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Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Juvenile Myelomonocytic Leukemia

Table 5. Diagnostic Criteria for Juvenile Myelomonocytic Leukemia (JMML) continued...

Children with neurofibromatosis 1 (NF1) and Noonan syndrome are at increased risk for developing JMML,[6,7] and up to 14% of cases of JMML occur in children with NF1.[8] Approximately 75% of JMML cases harbor one of three mutually exclusive mutations leading to activated RAS signaling, including direct oncogenic RAS mutations (approximately 20%),[9,10] NF1 inactivating mutations (approximately 15%–25%),[11] or protein tyrosine phosphatase, non-receptor type 11 (PTPN11) (SHP-2) mutations (approximately 35%).[12,13] Mutations of the E3 ubiquitin ligase CBL are observed in 10% to 15% of JMML cases,[14,15] with many of these cases occurring in children with germline CBL mutations.[16,17]CBL germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML.[16] Some individuals with CBL germline mutations experience spontaneous regression of their JMML, but develop vasculitis later in life.[16]CBL mutations are mutually exclusive with RAS/PTPN11 mutations.[14] Noonan syndrome, which is usually inherited as an autosomal dominant condition, but can also arise spontaneously, is characterized by facial dysmorphism, short stature, webbed neck, neurocognitive abnormalities, and cardiac abnormalities. Importantly, some children with Noonan syndrome have a hematologic picture indistinguishable from JMML that self-resolves during infancy, similar to what happens in children with Down syndrome and transient myeloproliferative disorder.[3]

Historically, more than 90% of patients with JMML died despite the use of chemotherapy,[18] but with the application of hematopoietic stem cell transplant (HSCT), survival rates of approximately 50% are now reported.[19] Patients appeared to follow three distinct clinical courses: (1) rapidly progressive disease and early demise; (2) transiently stable disease followed by progression and death; and (3) clinical improvement that lasted up to 9 years before progression or, rarely, long-term survival. Favorable prognostic factors for survival after any therapy include being younger than 3 years, having a platelet count of greater than 33 × 109 /L, and low age-adjusted fetal hemoglobin levels.[8,20] In contrast, being older than 3 years and having high blood fetal hemoglobin levels at diagnosis are predictors of poor outcome.[8,20] It remains controversial whether specific mutations are predictive of outcome.[21]

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