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.     

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.     

Acute promyelocytic leukemia

Opinion statement The treatment of acute promyelocytic leukemia (APL) is different from other subtypes of acute myelocytic leukemia (AML). All trans-retinoic acid (ATRA) is an essential component of the standard remission induction for all newly diagnosed APL patients. Remission induction with ATRA and chemotherapy given concurrently appears to be associated with fewer relapses. With further consolidation chemotherapy without high-dose cytosine arabinoside, the disease-free survival rate can reach 70% to 80%, and many of these patients are cured, more so than in any other AML subtype. APL is especially sensitive to anthracyclines, which should be included in the chemotherapy cycles at a higher dose than in other AML subtypes. Maintenance with low-dose chemotherapy (oral daily 6-mercaptopurine with weekly methotrexate) or ATRA further improves the long-term outcome. New approaches are also available for relapsing patients, although the optimal treatment is unknown. Patients who did not receive oral ATRA in first relapse can be treated with this agent, as can first relapsing patients who have been off the drug for more than 1 year. Because of poor remission rates, ATRA should not be used in patients with second or subsequent relapses (whether ATRA was given in the past), in patients with relapses early after ATRA discontinuation, or in patients relapsing while on ATRA therapy. Arsenic trioxide can also be used, especially in patients resistant to ATRA. Because arsenic trioxide is still experimental and not yet widely available, patients who are unlikely to respond to ATRA or who unsuccessfully undergo ATRA reinduction should be treated with chemotherapy. Patients in second or subsequent remission induced with ATRA or chemotherapy should receive consolidation chemotherapy. When arsenic trioxide is used for reinduction, the drug should be continued for several cycles; however, adding consolidation chemotherapy might improve the results. Because it is unknown whether APL in second or subsequent remission is curable with salvage therapy, allogeneic hematopoietic stem cell transplantation is often considered for patients with a human leukocyte antigen (HL-A)-identical sibling and autologous transplantation when a donor does not exist. However, compared with the new treatments, the role of transplantation for relapse is unclear. In first remission, there is no role for transplantation. A new liposomal formulation of intravenous ATRA is being investigated and seems effective in late first relapses, and it may be able to induce and maintain first remissions in selected patients without chemotherapy.     

三氧化二砷作用机制研究进展

砷化合物在我国作为药物应用已有2400多年的历史了。自从20世纪90年代,我国学者应用三氧化二砷（As2O3）治疗急性早幼粒细胞性白血病并获得成功以来,人们对砷化合物进行了深入的研究,发现As2O3不仅对各型白血病有效,对其他多种恶性肿瘤也有良好的治疗效果。As2O3主要是通过抑制肿瘤细胞生长和肿瘤新生血管形成、诱导肿瘤细胞部分分化和凋亡等发挥抗肿瘤作用的。本文不仅对上述问题进行总结,还展望了新发展起来的基因表达谱分析技术--基因芯片技术在研究As2O3作用机制方面的应用前景。     

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 trioxide/ascorbic acid therapy in patients with refractory metastatic colorectal carcinoma: a clinical experience

Arsenic trioxide (As₂O₃) has demonstrated effectiveness in treating acute promyelocytic leukemia (APL). Therefore the FDA has approved it to treat APL. In patients with refractory metastatic colorectal carcinoma (CRC), we assessed the efficacy and toxicity of As₂O₃/AA (ascorbic acid) as the outcome of this trial. Five patients with refractory metastatic CRC who failed all previous standard chemotherapy were enrolled in this study. They were treated with 0.25 mg/kg body weight/day As₂O₃ and 1000 mg/day of ascorbic acid for 5 days a week for 5 weeks. Each treatment cycle extended for 7 weeks with 5 weeks of treatment and 2 weeks of rest. All the patients developed moderate to severe toxic side effects to arsenic trioxide/AA therapy and therefore the study was discontinued. No CR (complete remission) or PR (partial remission) was observed. CT scans demonstrated stable or progressive disease. Three of the five patients died within 2 to 5 months after cessation of the therapy. None of the deaths could be related to this clinical trial. Two years of follow-up study showed that two patients were alive with stable disease. Under the current treatment regimen all patients developed moderate to severe side effects with no clinically measurable activity. As an alternate, efforts may be made to reduce the dose and arsenic trioxide may be combined with other standard regimen in reversing the chemo resistance.     

