to 10% and 2% to 5%, respectively. Chronic Myelomonocytic Leukemia (CMML) is a hybrid disorder that shares features of both MDS and MPN, and it also carries a significant risk of progression to AML.
How AML Risk is Assessed After Diagnosis
Once AML is diagnosed, the focus shifts to prognostic risk stratification, which guides treatment intensity and determines the likelihood of cure. The most widely accepted system for this assessment is the European LeukemiaNet (ELN) classification, which organizes patients into Favorable, Intermediate, and Adverse risk groups based on the genetic lesions found in the leukemic cells. This genetic analysis involves both cytogenetics, which examines large-scale chromosomal abnormalities, and molecular testing, which searches for specific gene mutations.
Favorable Risk Factors
The Favorable risk group is defined by the presence of specific chromosomal translocations, such as t(8;21) or inv(16), or mutations in genes like NPM1 or CEBPA. These genetic markers typically predict a higher chance of achieving long-term remission with standard chemotherapy alone.
Adverse Risk Factors
Patients in the Adverse risk category have a much poorer prognosis and often require more intensive treatment, such as allogeneic stem cell transplantation. Adverse risk is conferred by a complex karyotype (multiple chromosomal abnormalities), the loss of all or part of chromosomes 5 or 7, or mutations in genes like TP53 or RUNX1.
The Intermediate risk group includes all genetic abnormalities that do not fall into the other two categories, such as AML with an isolated FLT3-ITD mutation or a normal karyotype without the favorable mutations. Molecular testing is also crucial for treatment selection, as the presence of certain mutations can make a patient eligible for specific targeted inhibitors.
Clinical Monitoring for High-Risk Groups
Individuals who are identified as high-risk, either due to a genetic predisposition or a pre-leukemic condition like MDS, require a personalized and rigorous surveillance protocol. The goal of this monitoring is to detect the transformation to overt AML at its earliest stage, which significantly improves the chances of successful treatment.
This surveillance typically begins with frequent Complete Blood Counts (CBC) with differential, which track any changes in the number of healthy white cells, red cells, and platelets. For patients with higher-risk MDS, active monitoring often involves a bone marrow aspiration and biopsy performed at periodic intervals, which can range from every few months to annually, depending on the patient’s stability and risk score. This invasive procedure allows clinicians to microscopically check for morphologic changes, such as an increase in the percentage of immature blasts.
The cut-off for AML diagnosis is a blast count of 20% or more in the bone marrow or blood, but intervention may be considered before this threshold is reached. Genetic surveillance is increasingly incorporated into monitoring protocols, especially for patients with known predisposing germline mutations or high-risk MDS. This involves using deep sequencing techniques on peripheral blood or bone marrow samples to identify the acquisition of new somatic mutations or the evolution of existing mutations. Detecting these molecular events before a morphological change occurs allows physicians to initiate preemptive therapy or prepare for a stem cell transplant.