自噬途径在急性早幼粒细胞白血病中作用及其调控机制研究进展

正急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)是急性髓系白血病中的一种特殊类型,以具有t(15;17)染色体易位的细胞遗传学标志和特异性表达早幼粒细胞白血病-维甲酸α受体(PML-RARα)融合蛋白为发病特点。全反式维甲酸(ATRA)和三氧化二砷(ATO)都能引起PMLRARα融合基因下降,是治疗APL的有效药物,但     

复方黄黛片联合化疗治疗初治急性早幼粒细胞白血病的疗效观膊

急性早幼粒细胞白血病(APL)特征性细胞遗传学异常t(15;17)染色体的易位形成PML/RARα融合基因.三氧化二砷(As2O3)治疗复发、难治APL缓解率达52%～92%,初治患者可达57%～88%[1～3].复方黄黛片(曾用名:复方青黛片)含有效成分雄黄及青黛,治疗APL患者缓解率达98.3%[4].我们应用三氧化二砷或复方黄黛片与化疗方案联合治疗初治APL患者共20例,取得较好疗效,现报道如下.     

双色间期荧光原位杂交对隐匿性t(15;17)急性早幼粒细胞白血病的诊断价值

t(15 ;17)是急性早幼粒细胞白血病 (APL)的特异性染色体易位 ,分子水平上它导致PML/RARα融合基因。大约80 %的APL患者应用常规细胞遗传学 (CC)技术可检出该易位 ,其余 2 0 %的病例 ,CC检测常显示正常核型 ,而逆转录 PCR(RT PCR)仍能检出PML/RARα基因重排 ,提示存在着隐匿性t(15 ;17)易位[1] 。近年来我们应用PML和RARα两种序列探针和双色间期荧光原位杂交 (D FISH)技术对 7例CC检测缺乏典型t(15 ;17)的APL患者进行检测 ,以探讨该技术对隐匿性t(15 ;17)APL的诊断价值。一、资料和方法1.对象 :7例均为 1997年 8月至 2 …     

CD_(34)~+急性早幼粒细胞白血病的临床特点及预后

急性早幼粒细胞白血病(APL)的主要特点为染色体t(15;17)(q22;q12)易位形成PML/RARot融合基因,早期常伴有严重的凝血功能障碍而危及生命.FAB分型将APL分为2个亚型:典型粗颗粒型M3和细颗粒型M3v.APL免疫表型特点为CD_(13)~+,CD_(33)~+,CD_9~+和CD_(14)~-.目前以全反式维甲酸(ATRA)联合蒽环类为基础的化疗,使初治APL患者完全缓解(CR)率达90%～95%,早期死亡率明显下降,CR后巩固强化及维持治疗使得APL复发率明显下降,生存期明显延长[1].尽管大多数APL经过上述治疗取得了非常满意的疗效,仍有少部分患者表现为极差的临床过程.     

流式技术鉴别诊断急性早幼粒细胞白血病的可行性研究

目的 通过流式细胞仪检测急性早幼粒细胞白血病(APL)及非急性早幼粒细胞白血病(non-APL)的PG-M3表达荧光强度差异,为APL的鉴别诊断提供科学依据.方法 流式细胞仪检测APL患者骨髓幼稚细胞群、成熟粒细胞群的细胞表面及胞浆PG-M3的平均荧光强度(MFI).结果 APL组的幼稚细胞与成熟粒细胞胞浆MFI比值大于non-APL组(P<0.05).结论 PC-M3有可能作为APL鉴别诊断的辅助指标.     

伴有附加染色体异常的急性早幼粒细胞白血病临床特征

目的:探讨伴有附加染色体异常的急性早幼粒细胞白血病(APL)的临床特点、治疗及预后。方法:回顾性比分析108例单纯t(15;17)染色体易位及27例伴有附加染色体异常的初治APL的临床资料。结果:附加染色体异常的发生率为20%(27/135),最常见的附加染色体异常是三体8。伴有附加染色体异常的APL患者的年龄、性别、白细胞计数、血红蛋白、血小板计数、骨髓原始+早幼粒细胞比例与单纯t(15;17)染色体易位患者比较,均差异无统计学意义。2组患者诱导治疗的完全缓解率、达完全缓解的时间、早期病死率、维甲酸综合征、弥漫性血管内凝血、颅内岀血发生率均差异无统计学意义,2组缓解后总生存率及无复发生存率亦差异无统计学意义。结论:APL患者是否伴有附加染色体异常与临床疗效、预后无关。     

