Towards better combination regimens of cytarabine and FLT3 inhibitors in acute myeloid leukemia
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ORIGINAL ARTICLE
Towards better combination regimens of cytarabine and FLT3 inhibitors in acute myeloid leukemia Mohamed Elmeliegy1,5 · Jason Den Haese2,4 · Chetasi Talati2,3 · Meir Wetzler2 · William J. Jusko5 Received: 5 January 2020 / Accepted: 3 June 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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), MV411 (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. Keywords Pharmacodynamic modeling · AML · Cell cycle · Cytotoxicity · Combination
Introduction Despite recent progress in acute myeloid leukemia (AML) treatment, 5-year overall survival rate remains dismal at 27% [1] with cure rates for patients older than 60 years remaining M.E. is an employee of Pfizer and receives stock and stock options as part of his employment. The initial stages of this work were conducted while M.E. was affiliated with University at Buffalo. M.W. passed away before submitting this manuscript draft. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04114-z) contains supplementary material, which is available to authorized users. * Mohamed Elmeliegy [email protected]
less than 10% [2–4]. AML treatment typically involves induction chemotherapy for eligible patients with cytarabine (CYT) and an anthracycline [5]. Most of these aggressive malignancies are resistant to inten
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