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     

细胞遗传学在急性早幼粒细胞白血病的诊断及预后评估中的作用

目的探讨细胞遗传学在急性早幼粒细胞白血病（APL）的诊断及预后评估中的应用价值。方法应用常规细胞遗传学分析APL初诊患者39例,采用R显带技术进行染色体核型分析。随访分析完全缓解率、复发率。结果39例APL患者中,染色体异常38例,其中30例为典型t（15;17）易位,8例为涉及15和17号染色体的复杂核型。形态学误诊为M2和M5各1例,经核型分析确诊。经全反式维甲酸和（或）化疗联合诱导治疗,37例获完全缓解,2例具有复杂核型者未取得完全缓解,6例具有复杂核型者第1次完全缓解后3年内复发,复发率86％（6／7）,其他核型组完全缓解后3年内复发率仅10％（3／31）。结论细胞遗传学对细胞形态不典型APL具有确诊价值,复杂染色体异常者预后不佳。     

Use of arsenic trioxide in haematological malignancies: insight into the clinical development of a novel agent

BACKGROUND: Arsenic trioxide delivers high rates of complete clinical remission in patients with relapsed/refractory acute promyelocytic leukaemia (APL), and is associated with high rates of molecular remission as indicated by PCR negativity for the PML-RARalpha gene. OBJECTIVE: Mitochondria are considered to be the primary intracellular target of arsenic trioxide, and preclinical and mechanistic studies suggest that this agent may have broad applicability in haematological and other malignancies. Investigations of this agent are ongoing in a range of haematological malignancies, and studies in newly diagnosed APL, acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), multiple myeloma (MM) and chronic myelogenous leukaemia (CML) are reviewed here using published articles and presentations at international congresses to June 2004. Medline was used to source published preclinical and clinical data, and abstract databases and publications from relevant major international haematology/oncology congresses were searched to source updates of preclinical and clinical trial data. FINDINGS: Accumulating data indicate that arsenic trioxide may be a useful addition to the therapeutic regimens that have been so successful in treating newly diagnosed APL, and investigations are ongoing to incorporate this agent into the first-line APL treatment paradigm. Preliminary data from clinical studies indicate that arsenic trioxide has clinical activity as a single agent in MDS and MM, and combination therapies are being investigated. In MM, the combination regimens under study incorporate ascorbic acid, which can enhance the efficacy of arsenic trioxide by reducing intracellular glutathione concentrations. In CML, arsenic trioxide is being investigated in combination with imatinib mesylate in patients who have failed initial imatinib treatment. In AML, although results with single-agent arsenic trioxide were not encouraging, treatment using arsenic trioxide in combination with ascorbic acid is a proposed strategy in elderly patients not able to withstand intensive chemotherapy. CONCLUSION: This versatile agent has a predictable and manageable safety profile and avoids many of the severe toxicities associated with conventional chemotherapies. Ongoing clinical studies will help to define the role of arsenic trioxide in the treatment of haematological malignancies.     

Targeted therapies for the myeloid leukaemias

Although the standard approach to myeloid leukaemias remains chemotherapy, the agents currently available rarely result in cure. Recent advances in understanding the biology of these disorders have lead to the development of targeted treatment strategies. In acute promyelocytic leukaemia (APL), all-trans retinoic acid (ATRA), sodium phenylbutyrate and arsenic trioxide are agents which either induce differentiation or apoptosis and have been used to successfully achieve remission. The tyrosine kinase inhibitor, STI-571, antisense oligonucleotides, and bcr-abl vaccines are strategies which focus on the oncogenic events in chronic myelogenous leukaemia (CML). Two anti-CD33 monoclonal antibody conjugates, Y90-HuM195 and CMA-676, have been used in acute myelogenous leukaemia (AML) and have shown some efficacy. Although the preliminary results with these targeted therapies are promising, further studies are needed to establish them as effective, less toxic alternatives to the current standard of care.     