In the War Against Solid Tumors Arsenic Trioxide Need Partners

In the past decade, the therapeutic potential of arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL) was recognized. This encouraged other investigators to test the efficacy of ATO in the management of other hematological and solid tumor malignancies. Notably, as a single agent, arsenic trioxide did not benefit patients diagnosed with solid tumors. However, when it was combined with other agents, treatment benefit emerged. In this article, we have summarized the outcome of clinical trials that used arsenic trioxide as a single agent as well as in combination settings in patients diagnosed with solid tumors. We have also reviewed possible additional mechanisms by which ATO may be useful as a chemosensitizer in combination therapy. We hope that our review will encourage clinical investigators to rationally combine ATO with additional chemotherapeutic agents in treating patients diagnosed with solid tumors.     

Treatment of acute promyelocytic leukemia in the very elderly: case report and review of the literature

Acute promyelocytic leukemia (APL) is the most curable subtype of AML yet it is not known to what extent newer therapies will succeed in the very elderly. Conventional chemotherapeutic induction regimens are usually too toxic for older patients, however, all trans-retinoic acid (ATRA) and arsenic trioxide (ATO) may be useful therapeutic options if used judiciously. This case series describes three octogenarians with APL all treated with ATRA and achieved complete remissions. The last patient received ATO at the time of first relapse and achieved a second remission. To our knowledge, this is the first report of successful use of ATO for induction in an octogenarian with APL.     

Arsenic derivatives in hematologic malignancies: a role beyond acute promyelocytic leukemia?

The importance of arsenic trioxide (As2O3) has been underscored over the last decade due to its efficacy against acute promyelocytic leukemia (APL), a disease in which this agent has been associated with complete hematologic and molecular remission rates of 87% and 83%, respectively. The different molecular mechanisms of action of As2O3 suggest its applicability in hematologic malignancies other than APL. However, responses obtained thus far have consisted of improvements in signs and symptoms without the elimination of a given disease. Toxicities derived from As2O3 are significant but manageable and reversible. However, the risk/benefit ratio of As2O3 in hematologic malignancies other than APL is still unclear. The development of new generations of orally bioavailable inorganic, as well as new organic, arsenic compounds with improved toxicity profiles may bolster the therapeutic application of arsenic derivatives in hematologic malignancies such as leukemia, multiple myeloma and myelodysplastic syndromes.     

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。     

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 compounds as anticancer agents

In this paper the use of arsenic compounds as anticancer agents in clinical trials and in in vitro investigations is reviewed, including the experience at our institute. Treatment of newly diagnosed and relapsed patients with acute promyelocytic leukemia (APL) with arsenic trioxide (As2O3) has been found to result in complete remission (CR) rates of 85-93% when given by intravenous infusion for 2-3 h at a dose of 10 mg/day diluted in 5% glucose saline solution. Patients exhibit a response in 28-42 days. CR rates after administration of Composite Indigo Naturalis tablets containing arsenic sulfide and of pure tetraarsenic tetrasulfide reached 98% and 84.9%, respectively. At higher concentrations (1-2 microM), arsenic induced apoptosis, while at lower concentrations (0.1-0.5 microM), it triggered cell differentiation in vitro. As2O3-induced apoptosis has been observed in many cancer cell lines, including esophageal carcinoma, gastric cancer, neuroblastoma, lymphoid malignancies, and multiple myeloma. Its effectiveness was confirmed in the treatment of multiple myeloma. Arsenic compounds are effective agents in the treatment of APL and their activity against other types of cancer requires further investigation.     

Induction,consolidation, and maintenance therapies with arsenic as a single agent for acute promyelocytic leukaemia in a 11‐year follow‐up

The aim of this study was to evaluate the effect of arsenic trioxide as a single agent in acute promyelocytic leukaemia cases for induction, consolidation, and maintenance therapy in a long‐term, 11‐year follow‐up. We studied 60 patients with acute promyelocytic leukaemia. Sixty percent of the patients were aged between 12 and 24 years. Arsenic trioxide was infused at a 0.15 mg/kg daily dose until complete remission was achieved. After 2 weeks of rest, arsenic trioxide was infused daily for 28 days as a consolidation therapy. Then, arsenic infusions were given every 3–4 months for 14 days for 2 years, and the patients were followed until relapse or death. The rates of complete remission, disease‐free survival, overall survival, and drug toxicity were evaluated. The morphologic complete remission was observed in 55 out of the 60 patients. The most common causes of a remission failure were early mortality because of the APL differentiation syndrome and the lack of response to arsenic treatment. The mean follow‐up was 90 months. The primary outcomes for males and females were a mean disease‐free survival of 101 and 97 months, respectively, and a mean overall survival of 103 and 101 months, respectively. From the 55 cases with remission, three patients died (late mortality). Of the 60 patients, 85% are still alive. Arsenic trioxide was generally well tolerated. The long‐term follow‐up of patients with APL, treated with arsenic alone as induction, consolidation, and maintenance therapy, shows high cure rates and excellent outcomes. Copyright © 2015 John Wiley & Sons, Ltd.     

