Acute Myeloid Leukemia in Children: Understanding Your Pathology Report

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Acute myeloid leukemia is a cancer that starts in the bone marrow, the soft tissue inside bones where blood cells are made. Immature blood cells, called blasts, multiply quickly and fail to develop into functional red blood cells, white blood cells, and platelets. As blasts build up, the marrow can no longer make enough normal cells, leading to anemia, infections, and bleeding.

Acute myeloid leukemia accounts for roughly 15 to 20 percent of leukemia in children, and it is a different disease in children than it is in adults. The genetic changes differ, risk groups are defined differently, and outcomes are better. This article is written for parents and caregivers of a child with this diagnosis. Adults with acute myeloid leukemia should read our separate article, Acute myeloid leukemia in adults, because the numbers and treatments described there do not apply to children.

What causes acute myeloid leukemia in children?

Acute myeloid leukemia in children develops when genetic changes appear inside developing blood-forming cells in the bone marrow. These changes affect genes that normally control how blood cells grow and mature. In most children, the changes are acquired rather than inherited. They arise in that one group of cells rather than being present in every cell of the body from birth.

Many of the changes that drive childhood acute myeloid leukemia are fusions, formed when two genes join together. Studies of stored newborn blood spots show that some of these fusions are already present at birth, years before any symptoms appear. They arise during the rapid cell division of normal development, and they are not linked to diet, activity, infection, or anything in the home environment.

A minority of cases have an identifiable background. These include previous chemotherapy or radiation given for another cancer, an inherited condition affecting the bone marrow, and a preceding bone marrow failure disorder or myelodysplastic syndrome. Down syndrome carries its own distinct form of the disease, described in its own section below.

How is acute myeloid leukemia different in children and adults?

Acute myeloid leukemia in children and in adults share a name, a definition, and much of the diagnostic work. Beyond that, they diverge, which is why survival figures and treatment descriptions written for adults can be misleading for a child.

Different genetic changes. Children usually have a fusion gene driving the leukemia. The mutations that dominate adult disease, such as TP53, ASXL1, and DNMT3A, are uncommon in children, and several fusions seen in children are rarely found in adults.
A distinct Down syndrome-associated form. Myeloid leukemia associated with Down syndrome is essentially a disease of young children and has no adult counterpart.
A different risk system. Children are assigned to risk groups using criteria developed by the Children’s Oncology Group. The European LeukemiaNet system quoted in adult articles is not used.
No lower-intensity pathway. Adult treatment often turns on whether a person can tolerate intensive chemotherapy. Children receive intensive treatment, and the drug combinations used for older adults are not part of pediatric care.
The nervous system is checked. Leukemia cells reach the fluid around the brain and spinal cord more often in children, so doctors examine a sample of that fluid and deliver treatment into it.
Inherited predisposition matters more. Testing the DNA your child was born with is offered far more often than it would be for an adult.
Better outcomes. Roughly two-thirds of children are alive five years after diagnosis, compared with substantially fewer adults.

What are the symptoms of acute myeloid leukemia in children?

The symptoms of acute myeloid leukemia in children come from the shortage of normal blood cells, and they often develop over days to a few weeks. Many are mistaken at first for a viral illness, which is common and does not mean anything was missed.

Tiredness and pallor. From a low red blood cell count. A child may be short of breath with activity or unusually sleepy.
Bruising and bleeding. From a low platelet count. Bruises in unusual places, nosebleeds, bleeding gums, or pinpoint red spots on the skin.
Fevers and infections. From a shortage of working white blood cells. Infections that keep returning or take a long time to clear.
Bone or joint pain. From leukemia cells crowding the marrow. A young child may limp or refuse to walk rather than describe pain.
Swollen gums or lumps in the skin. More common in children than adults, and seen with certain subtypes.
A lump elsewhere in the body. Leukemia cells occasionally form a solid mass called a myeloid sarcoma, sometimes around the eye.

How is the diagnosis made?

Acute myeloid leukemia in children is diagnosed by examining blood and bone marrow. A blood count usually shows low red blood cells or platelets, and blasts may be visible on a blood smear. The diagnosis is confirmed with a bone marrow biopsy and aspiration, which take a small marrow sample from the hip bone. Children are usually asleep under general anesthesia for this, rather than awake with local anesthetic as most adults are.

