ATRA、ATO联合小剂量HHT治疗急性早幼粒细胞白血病疗效观察

目的探讨急性早幼粒细胞白血病（APL）的最佳治疗方案。方法将初诊的24例APL患者随机分为观察组13例和对照组11例。观察组予全反式维甲酸（ATRA）、三氧化二砷（ATO）联合小剂量高三尖杉酯碱（HHT）诱导治疗,HA方案巩固治疗2个疗程;对照组予ATRA＋ATO＋柔红霉素（DNR）治疗,DA方案巩固治疗2个疗程。治疗结束比较两组相关指标变化。结果诱导及巩固治疗结束时两组血液学缓解率、PML/RARa融合基因转阴率均无显著差异;观察组累计血浆输注量及血小板输注量、败血症发生率及平均住院费用均明显低于对照组,P均〈0.01。结论 ATRA、ATO联合小剂量HHT治疗初诊APL效果确切;且并发症发生率低,治疗费用少。     

急性早幼粒细胞白血病治疗方案的优化研究

正急性早幼粒细胞白血病(APL)是急性髓系白血病的亚型之一。超过95%的APL患者15号染色体的PML基因与17号染色体的RARA基因发生融合形成PML-RARA融合基因,其产生的融合蛋白导致髓系细胞分化障碍并停滞在早幼粒细胞阶段。自1990年以来,全反式维甲酸(ATRA)和三氧化二砷(ATO)被相继应用于APL的治疗方案中。ATRA联合蒽环类药物为主的方案作为目前的标准     

AIDA方案治疗急性早幼粒细胞白血病分子生物学疗效初步观察

目的：观察全反式维甲酸加去甲氧柔红霉素加阿糖胞苷（AIDA）方案治疗急性早幼粒细胞白血病（APL）患者的分子生物学疗效。方法：在全反式维甲酸（ATRA）诱导缓解后的32例APL患者中,予去甲氧柔红霉素（IDA）加阿糖胞苷巩固化疗2个疗程,治疗前后检测PML／RARα融合基因水平。结果：临床和血液学安全缓解29例（91％）,部分缓解2例（6％）,总有效率97％。分子生物学缓解率达31％,10例转阴者随访1年内连续2次检测基因持续阴性者3例（30％）。结论：AIDA方案是治疗APL达到分子生物学缓解的有效方法;年龄、治疗前白细胞数、ATRA诱导缓解时间及IDA应用的疗程和剂量,是影响APL患者分子生物学缓解的重要因素。     

全反式维甲酸治疗老年早幼粒白血病的临床观察

目的了解全反式维甲酸(ATRA)治疗老年急性早幼粒细胞白血病(APL)的近期疗效．方法13例老年APL患每天予ATRA25—60mg／m^2。直至完全缓解(CR)。结果1、ATRA治疗的CR率高，达84．6％．2、ATRA治疗存在一定副作用，伹老年患均能耐受。3、APL缓解后治疗以A了RA与化疗交替较宜．结论A了RA治疗老年APL疗效明确，CR率高。     

三联方案治疗初诊急性早幼粒细胞白血病临床效果分析

目的观察全反式维甲酸（ATRA）、亚砷酸（ATO）及柔红霉素（DNR）三联方案治疗急性早幼粒性白血病（APL）的疗效及安全性。方法将61例采用四种不同诱导方案治疗的临床初诊APL患者根据化疗方案不同分为四组,其中采用ATRA＋ATO＋DNR者为观察组、ATO＋DNR者为对照1组、ATRA＋DNR者为对照2组、DNR＋阿糖胞苷（Ara-c）为对照3组,对完全缓解（CR）率、病死率及毒副作用进行回顾性分析。结果观察组CR率显著高于其他三组,病死率显著低于对照3组,高白细胞血症持续时间显著短于对照1、2组,与对照1、2组比较维甲酸综合征（RAS）发生率无明显差异,肝功能损伤（均为可逆性）发生率显著高于其他三组。结论 ATRA、ATO及DNR三联方案治疗初诊APL患者疗效显著,且安全性较高。     