急性早幼粒细胞白血病的治疗进展和目前存在问题

急性早幼粒细胞白血病(APL)占急性髓系白血病(AML)的10%~15%,形态学上属于FAB(法国、美国和英国)分型中的AML-M3亚型,98%的APL具有t(15;17)(q22;q21)染色体异位和早幼粒细胞白血病-维A酸受体α(PML-RARA)融合基因[1]。因APL具有较高的出血倾向和早期死亡率,一度被认为是最凶险的急性白血病。1973年,Bernard     

急性早幼粒细胞白血病出血并发症的机制及治疗进展

<正>急性早幼粒细胞白血病(APL)是一种以骨髓及外周血中存在异常增多的早幼粒细胞为主要细胞学特征的髓系增生性疾病,在急性髓系白血病(AML)中占10%~15%,约98%的APL患者染色体中存在特征性改变t(15;17)(q22;q21),在分子水平上可见PML-RARα融合基因。因APL具有严重的出血倾向,并可快速进展至弥散性血管内凝血(DIC),曾一度被认为是急性白血病中恶性程     

伴附加染色体异常的急性早幼粒细胞白血病的临床观察

目的:观察伴附加染色体异常的急性早幼粒细胞白血病(APL)患者的临床特征、实验室检查、疗效及长期预后等。方法:回顾性分析64例单纯t(15;17)染色体易位APL患者和19例伴有附加染色体患者的临床资料。结果:伴有附加染色体异常发生率约为22.9%(19/83),其中+8染色体及del(9)异常多见,男性患者多于女性(15例∶4例)。与单纯t(15;17)染色体易位患者比较,伴有附加染色体患者的临床表现、实验室指标、疗效及长期预后等均差异无统计学意义。结论:伴有附加染色体异常发生率约为22.9%,其中男性多见,与单纯t(15;17)染色体易位APL患者比较,伴有附加染色体患者的临床表现、实验室检查、疗效及预后均差异无统计学意义,治疗方案无需调整。     

急性早幼粒细胞白血病药物治疗进展

急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)占急性髓系白血病的5%～8%,95%以上的患者具有特征性染色体t(15;17)(15q22;17q21),形成早幼粒细胞白血病-维甲酸受体α(PML-RARα)融合基因,并表达PML-RARα融合蛋白。其临床特点是骨髓及血液中有大量早幼粒细胞,易并发弥漫性血管内凝血。基于以上特点,APL的治疗与其他AML的治疗相比较有许多不同。现将APL的药物治疗进展作一综述。1诱导分化治疗1.1维甲酸(ATRA)1986年,上海第二医科大学附属瑞金医院、上海血液学研究所和上海维甲酸研究协作组,首先使用全反式维甲酸诱导…     

Incidence and implication of additional chromosome aberrations in acute promyelocytic leukaemia with translocation t(15;17)(q22;q21): a report on 50 patients

Acute promyelocytic leukaemia (APL) is characterized by the translocation t(15;17)(q22;q21). Usually t(15;17) is the sole cytogenetic abnormality, but some patients show other chromosome aberrations in addition to t(15;17). The influence of additional chromosome aberrations on the clinical outcome of patients with t(15;17) is unclear. We have analysed 50 cases of APL carrying the translocation t(15;17). Additional chromosome aberrations were observed in 17/47 patients (36%) studied at initial diagnosis and in all three patients studied at relapse. In nine cases (18%) an additional chromosome 8 and in six cases (12%) an isochromosome of the long arm of the derivative chromosome 17 was observed. Various structural rearrangements in addition to t(15;17) were detected in nine patients (18%). Clinical follow-up data were available for 44 patients studied at diagnosis. A complete remission (CR) was achieved in 34 patients (77%). 10 patients (23%) died within 1 month after diagnosis due to infection or bleeding, eight (24%) relapsed within 10–18 months after initial diagnosis. 28 patients are alive 2–93 months after diagnosis (25 in first CR, two in second and one in third CR) (median follow-up 18.5 months). Bone marrow transplantation was performed in six patients (three in first CR, two in second CR, one in third CR), all are alive and in CR. An influence of secondary chromosome anomalies on prognosis was not observed. However, if a higher rate of long-term remission can be reached, specific secondary chromosome aberrations might turn out to be of prognostic value.     

