-
摘要: 目的 探讨亲嗜性病毒整合位点1阳性急性髓系白血病[EVI1(+)AML)]患者的临床特征、治疗方案、治疗反应及生存情况。方法 收集30例14岁及以上的青少年和成人EVI1(+)AML患者的临床资料，对其临床特征、治疗方案、疗效及预后进行分析。结果 本EVI1(+)AML研究队列中，年龄＜60岁的成人患者占绝大多数(80.0%)，初诊时以骨髓原始细胞＜50%(73.3%)及白细胞计数＜30×109/L居多(63.3%)，FAB分型以M2多见(50.0%)。骨髓增生异常综合征(MDS)转化AML 5例，占16.7%。按WHO 2022分型，骨髓增生异常相关AML 10例，占33.3%。按细胞遗传学和ELN 2017预后分组，只有1例t(8；21)/RUNX1T1-RUNX1的低危组患者，其他均为中高危组。难治/复发性AML患者17例，占73.9%。初诊时临床与实验室参数与诱导治疗是否有效及是否为难治/复发性AML无关(P>0.05)。以DNA二代测序方法检测基因突变的患者24例，19例患者伴有至少1种基因突变，但与是否为难治/复发性AML无关(P>0.05)。第1个疗程治疗方案有效率(CR+PR)为52.2%，第1个疗程所有诱导治疗方案1年累计死亡率(CMR)为61.1%。其中采取标准及大剂量单纯化疗和去甲基化药物联合小剂量化疗和(或)小分子靶向药物的相对缓解率(P=0.667)和CMR(P=0.101)，差异均无统计学意义。行标准及大剂量单纯化疗方案患者的总生存期(OS)显著优于去甲基化药物联合小剂量化疗和(或)小分子靶向药物的患者(P=0.010)。以造血干细胞移植(SCT)作为巩固化疗方案，1年CMR显著优于非SCT方案(P=0.013)，且行SCT患者的OS明显优于未行SCT患者(P=0.001)。结论 EVI1(+)AML患者多为高危组，部分为MDS转化或骨髓增生异常相关AML，常伴有其他基因突变，多为难治/复发性，1年CMR高，预后差。临床特征及目前诱导治疗方案与治疗反应和1年CMR无关。诱导后行SCT可降低死亡率，改善生存。Abstract: Objective To investigate the clinical features, therapeutic regiments, treatment response and survival of EVI1(+) acute myeloid leukemia(AML).Methods Clinical charateristics, therapeutic regimens, treatment response and prognosis of 30 adolescent and adult EVI1(+) AML were analyzed.Results In this EVI1 (+) AML study cohort, the majority of adult patients (80.0%) were younger than 60 years old. At the initial diagnosis, the majority of them were low bone marrow primordial cells (73.3%) and low white blood cell count (63.3%). M2 type was the predominant FAB subtype and accounting for 50.0%. There were 5 MDS-AML, accounting for 16.7%. According to WHO 2022 classification, there were 10 cases of myelodysplasia-related AML, accounting for 33.3%. According to ELN 2017 classification, there was one case t(8; 21)/RUNX1T1-RUNX1 within favorable-risk group, whereas the other 29 cases belong to intermediate and high-risk groups. There were 17 cases of refractory/relapse, accounting for 73.9%. The parameters of clinical features and laboratory tests were correlated with treatment response and refractory/relapse status and there were no signicant associations(P>0.05). There were 24 cases examined with genetic mutational statuses with next generation sequencing. 19 of the 24 cases had at least one genetic muation. Meanwhile it did not show correlation between mutational statuses and refractory/relapse statuses. The overall remission rate of first cycle of inductive treatment was 52.2%, and the one-year cumulative mortality rate(CMR) was 61.1%. The different first cycle inductive treatment regimens did not significantly influence on either remission rate(P=0.667) or CMR(P=0.101). There were no significant differences between high/standard dose chemotherapeutic regimens and demethylation drug based combinatory treatments. Survival analysis suggested significant improvement of survival in patients treated with high/standard dose chemotherapeutic regimens verses demethylation drug based combinatory treatments(P=0.010). Consolidation treatment with SCT significantly improved 1 year CMR(P=0.013) and overall survival verses non-SCT treatment(P=0.001).Conclusion EVI1(+) AML are mostly in poor risk status, with the predomiant WHO 2022 subtype of myelodysplasia-related AML. EVI1(+) AML usually have at least one mutational alteration and are mostly relapsed and refractory with high 1 year CMR. It suggested that inductive treatment regimen with high/standard dose chemotherapy and SCT treatment significantly improve the survival of patients.
