Trioxide Treatment Research Articles

Balance between the toxicity and anticancer activity of arsenic trioxide in treatment of acute promyelocytic leukemia

Arsenic trioxide (ATO) has a long history and it is recognized as both poison and drug for more than two thousand years. Since the establishment of ATO as a frontline therapeutic agent for acute promyelocytic leukemia (APL), the survival of APL patients have been greatly improved and APL is turned from highly fatal to highly curable disease. Mechanistically, ATO can induce PML/RARα fusion protein degradation, causing APL cell differentiation and apoptosis. On the other hand, the side effects such as differentiation syndrome, cardiac conduction abnormalities and liver toxicity are often observed during the ATO treatment of APL in clinic. It is likely that the therapeutic and adverse effects of ATO is probably associated with its distinct pattern of metabolism and direct or indirect effects on different organs. In this review, we provided a comprehensive and in-depth elaboration of the cytotoxic mechanisms of ATO and its methylated metabolites based on in vivo or in vitro studies, trying to clarify the importance of achieving balance between the toxicity and anti-leukemic activity of ATO in APL treatment.

Efficacy analysis of decitabine monotherapy or combined with arsenic trioxide in treatment of myelodysplastic syndromes

Objective To analyze the therapeutic effect and tolerability of decitabine monotherapy or combined with arsenic trioxide for the treatment of patients with myelodysplastic syndromes (MDS). Methods Clinical characteristics of 32 patients with primary MDS in North Hospital of Ruijin Hospital Affiliated to Medical College of Shanghai Jiaotong University from January 2014 to April 2017 were retrospectively analyzed. The clinical data of these patients were collected, and the patients were followed up. Decitabine combined with arsenic trioxide was used in 23 cases, decitabine (20 mg·m-2·d-1) and arsenic trioxide (0.16 mg/kg) were administrated from day 1 to day 5 and was repeated every 4-6 weeks. For the remaining 9 cases, only decitabine was applied, decitabine(20 mg·m-2·d-1) was administrated from day 1 to day 5 and was repeated every 4-6 weeks. The clinicopathological characteristics and the effect of genetic mutations on the efficacy of treatment were investigated. Results Of the 32 patients with primary MDS, 18 were male and 14 were female. The patients were 17-72 years old with a median age of 56 years old. Genetic analysis revealed 10 cases with TP53 mutations, 8 cases with TET2 mutations, 4 cases with U2AF1 mutations, 3 cases with RUNX1 mutations, 3 cases with ASXL1 mutations, 2 cases with NRAS mutations, 2 cases with DNMT3A mutations and 1 case with JAK2 V617 mutation. The follow-up time was 2-23 months with a median follow-up time of 8 months. A total of 21 cases (65.6%) attained treatment response. Among them, there were 10 cases (31.3%) with complete remission (CR), 5 cases (15.6%) with bone marrow complete remission (MCR), and 6 cases (18.7%) with hematological improvement. There was no significant difference in the efficiency and CR rate between the combination group and the monotherapy group (P = 0.441, P = 0.681). Ten cases were found to have TP53 mutations, of which 7 cases had CR. Multivariate analysis demonstrated that TP53 mutation was an independent risk factor for CR (P = 0.037). All patients developed myelosuppression after treatment, of which 16 cases developed pulmonary infection. Conclusions Decitabine combined with arsenic trioxide in the treatment of MDS is effective and well tolerated. The therapeutic effects of decitabine monotherapy or decitabine combined with arsenic trioxide for treatment of patients with TP53 mutations are better than the average levels. Key words: Myelodysplastic syndromes; Decitabine; Arsenic trioxide; Curative effect

Efficacy and prognosis of arsenic trioxide in treatment of patients with acute promyelocytic leukemia

