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Juvenile Myelomonocytic Leukemia (JMML)

What is Juvenile Myelomonocytic Leukemia?

Like all leukemias, juvenile myelomonocytic leukemia is a cancer of the blood and bone marrow. JMML is a rare cancer diagnosed in infants and young children. JMML occurs when the bone marrow starts making too many cancer cells that crowd out healthy blood cells. Without enough healthy blood cells, the body can’t fight infection as well, and the blood doesn’t function correctly.

One to two children out of 1 million are diagnosed with JMML each year, which means 25 to 50 new cases a year. JMML occurs most often in children younger than 4 years. Ten percent of all cases develop in infants younger than 3 months.

JMML occurs when too many blood cell-producing (hematopoietic) cells in the bone marrow become white blood cells called monocytes and myelocytes. Unlike normal cells, these cancer cells do not die off naturally. They build up in the liver, spleen, bone marrow, and blood. About 90% of patients have either germline (inherited) or somatic (occurring spontaneously in the body – not inherited) mutations of PTPN11, KRAS, NRAS, CBL, or NF1. Determining the genetic mutation is important because it can help determine what treatment a patient receives.

The World Health Organization (WHO) also classifies JMML as a mixed myelodysplastic/myeloproliferative disease because it has features of two other types of blood cancer.

Risk Factors of Juvenile Myelomonocytic Leukemia

  • Boys are twice as likely to be diagnosed with JMML as girls.
  • JMML has been associated with a number of genetic mutations. About 90 percent of JMML cases are associated with a known mutation of PTPN11, KRAS, NRAS, CBL, or NF1 genes. (2016 WHO Revision)
  • Children who have neurofibromatosis type 1 (NF1) and Noonan syndrome (PTPN11) have an increased risk of developing JMML.
  • In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11, KRAS, and NRAS genes. 
  • Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall. 
  • Somatic disruptions of the GRAF gene have also been found in patients with JMML.

Signs and Symptoms of Juvenile Myelomonocytic Leukemia

An enlarged spleen and liver and tiny reddish and purplish bruises (petechiae) are hallmarks of the disease. 

Other symptoms of JMML may include:

  • Painless swelling of lymph nodes
  • Fever for no known reason
  • Paleness of skin
  • Infections, such as bronchitis or tonsillitis
  • Feeling very tired
  • Easy bruising or bleeding of the skin, nose, and mouth
  • Dry cough
  • Trouble gaining weight
  • Poor appetite
  • Failure to thrive
  • Feeling irritable
  • Bone and joint pain
  • Anemia
  • Thrombocytopenia (low platelets)

Diagnosis of Juvenile Myelomonocytic Leukemia

Diagnosing children with JMML is sometimes challenging because it has similar symptoms to a number of immune system disorders. 

Chromosomal and genetic testing is important in the diagnosis of JMML because the type of mutation may help determine how the disease is treated. JMML is associated with a number of genetic mutations. About 90 percent of JMML cases are associated with a known mutation of the PTPN11, KRAS, NRAS, CBL, or NF1 genes. (2016 WHO Revision) These mutations may be inherited from a parent (germline) or occur spontaneously in the body (somatic). 

Tests to diagnose JMML include:

  • Physical exam and history
  • Blood tests (complete blood count and blood chemistry)
  • Bone marrow test
  • Tests to examine chromosome and gene changes
  1. At first, a physician will take the patient’s medical history and will perform a physical exam. During the physical exam, the doctor will check general signs of health, including signs of disease, such as lumps or anything else that seems unusual. The eyes, mouth, skin, and ears will be looked at carefully, and a nervous system exam may be done. The doctor may feel the patient’s abdomen for signs of an enlarged spleen or liver.

  2. Complete blood count

    Doctors will order a blood test called a complete blood count. A sample of blood is drawn and checked for the:

    • Number of red blood cells and platelets
    • Number and type of white blood cells
    • Amount of hemoglobin in the red blood cells
    • Portion of the blood sample made up of red blood cells. 

