Juvenile Myelomonocytic Leukaemia (JMML)

Juvenile myelomonocytic leukaemia (JMML) is an excessive production of the monocyte white blood cells in the bone marrow, which infiltrate other organs including the spleen, liver, lung, and gastrointestinal tract.

Juvenile myelomonocytic leukaemia (JMML) is classed as an overlapping condition between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) in the 2016 World Health Organisation classification of blood and bone marrow cancers.

In MDS, bone marrow cells of all types reproduce uncontrollably and show abnormal (dysplastic) changes. MDS are identified by a poorly functioning bone marrow and an increased likelihood of developing acute myeloid leukaemia (AML).

MPNs are chronic disorders where the myeloid stem cells in the bone marrow make too many abnormal red blood cells, white blood cells, or platelets which do not function properly.

The term JMML replaces all the leukaemia conditions previously named as:

  • Juvenile chronic myeloid leukaemia
  • Chronic myelomonocytic leukaemia of infancy
  • Infantile monosomy 7 syndrome

JMML is identified by an excessive production of the monocyte white blood cells in the bone marrow, leading to increased numbers of monocytes in the blood, bone marrow and other organs. Some of these cells develop into immature monocytes called blasts or leukaemia cells, which are unable to do their job properly. These extra monocytes can interfere with the production of the other healthy blood cells such as the red blood cells, platelets and the other white blood cells in the bone marrow.

JMML is a very rare disease with an incidence of between 0.6 and 1.2 per million per year for children aged 0 to 14 years. JMML represents 2% to 3% of all childhood leukaemias. Around 75% of patients are diagnosed below three years of age. Around 40% of JMML cases present before one year of age.

Boys are affected more often than girls by a ratio of 2.5 to 1.

What causes JMML?

In 10% of children with JMML, there are no identifiable gene mutations. However, in approximately 90% of children with JMML, there is a mutation in at least one of the following genes:

PTPN 11 (Protein Tyrosine Phosphatase, Non-receptor type 11) gene mutation:

  • Occurs in around 35% of children with JMML.
  • Mutation in this gene can lead to the Noonan syndrome, which is characterised by unusual facial features, short stature, skeletal anomalies, heart defects, learning difficulties, and bleeding disorders.
  • Deletion of chromosome 7 is also seen in around 25% of these children.

K-RAS or N-RAS gene mutation:

  • Occurs in 20% to 25% of children with JMML.
  • These genes are part of the RAS signalling pathway.

NF1 (Neurofibromatosis type 1) gene mutation:

  • Occurs in 15% to 20% of children with JMML.
  • This gene functions as a tumour suppressor, and in some patients with a mutation in the NF1 gene, the condition neurofibromatosis type 1 is also present. Patients with this gene have benign or malignant tumours, larger than average head, learning and behavioural problems, fold freckling (freckles in areas not exposed to the sun) and multiple café-au-lait (milky coffee) coloured spots.

CBL (Casitas B-lineage Lymphoma) gene mutation:

  • Occurs in 10% to 15% of children with JMML.
  • The CBL gene functions as a tumour suppressor and is also known to prevent normal immune responses turning into autoimmune diseases. In children with CBL mutations, there is a high rate of the JMML resolving spontaneously.
  • These children also have diminished growth, developmental delays, undescended testes and inflammation of the blood vessels.

In addition to the genetic mutations, the RAS signalling pathway may show somatic mutations, which are mutations in an individual’s body that are not related to the individual’s genetic mutations, and therefore cannot be passed on to their offspring. These somatic mutations can be linked to progression of JMML. These somatic mutations include the SETBP1 (SET binding protein 1) gene, the JAK3 (Janus Kinase 3) gene and ASXL1 (Additional Sex combs like 1) gene.

Symptoms of JMML

JMML generally progresses slowly, so there may only be a few symptoms at the onset. The most common symptoms of JMML are listed below; however, children with JMML can show any combination of these symptoms:

  • Pale appearance
  • General fatigue or weakness
  • Decrease in appetite and/or weight loss
  • Irritability
  • Developmental delays
  • Fever
  • Rash
  • Recurrent infections
  • Bruising easily or bleeding
  • Enlarged liver, spleen or lymph nodes
  • Abdominal pain, bone and joint pain (due to overcrowding with monocytes)

Symptoms can appear over weeks or months.

