Acute Myeloid Leukemia (AML) Subtypes and Prognostic Factors

For most types of cancer, determining the stage (extent) of the cancer is very important. The stage is based on the size of the main tumor and how far the cancer has spread. This can be helpful in predicting a person’s outlook and deciding on treatment.

Acute myeloid leukemia (AML), on the other hand, does not usually form tumors. It generally is widespread throughout the bone marrow and bloodstream. In some cases, it has spread to other organs, such as the liver and spleen, as well.

 

Knowing the AML subtype can be very important, as it sometimes affects both a person’s outlook and choosing the best treatment options for them. For example, the acute promyelocytic leukemia (APL) subtype of AML is often treated with drugs that are different from those used for other subtypes of AML. If you're not sure which subtype of AML you have, ask your doctor about it, and how it might affect your treatment.

Two main systems can be used to classify AML into subtypes:

• World Health Organization (WHO) classification
• International Consensus Classification (ICC)

These systems are alike in many ways, although there are some small differences. Either system can be used, but some doctors might prefer one over the other.

In both systems, the percentage of blasts (very immature blood cells) in the bone marrow or blood is important in diagnosing AML. If the AML cells have certain gene or chromosome changes (see below), usually at least 10% of the cells in the bone marrow or blood must be blasts. If there are no major gene or chromosome changes in the AML cells, usually at least 20% of the cells in the bone marrow or blood must be blasts to diagnose AML. The classification of AML has become more complex over time, as doctors have learned more about the genetic changes inside AML cells. If you have questions about your subtype of AML and what it might mean for you, ask your doctor to explain it to you in a way you understand.

World Health Organization (WHO) classification of AML

The World Health Organization (WHO) classification system is based mainly on if there are certain gene or chromosome changes inside the AML cells, and if not, what other features the AML cells have, including how mature they are.

The WHO system classifies AML into groups:

AML with defining genetic abnormalities (gene or chromosome changes)

• APL (acute promyelocytic leukemia) with PML-RARA fusion
• AML with RUNX1::RUNX1T1 fusion
• AML with CBFB::MYH11 fusion
• AML with DEK::NUP214 fusion
• AML with RBM15::MRTFA fusion
• AML with BCR::ABL1 fusion
• AML with KMT2A rearrangement
• AML with MECOM rearrangement
• AML with NUP98 rearrangement
• AML with NPM1 mutation
• AML with CEBPA mutation
• AML with myelodysplasia-related changes
• AML with other defined genetic alterations

AML defined by differentiation (how the AML cells have matured/differentiated)

• AML with minimal differentiation
• AML without maturation
• AML with maturation
• Acute basophilic leukemia
• Acute myelomonocytic leukemia
• Acute monocytic leukemia
• Acute erythroid leukemia
• Acute megakaryoblastic leukemia

Secondary myeloid neoplasm (AML that arises in someone who has received DNA-damaging chemotherapy or who has an inherited gene mutation)

International Consensus Classification (ICC)

The International Consensus Classification (ICC) can also be used to determine the AML subtype. Like the WHO classification, it’s based mainly on the gene or chromosome changes in the AML cells, but other factors can be important, too.

• Acute promyelocytic leukemia (APL) with t(15;17)(q24.1;q21.2)/PML::RARA
• APL with other RARA rearrangements
• AML with t(8;21)(q22;q22.1)/RUNX1::RUNX1T1
• AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11
• AML with t(9;11)(p21.3;q23.3)/MLLT3::KMT2A
• AML with other KMT2A rearrangements
• AML with t(6;9)(p22.3;q34.1)/DEK::NUP214
• AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2; MECOM(EVI1)
• AML with other MECOM rearrangements
• AML with other rare recurring translocations
• AML with t(9;22)(q34.1;q11.2)/BCR::ABL1
• AML with mutated NPM1
• AML with in-frame bZIP CEBPA mutations
• AML with mutated TP53
• AML with myelodysplasia-related gene mutations (defined by mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2)
• AML with myelodysplasia-related cytogenetic abnormalities (defined by a complex chromosome pattern in the AML cells)
• AML not otherwise specified (NOS)
• Myeloid sarcoma

Prognostic factors for AML

The subtype of AML can be important in helping to determine a person's prognosis (outlook). But other factors can also affect why some people with AML have a better outlook than others. These are called prognostic factors. Prognostic factors help doctors determine a person's risk of the leukemia coming back after treatment, and therefore if they should get more or less intensive treatment.

Chromosome (cytogenetic) changes

AML cells can have many kinds of chromosome changes, some of which can affect a person’s prognosis (outlook). Those listed below are some of the most common, but there are many others. Not all leukemias have these abnormalities. People whose AML cells don't have any of these usually have an outlook between favorable and unfavorable.

Favorable abnormalities:

• Translocation between chromosomes 8 and 21
• Translocation or inversion of chromosome 16
• Translocation between chromosomes 15 and 17

Unfavorable abnormalities:

• Deletion (loss) of part of chromosome 5 or 7
• Translocation or inversion of chromosome 3
• Translocation between chromosomes 6 and 9
• Translocation between chromosomes 8 and 16
• Translocation between chromosomes 9 and 22
• Abnormalities of chromosome 11 (at the band q23)
• Loss of a chromosome, so the cell has only 1 copy instead of the normal 2 (known as monosomy)
• Complex changes (those involving 3 or more chromosomes)

Gene mutations

People whose leukemia cells have certain gene mutations may have a better or worse outlook.

For instance, people with AML that has a mutation in the FLT3 gene tend to have a poorer outlook, although new drugs that target cells with this abnormal gene might lead to better outcomes. Mutations in the TP53, RUNX1, ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2 genes also tend to be linked with a worse outlook.

On the other hand, people whose leukemia cells have changes in the NPM1 gene (and no other abnormalities) seem to have a better prognosis than people without this change. Changes in both copies of the CEBPA gene are also linked to a better outcome.

Age

In general, people over 60 tend not to do as well as younger people. Some of this may be because they are more likely to have unfavorable chromosome abnormalities or gene mutations in their AML cells. They’re also more likely to have other health conditions that can make it harder for them to handle more intense treatment regimens.

White blood cell count

A high white blood cell count (>100,000/mm³) when diagnosed is linked to a worse outlook.

Prior blood disorder leading to AML

Having a blood disorder such as a myelodysplastic syndrome that led to AML is linked to a worse outlook.

Therapy-related AML (t-AML)

AML that develops after a person is treated for another cancer with chemotherapy or radiation therapy tends to have a worse outlook.

Infection

Having a systemic (blood) infection when you are diagnosed with AML is linked to a worse outlook.

Leukemia cells in the central nervous system

Leukemia that has spread to the area around the brain and spinal cord can be hard to treat, since most chemotherapy drugs can’t reach that area.

AML status after treatment

How well (and how quickly) the leukemia responds to treatment also affects long-term prognosis. Better and more rapid initial responses have been linked with better long-term outcomes.

A remission (complete remission) is usually defined as having no evidence of disease (NED) after treatment. This means the bone marrow has fewer than 5% blast cells, the blood cell counts are within normal limits, and there are no signs or symptoms from the leukemia.

A complete molecular remission means there is no evidence of leukemia cells in the bone marrow, even when using very sensitive tests, such as PCR (polymerase chain reaction) or next generation sequencing (NGS) assays.

Measurable residual disease (MRD), also known as minimal residual disease, means that after treatment, leukemia cells can’t be found in the bone marrow using standard tests (such as looking at cells under a microscope), but more sensitive tests (such as flow cytometry, PCR, or NGS tests) show that there are still leukemia cells in the bone marrow or blood.