LAUSR

Acute myeloid leukemia (AML) is a heterogenous malignancy of immature myeloid cells developed due to uncontrolled proliferation. The underlying mechanism can partially be explained by variable number of chromosomal abnormalities, gene variations, epigenetic modifications and deregulated gene expressions. Other than cytogenetic abnormalities, driver and passenger variations have been described in more than 95% of AML patients and it is reported that an AML genome can bear more than ten somatic genetic variations [1]. This high heterogeneity also brings a challenge into the treatment of AML. The 5-year overall survival estimation in AML is around 24% [2], 50%− 60% of the AML patients relapse, and this rate decreases down to 10% in patients with advanced age (> 65 years) [3]. With the recent advancements in high throughput technologies, numerous molecular markers have been described in AML and based on these molecular markers the risk groups were released by the European LeukemiaNet (ELN) [4], which covers recurrent genetic variations in genes like FMS-like tyrosine kinase 3 (FLT3), Nucleophosmin 1 (NPM1) and CCAAT Enhancer Binding Protein Alpha (CEBPA).The discovery of new genetic biomarkers provided a high improvement in the targeted therapies for AML cases as well. FLT3-targeted tyrosine kinase inhibitors (TKIs) can be given as an effective example in the treatment of AML. FLT3, is a transmembrane tyrosine kinase, which is expressed both in myeloid and lymphoid cells. The FLT3 variations are found in around 30% of AML patients either as internal tandem repeats (ITD, 20–25%) or affecting tyrosine kinase domain (TDK, 7–10%) [5]. Both variations constitutively activate the FLT3, which leads to the proliferation and survival of AML cells. FLT3 variations are counted as driver mutations and studies report that the patients with FLT3 variations showed low prognosis, unfavorable outcome and lower overall survival than the patients without FLT3 variations. In the last 5 years, the therapeutic armamentarium of AML expanded extensively, and there are many options available both in the upfront and salvage settings [6], including those that target FLT3. FLT3 TKIs are classified either according to their mechanism of action (Type I and Type II) or in order of their development (First-generation and Second-generation). First-generation inhibitors were targeting both ITD and TDK variations but therapy-related variations in FLT3 lead to therapy resistance. The second-generation TKIs were developed to inactive the FLT3 conformation and may overcome resistance related variations. Gilteritinib, is a type I and second-generation inhibitor, which is effective against both ITD and mutant TKD [7]. Gilterinitib has been approved by the United States Food and Drug Administration (FDA) in the management of AML, following the promising results of the open-label, multicenter, randomized phase III ADMIRAL study (NCT02421939), where gilteritinib was compared with salvage chemotherapy in relapsed/refractory FLT3-mutated AML patients [8]. Despite all promising achievements, therapy-related resistance is still an important obstacle on the way to a successful treatment.