分化综合征的分子学研究进展北大核心CSCD

急性早幼粒细胞白血病(APL)特征为早幼粒细胞在分化成熟阶段受阻。通常表现为全血细胞减少、弥散性血管内凝血。以t(15;17)(q24.1;q21.2)易位为特征,形成PML-RARα融合基因。APL占新诊断急性髓系白血病的10%~15%,在欧洲的年发病率约为0.12/10万[1]。近年来,随着全反式维甲酸(ATRA)联合三氧化二砷(ATO)方案的引入,APL病死率明显下降,目前在临床可达到治愈[2-3]。但是诱导治疗过程中分化综合征(DS)的发生率显著增加。DS主要发生于APL患者在ATRA联合ATO方案诱导治疗期间,因其分化肿瘤细胞释放大量炎性细胞因子和黏附分子,并诱导分化细胞的迁移和黏附[4]。本文就DS的临床特征、发病机制及分子学研究进展进行综述。     

初发急性早幼粒细胞白血病不同治疗方案疗效比较

<正>2003年以来,我院采用全反式维甲酸(ATRA)、三氧化二砷(ATO)和高三尖杉酯碱(HHT)联合治疗初发急性早幼粒细胞白血病(APL)患者,取得较好的近期和远期疗效。为进一步阐明此三药联合治疗APL的疗效,我们将治疗结果与同期金华市中心医院采用ATRA、ATO、去甲氧柔红霉素(IDA)和甲氨蝶呤(MTX)联合治疗72例初发APL患者的结果进行比较分析。现报道如下。     

急性早幼粒细胞白血病经全反式维甲酸缓解后维持治疗的临床探讨

目的：探索急性早幼粒细胞白血病（APL）经全反式维甲酸（ATRA）治疗达完全缓解（CR）后理想的维持治疗方案，提高APL的长期无病生存时间.方法：将我院21例初治的APL患者均经ATRA治疗达CR后，维持治疗方法为三氧化二砷（As2O3）、ATRA及6-巯基嘌呤（6-MP）加甲氨喋呤（MTX）序贯交替治疗3年;观察治疗的效果及不良反应，监测微小残留病.结果：21例患者对上述治疗均有较好的顺从性，有11例患者维持治疗超过2年，无复发病例;PML/RARα融合基因初诊时均为阳性，12例持续转阴，其中维持治疗超过2年的11例患者均转阴;治疗相关的不良反应少见且较轻.结论：用上述维持治疗经ATRA达CR的APL初步取得了令人满意的效果，其不良反应较传统的联合化疗轻，作者认为As2O3、ATRA与6-MP加MTX序贯交替治疗可能是APL理想的维持治疗方法。     

维甲酸联合亚砷酸治疗伴FLT3-ITD突变的APL患者的预后分析

目的:探讨急性早幼粒细胞白血病伴FLT3-ITD患者以维甲酸(ATRA)联合三氧化二砷(ATO)为基础治疗方案下的预后影响。方法:回顾性分析101例初诊的成年急性早幼粒细胞白血病患者的临床资料并进行随访,患者初诊时被随机分为接受ATRA+ATO组(55例)及ATRA+化疗组(46例),使用PCR扩增,琼脂糖凝胶电泳检测FLT3-ITD基因突变,比较FLT3-ITD突变在2组的疗效及预后。结果:FLT3-ITD突变率24.75%(25/101),且FLT3-ITD突变与高白细胞计数、高血红蛋白水平、PML-RARA S亚型、Sanz危险分层高危有关(均P0.05)。2组FLT3-ITD阳性患者均诱导死亡率高、缓解率低,差异无统计学意义(均P0.05)。ATRA+化疗组中FLT3-ITD突变患者与FLT3-ITD未突变患者3年无复发生存率分别为68.6%、91.2%(P=0.048),ATRA+ATO组中FLT3-ITD突变患者与FLT3-ITD未突变患者3年无复发生存率分别为90.9%、100.0%(P=0.638);ATRA+化疗组中FLT3-ITD突变患者与FLT3-ITD未突变患者3年总生存率分别为80.8%、97.1%(P=0.077),ATRA+ATO组中FLT3-ITD突变患者与FLT3-ITD未突变患者3年总生存率分别为92.9%、97.6%(P=0.431)。结论:FLT3-ITD突变在ATRA+化疗治疗方案下复发率高,预后不良,诱导和巩固治疗前2个周期加入ATO治疗可能克服FLT3-ITD突变的影响,降低复发率,改善患者预后。     

