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Blood Res 2022; 57(S1):
Published online April 30, 2022
https://doi.org/10.5045/br.2022.2022017
© The Korean Society of Hematology
FLT3 mutations in acute myeloid leukemia: a review focusing on clinically applicable drugs
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
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.
Abstract
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
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Review Article
Blood Res 2022; 57(S1): S32-S36
Published online April 30, 2022 https://doi.org/10.5045/br.2022.2022017
Copyright © The Korean Society of Hematology.
FLT3 mutations in acute myeloid leukemia: a review focusing on clinically applicable drugs
Jae-Sook Ahn1,2, Hyeoung-Joon Kim1,2
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
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.
Abstract
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.
Keywords: Acute myeloid leukemia, FLT3-ITD, FLT3-TKD, Tyrosine kinase inhibitor, Gilteritinib, Midostaurin
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Table 1 . Summary of clinically applicable
FLT3 inhibitors forFLT3 -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/TKDRATIFY (Phase3) [7] Combination with 7+3 induction and consolidation chemotherapy Median OS (74.7 vs. 25.6 mo), P =0.009FDA, EMA Available Maintenance Midostaurin FLT3 -ITD/TKDRATIFY (Phase3) [7] Maintain until relapse for up to 12 monthsas the extension of RATIFY trial EMA Not available Post-HCT maintenance Sorafenib FLT3 -ITDSORMAIN (Phase 2) [9] Maintain untilrelapse for up to 24 months 2-year RFS (85 vs. 53%), P =0.002Off-label Not available Relapsed or refractory Gilteritinib FLT3 -ITD/TKDADMIRAL (Phase 3) Monotherapy Median OS (9.3 vs. 5.6 mo), P <0.001FDA, EMA Available Intensive induction ineligible Newly diagnosed Sorafenib FLT3 -ITDNCT02196857 (Phase 2) and NCT01254890 Phase 1/2) [35] Combination with azacitidine Median OS (8.3 mo) Off-label Not available Relapsed or refractory Sorafenib FLT3 -ITDNCT01254890 [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..
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