Characteristics and clinical influence factors of arsenic species in plasma and their role of arsenic species as predictors for clinical efficacy in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide

ABSTRACT

Background: Arsenic trioxide (ATO) is successfully applied to treat acute promyelocytic leukemia (APL). Arsenic species levels in blood are critical to reveal metabolic mechanism and relationship between arsenic species and clinical response. Characteristics and influence factors of arsenic species in APL patients have not been studied.

Methods: 305 plasma samples from APL patients treated with ATO were analyzed using HPLC-HG-AFS. Trough concentration (C_trough), distribution, methylation levels of arsenic species were evaluated. The influence factors on arsenic species levels of plasma and association between arsenic concentrations and clinical efficacy were explored.

Results: C_trough of arsenic in effective treatment groups provide basis for defining the target range of arsenic plasma concentrations in APL patients treated with ATO. Distribution trends: DMA^V > As^III, MMA^V> As^V (p < 0.0001) for continuous slow-rate (CS) infusion and DMA^V > MMA^V > As^III > As^V (p < 0.0001) for conventional infusion. Infusion methods and combined medication may affect arsenic metabolism. There was a weak correlation between ATO dose and plasma C_trough of arsenic species. C_trough of plasma arsenic species had predictive value for treatment efficacy.

Conclusion: Arsenic concentration monitoring in APL patients treated with ATO is required. These findings are critical to optimize treatment outcomes of ATO therapy.

KEYWORDS:

• Arsenic trioxide
• arsenic species
• efficacy prediction
• arsenic concentration monitoring
• acute promyelocytic leukemia

Article Highlights

• Arsenic trioxide (ATO) is successfully applied to treat acute promyelocytic leukemia (APL). However, at the same dosage, some APL patients can develop various toxic effects, relapse, or fail to achieve complete remission (CR). It is important to devise strategies to improve the efficacy of ATO, reduce toxicity effects, and achieve individualized treatment.

• Arsenic species levels in blood are critical to reveal metabolic mechanism and relationship between arsenic species and clinical response. Large-sample analysis of arsenic species in plasma of APL patients treated with ATO was performed for the first time.

• C_trough, distribution, and methylation levels of arsenic species were evaluated. The influence factors on arsenic species levels of plasma and the association between arsenic concentrations and clinical efficacy were explored.

• C_trough levels of arsenic species in effective treatment groups provide the basis for defining the target range of arsenic concentrations in plasma of APL patients treated with ATO. DMA^V was the dominant metabolites in plasma. As^V was the least arsenic species in plasma.

• Infusion methods and combined medication may affect arsenic metabolism.

• Arsenic levels of plasma cannot be assessed by the daily dose of ATO. C_trough of plasma arsenic species has predictive value for treatment efficacy. Arsenic-level monitoring is required in APL patients treated with ATO.

• These findings are critical to optimize treatment outcomes of ATO therapy.

Author contributions

Meihua Guo, Jin Zhou, Shengjin Fan, and Qilei Zhao performed the research, Xin Hai designed the research study, Limin Li and Xinyu Wang analyzed the data, Wensheng Liu and Zhiqiang Wu assisted interpretation of the results, Meihua Guo wrote the manuscript, Hongzhu Chen and Liwang Lin helped to revised the manuscript. All authors read and approved the final manuscript.

Declaration of interest

The authors 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 National Natural Science Foundation of China (No. 81700151), Natural Science Foundation of Heilongjiang Province for Excellent Youths (No. YQ2019H016), Excellent Youth Foundation of First Affiliated Hospital of Harbin Medical University (No. HYD2020JQ0018), Foundation of First Affiliated Hospital of Harbin Medical University (No. 2019M15), Foundation of Health Commission of Heilongjiang Province (No. 2017-029), and Bethune Medical Science Research Fund (SCZ167EN).