Objective To analyze the long-term survival and prognostic factors of patients with acute promyelocytic leukemia (APL) who were treated with arsenic trioxide (ATO). Methods From January 2007 to December 2017, a total of 154 newly diagnosed APL patients who were treated with ATO were included in the study from Tangdu Hospital, Air Force Military Medical University. According to the time of diagnosis and the treatment regimen, the subjects were divided into all trans-retinoic acid (ATRA) + chemotherapy-induced group (n= 87, diagnosed before 2012) and ATRA + ATO double-induced group (n= 67, diagnosed after 2012). The retrospective investigation method was used to collect early mortality, complete remission (CR) rate, conversion rate of PML/RARΑ fusion gene, recurrence rate, peripheral blood granulocyte ratio, bone marrow granulocyte ratio, PML/RARα fusion gene phenotype, risk stratification, CD2 and CD34 expression in ATRA+ chemotherapy-induced group and ATRA+ ATO double-induced group. And the efficacy and prognosis were compared between two groups. The follow-up time of this study was up to June 30, 2018, with a median follow-up of 58 months (6-134 months). The Chi-square test or Fisher′s exact test were used to compare the early mortalities, CR rates, and PML/PARα fusion gene conversion rates between the ATRA + chemotherapy-induced group and the ATRA + ATO double-induced group. The Kaplan-Meier method was used to map the survival curves of the patients in both groups. The life table method was used to compare the overall survival (OS) rate and recurrence-free survival (RFS) rates of patients in both groups. Univariate analysis was used to determine the influencing factors affecting the prognosis of patients with APL. The procedure followed in this study was in line with the requirements of Helsinki Declaration of the Word Medical Association revised in 2013. All individuals were routinely signed with informed consent for chemotherapy and toxic drugs before treatment. Results ① The CR rate of all patients in this study was 92.8% (143/154). The CR rate in ATRA + chemotherapy-induced group was 89.6% (60/67), and that of the ATRA + ATO double-induced group was 95.4 % (83/87), the difference was not statistically significant (χ2 = 1.953, P=0.162). There was significant difference in conversion rate of PML/RARα fusion gene between ATRA + chemotherapy-induced group and ATRA + ATO double-induced group(98.9% vs 89.5%; χ2=4.891, P=0.027). The early mortality during induction therapy was 7.1% (11/154). ② In the 154 APL patients, eleven patients had recurrence during consolidation and maintenance treatment. The recurrence rates of ATRA + chemotherapy-induced group and ATRA + ATO double induction group were 13.4% (9/67) and 2.3%(2/87), respectively, and the difference was statistically significant(χ2=5.495, P=0.019). ③ The 5-year OS rate and RFS rate in ATRA+ chemotherapy-induced group were 83.6% and 85.0%, respectively, which of ATO + ATRA double-induced group were 95.4% and 96.5%, respectively. The differences between two groups were statistically significant(χ2=6.838, P=0.029; χ2=3.297, P=0.040), respectively. ④ Results of univariate analysis showed that the 5-year OS rate of patients with duration of ATO usage≥84 d and 0.05). Conclusions Early death is still the main factor affecting the survival of APL, and ATO can improve the increase the CR rate and the molecular biology conversion rate during induction therapy. The cumulative treatment with ATO for more than 84 d is an important prognostic factor, but it cannot change the adverse effect of myeloblast in peripheral blood. Key words: Leukemia, promyelocytic, acute; Arsenicals; Antineoplastic combined chemotherapy protocols; Prognosis; Survival

Arsenic trioxide and all-trans retinoic acid (ATRA) treatment for acute promyelocytic leukemia in all risk groups: study protocol for a randomized controlled trial

BackgroundThe treatment of acute promyelocytic leukemia (APL) has been revolutionized in the past two decades by the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). It suggests that non-high-risk APL patients can be cured without chemotherapy. However, ATRA plus chemotherapy is still the standard therapy for the high-risk patients. Central nervous system (CNS) relapse remains a significant cause of treatment failure in high-risk patients. However, increasing the ATO concentration in cerebrospinal fluid (CSF) may reduce CNS relapse in high-risk patients. Mannitol can allow ATO to penetrate the blood-brain barrier (BBB) and reach therapeutically effective levels in the CSF. It is used for the treatment of CNS relapse in patients APL. We compare ATRA-ATO with ATRA-ATO plus chemotherapy in both high-risk and non-high-risk patients with APL.MethodsThis study was designed as a multicenter randomized controlled trial. Patients with APL were randomly assigned into two groups: the ATRA-ATO group (experimental group) and the ATRA-ATO plus chemotherapy group (control group). The experimental group receives therapy with ATRA-ATO for induction, consolidation and maintenance therapy. In the high-risk patients, mannitol will be used with ATO in the consolidation and maintenance therapy. Hydroxyurea will be used in patients who developed leukocytosis in the induction therapy. The control group receives therapy with ATRA-ATO plus chemotherapy for induction and consolidation therapy.DiscussionIn this study, a randomized clinical trial design is described. It aims to compare the efficacy of ATRA-ATO versus ATRA-ATO plus chemotherapy in all-risk patients with APL.Trial registrationChinese Clinical Trials Registry, ID: ChiCTR-IPR-15006821. Registered on 27 July 2015.

