混合谱系白血病-AF6融合基因阳性急性髓系白血病八例临床特点与预后

目的 探讨混合谱系白血病（MLL）-AF6融合基因[t（6;11） （q27;q23）]阳性急性髓系白血病（AML）患者的临床特点与预后.方法 收集安徽省立医院血液内科住院初治MLL-AF6融合基因阳性的AML患者8例,利用多重巢式反转录-聚合酶链反应（RT-PCR）检测治疗前后MLL-AF6融合基因动态变化,分析患者临床特征、免疫表型、细胞遗传学、患者首次诱导治疗后完全缓解（CR）率、总体生存率、造血干细胞移植效果与患者预后的关系.结果 2009年2月至2013年8月住院患者确诊为急性白血病（AL）患者472例,其中AML患者285例,包括MLL-AF6融合基因阳性AML患者8例,占AL的1.69％（8/472）,占AML的2.80％（8/285）.MLL-AF6融合基因阳性AML患者按WHO分型：M11例,M22例,M42例,M53例,以M4/M5为主（5例）.8例AML患者首次化疗后CR 5例,总体生存4例.4例单纯化疗患者中,有2例在第1个疗程结束后MLL-AF6融合基因转阴,且1例获得了血液学CR并已生存26个月,1例初诊后6个月复发,后经治疗后死亡;2例患者第1个疗程结束后MLL-AF6融合基因未转阴（1例转为弱阳性,1例仍为阳性）,均未获得血液学CR且死亡.4例造血干细胞移植患者中,3例移植前MLL-AF6融合基因转阴,均无复发,仍生存,平均生存时间28个月;1例患者移植前MLL-AF6融合基因未转阴（弱阳性）,移植后复发死亡.结论 MLL-AF6融合基因阳性AML患者在AML-M4/M5中发生率高,发病时常伴有高白细胞、器官浸润,且治疗效果差,易复发,预后差,造血干细胞移植可显著改善患者预后.RT-PCR检测治疗前后MLL-AF6融合基因的动态变化可在一定程度上帮助判断患者预后.     

维奈克拉联合阿伐替尼治疗伴KIT基因突变复发难治急性髓系白血病2例并文献复习

目的探讨维奈克拉联合阿伐替尼治疗伴KIT基因突变复发难治急性髓系白血病(AML)的效果。方法回顾性分析苏州沧浪医院2022年10月及2022年11月收治的2例接受维奈克拉联合阿伐替尼治疗的伴KIT基因突变AML患者的临床资料, 并复习相关文献。结果 2例患者均为女性, 分别为53、17岁, 均为高危复发难治AML, 均伴KIT基因突变。例1诊断为AML-M2, 基因检测示ASXL1、KIT、RUNX1基因突变均阳性;患者移植后再次复发, 接受维奈克拉联合阿伐替尼治疗达到形态学无白血病状态(MLFS)。例2诊断为AML, 检测到RUNX1-RUNX1T1(AML1-ETO)融合基因及KIT、DX15基因突变;复发后接受维奈克拉联合阿伐替尼方案治疗, 明显降低了肿瘤负荷, 桥接异基因造血干细胞移植后再次获得完全缓解。结论伴KIT基因突变AML具有一定的异质性, 部分患者治疗难度大, 预后极差;复发患者选择维奈克拉联合阿伐替尼治疗达MLFS或完全缓解后, 桥接(二次)造血干细胞移植可作为此类患者的较好治疗选择。     

