Juvenile Myelomonocytic Leukaemia
Juvenile chronic myelogenous leukaemia (JCML), Chronic myelomonocytic leukaemia of childhood, JMML
Juvenile myelomonocytic leukaemia is a very rare blood cancer that affects young children, usually those under four years old. It develops when the bone marrow produces too many abnormal white blood cells that don’t work properly.
Table of contents
- What is juvenile myelomonocytic leukaemia?
- Who gets JMML?
- Signs and symptoms
- Diagnosing JMML
- Understanding bone marrow and blood cells
- Genetic changes and related conditions
- Treatment options
- Outlook and survival
What is juvenile myelomonocytic leukaemia?
Juvenile myelomonocytic leukaemia (JMML) is a very rare type of slowly developing blood cancer that occurs in young children[1]. Although JMML has leukaemia as part of its name, the World Health Organisation does not classify it as a traditional leukaemia. It’s now included in a group of blood cancers called myeloproliferative and myelodysplastic disorders[2].
JMML happens when immature blood cells (called blasts) make too many myelocytes and monocytes, which are two types of white blood cells[1]. In this condition, a specific type of white blood cells called monocytes are abnormal. Monocytes are part of the immune system and help the body to fight infection. Too many are produced, and they are not developed enough to work properly[3].
- Bone marrow
- Blood
- Liver
- Spleen
- Lymph nodes
The myelocytes, monocytes, and blasts crowd the normal cells in the bone marrow and other organs in the body and cause problems[1]. The abnormal white blood cells are made in the bone marrow, enter the bloodstream and circulate around the body. They don’t work normally, so children with JMML don’t have the same protection against infection as they should[3].
It is also more difficult for the bone marrow to produce other blood cells such as red blood cells, platelets, and other white blood cells. This is because the abnormal monocytes take up a lot of space in the bone marrow[3].
Who gets JMML?
JMML is a rare blood cancer that occurs approximately ten times less frequently than acute myeloid leukaemia in children. The annual incidence is about 1 to 2 cases per 1 million people[6]. It is the most common myeloproliferative disease observed in young children, presenting at a median age of approximately 1.8 years[6].
JMML tends to happen in kids younger than age 4[1]. Over half of those diagnosed are under 2 years old[3]. It occurs more commonly in boys, with the male-to-female ratio being approximately 2.5 to 1[6].
We don’t know what causes, or how to prevent, JMML. It’s not something you or anyone has done, and no one is to blame[3].
Signs and symptoms
JMML develops over time, taking weeks to months. At first, kids can have very few symptoms[1]. The symptoms of JMML are similar to those of other childhood illnesses, and they vary between children. Remember JMML is rare, and it develops fairly slowly. This means that symptoms might develop over weeks or months[3].
Common signs at the time of diagnosis include enlarged liver and spleen (97%), swollen lymph nodes (76%), pale skin (64%), fever (54%), and skin rash (36%)[6]. Your child might notice that they have jumped a nappy or trouser size quickly due to the enlarged liver and spleen[3].
Eventually children may develop anaemia, which is when the body has too few red blood cells. This happens because the bone marrow stops making the usual amount of red blood cells. Kids with anaemia may look pale, feel very tired or weak, and get short of breath while playing[1].
When they don’t have enough platelets, kids with leukaemia may bruise easily, get nosebleeds, or bleed for a long time after even a minor cut[1]. Other symptoms include bleeding gums and being irritable, with young children taking longer to settle[3].
Additional symptoms can include pain in the bones or joints (sometimes causing a limp), poor appetite and weight loss, belly pain, cough and wheezing, and generally feeling unwell[1][3].
Because their white blood cells can’t fight infections properly, kids with leukaemia are more likely to get viral or bacterial infections[1]. Your child might have a lot of infections or find it more difficult to recover from infections they do have[3].
Sometimes leukaemia can spread, or metastasize. If it spreads to the brain, symptoms may include headaches, seizures, balance problems, or vision problems. If it spreads to the lymph nodes in the chest, symptoms may include breathing problems and chest pain[1].
Diagnosing JMML
Your child will need a number of tests if their doctor suspects they have JMML. Your child might have more than one test on the same day, and they only have the tests their team think are needed. These tests aren’t generally painful, but your child will have to keep still for some of them[3].
Doctors check for leukaemia with special tests. These include blood tests, such as a complete blood count, liver function and kidney function tests[1]. Patients may also present with an elevated white blood cell count and increased circulating monocytes[6].
