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北京大学学报（医学版） ›› 2021, Vol. 53 ›› Issue (5): 915-920. doi: 10.19723/j.issn.1671-167X.2021.05.017

• 论著 • 上一篇    下一篇

MLL-AF6融合基因阳性急性髓系白血病的临床特征及预后

张梅香1,史文芝2,刘建新1,王春键1,李燕1,王蔚1,江滨1,△()   

  1. 1.北京大学国际医院血液科,北京 102206
    2.山西长治医学院附属和平医院血液科,山西长治 046000
  • 收稿日期:2020-03-16 出版日期:2021-10-18 发布日期:2021-10-11
  • 通讯作者: 江滨 E-mail:jiangbin@pkuih.edu.cn

Clinical characteristics and prognosis of MLL-AF6 positive patients with acute myeloid leukemia

ZHANG Mei-xiang1,SHI Wen-zhi2,LIU Jian-xin1,WANG Chun-jian1,LI Yan1,WANG Wei1,JIANG Bin1,△()   

  1. 1. Department of Hematology, Peking University International Hospital, Beijing 102206, China
    2. Heping Hospital Affiliated to Changzhi Medical College, Changzhi 046000, Shanxi, China
  • Received:2020-03-16 Online:2021-10-18 Published:2021-10-11
  • Contact: Bin JIANG E-mail:jiangbin@pkuih.edu.cn

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摘要：

目的: 探讨MLL-AF6融合基因阳性的急性髓系白血病(acute myeloid leukemia, AML)患者的临床特征和预后。方法: 回顾分析11例初治MLL-AF6阳性AML患者的临床和实验室资料,复习文献,总结该类疾病的临床特征及预后。结果: 11例患者中男6例,女5例,中位年龄36岁,急性白血病的分型诊断标准FAB分型(French-American-British classification systems)M5 6例,M4 5例。起病症状为牙龈肿痛6例,发热5例,初诊时中位白细胞计数55.5×109/L,免疫分型可见髓系细胞、单核细胞系统及干细胞系列抗原表达。MLL-AF6融合基因水平(实时定量PCR法)为14.2%~214.5%,6/11例(54.5%)合并EVI1基因高表达。4例患者二代测序检测出合并KRAS、TET2、ASXL1、TP53、DNMT3A及FLT3-ITD基因突变。染色体G显带检查,2例为t(6;11)(q27,q23)伴复杂核型异常,4/9例(44.4%)伴有+8异常,2例为正常核型。给予患者常规诱导化疗,达到完全缓解者8/11例(72.7%),3例患者原发耐药。8例完全缓解的患者中,2例达到微小残留病(minimal residual disease, MRD)阴性,中位完全缓解的持续时间为4.5个月。2例MRD阳性及3例难治复发患者接受了异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation, allo-HSCT), 后均死于白血病进展。随访至2019年12月1日, 2例存活,9例死亡,中位生存时间9个月。结论: MLL-AF6融合基因阳性AML多为年轻患者,FAB分型以M4、M5居多,常以发热起病,白细胞增高,可伴器官浸润,合并EVI1基因高表达多见。本病常规化疗的缓解率不低,但达到分子学缓解困难,极易出现早期复发,持续分子学阴性状态下尽早行allo-HSCT可能获得长期完全缓解。

关键词: 白血病, 髓系, 基因融合, 基因重排, MLL-AF6, 疾病特征, 预后

Abstract:

Objective: To investigate the clinical features and prognosis of acute myeloid leukemia (AML) patients with the mixed lineage leukemia (MLL) gene rearrangements AF6 (MLL-AF6) positive. Methods: In the study, 11 patients who were newly diagnosed with MLL-AF6 positive AML were analyzed retrospectively, related literature was reviewed to clarify the clinical features and prognosis of MLL-AF6 positive patients. Results: Among the 11 patients, there were 6 males and 5 females, with a median age of 36 years. Six patients were diagnosed with AML M5 and five with M4 according to FAB classification (French-American-British classification systems). Gingival swelling and pain occurred in 6 cases and fever occurred in 5 cases. At first diagnosis, the median white blood cells were 55.5×109/L. Immunotype showed the expression of myeloid/monocyte and early stem cell series antigens. The expression level of MLL-AF6 fusion gene (real-time quantitative PCR) was 14.2%-214.5%, and 6/11 cases (54.5%) were associated with high EVI1 gene expression. Mutations of KRAS, TET2, ASXL1, TP53, DNMT3A, and FLT3-ITD were detected by next generation sequencing (NGS) in 4 patients. Chromosome G banding examination showed that 2 cases were t(6;11)(q27,q23) with complex karyotype abnormality, 4 cases with +8 abnormality and 2 cases with normal karyotype. Hematological complete remission (CR) was achieved in 8/11 patients (72.7%) after conventional induction chemotherapy, and primary drug resistance was observed in 3 patients. Two of the eight patients with CR were negative for minimal residual disease (MRD), with a median CR duration of 4.5 months. Two patients with positive MRD and three patients with refractory recurrence underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), but all died due to leukemia progression. At the end of follow-up on December 1, 2019, 2 patients were alive and 9 died, with median survival time of 9 months. Conclusion: The AML patients with MLL-AF6 positive were mostly young, the majority of FAB types were M4 and M5, and most of the patients often had fever as the first symptom, with increased white blood cells, accompanied by organ infiltration, and high EVI1 gene expression. The hematological remission rate of routine chemotherapy is not low, but it is difficult to achieve molecular remission, most of which have early recurrence. Early allo-HSCT in a molecular negative state may prolong the CR duration.

Key words: Leukemia, myeloid, Gene fusion, Gene rearrangement, MLL-AF6, Disease attributes, Prognosis

中图分类号: 

  • R733.71

表1

11例MLL-AF6阳性AML患者临床资料"

Case number Gender Age/years FAB type WBC/(×109/L) HGB/(g/L) PLT/(×109/L) Bone marrow blasts
1 M 19 M5 55.25 86 77 0.95
2 M 36 M5 55.58 102 23 0.71
3 M 16 M5 120.30 94 106 0.84
4 F 39 M4 68.98 80 28 0.78
5 M 36 M5 2.26 64 133 0.84
6 F 33 M5 9.10 80 21 0. 88
7 F 57 M4 1.76 73 90 0.67
8 M 25 M4 70.30 113 117 0.84
9 M 63 M4 34.90 73 31 0.83
10 F 39 M4 61.60 79 16 0.42
11 F 35 M5 180.00 69 34 0.95

表2

MLL-AF6阳性AML患者细胞遗传学特点"

Cytogenetic at diagnosis n (%) (n=11)
Normal karyotype 2 (18.2)
t(6;11)(q27;q23) abnormality 9 (81.8)
t(6;11)(q27;q23), +8 4 (36.4)
Complex karyotype 2 (18.2)
t(6;11)(q27;q23) sole abnormality 2 (18.2)
t(6;11)(q27;q23)t(2;13)(p25;q12) 1 (9.1)

表3

MLL-AF6阳性AML患者免疫表型、分子生物学特征及转归"

