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Fms-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML). Modern targeting of FLT3 with inhibitors has improved clinical outcomes and FLT3 inhibitors have been incorporated into the treatment of AML in all phases of the disease, including the upfront, relapsed/refractory and maintenance settings. This review will discuss the current understanding of FLT3 biology, the clinical use of FLT3 inhibitors, resistance mechanisms and emerging combination treatment strategies.

Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A mutation score was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: -1 to 0 points (Beat-AML intermediate) vs 1+ points (Beat-AML adverse). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined Beat-AML favorable-risk group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making.

Despite recent work linking mixed phenotype acute leukemia (MPAL) to certain genetic lesions, specific driver mutations remain undefined for a significant proportion of patients and no genetic subtype is predictive of clinical outcomes. Moreover, therapeutic strategy for MPAL remains unclear, and prognosis is overall poor. We performed multiomic single cell profiling of 14 newly diagnosed adult MPAL patients to characterize the inter- and intra-tumoral transcriptional, immunophenotypic, and genetic landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation potential demonstrate inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in the most stem-like MPAL cells, is applicable to bulk RNA sequencing data and is predictive of survival in an independent patient cohort, suggesting a potential strategy for clinical risk stratification.