General AML,   TET2

Synergistic effect of vitamin C with decitabine in AML – a Chinese study

Previous findings have demonstrated the efficacy of low-dose decitabine, granulocyte colony-stimulating factor (GCSF), aclarubicin and cytarabine (DCAG) in elderly Acute Myeloid Leukemia (AML) patients.1 However, it is not yet known whether low-dose Vitamin C has a synergistic effect with decitabine in clinic. Huihui Zhao and colleagues from The First Affiliated Hospital of Nanjing Medical University, China, evaluated this effect and the findings were published in the January 2018 issue of Leukemia Research.2

Firstly, Zhao et al. investigated the combinatorial effect of low-dose Vitamin C with decitabine in AML cell lines (HL60 and NB4 cells) in vitro. It was observed that the cytotoxicity of decitabine was enhanced by Vitamin C in AML cells. Additionally, vitamin C increased decitabine-induced apoptosis and cell cycle arrest in AML cell lines in vitro. Importantly, TET2 mRNA and TET2 enzyme activity was increased after simultaneous administration of decitabine and Vitamin C in AML cell lines. 

The authors then compared the outcomes of elderly AML patients treated with DCAG (decitabine [15mg/m2, days 1-5], G-CSF [300 μg/day, days 0-9], cytarabine [10 mg/m2, q12h, days 3-9], and aclarubicin [8 mg/m2 days 3-6]) alone or low-dose Intravenous Vitamin C (IVC [(50-80 mg/kg/day, days 0-9]) in combination with DCAG (A-DCAG). In total, 73 newly diagnosed elderly AML patients (median age = 68.2 years) who were deemed unfit for or refused intensive chemotherapy were included in this study. Patients were randomly assigned to receive one to two induction courses of A-DCAG (n= 39) or DCAG alone (n = 34).

Key findings:
  • Complete Remission (CR) rate after one course of treatment with A-DACG and DCAG were 79.9% and 44.1% respectively, P = 0.004
  • Median Overall Survival (OS) in the A-DACG and DCAG arm were 15.3 and 9.3 months respectively, P = 0.039
  • Toxicity was not significantly different between the A-DACG and DCAG treatment arms; most common grade 3–4 adverse events include neutropenia, thrombocytopenia, hemorrhage, and thrombosis

Zhao et al. concluded that the combination of decitabine with low-dose Vitamin C shows a “synergistic anti-neoplastic action against AML cell lines” via the modulation of TET2 expression and activity.

Additionally, patients in the A-DACG arm had prolonged OS and improved CR. This indicates that addition of low-dose Vitamin C to decitabine was effective and safe in elderly AML patients.

References
  1. Li J. et al. Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia. Oncotarget. 2015 Mar 20; 6(8): 6448–6458.
  2. Zhao H. et al. The synergy of Vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia. Leuk Res. 2018 Jan 2; 66: 1–7. DOI: 10.1016/j.leukres.2017.12.009. [Epub ahead of print].