FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

Abstract

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-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut 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 FLT3mut 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 FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut 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 FLT3mut AML.

FLT3 mutations in acute myeloid leukemia: a review focusing on clinically applicable drugs

“…An FLT3 -ITD low allelic ratio is not as favorable as the FLT3 -ITD wild-type in patients with AML and NPM1 mutations, as seen previously. Allogeneic HCT for post-remission therapy may be considered to reduce the relapse risk even in patients with FLT3 -ITD low allelic ratio, regardless of NPM1 mutation status [ 12 , 26 - 28 ].…”

“…Since 1996, when the FLT3 internal tandem duplication (ITD) mutation was first identified in AML, numerous studies have been conducted regarding its relevance in prognosis [ 4 - 6 ]. Moreover, several advances have been made in targeting FLT3 mutations, and currently, FLT3 inhibitors are actively used in clinical practice [ 7 - 12 ]. In this review, we summarize information on clinically available FLT3 inhibitors for the management of AML with FLT3 mutations.…”

Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy

“…Multiple factors including genetic alterations, chemical exposure, and radiation have been implicated as risk factors of AML [ 1 ]. Among the genetic factors, FLT3-ITD, an internal tandem duplications (ITD) in fms-like tyrosine kinase 3 (FLT3), is observed in approximately 20–30% of AML patients and is associated with aggressive disease progression, worse prognosis, high risk of relapse, and shorter overall survival [ 3 ]. Recent studies showed that somatic mutations at isocitrate dehydrogenases (IDHs) could also drive the development of AML due to the production of oncometabolite 2-hydroxyglutarate (2-HG) [ 4 ].…”

Hypomethylating agent and venetoclax with FLT3 inhibitor “triplet” therapy in older/unfit patients with FLT3 mutated AML

“…1 . Standard dose venetoclax (400 mg/day or dose reduced in accordance with the US label for patients on strong CYP34A inhibitors) was administered starting from day 1 to day 14 or day 28 (depending on the specific clinical trial the patient was enrolled in, or physician choice in off protocol cases) in patients who received triplet therapy, as previously described by our group[ 2 ] (see detailed treatment schema in Supplementary Fig. 1 ).…”

“…Internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations in the FLT3 gene are some of the most common mutations in patients with newly diagnosed acute myeloid leukemia (AML). FLT3- ITD mutations are associated with a higher risk of relapse and inferior overall survival (OS) [ 1 , 2 ]. Midostaurin, a first-generation FLT3 inhibitor, combined with intensive chemotherapy, improved OS in younger adult patients (<60 years) with FLT3 mutated AML [ 3 ].…”