Abstract
Juvenile myelomonocytic leukemia (JMML) is a rare pediatric leukemia characterized by mutations in five canonical RAS pathway genes. The diagnosis is made by typical clinical and hematological findings associated with a compatible mutation. Although this is sufficient for clinical decision-making in most JMML cases, more in-depth analysis can include DNA methylation class and panel sequencing analysis for secondary mutations. NRAS-initiated JMML is heterogeneous and adequate management ranges from watchful waiting to allogeneic hematopoietic stem cell transplantation (HSCT). Upfront azacitidine in KRAS patients can achieve long-term remissions without HSCT; if HSCT is required, a less toxic preparative regimen is recommended. Germline CBL patients often experience spontaneous resolution of the leukemia or exhibit stable mixed chimerism after HSCT. JMML driven by PTPN11 or NF1 is often rapidly progressive, requires swift HSCT and may benefit from pretransplant therapy with azacitidine. Because graft-versus-leukemia alloimmunity is central to cure high risk patients, the immunosuppressive regimen should be discontinued early after HSCT.
Highlights
Juvenile myelomonocytic leukemia (JMML) is a pediatric leukemia with shared features of myelodysplastic and myeloproliferative neoplasms, usually manifesting during early childhood with leukocytosis, thrombocytopenia, pronounced monocytosis, splenomegaly, immature precursors on peripheral blood (PB) smear, and bone marrow (BM) blast count below 20% [1,2,3]
We review the current knowledge of genetic and epigenetic properties of JMML and provide detailed recommendations for the clinical management of children diagnosed with this challenging disorder
The Ras pathway is a sequence of kinases in the cell that serves as a chain of communication between extracellular mitogens and the cell nucleus [10]
Summary
JMML is a pediatric leukemia with shared features of myelodysplastic and myeloproliferative neoplasms, usually manifesting during early childhood with leukocytosis, thrombocytopenia, pronounced monocytosis, splenomegaly, immature precursors on peripheral blood (PB) smear, and bone marrow (BM) blast count below 20% [1,2,3]. Its clinical and hematological picture, as well as natural history and outcome, are remarkably diverse [4]. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option, in contrast to a smaller percentage of children who survive long-term without HSCT and eventually experience spontaneous clinical remissions [6,7]. Clinical and molecular risk factors were established to help predict the disease course and guide therapeutic decisions, including age at diagnosis, percentage of fetal hemoglobin (HbF), platelet count, and aberrant DNA methylation patterns [8,9]. We review the current knowledge of genetic and epigenetic properties of JMML and provide detailed recommendations for the clinical management of children diagnosed with this challenging disorder
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