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

ABSTRACT

Background: Arsenic trioxide (ATO) was successfully applied to treat acute promyelocytic leukemia (APL).

Methods: Inorganic arsenic (iAs), monomethylarsonic acid (MMA^V) and dimethyarsinic acid (DMA^V) in plasma of 143 APL patients with different renal function were determined. Arsenic methylation capacity was evaluated by iAs%, MMA^V%, DMA^V%, primary methylation index (PMI, MMA^V/iAs), and secondary methylated index (SMI, DMA^V/MMA^V). Arsenic accumulation with administration frequency were explored. Moreover, safety assessments were performed.

Results: Compared with normal renal function, MMA^V and DMA^V 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 DMA^V% and PMI in plasma than those with normal renal function (P < 0.05). MMA^V, DMA^V, 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.

KEYWORDS:

• Arsenic species
• acute promyelocytic leukemia
• renal impairment
• accumulation
• safety

Article highlights

• Arsenic trioxide (ATO) is widely applied to treat acute promyelocytic leukemia (APL). Arsenic levels and methylation are critical to reveal metabolic mechanism and evaluate clinical response.

• Arsenic and its metabolites are mainly excreted through kidney.

• Arsenic metabolites in vivo reached a steady state after 7 days administration of ATO.

• Large-sample analysis of arsenic species in plasma of APL patients with renal dysfunction was performed for the first time.

• Arsenic species tend to increase with administration frequency in APL patients with renal dysfunction. Meanwhile, renal dysfunction may affect methylation capacity, then clinical safety in APL patients treated with ATO.

• Arsenic concentration monitoring should be carried out in APL patients with moderate and severe renal impairment. Dosing adjustment of ATO was not needed for APL patients with mild renal impairment, while considerations for dosing adjustment of ATO that may be warranted in APL patients with moderate and severe renal impairment.

• Arsenic concentration monitoring should be carried out in patients with moderate and severe renal impairment.

Declaration of interest

The author(s) have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (No. 81700151), Natural Science Foundation of Heilongjiang Province for Excellent Youths (No. YQ2019H016), Postdoctoral Foundation of Heilongjiang Province (No. LBH-Q20031), and Excellent Youth Foundation of First Affiliated Hospital of Harbin Medical University (No. HYD2020JQ0018).