MLL-AF4融合基因阳性急性白血病患者的临床特征及预后分析.pdf

Hematololalignancy血液系统肿瘤（编校：谈静）MODERNONCOI.31,No.1834272023年0 9 月现代肿瘤医学第31卷第18 期plasmic yes-associated protein(YAP)expression in mismatchrepair protein-proficient colorectal cancer with high-gradetumor budding and reduced autophagy activity J.Appl Immu-nohistochem Mol Morphol,2021,29(4):305-312.28MEHDI S,MOHAMMAD RK,AMIR HK,et al.Network-basedand machine-learning approaches identify diagnostic and prog-nostic models for EMT-type gastric tumorsJ.Genes(Basel),2023,14(3):750.29LEE J,CRISTESCU R,KIM KM,et al.Development of mesenchy-mal subtype gene signature for clinical application in gastric canc-er J.0ncotarget,2017,8:66305-66315.MLL-AF4 融合基因阳性急性白血病患者的临床特征及预后分析张梅香，王春键，史琳，李燕，任汉云北京大学国际医院血液科，北京10 2 2 0 6【摘要】目的：探讨MLLA F4融合基因阳性急性白血病（MLL-AF4AL）患者的临床特征和预后。方法：回顾性分析10 例成人MLLA F4A L患者的临床资料,复习文献总结患者的临床特征及预后。结果：10例患者中女性6 例，中位年龄34.5岁。起病时中位白细胞数114.8 910/L,5例合并弥散性血管内凝血,4例合并髓外侵犯。8 例免疫表型符合急性B淋巴细胞白血病(B-ALL),其中6 例pro-BA LL,2 例pre-B-ALL;2例混合表型急性白血病(MPAL),B/T淋系及B淋系/未分化型各1例。9例患者染色体具有t(4;11)（q 2 1;q 2 3）。7 例B-ALL患者1疗程诱导化疗后6 例获完全缓解（CR1）,4例行异基因造血干细胞移植（allo-HSCT）,2 例患者死于移植后感染、脑出血及中枢复发,2 例长期生存。2 例未移植者于2疗程内复发。2 例MPAL患者诱导化疗1例 CR。复发的3例患者予Blinatumomab挽救治疗,1例CR2后出现髓外复发,另2 例治疗无效。2 例B-ALL治疗中发生系别转换。结论：成人MLLA F4A L具有独特临床特征,pro-B-ALL多见。起病时白细胞水平较高，髓外浸润和凝血异常多见。常规化疗具有较高缓解率，但易早期复发，可能发生谱系转换。Blinatumomab细胞靶向治疗对该类型白血病有一定疗效，但MRD转阴后allo-HSCT是改善其预后的唯一希望。【关键词】急性白血病；基因重排；MLL；预后；谱系转换【中图分类号】R733.71【文献标识码】AD0I:10.3969/j.issn.1672-4992.2023.18.017【文章编号】16 7 2-4992-（2 0 2 3)18-342 7-0 5Clinical characteristics and prognostic analysis of MLL-AF4 positive acute leukemia pa-tientsZHANG Meixiang,WANG Chunjian,SHI Lin,LI Yan,REN HanyunDepartment of Hematology,Peking University International Hospital,Bejing 102206,China.【A b s t r a c t I Objective:To investigate the clinical features and prognosis of MLL-AF4 positive acute leukemia(AL).Methods:1O adult cases with MLL-AF4 positive AL were analyzed retrospectively and related literatureswere reviewed to clarify the clinical featrues and prognosis of MLL-AF4 patients.Results:6 out of the 10 patientswere females,with a median age of 34.5 years old.The number of median white blood cells at the time of diagnosiswas 114.89 10/L.5 cases complicated with disseminated intravascular coagulation(DIC)and 4 cases with extr-amedullary invasion.The immunophenotypic characterization of 8 patients was acute B-lymphoblastic leukemia(B-ALL),including 6 case of pro-B-ALL and 2 case of pre-B-ALL.2 patients showed mixed phenotype acute leu-kemia(MPAL),one displayed a