Clinical Pharmacokinetic Study of Arsenic Trioxide in an Acute Promyelocytic Leukemia (APL) Patient: Speciation of Arsenic Metabolites in Serum and Urine

Abstract

Acute promyelocytic leukemia (APL) is characterized M3 in the French-American and British (FAB) classification and represents approximately 5-10% of all leukemia in adults. 1) In about 95-98% of the cases, APL is associated with the reciprocal translocation, t(15; 17)(q22; q21) 2,3) and the reciprocal fusion of the retinoic acid receptor (RAR)a gene on chromosome 17 with the promyelocytic leukemia (PML) gene on chromosome 15. The resulting PML-RARa fusion gene encodes a chimeric protein 4,5) that causes the pathogenesis of APL. 2,6) Huang et al. reported that all-trans retinoic acid (ATRA)-a vitamin A derivative-yielded a high rate of complete remission for APL patients.7) Several clinical studies have shown that ATRA treatment in combination with chemotherapy induced survival rate of 67-84% at 2-4-years. [8][9][10][11] Currently, ATRA has become a first-line treatment of newly diagnosed APL. [8][9][10][11] The combination of ATRA with chemotherapy can obtain long-term survival in 70% of newly diagnosed APL. Nevertheless, the remaining 30% of patients relapse and are often resistant to further treatment with ATRA and chemotherapy. 12) In 1996, the Chinese Shanghai II Medical University Group reported that arsenic trioxide induced apoptosis of APL cells, 13) and 14 of 15 patients who relapsed after ATRA therapy achieved complete remission (CR) with no serious adverse events.14) Several studies reported that intravenous infusion of arsenic trioxide was effective in approximately 90% of relapsed APL patients who are resistant to ATRA and chemotherapy.14-16) However these studies have not accurately investigated the metabolism of arsenic trioxide after the intravenous infusion.In this study, arsenic trioxide was administered intravenously to ATRA-resistant APL patient, and we determined the efficacy of arsenic trioxide in APL as well as the serum or urine concentrations of inorganic arsenic and the methylated metabolites. MATERIALS AND METHODS PatientThe patient was a 72-year-old male patient weighing 57.5 kg. In September 1999, he was diagnosed with APL. The marrow smears showed increased promyelocytes (80%). Chromosome analysis revealed 47; ϩ8, t(15; 17)(q22; q11-21). He achieved first CR with ATRA and chemotherapy. Subsequently the consolidation therapy was started on Day 56, which led to PML-RARa negative, followed by one-year maintenance therapy with ATRA. In January 2001, He relapsed and achieved second CR with ATRA. However, in July 2001, the bone marrow smear obtained during the maintenance therapy revealed an increase of promyelocytes, and the patient was diagnosed as relapsed and ATRA resistant APL. Because the cumulative dose of anthracyclines had reached a limiting dose, and the patient was elderly, the induction therapy with further chemotherapy seemed to be highly risky. Before arsenic trioxide treatment, the protocol was reviewed and approved by the institutional ethical committee of our hospital, and written informed consent was obtained from the patient and his family (based on the ethical principle...

Application of Arsenic Trioxide Therapy for Patients with Leukaemia

“…In fact, ATO has usually been infused either in the dose of 0.16 mg/ kg (or 10 mg/day) in 250-500 ml of normal glucose saline solution over 2-3 h once a day in Chinese studies [6,10,141], or in the FDA-approved dose of 0.15 mg/kg in 100-250 ml of 5% dextrose in either water or 0.9% sodium chloride solution over 1-2 h daily [8,9,142]. In addition, a reduced dose of 0.08 mg/kg/day (low dosage) corresponding to a 50% of the conventional dosage (0.16 mg/kg/day), has also been applied in the treatment of APL patients [143,144]. It should be noted that in two clinical trials, treating APL patients with a low dose of ATO yielded a similar complete remission rate (80%) compared to that (85.1%) attained with a conventional dosage [143,145].…”

“…The pharmacokinetic studies in APL patients have been well discussed by using urine samples [6,144,169,176]. It has been demonstrated that urinary arsenic contents slightly increased during drug administration, and the total amounts of arsenic excreted daily into the urine accounting for approximately 1-8% of the daily dose [6].…”

“…On the other hand, our previous report revealed that the mean total arsenic excretion rate including inorganic arsenic and methylated arsenic was about 20% of daily dose on Day 1 and remained at about 60% of daily dose during subsequent weeks [169]. Moreover, a clinical pharmacokinetic study performed in an APL patient showed that in the urine sample collected for 24 h after administration of ATO, the total amount of inorganic arsenic and the methylated metabolites was almost 30% more of the daily dose [144]. As described above, there are large variations among individual patients with regard to the arsenic metabolic profiles and excretion patterns.…”

Validation du dosage des espèces de l'arsenic urinaire par HPLC-ICP-MS

“…Elle offre la meilleure résolution et les temps d'analyse les plus courts. De plus, cette technique peut être facilement appliquée à l'analyse de poudres suspectes, mais également à d'autres milieux biologiques comme le plasma ou le sang [2,29], ou à des matrices alternatives, cheveux ou ongles [30][31][32][33].…”

“…Nous avons au cours des dernières années été confrontés à plusieurs cas d'intoxication par l'anhydride arsénieux dans un cadre judiciaire (homicides, tentatives d'empoisonnement) ou médical (suicide). Depuis peu, l'arsenic est à nouveau prescrit en thé-rapeutique, ainsi l'anhydride arsénieux est employé dans le traitement de la leucémie aiguë promyélocytaire [2]. Parmi les sources alimentaires, citons les produits de la mer, riches en dérivés organiques non toxiques, arsénobétaïne (AB) en particulier, mais surtout l'eau de boisson pouvant contenir de l'arsenic inorganique toxique.…”