Immunophenotype of adult and childhood acute promyelocytic leukaemia: correlation with morphology, type of PML gene breakpoint and clinical outcome. A cooperative Italian study on 196 cases

Acute promyelocytic leukaemia (APL), characterized by a specific PML-RARα fusion gene resulting from translocation t(15;17) and by a high response rate to differentiation therapy with all- trans retinoic acid, presents clinical (varying WBC counts, age and treatment outcome), morphological (hypergranular M3 and hypogranular M3V) and molecular (three isoforms of PML breakpoint) heterogeneity.
We correlated leukaemic immunophenotype with these aspects in 196 molecularly confirmed APLs (63 children and 133 adults) in Italy. The bcr3 isoform ( P  = 0.05) and FAB M3V ( P  = 0.05) were more frequent in children. We confirmed in APL an immunophenotype characterized by frequent expression of CD13, CD33 and CD9 and rare expression of HLA-DR, CD10, CD7 and CD11b. However, we recognized CD2 in 28%, CD34 in 23% and CD19 in 11% of cases and demonstrated by double labelling that CD34 and CD2 may be co-expressed. CD2, CD34 and CD19 were significantly intercorrelated, and variably associated to other features: CD2 and CD34 with PML bcr3 ( P  < 0.001 and P  < 0.001, respectively) and with M3V ( P  < 0.001 and P  = 0.002), whereas only CD19 was directly correlated with WBC counts and only CD2 positively influenced CR rate (logistic model) and event-free survival (Cox model). We conclude that immunophenotype plays a role in the determination of the biological and clinical heterogeneity of childhood and adult APL.     

细胞遗传学和PT-PCR对APC诊断的临床意义

目的：探讨细胞遗传学及ＲＴ-ＰＣＲ检测对ＡＰＬ诊断的临床意义。方法：直接法或 ２４ ｈ培养法处理骨髓标本,采用Ｒ带或Ｇ带方法显带检测ｔ（１５;１７）易位,ＲＴ－ＰＣＲ检测ＰＭＬ－ＲＡＲａ融合基因。结果：形态诊断Ｍ３５５例,３例疑诊Ｍ３或Ｍ２;染色体检测５０例发现ｔ（１５;１７）,敏感率９０．９１％,３例形态不能肯定诊断者染色体发现ｔ（１５;１７）,诊断为Ｍ３Ｖ型;有ｔ（１５;１７）易位者均检测到ＰＭＬ－ＲＡＲａ融合基因,３例无ｔ（１５;１７）易位者,ＲＭＬ－ＲＡＲａ检测阳性。３例误诊者均经染色体及融合基因检测排除。结论：细胞遗传学ｔ（１５;１７）及融合基因ＲＭＬ－ＲＡＲａ检测是诊断ＡＰＬ的可靠指标,ＲＴ－ＰＣＲ融合基因检测更为敏感。     

Prognostic significance of CD56 antigen expression in acute myeloid leukemia

BACKGROUND AND OBJECTIVES. CD56 antigen expression has been reported in several hematologic malignancies. In acute myeloid leukemia (AML)M2 with t(8;21) and acute promyelocytic leukemia (APL) it has been found to be consistently associated with an unfavorable prognosis, whereas in other AML subtypes its role remains uncertain. We investigated CD56 expression in a cohort of AML patients in order to assess its frequency and prognostic relevance. DESIGN AND METHODS. Immunophenotypic analysis including that of CD56 antigen was available for 171 consecutive AML patients (139 with AML and 32 with APL), enrolled between December 1995 and December 1999 at a single institution. A sample of fresh bone marrow cells taken at diagnosis was recorded as positive when at least 20% of the cells double-stained with specific monoclonal antibodies against CD56 and CD33 antigens. RESULTS. CD56 positivity was demonstrated in 37 cases (21.6%). Its frequency was lower in M4 (6%) and higher in M5 (37%). The median percentage for CD56+ blasts was 56% (range 21-99%). CD56 positivity did not correlate with age, sex, blast count, favorable or unfavorable cytogenetics at diagnosis, nor did it influence the outcome in terms of complete remission (CR) duration (606 vs. 417 days, p=n.s.) or overall survival (OS) (210 vs. 277 days, p= n.s.). In the APL subgroup a significant difference in relapse rate was found at 3 years (71.4% in the CD56 positive group vs. 12% in the CD56 negative group, p=0.005). INTERPRETATION AND CONCLUSIONS. Our data confirm that CD56 positivity in APL patients at diagnosis is associated with a worse prognosis, suggesting that close molecular monitoring is necessary in CD56 positive APL patients. In contrast, the prognostic role of CD56 remains uncertain in the other AML subtypes.     

