100th Anniversary of Nagoya J Med Sci: Comments to the Highly Cited Articles
Nagoya J. Med. Sci. 85. 27–29, 2023
doi:10.18999/nagjms.85.1.27

A never-ending FLT3 story
Hitoshi Kiyoi
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

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Kiyoi H. FLT3 inhibitors: recent advances and problems for clinical application. Nagoya
J Med Sci. 2015; 77(1–2): 7–17.
FLT3, a type III receptor tyrosine kinase, expresses on most acute leukemia cells aswell as normal hematopoietic stem/progenitor cells. Mutation in the FLT3 gene is the mostfrequent genetic alteration in acute myeloid leukemia (AML) and is well known as animportant driver mutation for the development of myeloid malignancies. FLT3 mutation isa strong poor prognostic factor for the long-term survival in AML patients, while neither
high-dose chemotherapy nor allogeneic hematopoietic stem cell transplantation can overcome
a poor prognosis. Development of an FLT3 inhibitor is, therefore, much awaited. To date,
several potent FLT3 inhibitors have been developed and some of them were evaluated for
efficacy in clinical trials, although no FLT3 inhibitor has been yet approved. Moreover, severalproblems for clinical use, such as adverse effects, blood concentration and resistance havebeen apparent. Recently developed AC220 is a highly selective and sensitive FLT3 inhibitor.
In Phase I and II trials, AC220 so far showed the best efficacy of AML cells harboring FLT3mutation among clinically evaluated FLT3 inhibitors, while severe bone marrow suppression
and QTc prolongation should be resolved for the clinical use. In this review, I summarize
the characteristics of FLT3 inhibitors in clinical development and discuss important issues tobe resolved for clinical use.
Keywords: FLT3, inhibitors, leukemia, molecular target, resistance
I would like to congratulate the “Nagoya Journal of Medical Science” on its 100th anniversary.
My review article entitled “FLT3 inhibitors: Recent advances and problems for clinical application” was published in the Nagoya J Med Sci in 2015,1 and I sincerely appreciate the opportunity
to present subsequent progress in this field in this 100th anniversary issue.
There has been a remarkable progress in the development of FLT3 inhibitors since thepublication of my article. A randomized phase 3 study for newly diagnosed FLT3-mutated acute
myeloid leukemia (AML) patients (RATIFY study) demonstrated the superiority of midostaurin
Received: September 7, 2022; accepted: October 18, 2022
Corresponding Author: Hitoshi Kiyoi, MD, PhD
Department of Hematology and Oncology, Nagoya University Graduate School of Medicine,
65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Tel: +81-52-744-2136, Fax: +81-52-744-2157, E-mail: kiyoi@med.nagoya-u.ac.jp27

Hitoshi Kiyoi

Table 1

FLT3 inhibitors approved in Japan

Gilteritinib

Quizartinib

FLT3 kinase inhibition
IC50 (nM)