Current criteria for a definitive diagnosis require several findings. Clinical, blood, and laboratory criteria include: peripheral blood monocyte count of at least 1 × 10⁹/L; blasts and promonocytes making up less than 20% of peripheral blood and bone marrow; clinical evidence of organ infiltration (most commonly splenomegaly); absence of the BCR::ABL1 fusion gene; and absence of a KMT2A rearrangement[6].
Laboratory findings include high white blood cell count, increased monocytes, increased haemoglobin-F levels, and circulating myeloid precursors[2]. The blast cells in the peripheral blood or bone marrow are less than 20%, and the absence of the BCR-ABL translocation helps to differentiate JMML from chronic myeloid leukaemia[2].
Understanding bone marrow and blood cells
Bone marrow is a spongy material that fills the bones. It contains early blood cells, called stem cells. These develop into the 3 different types of blood cells[3]. Bone marrow makes white blood cells, red blood cells, and platelets[1].
Normally stem cells in your bone marrow keep dividing to make new blood cells. This keeps the numbers of cells circulating in your blood within a normal range. Doctors can measure the number of blood cells your child has from a blood test. They call this their blood count[3].
A myeloproliferative disorder is a condition where there are too many blood cells made. A myelodysplastic disorder is where the blood cells made are abnormal and not fully mature. In reality, the two disorders often overlap, which is why the WHO has put them together in the same category[3].
Genetic changes and related conditions
Many kids have a change in their genes (a mutation) that affects the monocytes[1]. JMML is associated with mutations in the RAS pathway genes, resulting in the myeloid progenitors being sensitive to granulocyte monocyte colony-stimulating factor (GM-CSF). Additional genetic abnormalities and epigenetic alterations can also be found in JMML[2].
Some medical conditions make a child more likely to develop this disease. Neurofibromatosis type 1 and Noonan syndrome have a predisposition for JMML[1][2]. Children with neurofibromatosis 1 are more at risk of developing JMML, but this only happens in between 10 to 15 out of every 100 cases (between 10 to 15%)[3].
In a few patients, the RAS genes (NRAS, KRAS, and PTPN11) are mutated at the germline and this usually results in a transient myeloproliferative disorder with a good outlook. JMML with changes in these genes that occur during a person’s lifetime (somatic mutations) behaves more aggressively[2].
JMML can happen spontaneously (by chance) or can be associated with other genetic disorders in some children[4].
Treatment options
JMML is not easily treated, though several approaches offer hope for a successful outcome. Treatment decisions are based on your child’s age, overall health, and medical history; the extent of the disease; your child’s tolerance for certain medications, procedures, or treatments; how your child’s doctors expect the disease to progress; and your opinion and preferences[12].
Allogeneic hematopoietic stem cell transplant (HSCT) is the only known cure for JMML to date[2]. A stem cell transplant is the best option for treatment[12]. When your child’s stem cells are replaced with those of a healthy and compatible donor, it is called an allogeneic transplant[12].
The prognosis of JMML is poor with about 50% of patients surviving after an allogeneic hematopoietic stem cell transplant. Myeloablative conditioning is most commonly used with measures to prevent graft versus host disease tailored to the aggressiveness of the disease. Relapses are common even after HSCT and a second HSCT can salvage a third of these patients[2].
Chemotherapy may be employed as a bridge to HSCT, except in a few with less aggressive disease, in which chemotherapy alone can result in long-term remission[2]. Azacitidine has shown promise as a single agent to stabilize the disease[2].
Novel options in the treatment of JMML such as hypomethylating agents, MEK inhibitors, JAK inhibitors, and tyrosine kinase inhibitors are being explored[2]. Your child’s team of doctors will help determine the best approach for your child’s unique situation[12].
You might not need treatment straight away. Instead, you may have regular check-ups and blood tests. You might also have treatment to prevent or manage symptoms or side effects[5].
Outlook and survival
JMML should be differentiated from immunodeficiencies, viral infections, intrauterine infections, haemophagolymphohistiocytosis, other myeloproliferative disorders, and leukaemias[2].
JMML presents with low blood cell counts (cytopenias) and leukaemic infiltration into organs[2]. Most kids and teens treated for leukaemia are cured of the disease[1].
Given the advanced median age at presentation and associated health conditions, allogeneic stem cell transplant is an option for only a few affected patients[2]. Your child’s healthcare team will provide specific information about your child’s situation and expected outcomes.