Elacytarabine Is More Effective Preclinically Than Cytarabine In Combination With Daunorubicin In Primary Patient Xenografts Of AML

Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis. The overall survival rate in AML patients has changed little in the last 20 years with overall survival rates for young patients (< 60 years) remaining at 35%. However, for elderly patients (> 60 years), survival is less than 10%. Despite the fact that AML represents one of the most molecularly characterized malignancies, the standard therapeutic option is unaltered in the last 15 years i.e. we still solely rely upon a combination of anthracycline and Cytarabine (Ara-C) as the cornerstone of induction therapy.

Recently many potentially drugable targets have been discovered 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. Elacytarabine (ELA; CP-4055) is a fatty acid derivative (elaidic acid ester) of Ara- C, currently in undergoing phase II clinical trial as second-course remission-induction therapy in combination with anthracycline.

In this study we determined the maximum tolerated dose for the combination of ELA with Daunorubicin (DAN) in immunodeficient NOD-scid-IL2Rγc^null (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 a primary patient xenograft model of refractory AML following relapse after Ara-C+DAN therapy (n = 24). Efficacy was evaluated employing a novel time-domain imaging strategy utilizing targeted monoclonal antibodies conjugated to near infrared dye that specifically recognize and bind to epitopes on AML cells enabling non-invasive monitoring of disease progression following therapy. Similarly, bone marrow aspirates were assayed for AML content by flow cytometry (CD45⁺/34⁺/33⁺) and IHC analysis.

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 dissemination illustrated lower disease burden in Ara-C + DAN treated mice than controls (p<0.05), those treated with ELA+DAN demonstrated significantly reduced disease progression, both in comparison to controls (p<0.001) and Ara-C+DAN (p<0.01) treated NSG 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<0.0001) and Ara-C+DAN treated NSG mice (39 ± 3.2 days; p<0.039).

ELA is more effective preclinically than Ara-C in combination with DAN in primary patient xenografts of refractory AML. ELA was found to be well tolerated and significantly increased survival in combination with Daunorubicin. Despite withdrawal of Elacytarabine as a single agent (following Phase III clinical trial earlier this year in relapsed and refractory AML versus investigators choice of treatment) our preclinical results demonstrate combined therapy of ELA+DAN may promise enhanced survival advantages over current standard therapy for AML patients.