A pathologist counts the proportion of blasts in the marrow. Acute myeloid leukemia is usually diagnosed when blasts make up 20 percent or more of the cells, although this threshold does not apply when a defining genetic change is found. Flow cytometry then measures proteins on the surface of thousands of individual cells, confirming that the blasts are myeloid and separating this diagnosis from acute lymphoblastic leukemia.

Genetic testing follows and carries more weight in children than cell appearance. A karyotype examines chromosomes, FISH and PCR look for specific changes, and next-generation sequencing reads many genes at once. Sequencing matters here because some childhood fusions are invisible on a karyotype. In one large study, sequencing found that about 1 in 10 children whose chromosomes looked normal carried a high-risk fusion.

A sample of the fluid around the brain and spinal cord is also examined, because leukemia cells reach it more often in children than in adults.

What are the subtypes of acute myeloid leukemia in children?

Acute myeloid leukemia in children is divided into subtypes defined by genetic changes in the leukemia cells. The subtype is stated on the pathology report or in a separate genetics report, and it is one of the two things that set the risk group.

KMT2A rearrangement. Around 20 to 25 percent of childhood cases, and about half of cases in babies under 1. The KMT2A gene joins one of many different partner genes, and which partner is involved changes the outlook considerably.
Core binding factor leukemia. Covers RUNX1::RUNX1T1 and CBFB::MYH11, together about a quarter of childhood cases, which is a larger share than in adults. Both respond well to chemotherapy and sit in the favorable group.
Acute promyelocytic leukemia with PML::RARA. Roughly 5 to 10 percent. It is treated with different drugs from all other subtypes and needs urgent attention because of a serious bleeding problem, but it is now among the most curable leukemias.
NUP98 rearrangement. About 10 percent of childhood cases and rare in adults. NUP98::NSD1 and NUP98::KDM5A are the commonest partners, and both place the leukemia in the high-risk group.
CBFA2T3::GLIS2. Seen in infants and young children, usually with megakaryoblastic features. It is invisible on a karyotype and found only by sequencing, and it is high risk.
NPM1 or CEBPA mutation. Each is found in fewer than 1 in 10 children, far less often than in adults. Both are favorable findings.
FLT3 internal tandem duplication. Found in roughly 15 percent. Whether it raises the risk depends on how much is present and on what other changes accompany it.
Loss of chromosome 7 or part of chromosome 5. High risk, and a finding that often prompts testing for an inherited condition.

Flow cytometry occasionally identifies a pattern of surface proteins known as the RAM phenotype. It is treated as high risk in its own right, even when no matching genetic change has been found.

Myeloid leukemia associated with Down syndrome

Children with Down syndrome have a much higher risk of acute myeloid leukemia before the age of 5. The disease they develop is a separate entity with its own biology and its own treatment. It is defined by a mutation in the GATA1 gene that occurs alongside the extra copy of chromosome 21. The leukemia cells are usually megakaryoblastic, meaning they resemble the cells that make platelets.

It often has a forerunner. About 1 in 10 newborns with Down syndrome develop transient abnormal myelopoiesis, in which blasts appear in the blood in the first weeks of life. In most babies, this resolves on its own within about three months without treatment. Between 20 and 30 percent of these babies later develop myeloid leukemia of Down syndrome, usually between 3 months and 4 years of age. This is why blood counts are followed after transient abnormal myelopoiesis resolves.

Two features set this leukemia apart. It is unusually sensitive to chemotherapy, and children with Down syndrome experience more side effects from those drugs. Treatment therefore uses reduced doses, and outcomes are among the best of any acute leukemia. Children with Down syndrome who develop acute myeloid leukemia after about age 5 usually have conventional disease without a GATA1 mutation. They are treated in the same way as other children.

Measurable residual disease and risk groups

After the first round of chemotherapy, doctors test the bone marrow again for small numbers of remaining leukemia cells. This is called measurable residual disease, or MRD, and flow cytometry detects it at levels far below what can be seen under a microscope. A result below 0.1 percent is usually reported as MRD negative.

MRD is one of the two things that determine your child’s risk group, alongside the genetic subtype, and it can override the genetics. A child whose leukemia carries a favorable change but who has detectable disease after the first round is moved into a higher risk group and treated more intensively. A child with a worrying genetic change who clears the marrow completely may be treated less intensively than the genetics alone would suggest.