Children who have neurofibromatosis type 1 or Noonan’s syndrome will also display the symptoms specific to those conditions as previously described.


The haematologist may suspect your child has a type of leukaemia, either following the results of a blood test or symptoms that you have reported to them. Further tests are required to reach and confirm a diagnosis. These test results can take a little while, which may be a worrying time for you and your child, but it is worth remembering that they are essential so your child’s haematologist can reach the correct diagnosis.

Tests used to make a diagnosis

JMML is diagnosed by the use of blood tests, bone marrow aspiration/biopsy, analysis of chromosomes and gene mutations. The tests that your child may have include:

  • Full blood count: This is a routine blood test which measures the number of red cells, the different types of white cells, and the platelets in the blood. The blood is smeared onto a microscope slide, allowing the blood cells to be examined under the microscope.
  • Bone marrow aspiration/biopsy: The bone marrow sample can be taken from the hip bone under local anaesthetic, using special biopsy needles. In an aspirate, liquid bone marrow is taken and/or a tiny core of bone marrow tissue using a trephine (a surgical instrument with a cylindrical blade).
  • Chromosome abnormalities or gene mutations tests: Blood or bone marrow may be tested to check for chromosome abnormalities or gene mutations of the leukaemia cells.
  • Immunophenotyping: A process that analyses the types of antigens or markers on the surface of the leukaemia cells based on antibodies to them that are present in the patient’s blood. According to which antibodies are present, it is possible to identify the type of leukaemia.
  • Minimal residual testing (MRD) testing: This test measures the presence of leukaemia at a molecular level rather than at a cell level. Biomarkers (a specific characteristic that helps to identify something) linked to the leukaemia cells are measured using molecular techniques such as flow cytometry to determine the very small level of leukaemia cells which are still remaining in the bone marrow of patients, but may not be seen under a microscope. MRD testing is important in planning the next phase of your treatment.
  • Imaging investigations: X-rays, ultrasounds or scans, including computer tomography (CT) and magnetic resonance imaging (MRI) can be done to assess the impact of the JMML on the body’s organs.
  • Measurement of hypersensitivity to GM-CSF (Granulocyte macrophage colony-stimulating factor): GM-CSF is a growth factor which stimulates the growth of living cells. Increased amounts of GM-CSF are added to samples of blood or bone marrow in which healthy cells will not grow, but JMML cells will grow. However, this test takes weeks to complete, and is neither standardised nor widely available.
  • Human leukocyte antigen (HLA) typing: Also called tissue typing, this process is used to find a suitable donor for a stem cell transplant. For children with aggressive JMML, the search for a donor is started soon after diagnosis. The proteins on the surface of the child’s blood cells are matched with those of a potential donor. The greater the number of HLA markers that are shared by the patient and donor, the better the chance of a successful transplant.

Blood tests, bone marrow samples and scans will be repeated throughout treatment to monitor your child’s response to treatment.

Diagnosis of JMML

JMML is a rare type of leukaemia with unusual symptoms and signs which may lead to a misdiagnosis. Prior to reaching a diagnosis of JMML, other diagnoses are generally excluded, particularly if the child is older than the average age of two years at diagnosis. Conditions which can be similar to JMML are chronic myeloid leukaemia, acute myeloid leukaemia or other MPNs. A definite diagnosis of JMML can be reached if the criteria set out in the 2016 World Health Classification of blood and bone marrow cancers are met. They are as follows:

  • Presence of all four of the following clinical and haematologic features:
    • Number of monocytes in the blood equal to or greater than 1×109/l
    • Percentage of leukaemia cells in the blood and bone marrow less than 20%
    • Enlarged spleen
    • No presence of the Philadelphia chromosome, which is an abnormal chromosome seen in all patients with chronic myeloid leukaemia and some patients with acute lymphoblastic leukaemia. Therefore, if there is no Philadelphia chromosome, the doctors know it is not ALL or AML instead. This abnormal chromosome results from the swapping over and fusion of sections of DNA between chromosomes 9 (ABL1) and 22 (BCR), resulting in a new fusion gene BCR-ABL1.
  • Presence of one of these genetic findings:
    • PTPN11, K-RAS or N-RAS mutation, except for Noonan syndrome
    • NF1 mutation or clinical diagnosis of neurofibromatosis
    • CBL mutation and loss of a gene contribution from one parent
  • For patients with no genetic mutations, the four clinical and haematologic features listed above must be present and they must be accompanied by:
    • Monosomy 7 (one copy of a chromosome pair, instead of two) or any other chromosomal abnormality
    • Or at least two of the following criteria:
      • Haemoglobin F (foetal haemoglobin or HbF) must be increased for the child’s age
      • Immature bone marrow cells or red blood cells seen in the blood
      • Hypersensitivity to GM-CSF


