Outcomes of treating high-risk acute promyelocytic leukemia with all-trans retinoic acid combined with arsenic trioxide

目的 观察全反式维甲酸(ATRA)与亚砷酸(ATO)联合化疗对急性早幼粒细胞白血病(APL)患者的疗效.方法 回顾性分析86例不同危险分级的初治APL患者的临床资料.根据治疗前白细胞和血小板数将APL患者分为低、中、高危三组.采用ATRA+ATO+蒽环类药诱导缓解,蒽环类药+阿糖胞苷巩固治疗,ATRA+ ATO+甲氨蝶呤(MTX)[部分加用6-巯基嘌呤(6-MP)]维持治疗.结果 治疗后,完全缓解(CR)率高达95.3％(82/86).中位随访37个月,高危组和中低危组无事件生存率及中枢神经系统累积复发率差异均无统计学意义(P＞0.05).维持治疗单用MTX者或MTX+6-MP者CR率均为100％.结论 APL患者尤其是高危患者可以从ATO +ATRA+化疗中受益;该方案作为初治APL的一线治疗方案优势明显.     

维甲酸联合三氧化二砷治疗初发APL的临床疗效观察

目的:探讨全反式维甲酸(ATRA)和三氧化二砷(As2O3)治疗初发急性早幼粒细胞白血病(APL)的疗效和不良反应。方法:对16例初治病人给予ATRA联合As2O3以诱导缓解,完全缓解(CR)后用DA(D:柔红霉素,A:阿糖胞苷)、HA(H:高三尖杉酯碱,A:阿糖胞苷)和中剂量Ara-C(阿糖胞苷)方案巩固化疗,维持治疗方案用ATRA、MTX(甲氨蝶呤)和As2O3依次序贯治疗。结果:16例患者均获CR,其中15例目前仍保持CR状态,持续CR的时间8～46个月,l例因为皮肤浸润复发而死亡。结论:ATRA联合As2O3诱导缓解治疗APL以及维持治疗阶段以ATRA、As2O3、MTX序贯治疗,不良反应无显著增加,不仅能提高CR率,缩短达到CR的时间,并可降低复发率,有助于延长APL患者的持续缓解时间及无病生存时间。     

单诱导及双诱导治疗急性早幼粒细胞白血病的临床观察

目的：观察全反式维甲酸（ATRA）联合三氧化二砷（ATO）双诱导与ATRA单诱导、ATO单诱导治疗急性早幼粒细胞白血病（APL）的临床疗效。方法：观察比较双诱导组（23例）、ATRA组（21例）和ATO组（20例）治疗APL的完全缓解（CR）率、早期病死率和不良反应发生情况。结果：双诱导组、ATRA组和ATO组的CR率分别为91．4％、81．0％和85．0％,早期病死率分别为4．3％、9．5％和5．0％,三组CR率及早期病死率无统计学差异（P〉0．05）。双诱导组患者治疗期间肝功能异常较为明显。结论：ATRA＋ATO双诱导方案治疗APL与ATRA或ATO单诱导方案相比,同样具有可靠的临床疗效,CR率提高,用药至缓解时间相对较短,早期病死率也较低。     

急性早幼粒细胞白血病缓解后治疗的随访观察

目的 :观察经全反式维甲酸 (ATRA)诱导治疗取得完全缓解 (CR)的急性早幼粒细胞性白血病 (APL)的缓解后治疗的疗效。方法 :34例经ATRA治疗取得CR的APL患者 ,随机分为二组进行缓解后治疗 ,化疗组 1 6例 ,CR后予HA、DA等方案定期巩固化疗 ,持续 3a～ 4a停药 ;化疗与ATRA交替治疗组 1 8例 ,CR后采用化疗与ATRA每月交替方案进行治疗 ,持续 3a～ 4a停药。结果 :随访 1 3个月～ 85个月 ,复发 8例 ,复发率 2 3 5 %,其中化疗组复发 5例 ,复发率 31 3%,化疗与ATRA交替治疗组复发 3例 ,复发率 1 6 7%,总生存例数 2 8例 ,总生存率 (OS) 82 4 %,其中化疗组生存 1 2例 ,OS 75 %,生存 3a以上 8例 ,化疗与ATRA交替治疗组生存 1 6例 ,OS 88.9%,生存 3a以上 1 1例 ,两组复发率及OS无显著性差异 (P >0 0 5 ) ,复发后 6例接受重新诱导治疗 ,4例取得第二次CR(CR2 ) ,CR2 率 6 6 7%。结论 :APLCR后予积极治疗 ,可减少患者复发率 ,延长患者生存期。CR后采用化疗与ATRA交替治疗方案 ,与单用化疗巩固治疗比较 ,复发率低、生存率高 ,但无统计学意义。APL复发后重新诱导治疗 ,仍可取得CR2 ,但CR2 期较短。     