-
Key words:
- EVI1 /
- acute myeloid leukemia /
- clinical characteristics /
- treatment
-
-
表 1 EVI1(+)AML患者临床及实验室特征
特征 例数 百分比/% 年龄/岁 < 60 24 80.0 ≥60 6 20.0 性别 男 16 53.3 女 14 46.7 原始细胞比例/% ≥50 5 16.7 20~49 22 73.3 未知 3 10.0 白细胞计数/(×109·L-1) ≥30 7 23.3 < 30 19 63.3 未知 4 13.3 AML类型 初诊AML 24 80.0 MDS转化AML 5 16.7 tAML 1 3.3 FAB分型 M1 7 23.3 M2 15 50.0 M4 2 6.7 M5 3 10.0 未知 3 10.0 细胞遗传学分组 低危 1 3.3 中危 9 30.0 高危 15 50.0 未知 5 16.7 ELN 2017分层 低危 1 3.3 中危 4 13.3 高危 20 66.7 未知 5 16.7 WHO 2022 AML伴RUNX1∷RUNX1T1融合 1 3.3 AML伴KMT2A重排 4 13.3 AML伴MECOM重排 6 20.0 骨髓增生异常相关AML 10 33.3 AML伴其他未定义遗传改变 6 20.0 未知 3 10.0 诱导缓解治疗 CR/PR 12 52.2 未缓解 11 47.8 难治/复发性AML 是 17 73.9 否 6 26.1 
下载: 导出CSV
表 2 EVI1(+)AML患者临床及ELN 2017分层与诱导缓解治疗反应及是否难治/复发性AML的相关性
例 参数 诱导缓解治疗反应 难治/复发性AML 例数/总数a) CR/PR 未缓解 P 例数/总数a) CR/PR 未缓解 P 年龄≥60岁 2/23 1/2 1/2 1.000 2/23 2/6 0/6 1.000 原始细胞≥50% 9/20 5/9 4/9 0.653 9/20 7/12 2/12 1.000 白细胞计数≥30×109/L 7/20 4/7 3/7 1.000 7/20 5/7 2/7 0.270 CRP升高 12/19 5/12 7/12 0.650 12/19 10/12 2/12 1.000 LDH升高 13/16 7/13 6/13 1.000 13/16 10/13 3/13 1.000 ELN 2017分层 0.453 0.086 低危 1/20 1/1 0/1 1/20 0/1 1/1 中危 3/20 2/3 1/3 3/20 2/3 1/3 高危 16/20 7/16 9/16 16/20 14/17 2/17 a)总数指该项目总被检测数
下载: 导出CSV
表 3 EVI1(+)AML患者分子生物学特征与治疗反应相关性
例 参数 总例数 难治/复发性AML P 是 否 NA 总体 24 13 4 7 基因突变 NRAS 6 3 2 1 0.538 ASXL1 4 0 2 2 1.000 KRAS 4 4 0 0 1.000 FLT3-ITD 4 3 0 1 0.541 PTPN11 3 1 1 1 0.426 RUNX1 3 1 1 1 0.426 DNMT3A 3 2 1 0 1.000 SETBP1 2 1 0 1 1.000 SF3B1 2 1 0 1 1.000 TET2 2 1 0 1 1.000 CBL 2 1 1 0 0.426 GATA2 2 2 0 0 1.000 U2AF1 2 2 0 0 1.000 TP53 2 1 0 1 1.000 KMT2C 2 1 1 0 0.426
下载: 导出CSV
表 4 诱导及巩固治疗方案与1年CMR的相关性分析
治疗方案 例数 存活/例 死亡/例 1年CMR/% P 第1个疗程诱导缓解 所有方案 18 7 11 61.1 0.101 单纯化疗 13 7 6 46.2 去甲基化药物治疗方案 5 0 5 100.0 巩固强化治疗 所有方案 18 7 11 61.1 0.013 移植巩固治疗 8 6 2 25.0 非移植巩固治疗 10 1 9 90.0
下载: 导出CSV
-
[1] Hinai AA, Valk PJ. Review: Aberrant EVI1 expression in acute myeloid leukaemia[J]. Br J Haematol, 2016, 172(6): 870-878. doi: 10.1111/bjh.13898
[2] Wu X, Wang H, Deng J, et al. Prognostic significance of the EVI1 gene expression in patients with acute myeloid leukemia: a meta-analysis[J]. Ann Hematol, 2019, 98(11): 2485-2496. doi: 10.1007/s00277-019-03774-z
[3] Zheng Y, Huang Y, Le S, et al. High EVI1 Expression Predicts Adverse Outcomes in Children With De Novo Acute Myeloid Leukemia[J]. Front Oncol, 2021, 11: 712747. doi: 10.3389/fonc.2021.712747
[4] Khoury J D, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms[J]. Leukemia, 2022, 36(7): 1703-1719. doi: 10.1038/s41375-022-01613-1
[5] 张之南, 沈悌. 血液病诊断及疗效标准[M]. 3版. 北京: 科学出版社, 2008: 106-115.