    Abnormal numbers of monocytes (a type of white blood cell) is a feature of JMML.

    Blood chemistry studies

    A blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease. In JMML, one of the examples is hypergammaglobulinemia (a higher than normal amount of gammaglobulin-an infection-fighting protein.)

  3. Bone marrow tests, like a bone marrow aspiration and biopsy, will confirm a diagnosis of cancer and pinpoint the type of cancer. Most children are asleep (sedated) during the procedure. If awake during the procedure, patients are given appropriate pain medicine.

    Bone marrow aspiration: Doctors will obtain a bone marrow sample by inserting a thin, hollow needle into the hipbone. A pathologist will view the bone marrow under a microscope to look for signs of cancer.

    Bone marrow biopsy: Doctors will remove a small piece of bone tissue to determine how much the cancer has spread in the bone marrow. The biopsy is typically performed right before or after the aspiration.

    How is a bone marrow aspiration / biopsy performed?

    • Patients will lie on their side on the bed, or, less commonly, sit up with legs bent and crossed at the ankles. 
    • The doctor or nurse practitioner will feel the patient’s lower back to find the right spot for the test. 
    • Next, the health care provider will put on gloves and clean the patient’s back with a germ-killing soap. Then, the health care provider might place plastic towels over the back, leaving only a small area of skin showing. 
    • If the health care provider is going to be awake during the aspirate or biopsy, numbing cream will be placed on the spot where the bone marrow aspirate or biopsy will be taken about one hour before the procedure. Liquid numbing medicine might be injected at the procedure site. 
    • The health care provider will push a needle through the skin into the bone marrow. If both an aspiration and biopsy are done, a separate needle will be used for each procedure.
    • The health care provider will take out the needle, clean the spot with alcohol, and put on a bandage.

If cancer is determined, more tests will be performed to pinpoint the subtype of the cancer. These tests include:

  1. Immunophenotyping is used to diagnose specific types of leukemia by comparing the cancer cells to normal cells of the immune system.

    Immunohistochemistry and flow cytometry are the laboratory tests.

    • Immunohistochemistry is a test that uses antibodies to show specific proteins in a sample of tissue. The complexes of proteins and antibodies are stained brown or red and can be seen under a microscope.
    • In flow cytometry, cells are stained with a light-sensitive dye, placed in a fluid, and passed in a stream before a laser or other type of light. The test measures the number of cells, the percentage of live cells, and certain characteristics of cells, such as size, shape, and the presence of tumor markers on the cell surface.
  2. Cytogenetic analysis involves laboratory tests in which pathologists look for certain changes in the chromosomes. There are several cytogenetic changes in JMML. The most common are abnormalities of chromosome 7 and 8. Loss of chromosome 7 (monosomy 7) occurs in about 30% of the children with JMML.

    One such test is FISH (fluorescence in situ hybridization). This test looks at genes or chromosomes in cells and tissues. Pieces of DNA that contain a fluorescent dye are made in the laboratory and added to cells or tissues on a glass slide. When these pieces of DNA attach to certain genes or areas of chromosomes on the slide, they light up.

  3. Molecular and genetic testing is the most important component of the diagnosis of JMML. The doctor may recommend running laboratory tests to identify specific genes, proteins, and other factors involved in leukemia. This examination is important because cancer is caused by mistakes (mutations) in the cell’s genes. The vast majority of children with JMML have somatic and/or germline mutations of genes involved in the RAS/MAPK signaling pathway. A signaling pathway is a group of molecules in a cell that works together to control one or more cell functions, such as cell division or cell death. After the first molecule in a pathway receives a signal, it activates another molecule. This process is repeated until the last molecule is activated and the cell function is carried out. Abnormal activation of signaling pathways can lead to cancer, and drugs are being developed to block these pathways. These drugs may help block cancer cell growth and kill cancer cells. Mutations in NF1, PTPN11, KRAS, NRAS, or CBL are found in about 90 percent of patients with JMML.

