Arsenic trioxide — An old drug rediscovered

doi:10.1016/j.blre.2010.04.001

Blood Reviews

Volume 24, Issues 4–5, July–September 2010, Pages 191-199

https://doi.org/10.1016/j.blre.2010.04.001 Get rights and content

Abstract

Over the last 17 years, clinical trials conducted worldwide have demonstrated the efficacy of arsenic trioxide (As₂O₃) in the treatment of relapsed acute promyelocytic leukemia (APL). Currently, the role of As₂O₃ in front-line therapy is under investigation. Recent trials in the US have demonstrated that the addition of As₂O₃ to standard treatment regimens improves survival outcomes in patients with APL and may allow a reduction in cytotoxic chemotherapy exposure. As₂O₃ has also shown efficacy in other malignancies, particularly multiple myeloma and myelodysplastic syndromes. Therapeutic doses of As₂O₃ are well tolerated, with no evidence of long-term toxicity. Adverse events include APL differentiation syndrome, electrocardiographic abnormalities, and mild elevations in liver enzymes. This review highlights trials investigating the role of As₂O₃ in induction and consolidation for newly diagnosed APL, as well as its role in other hematologic malignancies. The chemistry, mechanisms of action, and clinical side effects of As₂O₃ are also discussed.

Introduction

Arsenic has been used in medicine for more than 2400 years for a variety of ailments including ulcers, the plague, and malaria.¹ In 1878, potassium arsenite was reported to have an anti-leukemic effect and was used for this purpose in the late 19th and early 20th centuries until it was replaced by busulfan in the 1950s.2, 3, 4

In the modern era, interest in arsenic as a chemotherapy was rekindled after it was identified as an active ingredient in traditional medicines in China.⁵ Researchers evaluated arsenic compounds for the treatment of various cancers and in 1992 published the results of a trial in which intravenous administration of arsenic trioxide (As₂O₃) produced a complete response (CR) in 21 (66%) of 32 patients with acute promyelocytic leukemia (APL).5, 6 In two subsequent studies, Zhang et al. reported that As₂O₃ induced a CR in 22 (73%) of 30 newly diagnosed and 22 (52%) of 42 relapsed APL patients,5, 7 and Shen et al. observed a CR in nine (90%) of 10 relapsed APL patients.⁸

Based on the results from the Chinese studies, a US pilot study was conducted in patients who had relapsed after one or more courses of all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy.⁹ Most patients had experienced multiple relapses and 58% were resistant to retinoid therapy. Eleven of 12 patients achieved a CR with As₂O₃ alone. Eight of these 11 responders also achieved a molecular remission, as defined by the absence of detectable PML-RARα fusion gene expression.

Following the success of the pilot study, a larger, multicenter, single-arm trial was conducted in patients who had relapsed after ATRA-based therapy. More than one third of these patients had multiple relapses and were heavily pretreated (including five patients with prior BMT). CR was achieved in 34 (85%) of 40 patients (Table 1).¹⁰ All patients who achieved a CR also showed evidence of elimination of the t(15;17), as measured either directly by traditional cytogenetics or by assays using FISH or RT-PCR for PML/RAR-α. Many of the remissions were durable. The estimated 2-year overall survival (OS) and relapse-free survival (RFS) rates for patients in first relapse were 77% and 58%, respectively. These results are somewhat confounded because eleven patients underwent bone marrow transplant in remission after induction or consolidation with As₂O₃. Among the 27 patients who did not receive transplant, one third remained alive with duration of remission ranging 22 to 42 months. This pivotal trial provided support for the approval of As₂O₃ in patients with APL who failed to respond to or relapsed following ATRA/anthracycline therapy.

Section snippets

Mechanisms of action

As₂O₃ affects multiple cellular functions via different molecular targets (summarized in Fig. 1). Although the fundamental mechanism is the favorable chemical reaction between arsenic and thiol groups within a protein, the final outcome depends on the cell type as well as the dose and duration of arsenite exposure. For example, in APL cells, As₂O₃ at low concentrations (< 0.5 μM) induces differentiation; at higher concentrations (0.5–2.0 μM) it causes apoptosis.14, 15

Efficacy of As₂O₃ in newly diagnosed APL

The standard of care for newly diagnosed APL is differentiation therapy with ATRA plus anthracycline-based chemotherapy.⁴⁰ This combination results in high response rates and prolonged survival (Table 1).11, 12, 13 Incorporating As₂O₃ into the initial treatment of APL may further reduce the relapse rate and provide a more tolerable treatment option for patients who are not candidates for chemotherapy.

Multiple myeloma (MM)

In preclinical studies, As₂O₃ inhibited the proliferation of MM cell lines at pharmacological (micromolar) concentrations.31, 48 As₂O₃ treatment of cultured bone marrow mononuclear cells from MM patients selectively induced apoptosis in myeloma cells while sparing most myeloid cells.⁴⁸ Initial clinical studies of As₂O₃ as a single agent in heavily pretreated relapsed or refractory patients demonstrated a ≥ 25% reduction in serum levels of M-protein in 21–33% of patients, with durations of

Safety and toxicity

Arsenic is well known as a toxic agent. Inorganic arsenic has been classified by the US Department of Health and Human Services, the International Agency for Research on Cancer, and the US Environmental Protection Agency as a known carcinogen. Chronic exposure to low levels of environmental arsenic has been reported to increase the incidence of skin, liver, bladder, and lung cancers.⁸⁰ Other potential signs of arsenic poisoning include peripheral neuropathy, cardiomyopathy, and renal failure.⁸¹

