A recent experience at CHOP illustrates well the importance of integrated genomic workup for AML. An 11-year-old patient with cytogenetically normal AML (CN-AML) was referred for further genetic testing for risk stratification. The Comprehensive Hematological Cancer Panel identified a FLT3 internal tandem duplication (FLT3 ITD) (Figure 1C) along with two other somatic variants, IDH2 p.R140Q and GATA2 p.W10*. FLT3 ITD is often missed by NGS-based assays due to the size of the duplications. However, we have designed our panel and bioinformatics analysis pipeline to enable the detection of this mutation. The FLT3 variant changes the patient's prognosis from intermediate (based on CN-AML) to poor. Moreover, recent clinical trials suggest adding FLT3 inhibitor to frontline chemotherapy in FLT3-mutated AML confers a survival benefit. The FLT3 ITD present in this patient qualifies her for clinical trials investigating FLT3 ITD targeted therapies.
Juvenile myelomonocytic leukemia (JMML) is a rare type of leukemia found mainly in children less than 2 years of age. The prognosis of JMML is poor, and without treatment it is most often fatal within 5 years of life. Hematopoietic stem cell transplant is currently the only curative approach for JMML. Since both the clinical presentation and the morphologic features of JMML can resemble reactive processes, molecular studies are usually required for diagnosis. Most individuals with JMML have mutations in the RAS pathway, particularly PTPN11, KRAS, NRAS, CBL, or NF1. Some mutations in the RAS-MAPK pathway genes can occur in the germline and these patients are at risk for JMML-like myeloproliferations. JMML patients without RAS mutations may have mutations in ASXL1, SETBP1, RUNX1, JAK3, and SH2B3, all of which have also been observed as secondary mutations in RAS-mediated JMML. In the 2016 WHO classification, the RAS-pathway mutations are among the diagnostic criteria for JMML.