序贯诱导治疗急性早幼粒细胞白血病长期生存分析

近年来急性早幼粒细胞白血病(APL)的分子学发病机制逐渐被阐明,其治疗经历了蒽环类药物为主的联合化疗、全反式维甲酸(ATRA)和亚砷酸(ATO)治疗3个阶段。ATRA的应用使得诱导完全缓解(CR)率从单纯蒽环类为主化疗的50%〔1〕提     

Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years of minimal follow-up

Shortly before the all-trans retinoic acid (ATRA) era, the GIMEMA cooperative group initiated a randomized study comparing idarubicin (IDA) alone with IDA plus arabinosylcytosine (Ara-C) as induction treatment in patients with newly diagnosed hypergranular acute promyelocytic leukemia (APL). Of the 257 patients evaluable for induction treatment, 131 were randomized to receive IDA alone (arm A) and 126 to receive IDA + Ara-C (arm B). Treatment in arm A consisted of 10 mg/m(2) IDA daily for 6 consecutive days, whereas in arm B it consisted of 12 mg/m(2) IDA daily for 4 days combined with 200 mg/m(2) Ara-C daily in continuous infusion for 7 days. Once in complete remission (CR), patients received 3 consolidation courses of standard chemotherapy, and those still in CR at the end of the consolidation were randomized to receive or not receive 1 mg/kg 6-mercaptopurine daily and intramuscular injections of 0.25 mg/kg methotrexate weekly for 2 years. Overall, 100 (76.3%) patients in arm A and 84 (66.6%) patients in arm B achieved CR (P = NS). Event-free survival (EFS) rates were 35% and 23% for patients in arm A and arm B, respectively (P =.0352). Multivariate analysis revealed that EFS was favorably influenced by induction treatment with IDA alone (P =.0352) and unfavorably influenced by white blood cell (WBC) counts greater than 3000/microL (P =.0001) and increasing age (P =.0251). These results indicate that anthracycline monochemotherapy with IDA favorably influences the EFS of patients with newly diagnosed hypergranular APL.     

Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: a bridge to transplantation

BACKGROUND AND OBJECTIVES: Arsenic trioxide (ATO) has been reported to be a safe and effective treatment for relapsed acute promyelocytic leukemia (APL). The aim of this study was to evaluate the efficacy and toxicity as well as the eligibility to stem cell transplantation (SCT) in a series of 7 patients with relapsing APL, managed with ATO. DESIGN AND METHODS: Seven patients with relapsing APL while on maintenance treatment with all-trans-retinoic acid (ATRA) or who were ATRA refractory-received ATO at a dose of 10 mg daily by 2-hour intravenous infusion until complete remission (CR). After consolidation chemotherapy, patients were programmed to receive autologous or allogeneic stem cell transplantation (SCT) according to donor availability. The median age of the patients was 55 (21-71) years: 2 patients presented with concomitant extramedullary relapse. RESULTS: Six patients (86%) achieved CR after a median of 35 ATO doses (20-49) with negligible toxicity; one patient died from pneumonia. After consolidation with a four-day course of cytarabine at 1 g/m2 and mitoxantrone 6 mg/m2, two patients underwent allogeneic SCT, two received PML/RARa negative autologous peripheral blood stem cells collected after consolidation plus granulocyte colony-stimulating factor, one failed mobilization and received a second consolidation course. One elderly patient refused further treatment and relapsed 6 months later. After a median follow-up of 15 months from CR2 achievement, 5 patients are alive in continuous CR. INTERPRETATION AND CONCLUSIONS: The high CR rate and the mild toxicity confirm that ATO represents a valid alternative to salvage chemotherapy for patients relapsing while on ATRA treatment or who are ATRA-refractory. Allogeneic or autologous SCT after ATO-induced CR is feasible in the majority of patients.     

