Juvenile Myelomonocytic Leukemia
Juvenile myelomonocytic leukemia (JMML) is a rare cancer of the blood-forming tissue that begins in infants and young children, when the bone marrow overproduces white blood cells called monocytes and granulocytes. It is linked to overactive RAS signaling, and a stem cell transplant is currently the treatment most likely to cure it. This page explains the causes, signs, diagnosis, treatment, and outlook.
Key Takeaways
- JMML is a rare leukemia of early childhood. It is usually diagnosed around age 2 and is seen more often in boys than in girls.
- The disease is driven by overactive RAS signaling, most often from changes in one of five genes: PTPN11, NRAS, KRAS, NF1, or CBL. Neurofibromatosis type 1 and Noonan syndrome raise the risk.
- Typical findings at diagnosis include an enlarged liver and spleen, swollen lymph nodes, pale skin, fever, and rash, along with a high monocyte count in the blood.
- A stem cell transplant is the approach most likely to cure the disease, although a few children with particular inherited changes may improve without intensive treatment.
- The leukemia can return after transplant, so outcomes depend on the child’s genetic profile and on long-term follow-up with a pediatric oncology team.
What Is Juvenile Myelomonocytic Leukemia?
Juvenile myelomonocytic leukemia, usually shortened to JMML, is a rare cancer of the blood-forming tissue that begins in young children. In this disease the bone marrow overproduces two kinds of white blood cells, granulocytes and monocytes. These cells fill the marrow and circulate in the blood, and they can also settle in other tissues. The liver, spleen, lymph nodes, skin, and airways are the most common sites.
JMML is uncommon. According to the National Cancer Institute, about 1 to 2 people per million are diagnosed each year, roughly ten times fewer than with acute myeloid leukemia in childhood. Doctors classify it as a myeloproliferative neoplasm driven by overactive RAS signaling, described in the next section.
Who Gets JMML and What Causes It
JMML mostly affects babies and toddlers. The typical age at diagnosis is about 1.8 years, and boys are affected roughly two and a half times as often as girls.
The RAS pathway is a chain of signals that tells a cell when to grow and divide. In JMML this pathway is switched on too strongly. The genetic profile of the disease centers on five genes: NF1, NRAS, KRAS, PTPN11, and CBL. PTPN11 changes are the most frequent. Usually only one of these genes is altered, but in roughly 4% to 17% of children changes are found in two of them, which has been linked to a poorer outlook.
Some of these gene changes are inherited (germline), so the child carries them in all body cells. Others arise only within the leukemia cells (somatic). The two look the same in the clinic, so doctors examine both normal and leukemic tissue to tell them apart.
Certain inherited conditions raise the risk:
- Neurofibromatosis type 1 (NF1): as many as 14% of JMML diagnoses are made in children who already have NF1, a condition known to raise leukemia risk in general.
- Noonan syndrome: a condition with distinctive facial features, short stature, and often heart defects, usually passed down in families but sometimes arising on its own. Some babies with Noonan syndrome and a PTPN11 change have blood findings that look just like JMML yet clear up during infancy.
- CBL-related disorder: between 10% and 15% of JMML cases involve CBL, frequently as an inherited change. The inherited condition can bring slow growth, developmental delay, and undescended testicles in boys, along with a predisposition to JMML.
Signs and Symptoms
Symptoms can begin in infancy or later in childhood. Features reported at diagnosis include:
- An enlarged liver and spleen, the most common finding
- Swollen lymph nodes
- Pale skin
- Fever
- Skin rash
Blood tests often show a raised white blood cell count with many circulating monocytes. Some children also have a low platelet count. None of these signs proves that a child has JMML, and only a set of laboratory and genetic tests can confirm it.
How JMML Is Diagnosed
Diagnosis rests on blood and bone marrow samples read together with the child’s physical findings. All of the following must be present:
- A blood monocyte count of at least 1 billion per liter
- Immature blast-type cells making up less than 20% of the cells in the blood and bone marrow
- Signs that leukemia cells have spread to organs, most often an enlarged spleen
- No BCR::ABL1 fusion gene
- No KMT2A gene rearrangement
The laboratory must also find a qualifying genetic change: a change in PTPN11, KRAS, or NRAS in the leukemia cells, a qualifying change in NF1 or CBL, or another RAS-pathway change or gene fusion (for example involving ALK, PDGFRB, or ROS1). When genetic testing is unavailable or shows none of these, doctors instead look for at least two other features, such as immature blood-cell precursors in the blood, fetal hemoglobin that is high for the child’s age, or low platelets with a crowded bone marrow.
Genetic results also matter because inherited changes in PTPN11, KRAS, or NRAS, the changes behind Noonan syndrome, can produce a temporary JMML-like blood disorder.
Treatment Options
Children with JMML should be cared for at a pediatric cancer center where a team of specialists, including pediatric oncologists, hematologists, and nurses, works together. Treatment choices depend on the child’s genetic findings and overall condition and should always be made with the child’s oncology team.
Stem cell transplant. Hematopoietic stem cell transplantation, in which diseased marrow is replaced with donor cells, is the approach considered most likely to cure JMML.
Medicines before transplant. Chemotherapy given before transplant has had a mixed and overall unsatisfactory effect on survival, although various regimens have helped control symptoms. The FDA has since broadened the approved uses of one medicine to cover newly diagnosed children with JMML.
Watchful approaches in selected children. Some children with inherited CBL changes have seen their JMML regress without treatment, although they may develop inflammation of the blood vessels (vasculitis) later in life. Children whose CBL changes exist only in the leukemia cells need treatment, and the blood findings of Noonan syndrome can clear on their own in infancy. Whether a child can be watched rather than treated is a decision for the oncology team, based on careful testing.
If the leukemia returns. A second transplant can succeed for about half of the children whose leukemia relapses. An oral MEK inhibitor has also been tried in children with relapsed or refractory JMML.
Outlook and Follow-Up
Outcomes have changed over time. The NCI notes that historically more than 90% of children with JMML died despite chemotherapy, whereas survival of about 50% is now seen with transplantation.
Factors linked to a better outlook include diagnosis before age 2, a platelet count above 33 billion per liter, and a low fetal hemoglobin level for age. A diagnosis after age 2, or a high fetal hemoglobin level at that time, points to a harder course. Genetic findings also matter: children with extra gene changes beyond the main RAS-pathway change have a poorer outlook than those without them.
Relapse is the main reason transplant fails, occurring in about 30% to 40% of children. Questions about follow-up after treatment are best discussed with the child’s oncology team.
Frequently Asked Questions
Can JMML go away without treatment?
In a small group of children, yes. Blood findings linked to Noonan syndrome can clear in infancy, and some children with inherited CBL changes improve on their own. Only the oncology team can decide whether observation is appropriate.
Is JMML inherited?
Sometimes. Some children carry inherited changes, such as those seen in NF1, Noonan syndrome, or CBL-related disorder, while in others the changes occur only in the leukemia cells. Testing normal and leukemic tissue shows which applies.
Where should a child with JMML be treated?
Ideally at a pediatric cancer center with a multidisciplinary team experienced in childhood cancers, where clinical trials may also be available.
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