亚砷酸联合全反式维甲酸治疗急性早幼粒细胞白血病16例疗效观察

目的:观察亚砷酸(As2O3)与全反式维甲酸(ATRA)联合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:As2O3联合ATRA治疗初治APL患者16例,As2O30.1%注射液10ml加入5%葡萄糖溶液500ml静脉点滴,持续4h,1次/d;ATRA40-60mg/d,分2次口服,观察完全缓解(CR)率,获得CR所需时间、不良反应.结果:15例患者获得CR,CR率93.8%,获得缓解时间(27.3±3.6)d,没有发现明显的不良反应.结论:As2O3,联合ATRA治疗初发APL患者疗效好,能缩短CR的时间,长期CR时间需要进一步观察.     

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 。     

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50例疗效观察

 目的　观察三氧化二砷（ATO）联合全反式维甲酸（ATRA）治疗初发急性早幼粒细胞白血病（APL）的疗效。方法　98例初发APL患者分为对照组和治疗组,对照组48例,治疗组50例。对照组采用常规ATRA+DA双诱导方案治疗;治疗组采用ATRA每天25 mg／m2,ATO每天0.15 mg／kg（ATRA后第10天开始）联合治疗,直至完全缓解（CR）,CR后接受ATO和ATRA联合巩固治疗。比较两组CR率、PML-RARα融合基因转阴时间及5年无病生存率。结果　对照组和治疗组CR率分别为89.5 %（43／48）和90.0 %（45／50）,获得CR时间分别为（30.0±5.1）d和（28.1±4.4）d,两组CR率（χ2＝-0.068,P＝0.946）及获得CR时间（t＝1.757,P＝0.083）相比差异均无统计学意义。在所有获得CR的患者中,3例分别在CR后第276、385和394天复发。所有患者发病时PML-RARα融合基因均阳性,对照组和治疗组CR时分别有25.0 %（5／20）和29.4 %（5／17）转阴,巩固后分别有92.5 %（37／40）和97.6 %（41／42）转阴。对照组和治疗组5年无病生存率分别为（85.3±5.9）%和（87.6±5.6）%,差异无统计学意义（χ2＝0.232,P＝0.630）。结论　ATO联合ATRA能有效治疗初发APL患者,可以作为常规化疗方案外的另一选择。     

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。     

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.     

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.     

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.     

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.     

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.     

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.     

An efficient therapeutic approach to patients with acute promyelocytic leukemia using a combination of arsenic trioxide with low-dose all-trans retinoic acid

The use of arsenic trioxide (As2O3, ATO) combined with all-trans retinoic acid (ATRA) has recently been reported to induce remission in patients with acute promyelocytic leukemia (APL). However, its efficiency remains inconclusive mainly due to the small number of the available cases. In this study, therefore, we present a clinical study using a combination of ATO with low-dose ATRA (LD-ATRA) to treat 108 APL patients (80 newly diagnosed patients, 28 relapsed patients). Therapeutic outcomes using the ATO/LD-ATRA approach were compared with those of APL patients treated either with ATO alone (65 patients) or ATRA alone (51 patients). The results showed that the ATO/LD-ATRA approach provided significantly better therapeutic outcomes as compared to either ATO or ATRA alone, as evidenced by lower mortality, a higher CR rate and a reduced period to CR. In addition, the toxic side-effects have been no worse with the combined ATO/LD-ATRA treatment than with either ATO or ATRO alone and in some cases have been reduced. These data suggest that the ATO/LD-ATRA regimen is superior to either regimen given alone to patients with APL.     

Upfront maintenance therapy with arsenic trioxide in acute promyelocytic leukemia provides no benefit for non‐t(15;17) subtype

Aims: The optimal maintenance therapy for patients with acute promyelocytic leukemia (APL) who achieved complete remission (CR) and complete consolidation chemotherapy is still controversial. Whether the use of arsenic trioxide (ATO) alone or along with all‐trans retinoic acid (ATRA) improves overall survival (OS) or disease‐free survival (DFS) is still debated. Methods: A retrospective reivew was conducted of 20 patients diagnosed with APL according to the French – American – British system. After achieving CR and receiving consolidation chemotherapy, nine patients were given maintenance therapy for 1 year (ATRA 45 mg/m²/day p.o., mercaptopurine 60 mg/m²/day p.o. and ATO 0.15 mg/kg/day × 5 days/week for six cycles in five patients; ATRA 45 mg/m²/d p.o. alternating with ATO 0.15 mg/kg/day × 5 days/week in 1 patient; ATRA only in three patients). Results: In all patients the rates of CR, 3‐year OS and 5‐year OS were 75, 71 and 57%, respectively. For patients treated with ATO maintenance, the rates were 100% for both 5‐year OS and 5‐year DFS. Four of six patients on ATO maintenance had grade 1 or grade 2 adverse events. Excluding the two patients who died from intracerebral hemorrhage within 4 days after diagnosis, these rates were 85, 82 and 78%, respectively. Conclusion: Upfront ATO maintenance therapy for one year is safe and appears to be effective, with the benefits restricted to patients with APL with t(15;17) translocation. Larger studies will be required to confirm this observation.     