At present, the only potential cure for JMML is an allogeneic stem cell transplant (Allo-SCT), which is a stem cell transplant from a matching donor. Without an Allo-SCT, the median time of survival from diagnosis is often less than two years. Chemotherapy may lessen the symptoms of JMML, but it cannot offer a cure. Combinations of chemotherapies are regularly used to keep the disease under control while arrangements for the child to have an Allo-SCT are made.

Chemotherapy can improve the symptoms of JMML in patients who do not suffer from an aggressive form of the disease or those with no matching donor.

However, for some children, particularly those with genetic PTPN-11 mutations, CBL mutations and some somatic N-RAS mutations, their JMML resolves spontaneously for no apparent reason (spontaneous remission). These children are generally in good health and have a low level of HbF. The best treatment approach for these patients is a ‘Watch and Wait’ strategy, where the child is closely monitored but treatment is not started until symptoms appear or worsen.

The treatment pathway chosen for your child will be explained to you by the medical team.

How is JMML treated?

At present, the only successful treatment option for the cure of JMML is an allogeneic stem cell transplant (ASCT). Chemotherapy may alleviate symptoms but cannot offer a cure. Splenectomy before transplantation has not been shown to be of benefit.

Stem cell transplantation

The only effective treatment for JMML currently is an ASCT, which achieves a cure in approximately 50% of patients. Without an ASCT, median survival time for patients with JMML is around one year.

An ASCT is indicated for the majority of children with JMML, particularly for those with NF1 and somatic PTPN11 mutations, and most of those with somatic K-RAS mutations and somatic N-RAS mutation. A certain proportion of patients with somatic N-RAS mutation or CBL mutation have spontaneous regression; therefore, a ‘watch and wait’ strategy is more appropriate for these patients.

A better outcome with an ASCT is often seen for patients of a younger age.

However, an ASCT for these children carries the risk of severe toxicity, during the procedure and later in life.

Conditioning regimen

Prior to children patients receiving the infusion of donor blood cells as part of their ASCT, they normally receive a conditioning regimen. This usually consists of high-dose chemotherapy to eliminate the cancer cells and prevent the immune system rejecting the new stem cells. A period of two to four weeks is generally needed for the stem cells to multiply and make new blood cells, a process which is called engraftment.

Patients are generally conditioned for the ASCT with a regimen of busulfan, cyclophosphamide and melphalan. Total body irradiation is sometimes used as part of the conditioning regimen; however, this is controversial given the possible side effects later in life, such as short stature, learning difficulties, secondary cancers, and sterility.

Graft-versus-host disease

Graft-versus-host disease is a serious problem that occurs with ASCTs. It happens when the graft (donated marrow or stem cells) reacts against the host (patient receiving the stem cells). The T-cells in the donated stem cells attack and destroy the host’s cells as they see them as foreign bodies. Symptoms of graft-versus-host disease include skin rashes, diarrhoea and liver damage. Graft-versus-host disease can be very mild and short-lived (acute form) or it can be severe and even life threatening, lasting for years (chronic form).

Graft-versus-host disease has been shown to have an important role in the treatment of JMML. Acute or chronic graft-versus-host disease is linked to a lower relapse rate in patients with JMML. Children who receive fewer immunosuppressant drugs in the conditioning regimen have lower relapse rates.

Small studies have reported that not using melphalan and/or substituting cyclophosphamide with fludarabine in the conditioning regimens may decrease acute graft-versus-host disease without affecting overall survival.

Relapse and second ASCT

A relapse represents the main failure of an ASCT for a child with JMML, with the rate being as high as 50%. ASCTs using HLA matched family donors, HLA-matched unrelated donors and HLA-matched unrelated umbilical cord blood donors have generated similar relapse rates, which means that the lack of an HLA matched donor does not prevent good ASCT outcomes. However, despite recent reductions in ASCTs-related deaths, the deaths are still higher with HLA matched unrelated donors, mostly due to infection.