Treatment for Juvenile Myelomonocytic Leukemia

Doctors can use chromosomal and genetic information along the patient’s age to determine treatment based on how well patients are predicted to respond. This approach is called risk-adapted or risk-stratified.

Low-risk

Patients with inherited mutation of the PTPN11 (Noonan syndrome) or a CBL (CBL syndrome) genes are considered low-risk. Sometimes these cases go into remission without treatment. Physicians closely monitor these patients. Chemotherapy may be used in patients who develop symptoms such as an enlarged spleen and recurrent infections.

Intermediate-risk

JMML cases with a somatic NRAS mutation who are younger than 1 are considered intermediate risk. These cases may also be closely monitored or treated with chemotherapy, if necessary. The drug, azacytidine, has shown some success. Hematopoietic cell transplant (also known as bone marrow transplant or stem cell transplant) may also be a treatment option.

High-risk

Patients with somatic KRAS, NF1, PTPN11 mutations are considered high-risk because they are either predicted to be resistant to treatment (refractory) or the disease is likely to recur (relapse). Chemotherapy with the drugs fludarabine and cytarabine and hematopoietic cell transplant (also known as bone marrow transplant or stem cell transplant) (with the drugs busulfan, cyclophosphamide, and melphalan given before transplant (conditioning)) is a possible treatment.

At present, the only treatment for high-risk JMML that offers hope of a long-term cure is a hematopoietic cell transplant. Sometimes this procedure is followed by a transplant of natural killer cells, a type of white blood cell. Chemotherapy, or in limited cases, targeted therapy may be options.

A patient’s brother or sister is usually the best match to donate cells for transplantation. If a sibling is not available, one of the patient’s parents or someone outside of the patient’s family can be a suitable donor. The transplant should occur as soon as possible after diagnosis because successful transplant rates are highest in younger children. If the cancer relapses, a second hematopoietic cell and natural killer cell transplant have shown success.

Umbilical cord blood transplants are also a treatment option.

There are also ongoing clinical trials for HLA-haploidentical (partially matched) relative donor blood stem cell transplantation. It can be considered as an option for patients who don’t have an HLA-matched blood stem cell or umbilical cord blood donor.

Other treatment options

In a few cases, removal of the spleen may be recommended if the organ has become severely enlarged.

Because JMML is hard to treat with current chemotherapy drugs, taking part in a clinical trial looking at newer drugs may be a good option for children who don’t have a suitable donor.

Side effects of treatment

The severity of side effects of a transplant generally depend on the overall health of the patient before the procedure.

Side effects of bone marrow transplants may include:

  • Infections because of immune system suppression
  • Graft-versus-host disease
  • Sinusoidal obstruction syndrome/veno-occlusive disease
  • Transplant-associated microangiopathy
  • Idiopathic pneumonia syndrome
  • Epstein-Barr virus (EBV)–lymphoproliferative disorder

Prognosis of Juvenile Myelomonocytic Leukemia Treatment

With a hematopoietic cell transplant, more than 50% of affected children are cured.

In about 35% to 40% of children who achieve remission with a donor stem cell transplant, the JMML comes back within the first year. A second stem cell transplant has been shown to be effective for these patients.

About half of the children with JMML who get a transplant are still free of leukemia after several years.

Life After Juvenile Myelomonocytic Leukemia

Late effects of hematopoietic cell transplant may include:

  • High blood pressure
  • Diabetes
  • Cardiovascular problems
  • Possible decline in cognitive function, particularly if the transplant occurred in a young child
  • Thyroid problems
  • Growth impairment
  • Metabolic syndrome
  • Osteopenia or osteoporosis
  • Osteonecrosis
  • Delayed, absent, or incomplete puberty
  • Infertility 
  • Lung problems
  • Kidney disease


Reviewed: June 2018

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