Juvenile Myelomonocytic Leukemia (JMML)

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What is Juvenile Myelomonocytic Leukemia?

Juvenile myelomonocytic leukemia (JMML) is a rare cancer of the blood and bone marrow.

JMML occurs most often in children younger than 4 years. About 10% of all cases develop in infants younger than 3 months.

Each year 1-2 children out of 1 million are diagnosed with JMML in the United States. That is 25-50 new cases a year.

JMML occurs when too many blood stem cells in the bone marrow become white blood cells called monocytes and myelocytes. They build up in the liver, spleen, bone marrow, and blood. The body can’t fight infection as well. The blood doesn’t function correctly.

JMML can be aggressive. Hematopoietic cell transplant is the most common treatment. But in 15% of cases, JMML will go away on its own without treatment. Doctors will closely monitor these cases.

The World Health Organization (WHO) classifies JMML among the myelodysplastic/myeloproliferative diseases because it has features of both types of diseases. JMML also shares some of the features of chronic myelomonocytic leukemia in adults.

Causes and Risk Factors of Juvenile Myelomonocytic Leukemia

Boys are twice as likely to be diagnosed as girls.

About 90% of patients have changes in certain genes that cause this cancer to develop. These changes are called mutations:

A gene mutation can either be inherited from a parent or it can occur in the body some time during the person’s life.
An inherited mutation is called a germline mutation.
Other mutations are called somatic or acquired mutations.
Knowing the specific genetic mutation and whether it is inherited or acquired later is important. This information helps determine treatment approaches.
But just because someone has a genetic mutation or condition does not mean he or she will develop cancer.

Genetic Mutations in JMML

The names of the most common mutated genes are:

Gene	Percentage of cases	Features	Treatment
PTPN11	38%	There is a high chance of relapse. Associated with Noonan syndrome	Hematopoietic cell transplant
NFI	12%	Patients are usually older than infants at diagnosis. They may have a higher platelet count and percentage of bone marrow blasts than occur in other subtypes of JMML.	Hematopoietic cell transplant
CBL	9%	One or more café-au-lait spots on skin may be observed. This subtype involves a missing form of CBL gene in blood-forming cells. In some cases, the disease will go away on its own without treatment.	Hematopoietic cell transplant may be an option.
KRAS	18%	This subtype occurs mostly in infants. Frequent association with monosomy 7 Low risk of relapse after hematopoietic cell transplant	Hematopoietic cell transplant
NRAS	14%	In some cases, the leukemia will regress on its own without treatment. This typically occurs in infants or in cases with G12S mutation. In other cases, there is a high relapse rate after hematopoietic cell transplant. This typically occurs in older children with high level of fetal hemoglobin.	Close monitoring in cases that are likely to have spontaneous remission. Hematopoietic cell transplant may be an option.

Signs and Symptoms of Juvenile Myelomonocytic Leukemia

Signs and symptoms of JMML are often similar to other childhood leukemias and blood disorders.

Many children will have:

Fever
Signs and symptoms of an upper respiratory infection, such as bronchitis or tonsillitis
Enlarged spleen
Painless swelling of lymph nodes
Skin rash

Other signs and symptoms of JMML may include:

Paleness of skin
Easy bruising or bleeding of the skin, nose, and mouth caused by low platelets
Dry cough
Feeling very tired
Anemia

Diagnosis of Juvenile Myelomonocytic Leukemia

Diagnosis of JMML is sometimes challenging. JMML has similar symptoms to viral or bacterial infections and other childhood leukemias and blood disorders.

Chromosomal and genetic testing is important because the type of mutation can help determine treatment.

Tests to diagnose JMML include:

Physical exam and history
Blood tests (complete blood count and blood chemistry)
Bone marrow tests
Tests to examine chromosome and gene changes
Genetic testing (skin or hair follicles) to help determine if mutations are inherited or acquired (occurring after birth).

The doctor will check general signs of health. That includes signs of disease such as lumps or anything else that seems unusual. The doctor will examine the eyes, mouth, skin, and ears. He or she may conduct a nervous system exam. The doctor will also feel the patient’s abdomen for signs of an enlarged spleen, liver, and lymph nodes.

The doctor will take a record the patient’s personal and family medical history. It is important to know this information. Many patients with JMML inherited the genetic mutation through their mother or father. The doctor will note any signs that may indicate an inherited genetic disorder such as neurofibromatosis 1 or Noonan syndrome.
Types of blood tests may include:
- Complete blood count — This test measures red blood cells, white blood cells, platelets, and hemoglobin. Increased numbers of monocytes, abnormal forms of myelocytes and monocytes, and low platelet counts may indicate JMML. It may also show higher levels of hemoglobin F, also known as fetal hemoglobin.
- Blood chemistry studies — This test measures 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, patients may have a higher than normal amount of gammaglobulin, an infection-fighting protein.
Bone marrow tests, such as bone marrow aspiration and biopsy, may suggest JMML but do not confirm a diagnosis.

If blood and bone marrow tests are suggestive of JMML, doctors will order more tests to pinpoint the type. These tests may include:
- Cytogenetic analysis
- Molecular and genetic testing
Cytogenetic Analysis and Molecular and Genetic Testing

Cytogenetic analysis

Cytogenetic analysis may show certain changes in chromosomes.