三氧化二砷治疗初治急性早幼粒细胞白血病疗效分析

 目的　分析以三氧化二砷（ATO）为基础的诱导和维持治疗方案治疗初发急性早幼粒细胞白血病（APL）的长期疗效。方法　回顾性分析62例初诊成年APL患者诱导缓解治疗和缓解后巩固维持治疗经过,并作5、7年随访分析。结果　诱导治疗阶段,ATO+全反式维甲酸（ATRA）双药联合化疗组与ATRA联合化疗组完全缓解（CR）率差异无统计学意义,但前者达到CR时间明显缩短。诱导治疗后PML-RARα融合基因转阴率两组分别为86.2 %、56.3 %,差异有统计学意义（P＜0.05）。巩固维持治疗阶段,ATO序贯维持组和化疗序贯维持组5年总生存（OS）率分别为（94.4±5.4）%和（45.5±10.2）%,7年OS率分别为（52.5±23.7）%和（27.3±9.3）%;两组5年无病生存（DFS）率分别为（94.7±5.5）%和（41.3±10.1）%,7年DFS率分别为（52.6±23.7）%和（27.5±9.4）%,两组差异有统计学意义（P＜0.05）。并且,ATO序贯维持组复发率（14.7 %）低于化疗序贯维持组（37.0 %）,差异有统计学意义（P＜0.05）。结论　以ATO联合ATRA、化疗的诱导化疗方案可缩短诱导化疗时间,提高PML-RARα融合基因转阴率,而且,包含ATO的序贯维持治疗明显改善APL患者的长期生存,减少复发,安全性高,患者耐受性好。     

Combination therapy with arsenic trioxide, all-trans retinoic acid, and gemtuzumab ozogamicin in recurrent acute promyelocytic leukemia

BACKGROUND: From 20% to 30% of patients with acute promyelocytic leukemia (APL) who are treated with all-trans retinoic acid (ATRA) develop recurrent disease. Arsenic trioxide (ATO) is an effective agent for the salvage of patients with recurrent APL, and gemtuzumab ozogamicin (GO) has shown activity in patients with APL. METHODS: The authors investigated the efficacy of a combination of ATO, ATRA, and GO in 8 patients with APL in first recurrence (7 patients with hematologic recurrences and 1 patient with a molecular recurrence). All patients had received previous treatment with ATRA either alone or in combination with other agents. Patients received ATO 0.15 mg/kg intravenously until they achieved a bone marrow complete remission (CR). Once in CR, patients received consolidation with ATO, ATRA, and GO for 10 months. Patients then received maintenance with idarubicin, ATRA, 6-marcaptopurine, and oral methotrexate for 11 months. RESULTS: All 7 patients who had hematologic recurrences achieved CR after a median of 39 days (range, 21-56 days). After a median follow-up of >/=36 months (range, 4-55 months), 6 patients remained alive in CR, and 2 patients died in CR. Six of 8 patients remained in second CR that was longer than their first CR. All 7 evaluable patients achieved molecular remission. There were no grade 3 or 4 extramedullary toxicities. Two patients died, 1 secondary to a complication of metastatic lung adenocarcinoma, and the other of sepsis. CONCLUSIONS: The combination of ATO, ATRA, and GO was effective and may achieve durable remissions in patients with APL in first recurrence. It should be considered as an effective alternative to allogeneic or autologous transplantation.     

Granulocyte colony-stimulating factor potentiates differentiation induction by all-trans retinoic acid and arsenic trioxide and enhances arsenic uptake in the acute promyelocytic leukemia cell line HT93A

