Juvenile myelomonocytic leukemia (JMML), formerly termed juvenile chronic myeloid leukemia, is a rare hematopoietic malignancy of childhood accounting for less than 1% of all childhood leukemias. A number of clinical and laboratory features distinguish JMML from adult-type chronic myeloid leukemia. Children with neurofibromatosis 1 (NF1) and Noonan syndrome are at increased risk for developing JMML [2,3] and up to 14% of cases of JMML occur in children with NF1. Approximately 75% of JMML cases harbor one of three mutually exclusive mutations leading to activated RAS signaling, including direct oncogenic RAS mutations (approximately 20%),[5,6] NF1 inactivating mutations (approximately 15% to 25%), or protein tyrosine phosphatase, non-receptor type 11 (PTPN11) (SHP-2) mutations (approximately 35%).[8,9] Mutations of the E3 ubiquitin ligase CBL are observed in 10% to 15% of JMML cases,[10,11] with many of these cases occurring in children with germline CBL mutations.[12,13]CBL germline mutations result in an autosomal dominant developmental disorder that is characterized by impaired growth, developmental delay, cryptorchidism, and a predisposition to JMML. Some individuals with CBL germline mutations experience spontaneous regression of their JMML, but develop vasculitis later in life.CBL mutations are mutually exclusive with RAS/PTPN11 mutations.
Historically, more than 90% of patients with JMML died despite the use of chemotherapy, but with the application of hematopoietic stem cell transplant (HSCT), survival rates of approximately 50% are now reported. 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. Children aged 2 years or older and high blood fetal hemoglobin levels at diagnosis are predictors of poor outcome.[4,16]
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Incidence and Mortality
Estimated new cases and deaths from colon cancer in the United States in 2011:
New cases: 101,340 (colon cancer only).
Deaths: 49,380 (colon...
The role of conventional antileukemia in the treatment of JMML is not defined. The absence of consensus response criteria for JMML complicates determination of the role of specific agents in the treatment of JMML. Among the agents that have shown antileukemia activity against JMML include etoposide, cytarabine, thiopurines (thioguanine and 6-mercaptopurine), and isotretinoin.[17,18] Acute myeloid leukemia (AML) induction chemotherapy can induce remissions in children with JMML, but resistant disease is much more common for JMML than for de novo AML and the role of AML-type therapy in the treatment of JMML is not clear.
HSCT offers the best chance of cure for JMML.[15,20,21] A report from the European Working Group on Childhood myelodysplastic syndrome notes a 55% and 49% 5-year event-free survival for a large group of children with JMML transplanted with HLA-identical matched family donors or unrelated donors, respectively. The trial included 100 recipients at multiple centers using a common preparative regimen of busulfan, cyclophosphamide, and melphalan, with or without antithymocyte globulin. Recipients had been treated with varying degrees of pretransplant chemotherapy or differentiating agents and some patients had splenectomy performed. Multivariate analysis showed no effect on survival of prior AML-like chemotherapy versus none or low-dose chemotherapy, the presence or absence of a spleen or difference in spleen size, or related versus unrelated donors. Only gender and age older than 4 years were shown to be poor prognostic factors for outcome (relative risk [RR] 2.24 [1.07-4.69], P = 0.032, RR 2.22 [1.09-4.50], P = 0.028 for older age and female gender, respectively). Disease recurrence is the primary cause of treatment failure for children with JMML following HSCT and occurs in 30% to 40% of cases.[15,20,21]