Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia
Abstract
:1. Introduction
2. Prognostic Impact of FLT3 Mutations
3. Classification of FLT3 Inhibitors by Its Pharmacodynamics
4. Current Clinical Role of FLT3 Inhibitors
5. Mechanisms of Resistance to FLT3 Inhibitors
5.1. Primary Resistance
5.2. Secondary Resistance Due to Additional FLT3 Mutations (on-Target Resistance)
5.3. Secondary Resistance Due to Non-FLT3 Abnormalities (off-Target Resistance)
6. Strategies to Overcome Resistance to FLT3 Inhibitors
6.1. Development of Novel Agents
6.2. Combination with Different Class Agents
6.3. Genetic Mutation Analysis
7. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Agent | Generation | Type | Selectivity | IC50 (nM) | Drug Sensitivity | ||||
---|---|---|---|---|---|---|---|---|---|
ITD | D835Y | ITD-D835Y | F691L | ||||||
Midostaurin | (PKC412) | First | I | Low | 139 | S | S | R | R |
Sunitinib | (SU11248) | First | I | Low | 250 | S | R | R | R |
Lestaurtinib | (CEP701) | First | I | Low | 5 | S | Int | S | − |
Gilteritinib | (ASP2215) | Second | I | Moderate | 1.6 | S | S | Int | R |
Crenolanib | (CP868596) | Second | I | Moderate | 2 | S | S | Int | R |
Sorafenib | (BAY43-9006) | First | II | Moderate | 58 | S | R | R | R |
Tandutinib | (CT53518) | First | II | High | 100 | S | R | − | − |
Quizartinib | (AC220) | Second | II | High | <1.0 | S | R | R | R |
SORAFENIB (BAY 43-9006) | ||||||||||
Authors and Jounals | Trial Name | Objectives | Disease Status | Agents * Controls Not Shown | Phase/Design | Response Rate | Median PFS | Median OS | Sequential allo-SCT | |
Rolling, et al. Lancet Oncol 2015 | SORAML | AML (age < 60) | Newly diagnosed | Sorafenib + Standard therapy | II | CR | 60% (81/134) | 21 mo. [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32] | Not Reached (3-yr OS 63%) | 31% (42/132) |
Uy, et al. Blood Advances 2016 | CALGB 11001 | AML (age > 60) with FLT3-ITD and/or TKD | Newly diagnosed | Sorafenib + Standard therapy | II | CR | 74% (40/54) | 8.8 mo. (FLT3-ITD) 7.8 mo. (FLT3-TKD) | 15.0 mo. (FLT3-ITD) 16.2 mo. (FLT3-TKD) | 53% (22/54) |
Ohanian, et al. Am J Hematol 2018 | − | AML (age > 60) with FLT3-ITD | Newly diagnosed | Sorafenib + Azacitidine | I/II | CR/Cri PR | 70% (19/27) 7% (2/27) | 7.1 mo. (only in responders) | 8.3 mo. (in all participants) | 11% (3/27) |
Sasaki, et al. Cancer 2019 | − | AML with FLT3-ITD | Newly diagnosed | Soragenib + Standard therapy | Retrospective | CR/CRi | 99% (78/79) | 31 mo. [5.7–56.8] | 17 mo. [11.1–22.4] | 67% (53/79) |
Muppidi, et al. Clinical Lymphoma Myeloma and Leukemia 2015 | − | AML with FLT3-ITD | Newly diagnosed or relapsed | Sorafenib + Decitabine | Case Series | CR/CRi | 83% (5/6) | Not Reported | 5.1 mo. [1.9–14.5] | 33% (2/6) |
Ravandi, et al. Blood 2013 | − | AML with FLT3-ITD | Relapsed or refractory (including prior allo-SCT) | Sorafenib + Azacitidine | II | CR/Cri PR | 43% (16/37) 3% (1/37) | 3.8 mo. [1.0–16.4] | 6.2 mo. | 16% (6/37) |
Bazarbachi, et al. Heamatologica 2019 | − | AML with FLT3-ITD | Relapsed ater allo-SCT | Sorafenib as part of/after salvage | Retrospective | CR | 39% (10/26) | Not Reported | (2-yr. OS 38%) | 13% (3/26) |
