Elemental Arsenic Levels in Plasma, Cellular and Tissue Compartments After Oral Arsenic Trioxide Maintenance Treatment: Implications On Long-Term Safety.
Authors: Au Wing , Tam Sidney , Fong Bonnie , Kwong Yok-lam 
Published: October 2019

Abstract
Abstract 2064
Poster Board II-41

Background.
Arsenic trioxide (As2O3) is a standard medication in the management algorithm of patients with acute promyelocytic leukemia (APL). With the advent of oral As2O3, outpatient treatment, convenient dosing and long-term post-remission maintenance therapy have become possible. The pharmacokinetics, efficacy and safety profile of short-term oral As2O3 therapy are well-defined. With prolonged oral-As2O3 therapy, possible accumulation of elemental arsenic and its possible long-term side effects must be determined.

Materials and methods.
Paired peripheral blood (PB) and bone marrow (BM) (aspirate and trephine biopsy) specimens were prospectively collected as part of an oral-As2O3 treatment protocol of patients. The samples were separated into plasma (P), white blood cell (WBC) and red blood cell (RBC) fractions. Elemental arsenic was measured by inductively coupled plasma-mass spectrometry (ICP-MS, ELAN DRCplus 6100, PerkinElmer-SCIEX, Canada) after dilution with 2% nitric acid +/– 3% methanol. Bone marrow trephine biopsies were dried at 65°C overnight, completely digested with acid, and diluted to appropriate concentrations.

Results.
There were 15 male and 11 female APL patients. Seven WBC specimens could not be analyzed due to inadequate material. Specimens were collected at 1 month (Group 1), 2–12 months (Group 2) and 24–41 months (Group 3) after cessation of oral-As2O3 treatment. The median cumulative dose of oral-As2O3 was 1980 (560–3680) mg. As control, samples were obtained from 12 anonymous individuals, whose specimens were collected as part of their diagnostic evaluations. These controls had no known medicinal exposure to arsenic. The mean elemental arsenic levels in the specimens were shown below.
Elemental arsenic levels in group 1 were significantly higher than groups 2 and 3 in all specimens tested. However, groups 2 and 3 were comparable to controls, indicating that arsenic was rapidly excreted once oral-As2O3 treatment was stopped. In group 1 patients, all specimens tested showed comparable arsenic levels. In group 2 patients, arsenic levels were significantly higher in BM–WBC (but not PB-WBC) as compared with PB-P and BM-P (p=0.043 for both). In group 3 patients, all cellular specimens tested showed comparable arsenic levels to plasma levels. Conclusion. Immediately after cessation of treatment when plasma arsenic level was still high, elemental arsenic was distributed comparably in different compartments. However, when plasma arsenic levels started to decline, preferential concentration of arsenic occurred in the cellular compartments. This could be related to transfer of arsenic in bones to the developing hematopoietic cells in the marrow milieu. Finally, two or more years after cessation of As2O3 therapy, elemental arsenic levels returned to control levels; a reassuring observation that long-term arsenic accumulation did not take place when oral-As2O3 was used therapeutically during a finite period of time.

Disclosures:
Off Label Use: Oral arsenic trioxide is a novel preparation or arsenic trioxide currently under consideration for registration in Hong Kong for APL treatment. The University of Hong Kong holds the patent for the product.