Pharmacokinetics

In a study of 12 Japanese patients receiving As₂O₃ (0.15 mg/kg IV over 2 h), the mean maximum plasma concentration of inorganic arsenic (As^III and As^V) of 22.6 ± 11.4 ng/mL occurred at completion of the infusion, then declined biphasically, with an initial distribution phase followed by an elimination phase with a terminal half-life of 17 h.⁸⁵ The volume of distribution was large (55.9 L/kg), indicating extensive distribution throughout the body. In a separate case report of a patient with relapsed

Conclusions

As₂O₃ has demonstrated remarkable efficacy in APL. The use of As₂O₃ in induction or consolidation strategies reduces the relapse rate and improves survival in patients with APL, especially in high-risk patients.43, 44, 46 The addition of As₂O₃ to ATRA/chemotherapy regimens may allow a reduction in chemotherapy exposure and associated toxicities without compromising cure rates.⁴⁷ In select patients, chemotherapy may be eliminated altogether, providing an alternative treatment option for patients

Practice points

At the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins University, patients with APL are treated as follows:

•
Whenever possible, they are enrolled in clinical trials.
•
Outside of clinical trials, patients should be treated according to a published treatment protocol, from induction through maintenance and post-maintenance monitoring.
•
Remission can be achieved with ATRA plus an anthracycline. The use of 60 days of ATRA (rather than administration of ATRA until normalization of

Research agenda

•
There are 87 recently completed or ongoing clinical trials listed on www.clinicaltrials.gov evaluating As₂O₃ alone or in combination with other agents for treatment of APL, AML, multiple myeloma, MDS, primary myelofibrosis, hepatocellular carcinoma, metastatic melanoma, CNS tumors, and breast, lung, colorectal, and kidney cancers.
•
In APL, the role of chemotherapeutic CNS prophylaxis, in all patients or high-risk patients, needs to be addressed in clinical trials.
•
In APL, the role of maintenance

Conflict of interest statement

Dr. Gore received As₂O₃ from Cephalon, Inc., as part of a phase 2 trial of As₂O₃ in consolidation therapy of APL.

Dr. Emadi declares no conflict of interest.

Acknowledgements

The authors thank Jill Luer, PharmD, and Janis Leonoudakis, PhD, of Helix for providing medical writing assistance supported by Cephalon, Inc. The authors, however, are fully responsible for the content and editorial decisions for this manuscript.

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¹: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, The Bunting/Blaustein Cancer Research Building, 1650 Orleans Street, Suite 191, Baltimore, MD 21231-1000, United States. Tel.: + 1 410 614 4459; fax: + 1 410 955 0125.

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REVIEWArsenic trioxide — An old drug rediscovered

Abstract

Introduction

Section snippets

Mechanisms of action

Efficacy of As2O3 in newly diagnosed APL

Multiple myeloma (MM)

Safety and toxicity

Pharmacokinetics

Conclusions

Practice points

Research agenda

Conflict of interest statement

Acknowledgements

Blood

Am J Med Sci

Blood

Blood

Blood

Blood

Blood

Cell

Blood

Biochem Biophys Res Commun

Exp Cell Res

Cancer Lett

Blood

Biochem Pharmacol

Int J Biochem Cell Biol

Blood

Blood (ASH Annual Meeting Abstracts)

Blood

Blood

Biol Blood Marrow Transplant

Blood (ASH Annual Meeting Abstracts)

Leuk Res

Leuk Res

Blood

Blood

Leuk Res

History of the development of arsenic derivatives in cancer therapy

Oncologist

Action of iron, cod-liver oil, and arsenic on the globular richness of the blood

Am J Med Sci

Arsenic trioxide treated 32 cases of acute promyelocytic leukemia

Chin J Integrated Tradit West Med

Arsenic trioxide treated 72 cases of acute promyelocytic leukemia

Chin J Hematol

Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide

N Engl J Med

United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia

J Clin Oncol

Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group

J Clin Oncol

Mechanisms of action of arsenic trioxide

Cancer Res

Thermodynamics of the As(III)-thiol interaction: arsenite and monomethylarsenite complexes with glutathione, dihydrolipoic acid, and other thiol ligands

Inorg Chem

Role of cysteines 640, 656, and 661 in steroid binding to rat glucocorticoid receptors

J Biol Chem

PML is essential for multiple apoptotic pathways

Nat Genet

Opportunities for Trisenox ® (arsenic trioxide) in the treatment of myelodysplastic syndromes

Leukemia

The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis

Science

An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9

J Biol Chem

Cytochrome c and dATP-mediated oligomerization of Apaf-1 is a prerequisite for procaspase-9 activation

J Biol Chem

The biochemistry of apoptosis

Nature

Dual effects of arsenic trioxide (As2O3) on non-acute promyelocytic leukaemia myeloid cell lines: induction of apoptosis and inhibition of proliferation

Br J Haematol

Induction of autophagic cell death in malignant glioma cells by arsenic trioxide

Cancer Res

REVIEW
Arsenic trioxide — An old drug rediscovered

Efficacy of As₂O₃ in newly diagnosed APL

Dual effects of arsenic trioxide (As₂O₃) on non-acute promyelocytic leukaemia myeloid cell lines: induction of apoptosis and inhibition of proliferation