Dear Editor,

Arsenic trioxide (ATO), as a single agent, is most commonly used at present in cases of relapsed acute promyelocytic leukemia (APL) for induction of remission. It has been shown that it is equally effective in newly diagnosed cases of APL, with much less toxicity [1]. Therefore, for the elderly APL patients, especially for those truly frail patients who are considered unfit for chemotherapy, ATO could be a reasonable alternative to the current standard approach. Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative patients is a well-known complication of lymphoma treatment in the rituximab era [2]. To our knowledge, this is the first case of HBV reactivation in an APL patient treated with ATO.

A 62-year-old man with diabetes who presented with epistaxis and general malaise was admitted to our hospital. He was given a diagnosis of APL and was immediately treated with induction therapy consisting of idarubicin, cytarabine, and all-trans retinoic acid. He achieved complete hematology and molecular remission after the first course of induction therapy. After consolidation therapy with mitoxantrone and cytarabine, he developed acute lung injury and acute respiratory distress syndrome following severe infection. Therefore, he was given single-agent ATO intravenously (0.15 mg kg−1 day−1, 5 days/week for 5 weeks), as this was considered to be less toxic than conventional chemotherapy. Treatment was interrupted in the first week of therapy because he developed hematologic toxicities including neutropenia (grades 3 to 4). ATO was carefully resumed, and no further severe complications occurred. As this patient had prior resolved HBV infection, negative for HBsAg but positive for antibody to hepatitis B core antigen (anti-HBc) and antibody to HbsAg (anti-HBs), HBV DNA surveillance was regularly performed before initiating the second treatment course. Quantitative PCR assay for serum HBV DNA indicated 4.0 log copy/mL (normal range, <2.1 log copy/mL), and HBsAg and anti-HBs were converted to positive and negative, respectively. Anti-HBc remained positive, but no significant elevations in serum transaminases were observed. HBV reactivation was diagnosed. The patient was immediately given antiviral therapy consisting of entecavir 0.5 mg day−1 orally. Serum HBV DNA values became negative 3 weeks after this treatment. He completed a second course of ATO treatment without developing hepatotoxicity under the preventive treatment of entecavir. Two weeks after the treatment, he experienced varicella zoster virus (VZV) reactivation, which was treated with oral valaciclovir. The characteristic clinical feature was resolved without subsequent complications like postherpetic neuralgia. The patient then received all-trans retinoic acid as a maintenance therapy, and he maintains complete molecular remission.

Despite arsenic is well-known as a toxic agent, as a therapeutic entity, ATO has been generally well tolerated. Common potentially serious toxicities include APL differentiation syndrome and electrocardiogram abnormalities. Although no significant hepatotoxicity was reported, the overall hepatotoxicity was observed in approximately 35 % of patients in the Iranian and Indian studies, which were administered with single-agent ATO for the frontline therapy of APL [1, 3]. The underlying mechanism of HBV reactivation during chemotherapy has remained unclear. The promyelocytic leukemia (PML) protein critically regulates several cellular functions that oppose tumorigenesis such as oncogene-induced senescence, apoptosis, and the response to DNA damage and to viral infections. Its associated PML nuclear bodies (PML NBs) have been implicated in host immune response to viral infection [4]. Several viral proteins in herpes viruses and HBV interact with PML and PML NBs [5, 6]. ATO was shown to induce the degradation of PML as a direct target of ATO by the SUMOylation [7]. ATO possibly affects HBV and herpes virus reactivation by degradation of PML. Indeed, a previous report [8] showed that VZV reactivation is a common complication of ATO treatment. Thus, clinicians should be aware of possible HBV reactivation when patients with resolved HBV infection are treated with regimens containing arsenic compounds, especially in HBV endemic areas.