Mutations within the Activation Loop Domain of FLT3 in Two Pediatric Patients with Refractory Infant Acute Myeloid Leukemia.

Approximately 24% of all pediatric acute myeloid leukemia (AML) cases have mutations in the FMS-like tyrosine kinase 3 () receptor gene. FLT3-TKD point mutations are rare in pediatrics and often occur in younger patients and in combination with 11q23 abnormalities. There is a paucity of data related to their prognostic implications in children. We describe 2 pediatric patients with FLT3-activating mutations as a feature of their AML. Both were diagnosed in infancy. The first experienced induction failure and had refractory disease without expression of FLT3-TKD mutation on subsequent bone marrow evaluations. His disease also harbored a KMT2A-PICALM gene rearrangement. He died of invasive fungal disease nine months after diagnosis. The second had a post-induction remission but developed swelling of the left calcaneus shown on biopsy to be a myeloid sarcoma positive for a new BRAF V600E mutation in addition to his known KMT2A rearrangement but without FLT3-TKD mutation. Despite multiple courses of therapy including BRAF/MEK-inhibition, he died of progressive disease nine months after diagnosis. FLT3 inhibition was not utilized in either patient as studies have largely focused on its role in internal tandem duplication (ITD) mutations and because the mutation was no longer detectable in either patient on subsequent evaluation. However, these cases add to the suggestion that these mutations confer a worse prognosis in pediatric AML patients.