急性早幼粒细胞白血病临床治疗观察

目的：研究ATRA（维甲酸）＋ATO（三氧化二砷）＋小剂量HHT（高三尖杉酯碱）治疗急性早幼粒细胞白血病（APL）的临床疗效。方法将20例APL患者分为研究组和对照组各10例,两组均进行诱导治疗和巩固治疗,研究组行ATRA＋ATO＋小剂量HHT治疗,行HA化疗,对照组行ATRA＋ATO＋DNR（柔红霉素）治疗,行DA化疗。比较两组疗效。结果研究组治疗费用（19209±4530）元及不良反应率60%均明显低于对照组（P＜0.05）,两组在治疗时间、细胞形态学CR及融合基因转阴率方面差异无统计学意义（P〉0.05）。结论 ATRA＋ATO＋小剂量HHT治疗APL临床疗效显著,且治疗费用低廉,不良反应少,是高效、安全、经济的治疗方法,值得重视。     

维甲酸与亚砷酸联合蒽环类抗生素治疗急性早幼粒细胞白血病

目的 观察以全反式维甲酸（ATRA）、亚砷酸（As₂O₃）联合蒽环类（ATC）抗生素为主的方案治疗初治急性早幼粒细胞白血病（APL）的疗效与不良反应。方法 对初治APL患者以ATRA和As₂O₃双诱导,白细胞（WBC）≥15.0×109•L^-1时,加用DA方案化疗。达完全缓解（CR）后,以ATC抗生素为主的方案巩固化疗6个疗程,以后以化疗、ATRA、As2O3交替序贯维持治疗共2 a,以ATC抗生素联合阿糖胞苷（Ara-C）为主要化疗方案。观察维甲酸综合征、心脏毒性等不良反应。16例患者进行PML/RARα融合基因监测。结果 32例初治APL患者中,除3例早期死亡外,其余29例诱导治疗后均达CR,经巩固、维持治疗,此29例患者至今均为持续完全缓解（CCR）状态,其中CCR＞ 5 a 4例,＞3 a 8例。无患者出现严重或不可逆的不良反应。初诊时接受PML/RARα融合基因检测的16例患者,治疗前均为阳性,巩固治疗结束时均转为阴性,在以后监测中无一例转阳。结论 ATRA、As2O3双诱导联合ATC抗生素为主的方案治疗初治APL,疗效可靠,不良反应小。     

全反式维甲酸、三氧化二砷联合化疗治疗初治急性早幼粒细胞性白血病30例疗效观察

目的探讨全反式维甲酸、三氧化二砷联合HAE化疗治疗初治急性早幼粒细胞性自血病的疗效。方法应用ATRA和As2O3进行双诱导治疗,同时联合HAE方案化疗,直至骨髓形态学缓解。完全缓解（CR）后给予3—5个疗程HAE方案巩固治疗,再给予应用ATRA、As2O3HAE方案的序贯治疗,维持治疗2年。观察患者治疗后的缓解率及PML-RARα融合基因阴性率的变化。结果30例APL患者中29例达CR,CR率96．6％,达CR时间21-42d;3个疗程HAE方案巩固化疗后PML-RARα融合基因转阴患者29例,转阴率为96．6％;随访2年所有患者PML-RARα融合基因持续转阴,处于CCR状态。结论全反式维甲酸、三氧化二砷联合HAE方案的序贯治疗对APL疗效可靠。     

