Current Treatment of Juvenile Myelomonocytic Leukemia

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.

Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging

“…Further backtracking research on the prenatal origin of pediatric AML, using neonatal blood spots and UCBs sourced at birth, is ongoing within registered clinical trials ( ; accessed 28 November 2021). In utero, preleukemic events would of course also include such genetic or inherited predispositions as Noonan and CBL Syndromes and Neurofibromatosis type-1 (NF-1), which place such children at higher risk of developing, although not necessarily exclusively, myeloid leukemias [ 121 , 133 , 204 , 205 ]. Individuals with NF-1 or CBL and Noonan Syndromes, which dysregulate the RAS pathway genes, are predisposed to JMML [ 204 , 205 ].…”

“…In utero, preleukemic events would of course also include such genetic or inherited predispositions as Noonan and CBL Syndromes and Neurofibromatosis type-1 (NF-1), which place such children at higher risk of developing, although not necessarily exclusively, myeloid leukemias [ 121 , 133 , 204 , 205 ]. Individuals with NF-1 or CBL and Noonan Syndromes, which dysregulate the RAS pathway genes, are predisposed to JMML [ 204 , 205 ]. While the majority of those with Noonan Syndrome carry germline mutations in RAS pathway genes (e.g., PTPN11, KRAS, NRAS, SOS-1, RAF1, BRAF ), not all develop JMML.…”

“…While the majority of those with Noonan Syndrome carry germline mutations in RAS pathway genes (e.g., PTPN11, KRAS, NRAS, SOS-1, RAF1, BRAF ), not all develop JMML. About 5% develop a transient myeloproliferative disorder, which spontaneously resolves, although in some cases, this will progress to JMML [ 204 , 205 ]. This contrasts with children without Noonan Syndrome bearing somatic RAS mutations in PTPN11, NRAS and KRAS , who account for a significant proportion of JMML cases [ 205 ].…”

“…About 5% develop a transient myeloproliferative disorder, which spontaneously resolves, although in some cases, this will progress to JMML [ 204 , 205 ]. This contrasts with children without Noonan Syndrome bearing somatic RAS mutations in PTPN11, NRAS and KRAS , who account for a significant proportion of JMML cases [ 205 ]. An analysis of neonatal blood spots has identified such somatic RAS pathway mutations (most commonly in PTPN11, NRAS and KRAS ) in 38% of children ( n = 34) without Noonan Syndrome but presenting with JMML at a median age of 1.5 years [ 206 ].…”

“…JMML, which accounts for 1% of pediatric leukemias, has a median age of onset of 2 years [ 189 , 204 , 205 , 224 , 225 ]. Over 90% of JMML driver mutations involve five genes in the canonical RAS pathway ( PTPN11, NRAS, KRAS, NF1 , CBL) , with approximately 35% being somatic PTPN11 (gain of SHP-2 function) exon 3 or 13 mutations [ 133 , 189 , 190 , 204 , 205 , 224 , 225 , 226 , 227 , 228 , 229 ].…”