NORD gratefully acknowledges the Children’s Tumor Foundation and Elliot Stieglitz, MD, Assistant Professor, UCSF School of Medicine, for assistance in the preparation of this report.
Juvenile myelomonocytic leukemia (JMML) is a rare 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 monocytes. 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. JMML cells can accumulate in other organs of the body including the lungs, skin, liver, and intestines. JMML is an aggressive and difficult to treat disease but is currently cured in about 50% of cases. Currently, the only effective treatment for most patients is allogeneic hematopoietic stem cell transplantation (HSCT). The exact, underlying causes of JMML are unknown, but nearly all patients will have a mutation that changes the DNA inside their blood cells in a RAS gene or in a gene that controls the activation levels of Ras proteins.
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 that lead to cytopenias (low red cell and platelet count). 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, 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 and result in labored breathing and a lack of appetite. 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, nausea 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. Rarely, these rashes represent infiltration of the leukemia cells into the skin. 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. Unfortunately, it is very challenging to identify these patients at diagnosis.
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 most patients with 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. NF1 is a tumor suppressor gene and certain children are born with a mutation in this gene that causes neurofibromatosis, type 1 (NF1). Children with NF1 are greatly increased risk of JMML because all of their cells carry one mutated copy of the NF1 gene. These children are at risk to develop JMML when they acquire a mutation that damages the other (normal) copy of this gene or delete it entirely. 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.
In the last few years, several research groups have shown that patients who have additional mutations (also called secondary mutations) in genes besides NF1, PTPN11, CBL, or RAS have a reduced chance of being cured compared to those patients who only have one mutation. In particular, a gene called SETBP1 is mutated in about a quarter of JMML patients and these children appear to have a greater chance of relapse and death.
With an incidence of 1 in 3000, NF1 is the most common familial cancer syndrome. Affected persons 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. However, many of these findings may not be present in very young children. For more information on this disorder, choose “neurofibromatosis” as your search term in the NORD Rare Disease Database.
Other genetic disorders are also associated with JMML. Some children with Noonan syndrome, which is most often caused by mutations in the 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 appears earlier than sporadic JMML, and can appear in infancy. Additionally, this 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 affected children may have additional symptoms including impaired growth, developmental delays, and failure of the testes to descend into the scrotum (cryptorchidism). Children with CBL mutations also 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.
JMML accounts for ~ 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 0.6 per million. Childhood leukemia as a whole is estimated to affect approximately 4,000 children each year in the United States.
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 five findings that are required for a diagnosis of JMML including the presence of a large spleen, the absence of the Philadelphia BCR/ABL1 fusion gene (this 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 and other types of leukemia).
Additionally, a patient should meet one criterion from category 2: a somatic mutation in RAS, NF1, PTPN11 or CBL, a clinical diagnosis or NF1 or monosomy 7. If the patient does not meet criteria from category 2, two of the following from category 3 suffice: A white blood cell count > 10,000/uL, circulating myeloid blasts, increased fetal hemoglobin, any cytogenetic abnormality, or hypersensitivity of myeloid progenitor cells to cytokine granulocyte macrophage colony stimulating factor (GM-CSF).
Clinical Testing and Workup
A complete blood count (CBC) can be taken to evaluate the size, number, and maturity of blood cells. In JMML, the CBC frequently reveals 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 useful test for diagnosing. This exam requires bone marrow or peripheral blood samples to be sent to a specialized lab. GM-CSF is a growth factor, a substance that is required to stimulate the growth of living cells. Increasing amounts of GM-CSF are added to the samples. Healthy cells do not grow when low levels of GM-CSF are present, but JMML cells 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 reveal characteristic RAS, PTPN1, NF1, or CBL gene and this is now used routinely at pediatric centers to evaluate children suspected of having JMML.
The treatment of JMML requires 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. Combination 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 preparing a patient 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 or an unrelated donor including cord blood units. 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 remissions. 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 in 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.
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. One of the most promising therapies being investigated for JMML is called a MEK inhibitor, which will be tested in a Children’s Oncology Group sponsored trial, ADVL1521 for children with relapsed or refractory JMML.
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. Azacitidine is currently being testing in clinical trials in Europe.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov 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
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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