Juvenile myelomonocytic leukemia (JMML) is a rare form of chronic leukemia (cancer of the blood) that affects children, commonly those aged four and younger. 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. The average age of patients at diagnosis is two (2) years old. The World Health Organization has included JMML as a subcategory of myelodysplastic and myeloproliferative disorders.
Signs and symptoms The following symptoms are typical ones that lead to testing for JMML, though children with JMML may exhibit any combination of them:
pallor fever infection bleeding cough poor weight gain a maculopapular rash (discolored but not raised, or small and raised but not containing pus) lymphadenopathy moderate hepatomegaly marked splenomegaly leukocytosis absolute monocytosis anemia thrombocytopenia Most of these conditions show common nonspecific signs and symptoms. 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, or thinning of the shin bone. Noonan syndrome (NS) may predispose to the development of JMML or a myeloproliferative disorder (MPD) associated with NS (MPD/NS), which resembles JMML in the first weeks of life. However, MPD/NS may resolve without treatment. 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
Genetics About 90% of JMML patients have some form of a genetic abnormality in their leukemia cells that is identifiable 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).
Diagnosis The following criteria are required in order to diagnose JMML: All 4 of the following:
No Philadelphia chromosome or BCR/ABL fusion gene. Peripheral blood monocytosis >1 billion/L. Less than 20% blasts (including promonocytes) in the blood and bone marrow (blast count is less than 2% on average) Splenomegaly At least one of:
Mutation in RAS or PTPN11 Diagnosis of neurofibromatosis 1 Chromosome 7 monosomy Or 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 >10 billion/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. The differential diagnosis list includes infectious diseases like Epstein–Barr virus, cytomegalovirus, human herpesvirus 6, histoplasma, mycobacteria, and toxoplasma, which can produce similar symptoms.
Treatment There are two widely used JMML treatment protocols: stem cell transplantation and drug therapy. There are four common subtypes of internationally accepted treatment protocols, which are based and clinically tested in the geographical location of the patient:
North America: the Children's Oncology Group (COG) JMML study Europe: the European Working Group for Myelodysplastic Syndromes (EWOG-MDS) JMML study The following procedures are used in one or both of the current clinical approaches listed above:
Splenectomy The theory behind splenectomy in JMML is that the spleen may trap leukemic cells, leading to the spleen's enlargement, by harboring dormant JMML cells that are not eradicated by radiation therapy or chemotherapy for the active leukemia cells, thus leading to later relapse if the spleen is not removed. However, the impact of a splenectomy on post-transplant regression is unknown. The COG JMML study includes splenectomy as a standard component of treatment for all clinically stable patients. The EWOG-MDS JMML study allows each child's physician to determine whether or not a splenectomy 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 pneumoniae and Haemophilus influenza at least two weeks prior to the procedure. Following splenectomy, penicillin may have to be administered daily to protect the patient against bacterial infections that the spleen would otherwise have protected against; this daily preventative regimen will often continue indefinitely.
Chemotherapy The role of chemotherapy or other pharmacologic treatments against JMML before bone marrow transplant has not undergone final clinical testing, and its importance is still unknown. Chemotherapy by itself has proven unable to bring about long-term survival in JMML.
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