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. They are added to cells or tissues on a glass slide. These pieces of DNA light up when attached to certain genes or areas of chromosomes on the slide.

A cytogenetic abnormality called monosomy 7 is found in 25 percent of JMML cases and is one of the criteria for JMML.

Molecular and genetic testing

The doctor may recommend laboratory tests to identify specific genes, proteins, and other factors. Doctors use this information to establish the diagnosis and choose treatment options.

For example, doctors may prescribe less intensive treatments or observation only to children whose leukemia shows mutations associated with a good outcome. On the other hand, doctors may prescribe more intensive treatments, including hematopoietic cell transplant (commonly known as bone marrow transplant or stem cell transplant) for patients with a leukemia with mutations associated with poorer outcomes.

Criteria for JMML diagnosis

Diagnostic Criteria for Juvenile Myelomonocytic Leukemia (JMML) Per the 2016 Revision to World Health Organization Classification

Category 1 (All are Required)	Category 2 (One is Sufficient)^a	Category 3 (Patients Without Genetic Features Must Have the Following in Addition to Category 1^b)
Clinical and Hematologic Features	Genetic Studies	Other Features
Absence of the BCR-ABL1 fusion gene	Somatic mutation in KRAS, NRAS, or PTPN11 (germline mutations need to be excluded)	Monosomy 7 or other chromosomal abnormality, or at least 2 of the criteria listed below:
>1 × 10⁹/L circulating monocytes	Clinical diagnosis of NF1 or NF1 gene mutation	— Circulating myeloid or erythroid precursors
<20% blasts in the peripheral blood and bone marrow	Germline CBL mutation and loss of heterozygosity of CBL	— Increased hemoglobin F for age
Splenomegaly		— Hyperphosphorylation of STAT5
		— GM-CSF hypersensitivity

GM-CSF = granulocyte-macrophage colony-stimulating factor; NF1 = neurofibromatosis type 1.
^aPatients who are found to have a category 2 lesion need to meet the criteria in category 1 but do not need to meet the category 3 criteria. Patients who are not found to have a category 2 lesion must meet the category 1 and 3 criteria.
^bNote that only 7% of patients with JMML will NOT present with splenomegaly, but virtually all patients develop splenomegaly within several weeks to months of initial presentation.
Source: PDQ Cancer Information Summaries https://www.ncbi.nlm.nih.gov/books/NBK66019/#CDR0000062896__78

Treatment for Juvenile Myelomonocytic Leukemia

Treatment ranges from watchful observation to hematopoietic cell transplantation.

Doctors prescribe treatment based on how well patients are predicted to respond. This approach is called risk-adapted or risk-stratified.

The course of the disease and treatment response varies widely. Doctors may use age, level of fetal hemoglobin, and platelet count in part to help predict these things. Most children require transplant. In about 15% of cases, the disease will eventually resolve on its own without treatment.

Risk-Adapted Treatment

Low-risk

Low-risk includes patients with inherited mutation of the PTPN11 (Noonan syndrome) or CBL (CBL syndrome). Sometimes these cases go into remission without treatment.

Physicians closely watch these patients. Patients may have chemotherapy if they develop signs and symptoms such as an enlarged spleen and recurrent infections.

Intermediate-risk

Immediate risk includes patients with a somatic NRAS mutation who are younger than 1.

Patients are 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

High-risk may include patients with somatic KRAS, NF1, PTPN11 mutations. These cases are either predicted to be resistant to treatment (refractory) or the disease is likely to recur (relapse).

Doctors may prescribe chemotherapy with the drugs fludarabine and cytarabine.

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 an infusion of natural killer cells, a type of white blood cell. Chemotherapy, or in limited cases, targeted therapy may be options.

At present, hematopoietic cell transplant (also known as bone marrow transplant or stem cell transplant) is the only treatment that can provide cure. Patients must have a suitable donor to get this treatment.

The transplant should occur as soon as possible after diagnosis because successful transplant rates are highest in younger children. If the JMML relapses, a second hematopoietic cell and natural killer cell transplant have shown success.

Umbilical cord blood transplants are also a treatment option.

Other treatments may include:

Chemotherapy
Targeted therapy drugs
Surgical removal of the spleen if it has become severely enlarged

Treatment of children with inherited syndromes may be different that of children who acquired the mutation.

Prognosis of Juvenile Myelomonocytic Leukemia Treatment

A hematopoietic cell transplant may successfully treat more than 50% of cases.
In about 35% to 40% of children who achieve remission with a transplant, the JMML comes back within the first year. Doctors may recommend a second transplant.

Focus of Current JMML Research

Developing targeted therapies is a current focus of research. Scientists are studying new ways to create renewable sources of cells for research on JMML. This may help in researching potential new targeted therapy approaches.

Researchers are developing better ways to predict the course of disease. These include study of a cellular process called DNA methylation. Diseases such as cancer may develop when DNA methylation is abnormal.

Researchers are looking for ways to reduce the rate of relapse that occurs in 35% of cases. One approach under study is an oral MEK inhibitor drug called trametinib in relapsed JMML.

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Reviewed: December 2019