NPM-MLF1融合基因呈阳性成年人急性髓细胞白血病的诊治并文献复习

目的 探讨核仁磷酸蛋白(NPM)-骨髓增生异常/髓细胞白血病因子(MLF)1融合基因呈阳性急性髓细胞白血病(AML)成年患者的临床特征、治疗策略及预后.方法 选择2016年2月16日,第二军医大学附属长海医院收治的1例AML成年患者为研究对象.于患者入院时进行骨髓细胞形态学检查、骨髓白血病细胞化学染色、白血病细胞免疫表型分析、细胞遗传学、分子遗传学检测等实验室检查,并依据检查结果进行诊断.患者于2016年2月17日接受2个疗程柔红霉素+阿糖胞苷(DA)3+7方案化疗;随后,患者接受1次氟达拉滨+阿糖胞苷+粒细胞集落刺激因子(FLAG)方案,5次大剂量阿糖胞苷方案巩固化疗.在化疗期间对患者进行骨髓细胞形态学检查和微小残留病(M RD)检测,以监测疗效.患者于2017年4月6日门诊复诊时,进行骨髓细胞形态学检查、白血病细胞免疫表型分析、分子遗传学检测.回顾性分析本例患者临床特征、诊断及治疗经过,并且对相关文献进行复习.结果 ①本例患者入院时骨髓细胞形态学检查结果显示:有核细胞增生明显活跃,白血病细胞比例为48.0％.患者骨髓白血病细胞化学染色显示:部分白血病细胞过氧化物酶(POX)染色呈阳性;少数白血病细胞氯乙酸AS-D萘酚酯酶(CE)染色呈阳性;部分白血病细胞非特异性酯酶(NSE)染色呈阳性.白血病细胞免疫表型分析结果显示:原始细胞群占有核细胞的比例约为39.9％;幼稚细胞群占有核细胞的比例约为13.6％.染色体R显带为46,XX,t(3;5) (q25;q34) 3]/46,XX7].分子遗传学检测结果显示:NPM-MLF1融合基因呈阳性.依据实验室检查结果诊断患者为NPM-MLF1融合基因呈阳性AML-M4型.②患者接受第1个疗程化疗后,复查骨髓细胞形态学结果提示:患者获得部分缓解(PR).第2个疗程后,骨髓细胞形态学结果提示:患者获得完全缓解(CR).随后,患者完成6次巩固化疗时,骨髓形态学检查结果提示:患者持续CR.门诊复诊时,骨髓细胞形态学检查结果显示:白血病细胞占有核细胞比例为25.0％,其中原始细胞比例为21.0％,幼稚细胞比例为4.0％,提示AML复发.白血病细胞免疫表型分析结果显示:骨髓中存在约28.5％早期髓细胞,符合AML复发诊断.分子遗传学检测结果显示:NPM-MLF1融合基因呈阳性(融合基因阳性率为66.1％).患者接受治疗期间骨髓MRD呈现减低后增高的变化趋势.患者复发后回当地医院接受后续治疗.结论 NPM-MLF1融合基因呈阳性AML-M4型患者经化疗可达CR,但是易发生早期复发,NPM-MLF1融合基因可能为AML的不良预后因素.

Diagnosis and treatment of adult acute myeloid leukemia with NPM-MLF1 fusion gene and literatures review

Objective To evaluate the clinical features,treatment and prognosis of acute myeloid leukemia (AML) with nucleophosmin (NPM)-myelodysplasia/myeloid leukemia factor (MLF)1 fusion gene.Methods On 16 February 2016,a case of AML patient with NPM-MLF1 fusion gene who was admitted to Changhai Hospital Affiliated to Second Military Medical University was included in this study.When the patient was admitted,bone marrow morphology,cytochemical staining and immunophenotype analysis of leukemia blasts,cytogenetics and molecular genetic analysis were conducted and diagnosis was made base on those test results.On 17 February 2016,the patient recieved two courses of daunorubicin-F arabinosylcytosin (DA) 3 + 7 induction therapy.Subsequently,the patient recieved one course of fludarabine,cytarabine and granulocyte colony-stimulating factor (FLAG) regimen and 5 courses of highdose of cytarabine.In the meantime,bone marrow morphology and minimal residual disease (MRD) were conducted during the chemotherapy.On 6 April 2017,the patient received bone marrow morphology,immunophenotype analysis of leukemia blasts and molecular genetic analysis on her visit.The clinical features,diagnosis and treatment of this patient were analyzed retrospectively,and the related literatures were reviewed.Results ①When the patient was admitted,bone marrow morphology revealed hypercellular marrow with 48.0％ leukemia blasts.Cytochemical staining showed that peroxidase (POX) staining in some leukemia blasts were positive,and naphthol AS-D chloroacetate esterase (CE) staining in a few leukemia blasts were positive,and non-specific estertase (NSE) staining in some leukemia blasts were positive.The results of immunophenotype analysis revealed the ratio of the blasts cell was about 39.9％,and the ratio of immature cell was about 13.6 ％.R banding karyotype analysis marked with 46,XX,t (3;5)(q25;q34) 3]/46,XX7].Molecular genetic analysis showed NPM/MLF1 fusion gene was positive.According to above,the diagnosis of patient was AML-subtype M4 with NPM-MLF1 fusion gene.②After the patient was treated with the first course of induction therapy,and the reexamined bone marrow morphology post therapy showed partial remission (PR).The patient received complete remission (CR)after the second course of induction therapy.After the patient received consolidation therapy,and bone marrow morphology showed the patient obtained sustained CR status.On the patient's last visit,bone marrow morphology revealed a total of 25.0％ leukemia blasts,consisting of 21.0％ blasts and 4.0％ immature cell,suggesting AML recurrenced.Immunophenotyping of leukemia blasts showed approximately 28.5％ of the early myeloid cells in bone marrow which was consistent with AML recurrence.Molecular genetic analysis showed that the MPM-MLF1 fusion gene was positive (66.1％).During the treatment,bone marrow MRD decreased,then increased.The patient went back to local hospital for treatment after AML relapsed.Conclusions AML-subtype M4 patient with NPM-MLF1 fusion gene can achieve CR after chemotherapy,but prone to early recurrence,and NPM-MLF1 fusion gene may be a poor prognostic factor for AML.