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。     

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观察

 目的　观察全反式维甲酸（ATRA）联合三氧化二砷（As2O3）治疗初诊急性早幼粒细胞白血病（APL）的疗效及不良反应。方法　对ATRA每天25 mg／m2联合As2O3 10 mg／d（联合组）治疗的35例APL患者达完全缓解（CR）时间、CR率、早期病死率及不良反应进行观察,并与单用As2O3 10 mg／d（单药组）治疗的33例进行比较。结果　联合组CR率为94.3 %（33／35）,与单药组[90.9 %（30／33）]比较差异无统计学意义（P＞0.05）;联合组获得CR时间为26.1 d,短于单药组的30.5 d,差异有统计学意义（P＜0.05）;联合组与单药组APL分化综合征及不良反应发生率、早期病死率比较,差异均无统计学意义（均P＞0.05）;高WBC组比中、低WBC组CR率低,死亡率高,差异均有统计学意义（均P＜0.05）,低WBC组与中WBC组差异无统计学意义（P＞0.05）。结论　As2O3联合ATRA较单用As2O3治疗初诊APL获得CR时间短,WBC＞10×109／L为预后不良的因素,APL分化综合征应尽早发现,及时处理。     

全反式维甲酸联合三氧化二砷治疗急性早幼粒细胞白血病疗效分析

 目的　比较全反式维甲酸（ATRA）联合三氧化二砷（As2O3）双诱导与ATRA单药诱导治疗初发急性早幼粒细胞白血病（APL）的临床疗效。方法　我院收治的APL患者51例,分别采用ATRA联合As2O3双诱导、ATRA单药诱导治疗方案治疗4周以上,比较两组患者的完全缓解（CR）率和达CR的时间。结果　ATRA联合As2O3双诱导组和ATRA单药诱导组的CR率分别为83.3 %（20／24）和96.3 %（26／27）,差异无统计学意义（χ2＝1.44,P＞0.05）。ATRA联合As2O3双诱导组达到CR的时间[（36.8±6.12）d]明显短于ATRA单药诱导组的时间[（45.1±8.14）d],差异有统计学意义（t＝4.075,P＜0.05）,且不良反应少,更易于控制。结论　ATRA联合As2O3双诱导方案能缩短APL患者达到CR的时间,较ATRA单药诱导治疗具有更好疗效。     

全反式维甲酸联合亚砷酸治疗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)治疗急性早幼粒细胞白血病(APL)患者的疗效。方法:应用ATRA联合As2O3治疗初治APL共39例,ATRA 40mg/d分2次口服;As2O30.1%注射液10ml加入0.9%氯化钠溶液250ml静脉滴注,持续4-6h,1次/d。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ATRA和As2O3的剂量。缓解后巩固治疗:DA(柔红霉素+阿糖胞苷)方案或HA(高三尖杉酯碱+阿糖胞苷)方案交替治疗4-6个疗程,ATRA与As2O3交替治疗。结果:39例初治患者中,仅2例因剧烈头痛(排除脑出血)退出,其余37例均达到CR,CR率94.87%(37/39),取得CR的平均时间是(26.9±4.3)d,均无早期复发并持续完全缓解,联合用药的不良反应患者均能耐受,毒副作用未增加。结论:ATRA联合As2O3治疗初治APL具有疗效好,达CR时间短,不良反应少,无病生存时间长的优点。     

小剂量三氧化二砷、维A酸双诱导并化疗序贯治疗急性早幼粒细胞白血病远期疗效观察

 目的 探讨三氧化二砷（As2O3）联合全反式维A酸（ATRA）双诱导治疗急性早幼粒细胞白血病（APL）的近期疗效及化疗序贯治疗的远期疗效观察。方法 对51例APL患者应用As2O3联合ATRA双诱导治疗;对其中47例CR患者采用DA,HA,MDAra-C,As2O3序贯巩固治疗。结果 51例APL患者47例获CR,CR率92.2 %。47例CR患者中,42例生存至今,生存时间8 ~ 83个月,中位生存时间41.2个月。 结论 As2O3联合ATRA诱导治疗APL完全缓解率高,毒副作用小,结合化疗及As2O3序贯治疗,复发率低,长生存率高。     

亚砷酸、全反式维甲酸联合化疗治疗儿童急性早幼粒细胞白血病八例

 目的　观察亚砷酸（As2O3）、全反式维甲酸（ATRA）联合化疗治疗儿童急性早幼粒细胞白血病（APL）的疗效。方法　8例APL患儿采用ATRA及柔红霉素（DNR）联合进行诱导、巩固及维持治疗,并定期检测PML-RARα融合基因。结果　完全缓解（CR）率为87.5 ％,达CR中位时间为26 d,并于巩固治疗期间采用As2O3与ATRA及蒽环类药物交替进行,并予以维持治疗,总疗程为3.5年。目前1例已停药,6例处于维持治疗阶段。7例患儿每3个月检测PML-RARα融合基因均为（-）,仅1例患儿未达CR死亡。结论　As2O3与ATRA联合化疗治疗儿童APL的疗效较满意 。     

