AML is characterized by the clonal expansion of myeloid blasts in the BM, peripheral blood and extramedullary tissues which disrupts normal hematopoiesis. It is a heterogeneous disease, encompassing a large number of distinctly subtypes that may have different clinical presentations and responses to treatment. AML is defined by the WHO as a myeloid neoplasm with 20% or more blasts in the peripheral blood or BM.

Internal tandem duplication (ITD) in the FLT3 gene is one of the most frequent mutations found in AML. FLT3-ITD is associated with poor prognosis and has emerged as a relevant therapeutic target. FLT3-ITD is usually conserved at relapse, suggesting that FLT3-ITD AML-initiating cells are key targets for long-lasting remission. FLT3-TKI, developed as ATP-competitive inhibitors, are currently the focus of new development strategies in FLT3-mutated AML, particularly in combination with intensive or non-intensive chemotherapies in newly diagnosed (ND) FLT3 mutated AML or in R/R situation. Type I inhibitors, including midostaurin, gilteritinib, and crenolanib, have activity against FLT3-ITD and tyrosine kinase domain (TKD) mutations. Type II inhibitors, including sorafenib and quizartinib, do not have activity against FLT3-TKD mutations. Although first-generation FLT3 inhibitors, such as midostaurin 10 and sorafenib 11, have marginal single-agent activity in active disease, they have shown promising activity as maintenance therapies, notably after HSCT for sorafenib 14. Conversely, several FLT3-TKI, such as quizartinib, crenolanib, and gilteritinib, have single-agent activity that lead to complete or near-complete remission, providing a strong rationale to combine these agents with other chemotherapies.

The ADMIRAL phase 3 trial, also designed for R/R FLT3-mutated AML patients, recently demonstrated the superiority of gilteritinib as single agent over the control treatment arm, which was determined by investigators prior to 2:1 randomization between mitoxantrone, etoposide, cytarabine; fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin; AZA or LDAC. These regimens are recognized as acceptable salvage strategies in this situation, although other combinations based on intermediate- or high-dose cytarabine or even single-agent cytarabine are also widely used. In the ADMIRAL trial, OS was significantly improved in the gilteritinib arm compared to the control arm with HR at 0.64 (95%CI: 0.49-0.83; p \< 0.001). The median OS was 9.3 months in the gilteritinib arm and 5.6 months in the control arm. The CR and CRi rates were 21.1% and 25.5% in the gilteritinib arm vs. 10.5% and 4.8% in the standard arm 2. Gilteritinib was generally well tolerated but was associated with increased incidence of GI side effects, most frequently diarrhea although nausea has been occasionally observed. Increase in bilirubin and transaminase can be seen with gilteritinib but are usually self-resolving and transient. Posterior reversible encephalopathy and pancreatitis are rare (\<1-2%) but important side effects to be aware of. These results led to the approval of gilteritinib monotherapy in the US and Europe in patients with R/R FLT3 mutated AML and it is now the gold standard treatment in such situation. However, long lasting remission with gilteritinib as single agent are uncommon since various resistance mechanisms allow AML to escape. Innovative strategies have to be established in order to improve these results. In that setting, associations with ICT, HMA, other targeted therapies are currently developed.

AZA was first investigated as a cytotoxic agent in the 1960s and 1970s in R/R AML and a dose- and time-dependent effect of AZA was evident, with higher remission rates and reduced toxicity reported in patients who received lower doses or continuous infusion schedule of AZA

QUAZAR trial used an oral formulation of AZA (oral-AZA) that is not bioequivalent to injectable AZA, as maintenance therapy in patients with AML who were in CR/CRi after ICT 22. Median OS from randomization was significantly longer with oral-AZA than with placebo (24.7 months vs. 14.8 months, respectively; p\<0.001). Median RFS was also significantly longer with oral-AZA than with placebo (10.2 months vs. 4.8 months, respectively; p\<0.001). The most common AE in both groups were grade 1 or 2 GI events. Common grade 3 or 4 AE were neutropenia (in 41% of patients in the oral-AZA group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during oral-AZA treatment. Among those who were MRD+ at baseline, patients in the oral-AZA arm had a higher rate of conversion to MRD- status vs. placebo: 37% versus 19%, respectively. These data suggest an effective anti-leukemic therapy and not only an ability to maintain a stable situation, among these MRD responders, 9 of 38 (24%) patients in the oral-AZA arm converted to MRD-negativity after \> 6 months on treatment, vs. only 1of 22 (5%) patients in the placebo arm. Moreover, during the 63rd ASH annual meeting, Döhner et al. confirmed that Oral-AZA, NPM1 and FLT3 mutational status, cytogenetic risk, as well as MRD status at baseline were independent predictors of survival.

In front line situation, LACEWING study was a phase 3, randomized study comparing gilteritinib+AZA vs. AZA for ND FLT3-mutated AML in patients unfit for ICT. In this trial in patients with ND FLT3 mutated AML unfit for ICT, gilteritinib+AZA led to significantly higher CRc rates but similar OS vs. AZA alone. Based on these results, an independent data monitoring committee recommended the study be terminated for futility, citing that the results are unlikely to demonstrate a statistically significant increase in OS. However subsequent therapy after AZA failure, notably with other regimen including FLT3-TKI, could have precluded transition of better CRc results to better OS results