Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia
Abstract
:1. Introduction
2. LSCs and Relapse
3. Current Treatments
4. Genetic Mutations in AML
5. FLT3 Mutation
6. Targeting FLT3
6.1. First-Generation FLT3 Inhibitors
6.2. Midostaurin
6.3. Sorafenib
6.4. Second-Generation FLT3 Inhibitors
6.5. Quizartinib
6.6. Gilteritinib
7. TKI Resistance and Disease Relapse
8. The mTOR Pathway
9. NK Cells
10. Engaging Immune Cells with IL-15
11. Engaging Immune Cells by Blocking TGF-β
12. Combination Treatments
13. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Inhibitor | Type | Targets | Adverse | Outcome |
---|---|---|---|---|
First Generation | ||||
Midostaurin | Type I | Other kinases (KIT, PDGFR, RAS/RAF/MEK, JAK) | Cytopenias, flu-like symptoms, cardiac failure (<5%), nausea, vomiting, diarrhea | OS, RFS |
Sorafenib | Type II | Other kinases (KIT, PDGFR, RAS/RAF/MEK, JAK) | Cytopenias, flu-like symptoms, hypertension, cardiac ischemia (<5%), diarrhea, rash, hand-foot | OS, RFS, CIR, NRM, GVHD, AE |
Second Generation | ||||
Gilteritinib | Type I | Higher potency, more specific, less off-target | Cytopenias, diarrhea, pancreatitis, headaches | OS, RFS, CIR, AE |
Quizartinib | Type II | Higher potency, more specific, less off-targe | Cytopenias, flu-like symptoms, cardiac arrythmia, nausea, anorexia | OS, RFS, AE |
Trial | Developmental Phase | |
---|---|---|
First Generation Inhibitors | ||
Midostaurin + 7+3 chemotherapy | RATIFY (NCT00651261) | Phase III |
Midostaurin + Azacitidine | Internal Trial at MD Anderson Cancer Center | Phase I/II |
±Midostaurin + Allo-HCT | RADIUS (NCT01883362) | Phase II |
Sorafenib | SORMAIN (DRKS00000591) | Phase II |
Sorafenib + 7+3 chemotherapy | SORAML (NCT00893373) | Phase II |
Second Generation Inhibitors | ||
Quizartinib + Cytarabine/Daunorubicin | NCT 01390337 | Phase I |
Quizartinib + Allo-HCT | 2689-CL-0011 | Phase I |
Quizartinib + Allo-HCT | NCT00462761 | Phase I |
Quizartinib + 7+3 chemotherapy | QuANTUM-First (NCT02668653) | Phase III |
Gilteritinib or salvage chemotherapy | QuANTUM-First (NCT02668653) | Phase III |
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Leifheit, M.E.; Johnson, G.; Kuzel, T.M.; Schneider, J.R.; Barker, E.; Yun, H.D.; Ustun, C.; Goldufsky, J.W.; Gupta, K.; Marzo, A.L. Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia. Int. J. Mol. Sci. 2024, 25, 9448. https://doi.org/10.3390/ijms25179448
Leifheit ME, Johnson G, Kuzel TM, Schneider JR, Barker E, Yun HD, Ustun C, Goldufsky JW, Gupta K, Marzo AL. Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia. International Journal of Molecular Sciences. 2024; 25(17):9448. https://doi.org/10.3390/ijms25179448
Chicago/Turabian StyleLeifheit, Malia E., Gunnar Johnson, Timothy M. Kuzel, Jeffrey R. Schneider, Edward Barker, Hyun D. Yun, Celalettin Ustun, Josef W. Goldufsky, Kajal Gupta, and Amanda L. Marzo. 2024. "Enhancing Therapeutic Efficacy of FLT3 Inhibitors with Combination Therapy for Treatment of Acute Myeloid Leukemia" International Journal of Molecular Sciences 25, no. 17: 9448. https://doi.org/10.3390/ijms25179448