全反式维甲酸联合化疗治疗小儿急性早幼粒细胞白血病

目的观察全反式维甲酸（ATRA）联合化疗治疗小儿急性早幼粒细胞白血病（APL）的疗效。方法22例初治患儿用ATRA诱导治疗;当患儿获完全缓解（CR）后,给予DA方案或IDA方案或HA方案或AA方案巩固治疗3个疗程;以后再用ATRA、化疗交替巩固治疗36个月。结果2例在诱导治疗前死于弥散性血管内凝血（DIC）、颅内出血;22例获CR,CR率100％（20／20）。1、3、5年无病生存（DFS）率分别为100％（20／20）、93．3％（14／15）、84．7％（11／13）。ATRA常见毒副作用依次为皮肤和口唇干燥、头痛、恶心、呕吐、肝功能损害及维甲酸综合征。结论ATRA联合化疗治疗小儿APLCR率高、远期疗效好;在诱导治疗前,DIC、颅内出血仍是APL患儿死亡的主要原因;ATRA毒副作用可耐受。     

全反式维A酸联合三氧化二砷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A酸（ATRA）与三氧化二砷（As2O3）联合治疗急性早幼粒细胞白血病（APL）的疗效和毒副作用。方法 As2O3联合ATRA治疗初治和复发APL患者12例,As2O3 0.1 %注射液10 ml加入5 %葡萄糖溶液500 ml静脉滴注,持续4 ~ 5 h,1次／d, 28 d为一疗程。ATRA 25 mg·m-2·d-1,分3次口服,根据外周血白细胞计数、 维A酸综合征以及肝功能变化调整As2O3和ATRA的剂量。结果 11例均达完全缓解（CR）,获得CR的平均时间为（28.2±4.5）d,未发现严重毒副反应。结论 As2O3联合ATRA治疗初发及复发APL患者疗效好, 能缩短CR的时间。     

全反式维甲酸联合亚砷酸诱导治疗急性早幼粒细胞白血病凝血及纤溶指标改变的初步研究

目的探讨全反式维甲酸（ATRA）联合亚砷酸（As2O3）诱导治疗急性早幼粒细胞白血病（APL）凝血及纤溶指标的变化。方法治疗组18例，采用ATRA 20～30mg／d，分3次口服，直至完全缓解，0．1％As2O3 10ml加入5％葡萄糖注射液500ml静脉滴注，1次／d，连续28d。对照组10例，单用ATRA 45～60mg／d，分3次口服，直至完全缓解。结果治疗组CR17例，对照组CR8例，治疗组CR率高于对照组（P〈0.05）；对照组出现不同程度的口干、维甲酸综合征等，有2例被迫停药，治疗组上述反应轻，出现肝功能损害，需加强保肝治疗；治疗组纤维蛋白原含量（Fbg）、D-二聚体（D—dimer）恢复时间分别为7、21d，对照组Fbg、D—dimer恢复时间分别为14、28d。结论ATRA联合As2O3诱导治疗APL CR率高，副作用小，凝血、纤溶指标恢复快，D—dimer作为早期诊断及观察治疗变化意义重大。     

全反式维A酸+三氧化二砷联合诱导分化治疗急性早幼粒细胞白血病

 目的 研究联合应用全反式维A酸（ATRA）+三氧化二砷（As2O3）诱导分化治疗急性早幼粒细胞白血病（APL）的疗效及毒副作用。方法 治疗组共46例患者,均给予ATRA+As2O3诱导分化治疗,对照组30例给予ATRA诱导分化治疗,分别判别疗效及毒副作用。结果 治疗组及对照组获得CR时间分别为（26.2±4.0）d,（49.5±8.5）d,差异有统计学意义（P＜0.05）,而两组毒副作用发生率差异无统计学意义（P＞0.05）。结论 联合应用ATRA+ As2O3诱导分化治疗APL获得CR时间明显缩短,而且毒副作用无明显增加。     

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.     

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.     

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.     

Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death.

Acute promyelocytic leukemia (APL) is efficiently treated with a cell differentiation inducer, all-trans retinoic acid (ATRA). However, a significant percentage of patients still develop resistance to this treatment. Recently, arsenic trioxide (As2O3), alone or in combination with ATRA, has been identified as an alternative therapy in patients with both ATRA-sensitive and ATRA-resistant APL. Previous investigations restricted the mechanism of this synergism to the modulation and/or degradation of PML-RARalpha oncoprotein through distinct pathways. In this study, using several ATRA maturation-resistant APL cell lines, we demonstrate in vitro that the success of ATRA/As2O3 treatment in APL pathology can be explained, at least in part, by a synergistic effect of these two drugs in triggering downregulation of telomerase efficient enough to cause telomere shortening and subsequent cell death. Such long-term low-dose combinatorial therapy strategies, developed also to avoid acute side effects, reinforce the notion that the antitelomerase strategy, based on a combination of active agents, should now be considered and evaluated not only in APL but also in other malignancies.