AC220, a Potent and Specific FLT3 Inhibitor, Enhances the Activity of Combined Cytarabine and Daunorubicin Chemotherapy in a FLT3-ITD Model of AML

Abstract 1538

Acute myeloid leukemia patients harboring an activated FLT receptor have a poorer prognosis following standard chemotherapy treatment compared to patients with a wild type receptor. This suggests that the combination of FLT3 inhibitor with chemotherapy may improve clinical outcome in this patient population. AC220, a potent and selective FLT3 inhibitor, has a subnanomolar anti-proliferative EC50 against cells containing activated FLT3 receptor. Using the homozygous FLT3-ITD (internal tandem duplication) cell line MV4-11 we previously demonstrated that treatment of cells with AC220 concurrent with or the day following treatment with the individual chemotherapeutic agents generally provided additive to slightly synergistic effects in vitro, with no indications of drug antagonism or increased toxicity as measured by body weight changes and CBC analysis (ASH 2009).

Because induction therapy in AML patients is typically comprised of Cytarabine (Ara-C) plus an anthracyline, we sought to more closely approximate this chemotherapeutic dosing regimen in a preclinical model. In the current study, we treated MV4-11 tumor bearing animals with two cycles of ‘5+3 therapy’; 5 days of Ara-C at 80mg/kg IP concurrent with 3 days of daunorubicin (DNR) at 1 mg/kg IV with cycles separated by 10 days. These doses were at or near the MTD for tumor bearing SCID mice. AC220 at 0.5 mg/kg PO was delivered either concurrently and continuously throughout the two cycles or was delivered episodically for 7 days immediately following the end of the DNR dosing period or the end of the Ara-C dosing period. Monotherapy with the chemotherapeutic agents alone or in a 5+3 combination dosing regimen provided measurable but statistically non-significant anti-tumor benefit with a tumor growth delay (TGD) of 7 days for the 5+3 cohort (endpoint =1500 mm3). AC220 alone delivered continuously at 0.5 mg/kg from the beginning of the dosing period did provide significant anti-tumor benefit, with a tumor growth delay (TGD) of 21 days and a tumor growth inhibition (TGI) of 17% when measured at the end of the first cycle (day 30). Continuous AC220 treatment initiated on day 1 in conjunction with 5+3 therapy led to a slightly increased TGD of 23 days and further reduced the TGI to 12%. AC220 alone delivered episodically for 7 days at 0.5 mg/kg starting on either day 4 or on day 6 (mimicking post-DNR or post-Ara-C treatment, respectively) provided a TGD of 11 days. Layering 7 day episodic dosing of AC220 immediately following treatment with DNR or Ara-C in a 5+3 regimen led to a TGD of 16 or 18 days, respectively. However, comparison of the TGI at the end of the first cycle of therapy suggests that episodic dosing of AC220 post-AraC is more efficacious (TGI 22%) than episodic dosing of AC220 post-DNR (TGI 35%). These results suggest that episodic dosing of AC220 post-5+3 therapy or continual dosing of AC220 plus 5+3 induction therapy may provide additional benefit over chemotherapy alone.