Analysis of mutations after diagnosis with juvenile myelomonocytic leukemia (JMML) will aid in patient stratification and treatment personalization, according to a set of recommendations published in Blood Advances.

JMML, a rare disease that affects approximately 1.2 individuals per million, is often fatal, although the prognosis is highly variable. Although some cases resolve spontaneously, others progress to acute myeloid leukemia, which is often fatal. The median age of disease onset is approximately 2 years.

Although hematopoietic cell transplantation (HCT) is nearly always necessary for achieving a cure, the heterogeneity in JMML cases suggests that this strategy may not yield optimal outcomes; watch-and-wait may, in some cases, be recommended. In the clinical guide published in Blood Advances, several experts in JMML treatment outlined the diverse set of prognoses clinicians may expect from individual cases of JMML, depending on patient and disease characteristics.

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The authors noted, in particular, 5 genomic JMML subtypes with varying characteristics and associated outcomes. These included:

  • PTPN11, the most common genomic subtype, with a prevalence of up to 40%. This subtype is associated with myeloproliferative disease of infancy, older age at diagnosis, a greater risk of fatality without HCT, and a high rate of relapse with HCT;
  • KRAS, which affects approximately 15% of patients, and is linked with heterogeneous outcomes;
  • NRAS, which affects up to 20% of patients, and is most frequently found in younger patients. NRAS is associated with heterogeneous outcomes;
  • NF1, which affects up to 15% of patients. NF1 is most frequently diagnosed in older patients, associated with a higher platelet count, and often fatal without HCT. There is also a higher risk of treatment-related mortality among these patients; and
  • CBL, which affects up to 15% of patients, and which may resolve spontaneously. Whether HCT is useful among these patients is currently unknown.

The authors presented 2 figures for determining the best clinical strategy depending on disease characteristics. Depending on whether patients are in a high-risk or intermediate-risk category, and depending on whether the genomic mutations are germline or somatic, a varying combination of observation, HCT, or chemotherapy is recommended.

“Mutation analysis at follow-up visits should be performed as standard of care to detect emerging cooperative events, especially in patients who do not proceed to HCT,” the authors wrote. “Risk-stratified algorithms will improve with the introduction of clinically available DNA methylation testing and will allow for the identification of patients most likely to experience spontaneous resolution.”


Wintering A, Dvorak CC, Stieglitz E, Loh ML. Juvenile myelomonocytic leukemia in the molecular era: a clinician’s guide to diagnosis, risk stratification, and treatment. Blood Adv. 2021;5(22):4783-4793. doi:10.1182/bloodadvances.2021005117