mixture of B/T lymphoid features and the other was B lymphoid/undifferentiatedtype.9 patients had chromosome t(4;11)(q21;q23).6 of 7 cases with B-ALL achieved the first complete remission(CR)after conventional chemotherapy.4 patients underwent allogeneic hematopoietic stem cell transplantation(allo-HSCT)in CR,2 cases died of post-transplantation infection,cerebral hemorrhage,and central recurrence,2 cases【收稿日期】2023-04-03【修回日期】2 0 2 3-0 5-19【作者简介】张梅香（197 1一），女，山西人，副主任医师，硕士，主要从事急性白血病的临床诊治工作。E-mail：150 11558 12 1 16 3.c o m【通信作者】任汉云（1959一），男，山东人，主任医师，博士生导师，主要从事骨髓移植及血液系统肿瘤的诊治工作。Modern Oncology 2023,:3427-34313428MLL-AF4融合基因阳性急性白血病患者的临床特征及预后分析张梅香，等gained long term survival.2 patients without transplantation both relapsed within 2 courses of treatment.One patient of2 patients with MPAL achieved CR after induction chemotherapy.Three relapsed patients were treated with Blinatu-momab,one developed extramedullary relapse after CR2,and treatment failed in other two.Lineage switch occurred in2 B-ALL patients during therapy.Conclusion:Adult MLL-AF4 positive AL has unique clinical characteristics.Themajority is pro-B-ALL and few is pre-B-ALL and MPAL,often onset with high white blood cell counts,extr-amedullary infiltration and coagulable abnormality.Conventional chemotherapy has a higher response rate,but its easyto relapse and lineage switch.Blinatumomab is effective as a salvage therapy,but allo-HSCT in MRD negative statusshould have the only potential to improve the prognosis of MLL-AF4*AL.Key words J acute leukemia,gene rearrangement,MLL,prognosis,lineage switch细胞和分子遗传学异常是急性白血病（acute leukemia，AL)发病的基础,充分认识具有关键致病作用的特殊基因，有助于对疾病进行精准化诊断分层及个体化治疗。位于11号染色体长臂2 区3带（11q23）的MLL基因（mixed lineageleukemia,也称KMT2A)异常是AL较为常见的分子学异常，其断裂点序列可以与超过10 0 个不同的伙伴基因发生重排，形成的融合基因转录蛋白缺失了MLL基因的激活区，干扰下游HOX基因表达的调节，导致白血病的发生。世界卫生组织（WorldHealthOrganization，W H O）分类认定11q23/MLL重排(MLL-r)白血病为急性髓系白血病（AML）、急性B淋巴细胞白血病（B-ALL）和混合表型急性白血病(MPAL)中的一种重现性细胞遗传学异常2 。MLL基因与位于4q21上的AF4基因（也称AFF1）融合形成的MLLAF4多见于婴儿及儿童中，成人ALL中的占比不到10%，仅有1%发生于AML3。M PA L中MLL基因重排比例小于5%4。成人MLL-AF4融合基因阳性AL（M LLA F4*AL)总体病例数不多，但其具有独特的临床和生物学特点，国内相关报道少见。现将我中心收治的10 例成人MLL一AF4+AL患者的临床和实验室资料进行回顾性总结分析，以期增强对这类疾病的认识1资料与方法1.1一般资料以2 0 17 年0 6 月至2 0 2 1年0 6 月本中心收治的10 例MLLA F4A L患者作为研究对象。所有病例均经骨髓细胞形态学结合组织化学染色、流式细胞术免疫分型、染色体核型分析以及白血病相关基因检查，依据WHO(2016版）诊断分型标准2 确诊。本研究获得本单位伦理委员会批准,所有研究对象均签署知情同意书。1.2方法1.2.1免疫表型分析取肝素抗凝骨髓5mL,参照文献5 对10 例MLL-AF4+AL患者进行相关抗体标记1.2.2细胞遗传学分析取肝素抗凝骨髓细胞标本，通过2 4h培养法制备染色体，应用G显带技术显带处理，经过图像采集、分析，参照人类细胞遗传学国际命名体制（ISCN2009）进行染色体核型分析。1.2.3分子生物学分析10例患者均进行MLL-AF4融合基因的检测,4