Arsenic Trioxide Inhibited Bacterial Growth but Increased the Incidence of Herpes Zoster among Patients with APL; Results from In Vitro and Clinical Studies.
Authors: Takeshita Akihiro , Shinjo Kaori , Shigeno Kazuyuki , Sahara Naohi , Ono Takaaki , Nakamura Satoki , Maekawa Masato , Ohnishi Kazunori , Ohno Ryuzo 
Published: April 2020

The clinical result of has been significantly improved by arsenic trioxide (ATO) in acute promyelocytic leukemia (APL). ATO induces apoptosis of various cells and also bone marrow damage in relapsed or refractory patients who had frequently received anti-leukemia agents. Therefore, neutropenia persists over a longer period of time after ATO treatment than after retinoic acid treatment. The neutropenia might be associated with a high incidence of infection. On the other hand, salvarsan, an arsenic-containing compound, had been used for the treatment of syphilis and trypanosomiasis. However, ATO has not been analyzed with regard to its potential as an anti-microbial agent and anti-leukemic agent. We analyzed the in vitro anti-microbial effects of ATO, and studied the incidence and severity of infection among APL patients who were treated with ATO.

(Methods) ATO discs were specially prepared for the disc diffusion method. Bacteria isolated from clinical samples were suspended in McFarland 0.5, and uniformly applied onto appropriate culture media with an ATO disc. After incubation in humidified air with 5%CO2 at 37°C for 24 hours, the bacterial growth-inhibitory zone was measured. In other experiments, bacteria and APL NB4 cells were co-cultured in 5%FCS-RPMI medium containing ATO (10−6–10−7M). The number of bacteria was counted after 24-hour incubation.

(Patients) Thirty-eight patients with relapsed/refractory APL were treated with ATO (0.15mg/kg/day): 30 patients were treated with ATO alone, and 8 were treated with a combination of ATO and chemotherapy. Thirty-four cases achieved complete remission. The body temperature, duration of febrile neutropenia, neutrophil count, immunoglobulin level, focus of infection, and pharmacokinetics of ATO were studied. The incidence and kinds of viral infection were also analyzed.

(Results) ATO significantly inhibited in vitro growth of 17 different bacteria isolated from clinical samples. The growth of E. coli, S. aureus (MSSA), H. influenzae, and St. pneumoniae among others was inhibited by the concentration of ATO that is clinically used. Fever with temperatures above 38°C was observed in 16 patients and the fever persisted for 4.4±2.2 (mean±SD) days. The duration of neutropenia of &lt;500 or &lt;100/μl was 34.2 ±21.2 and 7.3 ±11.5 days, respectively. Febrile neutropenia was observed in 7 cases, and severe bacterial infection was not observed. Twenty-three and 16 cases were not administered any antibiotics before or during ATO treatment, respectively. Herpes zoster infection occurred during or after ATO treatment in 9 patients (in 5 of 8 patients treated with ATO and chemotherapy, and 4 of 30 patients treated with ATO alone). The lymphocyte count and immunoglobulin level did not significantly differ between patients with or without herpes zoster. In our previous study on the synthetic retinoid, Am80, among 39 cases with relapsed/refractory APL (of whom 9 cases were treated with Am80 and chemotherapy), only one patient was suspected of having herpes zoster infection.

(Conclusion) ATO inhibit bacterial growth in vitro, and did not increase clinical bacterial infection while the duration of neutropenia in ATO-treated patients was relatively long. On the other hand, ATO increased the incidence of herpes zoster infection, especially among patients who concomitantly received ATO and chemotherapy.