Risk/benefit profile of arsenic trioxide

Approximately 20%-30% of patients with acute promyelocytic leukemia (APL) who are treated with the current standard all-trans retinoic acid and anthracycline-based chemotherapy regimen suffer relapse. In the mid-1990s, studies from China reported the effective use of arsenic trioxide in achieving complete remission in patients with APL. In the United States, a multicenter trial of this agent in 40 patients with relapsed APL following conventional therapy confirmed the positive safety and efficacy outcomes of a smaller 12-patient pilot study. Common adverse events were hyperleukocytosis, APL differentiation syndrome, prolonged QT interval on electrocardiogram, skin rash, and hyperglycemia.     

Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies.

Arsenic trioxide has shown great promise in the treatment of patients with relapsed or refractory acute promyelocytic leukemia (APL). In clinical trials, arsenic trioxide induces complete remission in 87% of patients and molecular remission in 83% of patients. Two-year overall and relapse-free survival estimates are 63% and 49%, respectively. Treatment with arsenic trioxide may be associated with the APL differentiation syndrome, leukocytosis, and electrocardiographic abnormalities. The expanded use of arsenic trioxide in APL for postremission therapy, in conjunction with transplantation, and in patients with newly diagnosed APL is under investigation. The multiple mechanisms of action of arsenic trioxide suggest that it may have antitumor activity in malignancies other than APL and that it may be used in combination with other agents to expand its potential use. This article reviews the clinical use of arsenic trioxide to date and discusses new therapeutic strategies evolving from its diverse biologic activities.     

Effect of arsenic trioxide on QT interval in patients with advanced malignancies.

PURPOSE: Arsenic trioxide is an effective treatment for patients with acute promyelocytic leukemia (APL) who have relapsed from or are refractory to all-trans-retinoic acid and anthracycline chemotherapy. Since arsenic can prolong the QT interval and lead to torsade de pointes, a life-threatening ventricular arrhythmia, this retrospective analysis was conducted to determine the degree of QT prolongation in patients treated with arsenic trioxide. PATIENTS AND METHODS: Clinical data and serial ECGs from 99 patients with advanced malignancies who received 170 courses of arsenic trioxide in either a phase I or phase II investigational study were reviewed. RESULTS: Prolonged QT intervals developed in 38 patients (26 patients had intervals >/= 500 milliseconds). Compared with baseline, the heart rate-corrected (QTc) interval was prolonged by 30 to 60 milliseconds in 36.6% of treatment courses, and by more than 60 milliseconds in 35.4% of patients. The degree of prolongation was higher in men than in women during the first course of therapy, and in patients with hypokalemia. In patients receiving multiple courses, QTc intervals returned to pretreatment levels before the second course, signifying that arsenic trioxide does not permanently prolong the QTc interval. One hypokalemic, arsenic trioxide-treated patient with relapsed APL developed asymptomatic torsade de pointes, which resolved spontaneously and did not recur after electrolyte replacement. There were no sudden or arrhythmia-related deaths. CONCLUSION: This analysis shows that arsenic trioxide can prolong the QTc interval. However, with appropriate ECG monitoring and management of electrolytes and concomitant medications, arsenic trioxide can be safely administered in patients with relapsed APL.     

Clinical activity of arsenic trioxide for the treatment of multiple myeloma.

Arsenic has been used since ancient times as a therapeutic agent. However, until recently its use in modern medicine has been restricted to the treatment of a limited number of parasitic infections. In the early 1990s, reports from China described impressive results with arsenic trioxide in patients with de novo, relapsed, and refractory acute promyelocytic leukemia (APL). Other investigators subsequently confirmed these results leading to approval of its use for relapsed or refractory APL in the United States. Investigations of this agent have demonstrated that its efficacy in APL and preclinical tumor models is dependent upon a number of mechanisms, including induction of apoptosis, effects on cellular differentiation, cell cycling, and tumor angiogenesis. Subsequent preclinical studies showed significant activity of arsenic trioxide in multiple myeloma (MM). Based on this, in a phase II trial, we have evaluated the activity of arsenic trioxide in 14 patients with relapsed MM, refractory to conventional salvage therapy. With the dose and schedule used, treatment with arsenic trioxide produced responses in three patients and prolonged stable disease in a fourth patient, with the longest response lasting 6 weeks. Although treatment was reasonably well tolerated, in these patients with extensive prior therapy, 11 developed cytopenia, five associated with infectious complications and three developed deep vein thromboses. The results of this small trial support further investigation of this novel drug for the treatment of patients with relapsed or refractory MM.     

