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Targeting FLT3-ITD in AML
with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive (FLT3+), in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. This combination therapy is, however, not suitable for NK AML patients with FLT3-ITD in relapse or refractory to conventional induc- tion treatment or unfit for intensive treatment. For the subset of AML patients with a high ratio of FLT3-ITD and adverse prognosis, the combined use of non-genotoxic tar- geted compounds, such as the combination of midostau- rin and NVP-HDM201, may represent a promising treat- ment option. Synergistic effects on cell viability with midostaurin and NVP-HDM201 were observed independ- ent of sequence of application, indicating that the order of target inhibition for FLT3 and MDM2 was not important. Sequential application of NVP-HDM201 and midostaurin
had the same effects on cell viability as direct combination treatment. Pretreatment with one inhibitor did not enhance the susceptibility of AML cells to the second inhibitor. This leaves several options for treatment regi- mens in a prospective clinical trial. The best therapy regi- men in combination treatments with midostaurin and NVP-HDM201 for AML patients will have to be defined empirically.
Acknowledgments
We thank Novartis for providing the investigational com- pounds NVP-HDM201 and NVP-CGM097.
Funding
This work was supported by a grant from the Swiss National Science Foundation (SNF) #310030_127509 to TP.
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