<p>Quizartinib (AC220): a promising option for acute myeloid leukemia</p>

Abstract

Quizartinib is an effective therapy for patients with FLT3-ITD acute myeloid leukemia (AML) by continuing to inhibit the activity of FLT3 gene, leading to apoptosis of tumor cells. Multiple clinical trials have proved that it is effective in relapsed or refractory AML with an FLT3-ITD mutation. In this review, we focus on the characteristics of FLT3/ITD mutations, the mechanism and pharmacokinetics of quizartinib, and the mechanisms of resistance to quizartinib. We also summarize clinical experiences and adverse effects with quizartinib and recommend crucial approaches of quizartinib in the therapy of patients with newly diagnosed AML and patients with relapsed/refractory AML, particularly those with FLT3-ITD mutation. Quizartinib presents its advantages as a very promising agent in the treatment of AML, especially in patients with FLT3-ITD mutations. FLT3/ITD mutation can lead to constitutive autophosphorylation of FLT3 and activation of its downstream effectors including RAS/RAF/MEK, MAPK/ERK, PI3K/AKT/mTOR and JAK/STAT5 signal pathways, while Quizartinib can inhibit these downstream pathways through specific FLT3 inhibition. Quizartinib has received US Food and Drug Administration breakthrough therapy designation in patients with relapsed/refractory FLT3-ITD AML based on clinical trials. A larger sample of clinical trials are needed to verify its safety and efficacy, and the efficacy of quizartinib combined with chemotherapy or allogeneic hematopoietic cell transplantation should also be estimated in clinical trials. Meanwhile, for the side effects of quizartinib, further studies are needed to find a way to reduce its toxicity.

New directions for emerging therapies in acute myeloid leukemia: the next chapter

“…Several FLT3 inhibitors have been evaluated in clinical trials of patients with AML 56 . Among these, the second-generation FLT3 inhibitors quizartinib and gilteritinib as single agents improved marrow remission rates and OS compared with traditional salvage chemotherapies (investigator’s choice of high-intensity therapies such as fludarabine–Ara-C–granulocyte colony-stimulating factor–idarubicin or mitoxantrone-etoposide-cytarabine, or low-intensity therapies such as HMAs or LDAC) in relapsed/refractory FLT3 -mutated AML patients 57 – 60 . Midostaurin is used in combination with induction chemotherapy for the first-line treatment of patients with FLT3- ITD– or FLT3- TKD–mutated AML 61 .…”

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…Targeting mutant FLT3 by small molecule inhibitors has rapidly emerged as a new therapeutic approach in patients with AML. Different FLT3 inhibitor therapeutic agents have been developed and are summarized in Tables 1, 2 [9,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53].…”

“…[37] EFS and OS at 2 years were 39% and 34% in younger and 53% and 46% in older patients, respectively [38] Recommended as front line therapy for AML with FLT3-ITD and FLT3-TKD [9,39] Sunitinib Some promising results in phase I/II clinical trials, but with high incidence of adverse effects [40,41] Gilteritinib a R/R FLT3-mutated AML, median OS for single agent gilteritinib was significantly longer than chemotherapy (9.3 months vs. 5.6 months). Median EFS was 2.8 months in the gilteritinib group and 0.7 months in chemotherapy group [42] Recommended as new standard therapy for R/R FLT3-mutated AML [43] Lestaurtinib Failed to demonstrate any overall clinical benefit in a phase III trial when combined with intensive chemotherapy in patients with newly diagnosed FLT3-ITD-mutated AML [9,44,45] Crenolanib a Combine with 7 + 3 regimen can overcome the poor prognostic implication of adverse mutations co-occurring with mutated FLT3 [46] Incorporation of crenolanib into frontline intensive chemotherapy resulted high ORR and may replace Midostaurin in the upfront setting [47] Type 2 Quizartinib a Showed efficacy in multiple clinical trials in R/R AML with FLT3-ITD mutation [48][49][50] Recommended for patients with rapidly proliferative disease and very poor prognosis [51] Sorafenib Combine with intensive chemotherapy improves OS in newly diagnosed, FLT3-ITD mutated AML regardless allogeneic HSCT [52] Improved OS for FLT3-ITD AML relapsing after allo-HSCT […”

Ganoderma Lucidum Polysaccharide, an Extract from Ganoderma Lucidum, Exerts Suppressive Effect on Cervical Cancer Cell Malignancy through Mitigating Epithelial-Mesenchymal and JAK/STAT5 Signaling Pathway

“…The results showed that the expression of E-cadherin was upregulated, and the expression of N-cadherin, Vimentin, and Slug was downregulated, demonstrating that the EMT pathway was blocked in cervical cancer cells after GLP treatment. The JAK/STAT5 signaling pathway is involved in numerous important biological processes including cell proliferation, differentiation, apoptosis, and immune regulation [29]. Data from Giordano et al [30] illustrated that the changes of the JAK/STAT5 signaling pathways in colorectal cancer can improve the therapeutic effects mediated by LY6G6D.…”