18例急性早幼粒细胞白血病序贯治疗临床观察

目的观察亚砷酸(AS2O3),全反式维甲酸(ATRA)联合化疗方案序贯治疗成人急性早幼粒细胞白血病(APL)的疗效。方法 18例APL患者,采用ATRA及亚砷酸(出现高白细胞淤积症时,给予柔红霉素)联合进行诱导,巩固及维持治疗,并定期检测PML_RARa融合基因。结果完全缓解(CR)率为87.5%,达CR中位时间为26d,并于巩固治疗期间采用AS2O3与ATRA及蒽环类药物交替进行,并于以维持治疗,总疗程为3年。目前已12例停药,13例患者每3个月检测PML-RARa融合基因均为(-),3例处于维持治疗阶段。仅2例患者未达CR因脑出血死亡。结论 AS2O3与ATRA联合化疗治疗成人APL的疗效较满意。     

全反式维甲酸和三氧化二砷治疗初治急性早幼粒细胞白血病的疗效观察

目的观察全反式维甲酸(ATRA)联合三氧化二砷(As2O3)治疗初治急性早幼粒细胞白血病(APL)的疗效。方法对应用ATRA和As2O3联合诱导治疗的20例APL患者的完全缓解(CR)率、达CR所需时间和不良反应进行观察,并与单独应用ATRA组30例进行比较。联合用药组治疗方法为ATRA 25mg/(m2.d),0.1%As2O310ml/d直至CR。结果联合用药组与单独应用ATRA组相比,CR率差异无统计学意义(分别为95%、86.7%,均P>0.05);联合用药组获得CR所需的时间短于单独用药组(平均时间分别为24d、45d,均P<0.05),早期死亡率较单独用药组差异无统计学意义(分别为5%、13.3%,均P>0.05);与单独用药组相比,联合用药组的不良反应并未增加。结论联合用药诱导初发APL缓解的疗效优于单用药组,不良反应少,是一种值得推广应用的方案。     

三氧化二砷治疗急性早幼粒细胞白血病的新认识

三氧化二砷(arsenic trioxide,As2O3,ATO)为中药砒霜的主要成分.1992年哈尔滨医科大学第一附属医院开始单用三氧化二砷(ATO)治疗急性早幼粒细胞白血病(APL)取得良好效果以来,越来越多的临床资料证实ATO不仅可使初治APL完全缓解率达70%,对全反式维甲酸(ATRA)和化疗耐药、复发病人的CR率高达70%～90%[1],而且不引起严重的出血和骨髓抑制.目前ATO应用治疗MM、CML、CLL、MDS、AML、ALL和淋巴瘤等也都取得一定进展.本文就ATO治疗APL的几点新认识作一探讨.     

亚砷酸持续输注联合小剂量维A酸治疗急性早幼粒细胞性白血病临床观察

目的 探讨亚砷酸（ATO）持续输注联合小剂量维A酸（LD—ATRA）治疗急性早幼粒细胞白血病（APL）的有效性及安全性。方法6例初治APL采用ATO持续输注联合LD—ATRA方法治疗,ATO按10mg·d^-1加入5％葡萄糖500ml稀释,持续输注18h;ATRA按15mg·d^-1,连续口服1周：观察疗效、外周WBC、出凝血指标及不良反应？结果6例均达到CR,获CR时间为（25．3±1．03）d,无早期死亡与CNS—L发生。所有病例在治疗1周后,出凝血指标均恢复正常。外周血WBC均有增多,仅1例WBC超过30×10^9／L。不良反应轻,主要为Ⅰ～Ⅱ度肝功能损害,Ⅰ度恶心呕吐。结论ATO持续输注联合LD—ATRA方法治疗APL,具有疗效好,不良反应轻等优点,值得进一步研究.     

Arsenic trioxide in hematological malignancies: the new discovery of an ancient drug

