Emerging Targeted Therapy for Specific Genomic Abnormalities in Acute Myeloid Leukemia
Abstract
:1. Introduction
2. Targeting Specific Mutant Genes
2.1. Fms-like Tyrosine Kinase 3 Mutation
2.2. Isocitrate Dehydrogenase Mutations
2.2.1. Targeting IDH1 and IDH2 Mutations
2.2.2. Targeting Anti-Apoptotic BCL-2
2.3. Menin-MLL Complex-Associated Gene Mutations
2.3.1. Targeting MLL-Rearrangement
2.3.2. Targeting NPM1 Mutations
2.3.3. Targeting NUP98 Fusion
2.3.4. Targeting SYK Signaling
2.4. TP53 Mutations
2.4.1. p53 Stabilizers
2.4.2. Targeting CD47
2.5. Other Potential Molecular-Targeting Agents Currently Available in Solid Tumors
2.5.1. KIT Inhibitors
2.5.2. Targeting RAS Pathway-Related Genes
3. Conclusions and Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Author and Jounal | Object(s) | Disease State | Agent(s) | Phase | Response Rate | Median Survival | |
---|---|---|---|---|---|---|---|
Stone, et al. [14] N Engl J Med 2017 | FLT3-mutated AML (both ITD and TKD) | ND | Midostaurin | III | CR | 70% (504/717) | 8.2 mo. [5.4–10.7] |
+ StdCTx | |||||||
Perl, et al. [15] N Engl J Med 2019 | FLT3-mutated AML (both ITD and TKD) | R/R | Gilteritinib | III | CR/CRi PR | 54% (134/247) 13% (33/247) | 9.3 mo. [7.7–10.7] |
Cortes, et al. [16] Blood 2019 | FLT3-mutated AML (ITD only) | R/R | Quizartinib | III | CR/CRi | 48% (118/245) | 18.5 mo. [10.8–28.8] |
Author and Jounal | Object(s) | Disease State | Agent(s) | Phase | Response Rate | Median Survival | |
---|---|---|---|---|---|---|---|
Ohanian, et al. [22] Am J Hematol 2018 | FLT3-mutated AML (ITD only) | NDi | Sorafenib + AZA | I/II | CR | 26% (7/27) | 7.1 mo. [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29] |
Strati, et al. [23] Am J Hematol 2015 | FLT3-mutated AML or MDS (both ITD and TKD) | NDi or R/R | Midostaurin + AZA | I/II | ORR | 26% (14/48) | 22 wk. [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29] |
Swaminathan, et al. [24] Haematologica 2020 | FLT3-mutated AML or MDS (ITD only) | NDi or R/R | Quizartinib + AZA/LDAC | I/II | CR CRi | 17% (12/70) 37% (26/70) | 19.2 mo. for AZA 8.5 mo. for LDAC |
Wang, et al. [25] Blood 2020 | FLT3-mutated AML (both ITD and TKD) | NDi | Gilteritinib + AZA | III | Did NOT meet the primary endpoint 39% were alive when study halted |
Author and Jounal | Target(s) | Disease State | Agent(s) | Phase | Response Rate | Duration of Response | |
---|---|---|---|---|---|---|---|
DiNardo, et al. [3] N Engl J Med 2018 | IDH1-mutated AML | R/R | Ivosidenib | Ib | CR ORR | 21.6% (56/258) 41.6% (107/258) | 8.2 mo. [5.5–12.0] |
Stein, et al. [4] Blood 2018 | IDH2-mutated AML | R/R | Enasidenib | Ib/II | CR ORR | 19.3% (34/176) 40.3% (71/176) | 5.8 mo. [3.9–7.4] |
DiNardo, et al. [36] N Engl J Med 2018 | IDH1-mutated AML | NDi | Ivosidenib + AZA | Ib | CR ORR | 60.9% (14/23) 78.3% (18/23) | Not reached Median f/u 16 mo. |
Stein, et al. [37] Blood 2018 | IDH1-mutated AML | ND | Ivosidenib + StdCTx | I | ORR | 78.0% (32/41) | 41% proceeded to HSCT |
IDH2-mutated AML | Enasidenib + StdCTx | ORR | 68.8% (53/77) | 43% proceeded to HSCT |
Author and Reference | Category | Object(s) | Disease State | Agent(s) | Phase | Response Rate | Median Survival | |
---|---|---|---|---|---|---|---|---|
Walker, et al. [85] Clin Cancer Res 2020 | SYK inhibitor | de novo AML | ND | Entospletinib + StdCTx | Ib/II | CR CR/CRi | 56% (19/34) 71% (24/34) | 37.1 mo. [16.8–Inf.] |
Sallman, et al. [91] J Clin Oncol 2021 | p53 stabilizer | TP53-mutated AML or MDS | HMA-naïve | Eprenetapopt + AZA | Ib/II | ORR * | 64% (7/11) | 10.8 mo. [8.1–13.4] |
NCT03745716 [92] | p53 stabilizer | TP53-mutated MDS | HMA-naïve | Eprenetapopt + AZA (vs. AZA alone) | III | Did NOT primary endpoint (CR 33.3% vs. 22.4%) | ||
Sallman, et al. [96] ASH meeting 2020 | Anti-CD47 antibody | AML | NDi | Magrolimab + AZA | Ib | CR ORR | 44% (15/34) 65% (22/34) | 12.9 mo. ** |
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Chi, S.-G.; Minami, Y. Emerging Targeted Therapy for Specific Genomic Abnormalities in Acute Myeloid Leukemia. Int. J. Mol. Sci. 2022, 23, 2362. https://doi.org/10.3390/ijms23042362
Chi S-G, Minami Y. Emerging Targeted Therapy for Specific Genomic Abnormalities in Acute Myeloid Leukemia. International Journal of Molecular Sciences. 2022; 23(4):2362. https://doi.org/10.3390/ijms23042362
Chicago/Turabian StyleChi, Sung-Gi, and Yosuke Minami. 2022. "Emerging Targeted Therapy for Specific Genomic Abnormalities in Acute Myeloid Leukemia" International Journal of Molecular Sciences 23, no. 4: 2362. https://doi.org/10.3390/ijms23042362