FLT3 mutations in acute myeloid leukemia: a review focusing on clinically applicable drugs

Jae-Sook Ahn; Hyeoung-Joon Kim

doi:10.5045/br.2022.2022017

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Blood Res 2022; 57(S1):

Published online April 30, 2022

https://doi.org/10.5045/br.2022.2022017

FLT3 mutations in acute myeloid leukemia: a review focusing on clinically applicable drugs

Jae-Sook Ahn^1,2, Hyeoung-Joon Kim^1,2

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¹Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University, Gwangju,
²Genomic Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Hwasun, Korea

Correspondence to : Jae-Sook Ahn, M.D., Ph.D.
Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun, Hwasun 58128, Korea
E-mail: f0115@jnu.ac.kr

Received: January 19, 2022; Revised: February 28, 2022; Accepted: February 28, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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FMS-like tyrosine kinase 3 (FLT3) mutations, the most frequently detected genetic aberrations in patients with acute myeloid leukemia (AML), are identified in approximately 30% of patients with newly diagnosed AML and are more common in patients with normal karyotypes. Since the discovery of FLT3 mutations in AML, clinical trials have been actively conducted in patients with FLT3 mutated AML, and FLT3 inhibitors have been introduced into clinical practice. The current standard treatment for patients with newly diagnosed FLT3-mutated AML is 7+3 induction chemotherapy combined with midostaurin. Additionally, gilteritinib is more effective than salvage chemotherapy for relapsed or refractory FLT3-mutated AML. Ongoing trials are expected to provide additional treatment options depending on the disease state and patient vulnerability. This review summarizes information on clinically available FLT3 inhibitors for the management of AML with FLT3 mutations.

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Keywords: Acute myeloid leukemia, FLT3-ITD, FLT3-TKD, Tyrosine kinase inhibitor, Gilteritinib, Midostaurin

Article

Review Article

Blood Res 2022; 57(S1): S32-S36

Published online April 30, 2022 https://doi.org/10.5045/br.2022.2022017

FLT3 mutations in acute myeloid leukemia: a review focusing on clinically applicable drugs

Jae-Sook Ahn^1,2, Hyeoung-Joon Kim^1,2

Correspondence to:Jae-Sook Ahn, M.D., Ph.D.
Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University, 322 Seoyang-ro, Hwasun-eup, Hwasun-gun, Hwasun 58128, Korea
E-mail: f0115@jnu.ac.kr

Received: January 19, 2022; Revised: February 28, 2022; Accepted: February 28, 2022

Abstract

Keywords: Acute myeloid leukemia, FLT3-ITD, FLT3-TKD, Tyrosine kinase inhibitor, Gilteritinib, Midostaurin

Abstract

Table 1 . Summary of clinically applicable FLT3 inhibitors for FLT3-mutated AML..

Patient eligibility	Disease status	Drug	Target mutated lesion	Representative trial	Usage	Benefit	Approval	In Korea
Intensive induction eligible	Newly diagnosed	Midostaurin	FLT3-ITD/TKD	RATIFY (Phase3) [7]	Combination with 7+3 induction and consolidation chemotherapy	Median OS (74.7 vs. 25.6 mo), P=0.009	FDA, EMA	Available
	Maintenance	Midostaurin	FLT3-ITD/TKD	RATIFY (Phase3) [7]	Maintain until relapse for up to 12 monthsas the extension of RATIFY trial		EMA	Not available
	Post-HCT maintenance	Sorafenib	FLT3-ITD	SORMAIN (Phase 2) [9]	Maintain untilrelapse for up to 24 months	2-year RFS (85 vs. 53%), P=0.002	Off-label	Not available
	Relapsed or refractory	Gilteritinib	FLT3-ITD/TKD	ADMIRAL (Phase 3)	Monotherapy	Median OS (9.3 vs. 5.6 mo), P<0.001	FDA, EMA	Available
Intensive induction ineligible	Newly diagnosed	Sorafenib	FLT3-ITD	NCT02196857 (Phase 2) and NCT01254890 Phase 1/2) [35]	Combination with azacitidine	Median OS (8.3 mo)	Off-label	Not available
Intensive induction ineligible	Relapsed or refractory	Sorafenib	FLT3-ITD	NCT01254890 [36]	Combination with azacitidine	Response rate: 46%	Off-label	Not available

Abbreviations: AML, acute myeloid leukemia; EMA, European Medicines Agency; FDA, Food and Drug Administration; FLT3, FMS-like tyrosine kinase 3; HCT, hematopoietic cell transplantation; ITD, internal tandem duplication; mo, months; OS, overall survival; RFS, relapse-free survival; TKD, tyrosine kinase domain..