Juvenile myelomonocytic leukemia-A comprehensive review and recent advances in management

Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric myelodysplastic/myeloproliferative neoplasm overlap disease. JMML is associated with mutations in the RAS pathway genes resulting in the myeloid progenitors being sensitive to granulocyte monocyte colony-stimulating factor (GM-CSF). Karyotype abnormalities and additional epigenetic alterations can also be found in JMML. Neurofibromatosis and Noonan's syndrome have a predisposition for JMML. In a few patients, the RAS genes (NRAS, KRAS, and PTPN11) are mutated at the germline and this usually results in a transient myeloproliferative disorder with a good prognosis. JMML with somatic RAS mutation behaves aggressively. JMML presents with cytopenias and leukemic infiltration into organs. The laboratory findings include hyperleukocytosis, monocytosis, increased hemoglobin-F levels, and circulating myeloid precursors. The blast cells in the peripheral blood/bone-marrow aspirate are less than 20% and the absence of the BCR-ABL translocation helps to differentiate from chronic myeloid leukemia. JMML should be differentiated from immunodeficiencies, viral infections, intrauterine infections, hemophagolymphohistiocytosis, other myeloproliferative disorders, and leukemias. Chemotherapy is employed as a bridge to HSCT, except in few with less aggressive disease, in which chemotherapy alone can result in long term remission. Azacitidine has shown promise as a single agent to stabilize the disease. The prognosis of JMML is poor with about 50% of patients surviving after an allogeneic hematopoietic stem cell transplant (HSCT). Allogeneic HSCT is the only known cure for JMML to date. Myeloablative conditioning is most commonly used with graft versus host disease (GVHD) prophylaxis tailored to the aggressiveness of the disease. Relapses are common even after HSCT and a second HSCT can salvage a third of these patients. Novel options in the treatment of JMML e.g., hypomethylating agents, MEK inhibitors, JAK inhibitors, tyrosine kinase inhibitors, etc. are being explored.

Keywords: Juvenile myelomonocytic leukemia; azacitidine; hematopoietic stem cell transplant; monocytosis; mutations; myelodysplastic; myeloproliferative.

Figure 1

The RAS Signalling Pathway (90% of JMML cases involve mutations in the RAS pathway): N/KRAS proteins (in Pink) alternate between “ACTIVE” and “INACTIVE” states. They are activated in response to signals transferred by surface receptors resulting in the recruitment of guanine exchange factors (GEFs), which stimulates binding of GTP to RAS in place of GDP. The RAS is interrupted by GTPase-activating a protein (GAPS) which hydrolyses GTP to GDP. Mutations of RAS (*) prevent the conversion of RAS-GTP to RAS-GDP - resulting in its constitutive stimulation and hence activation of downstream effectors to induce cell proliferation, differentiation, and survival; PTPN11 gene encodes for Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2). SHP2 binds to RAS and dephosphorylates it, allowing it to bind to RAF and, hence activating the downstream effectors. It can also bind to GRB2 which in turn can bind GEFs and convert RAS-GDP to RAS-GTP. Gain-of-function mutations in PTPN11 (*) increase its phosphatase activity resulting in constitutive activation of the RAS pathway; CBL helps in the regulation of the RAS pathway by inhibiting GRB2 and downregulating JAK2. In the presence of mutations in CBL (*), GRB2 activity becomes unchecked resulting in the activation of the RAS/RAF/MEK/ERK pathway; NF-1 can bind to RAS-GTP and converts it to RAS-GDP. When NF-1 is mutated (*), GAP activity is reduced which leads to increased levels of RAS-GTP and hence activation of downstream pathways.

Figure 2

Peripheral blood smears (PBS) from a patient with JMML (Jenner-Giemsa × 600). A. Pre-transplant PBS showing increased leucocyte count, monocytosis, myeloid precursors, and reduced platelet counts. B. Post-transplant PBS of the same patient showing normal leucocyte count and platelet counts.

Figure 3

Diagnostic approach to juvenile myelomonocytic leukemia (JMML) [PB = peripheral blood; BM = bone marrow; CMV = Cytomegalovirus; EBV = Epstein-Barr virus; GM-CSF = Granulocyte-macrophage colony-stimulating factor; HbF = Hemoglobin F; HHV-6 = Human herpesvirus 6; LCH = Langerhans cell histiocytosis; LAD = Leukocyte adhesion defect; STAT-5 = Signal transducer and activator of transcription-5].