Genetic alterations in acute myeloid leukemia: Key facts to understand
Acute Myeloid Leukemia (AML) is a type of cancer that affects the bone marrow, causing an overproduction of immature white blood cells. Understanding the role of certain gene mutations in AML can help guide treatment decisions and predict prognosis.
Key Gene Mutations in AML
Specific gene mutations significantly impact the risk, treatment response, and prognosis of AML. These include FLT3, NPM1, CEBPA, RUNX1, ASXL3, and TP53.
- FLT3 mutations, particularly the FLT3-ITD variant, are associated with increased risk of rapid disease progression and higher relapse rates, leading to poorer overall prognosis. Their allelic ratio (AR) and co-occurrence with mutations like NPM1 and DNMT3A worsen outcomes and influence treatment with FLT3 inhibitors.
- NPM1 mutations often co-occur with FLT3-ITD but tend to have a more favorable prognosis if FLT3-ITD is absent or has a low AR. However, when NPM1 mutations coexist with FLT3-ITD and DNMT3A mutations, patients face a significantly worse prognosis with shorter overall survival and disease-free survival.
- CEBPA mutations, particularly double mutations, are generally considered prognostically favorable in non-M3 AML, suggesting a better response to treatment and survival. Variants in the CEBPA 3′UTR region continue to be explored for their clinical relevance.
- RUNX1 mutations are typically associated with adverse prognosis in AML, indicating poor risk and often resistance to conventional chemotherapy, although specific treatment implications are evolving as targeted therapies develop.
- ASXL3 mutations are less commonly characterized but belong to the epigenetic regulator family. Mutations in ASXL genes generally are linked to poor prognosis and may affect treatment response through epigenetic dysregulation.
- TP53 mutations are strongly associated with high-risk AML, poor response to standard treatments, resistance to chemotherapy, and very poor overall survival. TP53-mutated AML often requires alternative therapeutic strategies including stem cell transplantation or novel agents.
AML Treatment and Prognosis Factors
AML treatment typically consists of two phases: remission induction and consolidation. During the remission induction phase, a person receives drugs to destroy as many leukemia cells as possible to reach AML remission. In the consolidation phase, the goal is to destroy any remaining cancer cells and prevent relapse. Consolidation therapy might consist of multiple chemotherapy cycles with cytarabine, allogeneic stem cell transplant, or any combination of the above.
When determining the best AML consolidation treatment, doctors consider factors such as remission time, donor stem cell availability, prognostic factors, age, and health. Older individuals or those with other health issues may not be able to tolerate some intensive therapies. In such cases, doctors may recommend different levels of cytarabine, standard levels of cytarabine with other chemotherapy drugs, or lower doses of chemotherapy for a stem cell transplant.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can improve outcomes across mutation profiles but may show less benefit in triple-mutated cases involving FLT3-ITD, NPM1, and DNMT3A mutations. Targeted therapies, such as FLT3 inhibitors, are tailored depending on mutation status and allelic burden, with early detection of minor clones being important for relapse prevention.
Other factors that influence prognosis include AML subtype, chromosome abnormalities, other conditions, leukemia cells in the nervous system, and the presence of another blood condition, blood infection, or history of cancer at the time of diagnosis.
Understanding a person's AML type can help doctors determine the best treatment plan and potentially affect the person's outlook. Approximately half of AML patients older than 60 go into remission after standard induction chemotherapy. The 5-year survival rate during 2012-2018 was around one-third.
AML is classified using the French-American-British (FAB) and World Health Organization (WHO) systems, which divide AML into different subtypes based on factors such as the type of cell from which the leukemia develops and the cell maturity, as well as other factors that may affect the outlook. Mixed-phenotype acute leukemias, also known as undifferentiated and biphenotypic acute leukemias, are not strictly AML but share some similar features.
People with CD33-positive AML may receive gemtuzumab ozogamicin (Mylotarg) intravenously to deliver chemotherapy directly to the CD33 protein.
In summary, these gene mutations stratify AML patients into distinct prognostic categories and guide the choice and intensity of treatments, with combinational mutational status critical in predicting disease course and survival.
- Specific gene mutations, such as FLT3, NPM1, CEBPA, RUNX1, ASXL3, and TP53, significantly impact the risk, treatment response, and prognosis of Acute Myeloid Leukemia (AML).
- FLT3 mutations, specifically the ITD variant, are associated with a higher risk of rapid disease progression, higher relapse rates, and poorer overall prognosis.
- NPM1 mutations, when they coexist with FLT3-ITD and DNMT3A mutations, lead to a significantly worse prognosis with shorter overall and disease-free survival.
- CEBPA mutations, particularly double mutations, are generally considered prognostically favorable in non-M3 AML, suggesting a better response to treatment and survival.
- RUNX1 mutations are typically associated with adverse prognosis in AML, indicating poor risk and often resistance to conventional chemotherapy.
- ASXL3 mutations, belonging to the epigenetic regulator family, are linked to poor prognosis and may affect treatment response through epigenetic dysregulation. TP53 mutations are strongly associated with high-risk AML, poor response to standard treatments, resistance to chemotherapy, and very poor overall survival.