Currently, Arsenic Trioxide (ATO) is considered the treatment of choice for patients with relapsed acute promyelocytic leukemia (APL). Recently, a durable remission with minimal toxicity by single agent ATO or ATO + ATRA in newly diagnosed APL was reported by different groups. These regimens have minimal toxicity and can be administered on an outpatient basis after remission induction, thus they could become a real, less toxic and more economic option to ATRA + anthracyclines in particular in low risk APL, or in patients that cannot undergo chemotherapy because of age or comorbid conditions and in patients that refuse chemotherapy. Significantly, these therapies are a successful attempt to cure a tumoral disease without chemotherapy. The results of clinical trials of ATO administration as single agent in multiple myeloma (MM) and myelodisplastic syndromes (MDS) were encouraging and showed clinical effects but they were not close to APL success. On the contrary, results of clinical trials to treat non-APL acute myeloid leukemia (AML) were disappointing. We suggest that a combination therapy with drugs targeting specific pro-survival molecules or capable to enhance pro-apoptotic pathways may lead to an improvement of ATO efficacy against hematological malignancies, in particular AML. Our pre-clinical studies showed that ATO is capable to induce cell death in acute leukemia cells but the apoptotic function is limited since it can induce also a mechanism of cell defense by activating pro-survival molecules such as MEK-ERK, Bcl-xL, Bcl-2. By combining ATO with specific MEK inhibitors, we demonstrated that the block of MEK-ERK phosphorylation, the induction of Bad de-phosphorylation, and activation of p53AIP1 apoptotic pathway interrupt the pro-survival mechanisms of ATO and kill the leukemic cells by apoptotic synergism. Our results provide an experimental basis for combined or sequential treatment with MEK inhibitors and ATO in AML. The renaissance of ATO as a drug in moderne medicine may be considered, together with ATRA success, a victory of empirical analysis, that had (and has) great impact on Chinese culture.     

Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease

INTRODUCTION: Acute promyelocytic leukemia (APL), the most rapidly fatal leukemia only two decades ago, has been converted into the most frequently curable leukemia by the advent of all-trans retinoic acid (ATRA) and its combination with anthracycline-based chemotherapy. More recently, arsenic trioxide (ATO) has been shown to be the most effective single agent in this disease and has been approved for the treatment of relapsed patients both in the United States and Europe. Moreover, ATO has been included in the design of several front-line studies, with the aim to reduce therapy-related toxicity while maintaining the potential of cure. AREAS COVERED: First, this review briefly discusses the mechanisms of action and the toxicity profile of ATO. Furthermore, the reported experience on the use of ATO as single agent or in combinatorial schemes both in relapsed and in newly diagnosed patients with APL is critically reviewed. Finally, the use of this agent in special subsets of patients unfit to receive conventional chemotherapy is discussed, along with its potential role in maintenance therapy. EXPERT OPINION: While the role of ATO as single agent or in combination with ATRA is well established and recommended by the European LeukemiaNet guidelines as a first option for relapsed patients, the role of the drug in newly diagnosed patients is still uncertain and based only on evidence levels mostly originating from non-randomized trials. The results of ongoing randomized studies should better define the role of ATO in front-line therapy.     

A practical strategy to subcutaneous administered in-situ gelling co-delivery system of arsenic and retinoic acid for the treatment of acute promyelocytic leukemia

Arsenic trioxide (ATO) combined with all trans retinoic acid (ATRA) is the first choice for the treatment of low and medium risk acute promyelocytic leukemia (APL). Clinical studies reported that the combination of ATO and ATRA could achieve a significant curative effect. However, the retinoic acid syndrome, serious drug resistance and the short half-life in vivo which lead to frequent and large dose administration limit the application of ATRA. In addition, the preparations of arsenic are conventional injections and tablets in clinic, which has poor patients' compliance caused by frequent long-term administration and serious side effects. In order to overcome the above limitations, a phospholipid phase separation gel (PPSG) loaded with ATO and ATRA was developed. ATO+ATRA-PPSG (AAP), as a biodegradable sustained-release delivery system, was the first achievement of co-delivery of hydrophilic ATO and lipophilic ATRA with high drug loading which is the main problem in the application of nano preparation. The prepared PPSG displayed high safety and biocompatibility. The drug in PPSG was released slowly and continuously in vivo and in vitro for up to 10 d, which could reduce the side effects caused by the fluctuation of blood drug concentration and solve the problem of the long treatment cycle and frequent administration. In vivo pharmacokinetics depicted that PPSG could improve the bioavailability, decrease the peak concentration, and prolong the t_1/2 of ATO and ATRA. Particularly, AAP significantly inhibited the tumor volume, extended the survival period of tumor-bearing mice, and promoted the differentiation of APL cells into normal cells. Therefore, ATO+ATRA-PPSG not only could co-load hydrophilic ATO and lipophilic ATRA according to the clinical dosage, but also possessed the sustained-release and long-acting treatment effect which was expected to reduce administration time and ameliorate compliance of patients. Thus, it had great potential for clinical transformation and application.     