Factors which predict an increased risk of relapse are an age of over four years and having a bone marrow blast percentage greater than 20%. A second ASCT may achieve a cure, particularly when combined with decreased immunosuppression, as this produces a stronger graft-versus-leukaemia effect. Second ASCTs were successfully carried out in 15 patients from the European Working Group/European Bone Marrow Transplant Group (EWOG/EBMT) trial, using the original donor as often as possible, and total body irradiation being the most common conditioning regimen. However, the intentional reduction in the cyclosporine conditioning regimen to prevent relapse did lead to an expected high rate of graft-versus-host disease.

These findings suggest that relapse does not inevitably mean a poor prognosis and that a second ASCT is a valid option for patients in good physical condition. However, whether or not the same donor would be used, if this was feasible, would be up to the discretion of your child’s medical team and what they feel would provide the best outcome for your child.


Without treatment, around one third of patients with JMML will progress rapidly leading to early death. However, there have been reports of some patients remaining in a stable condition despite not receiving treatment for up to 12 years. Nevertheless, without an ASCT, survival time of children with JMML is 10 to 12 months.

Two JMML treatment protocols are commonly used, although they are not internationally accepted as yet:

  1. The European Working Group of Myelodysplastic Syndromes in Childhood (EWOG-MDS) study protocol: An ASCT after a conditioning regimen of busulphan, cyclophosphamide and melphalan.
  2. The North American Children’s Oncology Group (COG) study protocol: An ASCT after conditioning with combination of busulfan and fludarabine.

Busulfan, cyclophosphamide, and melphalan are currently recommended as a conditioning regimen for all patients undergoing an ASCT until an appropriate reduced-toxicity regimen can be identified.

Long-term remission of JMML with chemotherapy treatment alone has not been achieved. Nevertheless, chemotherapy can improve the symptoms of JMML in patients who do not suffer from an aggressive form of the disease. Patients with JMML may be given 6 mercatopurine or low-dose intravenous cytarabine to control their symptoms; however, responses are usually temporary. In addition, chemotherapy treatment is given as part of the conditioning regimen prior to an ASCT.

New treatments

Research into alternative treatments for JMML is focussed on targeted therapies (drugs that specifically interrupt the ability of the leukaemia to grow in the body) and immunotherapies (treatment that uses the body’s own immune system to fight the cancer). These include:

  • Azacitidine: This anti-cancer drug works by ‘switching on’ genes that prevent the cancer cells growing and dividing.
  • 13-cis retinoic acid: This retinoid drug (related to Vitamin A) is known to inhibit the growth of JMML cells in the laboratory.
  • Tipifarnib: This is a farnesyl transferase inhibitor that works by blocking the enzymes necessary for cancer cell growth.
  • Trametinib: This is a MEK (mitogen-activated protein kinase kinase enzyme) inhibitor which is being investigated in a COG-sponsored trial, for children with relapsed or refractory JMML.

Other agents that are being investigated for use in JMML include RAS mimetics, SHP-2 (Src homology phosphotyrosine phosphatase 2) inhibitors, anti-GM-CSF antibodies, and chimeric antigen receptor (CAR) T-cell therapy, which involves genetically engineering the patient’s T-cells to target and kill leukaemia cells.

Questions to ask your medical team about JMML

We understand going through a blood cancer through journey can be difficult. It may help to talk to a close friend or relative about how you are feeling. Here are some questions that may be useful to ask your doctor.

  • How would I know if I had JMML?
  • What tests will I need to have?
  • What will the tests show?
  • How long will the results take?
  • How rare is JMML?
  • What sort of treatment will I need?
  • How long will my treatment last?
  • What will the side effects be?
  • Is there anything I should or shouldn’t eat?
  • Will I be able to go back to work?
  • Where can I get help with claiming benefits and grants?
  • Where can I get help dealing with my feelings?

Further resources

We have free patient information available about JMML.

You can download the booklets on our information pages here.

Alternatively, you can have the information delivered free of charge by requesting it through our resources page. 

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Published: December 2020

Review date: December 2023