Risk groups in childhood acute myeloid leukemia are usually described as low, standard or intermediate, and high. The risk group is what decides how many rounds of chemotherapy are given and whether a stem cell transplant is recommended in the first remission. The treating team assigns it once the genetic results and the first MRD result are both available, so it may not appear on the initial pathology report.

Could my child’s leukemia be part of an inherited condition?

A small but meaningful proportion of children with acute myeloid leukemia carry an inherited change that made the leukemia more likely. Estimates range from about 4 to 15 percent depending on how thoroughly children are tested. Testing looks at the DNA your child was born with, which is present in every cell, and differs from tests done on the leukemia cells themselves.

The genes involved include GATA2, RUNX1, CEBPA, ETV6, and ANKRD26, along with the genes responsible for Fanconi anemia, severe congenital neutropenia, and disorders affecting the ends of chromosomes. Findings that prompt testing include loss of chromosome 7 and low blood counts or unusual infections before the leukemia appeared. Others include more than one cancer in the same child and a pattern of blood disorders or cancers in the family.

This matters beyond the family. If a stem cell transplant is planned and a brother or sister is being considered as the donor, that sibling is tested for the same inherited change. A donor who carries it cannot be used. You can read more in our article What is a hereditary cancer syndrome?

What is the prognosis?

Outcomes for children with acute myeloid leukemia have improved substantially over the past three decades. Roughly 65 to 70 percent of children are alive five years after diagnosis. The proportion who never relapse is lower, in the range of 50 to 60 percent, because some children whose leukemia returns are cured with further treatment including a transplant.

Averages hide a wide range, and the risk group matters for an individual child.

Acute promyelocytic leukemia. The most favorable subtype, with more than 9 in 10 children cured using drugs that are not chemotherapy in the usual sense.
Myeloid leukemia of Down syndrome. Also among the most favorable, with around 9 in 10 children cured on reduced-dose treatment.
Low-risk disease. Includes core binding factor leukemia and children who clear their marrow after the first round. Around 4 in 5 are alive at five years.
Standard or intermediate risk. Roughly 60 to 65 percent long-term survival.
High-risk disease. Includes NUP98 fusions, CBFA2T3::GLIS2, loss of chromosome 7, and leukemia that does not clear after the first round. Five-year survival is below 50 percent, and most current research focuses on this group.

Around 3 in 10 children relapse, most within the first two years. These figures come from large groups of children treated over many years and cannot predict what will happen to one child. The oncology team can give numbers that match your child’s subtype, MRD result, and risk group.

What happens after the diagnosis?

Treatment for acute myeloid leukemia in children begins quickly, usually within days, and is given at a children’s cancer center. Most children in North America and Europe are treated on a protocol developed by a cooperative research group, which is standard care in pediatric oncology rather than an experimental option.

Treatment is built around four to five rounds of intensive chemotherapy, usually combining cytarabine with an anthracycline. An antibody-based drug called gemtuzumab ozogamicin is added when the leukemia cells carry the CD33 protein, which most do. Chemotherapy is also given directly into the fluid around the brain and spinal cord. Acute promyelocytic leukemia is the exception and is treated mainly with all-trans retinoic acid and arsenic trioxide.

Each round is followed by several weeks in hospital while the blood counts recover, so treatment usually takes five to six months in total. A stem cell transplant in the first remission is recommended for high-risk disease and considered individually for intermediate risk. After treatment ends, follow-up continues for many years, with particular attention to the heart because of the anthracycline drugs, and to growth, fertility, and hearing.

Questions to ask your doctor

What genetic change was found in my child’s leukemia, and what subtype does that make it?
Were all the genetic tests completed, including sequencing for changes that a karyotype cannot see?
Which risk group is my child in, and what determined it?
What was the MRD result after the first round of chemotherapy?
Were leukemia cells found in the fluid around the brain and spinal cord?
Does my child have Down syndrome-associated leukemia, and does that change the doses used?
Should my child be tested for an inherited condition that made this leukemia more likely?
If a transplant is being considered, will siblings be tested before being used as donors?
How many rounds of chemotherapy are planned, and how long will treatment take?
Is a stem cell transplant recommended in the first remission, and why?
Is treatment being given on a cooperative group protocol or clinical trial?
What outcomes are expected for children in this specific risk group?
What long-term follow-up will be needed, especially for the heart and for fertility?