三氧化二砷联合全反式维甲酸治疗初发急性早幼粒细胞白血病临床分析

目的三氧化二砷联合全反式维甲酸治疗初发急性早幼粒细胞白血病的临床疗效(即完全缓解率和融合基因PML-RARα转阴情况)及不良反应。方法 46例初发APL患者随机分成研究组予As2O3联合ATRA治疗24例,对照组仅予ATRA治疗22例,均治疗直至CR。根据外周血白细胞计数、维甲酸综合征以及肝功能变化调整两药物的剂量。观察CR率、获得CR和不良反应。结果 46例初发APL患者,ATRA联合As2O3组24例患者中,CR23例,1例未缓解,缓解率95.8%,ATRA单药组22例患者中,CR17例,5例未缓解,缓解率77.3%。两组间CR率差异有统计学意义。65.0%患者在治疗开始后出现白细胞升高,63.8%出现肝功能异常,多在减量或停用后1周内恢复。所有患者融合基因PML-RARα初发时均为阳性,CR时9.8%转阴。结论 As2O3联合ATRA治疗初发APL疗效好,不良反应少。长期完全缓解时间需要进一步观察。     

三氧化二砷治疗急性早幼粒细胞白血病疗效观察

目的 :观察三氧化二砷 (As2 O3)治疗急性早幼粒细胞白血病的完全缓解率、高白细胞发生率、肝功损害及融合基因转阴率 ,并与维甲酸 (ATRA )的治疗情况进行比较。方法 :随机分为两组 ,As2 O3组 17例 ,ATRA组 2 1例 ,分别选用 0 .1% As2 O310 m L/ d,静脉滴注 ;ATRA2 5 mg· m- 2 · d- 1 ,分 3次服用。分别观察两组的完全缓解率 (CR)、不良反应以及融合基因转阴率。结果 :As2 O3组 15 / 17例 (88.2 % )获 CR,获得 CR时间为 (2 8.1± 4 .6 ) d;ATRA组 19/2 1例 (90 .4 % )获 CR,获得 CR时间为 (39.4± 8.6 ) d,两组之间 CR无明显差别 ,但 As2 O3组获得 CR时间明显缩短。高白细胞发生率 As2 O3组 10 / 15例 (6 6 .7% ) ,ATRA组 18/ 19例 (94 .7% ) ,P<0 .0 5。肝功能异常 ,As2 O3组 11/ 17例(6 4 .7% ) ,ATRA组 13/ 19例 (6 8.4 % ) ,P>0 .0 5。所有患者治疗前 PML- RARα融合基因阳性。 As2 O3组 CR时 ,2 /14例 (14 % )转阴 ,ATRA组 2 / 19例 (10 .5 % )转阴 ,P<0 .0 5。CR后 1a,As2 O3组 5 / 8例 (6 2 .5 % )转阴 ,ATRA组 4 /11例 (36 .3% )转阴 ,P<0 .0 5。As2 O3组 15例获 CR者 ,无 1例复发。ATRA组 19例获 CR者 ,4例 (2 1% )复发。结论 :与 ATRA相比 As2 O3获得 CR时间缩短 ,高白细胞发生率低 ,CR及 CR     

Arsenic trioxide for management of acute promyelocytic leukemia: current evidence on its role in front-line therapy and recurrent disease

Introduction: Acute promyelocytic leukemia (APL), the most rapidly fatal leukemia only two decades ago, has been converted into the most frequently curable leukemia by the advent of all-trans retinoic acid (ATRA) and its combination with anthracycline-based chemotherapy. More recently, arsenic trioxide (ATO) has been shown to be the most effective single agent in this disease and has been approved for the treatment of relapsed patients both in the United States and Europe. Moreover, ATO has been included in the design of several front-line studies, with the aim to reduce therapy-related toxicity while maintaining the potential of cure.

Areas covered: First, this review briefly discusses the mechanisms of action and the toxicity profile of ATO. Furthermore, the reported experience on the use of ATO as single agent or in combinatorial schemes both in relapsed and in newly diagnosed patients with APL is critically reviewed. Finally, the use of this agent in special subsets of patients unfit to receive conventional chemotherapy is discussed, along with its potential role in maintenance therapy.

Expert opinion: While the role of ATO as single agent or in combination with ATRA is well established and recommended by the European LeukemiaNet guidelines as a first option for relapsed patients, the role of the drug in newly diagnosed patients is still uncertain and based only on evidence levels mostly originating from non-randomized trials. The results of ongoing randomized studies should better define the role of ATO in front-line therapy.