Abstract 3274: Combination of elacytarabine and daunorubicin is significantly more effective than combination of cytarabine and daunorubicin in primary patient xenografts of AML.
Authors: Osdal Tereza , Jordheim Lars P. , Popa Mihaela , Vikebø Lene M. , Sulen Andre , Bedringaas Siv Lise , Sandvold Marit Liland , Booij Birgitte , Bruserud Øystein , Gjertsen Bjørn Tore , Dumontet Charles , McCormack Emmet 
Published: August 2014

Background: The overall survival rate in patients with acute myeloid leukaemia has changed little in the last 20 years with overall survival rates for young patients (60 years, survival statistics are less than 10% being cured (2). Although AML has become one of the most molecularly characterised malignancies, the core therapeutic option remains unchanged in the last 15 years i.e. We continue to be solely reliant upon a combination of anthracycline and Cytarabine (Ara-C) as the cornerstone of induction therapy. Recently many potentially drugable targets have been revealed (3-7) and while responses have been observed, these are generally amongst sub-sets of patients with good to intermediate prognostic factors and most often in combination with conventional therapy.

Aims and methods: Elacytarabine (ELA; CP-4055) is a fatty acid derivative of Ara-C, currently in undergoing phase II and phase III clinical trial as second-course remission-induction therapy and in late stage AML, respectively. In this study we determined the MTD for the combination of ELA in combination with Daunorubicin (DAN) in NSG mice. Subsequently, we compared the preclinical efficacy of the combination of ELA (30 mg/kg; q.d.x5) or Ara-C (500 mg/kg; q.d.x2) with DAN (2.5 mg/kg; q.d.x3) in primary xenografts in NSG mice (n = 24) from relapsed (Ara-C+DAN) AML patients. Employing a novel time-domain imaging strategy (8) we non-invasively monitored disease progression following therapy. Similarly marrow aspirates were assayed for AML content by flow cytometry and IHC analysis.

Results: The combination of ELA and DAN was well tolerated in NSG mice xenografted with primary patient AML cells. While longitudinal near infrared optical imaging of AML disease burden illustrated lower disease burden in Ara-C + DAN treated mice than controls (p&lt;0.05), those treated with ELA+DAN demonstrated significantly reduced disease burden, both in comparison to controls (p&lt;0.001) and Ara-C+DAN (p&lt;0.01) treated mice. Flow cytometry analysis of bone marrow aspirates revealed similar reductions in ELA treated mice. Ultimately, combination of ELA+DAN exhibited significant increases in mean survival time (45 ± 4.6 days) over control (31.6 ± 1.7 days; p&lt;0.0001) and Ara-C+DAN treated mice (39 ± 3.2 days; p&lt;0.039).

Conclusions: The combination of ELA+DAN is well tolerated and significantly increase survival in comparison to Ara-C+DAN in primary patient xenografts of refractory AML.

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Citation Format: Tereza Osdal, Lars P. Jordheim, Mihaela Popa, Lene M. Vikebø, Andre Sulen, Siv Lise Bedringaas, Marit Liland Sandvold, Birgitte Booij, Øystein Bruserud, Bjørn Tore Gjertsen, Charles Dumontet, Emmet McCormack. Combination of elacytarabine and daunorubicin is significantly more effective than combination of cytarabine and daunorubicin in primary patient xenografts of AML. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3274. doi:10.1158/1538-7445.AM2013-3274