Clinical experience of arsenic trioxide in relapsed acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) has unique clinical, cytogenetic, and molecular features and is one of the most potentially curable human malignancies. The current standard treatment given to patients with newly diagnosed APL consists of all-trans retinoic acid and anthracycline-based cytotoxic chemotherapy, which is highly effective for remission induction. However, despite the potential for cure with existing treatments, approximately 20%-30% of patients relapse and require salvage therapy. Reports of the safety and efficacy of arsenic trioxide from centers in China led to a pivotal trial of this agent in the United States for patients with relapsed APL. In an initial pilot study, 11 of 12 patients experienced a complete response, and a subsequent multicenter trial confirmed the efficacy and safety of arsenic trioxide for remission induction in this patient population. Additional trials are under way to evaluate the use of this agent alone or as part of a chemotherapy regimen for consolidation and maintenance of patients with APL.     

Successful treatment of all-trans retinoic acid resistant and chemotherapy naïve acute promyelocytic patients with arsenic trioxide--two case reports

Arsenic trioxide(As2O3) has proved highly effective in treating both refractory or primary cases of acute promyelocytic leukemia (APL). The role of arsenic trioxide in APL treatment has been confirmed by study groups in China and in the USA. However, what is the role of As2O3 in treating APL? Should it be used as first line therapy, or should it be used as a second line drug. This still remains to be defined. Here, we report two cases of APL, who were treated successfully with As2O3 when they relapsed. Initially, both received all-trans retinoic acid (ATRA) for primary remission induction therapy, and obtained a complete remission. For ethical or personal reasons, they did not receive chemotherapy as consolidation therapy and when they relapsed at 23 months and 12 months later respectively, they both received As2O3 therapy after being resistant to ATRA treatment. Two courses of As2O3 were given and both reached complete remission. There were very few adverse reactions to the drug, only mild abdominal cramps, mild fluid retention, and transient elevation of transaminases. They both had rather good quality of life throughout the treatment and both remain in remission for 32 months and 10 months since therapy, respectively.     

Acute promyelocytic leukemia and variant fusion proteins: PLZF-RARα fusion protein at a glance

Classical acute promyelocytic leukemia (APL) cases are associated with the promyelocytic leukemia-retinoic acid receptor α (PML-RARα) chimeric fusion protein. Almost all the variant chimeric proteins share the same RARα component. Currently, more than 11 fusion partners of RARα have been identified, of which PML accounts for 95%, promyelocytic leukemia zinc finger (PLZF) take up2%, and the remaining are other variants. Although all-trans retinoic acid and arsenic trioxide have shown remarkable induction of molecular remission in classical APL, they have no appreciable effects on APL associated with other variant gene fusions (eg, PLZF-RARα and STAT5b-RARα). Here, we summarize all variant translocations, their key features, their leukemogenic potential as well as recent advances in studies of PLZF-RARα-associated APL. Basic pathogenic differences between classical APL and PLZF-RARα-associated APL are further discussed. We also highlight the critical leukemogenic events that are the backbone of these variant translocations so as to gain new insights into refractory APL.     

Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide.

PURPOSE: Arsenic trioxide, like all-trans-retinoic acid (RA), induces differentiation of acute promyelocytic leukemia (APL) cells in vivo. Treatment of APL patients with all-trans RA is commonly associated with leukocytosis, and approximately 50% of patients develop the RA syndrome. We reviewed our clinical experience with arsenic trioxide to determine the incidence of these two phenomena. PATIENTS AND METHODS: Twenty-six patients with relapsed or refractory APL were treated with arsenic trioxide for remission induction at daily doses that ranged from 0.06 to 0.17 mg/kg. RESULTS: Twenty-three patients (88%) achieved complete remission. Leukocytosis was observed in 15 patients (58%). The median baseline leukocyte count for patients with leukocytosis was 3,900 cells/microL (range, 1,200 to 72,300 cells/microL), which was higher than that for patients who did not develop leukocytosis (2,100 cells/microL; range, 500 to 5,400 cells/microL; P =.01). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in eight patients (31%). Patients who developed leukocytosis were significantly more likely to develop the RA syndrome (P <.001), and no patient without a peak leukocyte count greater than 10,000 cells/microL developed the syndrome. Among the patients with leukocytosis, there was no observed relation between the leukocyte peak and the probability of developing the syndrome (P =.37). CONCLUSION: Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.     

