Abstract 5053: Arsenic trioxide metabolism in patients with acute promyelocytic leukemia
Authors: Khan Mohammad T. , Tariq Sara , Ghiuzeli Cristina M. , Styblo Miroslav , Saunders Jesse , Calabro Anthony , Kohn Nina , Budman Daniel , Allen Steven , Devoe Craig 
Published: July 2017

BACKGROUND:

Arsenic trioxide (ATO) is a mainstay of therapy for Acute Promyelocytic Leukemia (APL). Its long term effects and pharmacokinetics have not been well -described. ATO is metabolized by a series of reactions involving inorganic arsenic (iAs) methylation and reduction steps resulting in mono- (MAs), di- (DMAs) and trimethylated arsenic (TMAs) metabolites which are subsequently excreted mainly in the urine:

iAsIII →MAsV→MAsIII→DMAsV→DMAsIII→TMAsVO→TMAsIII

Individual polymorphisms in arsenic methyltransferase, a key enzyme in this reaction, contribute to differences in the metabolism of ATO. iAsIII, MAsIII and DMAsIII are more biologically active and more toxic than pentavalent forms. In this study, we measured the total iAs, MA's and DMA’s in plasma and urine.

METHODS:

Blood and urine samples from 10 control patients and 26 APL patients treated with ATO were collected. The treated patients had blood drawn immediately prior to and at 1, 2, 4, 6, and 24 hours, days 4, 8 and 15, and 4 weeks after the administration of ATO. Total iAs (iAsIII+iAsV), MAs (MAsIII+MAsV) and DMAs (DMAsIII+DMAsV) were measured in plasma using hydride generation-cryotrapping-atomic-absorption spectrometry. The same arsenic species were measured in spot urine at several time points.

For statistical analysis, repeated measures analysis of variance (RMANOVA) were done to compare subject groups over time. Two subjects were missing iAs urine values at 24 hours and so were excluded from this analysis.

RESULTS:

iAs levels differed over time (p&lt;0.0001), with a rapid increase noted after ATO administration followed by a linear decline, reaching minimum levels by 4-6 hours. Between 6 hours and 24 hours, two distinct groups of iAs metabolizers became apparent: 15 subjects had stable or decreased iAs levels at 24 hours (Group A) versus 9 subjects with at least a 5% increase in iAs at 24 hours (Group B). Methylated metabolites in the urine were also higher at all measured time points in Group A versus Group B; however, the difference between the two groups was statistically significant only for urine DMAs (p&lt;0.0390).

CONCLUSIONS:

Chronic iAs exposure has been associated with increased risk of diabetes and lung, bladder and skin cancer. In patients treated with therapeutic dose ATO, we identified 2 distinct groups of arsenic metabolizers: Group A patients who rapidly converted iAs to MMA and DMA and excreted the metabolites in the urine, and Group B patients who metabolized arsenic slowly and had a lower rate of excretion of metabolites in the urine. These results suggest that Group B patients had a longer exposure time to iAs and its metabolites and may be more susceptible to ATO toxicity. Prospective clinical trials are needed to determine long term ATO toxicity in these patients.

Note: 2 first co-authors: MK and ST

Citation Format: Mohammad T. Khan, Sara Tariq, Cristina M. Ghiuzeli, Miroslav Styblo, Jesse Saunders, Anthony Calabro, Nina Kohn, Daniel Budman, Steven Allen, Craig Devoe. Arsenic trioxide metabolism in patients with acute promyelocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5053. doi:10.1158/1538-7445.AM2017-5053