What Are Acute Myelogenous Leukemia (AML) Subtypes?

Acute myeloid (or myelogenous) leukemia (AML) subtypes are becoming better understood, with new avenues of research being explored. AML varies greatly from one person to the next and the prognosis is often poor. This makes research that could help improve survival rates crucial.

New advances over the past several years are improving diagnostics, treatments, and survival rates, all of which provide a more hopeful outlook.

AML is a cancer of the blood and bone marrow (the spongy insides of bones where blood cells are made). It's "acute" because it progresses rapidly. "Myeloid" means it involves myeloid cells, which develop into various types of blood cells (e.g., red and white blood cells, platelets).

A Black female doctor examines a bruise on a woman's arm.

Albina Gavrilovic / Getty Images

Symptoms of AML include:

  •    Fever
  •    Bone pain
  •    Lethargy and fatigue
  •    Frequent infections
  •    Easy bruising
  •    Unusual bleeding

Subtypes vs. Staging

When most cancers are diagnosed, they're "staged." The stage tells you how advanced the cancer is, determines your prognosis, and can guide treatment decisions.

AML isn't staged. Instead, your outlook and treatment depend on your subtype, which is determined by lab tests.

Most AML subtypes are defined in part by how developed and abnormal cancer cells look under a microscope when the disease is first diagnosed. Additionally, AML classification is now being augmented by new discoveries about genetic changes or mutations that are involved.

Two AML classification systems are currently in use:

  • The French-American-British (FAB) classification
  • The World Health Organization (WHO) classification

Further classification by complex genetic subtypes is evolving, thanks to a groundbreaking study published in 2016.

Why Subtype Matters

Knowing the genetic make-up of your leukemia can help your doctor predict whether current treatments would be effective. This has already made more extensive genetic testing at the time of diagnosis routine.

Understanding subtypes can also help researchers design new clinical trials to develop the best treatments for each AML type.

Classifying AML Subtypes

The FAB classification system has been around since the 1970s, but the subtyping process has changed a couple of times in recent years. The WHO classification system became standard in 2008, grouping people based on genetic changes that underlie their cancer (called "driver mutations").

Then, in 2016, pivotal research came out in the New England Journal of Medicine (NEJM) that has taken subtyping even further.

This study demonstrated that the WHO molecular classifications don't work well for nearly half of AML cases—48% of study participants couldn't be classified based on the WHO molecular groups, even though 96% of them did have driver mutations.

Investigators have now begun reevaluating genomic classification of AML from the beginning, based on:

  • The discovery of many new leukemia genes
  • The discovery of multiple driver mutations per patient
  • Complex mutation patterns

FAB Classification of AML

More than 40 years ago, a group of French, American, and British leukemia experts divided AML into subtypes M0 through M7 based on the type of cell the leukemia develops from and how mature the cells are.

  • M0 through M5 all start in immature forms of white blood cells.
  • M6 starts in very immature forms of red blood cells.
  • M7 starts in immature forms of cells that make platelets.
SUBTYPE  SUBTYPE NAME % OF AML DIAGNOSES PROGNOSIS VS. AML AVERAGE
M0 Undifferentiated acute myeloblastic 5% Worse
M1  Acute myeloblastic with minimal maturation 15%  Average 
M2  Acute myeloblastic with maturation 25%  Better 
M3  Acute promyelocytic (APL) 10%  Best 
M4  Acute myelomonocytic 20%  Average 
M4 eos Acute myelomonocytic with eosinophilia 5% Better
M5  Acute monocytic 10% Average 
M6  Acute erythroid 5%  Worse 
M7  Acute megakaryoblastic 5%  Worse 
Source: Canaani et al.

WHO Classification of AML

The FAB classification system is still commonly used to group AML into subtypes; however, knowledge has advanced with respect to factors that influence prognosis and outlook for various types of AML.

Some of these advances were reflected in the 2008 World Health Organization (WHO) system, which divides AML into several groups:

  1. AML with myelodysplasia-related changes
  2. AML related to previous chemotherapy or radiation
  3. Myeloid sarcoma (also known as granulocytic sarcoma or chloroma)
  4. Myeloid proliferations related to Down syndrome
  5. AML with chromosomal translocations and inversions
  6. AML not otherwise specified
  7. Undifferentiated and biphenotypic acute leukemias

Groups 5, 6, and 7 are further broken down.

AML With Chromosomal Translocations and Inversions

In chromosomal translations, a portion of the genetic material breaks off of its original location and re-attaches itself to a different chromosome. In inversions, a segment comes out, flips upside down, and reattaches to its original chromosome.