三氧化二砷(As_2O_3)治疗2例儿童难治性急性早幼粒细胞白血病

为探讨三氧化二砷治疗儿童白血病的效果。对2例难治性儿童患者进行了治疗。1例达CR。使用过程无明显毒副反应，且与全反式维甲酸（ATRA）无交叉耐药。细胞形态学检查显示：AS2O3有诱导分化及促凋亡双重作用。     

History of the development of arsenic derivatives in cancer therapy

Arsenic is a natural substance that has been used medicinally for over 2,400 years. In the 19th century, it was the mainstay of the materia medica. A solution of potassium arsenite (Fowler's solution) was used for a variety of systemic illnesses from the 18th until the 20th century. This multipurpose solution was also primary therapy for the treatment of chronic myelogenous leukemia until replaced by radiation and cytotoxic chemotherapy. The past 100 years have seen a precipitous decline in arsenic use and, by the mid-1990s, the only recognized indication was the treatment of trypanosomiasis. Much of this decline was due to concerns about the toxicity and potential carcinogenicity of chronic arsenic administration. The rebirth of arsenic therapy occurred in the 1970s when physicians in China began using arsenic trioxide as part of a treatment for acute promyelocytic leukemia (APL). Their accumulated experience showed that a stable solution of arsenic trioxide given by intravenous infusion was remarkably safe and effective both in patients with newly diagnosed APL leukemia and in those with refractory and relapsed APL. The mechanisms of action of arsenic derivatives in this disease and other malignancies are many and include induction of apoptosis, partial cytodifferentiation, inhibition of proliferation, and inhibition of angiogenesis. Molecular studies and ongoing clinical trials suggest that, as a chemotherapeutic agent, arsenic trioxide shows great promise in the treatment of malignant disease.     

Introduction: the history of arsenic trioxide in cancer therapy

Although arsenic can be poisonous, and chronic arsenic exposure from industrial or natural sources can cause serious toxicity, arsenic has been used therapeutically for more than 2,400 years. Thomas Fowler's potassium bicarbonate-based solution of arsenic trioxide (As(2)O(3)) was used empirically to treat a variety of disorders, and in 1878, was reported to reduce white blood cell counts in two normal individuals and one with "leucocythemia." Salvarsan, an organic arsenical for treating syphilis and trypanosomiasis, was developed in 1910 by Paul EHRLICH: In the 1930s, arsenic was reported to be effective in chronic myelogenous leukemia. After a decline in the use of arsenic during the mid-20th century, reports from China described a high proportion of hematologic responses in patients with acute promyelocytic leukemia (APL) who were treated with arsenic trioxide. Randomized clinical trials in the U.S. led to FDA approval of arsenic trioxide for relapsed or refractory APL in September 2000.     

Arsenic-induced APL differentiation in cerebrospinal fluid

Although new approaches have dramatically improved, the treatment of acute promyelocytic leukemia (APL) involvement of the central nervous system (CNS) confers a bad prognosis in the disease. Here, we report a patient who was diagnosed with relapsed APL preferentially involving the CNS. Treatment with arsenic trioxide led to impressive morphological changes in CNS cellularity consistent with the induction of a differentiation syndrome. Since arsenic trioxide could be identified in the CNS, we provide evidence that the drug can cross the blood-brain barrier and can be used for treatment of extramedullary APL.     

Arsenic trioxide (trisenox) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation

The relapse-free survival of patients with acute promyelocytic leukemia (APL) has significantly increased during the last decade. The introduction of all-trans retinoic acid (ATRA) doubled the survival of patients with this disease. However, despite ATRA and anthracycline-based chemotherapy, 12%-30% of patients will still relapse. Arsenic trioxide (ATO) has demonstrated efficacy and safety in patients with first and subsequent relapsed or refractory APL, regardless of the disease-free interval. Treatment of relapsed and refractory patients with this novel therapy produces complete remission in 87% of patients and molecular remission in 83%. Studies have documented the efficacy of autologous and allogeneic transplantation as salvage therapy in relapsed and refractory APL. The introduction of ATO into the treatment regimen for APL has stimulated discussion on its role in the transplantation setting. Investigators recently met to discuss the issue and make recommendations regarding ATO therapy in patients who are in their second or subsequent complete remission and are candidates for transplantation. This article describes the pivotal studies of this novel agent, discusses risk factor stratification for relapse in patients with APL, and proposes protocols for treatment incorporating ATO therapy. In addition, it describes scientific issues in ongoing and proposed clinical trials of ATO therapy for this disease.     