Comparison of Curative Effect between Fu Fang Huang Dai Pian and Arsenic Trioxide in Treatment of 45 Patients with Acute Promyelocytic Leukaemia

To investigate the clinical efficacy of Fu Fan Huang Dai Pian(RIF) and arsenic trioxide (ATO) regimens for treatment of children with acute promyelocytic leukemia (APL) and to explore the risk factors affecting the prognosis of patients. The clinical data of 45 newly diagnosed APL children admitted in our hospital from January 2004 to May 2017 were analyzed retrospectively. Among 45 APL children, 25 children were treated by chemotherapetic regimen including RIF (RIF group), another 20 children were treated by chemotherapeutic regimen including ATO (ATO group). The follow-up was performed in all APL children. The prognosis and incidence of side reactions from drugs in 2 groups were compared, and the high risk factors affecting the prognosis of patients were analyzed. The median follow-up time was 49.8% months. In RIF group, no early death occured in 25 APL children; 5 cases did not achieve complete remission (CR) after induction therapy, CR rate was 88%. Out of 25 cases 2 caes relapsed, 3 cases died, 20 cases maintained contined CR (CCR), 2 cases failed to be followed-up. In ATO group, 2 cases suffered from early death, 5 cases did not achieve CR after induction therapy, CR rate was 90%, 2 caese relapsed and died, 15 cases maintained CCR, the follow-up failed in 1 caes. The 5 year- OS and EFS rate in all the patients were predicted as (82.2±6.2)% and (76.4±6.6)% respectively. The OS and EFS rate in RIF group were (86.1±7.4)% and (78.4±8.6)% respectively, which were significantly different from OS and EFS rate (76.4%±10.6%) and (74.0%±10.1%) respectively in ATO group (all P>0.05). As for the side reaction from drug, except for the cardiac damage (P<0.05), incidence of other side reactions was not significantly different between 2 groups (P>0.05). In addition, the 5 year-OS and EFS rates in APL children with CNSL were significantly lower than those in APL children without CNSL (all P<0.05), the 5 year OS and EFS rate in APL children did not reache M1 and with high risk were significantly lower than those in APL children reached M1 after induction therapy and with low and standerd risk (P<0.05 and P<0.05); the 5 year-OS and EFS rates did not correlate with age and sex. The Fu Fang Huang Dai Pian shows the therapeutic efficacy on APL children same as ATO, moreover, no obvious enhancement in incidence of side reactions is observed, therefore, the Fu Fang Huang Dai Pian is effective and safe for treatment of APL children. The CNSL, poor respond to treatment, high risk in clinical stratification are high risk factors affecting prognosis of patients.

New Cases of Acute Promyelocytic Leukemia Treatment by Arsenic Trioxide Alone and Their Long Term Follow up

AbstractAbstract 506Long term follow-up of APL patients treated by ATRA and chemotherapy is available and shows promising results of DFS and OS. Although several studies show acceptable efficacy of Arsenic Trioxide in new cases of APL, its long term result needs better clarification. Materials and methods:one hundred ninety seven, new cases of APL treated by Arsenic trioxide (0.15 mg/kg daily i.v infusion till complete remission). After achieving to CR patients received 4 more courses of Arsenic trioxide as consolidation. Then patients followed by CBC and RT-PCR on peripheral blood for detection of MRD every three months or till relapse or death. Results:Morphologic complete remission rate was 85.8% and most common cause of remission failure was early death due to hemorrhage of APL differentiation syndrome.(14.7%) Most important prognostic factor for early mortality is high WBC count at presentation. Disease free survival was 90%+/−2%, 72.7%+/−3% and 66.7%+/−4% for 2, 3 and 5 years respectively. Relapse for patients who remained in CR after 5 years was very uncommon. Overall survival for patients after diagnosis by intention to treat analysis was 80.2%+/−3%, 75.9%+/−3% and 64.4%+/− 4% for 2, 3 and 5 years. Also OS and DFS were the same between patients with high and low WBC count. Conclusion:Long term follow up of newly diagnosed cases of APL, treated with single agent Arsenic Trioxide shows promising result. Arsenic trioxide potentially eliminates the adverse effect of prognostic factors of APL treatment such as high WBC count. We suggest that it is time to integrate Arsenic trioxide in treatment of new cases of APL. Disclosures:No relevant conflicts of interest to declare.

