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Prolonged oral arsenic trioxide therapy and neprholithiasis

Arsenic trioxide (As2O3) is the treatment of choice for relapsed acute promyelocytic leukemia (APL), and is also used in clinical trials for other hematologic malignancies [1]. For intravenous formulation, protracted daily administration is not practical and cumulative arsenic toxicity is seldom an issue. However, the availability of oral As2O3 allows longterm outpatient maintenance treatment [2], and novel data on the potential side effects of prolonged treatment is emerging. Such data will have important bearings on the study of environmental or occupational arsenic exposure, where the implicated arsenic doses are often merely estimated. Urinary excretion is the main route of elimination of arsenic [1], and arsenic-related uroepithelial cancer has been reported [3]. In 84 consecutive Chinese patients with cumulative oral arsenic dose exceeding 1 g, two cases of symptomatic urolithiasis were detected. These patients were not pre-screened for nephrolithiasis before treatment, and neither patient with urolithiasis had hyperurciemia or hypercalcaemia. Their urinary stones were dried, aciddigested, and diluted with ultra-pure distilled water and acid-methanol. Total arsenic content was then measured by inductively coupled plasma-mass spectrometry (ICP-MS) with the ELAN DRC 6100 analyser (PerkinElmer-SCIEX, Canada) equipped with an auto-sampler and a quartz nebuliser [4]. Stones from four control individuals, and plasma/ urine from 20 local volunteers with background diet exposure only were also assayed. Urinary arsenic was expressed as arsenic (nmol)/creatinine (mmol), and inter-experiment variability of our arsenic assay was below 2% (Trace Element External Assessment Scheme, EQAS, UK). Patient 1 was an 85-year-old man disabled by a previous stroke, who developed relapsed follicular lymphoma 3 years after rituximab-containing combination chemotherapy. He received oral As2O3 therapy for 15 months, initially at 5 mg daily, which was tailed down to 3 mg on alternate days, to a cumulative dose of 1450 mg. There was satisfactory control of cervical and groin lymphadenopathy. Investigations for an episode of urinary retention showed a 1.5 cm calcified bladder stone, which was extracted by cytoscopy. His trough plasma arsenic levels ranged from 60 to 103 nmol/L during treatment (reference range: 43 – 269), and his urinary arsenic was 277 nmol arsenic/mmol creatinine (reference range: 1.2 – 44). The bladder stone showed an arsenic concentration of 0.71 mg/g, which was comparable with that of a control bladder stone (72-year-old man, 0.87 mg/g). Full chemical analysis showed calcium ammonium phosphate as the main component, with insignificant urate and oxalate content. Patient 2 was a 56-year-old woman with repeated relapsed APL, but now in stable remission (cumulative As2O3: 4100 mg). At diagnosis in 1997, a 4-cm left renal calcified staghorn stone was already present. In 2006, 20 months after cessation of As2O3 therapy, the stone had enlarged to 6 cm. Two sessions of extracorporeal shock wave lithotripsy were performed with partial stone removal. Her residual plasma arsenic level was 51.9 nmol/L, and the urinary arsenic was 101.93 nmol arsenic/mmol