实时定量荧光反转录-聚合酶链反应检测急性白血病AML1／ETO融合基因

  【摘要】　目的　建立实时定量荧光反转录-聚合酶链反应（RQ RT-PCR）的方法并用来检测AML-M2患者中AML1／ETO融合基因的拷贝数,观察患者体内融合基因阳性率、该融合基因转录水平的变化情况及AML1／ETO融合基因阳性患者对治疗的反应。方法　利用含AML1／ETO融合基因的Kasumi-1细胞株构建质粒标准品并制作标准曲线,检测25例AML-M2患者的骨髓及外周血标本45份,个别患者连续监测融合基因转录表达水平。25例患者均同时行流式细胞术免疫分型检测及骨髓细胞染色体检查,确诊后给予MA方案进行诱导缓解。结果　在28 %（7／25）的AML-M2初发确诊患者中检测到AML1／ETO阳性（AML1／ETO：ABL为0.01～19.2）,其中5例（20 %）有t(8;21)(q22;q22)。连续监测患者融合基因转录表达水平与临床缓解和复发的变化情况相吻合。7例AML1／ETO融合基因阳性患者均在MA治疗1个疗程后达完全缓解,AML1／ETO融合基因下降3个数量级。其余18例完全缓解11例。连续监测7例AML1／ETO融合基因阳性患者6个月均处于完全缓解状态。结论　实时定量荧光PCR技术成熟、操作简便,检测白血病融合基因结果准确稳定,对于临床明确诊断、具体分型、动态观测肿瘤负荷、选择治疗方案、评估治疗效果和预后都有较大价值。     

DEK-CAN融合基因阳性急性髓系白血病患者临床特征及预后分析

目的:探讨DEK-CAN融合基因阳性急性髓系白血病（AML）患者的临床特征及预后。方法:回顾性分析2014年8月至2018年1月郑州大学第一附属医院收治的6例DEK-CAN融合基因阳性AML患者的临床资料,总结其临床特征、治疗及转归。结果:6例患者均为女性,中位年龄29岁（4~64岁）。6例患者中,原始粒细胞白血病部分分化型（M 2）5例,急性单核细胞白血病（M 5）1例。外周血白细胞数升高5例,骨髓病态造血1例,嗜碱性粒细胞增多2例。6例患者免疫表型均CD34、CD13、CD38、CD33阳性。融合基因检测示患者DEK-CAN均为阳性,NPM1突变均为阴性,3例合并FLT3-ITD突变,2例合并WT1突变。染色体核型分析示2例未见分裂象,其余均为t（6;9）。6例患者中仅1例儿童患者第1个疗程诱导化疗取得完全缓解,5例成年患者第1个疗程化疗均未达到完全缓解,且在短期内死于并发症。 结论:DEK-CAN融合基因阳性AML患者预后极差,初次诱导缓解率低,死亡率高。     

CLAG方案治疗复发难治急性髓系白血病六例并文献复习

目的 分析CLAG方法治疗复发难治急性髓系白血病(AML)患者的临床疗效及不良反应.方法 对河南省肿瘤医院血液科6例复发难治AML患者采用CLAG(克拉屈滨+阿糖胞苷+粒细胞集落刺激因子)方案治疗,分析6例患者临床资料,并结合文献进行复习.结果 6例复发难治AML患者中,男性5例,女性1例;中位年龄45岁(13～ 63岁);复发和难治各3例.应用CLAG方案后5例达完全缓解,1例未缓解;6例患者均出现骨髓抑制,但是治疗期间无严重不良反应发生.结论 CLAG方案治疗复发难治AML疗效确切,不良反应耐受性较好,并需后续行异基因造血干细胞移植等积极治疗.     

SET/CAN和DEK/CAN融合基因阳性急性髓系白血病一例并文献复习

目的 提高对SET/CAN和DEK/CAN融合基因阳性急性髓系白血病(AML)诊治的认识.方法 对1例SET/CAN和DEK/CAN融合基因阳性AML患者的临床特点进行分析,并结合相关文献进行复习.结果 该例SET/CAN和DEK/CAN融合基因阳性AML患者以发热起病,化疗2个周期后获得完全缓解,但很快复发,生存期仅8个月.结论 SET/CAN和DEK/CAN融合基因阳性AML患者罕见,生存期短,预后较差,对化疗不敏感.     