Retrospective study of arsenic trioxide for childhood acute promyelocytic leukemia in China: a single-center experience

There are very limited reports about childhood acute promyelocytic leukemia (APL), especially about arsenic trioxide (ATO) treatment in both induction and post-remission regimens. 35 newly diagnosed APL patients received ATO treatment in our center and the clinical course as well as the outcome of them was investigated. The dose of intravenous ATO was 0.15-0.17 mg/kg per day, only one patient got 0.33 mg/kg per day, maximum dose was 10 mg per day in induction therapy with minimal chemotherapy treatment (CT) for hyperleukocytosis. Anthracycline or anthracycline-based CT was used for consolidation therapy and followed by 0.10-0.15 mg/kg per day ATO treatment in maintenance therapy. The continuous detection for morphology of bone marrow and PML-RARa were necessary for administrating CT or not. 3 patients died during induction therapy for intracranial hemorrhage, leukocytosis and septic shock. Total of 30 patients achieved complete remission (CR) and were followed-up for 10-108 months. The overall survival (OS) for all patients was 82.7%, whereas the OS for patients obtained CR was 95.8%. The event-free survival for 5 years was 80.3%. Disseminated intravascular coagulation could be under control to reduce induction mortality with adequate supportive care, especially in the first 2 weeks. The side effects of ATO were mild and transient. This regimen of ATO treatment both in induction and post-remission therapy was effective and safe for childhood APL to get long-term survival.

Abstract 2513: Arsenic trioxide induces depolymerization of microtubules in an acute promyelocytic leukemia cell line

Abstract Arsenic trioxide (ATO) treatment has been used in recent decades to achieve clinical remission in patients with acute promyelocytic leukemia (APL). The biological basis for ATO treatment has been explained as being mediated through anti-proliferation, anti-angiogenesis, and apoptosis in both APL and solid tumor cells. Arsenic trioxide has been shown to affect microtubules such that dysfunction of the cellular cytoskeleton is induced, which ultimately leads to cell death. In this study, we reported that ATO disrupts tubulin assembly and results in microtubule dysfunction, inducing cell death in an APL cell line. ATO markedly enhanced the depolymerization of microtubules. Analysis of posttranslational modifications of microtubules also revealed that ATO decreased modified forms of the polymerized tubulin portion in adose-dependent manner. Immunocytochemical investigation showed that ATO changed the cellular microtubule network and inhibited the formation of polymerized microtubules. These alterations in microtubules suggest that ATO increases the depolymerized form of tubulin in the cells, potentially through its effect on the attenuation of spindle dynamics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2513.

Intracavitary administration of Arsenic Trioxide in treatment of lung cancer complicated with pleural effusion

Intracavitary administration of Arsenic Trioxide in treatment of lung cancer complicated with pleural effusion

Arsenic trioxide and olanzapine co-administration: case analysis

QTc prolongation is associated with arsenic trioxide (ATO) treatment of acute promyelocytic leukemia (APL). Olanzapine was safely co-administered with ATO to treat co-morbid psychiatric diagnoses. It is important to closely monitor for drug-drug interactions and cumulative drug adverse effects in patients receiving oncology agents and psychotropics. Further research is indicated to determine risk/benefit profiles of psychotropics co-administered with ATO. In light of current limited data, co-administration of psychotropics with ATO should be reported presenting both instances wherein no interactions are noted and those with adverse effects.

Arsenic trioxide for treatment of myelodysplastic syndrome: An experience from India