Mechanisms of action of arsenic trioxide

Arsenic trioxide has shown substantial efficacy in treating both newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL). As a single agent, it induces complete remissions, causing few adverse effects and only minimal myelosuppression. These successes have prompted investigations to elucidate the mechanisms of action underlying these clinical responses. Substantial data show that arsenic trioxide produces remissions in patients with APL at least in part through a mechanism that results in the degradation of the aberrant PML-retinoic acid receptor alpha fusion protein. Studies have also investigated concerns about the toxicity and potential carcinogenicity of long-term exposure to environmental arsenic. Arsenic apparently affects numerous intracellular signal transduction pathways and causes many alterations in cellular function. These actions of arsenic may result in the induction of apoptosis, the inhibition of growth and angiogenesis, and the promotion of differentiation. Such effects have been observed in cultured cell lines and animal models, as well as clinical studies. Because arsenic affects so many cellular and physiological pathways, a wide variety of malignancies, including both hematologic cancer and solid tumors derived from several tissue types, may be susceptible to therapy with arsenic trioxide. These multiple actions of arsenic trioxide also highlight the need for additional mechanistic studies to determine which actions mediate the diverse biological effects of this agent. This information will be critical to realizing the potential for synergy between arsenic trioxide and other chemotherapeutic agents, thus providing enhanced benefit in cancer therapy.     

Arsenic compounds in the treatment of multiple myeloma: a new role for a historical remedy

Arsenic compounds have been used since ancient times to treat a wide variety of ailments. Although the use of arsenic to treat hematologic cancers has been documented since the 19th century, widespread use of arsenic compounds in patients with hematologic malignancies did not occur until the 1990s, when several groups in China reported impressive clinical response rates in patients with acute promyelocytic leukemia who had received arsenic trioxide. Subsequently, clinical studies conducted in the United States confirmed earlier reports, and arsenic trioxide was approved by the Food and Drug Administration for the treatment of relapsed/refractory acute promyelocytic leukemia. The use of arsenic compounds in the treatment of multiple myeloma (MM) is supported by the proposed mechanisms of action underlying the antitumor activity of arsenic and by preclinical studies showing antiproliferative and cytotoxic activities in cell culture and animal models. Moreover, clinical studies of arsenic compounds, particularly arsenic trioxide-based regimens, have shown that this drug is clinically active in patients with relapsed/refractory MM. Combination studies with other antimyeloma agents have shown evidence of synergy with arsenic trioxide. Furthermore, arsenic trioxide-based regimens in MM appear to be well tolerated, particularly with regard to cardiac toxicity. The activity and tolerability observed in clinical studies promise to make arsenic-based chemotherapy a viable treatment option for patients whose disease does not respond to or who cannot tolerate other chemotherapy regimens.     

三氧化二砷诱导恶性肿瘤细胞凋亡机制的研究进展

三氧化二砷已广泛应用于白血病和各种实体瘤化学治疗的基础研究和临床实践中。近年来国内外多项研究证实三氧化二砷诱导凋亡是其杀伤肿瘤的主要机制,其分子机制尚未得到系统阐明,本文就其抗凋亡作用机制的研究进展作一综述。     

Combined effect of arsenic trioxide and sulindac sulfide in A549 human lung cancer cells in vitro

Arsenic trioxide has shown substantial efficacy in treating patients with relapsed or refractory acute promyelocytic leukemia (APL) as well as solid tumors. Arsenic can act through a considerable number of different pathways including mitochondrial respiration and tubulin formation, affecting growth, blood flow, differentiation, and apoptosis. Recent studies on the apoptotic potential of arsenic trioxide have elucidated some of its causal mechanisms, including elevation of intracellular H2O2, inhibition of NF-kappaB activity, and inhibition of GTP-induced polymerization of tubulin. Because of the variety in cellular approaches available to arsenic, it has been hypothesized that the combination of arsenic trioxide and other chemotherapeutic agents may result in cytotoxic synergy. Recent studies have proven this true, with all-trans retinoic acid, IFN-alpha, and ascorbic acid all yielding promising results when used in conjunction with arsenic trioxide. In this study we tested sulindac sulfide, a nonsteroidal anti-inflammatory drug (NSAID) to test its effects with arsenic. Sulindac was used because it functions by some of the same pathways as arsenic, including the mitochondrial apoptotic pathway and the NF-kappaB pathway. Our results show that sulindac sulfide enhances cytotoxicity when combined with arsenic trioxide, and that further studies on the exact mechanisms of their interaction are needed.