三氧化二砷治疗急性早幼粒细胞白血病心脏副作用临床观察

目的探讨常规剂量三氧化二砷（As2O3）对急性早幼粒细胞白血病（APL）患者的心脏副作用。方法通过对52例成人急性早幼粒细胞白血病患者146例次砷剂治疗过程中的临床症状,心电图改变、心肌酶、年龄、联合化疗方案合用、累积剂量、用药方法等的回顾调查,分析三氧化二砷治疗相关性心脏副作用的发生规律和影响因素。结果146例次砷剂治疗中心脏症状发生率22．6％,心肌酶异常发生率1．3％,ECG异常发生率63．0％。50—60岁人群的治疗相关心脏事件发生率最高（82．8％,P〈0．05）,合并传统化疗比砷剂单药的心脏事件发生率高（P〈0．05）。间歇用药比连续用药的ECG异常发生率低（44．7％对66．2％,P〈0．05）。累积剂量达1000mg时心脏不良事件发生率达高峰。低钾血症是加重心脏毒副作用的因素之一。结论常规剂量的三氧化二砷治疗APL有一定的心脏毒副作用,在临床上应引起注意。     

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.     

Treatment of acute promyelocytic leukemia: strategy toward further increase of cure rate.

Acute promyelocytic leukemia (APL) has become a curable disease by all-trans retinoic acid (ATRA)-based induction therapy followed by two or three courses of consolidation chemotherapy. Currently around 90% of newly diagnosed patients with APL achieve complete remission (CR) and over 70% of patients are curable. To further increase the CR and cure rates, detection and diagnosis of this disease at its early stage is very important, hopefully before the appearance of APL-associated coagulopathy. In induction therapy, concomitant chemotherapy is indispensable, except for patients with low initial leukocyte counts. Prophylactic use of intrathecal methotrexate and cytarabine should be done, particularly for patients with hyperleukocytosis. If patients relapse hematologically or even molecularly, arsenic trioxide will be the treatment of choice under careful electrocardiogram monitoring. Am80, liposomal ATRA, gemtuzumab ozogamicin or ATRA in combination with cytotoxic drugs may be used at this stage or later. Allogeneic SCT will be the treatment of choice after patients of age <50 years have relapsed, provided that they have HLA-identical family donors or DNA-identical unrelated donors.     

The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral,outpatient therapy

The therapeutic potential of arsenic derivatives has long been recognized and was recently rediscovered in modern literature. Early studies demonstrated impressive activity of this compound in patients with relapsed acute promyelocytic leukemia (APL). Over the last 2 decades, intravenous arsenic trioxide has been used successfully, both alone and in combination with other agents, for the treatment of APL and, with some success, of other myeloid neoplasms. Arsenic trioxide is currently part the standard of care for patients with APL. More recently, oral formulations of this compound have been developed and are entering clinical practice. In this review, the authors discuss the evolution of arsenic in the treatment of APL and other myeloid neoplasms. Cancer 2016;122:1160–8. © 2015 American Cancer Society.     

Anti-leukemic and anti-angiogenesis efficacy of arsenic trioxide in new cases of acute promyelocytic leukemia

Arsenic trioxide is now considered the standard agent in treatment of refractory cases of acute promyelocytic leukemia (APL). This drug is also shown to have anti-angiogenesis effect against APL cells in vitro. This study evaluated clinical efficacy and anti-angiogenesis effect of arsenic trioxide in 17 new cases of APL. Arsenic trioxide was given in a dosage of 0.15 mg kg(-1) and remission rate, survival rate, toxicities and effect on vascular density of bone marrow was studied. The bone marrow vascular density was examined using immunohistochemistry for von Willebrand Factor (vWF) and CD31 markers. Bone marrow vascular density was determined by calculating mean vessel number in 3 hot spot, high power microscopic fields. Bone marrow vascular density was reduced as identified by anti-vWF immunohistochemical staining (Mean before treatment = 201.6 mm(-2) +/- 20.4 (SEM), mean after treatment = 109.4 +/- 17.2 (SEM), p < 0.001) and anti-CD31 immunostaining (mean before treatment = 199.17 mm(-2) +/- 21.5 (SEM), mean after treatment = 99.5 mm(-2) +/- 22.1 (SEM), p < 0.05). Treatment efficacy results showed 100% complete remission rate after median of 30 days and 72% survival rate after median 860 days of follow-up. Main toxicities included hyper-leukocytosis, hepatic toxicity and APL differentiation syndrome. The results imply that arsenic trioxide is an effective anti-leukemia and anti-angiogenesis agent in new cases of APL.