Acute myelogenous/myeloid leukemia (AML) is one of the malignant diseases of the bone marrow. In this disease, hematopoietic precursor cells become arrested in early stages of development. Typically, AML is distinguished from other blood disorders by the presence of greater than 20% blasts seen in the bone marrow. AML has many names including acute myelocytic leukemia, acute myelogenous leukemia, acute myeloid leukemia, acute granulocytic leukemia, and acute non-lymphocytic leukemia.
The immature myeloid progenitors (blasts) proliferate in the bone marrow and blood. These blast cells vary in size from slightly larger than lymphocytes to larger than monocytes. Rarely, these blasts can show features of both myeloid and lymphoid cells making it hard to classify their origin. In approximately 52% of patients with primary AML, non-random chromosomal abnormalities have been observed. Certain of these abnormalities carry prognostic capability. For example, the cytogenic abnormalities t(8;21)(q22;q22), t(15;17)(q22;q12) and inv(16)(p13.1;q22) are associated with longer remissions and survival. Alternations in chromosomes 5, 7, complex karyotype and 11q23 predict poor response to therapy and shorter survival.
In the US, AML is the most common acute leukemia seen in adults making up about 80% of these cases. The incidence ranges from 3 to 5 cases per 100,000 people. The incidence increases with age and reaches 12.2 cases per 100,000 in those over the age of 65 years. The prognosis for this age group remains poor with a 1-year survival rate of approximately 30%. In children, it comprises 15-20% of acute leukemia cases. Rarely, it can be present at birth. The American Cancer Society predicts that in 2017 there will be 62,130 new cases of leukemia of which 21,380 will be AML. Most of the cases of AML will occur in adults resulting in 10.590 deaths. AML is slightly more common in men than women. The average age of patients afflicted with AML is 67 years.
AML is a very heterogenous disease and many attempts have been made for a classification system. The first attempt at classification was tried in 1976 and was named the French-American-British classification system. In this system, eight subtypes were identified (M0 through M7) and these were based on the morphology and cyto-chemistry of the leukemic cells. In 2001, the WHO developed a new system which was revised in 2008 and then again in 2016. This classification system identifies 6 major disease types based on genetic factors, morphology, immunophenotype, and clinical presentation.
Six Major AML Disease Entities as Outlined by the WHO:
- AML with recurrent genetic abnormalities
- AML with myleodysplasia related features
- Therapy related AML
- AML, not otherwise specified
- Myeloid sarcoma
- Myeloid proliferation related to Down Syndrome
Among AML with recurrent genetic abnormalities there have been 11 subtypes identified speaking to the great variety of this disorder.
While there are clear genetic factors of AML, there are several established risk factors. Smoking, as well as with many other malignancies, is a well-established life-style risk factor of developing AML. Several chemical including benzene and formaldehyde have also been identified as risk factors. Chemotherapeutic medications, especially alkylating and platinum agents are also associated with an increased risk of AML, which tends to peak at 8 years post-treatment. Patients tend to get a myelodysplastic syndrome prior to developing AML with the use of these agents. Chemotherapeutic agents known as topoisomerase II inhibitors also increase the risk of AML but tend to do so within a few years after treatment without the myelodysplastic syndrome preceding the onset. Other risk factors include radiation, certain blood disorders, genetic syndromes, family history, older age and male gender.
Diagnosis of AML includes initial blood work including CBC with differential. A bone marrow analysis with cytogenetics is essential for risk stratification and treatment. Several molecular markers are important assessing risk and may be helpful in guiding treatment decisions. Of extramedullary presentation (which is rare) is suspected, a PET/CT scan may be helpful. A brain MRI with contrast should be performed in cases where leukemic meningitis is a possibility. Because coagulopathy is a common finding in many leukemias, tests for coagulopathy should be done, especially before any invasive procedures. In patients in whom allogeneic HCT might be considered, human leukocyte antigen (HLA) typing should also be performed.
Although there has been significant research done on AML in recent years, little has changed in the treatment over the past 4 decades. Unless a patient is participating in a clinical trial, typically the patient newly diagnosed with AML will be offered the combination of cytarabine with either daunorubicin or idarubicin (the 7 + 3 regimen). Those patients with favorable risk factors are then offered high dose cytarabine (HiDAC) wheras those with less favorable risk factors are offered allogeneic stem-cell transplant (SCT) in first remission. There are several new drugs with different mechanisms of action that look promising. These include cytotoxic agents, small-molecule inhibitors, and targeted therapies.
Many current trials are investigating prognosis and risk stratification based on cytogenetic properties as well as targeted therapies. There are several genetic defects that have been well-established as prognostic indicators. Fms-like tyrosine kinase 3 (FLT3) is one of the receptor tyrosine kinases that play a role in hematopoiesis and mutations are common in AML. This include 2 common mutations: an internal tandem duplication (ITD) in the juxtamembrane and a point mutation in the tyrosine kinase domain (TKD). Patients with AML a normal karyotype and the FLT3 ITD mutation tend to have a poorer prognosis. In these patients, allogeneic transplantation is advised but patients still tend to have a poorer prognosis.
In one study looking at Nucleophosmin-1 (NPM1) mutations, researchers evaluated patients who were previously untreated. They concluded that NPM1 markers were stable markers and did not fluctuate during the course of disease as much as FLT3 markers did. This held especially true during relapse. Increasingly, monitoring minimal residual disease (MRD) by detecting mutations is being incorporated. These researchers believe that NPM1 mutation markers would be an ideal target to monitor since they are present in 40-50% of patients with AMl. Additionally, it was concluded that those patients with this mutation tended to have a better prognosis.
CEBPA (CCAAT/enhacer binding protein-C/EBP alpha) plays a key role in the differentiation of myeloid cells from hematopoietic stem cells. Mutations in the C/EBPa gene have been found in 7-15% of patients with AML. These mutations are more common in AML patients with the M1, M2, and M4 FAB subtypes and a normal karyotype. Patients with this mutation tend to have a more favorable prognosis.
KIT (v-KIT Hardy-Zuckerman 4 Feline Sa12rcoma viral oncogene homolog) is another receptor tyrosine kinase that plays a role in cell differentiation, proliferation and survival. Mutations most commonly affect exons 8 or 17. It is present in 2-14% of patients with AML. In core-binding factor leukemia, its incidence is higher being present in 7-46% of patients. This mutation tends to lead to a worse prognosis.
Many other mutations are also currently being studied. Clearly, these findings are going to have a huge impact on how we risk stratify and treat AML in the future. While there has been no significant improvement in the prognosis of AML in decades, the future looks to herald a plethora of options.
About the Author
Linda Girgis MD, FAAFP is a family physician practicing in South River, New Jersey and Clinical Assistant Professor at Rutgers Robert Wood Johnson Medical School. She was voted one of the top 5 healthcare bloggers in 2016. Follow her on twitter @DrLindaMD.