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Juvenile Myelomonocytic Leukemia

NORD is very grateful to Prof. Franco Locatelli, Full Professor of Pediatrics, University of Pavia, Director, Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy, for assistance in the preparation of this report.

Synonyms of Juvenile Myelomonocytic Leukemia

  • chronic myelomonocytic leukemia of infancy
  • JMML

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric form of blood cancer. JMML predominately affects young children, most often developing in children under the age of 4. The male/female ratio of affected children is 2-3:1.The disorder is characterized by the uncontrolled growth of an immature form of a specific type of white blood cell known as monocyte precursors. These abnormal cells accumulate in the bone marrow crowding out other healthy cells. The bone marrow produces specialized cells (hematopoietic stem cells) that grow and eventually develop into red blood cells, white blood cells and platelets. These cells are released into the bloodstream to travel throughout the body and perform specific functions. Red blood cells deliver oxygen to the body; white blood cells help the body to fight infection; and platelets allow the body to form clots to stop bleeding. When abnormal cells accumulate in the bone marrow, they can affect the production and function of these healthy blood cells. Abnormal cells can accumulate in other tissues and organs of the body such as the lungs, skin, liver, and intestines. JMML is an aggressive and difficult to treat disease. Currently, the main therapeutic option is allogeneic hematopoietic stem cell transplantation. The exact, underlying cause of JMML is unknown.

Over the years, several different classification systems have been used to define JMML. Currently, the World Health Organization (WHO) classifies JMML as an overlap myelodysplastic syndrome/myeloproliferative disorder because JMML shares characteristics with both of these groups of disorders. Myelodysplastic syndromes are defined as a group of disorders that are characterized by disordered development of blood cells in the bone marrow. Myeloproliferative disorders are defined as a group of disorders characterized by the overproduction (proliferation) of the three main blood cell lines, red or white blood cells or platelets. The first case of JMML was described in the medical literature in 1924.


Although the symptoms below are common to JMML, affected children can potentially exhibit these symptoms in any combination. Among individual cases, the specific symptoms and signs can vary. Symptoms can develop over a period of weeks or months.

Pallor, fatigue, weakness, fevers for no known reason, and a dry cough are common symptoms of JMML. Pallor is specifically described as an abnormal paleness of the skin. In some cases, affected children may develop an abnormally enlarged liver and/or spleen (hepatosplenomegaly), which can cause a swollen (distended) abdomen. The liver may be mildly or markedly enlarged, but the spleen is usually markedly increased in size. Abnormally enlarged lymph nodes (lymphadenopathy) can also occur.

Certain symptoms in children with JMML may result from abnormal bone marrow function due to cancer cells crowding out healthy cells. Anemia occurs when there are low levels of circulating red blood cells and may be associated with pallor, fatigue, and lightheadedness. Thrombocytopenia occurs when there are low levels of platelets resulting in easy bruising and bleeding of the skin, mouth, and nose. Although individuals with JMML have too many white blood cells, these cells do not function normally and affected children may develop recurrent infections such as bronchitis and tonsillitis.

Decreased appetite, poor weight gain, irritability, and failure to thrive may also occur in children with JMML. Some affected children may develop café au lait spots, which are smooth coffee-colored lesions on the skin, and a maculopapular rash, which is a red rash characterized by raised spotted lesions. Bone and joint pain has also been reported in affected children.

In very rare cases, certain children with specific gene mutations have experienced spontaneously resolution of their condition.


The exact underlying cause of JMML is unknown. Investigators are conducting ongoing basic research to learn more about the many factors that may result in cancer.

In individuals with cancer, including JMML, malignancies may develop due to abnormal changes in the structure and orientation of certain cells known as oncogenes or tumor suppressor genes. Oncogenes control cell growth; tumor suppressor genes control cell division and ensure that cells die at the proper time. The specific cause of changes to these genes is unknown. However, current research indicates that abnormalities of DNA (deoxyribonucleic acid), which is the carrier of the body’s genetic code, are the underlying basis of cellular malignant transformation. In JMML, these abnormal genetic changes appear to occur spontaneously for unknown reasons (sporadically).

DNA mutations that cause JMML have been linked to a variety of different genes located on various chromosomes. Most of these genetic mutations are acquired during life, are found only in the cancer cells and are not passed on to an affected individual’s children. In JMML, approximately 20%-25% of cases are due to a mutation in a gene in the RAS family of oncogenes. In approximately 15%-20% of cases there is a mutation in NF1 genes. In approximately 35% of cases there is a mutation of the PTPN11 gene. Mutations of the CBL gene are observed in approximately 10%-15% of cases. In approximately 10% of cases there is no identifiable gene mutation.

Abnormalities of chromosome structure or number (cytogenetic abnormalities) have also been reported in children with JMML. Approximately 30% of children have a deletion of the chromosome 7. Additional chromosomal anomalies have been reported in some children. The specific genes associated with these chromosomal anomalies are unknown.

