Genomic investigations of acute myeloid leukemia (AML) have demonstrated that several genes are recurrently mutated, leading to new genomic classifications, predictive biomarkers, and new therapeutic ...targets. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all AML cases, with the internal tandem duplication (ITD) representing the most common type of FLT3 mutation (FLT3-ITD; approximately 25% of all AML cases). FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. The prognostic value of a FLT3 mutation in the tyrosine kinase domain (FLT3-TKD), which has a lower incidence in AML (approximately 7-10% of all cases), is uncertain. Accumulating evidence demonstrates that FLT3 mutational status evolves throughout the disease continuum. This so-called clonal evolution, together with the identification of FLT3-ITD as a negative prognostic marker, serves to highlight the importance of FLT3-ITD testing at diagnosis and again at relapse. Earlier identification of FLT3 mutations will help provide a better understanding of the patient's disease and enable targeted treatment that may help patients achieve longer and more durable remissions. First-generation FLT3 inhibitors developed for clinical use are broad-spectrum, multikinase inhibitors; however, next-generation FLT3 inhibitors are more specific, more potent, and have fewer toxicities associated with off-target effects. Primary and secondary acquired resistance to FLT3 inhibitors remains a challenge and provides a rationale for combining FLT3 inhibitors with other therapies, both conventional and investigational. This review focuses on the pathological and prognostic role of FLT3 mutations in AML, clinical classification of the disease, recent progress with next-generation FLT3 inhibitors, and mechanisms of resistance to FLT3 inhibitors.
Acute myeloid leukemia (AML) is a heterogeneous disease linked to a broad spectrum of molecular alterations, and as such, long-term disease control requires multiple therapeutic approaches. Driven ...largely by an improved understanding and targeting of these molecular aberrations, AML treatment has rapidly evolved over the last 3-5 years. The stellar successes of immunotherapies that harness the power of T cells to treat solid tumors and an improved understanding of the immune systems of patients with hematologic malignancies have led to major efforts to develop immunotherapies for the treatment of patients with AML. Several immunotherapies that harness T cells against AML are in various stages of preclinical and clinical development. These include bispecific and dual antigen receptor-targeting antibodies (targeted to CD33, CD123, CLL-1, and others), chimeric antigen receptor (CAR) T-cell therapies, and T-cell immune checkpoint inhibitors (including those targeting PD-1, PD-L1, CTLA-4, and newer targets such as TIM3 and STING). The current and future directions of these T-cell-based immunotherapies in the treatment landscape of AML are discussed in this review.
Progress in the understanding of the biology and therapy of acute myeloid leukemia (AML) is occurring rapidly. Since 2017, nine agents have been approved for various indications in AML. These ...included several targeted therapies like venetoclax, FLT3 inhibitors, IDH inhibitors, and others. The management of AML is complicated, highlighting the need for expertise in order to deliver optimal therapy and achieve optimal outcomes. The multiple subentities in AML require very different therapies. In this review, we summarize the important pathophysiologies driving AML, review current therapies in standard practice, and address present and future research directions.
Approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITD
in AML ...has been clearly proven, the prognostic significance of FLT3-TKD
remains speculative. Current guidelines recommend rapid molecular testing for FLT3
at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3
can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3
AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3
AML have improved outcomes in patients with FLT3
AML. Nevertheless, the short duration of remission with single-agent FLT3i's in R/R FLT3
AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i's remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3
AML.
Cellular therapies have demonstrated limited efficacy thus far in acute myeloid leukemia (AML). A recent study shows that mTOR complex 1 activation downregulated CXCR4 reducing marrow infiltration of ...EpCAM-targeting chimeric antigen receptor (CAR) T-cells in AML. Abrogating mTOR signaling by cotreatment with mTOR inhibitors during IL2-mediated
expansion upregulated CXCR4 and bolstered bone marrow migration and AML elimination by CAR T-cells.
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