原发高白细胞型急性早幼粒细胞白血病66例临床特征及治疗研究

目的探讨原发高白细胞型急性早幼粒细胞白血病(APL)的临床特点及有效的治疗方法。方法回顾性分析1993年10月至2006年8月苏州大学附属第一医院收治的66例原发高白细胞型APL患者和152例非高白细胞型APL患者的临床资料,并对高白细胞型患者按治疗方案的不同进行了分组比较。结果高白细胞组APL患者早期病死率、弥散性血管内凝血(DIC)和维甲酸综合征(RAS)发生率分别为30.3%,57.6%和31.8%,均高于非高白细胞组(7.2%,38.1%和21.1%)(P<0.05),而完全缓解(CR)率较低(63.6%对88.2%)(P<0.05)。高白细胞组患者中61例接受了诱导治疗,其中31例单用维甲酸治疗,21例维甲酸联合亚砷酸治疗,9例单用亚砷酸治疗,各组早期病死率分别为27.3%,14.3%和55.6%,CR率分别为67.7%,81.0%和44.4%。61例患者中41例在接受诱导分化治疗的同时加用化疗,其CR率为80.5%,总病死率为19.5%;而未加用化疗的20例患者其CR率为45.0%,总病死率为55.0%,两组比较差异有显著性意义(P<0.05)。结论原发高白细胞型APL较非高白细胞型APLCR率低,早期病死率高,DIC、RAS发生率高。维甲酸加亚砷酸双诱导并联合小剂量化疗是治疗高白细胞型APL的最有效的方案,可明显减少早期病死率,提高CR率。     

应用形态学、核型和染色体原位抑制杂交方法联合检测急性早幼粒细胞白血病

对42例急性早幼粒白血病(APL,简称M3)患者在形态学检测的基础上,采用骨髓染色体G显带检测结果:t(15;17)检出率93%,12例同时进行了染色体原位抑制杂交(CISS)检测,结果:10例初诊患者t(15;17)的检出率100%,在42例中,NN型(中期分裂相皆正常)3例,AN型(正常和异常克隆嵌合体)22例,AA型(中期分裂相皆正常)17例,简单易位[只有t(15;17)]36例,复杂易位(同时有附加异常)2例,变异易位t(5;15)1例,FAB分型M3a 37例,M3b 5例.通过形态学、细胞遗传学和CISS(MCC)分析:形态学的确诊率88%,5例曾误诊为急性非淋巴细胞白血病(ANLL)的其他类型.另2例核型分析为NN型,后经染色体和染色体FISH分析确诊,5例误诊者4例为M3b(细颗粒型),MCC结合可明显提高确诊率,在临床资料可供评价的21例中19例达到完全缓解(CR),2例具有复杂异常核型和变异易位者未能取得缓解,分别进展为难治性白血病和呼吸窘迫综合征而死亡,核型与其他一些临床参数如:患者初诊时的白细胞数、初诊时DIC发生率、全反式维甲酸(ATRA)综合征的发生率和达到完全缓解的时间等无相关性(p>0.05).     

Adult precursor T-lymphoblastic leukemia/lymphoma with myeloid-associated antigen expression is associated with a lower complete remission rate following induction chemotherapy

Prognostic studies of T-cell lymphoblastic leukemia/lymphoma (T-ALL) have been performed in small patient cohorts with conflicting results. We systematically reviewed 67 adult T-ALL patients diagnosed and treated at our institute to identify clinical and pathologic prognostic factors. The median initial WBC was 21.3 x 10(9)/l. Blasts expressed at least one myeloid-associated antigen in 33%. Karyotypes were abnormal in 32% of the cases. Fifty-six of 64 patients (88%) achieved complete remission (CR). In univariate analysis, age, gender, initial WBC, CD10, CD34 and abnormal karyotype did not predict CR. Patients expressing at least one myeloid-associated antigen had a CR of 74% compared to 94% (p = 0.04) for those not expressing myeloid antigens. None of the above factors affected relapse-free or overall survival in this cohort. Our study indicates that expression of myeloid-associated antigens is associated with a lower CR rate in adult T-ALL and may be considered in risk stratification for induction chemotherapy.     