Successful treatment of relapsed and refractory acute promyelocytic leukemia with arsenic trioxide (As2O3)

It has been shown that arsenic trioxide (As2O3) may induce hematologic remissions in patients with acute promyelocytic leukemia (APL) refractory to all-trans retinoic acid (ATRA). We reported on a patient with ATRA and drug-resistant APL that was successfully treated with As2O3. The patient had been given a diagnosis of typical APL and was treated with ATRA and chemotherapy for 12 months. He achieved complete remission (CR), but leukemia relapsed with 43% APL cells in the bone marrow in the 16th month of treatment. ATRA and cytarabine plus daunorubicin were administered; however, the APL cells in the bone marrow increased to 97.2%. As2O3 was initiated intravenously, and bone marrow showed a decrease of APL cells (6.7%) and a partial differentiation after 9 days. The patient received idarubicin (IDA) and steroid pulse because of the development of ATRA-like syndrome, and achieved CR 37 days after the initiation of As2O3. He received an additional 2 courses of As2O3 with IDA, and is in CR. These results demonstrated the therapeutic efficacy of As2O3 in treating ATRA and drug-resistant APL.     

Effectiveness and pharmacokinetics of low-dose all-trans retinoic acid (25 mg/m2) in acute promyelocytic leukemia

It has been shown that all-trans retinoic acid (ATRA) at doses of 45 to 100 mg/m2/d induces complete remission (CR) of acute promyelocytic leukemia (APL) by a differentiation process. To date, ATRA dose-ranging studies have not yet been evaluated. Thus, we initiated in May 1990 a multicenter study with ATRA at a lower dose of 25 mg/m2/d until CR. Thirty patients with APL were treated with ATRA, of whom 12 were previously untreated, 14 were in first relapse, and 4 had failed after conventional first induction chemotherapy. Twenty-four of 30 achieved CR, 3 failed, and 3 died before day 30. Median time to CR was 45 days. Hyperleucocytosis (14 to 43 x 10(9) white blood cells per liter) was observed in 9 patients between days 10 and 23. Clinical complications that may have been related to the retinoic acid syndrome were observed in 8 patients, of whom 3 died. Pharmacokinetics studies were performed in 5 patients. Peak plasma concentrations and mean area under the concentration-time curve were not lower than previous levels obtained under the 45 mg/m2 dose. Overall, our study shows that there is no difference in terms of therapeutic efficacy, triggering of hyperleukocytosis, or retinoic acid syndrome and pharmacokinetic results with ATRA at 25 or 45 mg/m2/d.     

All-transretinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remissions in newly diagnosed acute promyelocytic leukemia: a pilot study on 26 cases.

