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A.J. Ambinder and M. Levis
interval 9.8-27.4%), respectively. Gilteritinib demonstrat- ed improved OS compared to chemotherapy with a medi- an OS of 9.3 months versus 5.3 months (P<0.001) and a hazard ratio for death of 0.65 (95%CI: 0.39-0.83).51 This trial established the importance of targeting mFLT3 and resulted in FDA approval of gilteritinib in the R/R setting. Similarly, in the phase III QUANTUM-R trial, patients randomized to single agent quizartinib had improved OS compared to those randomized to salvage chemotherapy, leading to the drug’s approval in Japan. These results are tempered by the fact that all of these patients relapse unless they undergo subsequent transplant. Furthermore, only 12.4% of patients in the ADMIRAL trial had previ- ously received a FLT3 inhibitor. As FLT3 inhibitors use in the frontline setting increases, the effectiveness of FLT3 inhibitors such as gilteritinib in the R/R setting may diminish.
FLT3 inhibitors
There are nearly a dozen FLT3 inhibitors in use or in clinical trials. Different pharmacologic properties and adverse effects may be preferred under different circum- stances. As more FLT3 inhibitors become available for use in different scenarios, appropriate selection will depend upon a nuanced understanding of their similarities and dif- ferences.
First generation FLT3 inhibitors
The first FLT3 inhibitors were tyrosine kinase inhibitors (TKI) with broad anti-kinase activity that were repurposed for use in mFLT3 AML. These TKI include sunitinib (SU11248), midostaurin (PKC412), lestaurtinib (CEP-701), and sorafenib (BAY43-9006). Midostaurin and lestaurtinib are class I inhibitors that bind to the ATP-binding site in the intracellular active pocket of the enzyme and are active against both ITD and TKD mutations. Sunitinib and sorafenib are class II inhibitors, which bind to the ATP- binding site and interact with an adjacent hydrophobic pocket. This hydrophobic pocket is only exposed in the inactive conformation and is made inaccessible by TKD mutations. Therefore, TKD mutations confer resistance to class II inhibitors. TKD mutations are rarely present along- side FLT3-ITD mutations at diagnosis, but mFLT3-ITD AML may acquire TKD mutations as a resistance mecha- nism under the selective pressure of class II FLT3 inhibitors.52
In vitro, first-generation inhibitors appear to be potent against the mFLT3 receptor. However, in vivo, they are highly protein bound in plasma, reducing their potency. In the plasma inhibitory activity (PIA) assay, 85% sustained kinase inhibition correlates with clinical response.53,54 In plasma, midostaurin and lestaurtinib have IC50s of 1000nM and 700nM, respectively,53 whereas second generation FLT3 inhibitors have IC50s in the range of 20-40nM.55,56 First generation inhibitors also have shorter half-lives. These characteristics explain their limited clinical efficacy as sin- gle agents.57,58 Furthermore, their broad anti-kinase activity contributes to worse toxicity profiles compared to those of second generation TKI.
First generation FLT3 inhibitors have been most success- ful in combination with chemotherapy in the upfront set- ting. In the phase II SORAML trial, 267 patients with newly diagnosed AML, most of whom had WT-FLT3, were randomized to sorafenib combined with intensive chemotherapy followed by sorafenib maintenance versus
chemotherapy alone.59 The sorafenib arm had significantly longer 3-year EFS compared to placebo (40% vs. 22%, HR 0.64, 95%CI: 0.45-0.91, P=0.013), but there was no statis- tical difference in OS between arms.
Midostaurin
Midostaurin is a class I FLT3 inhibitor that has activity against WT and mFLT3 (ITD and TKD), KIT, PDGFRa/β, VEGFR2, and members of the protein kinase C family.60 In early phase trials, midostaurin induced a reduction in peripheral and/or BM blasts (defined as a 50% reduction in either compartment) in the majority of R/R patients with mFLT3 AML, but rarely induced deeper clinical responses.61,62 It was subsequently studied in combination with standard of care chemotherapy and in the phase III RATIFY trial, in which it improved OS without improving rates of remission or impacting rates of alloHSCT, possi- bly by inducing deeper remissions in those who respond.22,63 Midostaurin has changed the standard of care for newly-diagnosed mFLT3 AML, but its limited potency against the mFLT3 receptor has limited its efficacy in other circumstances.50
Second generation FLT3 inhibitors
Second generation FLT3 inhibitors immediately distin- guish themselves from first generation inhibitors by virtue of their ability to more fully inhibit FLT3 in vivo. This is reflected in their capacity to trigger myeloid differentia- tion and their significant single-agent clinical activity.
Gilteritinib
Gilteritinib is the only FDA-approved second generation FLT3 inhibitor. It is far more potent than first generation FLT3 inhibitors, in part because it is bound to a lesser extent by plasma-protein. It has a long half-life and a large therapeutic window, achieving greater than 85% inhibi- tion of FLT3 phosphorylation at a dose far below the max- imally tolerated dose.64 While it has some activity against other tyrosine kinases including AXL, it is far more potent against mFLT3 than these other tyrosine kinases. As a result of these pharmacologic properties, gilteritinib induced higher rates of remission and better OS in the R/R setting than salvage chemotherapy, all while preserving a favorable toxicity profile.51 As a class I FLT3 inhibitor, gilteritinib is not as susceptible to the development of resistance via the acquisition of mutations in the FLT3 inhibitor, but resistance does eventually develop. Resistance most commonly develops as a result of acquired mutations in FLT3, such as the F691I/L gatekeep- er mutation, or in components of the pathway down- stream of the FLT3 receptor such as the RAS family.65 Resistance may also develop through the acquisition of driver mutations that activate other, unrelated pathways. Some of these may be targeted, as in the case of new IDH1/2 mutations or BCR-ABL fusions, highlighting the importance of performing mutational analyses for select, targetable genes at the time of disease progression on gilteritinib and other FLT3 inhibitors.
Quizartinib
Quizartinib is a class II, second generation FLT3 inhibitor. It is one of the most potent FLT3 inhibitors, but is ineffective against TKD mutations and is susceptible to the development of acquired resistance by the accumula- tion of point mutations in the TKD.52 In the phase III
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haematologica | 2021; 106(3)