Clinical aspects of acute myeloid leukemias of the FAB types M3 and M4Eo

Summary Acute promyelocytic leukemia (AML FAB M3, APL) and acute myelomonocytic leukemia with abnormal eosinophils (AML M4Eo) are considered distinct entities with characteristic clinical, morphological, cytogenetic, and prognostic features. Promyelocytic leukemia is characterized by abnormal promyelocytes replacing normal hematopoiesis associated with a translocation between the long arms of chromosomes 15 and 17 t (15; 17), severe coagulopathy, and responsiveness to all-trans retinoic acid (tretinoin). Characteristic features of AML M4Eo are a myelomonocytic marrow infiltration, eosinophils with abnormal immature granules positive for chloroacetate esterase, an inversion or translocation of chromosome 16, and an increased risk of meningeal relapses. Prognosis of both types of AML has been reported to be better than prognosis of the other entities combined. Since most of the published data were collected from heterogeneous patient populations treated with various chemotherapeutic regimens, we have analyzed treatment outcome of AML M3 and M4Eo in the AMLCG-85 study for patients younger than 60 years. For the total population of 594 patients of this study, CR rate was 68.89%, early death rate 11.60%, and no or partial remission was achieved in 19.51% of the cases. Of 40 patients with AML M3 or M3v complete remission was attained in 62.5%. Nine patients died within 42 days after the start of antileukemic therapy (22.5%). Of these nine, four died because of infection, five because of bleeding. Relapse-free survival rate was 59% after 3 years, significantly better than the respective curve of the other FAB types combined (35% after 3 years). In AML M4Eo, 91.7% of the 24 patients reached complete remission. The early death rate was 8.3%. No case of nonresponse was seen. Relapse-free survival rate was 49% after 3 years compared with 35% for the other types combined.     

全反式维甲酸联合三氧化二砷治疗初发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)治疗急性早幼粒细胞白血病(APL)的完全缓解(CR)率和不良反应。方法ATRA25mg.m-2.d-1,As2O3(0.1%溶液)10mL/d联合治疗初发APL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ATRA和As2O3的剂量。结果29例初发APL患者,早期死亡2例,27例获得CR,CR率93.1%。获得CR的平均时间为(25.2±3.5)d。没有发现严重不良反应。结论ATRA联合As2O3治疗初发APL疗效好,不良反应患者能耐受。     

HAA方案诱导治疗成人初发急性髓系白血病150例疗效观察

目的 观察高三尖杉酯碱(HHT)、阿糖胞苷(Ara-C)、阿克拉霉素(Acla)三药联合(HAA)方案治疗成人初发急性髓系白血病(AML)的疗效与安全性.方法 对1999年5月至2008年6月收治的150例初发AML患者以HAA方案诱导治疗,统计完全缓解(CR)率,并采用Cox生存分析方法评估患者的无复发生存(RFS)时间.结果 150例患者CR率为81%,其中1个疗程后CR率为68%.除外5例早期死亡,9例失访,136例患者中位随访时间16.5(1.5～100.5)个月,3年预计总生存(OS)率为45%.对于达到CR的患者,3年预计RFS率为52%.按FAB分型分组,急性粒-单核细胞白血病(M4)/急性单核细胞白血病(M5)组CR率为71%,其CR患者的3年预计RFS率为62%,急性粒细胞白血病未分化型(M1)/急性粒细胞白血病部分分化型(M2)组CR率为92%,CR患者的3年预计RFS率为47%.按染色体核型分组,低危、中危与高危组的CR率分别为97%、84%和38%,其中低危组3年OS率为59%,中危组为45%,高危组13%.结论 HAA方案可作为成人初发AML患者的首选方案.1～2个疗程后可获得较高的CR率和RFS率,且毒副作用可耐受.

Abstract：

Objective To explore the efficacy and safety of HAA regimen (homoharringtonine,cytarabine and aclarubicin) in the treatment of 150 newly diagnosed adult acute myeloid leukemia (AML).Methods All patients entered the study from May 1999 to June 2008 were treated with HAA regimen. Coxsurvival analysis was used to estimate the survival rate and differences between M1/M2 and M4/M5 were compared with 2-sided log-rank test. Results Out of the 150 patients, 121 (81%) achieved complete remission (CR). After the first course, CR rate was 68%. The CR rates of 97%, 84% and 38% were achieved in patients with favorable, intermediate and unfavorable cytogenetics, respectively. For the patients with CR, the median follow-up time was 16.5 ( 1.5-100.5 ) months, and the estimated 3-year survival rate was 45%. The estimated 3-year relapse free survival rate was 52% for the 121 patients with CR.Conclusions HAA regimen may be an efficacious and safe regimen with a good toleration in the induction therapy for newly diagnosed AML, and a high CR rate could be achieved with only one or two courses.