Children with certain disorders associated with the abovementioned gene mutations are a greater risk of developing JMML than the general population. Neurofibromatosis type 1 is a rare disorder caused by mutations in the NF1 gene. Affected children develop multiple noncancerous (benign) tumors of the nerves and skin (neurofibromas) and areas of decreased or increased coloration of the skin. Café-au-lait spots are common in neurofibromatosis type 1. Affected children have a 500-fold increased risk of developing JMML or a related form of cancer. For more information on this disorder, choose "neurofibromatosis" as your search term in the NORD Rare Disease Database.

Some children with Noonan syndrome, which is caused by mutations of PTPN11 gene, may develop a JMML-like disorder during the first year of life. Noonan syndrome is characterized by distinctive facial features, heart abnormalities, skeletal malformations, and growth retardation. JMML associated with Noonan syndrome tends to develop earlier, during infancy, than in sporadic JMML. Additionally, the JMML-like disorder usually resolves without treatment (spontaneously) by the age of 1. For more information on this disorder, choose "Noonan" as your search term in the NORD Rare Disease Database.

CBL mutations can occur as germline events (mutations that can be passed on to offspring) and in these cases affect children may have additional symptoms including impaired growth, developmental delays, and failure of the testes to descend into the scrotum (cryptorchidism). Children with homozygous CBL mutations have a high rate of spontaneous resolution of JMML. However, these individuals have a high risk of developing vasculitis, a serious condition characterized by inflammation of the blood vessels, which can result in weakening, narrowing or scarring of the vessels.

Affected Populations

JMML accounts for less than 2-3% of all childhood leukemias. The mean age at diagnosis is 2. Males are affected more often than females by a ratio of approximately 2:1. Studies conducted in Denmark and British Columbia placed the incidence at 1.2 cases per million in children each year. In the UK, a study found a lower incidence rate of .6 per million. Childhood leukemia as a whole is estimated to affect approximately 3,000 children each year in the United States.

Related Disorders

Symptoms of the following disorders can be similar to those of JMML. Comparisons may be useful for a differential diagnosis.

Other forms of leukemia are included in the differential diagnosis of JMML. These forms include chronic myelomonocytic leukemia (CMML), acute myeloid leukemia and chronic myeloid leukemia. CMML is extremely similar to JMML on both the clinical and molecular level and is also classified as an overlap myelodysplastic/myeloproliferative disorder. CMML commonly affects adults usually between the ages of 65-75 years of age. However, in rare cases, CMML can occur in children and may be difficult to distinguish from JMML. Common symptoms include fatigue, weakness, unexplained bruising, chronic infections, an abnormally enlarged liver, and an abnormally enlarged spleen.

Certain bacterial and viral infections can cause a response (leukemoid reaction) in the body that can resemble the clinical symptoms of JMML. During a leukemoid reaction there is a temporarily elevated white blood cell count in response to an infection or similar trigger. Additional nonspecific findings including fever and splenomegaly may also be present.

Standard Therapies

A diagnosis of JMML is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis of JMML is usually considered after other conditions have been ruled out.

Different sets of diagnostic criteria have been established for individuals suspected of having JMML. Such criteria are often revised and updated and more than one set of criteria may exist at one time. One common set of criteria lists three findings that are required for a diagnosis of JMML including the absence of the Philadelphia BRC/AB1 fusion gene (this chromosomal abnormality is associated with several forms of cancer including chronic myeloid leukemia); an absolute monocyte count of greater than 1,000/µL; and less than 20% blasts in the bone marrow (blasts are the immature/abnormal white blood cells that characterize JMML).

In addition, affected individuals will have two of the four following criteria: white blood cell count of > 10,000/µL; circulating myeloid precursors; increased fetal hemoglobin levels based on age; and hypersensitivity of hematopoietic stem cells to a protein known as granulocyte-macrophage colony-stimulating factor (GM-CSF).

Sometimes the presence of splenomegaly is included as being required for a diagnosis of JMML.

In recent years, additional criteria have been developed, which include identifying genetic/chromosomal abnormalities such as somatic mutations of the RAS, PTPN1, NF1, or CBL genes or monosomy 7.

Clinical Testing and Workup
Complete blood count (CBC) can be taken to evaluate the size, number and maturity of blood cells. A CBC can reveal high levels of white blood cells and low levels of red blood cells and platelets.

A bone marrow aspiration and biopsy is a procedure in which a small amount of fluid and cells (aspiration) are taken from the bone marrow along with a piece of bone. The biopsied material is then examined under a microscope for changes indicative of JMML.

A GM-CSF hypersensitivity assay is a test useful to diagnose JMML. GM-CSF is a growth factor, a substance that is required to stimulate the growth of living cells. This exam requires bone marrow or peripheral blood samples to be sent to a specialized lab. Increasing amounts of GM-CSF are added to the samples. Healthy cells will not grow when low levels of GM-CSF are present, but JMML cells will grow. So, if a patient’s sample responds to GM-CSF, it is indicative of JMML. There are disadvantages to this test, specifically that it requires a long turnaround time (weeks) and is not widely available (it can only be done in a specialized lab). Researchers are working to develop a quicker test based upon the same principle of GM-CSF hypersensitivity assay.

