*2.1.5 Mechanisms of resistance to FLT3i*

*Acute Leukemias*

*2.1.1 Midostaurin*

*2.1.2 Quizartinib*

countries.

*2.1.3 Gilteritinib*

November 2018.

Target drugs inhibiting FLT3 receptor showed different potency of inhibition, activity on FLT3-ITD versus TKD mutations, and on non-FLT3 targets (i.e., kinome

Type I FLT3i (Lestaurtinib, Midostaurin, Gilteritinib, Crenolanib) are active against both FLT3-ITD and TKD mutations because they interact with the gatekeeper domain near to the activation loop or with the ATP binding site, expleting their activity on both active dimeric and inactive monomeric tirosin kinase receptor. Type II FLT3i (Quizartinib and Sorafenib) bind to the hydrophobic region adjacent to the ATP binding site only when the receptor is in an inactive form and are therefore ineffective in the forms with the FLT3TKD mutations where the receptor

Midostaurin, a type I FLT3i, also targets c-KIT, PKC, PDGFR, and VEGFR [12] and is FDA, EMA and AIFA approved for the first line treatment of FLT3 mutated (FLT3-mut) AML in association with 7 + 3 in induction and high dose Cytarabine in consolidation, on the basis of the results of the multinational, randomized phase III trial RATIFY (CALBG 10603) [13]. Midostaurin or placebo were given during induction and consolidation, and could be given for up to one year as postconsolidation maintenance, allogeneic transplant was admitted after the stop of the experimental treatment. Midostaurin was associated with a significant improvement in OS (4-year OS rate: 51.4% versus 44.3%; median OS: 74.7 months versus 25.6 months, HR = 0.78; P = 0.009) regardless of the type of *FLT3* mutation (e.g.,

Quizartinib is a type II FLT3i, but also a potent inhibitor of c-KIT, PDGFR, and RET achieving 45-50% marrow remission rates as single-agent in relapsed/ refractory (R/R) *FLT3*-mut AML with an OS advantage over investigator choice salvage chemotherapy in the Quantum R-trial, a phase III randomized study of 367 patients with relapsed or refractory *FLT3-*ITD mutated AML (CRc rate 48% vs. 27%; median OS 6.2 months vs. 4.7 months, P = 0.0177) [14]. Neverthless Quizartinib failed FDA approval for this indication, due in part to concerns over treatment equipoise and robustness of OS improvement, while obtained approval in Japan in June 2019 and is being considered for approval in other

Gilteritinib is another potent second-generation type I inhibitor with activity against AXL, a receptor tyrosine kinase that may play a role in mediating resistance to earlier generation FLT3 inhibitors [15]. Gilteritinib was found to be well tolerated as single-agent in a randomized phase III study enrolling R/R FLT3-mut AML, with marrow remission rates of 54% superior to the 22% CRc rate observed after investigator choice salvage chemotherapy (both high- and low-dose chemotherapy), with also a longer median OS (9.3 months vs. 5.6 months, HR = 0.79; P = 0.007) [16]. More patients (26% vs. 15%) were able to proceed to HSCT with gilteritinib compared with salvage chemotherapy. These results led to Gilteritinib FDA approval for the treatment of R/R FLT3-mut AML (both ITD and TKD) in

specificity), with variable off-target toxicities [11].

ITD or D835 TKD) or ITD allele burden, (<0.7/≥0.7).

is always in the dimeric active form.

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Neverthless hematopoietic stem cell transplant (HSCT) is still necessary and recommended for the cure of the disease, since retrospective studies [18, 19] showed that HSCT improves RFS and OS and reduces incidence of relapse. The favorable predictive role of FLT3 allelic ratio in NPM1 mutated AML is still controversial due to lack of standardization of techniques and thresholds of this factor [20, 21]. Novel FLT3i might increase outcomes in this setting, but researchers have already identified multiple mechanisms of resistance as hereby reported [11].


MDM2 inhibitors such as Nutlin-3a are under study (NCT00623870) and there is a rationale for their association with FLT3 inhibitors [27].


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**Table 2.**

*Mechanisms of Resistence of New Target Drugs in Acute Myeloid Leukemia*

**of action of combination agent**

LGH447 + midostaurin Pim kinasi inhibitor Pim kinasi activity

Protein synthesis inhibitor

Palbociclib + sorafenib CDK4/6 inhibitor CDK4/6 regulate

Venetoclax + gilteritinb Bcl-2 inhibitor Upregolation of anti-

Hypomethylating

Hystone deacetylase inhibitor (vorinostat) Proteasome inhibitor (bortezomib)

agent Bcl-2 inhibitor

Crenolanib is a potent novel type I pan-FLT3 inhibitor, effective against both ITD and TKD, but the response in monotherapy is unfortunately transient. Zhang et al. performed WES of samples from R/R FLT3 pos AML patients before and after Crenolanib, administered in a phase II study (NCT 01522469, NCT 01657682). They interestingly observed that patients previously treated with FLT3i expressed RAS mutations at baseline more frequently than naive patients and were less likely to respond to Crenolanib. They identified mutations of NRAS and IDH2 arising in FLT3-independent subclones and of TET2 and IDH1 in FLT3-subclones as possible

> **Mechanism rationale for combination**

mediates FLT3 inhibitor resistance; combination increases apoptosis

restore p53 tumor suppression function

Synergistic with FLT3 inhibitors to suppress leukemic proliferation

transcription of FLT3 and Pim kinases (mechanism of FLT3 inhibitor resistance)

mediates FLT3 inhibitor resistance; combination increases apoptosis

apoptotic proteins (e.g. Bcl-2, BCL-xL and Mcl-1) mediates FLT3 inhibitor resistance

Hypomethylation of target genes

Histone deacetylase inhibitors

synergistically induce apoptosis with FLT3 inhibitors;

Proteasome inhibitors induce FLT3 ITD degradation through autophagy

MDM2 inhibitor MDM2 inhibitor

Pim kinase inhibitor Pim kinase activity

**Clinicaltrials.gov identifier**

NCT02078609

NCT03552029

NCT03170895 NCT03135054

NCT03132454

NCT03008187

NCT03625505

NCT04140487

NCT101534260

*DOI: http://dx.doi.org/10.5772/intechopen.94978*

*2.1.6 Novel FLT3i and future perspectives*

**Combination regimen Mechanism** 

Milademetan

+ sorafenib

+ quizartinib

inhibitor)

gilteritinib

sorafenib

(DS-3032b) + quizartinib

Omacetaxine mepesuccinate

Omacetaxine mepesuccinate

SEL24 (dual pan Pim/FLT3

Azacitidine + venetoclax +

Vorinostat + bortezomib +

*Trials with combinations of FLT3i and target drugs.*

*Mechanisms of Resistence of New Target Drugs in Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94978*