13156 Background: Myelodysplastic Syndrome (MDS) is a heterogeneous group of clonal diseases of the haematopoietic stem cells. The hallmark of the disease is ineffective haematopoiesis characterized by dysplasia with incomplete maturation and progressive increase in the percentage of myeloblast. No standard treatment is currently available for MDS. The early clinical experience has confirmed the activity of arsenic trioxide in MDS. The drug is able to induce differentiation and apoptosis and to inhibit cell proliferation or angiogenesis. It has the potential to be active in tumour models in MDS. The preliminary result of ongoing studies conducted in patients with MDS suggests that arsenic trioxide produces haematological improvement including durable transfusion independence in 30% of patients. The aim of our study was to see the response of MDS with arsenic trioxide and to see the toxicity profile of arsenic trioxide in Asian Indian population. Methods: During period from July 2005 to December 2005 we selected consecutive 10 patients of MDS in Refractory Anaemia, Refractory anaemia with ringed sideroblasts, Refractory anaemia with blast excess, Refractory anaemia with blast excess in transformations and chronic myelo monocytic leukemia phases. All patients had performance status more than 60%, some karyotypic abnormalities &amp; in cytopenic phase. Median age of the patients 65 years (range 42 to 70 years). All patients were treated with arsenic trioxide 10mg (Alkem/India) daily for 2 hours infusion 28 days. In 15 days interval 3 courses were repeated. Response assessments were done by haematological, cytogenetic &amp; quality of life assessment. All patients were evaluated after 3 courses of arsenic trioxide. Result: Sixty percent (6 patients) patients had shown major haematological response, forty percent minor &amp; twenty percent has major cytogenetic response. Twenty percent of the patients has disease progression where as 20% has stable disease. The only mild adverse effects were seen in forms of nausea, vomiting, diarrhea, abdominal pain &amp; dermatitis in 30% of patients. Only one patient (10%) had QT prolongation in ECG. Conclusion: We concluded that arsenic trioxide is very useful drug in myelodysplastic syndrome. It is also well tolerated in Asian Indian Population. No significant financial relationships to disclose.

Comparison of differential gene expression profiles in human esophageal squamous carcinoma EC8712 cells before and after arsenic trioxide (As2O3) treatment

To elucidate molecular mechanisms of AS2O3 induced apoptosis of cancer cellsin vitro, Atlas human cDNA expression analysis has been used for the profile of the known genes expressed in the human esophageal squamous carcinoma cells before and after treated by AS2O3. On treating EC8712 cells with AS2O3, most of the oncogenes have been down-regulated, while some tumor suppressor genes, such as DCC, up-regulated. Cyclin H decreases, while guanine nucleotide releasing protein CDC25 increases. Heat shock protein 86, a stress response protein, increases, suggesting that AS2O3 has a toxic effect on cells. Most stimulating cell reproduction factors have been down-regulated. Many apoptosis-related proteins have been up-regulated. DNA repair protein hMLH1 and DNase X have been up-regulated. Most transcription factors and general DNA binding proteins regulate upward. ICH-2 protease (ICErel-II) and apopain, cysteine protease Mch2 isoform beta rise. Results indicate that AS2O3 may induce change of expression of many genes and many genes may be involved in the process of apoptosis induced by AS2O3. These findings provide further evidence that AS2O3 might be clinically useful in solid tumor treatment.

Trivalent Antimonials Induce Degradation of the PML-RAR Oncoprotein and Reorganization of the Promyelocytic Leukemia Nuclear Bodies in Acute Promyelocytic Leukemia NB4 Cells

Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosomal translocation that fuses the genes encoding the promyelocytic leukemia protein (PML) and the retinoic acid receptor  (RAR). The resulting PML-RAR protein induces a block in the differentiation of the myeloid progenitor cells, which can be released by retinoic acid (RA) in vitro and in vivo. The RA-induced differentiation of APL blasts is paralleled by the degradation of the fusion protein and the relocation of wild-type PML from aberrant nuclear structures to its normal localization in nuclear bodies. Recently, arsenic trioxide (As2O3) treatment was proposed as an alternative therapy in APL, because it can induce complete remission in both RA-sensitive and -resistant APL patients. Intriguingly, As2O3 was also shown to induce degradation of the PML-RAR chimera and to reorganize PML nuclear bodies. Here we show that trivalent antimonials also have striking effects on RA-sensitive and RA-resistant APL cells. Treatment of the APL-derived NB4 cells and the RA-resistant subclone NB4R4 with antimony trioxide or potassium antimonyl tartrat triggers the degradation of the fusion protein and the concomitant reorganization of the PML nuclear bodies. In addition, as reported for As2O3, the antimonials provoke apoptosis of NB4 and NB4R4 cells. The mechanism of antimony action is likely to be similar to that of As2O3, notably both substances induce the attachment of the ubiquitin-like SUMO-1 molecule to the PML moiety of PML-RAR. From these data, we propose that, in analogy to As2O3, antimonials might have a beneficial therapeutic effect on APL patients, perhaps with less toxicity than arsenic.