Retinoic acid syndrome induced by arsenic trioxide in treating recurrent all-trans retinoic acid resistant acute promyelocytic leukemia

Arsenic Trioxide (As2O3) is an effective agent for treating acute promyelocytic leukemia achieving a complete remission rate of about 60% to 90%. It is similar to all-trans retinoic acid (ATRA) when treating acute promyelocytic leukemia (APL), because both agents have limited side effects compared to conventional chemotherapy, although the treatment period is more prolonged. During treatment, both agents may induce leukocytosis, and in patients taking ATRA, leukocytosis appears to be related to the development of retinoic acid syndrome (RAS). We report here a case of APL treated with ATRA in combination with chemotherapy 3 years earlier. During treatment, an episode of RAS with fever, edema, pericardiac effusion etc. was encountered. Recently, she had a relapse of leukemia, and As2O3 therapy was used. Leukocytosis developed again, and symptoms of fever, skin rash, edema resembling a RAS also developed, which was quickly relieved by steroid administration in a manner resembling response to RAS.     

Studies on the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia: a comparison with conventional dosage.

Twenty cases of patients with relapsed acute promyelocytic leukemia (APL) were entered into this study for evaluating the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide (As2O3). As2O3 was given at a daily dose of 0.08 mg/kg intravenously for 28 days. Pharmacokinetic study was carried out in eight patients. 16/20 (80%) patients achieved CR. The occurrence of some toxic events including gastrointestinal disturbance, facial edema and cardiac toxicity seemed reduced in the low-dose group than those in the standard-dose group. Differentiation changes were observed in peripheral blood, as well as in bone marrow (BM). Pharmacokinetic study showed that the plasma concentration increased soon after administration of As2O3 with the peak values of 1.535-3.424 micromol/l. After infusion, the plasma concentration was around 0.1-0.5 micromol/l. The arsenic concentration of the plasma of BM aspirates 24 h after administration in five patients was close to the level needed for differentiation-inducing effect. The estimated 2-year OS and RFS were 61.55+/-15.79% and 49.11+/-15.09% respectively, with no difference as compared with those in patients treated with conventional dose (P = 0.2865 and 0.7146, respectively). In conclusion, we demonstrated that low-dose As2O3 had the same effect as the conventional dosage and the mechanism of low-dose arsenic seemed to primarily induce differentiation of APL cells.     

全反式维甲酸联合三氧化二砷治疗儿童急性早幼粒细胞白血病疗效观察

 目的　观察全反式维甲酸（ ATRA ）联合三氧化二砷（ As2O3）治疗儿童初发急性早幼粒细胞白血病（ APL）的疗效和不良反应。方法　ATRA 联合As2O3治疗初发 APL患儿16例。治疗方案：ATRA 25 mg·m-2·d-1，分2～3次口服，As2O3 0.16 mg·kg-1·d-1，加入生理盐水或50 g／L葡萄糖溶液静脉滴注，持续 4～6 h，1次／d。结果　14 例患者获得完全缓解（CR），CR率87.5 ％，CR时间短，没有明显不良反应。结论　ATRA联合As2O3治疗儿童APL能获得很好疗效。     

Use of arsenic trioxide (As2O3) in the treatment of patients with acute promyelocytic leukemia: the M. D. Anderson experience

BACKGROUND: Approximately 20-30% of patients with acute promyelocytic leukemia (APL) who are treated with all-trans retinoic acid (ATRA) and an anthracycline develop recurrent disease. It has been reported that arsenic trioxide (As(2)O(3)) is effective in this setting. The authors report the experience of The M. D. Anderson Cancer Center with As(2)O(3) in the treatment of patients with recurrent APL. METHODS: Twelve patients who developed recurrent APL after treatment with ATRA were included. Patients received intravenous As(2)O(3) 0.15 mg/kg per day until they achieved a complete remission (CR) or up to a maximum of 60 days. Their median age was 44 years (range, 26-72 years), and the median duration of first remission was 52 weeks (range, 23-292 weeks). RESULTS: All 12 patients achieved a CR. The median time to achieve CR was 52 days (range, 27-75 days). Seven of 10 evaluable patients achieved a molecular remission (i.e., polymerase chain reaction [PCR] analysis was negative for the gene encoding fusion of the nuclear receptor for retinoic acid to the PML gene at the time of CR; 70% of patients; 95% confidence interval, 0.35-0.93), and all other patients had negative PCR results after they received post-remission therapy. All patients received subsequent therapy: Four patients received As(2)O(3) alone, six patients received As(2)O(3) with other chemotherapeutic agents, and two patients received idarubicin plus ATRA without As(2)O(3). Eight patients continued in CR after a median follow-up of 24 months (range, 9-45 months). Side effects were mild, except for two patients who developed Grade 2 and 3 peripheral neuropathy, respectively; one of those patients required discontinuation of therapy. CONCLUSIONS: As(2)O(3) is effective and well tolerated therapy for patients with recurrent APL. Molecular remission may be achieved at the time of CR in the majority of patients, and remissions are durable.     

