Pathophysiology

AML is a complex hematological malignancy characterized by the abnormal proliferation and differentiation of myeloid precursors in the bone marrow. It originates from a transformed hematopoietic stem cell (HSC) that undergoes clonal proliferation. This process begins with the acquisition of initiating leukemic mutations in early HSCs, leading to alterations in self-renewal capabilities. As these mutant HSCs accumulate additional mutations over time, they may develop into leukemia stem cells (LSCs) with the potential to transform into leukemia.¹

A crucial precursor to AML development is clonal hematopoiesis of indeterminate potential (CHIP). In this phenomenon, recurrent AML-related mutations accumulate within hematopoietic progenitor cells as individuals age, leading to clonal growth without immediate leukemia development (Figure 1). The progression from CHIP to AML is estimated at 0.5%–1% per year.¹

The genomic landscape of AML is highly complex, with an average of 13 mutations per case. Key genetic alterations include¹:

• Transcription factor fusions (18% of cases)
• Nucleophosmin (NPM1) mutations (27%)
• DNA-methylation-related gene mutations (44%)
• Signaling pathway mutations (59%)
• Chromatin-modifying gene mutations (30%)

The stem cell niche plays a crucial role in the transformation from clonal populations to AML. Factors contributing to a permissive microenvironment include aberrant cell adhesion, immunosuppression, changes in cytokine signaling, age-dependent vascular development, interactions with mesenchymal stromal cells, osteoblasts, and osteoclasts.¹

Inflammation has been implicated in AML development, with several key observations¹:

• CHIP with TET2 mutations is associated with increased interleukin-8 levels
• Chronic inflammation is linked to aging
• The VEXAS syndrome, characterized by UBA1 mutations, shows increased rates of myelodysplastic syndrome (MDS) and CHIP

The pathophysiological processes in AML ultimately result in ineffective erythropoiesis, impaired megakaryopoiesis, and bone marrow failure.² Based on genetic and cytogenetic abnormalities, AML can be categorized into 3 risk groups²:

Epidemiology

AML is a relatively rare but serious form of cancer that affects the blood and bone marrow.³

In 2024, it is estimated that³:

• About 20,800 new cases of AML will be diagnosed in the United States.
• Approximately 11,220 deaths will occur due to AML.

AML accounts for about 1% of all cancers and roughly one-third of all leukemias in adults.³

Demographics⁴

Age: AML primarily affects older adults, with the median age at diagnosis being 69 years. The disease is uncommon in people under 45 years old.

Sex: AML is slightly more common in men than women.

Race/Ethnicity: Incidence rates per 100,000 persons vary by race and ethnicity:

Risk and Survival⁴

The average lifetime risk of developing AML is about 0.5% for both men and women.

The 5-year relative survival rate for AML is 31.9%, based on data from 2014–2020. This rate has been steadily improving over the past few decades.

Trends⁴

• The rate of new AML cases has remained relatively stable over the past decade.
• Death rates have been declining slightly, with an average decrease of 0.8% per year from 2013 to 2022.

Risk Factors

AML can develop due to genetic mutations, prior diseases, environmental exposures, and therapy-related factors. Below are key risk factors associated with the development of AML¹:

1. Prior Disease: Myelodysplastic Syndromes and Bone Marrow Failure. AML, myelodysplasia-related (AML-MR) often evolves from pre-existing myeloid malignancies like MDS. AML-MR is characterized by mutations in specific genes and multilineage dysplasia. This form of AML is more common in older adults and is linked to clonal hematopoiesis and accumulated DNA damage over time. Patients with mutations in genes like SRSF2, SF3B1, and ASXL1 are highly likely to develop secondary AML (s-AML), which typically shows resistance to standard chemotherapy, requiring alternative treatment strategies like CPX-351.
2. Environmental Factors: Environmental exposures such as smoking, benzene, and dioxins have been linked to an increased risk of AML. Smoking is one of the strongest risk factors, leading to worse overall survival rates in AML patients. Additionally, exposure to chemicals like benzene and dioxins can cause genomic abnormalities, including chromosome deletions and DNA methylation alterations, which can increase AML risk.
3. Therapy-Related Myeloid Neoplasms (t-MN): Patients who have undergone chemotherapy or radiation therapy for other cancers, such as breast cancer, lymphoma, or multiple myeloma, are at risk of developing t-MN. t-MN typically arises 5–7 years after treatment and is associated with high-risk genetic features like complex karyotypes or TP53 mutations. These patients often face poorer outcomes due to increased resistance to chemotherapy and the presence of multiple mutations. Certain cancer therapies, such as topoisomerase II inhibitors, are linked to specific translocations like KMT2A and RUNX1, leading to a more rapid onset of AML but often a better response to treatment.
4. Germline and Genetic Predispositions: A significant subset of t-MN cases is linked to germline mutations in cancer predisposition genes. Patients with prior cancers such as breast cancer or lymphoproliferative disorders may have inherited mutations that increase their risk of developing AML.

These risk factors highlight the complexity of AML development, emphasizing the influence of prior conditions, environmental exposures, and cancer treatments in increasing an individual’s likelihood of developing AML. As molecular characterization of AML advances, understanding these risk factors will help tailor prevention and treatment strategies.

References

1. Wachter F, Pikman Y. Pathophysiology of acute myeloid leukemia. Acta Haematol. 2024;147(2):229-246. doi:10.1159/000536152
2. Vakiti A, Reynolds SB, Mewawalla P. Acute myeloid leukemia. In: StatPearls. StatPearls Publishing; 2024. Accessed September 30, 2024. http://www.ncbi.nlm.nih.gov/books/NBK507875/
3. Key statistics for acute myeloid leukemia (AML). American Cancer Society. Updated June 5, 2024. Accessed September 30, 2024. https://www.cancer.org/cancer/types/acute-myeloid-leukemia/about/key-statistics.html
4. Cancer stat facts: Leukemia — acute myeloid leukemia (AML). Surveillance, Epidemiology, and End Results Program (SEER). Accessed September 30, 2024. https://seer.cancer.gov/statfacts/html/amyl.html