We entered 26 patients with newly diagnosed acute promyelocytic leukemia (APL) in a pilot study of all-transretinoic acid (ATRA) followed by intensive chemotherapy. Median age was 46 (range 25 to 63). No patient presented with leukocytes > 10 x 10(9)/L or had the microgranular APL variant. Cytogenetic analysis (25 patients) found a t(15;17) in 24 cases. Patients were scheduled to receive ATRA (45 mg/m2/d) until complete remission, followed by an intensive daunorubicin (DNR) + Ara C course ("4 + 7" course), then three "2 + 5" DNR + Ara C courses and maintenance chemotheapy. However, the "4 + 7" course was administered in emergency if hyperleukocytosis rapidly developed to prevent leukostasis. Twenty-five patients (96%) achieved CR, 14 with ATRA alone and 11 after the addition of the "4 + 7" course on day 2 to 30 of treatment, because leukocytes rapidly increased (9 cases), because of resistance to ATRA (1 case), and development of organomegaly (1 case). The remaining patient died on day 6, from CNS bleeding. Apart from hyperleukocytosis, side effects were usually moderate. In the 11 patients who could be studied in vitro, a very good correlation was found between in vivo and vitro differentiation and proliferation of APL blasts with ATRA. Three patients were allografted after the "4 + 7" course. Four patients did not receive this course but received the subsequent "2 + 5" courses and maintenance. The remaining patients followed the scheduled protocol. Three patients relapsed after 8, 11, and 15 months (including one allografted patient). Two patients died in CR, after 6 and 17 months. The other 20 patients remained in CR after 18+ to 34+ months (median 21). Actuarial disease free interval (DFI) and event free survival (EFS) were 87% and 77%, respectively, after 18 months. These results were compared to those obtained in our previous APL 84 trial with chemotherapy alone in newly diagnosed APL (after excluding patients included in this trial who presented with hyperleukocytosis). In APL 84 trial, the CR rate was 76%, the actuarial DFI and EFS were 59% and 48% after 18 months, respectively. Differences with the pilot study of ATRA followed by chemotherapy were significant for DFI (P = .02), EFS (P = .006), but not for CR rate (P = .08). Although this is a historical comparison, these results suggest that ATRA followed by chemotherapy may prove superior to chemotherapy alone in newly diagnosed APL, by slightly increasing the CR rate, but perhaps more importantly by reducing the relapse rate.(ABSTRACT TRUNCATED AT 400 WORDS)     

低剂量全反式维甲酸治疗急性早幼粒细胞白血病的疗效

为了评价低剂量全反式维甲酸（ＡＴＲＡ）治疗急性早幼粒细胞白血病（ＡＰＬ）的临床效果，分别比较了正常个体单次口服１５ｍｇ／ｍ２和４５ｍｇ／ｍ２ＡＴＲＡ的药代动力学。结果显示：口服低剂量的最大峰浓度（Ｃｍａｘ）虽低于口服高剂量组，仍足以诱导ＡＰＬ细胞分化。于是，应用１５～２０ｍｇｍ－２ｄ－１ＡＴＲＡ连续治疗２７例ＡＰＬ初发病人。在临床评价的２６例中，２４例在治疗１３～６７天内达完全缓解（ＣＲ）。无任何病人发生维甲酸综合征和ＤＩＣ。在检测的３例病人中，ＣＲ时和首次服药时的药代动力学比较发现，２例Ｃｍａｘ明显下降而１例相似。尤其重要的是，和过去一组相对匹配的高剂量ＡＴＲＡ治疗病人比较，本组结果显示低剂量ＡＴＲＡ的疗效与高剂量相似，并且可能有利于降低高白细胞血症的程度及其他一些副反应。     

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.     

Treatment of older adults with acute promyelocytic leukaemia

Only 15 to 20% of acute promyelocytic leukaemia (APL) patients are older than 60 years, and the characteristics and outcome of APL in that age range are not well known. Published studies show that APL in elderly patients has haematological features similar to those of APL in younger patients. However, using the current combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy, the outcome for these patients, although it has much improved, remains less favourable than that for younger patients. This is due to a higher incidence of early deaths and deaths in complete remission (CR), during consolidation chemotherapy courses, whereas the relapse rate appears similar in older and younger adults.Treatment approaches with more limited myelosuppression, especially consolidation chemotherapy with an anthracycline alone (without Ara-C), low-dose maintenance treatment with 6-mercaptopurine, methotrexate and ATRA, and consolidation with arsenic trioxide, should be tested especially in elderly patients in order to replace more toxic 'classical' anthracycline-Ara-C consolidation treatment, after achieving CR with ATRA.