Arsenic trioxide cytotoxicity in steroid and chemotherapy-resistant myeloma cell lines: enhancement of apoptosis by manipulation of cellular redox state.

PURPOSE: We investigated the ability of pretreatment with buthionine sulfoximine (BSO) to overcome a priori resistance to arsenic trioxide (As(2)O(3)) in multiple myeloma (MM) cells and determine whether this was through an apoptotic mechanism that involves changes in the cellular redox state. EXPERIMENTAL DESIGN: Using a panel of dexamethasone and chemotherapy-resistant MM cell lines, we examined growth inhibition, induction of apoptosis, and changes in the redox state by As(2)O(3) alone or after preincubation with BSO. RESULTS: Whereas the sensitive cell lines showed 100% killing at 0.5 micromol/liter of As(2)O(3), the resistant cell lines required BSO pretreatment to achieve 100% killing at this dose. By comparison, the peak As(2)O(3) plasma concentration in acute promyelocytic leukemia in patients successfully treated was 5-7 micromol/liter with rapid decline to a sustained level of 1-2 micromol/liter. We demonstrated that BSO and As(2)O(3)-induced cytotoxicity was attributable to induction of apoptosis accompanied by activation of the death signals: caspases 3, 8, and 9. CONCLUSIONS: We have demonstrated that growth inhibition of highly resistant MM cell lines by As(2)O(3) is facilitated by BSO and that this effect is accompanied by caspase activation, presumably leading to activation of apoptosis. These data indicate that steroid and chemotherapy-resistant MM cell lines can be overcome by manipulation of the cellular redox state. Because BSO and As(2)O(3) can be used at clinically relevant concentrations, we believe that our observations may have important implications for the treatment of MM.     

Short-term intensive consolidation therapy after all-trans retinoic acid in acute promyelocytic leukemia.

Complete remission induced by all-trans retinoic acid (ATRA) in acute promyelocytic leukemia is short lived, and several consolidation chemotherapy courses usually are given to reduce the relapse rate. To assess the value of short-term intensive consolidation, 38 patients with newly diagnosed acute promyelocytic leukemia entered a prospective study in which induction therapy with ATRA immediately was followed by a single course of mitoxantrone plus high-dose cytarabine (3 g/m2 every 12 hours, days 1-4), with no further treatment. Complete remission was achieved in 31 patients (81.6%) after a median time of 49 days of ATRA (to which chemotherapy was added at entry in 10 patients with leukocytosis). Thirty patients received the planned consolidation course. After a median follow-up of 36 months, four of these patients have relapsed and 24 are still in first complete remission, for an estimated disease-free survival of 75% at 60 months. The authors conclude that this single course consolidation of ATRA-induced remission provides excellent long-term control of acute promyelocytic leukemia.     

Arsenic trioxide, a therapeutic agent for APL.

Acute promyelocytic leukemia (APL) is an interesting model in cancer research, because it can respond to the differentiation/apoptosis induction therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)). Over the past 5 years, it has been well demonstrated that As(2)O(3) induces a high complete remission (CR) rate in both primary and relapsed APL patients (around 85 to 90%). The side effects are mild to moderate in relapsed patients, while severe hepatic lesions have been found in some primary cases. After CR obtained in relapsed patients, chemotherapy in combination with As(2)O(3) as post-remission therapy has given better survival than those treated with As(2)O(3) alone. The effect of As(2)O(3) has been shown to be related to the expression of APL-specific PML-RARalpha oncoprotein, and there is a synergistic effect between As(2)O(3) and ATRA in an APL mouse model. Cell biology studies have revealed that As(2)O(3) exerts dose-dependent dual effects on APL cells. Apoptosis is evident when cells are treated with 0.5 approximately 2.0 microM of As(2)O(3) while partial differentiation is observed using low concentrations (0.1 approximately 0.5 microM) of the drug. The apoptosis-inducing effect is associated with the collapse of mitochondrial transmembrane potentials in a thiol-dependent manner, whereas the mechanisms underlying APL cell differentiation induced by low dose arsenic remain to be explored. Interestingly, As(2)O(3) over a wide range of concentration (0.1 approximately 2.0 microM) induces degradation of a key leukemogenic protein, PML-RARalpha, as well as the wild-type PML, thus setting up a good example of targeting therapy for human cancers.     