Targeted therapies for the myeloid leukaemias

Although the standard approach to myeloid leukaemias remains chemotherapy, the agents currently available rarely result in cure. Recent advances in understanding the biology of these disorders have lead to the development of targeted treatment strategies. In acute promyelocytic leukaemia (APL), all-trans retinoic acid (ATRA), sodium phenylbutyrate and arsenic trioxide are agents which either induce differentiation or apoptosis and have been used to successfully achieve remission. The tyrosine kinase inhibitor, STI-571, antisense oligonucleotides, and bcr-abl vaccines are strategies which focus on the oncogenic events in chronic myelogenous leukaemia (CML). Two anti-CD33 monoclonal antibody conjugates, Y90-HuM195 and CMA-676, have been used in acute myelogenous leukaemia (AML) and have shown some efficacy. Although the preliminary results with these targeted therapies are promising, further studies are needed to establish them as effective, less toxic alternatives to the current standard of care.     

From dissection of disease pathogenesis to elucidation of mechanisms of targeted therapies： leukemia research in the genomic era

Leukemia is a group of heterozygous diseases of hematopoietic stem/progenitor cells that involves dynamic change in the genome. Dissection of genetic abnormalities critical to leukemia initiation provides insights into the elusive leukemogenesis, identifies distinct subsets of leukemia and predicts prognosis individually, and can also provide rational therapeutic targets for curative approaches. The past three decades have seen tremendous advances in the analysis of genotype-phenotype connection of leukemia, and in the identification of molecular biomarkers for leukemia subtypes. Intriguingly, differentiation therapy, targeted therapy and chemotherapy have turned several subtypes of leukemia from highly fatal to highly curable. The use of all-trans retinoic acid and arsenic trioxide, which trigger degradation of PML-RARα, the causative fusion protein generated by t （15; 17） translocation in acute promyelocytic leukemia （APL）, has led to a dramatic improvement of APL clinical outcome. Imatinib mesylate/ Gleevec/STI571, which inhibits the tyrosine kinase activity of BCR-ABL oncoprotein, has now become the new gold standard for the treatmtent of chronic myeloid leukemia. Optimal use of chemotherapeutic agents together with a stringent application of prognostic factors for risk-directed therapy in clinical trials has resulted in a steady improvement in the treatment outcome of acute lymphoblastic leukemia. Hence, the pace of progress extrapolates to a prediction of leukemia control in the twenty-first century.     

急性早幼粒细胞白血病18例临床分析

目的　探讨急性早幼粒细胞白血病(APL)的临床特点、最佳治疗方案、维A酸综合征(RAS)的防治。方法　分析18例APL患者的临床资料。结果　18例APL患者中以出血起病16例。维A酸联合化疗治疗8例,疗程>6周期2例,分别于第2 6个月、第72个月复发死亡;2例早期死亡;4例<4周期者2例无病生存5年以上,2例于5年后复发,治疗后再次完全缓解。维A酸、砷剂联合化疗治疗10例无病生存2～37个月。结论　APL是一种特殊类型急性白血病,临床以出血为主要症状,RAS以预防为主。     

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.     

全反式维甲酸与亚砷酸联合化疗对急性早幼粒细胞白血病高危患者的疗效

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。     

Regulation of CYP26A1 expression by selective RAR and RXR agonists in human NB4 promyelocytic leukemia cells

