Juvenile Myelomonocytic Leukemia (JMML)

Juvenile Myelomonocytic Leukemia (JMML) is a serious chronic leukemia (cancer of the blood) that affects children mostly aged 4 and under. The average age of patients at diagnosis is 2 years old. The World Health Organization has included JMML in the category of Myelodysplastic and Myeloproliferative disorders. The name JMML now encompasses all diagnoses formerly referred to as Juvenile Chronic Myeloid Leukemia (JCML), Chronic Myelomonocytic Leukemia of Infancy, and Infantile Monosomy 7 Syndrome.

Frequency

 JMML accounts for 1-2% of childhood leukemias each year; in the United States, an estimated 25-50 new cases are diagnosed each year, which also equates to about 3 cases per million children. There is no known environmental cause for JMML. Since about 10% of patients are diagnosed before 3 months of age, it is thought that JMML is a congenital condition in these infants.

Genetics

 About 80% of JMML patients have some sort of genetic abnormality in their leukemia cells that can be identified with laboratory testing. This includes:

 - 15-20% of patients with neurofibromatosis 1 (NF1)

 - 25% of patients with mutations in one of the RAS family of oncogenes (only in their leukemia cells)

 - Another 35% of patients with a mutation in a gene called PTPN11 (again, only in their leukemia cells).

Symptoms

 The following symptoms are typical ones which lead parents and doctors to test for JMML, though children with JMML may exhibit any combination of them:

 - Pallor

 - Fever

 - Infection

 - Bleeding

 - Cough

 - Poor weight gain

 - Macular-papular (discolored but not raised, or small and raised but not containing pus), often red, skin rash

 - Lymphadenopathy (enlarged lymph nodes)

 - Moderate hepatomegaly (enlarged liver)

 - Marked splenomegaly (enlarged spleen)

 - Leukocytosis (high white blood cell count in blood)

 - Absolute monocytosis (high monocyte count in blood)

 - Anemia (low red blood cell count in blood)

 - Thrombocytopenia (low platelet count in blood)

 Children with JMML and Neurofibromatosis 1 (NF1) (about 14% of children with JMML are also clinically diagnosed with NF1, though up to 30% carry the NF1 gene mutation) may also exhibit any of the following symptoms associated with NF1 (in general, only young children with NF1 are at an increased risk of developing JMML):

 - 6 or more café-au-lait (flat, coffee-colored) spots on the skin

 - 2 or more neurofibromas (pea-size bumps that are noncancerous tumors) on or under the skin

 - Plexiform neurofibromas (larger areas on skin that appear swollen)

 - Optic glioma (a tumor on the optic nerve that affects vision)

 - Freckles under the arms or in the groin

 - 2 or more Lisch nodules (tiny tan or brown-colored spots on the iris of the eye)

 - Various bone deformations including bowing of the legs below the knee, scoliosis (curvature of the spine), or thinning of the shin bone

  Children with JMML and Noonan’s Syndrome may also exhibit any of the following most-common symptoms associated with Noonan’s Syndrome:

 - Congenital heart defects, in particular, pulmonic stenosis (a narrowing of the valve from the heart to the lungs)

 - Undescended testicles in males

 - Excess skin and low hair line on back of neck

 - Widely set eyes

 - Diamond-shaped eyebrows

 - Ears that are low-set, backward-rotated, thick outer rim

 - Deeply-grooved philtrum (upper lip line)

 - Learning delays

Diagnosis

 The following criteria are required in order to diagnose JMML:

 All 3 of the following:

 - No Philadelphia chromosome or BCR/ABL fusion gene.

 - Peripheral blood monocytosis >1 x 109/L.

 - Less than 20% blasts (including promonocytes) in the blood and bone marrow (blast count is less than 2% on average)

Two or more of the following criteria:

 - Hemoglobin F increased for age.

 - Immature granulocytes and nucleated red cells in the peripheral blood.

 - White blood cell count>1 x 109/L.

 - Clonal chromosomal abnormality (e.g., monosomy 7).

 - Granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro.

 These criteria are identified through blood tests and bone marrow tests.

 Blood tests: A Combined Blood Count (CBC) will be performed on a child suspected of having JMML and throughout the treatment and recovery of a child diagnosed with JMML.

 Treatment

 There is no internationally accepted treatment protocol for JMML. Currently, 2 clinical treatment protocols most widely used to study JMML and improve treatment for these children are geographically-based:

 - North America: The Children’s Oncology Group (COG) JMML Study

 - Europe: The European Working Group for Myelodysplastic Syndromes (EWOG-MDS) JMML Study

 - Other clinical trials open to patients with JMML may be searched for at the NIH Clinical Trials website.

 The following procedures are used in one or both of the current clinical trials listed above:

 Splenectomy: The theory behind splenectomy is that in JMML, the spleen acts as a trap for leukemic cells, which leads to their enlarged size. The fear is that since radiation and chemotherapy attack active leukemia cells rather than dormant ones, if the spleen is not removed it may harbor JMML cells that can later lead to relapse. The impact of splenectomy for post-transplant relapse, though, is unknown. The COG JMML Study includes splenectomy as a standard treatment for all clinically stable patients. The EWOG-MDS JMML Study allows each child’s physician to determine whether or not a spleenectomy should be done, and large spleens are commonly removed prior to bone marrow transplant. When a splenectomy is scheduled, JMML patients are advised to receive vaccines against Streptococcus pneumoneae and Haemophilus influenza at least 2 weeks prior to the procedure. Following splenectomy, penicillin may be administered daily in order to protect the patient against