No. Immunotype Level of
MLL-AF6/%		 Level of
EVI1/%		 Induction
regimen		 CR allo-HSCT Outcome OS/month
1 CD34, CD13, CD33, HLA-DR, CD15, CD4 14.2 - IA Y Y Dead 9
2 CD34, CD123, CD117, CD13, CD33, HLA-DR, CD64, CD11b, cMPO 57.6 - IA Y Y Dead 14
3 CD117, CD13, CD33, HLA-DR, CD64, CD56, cMPO 59.3 151.6 IA N Y Dead 7
4 CD34, CD117, CD33, CD13, CD9, HLA-DR, CD38, CD15 68.0 289.4 IA Y Y Dead 13
5 CD117, CD33, CD38, CD15, HLA-DR, CD56, CD64, CD11, cCD4, CXCR4, CD11b 70.1 - Dac+CAG Y N Dead 5
6 CD34, CD123, CD117, CD13, CD33, HLA-DR, CD38, CD64 138.2 339.6 IA Y N Dead 9
7 CD117, CD13, CD33, CD38, HLA-DR, CD16, CD11b, CD15, CD4, CD64, CD36, CD56, cMPO 25.0 - Dac+CAG N Y Dead 9
8 CD34, CD13, CD33, HLA-DR, CD4, CD15 36.6 75.8 IA Y N Dead 5
9 CD34, CD123, CD117, CD13, CD33, HLA-DR, CD9, CD64, cMPO, CD36, CD11b 96.8 34.1 IA Y N Dead 16
10 CD34, CD123, CD117, CD33, CD13, CD38, HLA-DR, CD11b, CD36, CD64, CD11c, CD14, CD15 214.5 154.4 Dac+DA N N Alive 2
11 CD34, CD33, HLA-DR, CD4, CD11b, CD38, CD56, CD64 29.1 - IA Y N Alive 11
[1] Liedtke M, Ayton PM, Somervaille TCP, et al. Self-association mediated by the Ras association 1 domain of AF6 activates the oncogenic potential of MLL-AF6 [J]. Blood, 2010, 116(1):63-70.
[2] Meyer C, Burmeister T, Gröger D, et al. The MLL recombinome of acute leukemias in 2017 [J]. Leukemia, 2018, 32(2):273-284.
doi: 10.1038/leu.2017.213 pmid: 28701730
[3] 刘艳荣, 于弘, 常艳, 等. 四色荧光标记抗体在白血病免疫分型中的应用及意义 [J]. 中国实验血液学杂志, 2002, 10(5):423-427.
[4] 主鸿鹄, 刘艳荣, 秦亚溱, 等. 实时定量PCR检测46例初诊急性早幼粒细胞白血病患者PML/RARα mRNA的分子表达 [J]. 中国实验血液学杂志, 2007, 15(1):1-5.
[5] 沈悌, 赵永强. 血液病诊断及疗效标准 [M]. 第4版. 北京: 科学出版社, 2018: 91-95.
[6] Jaffe ES, Harris NL, Stein H, et al. World Health Organization of tumors pathology & genetics, tumors of haematopoietic and lymphoid tissues [M]. Lyon: IARC Press, 2001: 86-87.
[7] Pigneux A, Labopin M, Maertens J, et al. Outcome of allogeneic hematopoietic stem-cell transplantation for adult patients with AML and 11q23/MLL rearrangement (MLL-r AML) [J]. Leukemia, 2015, 29(12):2375-2381.
doi: 10.1038/leu.2015.143 pmid: 26082270
[8] Mrózek K, Heinonen K, Lawrence D, et al. Adult patients with de novo acute myeloid leukemia and t (9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study [J]. Blood, 1997, 90(11):4532-4538.
pmid: 9373264
[9] Blum W, Mrózek K, Ruppert AS, et al. Adult de novo acute myeloid leukemia with t(6;11)(q27;q23): results from Cancer and Leukemia Group B Study 8461 and review of the literature [J]. Cancer, 2004, 101(6):1420-1427.
doi: 10.1002/cncr.v101:6
[10] Martineau M, Berger R, Lillington DM, et al. The t (6; 11)(q27; q23) translocation in acute leukemia: a laboratory and clinical study of 30 cases [J]. Leukemia, 1998, 12(5):788-791.
pmid: 9593282
[11] Gröschel S, Schlenk RF, Engelmann J, et al. Deregulated expression of EVI1 defines a poor prognostic subset of MLL-rearranged acute myeloid leukemias: a study of the German-Austrian Acute Myeloid Leukemia Study Group and the Dutch-Belgian-Swiss HOVON/SAKK Cooperative Group [J]. J Clin Oncol, 2013, 31(1):95-103.
doi: 10.1200/JCO.2011.41.5505 pmid: 23008312
[12] Manara E, Baron E, Tregnago C, et al. MLL-AF6 fusion oncogene sequesters AF6 into the nucleus to trigger RAS activation in myeloid leukemia [J]. Blood, 2014, 124(2):263-272.
doi: 10.1182/blood-2013-09-525741 pmid: 24695851
[13] Neff T, Armstrong SA. Recent progress toward epigenetic therapies: the example of mixed lineage leukemia [J]. Blood, 2013, 121(24):4847-4853.
doi: 10.1182/blood-2013-02-474833
[14] Krauter J, Wagner K, Schäfer I, et al. Prognostic factors in adult patients up to 60 years old with acute myeloid leukemia and translocations of chromosome band 11q23: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup [J]. J Clin Oncol, 2009, 27(18):3000-3006.
doi: 10.1200/JCO.2008.16.7981 pmid: 19380453
[15] Tamai H, Yamaguchi H, Takahashi S, et al. Treatment of adult AML with t(6;11)(q27;q23) by allogeneic hematopoietic SCT in the first CR [J]. Bone Marrow Transplant, 2008, 42(8):553-554.
doi: 10.1038/bmt.2008.200
[16] Mitterbauer G, Zimmer C, Pirc-Danoewinata H, et al. Monitoring of minimal residual disease in patients with MLL-AF6-positive acute myeloid leukaemia by reverse transcriptase polymerase chain reaction [J]. Br J Haematol, 2000, 109(3):622-628.
doi: 10.1046/j.1365-2141.2000.02076.x
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