Effect of renal impairment on arsenic accumulation, methylation capacity, and safety in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide

Abstract

ABSTRACT Background: Arsenic trioxide (ATO) was successfully applied to treat acute promyelocytic leukemia (APL). Methods: Inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in plasma of 143 APL patients with different renal function were determined. Arsenic methylation capacity was evaluated by iAs%, MMAV%, DMAV%, primary methylation index (PMI, MMAV/iAs), and secondary methylated index (SMI, DMAV/MMAV). Arsenic accumulation with administration frequency were explored. Moreover, safety assessments were performed. Results: Compared with normal renal function, MMAV and DMAV concentrations increased 1.5–4 fold in moderate and severe renal impairment groups, iAs increased 1.3–1.7 fold. APL patients with renal impairment showed lower iAs%, but higher DMAV% and PMI in plasma than those with normal renal function (P < 0.05). MMAV, DMAV, and tAs apparently accumulated with administration frequency in moderate and severe renal dysfunction groups. The incidence of QTc interval prolongation and liver injury increased with the increasing severity of renal impairment. Conclusion: Renal dysfunction may increase exposure to arsenic and arsenic accumulation and affect methylation capacity, then the clinical safety in APL patients treated with ATO. Arsenic-level monitoring and dosing regimen adjustment should be considered in APL patients with moderate and severe renal dysfunction.