The Synergy of Vitamin C with Decitabine Activates TET2 in Leukemic Cells and Significantly Improves Overall Survival in Elderly Patients with Acute Myeloid Leukemia

Abstract

Background: Decitabine is widely used in the treatment of acute myeloid leukemia (AML) in elderly patients. Low-dose ascorbic acid (Vitamin C) has also been indicated to induce DNA demethylation at the cellular level. Our previous study demonstrated its combined effect and safety with low-dose decitabine prior to aclarubicin andcytarabine (DCAG) in elderly patients with AML, in which it appeared to achieve a complete remission (CR) rate of 76.3% and a median overall survival of 10 months. Pharmacological concentrations of Vitamin C (10-1,000μM) induced a time- and dose-dependent increase in 5-hmC. However, little is known whether low-dose Vitamin C has a synergistic effect with decitabine in clinic. Methods: The effect of combined low-dose Vitamin C and decitabine on cell proliferation, the cell cycle, apoptosis and the expression level and activity of TET2 was investigated in HL-60 and NB-4 human leukemic cells. Additionally, we analyzed the clinical outcomes of 73 elderly AML patients who received A-DCAG (intravenous Vitamin C [IVC] plus DCAG [ n=39]) or DCAG (n=34) treatment. Patients received one of the two induction courses: DCAG or A-DCAG. DCAG consisted of 15mg/m2 of decitabine (intravenously, days 1-5) and 300 μg/day of granulocyte colony-stimulating factor (G-CSF, days 0-9) for priming its combination with 10 mg/m2 of cytarabine (q12h, days 3-9), 8 mg/m2 of aclarubicin (days 3-6, DCAG), or IVC (50-80 mg/kg/day, days 0-9; A-DCAG). The G-CSF priming was discontinued when white blood count (WBC) was ≥20×109/L. Results: We found that low-dose Vitamin C and decitabine has a synergistic efficacy on proliferation, apoptosis and TET2 activity, compared to drug-alone treatment in HL60 and NB4 cell lines in vitro . In clinic, feasibility and safety evaluations revealed that patients who received A-DCAG regimen have a higher complete remission (CR) rate than those who received the DCAG regimen (79.92 % vs. 44.11%; P=0.004) after one cycle of chemotherapy. IVC admission decision appeared to beat the discretion of attending physicians. The median overall survival (OS) was better in the A-DCAG group compared with the DCAG group (15.3 months vs. 9.3 months, P=0.039). Patients with adverse cytogenetics did benefit from CR. There was no clinically significant additional toxicity observed with the addition of IVC. Conclusion: On the basis of these results, the addition of IVC at low doses to DCAG appeared to improve CR and prolong OS, compared with DCAG, in elderly patients with AML. DisclosuresNo relevant conflicts of interest to declare.