MIDOSTAURIN (PKC412) | ||||||||||
Authorsand Jounals | Trial Name | Objectives | Disease Status | Agents * Controls Not Shown | Phase/Design | Response Rate | Median PFS | Median OS | Sequential allo-SCT | |
Stone, et al. N Engl J Med 2017 | RATIFY | AML with FLT3-ITD and/or TKD | Newly diagnosed | Midostaurin + Standard induction/consolidation | III | CR | 70% (504/717) | 8.2 mo. [5.4–10.7] | 74.7 mo. [31.5–inf.] | 57% (287/504) |
Schlenk, et al. Blood 2019 | AMLSG 16-10 | AML with FLT3-ITD and/or TKD | Newly diagnosed | Midostaurin + Standard induction/consolidation f/b Midostaurin maitenance | II | CR/CRi | 76% (217/292) | 13.2 mo. [10.0–18.3] | 26.0 mo. [18.9–37.0] | 62% (134/217) |
Fischer, et al. J Clin Oncol 2010 | − | AML or high-risk MDS | Relapsed or refractory or ineligible to standard therapy | Midostaurin | IIB | PR HI Blast | 1% (1/97) 46% (16/35 *) 71% (25/35 *) * only in FLT3-mt | Not Reported | 4.3 mo. [3.5–5.2] | 31% (42/132) |
Strati, et al. Am J Hematol 2015 | − | AML or high-risk MDS | Relapsed or refractory or ineligible to standard therapy | Midostaurin + Azacitidine | I/II | CR/Cri PR/MLFS | 15% (8/54) 13% (7/54) | 4.6 mo. [2.3–6.9] * Duration of Response | 5.1 mo. [3.5–6.7] | 0% (0/8) |
Walker, et al. Leukemia & Lymphoma 2016 | − | AML | Relapsed or refractory (including prior allo-SCT) | Midostaurin + Bortezomib + Chemotherapy(MEC) | I | CR/CRi | 83% (19/23) | Not Reported | 10.8 mo. | 63% (12/19) |
Maziarz, et al. Blood 2018 | RADIUS | AML with FLT3-ITD | in 1st CR after allo-SCT | Midostaurin + Standard of care | II | Not Applicable | (18mo.-PFS 89%) | Not Reported | Not Applicable | |
GILTERITINIB (ASP2215) | ||||||||||
Authors and Jounals | Trial Name | Objectives | Disease Status | Agents * Controls Not Shown | Phase/Design | Response Rate | Median PFS | Median OS | Sequential allo-SCT | |
Perl, et al. N Engl J Med 2019 | ADMIRAL | AML with FLT3-ITD and/or TKD | Relapsed or refractory | Gilteritinib | III | CR/Cri PR | 54% (134/247) 13% (33/247) | 2.8 mo. [1.4–3.7] | 9.3 mo. [7.7–10.7] | 26% (63/247) |
Perl, et al. Lancet Oncol 2017 | − | AML with FLT3-ITD and/or TKD | Relapsed or refractory | Gilteritinib | I/II | CR/Cri PR | 41% (69/169) 11% (19/169) | 4.6 mo. * Duration of Response | 7.1 mo. | 22% (37/169) |
Usuki, et al. Cancer Science 2018 | − | AML | Relapsed or refractory | Gilteritinib | I | CR/Cri PR | 60% (3/5 *) 20% (1/5 *) * only in FLT3-mt. | Not Reported | Not Reported | Not Reported |
QUIZARTINIB (AC220) | ||||||||||
Authors and Jounals | Trial Name | Objectives | Disease Status | Agents * Controls Not Shown | Phase/Design | Response Rate | Median PFS | Median OS | Sequential allo-SCT | |
Altman, et al. Blood 2018 | − | AML | Newly diagnosed | Quizartinib + Standard induction/consolidation f/b Quizartinib maitenance | I | CR/CRi | 74% (14/19) | (Maximum 16.3 mo.) | Not Reported | 47% (9/19) |
Cortes, et al. Blood 2019 | QuANTUM-R | AML with FLT3-ITD | Relapsed or refractory | Quizartinib | III | CR/Cri | 48% (118/245) | 1.4 mo. [0.0–1.9] | 6.2 mo. [5.3–7.2] | 32% (78/245) |