At least seven types of AML include translocations, inversions, or similar genetic abnormalities.

AML Not Otherwise Specified

Cases of AML that don't fall into one of the above groups are classified similarly to the FAB system.

 FAB SUBTYPE WHO SUBTYPE NAME
M0 AML with minimal differentiation
M1  AML without maturation
M2  AML with maturation
M4  Acute myelomonocytic leukemia
M5  Acute monocytic leukemia
M6  Acute erythroid leukemia
M7  Acute megakaryoblastic leukemia
-- Acute basophilic leukemia
--  Acute panmyelosis with fibrosis

Undifferentiated and Biphenotypic Acute Leukemias

These are leukemias that have both lymphocytic and myeloid features. They're sometimes called:

  • Acute lymphocytic leukemia (ALL) with myeloid markers
  • AML with lymphoid markers
  • Mixed acute leukemias

New Classifications: The NEJM Study

The 2016 study that's prompted recent change included 1,540 people with AML. Researchers analyzed 111 genes known to cause leukemia, with the goal of identifying “genetic themes” behind the development of the disease.

They found that participants could be divided into at least 11 major groups, each with different clusters of genetic changes, and with different disease characteristics and features.

According to the study, most people had a unique combination of genetic changes driving their leukemia, which may help to explain why AML survival rates vary widely. Thus, the researchers worked to develop a new AML classification system using this emerging information.

They concluded that three subgroups exist that weren't accounted for in the WHO classification system. They're called:

  • Chromatin-spliceosome
  • TP53-aneuploidy
  • IDH2R172

Using the proposed system to classify the 1,540 study participants:

  • 1,236 people with driver mutations could each be classified into a single subgroup
  • 56 patients met the criteria for two or more subgroups
  • 166 people with driver mutations remained unclassified

The authors recommended that, in the short term, five specific genetic types (called TP53, SRSF2, ASXL1, DNMT3A, and IDH2) should be incorporated into prognostic guidelines because they're common and strongly influence outcomes.

Prognostic vs. Diagnostic

The NEJM researchers called for two separate classification systems:

  • One for use in diagnosing people
  • One for use in predicting outcomes (prognosis)

They say the diagnostic system should be based on fixed properties while the prognostic system should change regularly based on available treatments.

Newer Research

Based largely on the NEJM study, other researchers have investigated certain genetic profiles of AML. According to studies published in 2020, some researchers have identified:

  • Potential new early diagnostic methods for certain subtypes
  • Potential new ways to identify people likely to be drug-resistant
  • Potential new combinations of treatments for drug-resistant cases

One study identified a new drug that researchers say is effective against drug-resistant AML subtypes and, once it's in use, "will have an immediate clinical impact."

Diagnosing AML Subtypes

Doctors have a lot of tools for diagnosing AML and determining your subtype. Diagnosis starts with a physical exam. During your exam, they'll look for signs such as:

  • Extensive bruising
  • Bleeding
  • Infection
  • Abnormalities in your eyes, mouth, liver, spleen, or lymph nodes

To confirm a suspected AML diagnosis, they may order any combination of the following tests:

Cytogenetics is especially important for determining your subtype. It involves examining your cell's genetic material under a microscope to look for genetic abnormalities, such as translocations and inversions.

Subtypes and AML Treatment

A wealth of new AML drugs have been approved by the Food and Drug Administration in the past few years; however, those all were in development well before the 2016 research came out.

Now, based largely on that research, numerous potential treatments currently are being studied for AML based on specific genetic subtypes.

Several investigational drugs that target certain genetic mutations have begun the research process, and researchers are also looking at new types of chemotherapy medications, drug and antibody combinations, and drugs called kinase inhibitors.

Some of these drugs are already on the market for other conditions, while others are showing promising results in trials. For example:

  • Potential treatments for an AML mutation called TET2 may include drugs called PARP inhibitors or HMAs combined with vitamin C.
  • A group of enzymes called KATs may help treat AML with mutations in genes called EP300 and CBP.
  • Drugs called p300 activators are being investigated in animal models of AML.

Several other AML genetic subtypes are being examined so researchers can figure out what drugs may target them.

A Word From Verywell

Acute myeloid leukemia has always been a daunting diagnosis with a poor outlook.

However, with new drugs available, more on the way, and constant new discoveries about genetic subtypes, the prognosis is improving and likely will continue to do so.

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