低剂量氧化砷治疗早幼粒细胞白血病的实验研究

背景与目的：低剂量三氧化二砷（arsenic trioxide,As2O3）是治疗急性早幼粒细胞性白血病（APL）的有效手段之一,它不仅对初发APL病人有效,而且对全反式维甲酸（ATRA）巳耐受的复发APL病人可获得完全缓解。然而,目前其诱导APL缓解的机制尚不清楚。为此,本研究试图探低剂量As2O3治疗APL的可能机制。方法：以APL细胞株NB4和来源于APL患者骨髓的原代细胞为模型。通过观察细胞形态、对四氮唑蓝的还原能力和细胞表面分化抗原的变化来鉴定细胞分化;并应用免疫荧光和Western blot分析细胞内PML-RARα融合蛋白的变化。结果：0.25μmol/L AS2O3联合环腺苷酸（cAMP）拟似物8-对氯苯硫基环腺苷酸（8-CPT-CAMP）可诱导NB4细胞和原代细胞分化,而且该效应能被蛋白激酶PKA的抑制剂H89抑制。进一步研究还显示8-CPT-CAMP可以促进AS2O3介导的PML-RARα融合蛋白降解。结论：cAMP可增强AS2O3对APL细胞的分化诱导效应。     

急性早幼粒细胞白血病耐药机制的研究进展

全反式维甲酸(ATRA)与三氧化二砷(As2O3)作为一线药物治疗急性早幼粒细胞白血病(APL)以来,APL患者的治愈率得到显著提高.但ATRA和(或)As2O3耐药的出现成为一个严重问题.现就近年来新提出的一些耐药机制如融合基因突变、细胞信号通路异常、染色质重构复合物异常、凋亡调控异常、骨髓微环境介导耐药等方面进行综述.     

Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis

The promyelocytic leukemia (PML) protein is a potent growth suppressor and proapototic factor, whereas aberrant fusions of PML and retinoic acid receptor (RAR)-alpha are causal agents in human acute promyelocytic leukemia. Arsenic trioxide (As(2)O(3)) treatment induces apoptosis in acute promyelocytic leukemia cells through an incompletely understood mechanism. We report here that As(2)O(3) treatment induces phosphorylation of the PML protein through a mitogen-activated protein (MAP) kinase pathway. Increased PML phosphorylation is associated with increased sumoylation of PML and increased PML-mediated apoptosis. Conversely, MAP kinase cascade inhibitors, or the introduction of phosphorylation or sumoylation-defective mutations of PML, impair As(2)O(3)-mediated apoptosis by PML. We conclude that phosphorylation by MAP kinase cascades potentiates the antiproliferative functions of PML and helps mediate the proapoptotic effects of As(2)O(3).     

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.     

不同方案治疗急性早幼粒细胞白血病169例疗效分析

 目的 探讨不同治疗方案对急性早幼粒细胞白血病（APL）的治疗效果。方法 对不同治疗方案的APL疗效进行回础性分析比较。结果 采用全反式维A酸（ATRA）+三氧化二砷（As2O3）或者两者交替组获得CR中位时间分别为34,35.5 d,与单用ATRA的62 d比较,差异有统计学意义（P＜0.05）。ATRA+As2O3组或两者交替组,3年无病生存率分别为78 %和80 %,与单用ATRA组比较,差异有统计学意义（P＜0.05）。15例行造血干细胞移植（HSCT）者,仅2例复发,其余13例中位无病生存时间（DFS）为11.5年, 该13例PCR检测PML-RARα融合基因转阴性。结论 应用ATRA+As2O3或两者交替加化疗治疗APL获得CR时间明显缩短,而且3年无病生存率相对较高。缓解后6个月进行HSCT者,DFS可进一步延长。     