Cortes, et al. Blood 2018 | − | AML with FLT3-ITD | Relapsed or refractory | Quizartinib | IIB | CR/Cri PR | 47% (36/76) 18% (14/76) | 12.3 mo. [9.7–16.1] | 22.6 mo. [19.9–28.3] | 37% (28/76) |
Cortes, et al. Lancet Oncol 2018 | − | AML | Relapsed or refractory | Quizartinib | II | CR/Cri PR | 50% (125/248) 25% (62/248) * only in ITD-mt. | 2.8 mo. [1.4–3.6] * duration of CR, only in ITD-mt. | 5.8 mo. [4.9–6.8] * only in ITD-mt. | 35% (61/176) |
Sandmaier, et al. Am J Hematol 2017 | − | AML with FLT3-ITD | in 1st CR after allo-SCT | Quizartinib maintenance | I | Not Applicable | (0.4–22.8 mo.) * duration of maitenance | (3.0–32.7 mo.) | Not Applicable | |
CRENOLANIB (CP868596) | ||||||||||
Authors and Jounals | Trial Name | Objectives | Disease Status | Agents * Controls Not Shown | Phase/Design | Response Rate | Median PFS | Median OS | Sequential allo-SCT | |
Wang, et al. Blood 2016 | − | AML with FLT3-ITD and/or TKD | Newly diagnosed | Crenolanib + Standard induction/consolidation f/b Crenolanib maintenance | II | CR/CRi | 96% (24/25) | Not Reported | Not Reached (6 mo. OS 85%) | 50% (12/24) |
Randhawa, et al. Blood 2014 | − | AML with FLT3-ITD and/or TKD | Relapsed or refractory | Crenolanib | II | CR/Cri MLFS HI | 23% (3/13) 8% (1/13) 31% (4/13) * only in TKI-naïve | 3.0 mo. * only in TKI-naïve | 12.7 mo. * only in TKI-naïve | 26% (9/34) |
Ohanian, et al. Blood 2016 | − | AML with FLT3-ITD and/or TKD | Relapsed or refractory | Crenolanib + Salvage chemotherapy (IDA/AraC) | I | CR/CRi | 36% (4/11) | Not Reported | 8.5 mo. | 75% (3/4) |
Iyer, et al. Blood 2016 | − | AML | Relapsed or refractory | Crenolanib + Chemotherapy (HAM) | I | CR/CRi | 67% (4/6) | Not Reported | Not Repoted | 25% (1/4) |
LESTAURTINIB (CEP701) | ||||||||||
Authors and Jounals | Trial Name | Objectives | Disease Status | Agents * Controls Not Shown | Phase/Design | Response Rate | Median PFS | Median OS | Sequential allo-SCT | |
Levis, et al. Blood 2017 | − | AML with FLT3-ITD and/or TKD | Relapsed | Slavage chemotherapy (MEC) f/b Lestaurtinib maintenance | II | CR/CRi | 26% (29/112) | Not Reported | 5.2 mo. | 20% (22/112) |
Knapper, et al. Blood 2017 | − | AML with FLT3-ITD and/or TKD | Newly diagnosed | Standard induction/consolidation f/b Lestaurtinib maintenance | III | CR/CRi | 92% (277/300) | (5-yr. PFS 39–40%) | (5-yr. OS 43–50%) | 21% (58/277) |
SORAFENIB (BAY 43-9006) | ||||
Trial Number | Objectives | Disease Status | Agents * Controls Not Shown | Phase/Design |
NCT01371981 | AML with FLT3-ITD (high allelic ratio) | Newly diagnosed | Sorafenib + Bertezomib | III |
NCT03170895 | AML with FLT3-ITD | Newly diagnosed or relapsed | Sorafenib + Homoharringtonine (STAT inhibitor) | II |
MIDOSTAURIN (PKC412) | ||||
NCT03686345 | Core binding factor AML | Newly diagnosed | Midostaurin + Standard induction | II |
NCT03280030 | AML with FLT3-ITD and/or TKD | Newly diagnosed | Midostaurin + Standard induction/consolidation f/b Midostaurin maitenance | II |
NCT03512197 | AML with FLT3-ITD and/or TKD | Newly diagnosed | Midostaurin + Standard induction/consolidation f/b Midostaurin maitenance | III |