AML1-ETO融合基因转阴对急性髓细胞白血病预后的影响

目的:探讨AML1-ETO融合基因阳性表达的急性髓细胞白血病（acute myelocytic leukemia,AML）患者治疗后融合基因转阴及转阴时间长短对AML患者预后的影响。方法:对2012年1月1日至2016年12月31日在中国医科大学附属盛京医院住院治疗的35例初诊AML1-ETO融合基因阳性AML患者的临床资料进行回顾性分析,总结其形态学、免疫学和分子生物学特征,用 Kaplan-Meier 曲线评估患者生存情况。结果:35例患者男女比例 1.33∶1,中位年龄为34岁(15~71岁)。中位随访时间为16(4~61)个月,诱导缓解率为82.9%,3个疗程或以上缓解占14.3%(n=5),始终未缓解占2.9%(n=1),复发率35.3％(n=12),复发中位时间 12（6~20）个月。其中11例治疗后融合基因转阴,包括3个月内转阴占63.6%（n=7）,大于3个月转阴占36.4%（n=4）。单因素分析表明AML1-ETO融合基因转阴患者OS和PFS高,预后较好,AML1-ETO融合基因转阴时间长短对患者长期生存的影响无统计学意义（P=0.707）。结论:AML1-ETO融合基因转阴的AML患者预后较好,AML1-ETO融合基因转阴时间长短对患者的长期生存无明显影响。     

多重巢式RT-PCR技术在急性髓系白血病中的应用

 目的　探讨急性髓系白血病（AML）染色体畸变所形成的融合基因与MICM分型及临床诊断、治疗、预后的关系。方法　采用多重巢式RT-PCR方法对60例AML患者的融合基因联合染色体核型、免疫表型、临床资料进行研究。结果　60例AML中有37例（61.67 %）具有5种融合基因：MLL-AF9、TLS-ERG、CBFβ-MYH1、AML1-ETO、PML-RARα。13例患者有HOX11原癌基因活化,10例为单纯表达HOX11原癌基因活化,3例同时伴有其他融合基因表达。伴AML1-ETO、PML-RARα的31例患者中接受化疗的23例全部达完全缓解（CR）,且无复发。结论　基因分型是AML最精确的分型方法,可为临床化疗提供指导。采用多重巢式RT-PCR方法可快速同时检测急性白血病29种染色体畸变所形成的融合基因,完善白血病的MICM分型,指导临床个体化治疗。     

地西他滨联合半量CAG方案治疗复发难治急性髓系白血病效果观察

目的 观察地西他滨联合半量CAG方案治疗复发难治急性髓系白血病(AML)的临床效果.方法 收集2015年1月至2017年1月大同市第三人民医院8例接受地西他滨联合半量CAG方案治疗的复发难治AML患者的临床资料,分析其疗效及不良反应.结果 1个疗程地西他滨联合半量CAG方案治疗后,完全缓解3例,部分缓解2例.主要不良反应为骨髓抑制及感染,8例患者均出现Ⅲ～Ⅳ级血液学不良反应,5例出现感染,2例出现Ⅰ级药物性肝损害,无治疗相关死亡发生.结论 地西他滨联合半量CAG方案治疗复发难治AML具有良好疗效,值得进一步研究.     

急性髓系白血病合并髓系肉瘤三例并文献复习

目的 分析急性髓系白血病(AML)合并髓系肉瘤(MS)的诊断和治疗方法.方法 收集3例在上海市北站医院按照常规方案诱导和巩固治疗并在骨髓缓解期发生MS的AML患者临床资料,分析其临床特点、诊断及治疗.结果 3例患者均为女性,其中2例CBFβ-MYH11阳性,1例AML1-ETO阳性;2例发生在第2次完全缓解(CR2),1例发生在CR1;3例分别发生于颅内、阴道、乳房.化疗后3例患者均短期有效,其中1例至截稿时骨髓仍处于缓解期,1例骨髓复发后死亡,1例失访.结论 AML缓解期合并髓外病灶时,应及时通过病理检查明确诊断.系统性化疗是MS的主要治疗方法,对于中枢神经系统受累者,可参照中枢神经系统白血病的治疗方式.异基因造血干细胞移植可能是患者的最佳选择.     

Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein.

The NPM-MLF1 chimeric protein is produced by the t(3;5)(q25.1;q34) chromosomal translocation, which is associated with myelodysplastic syndrome (MDS) prior to progression into acute myeloid leukemia (AML). Here we report that K562 human leukemia cells ectopically expressing NPM-MLF1, but not those with wild-type MLF1, were gradually eliminated from the culture by undergoing apoptosis. NIH3T3 mouse fibroblasts engineered to overexpress NPM-MLF1 grew normally but serum deprivation triggered apoptotic cell death with slower kinetics than did other well-known apoptotic inducers such as c-Myc or E2F-1. Quantitative analysis of apoptotic induction confirmed that, neither NPM nor MLF1, but the NPM-MLF1 fusion protein was able to induce apoptosis. Analyses using a variety of deletion mutants of NPM-MLF1 revealed that induction of apoptosis required the N-terminal domain of MLF1 and the NPM domain containing nuclear localization signal and that removal of the NPM dimerization domain markedly impaired the ability to induce apoptosis. Co-expression of Bcl-2 rescued NIH3T3 fibroblasts from NPM-MLF1-mediated cell death without affecting the expression level or the subcellular localization of NPM-MLF1 and enabled cells to progress into S phase in low serum. These findings provide an NPM-MLF1-mediated novel mechanism of apoptotic induction and imply that NPM-MLFI in collaboration with anti-apoptotic oncoproteins may play an important role in multi-step progression from MDS to AML.     

Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma.

The FIP1L1-PDGFRA fusion gene has been described in patients with eosinophilia-associated myeloproliferative disorders (Eos-MPD). Here, we report on seven FIP1L1-PDGFRA-positive patients who presented with acute myeloid leukemia (AML, n=5) or lymphoblastic T-cell non-Hodgkin-lymphoma (n=2) in conjunction with AML or Eos-MPD. All patients were male, the median age was 58 years (range, 40-66). AML patients were negative for common mutations of FLT3, NRAS, NPM1, KIT, MLL and JAK2; one patient revealed a splice mutation of RUNX1 exon 7. Patients were treated with imatinib (100 mg, n=5; 400 mg, n=2) either as monotherapy (n=2), as maintenance treatment after intensive chemotherapy (n=3) or in overt relapse 43 and 72 months, respectively, after primary diagnosis and treatment of FIP1L1-PDGFRA-positive disease (n=2). All patients are alive, disease-free and in complete hematologic and complete molecular remission after a median time of 20 months (range, 9-36) on imatinib. The median time to achievement of complete molecular remission was 6 months (range, 1-14). We conclude that all eosinophilia-associated hematological malignancies should be screened for the presence of the FIP1L1-PDGFRA fusion gene as they are excellent candidates for treatment with tyrosine kinase inhibitors even if they present with an aggressive phenotype such as AML.     

Results of imatinib mesylate therapy in patients with refractory or recurrent acute myeloid leukemia,high-risk myelodysplastic syndrome,and myeloproliferative disorders