全反式维甲酸、三氧化二砷、化疗联合治疗急性早幼粒细胞白血病疗效观察

 目的　评估全反式维甲酸（ATRA）、三氧化二砷（As2O3）、化疗联合治疗初诊急性早幼粒细胞白血病（APL）的疗效和患者不良反应。方法　对40例采用ATRA、As2O3、化疗三联疗法治疗的APL患者的临床资料进行回顾性分析,观察其疗效及不良反应。结果　总体CR率92.5 %（37／40）,完全缓解所需中位时间27（22～61）d;白细胞≥10×109／L组CR率72.7 %（8／11）,白细胞＜10×109／L组CR率100 %（29／29）,差异有统计学意义（χ2＝8.550,P＝0.004）;治疗过程中无严重不良反应,仅1例发生维甲酸综合征。结论　ATRA、As2O3、化疗联合应用可作为APL患者的首选治疗方案。     

Arsenic trioxide induces apoptosis in HTLV-I infected T-cell lines and fresh adult T-cell leukemia cells through CD95 or tumor necrosis factor alpha receptor independent caspase activation

Arsenic trioxide (As2O3) has been reported to induce apoptosis in human T-cell leukemia virus type-I (HTLV-I) infected T-cell lines and fresh adult T-cell leukemia (ATL) cells and to induce G1 phase accumulation in HTLV-I infected T-cell lines. The present study aimed to clarify the pathway of As2O3-induced apoptosis in HTLV-I infected T-cell lines, MT-1 and MT-2, and fresh ATL cells separated from peripheral blood of patients with acute or chronic type ATL. Cells were treated up to 72 h at clinically tolerable concentrations of As2O3 (1-2 micromol/l) shown to be safe in patients with acute promyelocytic leukemia (APL). Activation of caspases 3, 8, and 9, loss of mitochondrial transmembrane potential and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP) were observed during As2O3 treatment. Furthermore, prior exposure to a broad-spectrum caspase inhibitor blocked As2O3-induced apoptosis but not G1 phase accumulation. While pre-treatment with a CD95 receptor-blocking antibody (Ab) or a TNF-alpha neutralizing Ab did not show such inhibitions in these cells. In conclusion, As2O3 induces apoptosis in HTLV-I infected T-cell lines and fresh ATL cells through CD95 or TNF-alpha receptor independent caspase activation.     

Pregnancy after treatment of secondary acute promyelocytic leukemia following Hodgkin's disease: a case report

The authors report a case of therapy-related acute promyelocytic leukemia (t-APL), with typical cytogenetic translocation t(15;17), which appeared following chemotherapy (ABVD), and radiotherapy for Hodgkin's disease (IIB). After treatment with all-trans retinoic acid (Vesanoid(R) 45 mg/m2 daily) complete remission of t-APL was achieved. Then only one course of chemotherapy '3+7' (doxorubicin 45 mg/m2 1-3 d, cytosar 200 mg/m2 1-7d) was applied and the patient interrupted further treatment in July 1994. Four years later she had a normal pregnancy and delivered a healthy female infant in December 1998.     

急性早幼粒细胞白血病合并弥散性血管内凝血183例

目的探讨急性早幼粒细胞白血病（APL）合并弥散性血管内凝血（DIC）的治疗效果。方法对全反式维甲酸（ATRA）＋三氧化二砷（As2O3）或两者交替、单用ATRA、造血干细胞移植（HSCT）3种治疗方案的疗效进行比较。结果采用ATRA＋As2O3或者两者交替组获得CR中位时间分别为34d、35．5d,单用ATRA获得CR中位时间为62d,差异有统计学意义（P〈0．05）。ATRA＋As2O3组或两者交替组,3年无病生存率分别为78％和80％,与单用ATRA组比较,差异有统计学意义（P〈0．05）,DIC纠正时间为16～18d,三种治疗方案差异无统计学意义。15例行HSCT者,仅2例复发,其余13例中位无病生存时间（DFS）为13．5年,该13例PCR检测PML-RAα仅融合基因阴性。结论应用ATRA＋As2O3或两者交替加成分血、抗纤溶纠正DIC及其化疗治疗APL获得CR时间明显缩短,而且3年无病生存率相对较高。缓解后6个月讲行HSCT者．DFS可讲一步延长。