[6] Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel[J]. Blood, 2017, 129(4): 424-447. doi: 10.1182/blood-2016-08-733196
[7] 周强, 马洪兵, 刘作凤, 等. Evi1基因阳性急性髓细胞白血病14例临床分析[J]. 临床血液学杂志, 2015, 28(11): 949-953. https://www.cnki.com.cn/Article/CJFDTOTAL-LCXZ201511008.htm
[8] Qin Y Z, Zhao T, Zhu H H, et al. High EVI1 Expression Predicts Poor Outcomes in Adult Acute Myeloid Leukemia Patients with Intermediate Cytogenetic Risk Receiving Chemotherapy[J]. Med Sci Monit, 2018, 24: 758-767. doi: 10.12659/MSM.905903
[9] 李娟, 谢静, 李和兰, 等. EVI1基因阳性急性髓系白血病的临床特点与预后分析[J]. 实用临床医药杂志, 2016, 20(9): 32-36. https://www.cnki.com.cn/Article/CJFDTOTAL-XYZL201609009.htm
[10] 段文冰, 宫立众, 贾晋松, 等. 伴EVI1高表达的中高危急性髓系白血病临床特点及早期治疗效果[J]. 北京大学学报(医学版), 2017, 49(6): 990-995. https://www.cnki.com.cn/Article/CJFDTOTAL-BYDB201706010.htm
[11] Barjesteh V W V D, Erpelinck C, van Putten W L, et al. High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients[J]. Blood, 2003, 101(3): 837-845. doi: 10.1182/blood-2002-05-1459
[12] Groschel S, Lugthart S, Schlenk R F, et al. High EVI1 expression predicts outcome in younger adult patients with acute myeloid leukemia and is associated with distinct cytogenetic abnormalities[J]. J Clin Oncol, 2010, 28(12): 2101-2107. doi: 10.1200/JCO.2009.26.0646
[13] Huber S, Haferlach T, Meggendorfer M, et al. SF3B1 mutations in AML are strongly associated with MECOM rearrangements and may be indicative of an MDS pre-phase[J]. Leukemia, 2022, 36(12): 2927-2930. doi: 10.1038/s41375-022-01734-7
[14] Liu X X, Pan X A, Gao M G, et al. The adverse impact of ecotropic viral integration site-1(EVI1) overexpression on the prognosis of acute myeloid leukemia with KMT2A gene rearrangement in different risk stratification subtypes[J]. Int J Lab Hematol, 2022 Nov 10. doi:
10.1111/ijlh.13987.Epubaheadofprint .[15] Verhagen HJ, Smit MA, Rutten A, et al. Primary acute myeloid leukemia cells with overexpression of EVI-1 are sensitive to all-trans retinoic acid[J]. Blood, 2016, 127(4): 458-463. doi: 10.1182/blood-2015-07-653840
[16] Paubelle E, Plesa A, Hayette S, et al. Efficacy of All-Trans-Retinoic Acid in High-Risk Acute Myeloid Leukemia with Overexpression of EVI1[J]. Oncol Ther, 2019, 7(2): 121-130. doi: 10.1007/s40487-019-0095-9
[17] Nguyen C H, Bauer K, Hackl H, et al. All-trans retinoic acid enhances, and a pan-RAR antagonist counteracts, the stem cell promoting activity of EVI1 in acute myeloid leukemia[J]. Cell Death Dis, 2019, 10(12): 944. doi: 10.1038/s41419-019-2172-2
[18] Schmoellerl J, Barbosa I, Minnich M, et al. EVI1 drives leukemogenesis through aberrant ERG activation[J]. Blood, 2023, 141(5): 453-466. doi: 10.1182/blood.2022016592
-
图(2)
表(4)
计量
- 文章访问数: 1127
- PDF下载数: 333
- 施引文献: 0