Table 1.

Management of JMML according to driver mutation. HSCT, hematopoietic stem cell transplantation; GVHD, graft-versus-host disease; DLI, donor lymphocyte infusions; NF-1, neurofibromatosis 1.

Ras Pathway Mutation	Frequency in JMML	Features	DNA Methylation Profile	Recommendations for Treatment
Somatic NRAS	10–15%	Diverse	Mostly low, occasional IM or HM	HSCT for many, careful selection of candidates for watch-and-wait
Somatic KRAS	10–15%	Frequent monosomy 7, autoimmune phenomena	Intermediate or low	Azacitidine and/or HSCT
Somatic PTPN11	35%	Compromised clinical status at diagnosis, highest risk of unfavorable outcome	Mostly high	Swift HSCT (+pretransplant azacitidine) with low intensity GVHD prophylaxis, in absence of GVHD early withdrawal of prophylaxis, consider azacitidine plus DLI posttransplant
Germline NF1	10–15%	Café-au-lait spots, possibly positive family history, older age at diagnosis, less severe thrombocytopenia	High or intermediate	Swift HSCT (+pretransplant azacitidine) with low intensity GVHD prophylaxis, in absence of GVHD early withdrawal of prophylaxis
Germline CBL	15%	Syndromic rasopathy features, autoimmunity and vasculitis	Low	Watch-and-wait. HSCT if disease progresses, patients after HSCT often revert to stable mixed chimerism
All negative	5–10%	Rarely activating kinase fusions in RNA sequencing	Low or intermediate	Differentiate non-neoplastic disease, perform extended work-up for rasopathies. Most patients require HSCT