All-trans retinoic acid (ATRA) can induce complete remission in acute promyelocytic leukemia (APL), but resistance to this treatment develops rapidly partly due to increased ATRA metabolism. Among the cytochrome P450s (CYPs) involved in ATRA metabolism, the ATRA-inducible cytochrome P450 26A1 (CYP26A1) is particularly active although the molecular mechanisms involved in its regulation are not well defined in the target leukemia cells. To study CYP26A1 expression and regulation in APL cells, we used the NB4 promyelocytic leukemia cell line. CYP26A1 constitutive expression was barely detectable in NB4 cells, but ATRA could induce high levels of CYP26A1 expression, which reached a maximum at 72h. To further define CYP26A1 induction mechanisms in the NB4 leukemia cells, we used RARs and RXR selective agonists. The RARalpha agonist BMS753 could elicit maturation, as expected, but not CYP26A1 expression. Treatment with the RARbeta agonist BMS641, or the RARbeta/gamma agonist BMS961, could not elicit maturation, as expected, nor induce CYP26A1 expression. Because CYP26A1 expression could not be induced by RAR ligands alone, NB4 cells were then co-treated with the RXR agonist BMS649. The RXR agonist alone could not induce CYP26A1 expression, nor in combination with either the RARbeta agonist or the RARbeta/gamma agonist. However, the combination of the RXR agonist and the RARalpha agonist could elicit a marked induction of CYP26A1 expression. In conclusion, we have shown that CYP26A1 induction is not essential for the granulocytic maturation of NB4 leukemia cells, and that CYP26A1 induction requires the activation of both RARalpha and RXR in these cells.     

急性淋巴细胞性白血病bcr/abl融合基因表达的临床研究

目的：研究bcr/abl融合基因在急性淋巴细胞白血病（ALL）患的表达与临床疗效的关系。方法：利用逆转录多聚酶链反应（RT－PCR）方法检测了31例ALL患bcr/abl融合基因的表达。结果：患bcr/abl融合基因阳性表达9例（29％），其中完全缓解3例（33．3％）；bcr/abl融合基因阴性表达22例（71％），其中完全缓解17例（77．3％），两组比较具有差异性（P＜0．05）。结论：bcr/abl融合基因阳性表达的ALL患临床疗效较差。     

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。     

Pathogenesis and treatment of leukemia: an Asian perspective

INTRODUCTION: Leukemias occur worldwide, but there are important geographic differences in incidences. AREAS COVERED: Three leukemias with special Asian perspectives, acute promyelocytic leukemia (APL), T-cell large granular lymphocyte (T-LGL) leukemia and NK-cell leukemia. EXPERT OPINION: In APL, China has made contributions in discovering the efficacy of all-trans retinoic acid (ATRA) and arsenic trioxide. Some APL patients are potentially curable after treatment with ATRA or arsenic trioxide as a single agent. Combined treatment of APL with ATRA and arsenic trioxide induces remission with deeper molecular response. An oral formulation of arsenic trioxide is available, making outpatient treatment feasible. Future regimens for APL should examine how ATRA and arsenic trioxide can be optimally combined with other synergistic drugs. Asian patients with T-LGL leukemia present more frequently with pure red cell aplasia, but less frequently with neutropenia, recurrent infection, splenomegaly and rheumatoid arthritis as compared with Western patients. These differences have potential effects on treatment and disease pathogenesis. NK-cell leukemia is rapidly fatal and occurs almost exclusively in Asian and South American patients. Conventional anthracycline-based chemotherapy designed for B-cell lymphomas do not work in NK-cell leukemias. Novel therapeutic approaches targeting cellular signaling pathways or preferentially upregulated genes are needed to improve outcome.     

菏酸双酯钠在治疗急性早幼粒细胞白血病中的应用

采用DA或HA方案以及维甲酸治疗22例急性早幼粒细胞白血病,化疗时并用PSS(100mg.d×7d)。并发DIC的病人先给予治疗DIC,好转后进行化疗,并继续应用PSS至化疗结束。结果表明,常规化疗并用PSS治疗急性早幼粒细胞白血病的完全缓解率高达91％,明显高于文献报道的缓解率。     

Pregancy complicated by acute myeloid leukaemia.

Combination cytotoxic chemotherapy was used to treat a case of acute myeloid leukaemia presenting in the 25th week of pregnancy with a sustained complete remission of the leukaemia and the successful delivery of a normal infant. The management of leukaemia presenting in pregnancy is discussed.