The effects of arsenic trioxide (ATO), all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF), alone or in combination, were investigated by focusing on differentiation, growth inhibition and arsenic uptake in the acute promyelocytic leukemia (APL) cell line HT93A. ATO induced differentiation at low concentrations (0.125?μM) and apoptosis at high concentrations (1-2?μM). Furthermore, ATRA induced greater differentiation than ATO. No synergistic effect of ATRA and ATO was found on differentiation. G-CSF promoted differentiation-inducing activities of both ATO and ATRA. The combination of ATRA and G-CSF showed maximum differentiation and ATO addition was not beneficial. Addition of 1?μM ATRA and/or 50?ng/ml G-CSF to ATO did not affect apoptosis compared to ATO treatment alone. ATRA induced expression of aquaporin-9 (AQP9), a transmembrane transporter recognized as a major pathway of arsenic uptake, in a time- and dose-dependent manner. However, treatment with 1?μM ATRA decreased arsenic uptake by 43.7% compared to control subject. Although G-CSF addition did not enhance AQP9 expression in the cells, the reduced arsenic uptake was recovered to the same level as that in controls. ATRA decreased cell viability and addition of 50?ng/ml G-CSF to ATRA significantly increased the number of viable cells compared with that in ATRA alone treated cells. G-CSF not only promotes differentiation-inducing activities of both ATRA and ATO, but also makes APL cells vulnerable to increased arsenic uptake. These observations provide new insights into combination therapy using these three agents for the treatment of APL.     

The efficacy and safety of arsenic trioxide with or without all-trans retinoic acid for the treatment of acute promyelocytic leukemia: a meta-analysis

Arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) could induce apoptosis and differentiation in acute promyelocytic leukemia (APL) cells, respectively, thus the possibility of synergism between them was raised. This meta-analysis assessed the effectiveness and safety of ATO combined with ATRA in the treatment of APL. Compared with ATO alone, induction therapy with ATO/ATRA significantly increased the complete remission (CR) rate (RR: 1.08, 95% CI: 1.00-1.17, P = 0.04), shortened the time to achieve CR (WMD: −6.51, 95% CI: −11.32 to −1.70, P = 0.008), and improved the molecular remission rate after consolidation therapy (RR: 1.74, 95% CI: 1.14-2.66, P = 0.01) and the 1-year disease-free survival rate (RR: 1.22, 95% CI: 1.00-1.50, P = 0.05). There were no statistically significant differences between two treatments in terms of early death and main adverse events. These results suggested that ATO/ATRA could synergistically improve the overall outcome of newly diagnosed and relapsed APL patients, supporting the use of ATO/ATRA as an effective treatment for all APL patients previously untreated with ATO.     

Src family kinase inhibitor PP2 enhances differentiation of acute promyelocytic leukemia cell line induced by combination of all-trans-retinoic acid and arsenic trioxide

An all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) combination yields high-quality remission and survival in newly-diagnosed acute promyelocytic leukemia (APL). For subsequent similar data, NCCN guidelines indicate that ATRA plus ATO is one of the recommended regimens for the treatment of patients with APL. We demonstrated SFK (Src family kinase) inhibitor PP2-enhanced APL cell differentiation when combined with either ATRA or ATO with difference in activation of RA-induced genes. In this study, we investigated whether SFK inhibitor PP2 could enhance the differentiation of NB4 APL cells when combined with ATRA and ATO and the changes in the expression of intercellular adhesion molecule-1 (ICAM-1) derived from the retinoic acid receptor (RAR) target gene.     

Combination therapy with arsenic trioxide, all-trans retinoic acid, and chemotherapy in acute promyelocytic leukemia patients with various relapse risks

To improve the recovery rate of high-risk patients with acute promyelocytic leukemia (APL), we used all-trans retinoic acid (ATRA)/arsenic trioxide (ATO)/daunorubicin combination in remission induction, daunorubicin and cytarabine in consolidation, and ATRA/ATO/methotrexate ± 6-mercaptopurine in maintenance treatment of APL patients with various risks for relapse. Our results showed a high complete remission rate of 95.3%. Excluding the cases of early-death, no significant differences in event-free survival were observed between the intermediate-risk and high-risk group (p = 0.393) and the low-risk and high-risk group (p = 0.162). In addition, there were no significant differences between the groups in cumulative incidence of central nervous system relapse. In conclusion, our results suggest that APL patients benefit from combination ATO/ATRA/chemotherapy, and that this regimen is especially beneficial for patients with high-risk prognostic factors.     

Successful treatment after acute promyelocytic leukemia (APL) syndrome of relapsed API with arsenic trioxide

A 52-year-old female was diagnosed with relapsed APL in 2000. After obtaining informed consent, we administered 10 mg/day of arsenic trioxide intravenously. The complications were vomiting, increased transaminase and ATRA syndrome which included high fever, retention of body fluid, pleural effusion, pericardial effusion and respiratory failure from day 16. Administration of steroid and low dose chemotherapy (DNR 60 mg x day 1-2, BH-AC 250 mg x day 1-2) with arsenic was effective for APL syndrome, and complete remission (CR) was obtained at day 35 and PML-RAR mRNA became negative. After obtaining CR, consolidation chemotherapy was conducted and the patient was maintained the CR for more than 18 months. Although arsenic trioxide may be effective for relapsed APL, sufficient caution is needed because of the possibility of various complications.