BACKGROUND: Imatinib mesylate is a selective tyrosine kinase inhibitor of c-abl, bcr/abl, c-kit, and platelet-derived growth factor-receptor (PDGF-R). c-kit is expressed in most patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) and PDGF has been implicated in the pathogenesis of myeloproliferative disorders (MPD). METHODS: The authors investigated the efficacy of imatinib in patients with these disorders. Forty-eight patients with AML (n = 10), MDS (n = 8), myelofibrosis (n = 18), atypical chronic myeloid leukemia (CML; n = 7), chronic myelomonocytic leukemia (CMML; n = 3), or polycythemia vera (n = 2) were treated with imatinib 400 mg daily. RESULTS: None of the patients with AML or MDS responded. Among patients with myelofibrosis, 10 of 14 patients with splenomegaly (71%) had a 30% or greater reduction in spleen size, 1 patient had trilineage hematologic improvement, 2 had erythroid hematologic improvement, and 1 had improvement in platelet count. One patient with atypical CML had erythroid hematologic improvement. Both patients with polycythemia vera needed fewer phlebotomies (from 2-3 per year to none during the 8 months of therapy and from 3-6 per year to 1 during 9 months of therapy). None of the three patients with CMML responded. Treatment was well tolerated. The side effects were similar to those observed in patients with CML. CONCLUSIONS: Within these small subgroups of disease types, single-agent imatinib did not achieve a significant clinical response among patients with AML, MDS, atypical CML, or CMML without PDGF-R fusion genes. Preliminary data on polycythemia vera are promising and deserve further investigation. Responses among myelofibrosis patients were minor. Therefore, a combination treatment regimen including imatinib may be more effective.     

Diagnostic application of next-generation sequencing in ZMYM2-FGFR1 8p11 myeloproliferative syndrome: A case report

The 8p11 myeloproliferative syndrome (EMS), also known as 8p11 myeloproliferative neoplasm (8p11 MPN), is a collection of rare hematologic malignancies that are associated with fusion genes involving the tyrosine kinase receptor gene FGFR1 in chromosome 8p11. The entity is an aggressive disease with a high rate of transformation to acute myeloid leukemia (AML) and pathologically characterized by its associated eosinophilia. In this study, we reported a distinctive EMS case featuring an in-frame ZMYM2-FGFR1 fusion gene identified by next-generation sequencing technology (NGS). This patient exhibited not only typical EMS signs including elevated white blood cells in peripheral blood and hypercellular bone marrow with marked leukocytosis, but also exceptional characteristics including erythrocytosis in blood and bone marrow basophilia. Moreover, we detected 2 novel genomic mutations in 2 known leukemogenic genes, IKZF1 and ASXL1. Whether these 2 mutations play a part in EMS pathogenesis or contribute to its specific presentations clinically remain to be determined. In summary, we present a unique EMS case involving a ZMYM2-FGFR1 fusion with distinctive hematologic characteristics.     

急性髓系白血病M2b型分子生物学特征的鉴定

目的 :研究急性髓系白血病 (AML) M2 b细胞遗传学和分子生物学特征 ,探讨 AML- M2 b与 t(8;2 1)白血病的关系。方法 :应用 G显带技术分析染色体核型 ,用 RT- PCR法检测 AML 1/ MTG8融合基因转录本并进行微量残留白血病检测 ,采用 Southern Blot技术检测 AML 1及 MTG8基因重排。结果 :86 .1% (31/ 36例 )的 AML -M2 b具有 t(8;2 1) ,13.9% (5 / 36例 )无 t(8;2 1)。在 AML- M2 b中 ,AML1/ MTG8融合基因转录本的检出率为10 0 % (44 / 44例 ) ,其中包括 5例无 t(8;2 1)的病例 ,AML1基因和 MTG8基因的重排检出率分别为 81.8%和71.0 %。 13例完全缓解 (CR)的 AML- M2 b中 12例可检出 AML1/ MTG8融合基因转录本。结论 :AML- M2 b与国际上的 t(8;2 1)白血病所指为同一疾病实体 ,AML 1/ ETO融合基因是这种疾病的基因标志 ,AML - M2 b可分为 t(8;2 1) ( ) AML 1/ ETO( ) AML - M2 b和 t(8;2 1) (- ) AML 1/ ETO( ) AML - M2 b。经化疗获 CR的 AML - M2 b仍可检出微量残留白血病细胞。