The Development of Novel Therapies for the Treatment of Acute Myeloid Leukemia (AML)
Abstract
:1. Introduction
2. Molecular Targets of New Drug Development in AML
2.1. Gene Mutations
Treatment | Complete response % | Partial response % | Blast response % | Comments | Ref. |
---|---|---|---|---|---|
FLT3 inhibitors | |||||
Sorafenib n = 50; n = 39 with FLT3 ITD or D835 point mutation or both | 10% (13% FLT3 mutation) | 34% (all with FLT ITD) | Phase I, relapsed/refractory AML | [24] | |
Midostaurin n = 95; n = 35 FLT mutant | 0 | 1.6% | 71% FLT3 ITD 42% FLT3 WT | Phase II, relapsed/refractory MDS and AML | [25] |
Lestaurtinib n = 14 | 0% | 0% | 29% | Phase II, relapsed/refractory AML with FLT3 ITD | [26] |
Lestaurtinib n = 5 with FLT 3 mutation n = 22 WT | 0 | 0 | 60% (FLT3 mutated) 23% (WT) | Phase II, newly diagnosed AML in the elderly | [27] |
AC220 n = 76; n = 47 with FLT3 mutant | 12% (22% flt3 mutated; 6% WT; 18%unk) | 18% (33% flt3 mutated; 13% WT; 18%unk) | Phase I, relapsed refractory AML unselected for FLT3 ITD | [28] | |
Epigentic modulation | |||||
5-azacytidine n = 113 | 18% (vs. 16% in BSC) | Subanalysis of patients with low blast count in phase III trial | [29] | ||
Decitabine n = 485 | 17.8% (vs. 7.8% conventional care) | Phase III trial compared to conventional care (TC) AML | [30] | ||
mRNA processing and translation | |||||
Ribavirin n = 11 | 7% | 13% | 27% | AML FAB M4 and M5 M4 and M5 subtypes, phase II, refractory, relapsed or newly diagnosed, unfit for induction chemotherapy | [31] |
PI3K/Akt/mTOR | |||||
Deformolus (Rapamycin analogue) n = 22 | 0% | 0% | 0% | Phase II | [32] |
Protein recycling | |||||
Tosedostat n = 73 | 12% | 10% | Phase II, patients aged 60 and over with relapsed, refractory disease | [33] | |
CD33 | |||||
Gemtuzumab ozogamycin n = 142 | 29% | 17% | Phase II; relapsed AML; complete response includes patients with incomplete platelet recovery | [34] | |
Farnesylation and RAS targeting | |||||
Farnesyl Transferase Inhibitor R115777 n = 34 | 6% | 24% | Phase II; relapsed/refractory AML | [35] |
2.2. Epigenetic Changes
2.3. mRNA Processing and Translation
2.4. PI3/AKT/mTOR Pathways
2.5. Protein Recycling
2.6. Monoclonal Antibody Therapy against CD33: Gemtuzumab Ozogomycin
3. Phase II Clinical Trial Design Strategies for New Drug Development in AML
3.1. Clinical Trial Design
3.2. Designing Combination Agent Trials
3.3. Impact of Patient Factors in Clinical Trial Design
3.4. Using Molecular Correlates to Design Clinical Trials
4. Conclusions
Acknowledgements
References
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Assouline, S.; Cocolakis, E.; Borden, K.L.B. The Development of Novel Therapies for the Treatment of Acute Myeloid Leukemia (AML). Cancers 2012, 4, 1161-1179. https://doi.org/10.3390/cancers4041161
Assouline S, Cocolakis E, Borden KLB. The Development of Novel Therapies for the Treatment of Acute Myeloid Leukemia (AML). Cancers. 2012; 4(4):1161-1179. https://doi.org/10.3390/cancers4041161
Chicago/Turabian StyleAssouline, Sarit, Eftihia Cocolakis, and Katherine L. B. Borden. 2012. "The Development of Novel Therapies for the Treatment of Acute Myeloid Leukemia (AML)" Cancers 4, no. 4: 1161-1179. https://doi.org/10.3390/cancers4041161