Molecular genetic testing can potentially reveal characteristic mutations of specific genes associated with JMML such as RAS, PTPN1, NF1, or CBL mutations.

The treatment of JMML may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in the diagnosis and treatment of cancer in children (pediatric oncologists), physicians who specialize in the diagnosis and treatment of blood disorders (hematologists), surgeons, oncology nurses, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.

Individuals with JMML and their families are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families.

Historically, most chemotherapeutic regimens have had limited success in treating JMML. Chemotherapy, which is the use of multiple cancer drugs to kill cancer cells, may be used to treat children with JMML initially to keep the disorder under control while prepping for allogeneic hematopoietic stem cell transplant. However, whether pretransplant, high-dose chemotherapy improves the outcome of a stem cell transplant is unproven.

Currently, the only potentially curative option is allogeneic hematopoietic stem cell transplantation, a type of bone marrow transplant. Hematopoietic stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g., red blood cells, white blood cells, platelets). In allogeneic stem cell transplantation, intense chemotherapy is given to kill off JMML cells. However, healthy blood cells are also affected and the bone marrow is essentially wiped out. Affected individuals then receive stem cells donated from another person, usually from a closely matched family member. The transplanted cells travel to the bone marrow where they begin to produce healthy blood cells. Stem cell transplants have the potential to correct the inherent, genetic defect of the white blood cells of individuals with JMML. However, stem cell transplants can cause severe, even life-threatening complications.

Graft rejection and graft-versus-host disease are potential complications with any transplant procedure, including bone marrow transplants. Complications of graft-versus-host disease from a bone marrow transplant may range from mild to life-threatening. Drugs may be used to prevent or treat graft rejection or graft-versus-host disease. (For more information, choose "graft versus host disease" as your search term in the Rare Disease Database.)

Approximately 50% of children with JMML who undergo hematopoietic stem cell transplant will achieve long-term remission. However, in approximately 35-40% cases, relapse will occur, often within the first year. In these cases, a second stem cell transplant can be performed and have proven to be beneficial for many individuals.

Some individuals with JMML have undergone the surgical removal of the spleen (splenectomy) as part of their treatment plan. However, the necessity and benefit of this procedure is controversial. Some researchers believe that the spleen harbors leukemic cells that can be a potential source for relapse. However, the removal of the spleen increases the risk of infection and has shown no statistical benefit in terms of probability of definitive cure of the disease. Pretransplant splenectomy is generally no recommended unless clinically indicated for symptomatic relief.

Additional treatment is symptomatic and supportive. For example, antibiotics may be given to help prevent or fight infections.

Investigational Therapies

Targeted therapies are being studied for the treatment of children with JMML. Targeted therapies are drugs and other substances that prevent the growth and spread of cancer by blocking or inhibiting certain specific molecules (often proteins) that are involved in the development of specific cancers (these proteins are produced by mutated genes). Generally, targeted therapies are less toxic than other treatments for cancer. Targeted therapies being investigated for JMML include farnesyltransferase inhibitors, RAF1 inhibitors, Janus kinase (JAK) inhibitors.

Spontaneous growth of JMML myeloid progenitors in vitro can be inhibited by 13-cis-retinoic acid (isotretinoin). Based on these laboratory observations, 10 children with JMML were treated with isoretinoin daily. Response was evaluated by the reduction of WBC and decrease of organomegaly. Two children achieved complete remissions, and four had a partial or a minimal response. The remaining four had disease progression. The investigators concluded that isotretinoin could induce durable clinical and laboratory responses. This interpretation was questioned because the mean age of the patients was 10 months, and young age is a favorable prognostic feature in JMML. The value of this agent remains to be determined.

DNA-hypomethylating agents, such as decitabine or azacitidine, have been studied extensively in adults with myelodysplastic syndromes. The first case report on azacitidine therapy in a child with JMML, monosomy 7 and KRAS mutation described an impressive clinical and hematologic response, including reduction of liver and spleen size and resolution of monocytosis, thrombocytopenia, and elevated blast count. While it is unlikely that methylating agents will cure JMML, these drugs may play an important role in cytoreduction prior to HSCT.

Information on current clinical trials is posted on the Internet at All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010

For information about clinical trials sponsored by private sources, in the main, contact:

For more information about clinical trials conducted in Europe, contact:

Juvenile Myelomonocytic Leukemia Resources

NORD Member Organizations:

(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at

Other Organizations:


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Loh ML, Sakai DS, Flotho C, et l. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood. 2009;114:1859-1863.

Locatelli F, Nollke P, Zecca M, et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood. 2005;105:410-419.

Tartaglia M, Niemeyer CM, Fragale A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34:148-150.

Leukemia & Lymphoma Society. Chronic Myelomonocytic Leukemia (CMML) and Juvenile Myelomonocytic Leukemia (JMML). July 13, 2012. Available at:
Accessed On: November 15, 2012.

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Report last updated: 2013/05/08 00:00:00 GMT+0

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