NCT03379727 | AML with FLT3-ITD and/or TKD | Newly diagnosed | Midostaurin + Standard induction/consolidation f/b Midostaurin maitenance | III |
GILTERITINIB (ASP2215) | ||||
NCT02236013 | AML | Newly diagnosed | Gilteritinib + Standard induction/consolidation | I |
NCT02752035 | AML with FLT3-ITD and/or TKD | Newly diagnosed and ineligible to standard therapy | Gilteritinib + Azacitidine | III |
NCT03730012 | AML with FLT3-ITD and/or TKD | Relapsed or refractory | Gilteritinib + Atezolizumab (anti-PD-L1 antibody) | I/II |
NCT02310321 | AML | Newly diagnosed | Gilteritinib + Standard induction/consolidation | I/II |
NCT03182244 | AML with FLT3-ITD and/or TKD | Relapsed or refractory | Gilteritinib + Salvage chemotherapy | III |
QUIZARTINIB (AC220) | ||||
NCT02668653 | AML with FLT3-ITD | Newly diagnosed | Quizartinib + Standard induction/consolidation | III |
NCT03723681 | AML | Newly diagnosed | Quizartinib + Standard induction/consolidation | I |
NCT02834390 | AML | Newly diagnosed | Quizartinib + Standard induction/consolidation | IB |
NCT03552029 | AML with FLT3-ITD | Relapsed or refractory or ineligible to standard therapy | Quizartinib + Milademetan (MDM2 inhibitor) | I |
NCT03135054 | AML with FLT3-ITD | Newly diagnosed or relapsed | Quizartinib + Homoharringtonine (STAT inihibitor) | II |
NCT03661307 | AML with FLT3-ITD | Newly diagnosed or relapsed | Quizartinib + Decitabine + Venetoclax (BCL-2 inhibitor) | I/II |
NCT03735875 | AML with FLT3-ITD | Relapsed or refractory | Quizartinib + Venetoclax (BCL-2 inhibitor) | IB/II |
CRENOLANIB (CP868596) | ||||
NCT03258931 | AML with FLT3-ITD and/or TKD | Newly diagnosed | Crenolanib + Standard induction/consolidation | III |
NCT02283177 | AML with FLT3-ITD and/or TKD | Newly diagnosed | Crenolanib + Standard induction | II |
NCT03250338 | AML with FLT3-ITD and/or TKD | Relapsed or refractory | Crenolanib + Salvage chemotherapy | III |
NCT02400281 | AML with FLT3-ITD and/or TKD | Relapsed or refractory | Crenolanib + Salvage chemo. or Azacitidine | I/II |
NCT02626338 | AML | Relapsed or refractory | Crenolanib + Salvage chemotherapy | I/II |
NCT01522469 | AML with FLT3-ITD and/or TKD | Relapsed or refractory | Crenolanib + Standard induction/consolidation | IB |
OTHERS | ||||
NCT00783653 | AML with FLT3-ITD and/or TKD | Newly diagnosed | Sunitinib + Standard induction | I/II |
NCT00469859 | AML with FLT3-ITD and/or TKD | Relapsed or refractory | Lestaurtinib + Salvage chemotherapy | I/II |
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Eguchi, M.; Minami, Y.; Kuzume, A.; Chi, S. Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia. Biomedicines 2020, 8, 245. https://doi.org/10.3390/biomedicines8080245
Eguchi M, Minami Y, Kuzume A, Chi S. Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia. Biomedicines. 2020; 8(8):245. https://doi.org/10.3390/biomedicines8080245
Chicago/Turabian StyleEguchi, Motoki, Yosuke Minami, Ayumi Kuzume, and SungGi Chi. 2020. "Mechanisms Underlying Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia" Biomedicines 8, no. 8: 245. https://doi.org/10.3390/biomedicines8080245