0.29

1.6

Inhibitory target

FLT3-ITD, FLT3-TKD

FLT3-ITD

Other targets

AXL, LTK, ALKKITApproved usage and indicationsin Japan

Single agent for relapsed orrefractory AML with FLT3
mutation

Single agent for relapsed or
refractory AML with FLT3-ITD
mutationin addition to the conventional induction and consolidation chemotherapies for overall survival(OS).2 Based on the results of this study, midostaurin was approved as a combination agent withstandard chemotherapy by the US Food and Drug Administration in 2017. Although midostaurin
has not yet been approved in Japan, two FLT3 inhibitors, gliteritinib and quizartinib, havebeen approved (Table 1). Gilteritinib is a selective FLT3 inhibitor that inhibits internal tandem
duplication (ITD) and tyrosine kinase domain (TKD) mutations. A randomized phase 3 study
for relapsed or refractory (R/R) AML patients with FLT3 mutations (ADMIRAL study) showedthat the median OS of gilteritinib-treated patients significantly longer than that of conventional
chemotherapy-treated patients.3 Gilteritinib was approved for R/R AML patients with FLT3mutations as the first single-agent FLT3 inhibitor in Japan in 2018. Quizartinib has strong
inhibitory activity against FLT3-ITD but not against FLT3-TKD. Quizartinib also demonstrateda significantly longer OS than conventional chemotherapy in a randomized phase 3 study for
R/R AML patients with FLT3-ITD mutation (QuANTUM-R study),4 and was approved only inJapan in 2019. Furthermore, at the European Hematology Association 2022 Congress, quizartinib
combined with conventional induction and consolidation chemotherapies was shown to exhibit
superior OS in a randomized phase 3 study for newly diagnosed AML patients with FLT3-ITDmutation (QuANTUM-FIRST study).
Twenty years after the discovery of the FLT3 mutation, FLT3 inhibitors have become clinicallyavailable for AML patients with FLT3 mutations. However, several issues regarding the clinicaluse of FLT3 inhibitors have been raised.5 For example, several mechanisms of resistance toFLT3 inhibitors have been identified in clinical studies and daily clinical practice. In particular,
the gatekeeper FLT3-F691L mutation and RAS/MAPK pathway mutations are serious issues thatmust be resolved. To overcome the resistance of the FLT3-F691L mutation, we developed a novel
FLT3 inhibitor, FF-10101, in collaboration with FUJIFILM Corporation (Kanagawa, Japan), which
was designed to form a covalent binding between the C695 residue of FLT3.6 The formationof covalent binding induces irreversible inhibition of FLT3, maintaining the inhibitory activity
against FLT3 kinase harboring the gatekeeper mutation. Additionally, the most suitable therapeuticstrategy for each inhibitor remains unclear. Our study along with other studies demonstrated thatan allogeneic hematopoietic stem cell transplantation at the first complete remission improved
the relapse-free survival of AML patients with FLT3-ITD.7 Currently, synergizing chemotherapy
with an FLT3 inhibitor to reduce AML cell volume as much as possible before transplantation,
followed by maintenance therapy with an FLT3 inhibitor, is highly desirable. AML is a genetically heterogeneous disease and FLT3 mutation is a late event during leukemogenesis; hence,
further studies are required to establish biomarkers for selecting the best therapeutic strategy
and predicting the clinical response. We have established many patient-derived xenotransplantmodels to resolve this critical issue8 and are still in the middle of the never-ending FLT3 story.
Nagoya J. Med. Sci. 85. 27–29, 2023

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doi:10.18999/nagjms.85.1.27

Hitoshi Kiyoi

CONFLICT OF INTEREST
H Kiyoi received research funding from FUJIFILM, Kyowa-Kirin, Bristol-Myers Squibb,Otsuka, Perseus Proteomics, Daiichi Sankyo, Abbvie, CURED, Astellas Pharma, Chugai, Zenyaku
Kogyo, Nippon Shinyaku, Eisai, Takeda, Sumitomo Dainippon Pharma, and Sanofi, and honoraria
from Abbvie, Chugai, Astellas Pharma, and Novartis.

REFERENCES
1Kiyoi H. FLT3 inhibitors: recent advances and problems for clinical application. Nagoya J Med Sci.
2015;77(1–2):7–17.
2 Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemiawith a FLT3 mutation. N Engl J Med. 2017;377(5):454–464. doi:10.1056/NEJMoa1614359.
3 Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated
AML. N Engl J Med. 2019;381(18):1728–1740. doi:10.1056/NEJMoa1902688.
4 Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory
FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase
3 trial. Lancet Oncol. 2019;20(7):984–997. doi:10.1016/S1470-2045(19)30150-0.
5 Kiyoi H, Kawashima N, Ishikawa Y. FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm
beyond inhibitor development. Cancer Sci. 2020;111(2):312–322. doi:10.1111/cas.14274.
6 Yamaura T, Nakatani T, Uda K, et al. A novel irreversible FLT3 inhibitor, FF-10101, shows excellent efficacy
against AML cells with FLT3 mutations. Blood. 2018;131(4):426–438. doi:10.1182/blood-2017-05-786657.
7 Kawashima N, Ishikawa Y, Atsuta Y, et al. Allogeneic HSCT at the first remission for younger adults
with FLT3-internal tandem duplication AML: The JALSG AML209-FLT3-SCT Study. Cancer Sci.
2020;111(7):2472–2481. doi:10.1111/cas.14448.
8 Kawashima N, Ishikawa Y, Kim JH, et al. Comparison of clonal architecture between primary and immunodeficient mouse-engrafted acute myeloid leukemia cells. Nat Commun. 2022;13(1):1624–1634. doi:10.1038/s41467-022-29304-6.
References End

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