Unlike many cancers that are diagnosed by stage (indicating how advanced the cancer is), acute myeloid (or myelogenous) leukemia (AML) is diagnosed based on genetic subtypes or specific genetic mutations; these help determine outlook and treatment.

Subtypes are classified (grouped) based on the genetic changes underlying an individual’s cancer. Recent advances in subtype classification have improved diagnostics, treatments, and survival rates over the past several years, providing a more hopeful outlook for a disease that has, historically, not always had a great prognosis.

This article discusses staging versus subtypes and how healthcare providers classify, diagnose, and treat different AML subtypes.

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.

Symptoms of AML

Symptoms of AML include:

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

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) classificationThe 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 healthcare provider 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 genesThe discovery of multiple driver mutations per patientComplex 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.

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:

  • AML with myelodysplasia-related changesAML related to previous chemotherapy or radiationMyeloid sarcoma (also known as granulocytic sarcoma or chloroma)Myeloid proliferations related to Down syndromeAML with chromosomal translocations and inversionsAML not otherwise specifiedUndifferentiated and biphenotypic acute leukemias

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

AML With Chromosomal Translocations and Inversions

In chromosomal translocations, 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.

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 markersAML with lymphoid markersMixed 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-spliceosomeTP53-aneuploidyIDH2R172

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

  • 1,236 people with driver mutations could each be classified into a single subgroup56 patients met the criteria for two or more subgroups166 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.

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:

Prognostic vs. Diagnostic

The NEJM researchers called for two separate classification systems:

  • Potential new early diagnostic methods for certain subtypesPotential new ways to identify people likely to be drug-resistantPotential 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

Healthcare providers 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 bruisingBleedingInfectionAbnormalities in your eyes, mouth, liver, spleen, or lymph nodes

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

  • Complete blood count (CBC)
  • Bone marrow aspiration
  • Bone marrow biopsy
  • Lumbar puncture
  • Imaging tests (e.g., X-ray, CT scan, MRI)
  • Cytogenetics

Cytogenetics and molecular testing 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.

  • Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221. doi:10.1056/NEJMoa1516192

  • American Cancer Society. Acute myeloid leukemia (AML) subtypes and prognostic factors.

  • Chen S, Chen Y, Lu J, et al. Bioinformatics analysis identifies key genes and pathways in acute myeloid leukemia associated with DNMT3A mutation. Biomed Res Int. 2020;2020:9321630. Published 2020 Nov 23. doi:10.1155/2020/9321630

  • Estruch M, Reckzeh K, Vittori C, et al. Targeted inhibition of cooperative mutation- and therapy-induced AKT activation in AML effectively enhances response to chemotherapy [published online ahead of print, 2020 Dec 9]. Leukemia. 2020;10.1038/s41375-020-01094-0. doi:10.1038/s41375-020-01094-0

  • Jeon JY, Buelow DR, Garrison DA, et al. TP-0903 is active in models of drug-resistant acute myeloid leukemia. JCI Insight. 2020;5(23):e140169. doi:10.1172/jci.insight.140169

  • American Society of Clinical Oncology: Cancer.net. Leukemia - Acute myeloid - AML: Diagnosis.

  • Watts J, Nimer S. Recent advances in the understanding and treatment of acute myeloid leukemia. F1000Res. 2018;7:F1000 Faculty Rev-1196. doi:10.12688/f1000research.14116.1

  • Canaani J, Beohou E, Labopin M, et al. Impact of FAB classification on predicting outcome in acute myeloid leukemia, not otherwise specified, patients undergoing allogeneic stem cell transplantation in CR1: An analysis of 1690 patients from the acute leukemia working party of EBMT. Am J Hematol. 2017;92(4):344-350. doi:10.1002/ajh.24640

By Tom Iarocci, MD

Tom Iarocci, MD, is a medical writer with clinical and research experience in hematology and oncology.

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