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Cancer Chemotherapy and Pharmacology
Erschienen in:

03.08.2020 | Original Article

Towards better combination regimens of cytarabine and FLT3 inhibitors in acute myeloid leukemia

verfasst von: Mohamed Elmeliegy, Jason Den Haese, Chetasi Talati, Meir Wetzler, William J. Jusko

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 3/2020

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Abstract

Background

AML patients with FLT3/ITD mutations have poor response to cytarabine-based chemotherapy. FLT3 inhibitors (FLT3i) may resensitize cells to cytarabine (CYT). Improving treatment outcome of this combination may benefit from a mechanistic extrapolation approach from in vitro data.

Methods

The effects of CYT and several FLT3i on cell proliferation and cell cycle kinetics were examined in AML cell lines. The effect of FLT3i (quizartinib, midostaurin, sorafenib) on cell proliferation and cell cycle kinetics was assessed in AML cell lines with differing FLT3 status; HEL (negligible expression of wild-type FLT3), EOL1 (wild-type FLT3), MV4-11 (FLT3-ITD resulting in constitutively active isoform). Semi-mechanistic cell cycle models for CYT and FLT3i were developed. Clinical CYT and quizartinib pharmacokinetic dosage regimens were modeled. Survival of AML patients was described via a hazard model. Simulations exploring different CYT/quizartinib regimens were conducted with the goal of improving treatment outcome.

Results

FLT3 status was associated with sensitivity to CYT (HEL cells most sensitive > EOL1 > MV4-11 cells). This order of sensitivity is reversed for FLT3i. Cytarabine induced apoptosis in the S-phase while all FLT3i induced apoptosis and cell cycle arrest at G1 phase. Simulations of candidate clinical regimens predict better cell kill upon adding quizartinib simultaneously with or immediately after CYT exposure. Overall survival was predicted to be significantly better with quizartinib 200 mg administered every 48 h vs every 24 h in patients with FLT3 aberrations.

Conclusion

Simultaneous administration of quizartinib and CYT every other day is a promising combination regimen for AML patients with FLT3 mutations.
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Metadaten
Titel
Towards better combination regimens of cytarabine and FLT3 inhibitors in acute myeloid leukemia
verfasst von
Mohamed Elmeliegy
Jason Den Haese
Chetasi Talati
Meir Wetzler
William J. Jusko
Publikationsdatum
03.08.2020
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Chemotherapy and Pharmacology / Ausgabe 3/2020
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-020-04114-z

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