NPM- MLF1^(+)急性髓细胞白血病伴骨髓增生异常相关改变患儿的临床分析并文献复习

Clinical analysis on children with NPM-MLF1 fusion gene positive acute myeloid leukemia with myeloproliferation-related changes and literature review

目的探讨NPM-MLF1融合基因阳性(NPM-MLF1^(+))急性髓细胞白血病伴骨髓增生异常相关改变(AML-MRC)患儿的临床诊治, 并且进行相关文献复习。方法选择2019年8月12日, 联勤保障部队第九四〇医院血液科收治的1例6岁男性NPM-MLF1^(+) AML-MRC患儿为研究对象。采用回顾性分析方法, 收集患儿的临床病例资料, 并对其病史、相关实验室检查和基因检测结果进行分析。对患儿采取的化疗方案包括:① IA方案(伊达比星10 mg/d×3 d+阿糖胞苷200 mg/d×7 d, 7 d为1个疗程)诱导及巩固化疗各1个疗程;② EA方案(依托泊苷150 mg/d×3 d+阿糖胞苷3 g/d×7 d, 7 d为1个疗程)巩固化疗1个疗程, 并且行甲氨蝶呤150 mg、阿糖胞苷30 mg、地塞米松5 mg鞘内注射1次。以"急性髓系白血病""急性髓细胞白血病""骨髓增生异常综合征""NPM-MLF1""AML""MDS""acute myeloid leukemia""myelodysplastic syndromes"为中、英文关键词, 计算机检索博库外文全文数据库、中国知网数据库、万方数据服务知识平台, 并筛选NPM-MLF1^(+) AML/骨髓增生异常综合征(MDS)患者相关文献。文献检索时间设定为上述数据库建立至2021年7月15日。对本研究纳入文献报道的NPM-MLF1^(+) AML/MDS患者的临床表现、诊断与治疗进行总结。本研究符合2013年修订的《世界医学协会赫尔辛基宣言》要求。结果①本例患儿本次入院骨髓细胞形态学及免疫分型、白血病相关56种融合基因, 以及AML相关23种基因突变筛查结果显示, 骨髓原始粒细胞比例为22%, 粒、红、巨核三系细胞均可见病态造血;原始细胞比例为12.5%;NPM-MLF1融合基因呈阳性;NRAS基因第2、3号外显子错义突变呈阳性。其染色体核型为46, XY, t(1;22)(q42;q13), add(3)(q21), der(5)t(3;5)(p11;q31)[19]/46, XY[1]。患儿被诊断为NPM-MLF1^(+)AML-MRC, 伴NRAS基因第2、3号外显子错义突变阳性, 高危组。其接受IA、EA方案诱导及巩固化疗后达到完全缓解(CR), 遂于外院行异基因造血干细胞移植(allo-HSCT)根治治疗。截至2022年5月, 患儿一般情况良好。②文献复习结果:根据本研究设定的文献检索和筛选策略, 共计纳入6篇NPM-MLF1^(+) AML/MDS相关文献, 报道5例NPM-MLF1^(+) AML及6例NPM-MLF1^(+) MDS患者。患者主要接受以阿糖胞苷为基础的多种方案诱导及巩固化疗治疗, 疗效尚可, 生存期为7个月至8年。结论儿童NPM-MLF1^(+) AML-MRC临床罕见, 该病诊断困难, 患儿预后差。对NPM-MLF1^(+) AML-MRC患儿采取以阿糖胞苷为基础的诱导及巩固化疗稳定病情后, 行allo-HSCT, 可能是治愈该病的方法。

Objective To investigate clinical diagnosis and treatment of children with NPM-MLF1^(+)acute myeloid leukemia(AML)with myelodysplastic associated changes(AML-MRC),and to review relevant literature.Methods On August 12,2019,a 6-year-old male child with NPM-MLF1^(+)AML-MRC who was admitted to Department of Hematology of 940th Hospital of Joint Logistic Support Force was selected as the study subject.The clinical data of the child was collected by retrospective analysis method,and his clinical data,related laboratory examination and genetic test results were summarized.The chemotherapy regimen for this child included:①IA regimen(idarubicin 10 mg/d×3 d+cytarabine 200 mg/d×7 d,7 d as a course)for induction and consolidation chemotherapy,one course each;②EA regimen(etoposide 150 mg/d×3 d+cytarabine 3 g/d×7 d,7 d as a course)for one course of consolidation chemotherapy,and intrathecal injection of methotrexate 150 mg,cytarabine 30 mg and dexamethasone 5 mg was performed once.With"NPM-MLF1""AML""MDS""acute myeloid leukemia""myelodysplastic syndromes"as Chinese and English keywords,literature in Boku Foreign Language Full-text Database,China National Knowledge Infrastructure Database and Wanfang Data Service Knowledge Platform were searched by computer,and literature related to NPM-MLF1^(+)AML/MDS patients were screened.The literature retrieval time was set to establishment of above database until July 15,2021.Clinical manifestations,diagnosis and treatment of children with NPM-MLF1^(+)AML/MDS reported in included literature studies were summarized.This study was in line with World Medical Association Declaration of Helsinki revised in 2013.Results①Due to"poor appetite,fatigue and progressive aggravation for 1 month",this child was admitted to the Department of Hematology of our hospital with"severe anemia".The results of bone marrow cell morphology,immunotyping and screening for mutations of 56 fusion genes related to leukemia and 23 genes related to AML showed that the proportion of primitive granulocytes was 22%,and pathological hematopoiesis was observed in granulocytes,erythrocytes and megakaryocytes.The proportion of primitive cells was 12.5%.NPM-MLF1 fusion gene was positive.Missense mutation of NRAS gene exon 2 and 3 was positive.His chromosome karyotype was 46,XY,T(1;22)(q42;Q13),add(3)(q21),der(5)t(3;5)(p11;Q31)[19]/46,XY[1].The child was diagnosed as NPM-MLF1^(+)AML-MRC with positive missense mutation of NRAS gene exon 2 and 3,and was in high-risk group.Complete remission(CR)was achieved after induction and consolidation chemotherapy with IA and EA regimens.And in December 2019,allogeneic hematopoietic stem cell transplantation(allo-HSCT)was performed in other hospital.Until May 2022,the general condition of the child was good.②Results of literature review were as follow.According to the literature retrieval and screening strategy set in this study,a total of 6 literature related to NPM-MLF1^(+)AML/MDS were included,which reported 5 patients with NPM-MLF1^(+)AML and 6 cases with NPM-MLF1^(+)MDS.The patients were mainly treated with cytarabine-based induction and consolidation chemotherapy with satisfactory efficacy,and the survival time ranged from 7 months to 8 years.Conclusions NPM-MLF1^(+)AML/MRC in children is rare,and difficult to diagnose and with poor prognosis.Allo-HSCT may be a cure for NPM-MLF1^(+)AML-MRC children after taking cytarabine-based induction and consolidation chemotherapy to stabilize the disease.