急性全髓细胞增生症伴骨髓纤维化1例临床分析并文献复习

Clinical analysis of a case of acute panmyelosis with myelofibrosis and literature review

目的探讨急性全髓细胞增生症伴骨髓纤维化(APMF)患者的临床特征、诊疗策略及预后,并进行相关文献复习。方法选择2020年5月11日就诊于南京医科大学第一附属医院血液科的1例62岁APMF男性患者(患者1)为研究对象。采用回顾性分析方法,对其病史、临床特征、实验室及辅助检查结果等临床资料,以及诊治过程进行分析。对患者1的随访截至2022年11月12日。本研究以"急性全髓细胞增生症伴骨髓纤维化""acute panmyelosis with myelofibrosis""APMF"为中、英文关键词,在中国知网数据库、PubMed数据库中检索APMF相关文献,并总结相关病例的诊疗资料。文献检索时间设定为数据库建库至2023年5月1日。本研究符合2013年修订的《世界医学协会赫尔辛基宣言》要求,并获得患者1及其家属知情同意。结果①患者1因"血常规检查结果异常1周"入院。入院后,患者1血常规检查结果示,白细胞计数(WBC)、中性粒细胞计数、血小板计数、血红蛋白(Hb)值、红细胞计数分别为5.89×10^(9)/L、4.01×10^(9)/L、276×10^(9)/L、70 g/L、3.52×10^(12)/L。血清乳酸脱氢酶、铁蛋白水平升高。骨髓细胞形态学检查结果示,骨髓原始细胞比例为8.8%,三系增生减低伴明显病态造血。过氧化物酶染色及糖原染色结果均显示,原始细胞呈阴性;提示急性髓细胞白血病(AML)(APMF可能性大)。骨髓活组织病理学检查结果示,骨髓增生极度活跃,原幼细胞小簇增生,占有核细胞比例约为20%,原早红细胞比例明显增高,巨核细胞以细胞体小、少分叶的巨核细胞为主,纤维组织弥漫性增生,骨髓纤维化(MF)-3级,提示APMF。骨髓免疫分型结果示,CD34+细胞占有核细胞比例为1.1%,表达髓系标志物,成熟粒细胞比例明显减低伴轻度分化异常,红系比例异常增高,单核细胞比例减少。染色体核型分析结果为46,XY[11]。二代测序(NGS)结果提示,患者伴一级变异U2AF1和RUNX1突变,二级变异PHF6、SETBP和TET2突变。②患者1被诊断为APMF,采取阿扎胞苷+IAG(伊达比星+阿糖胞苷+粒细胞集落刺激因子)方案联合芦可替尼首次诱导治疗后达完全缓解(CR)。随后患者1接受原方案巩固治疗时出现Ⅳ级骨髓抑制和感染,后续调整巩固治疗方案为阿扎胞苷联合小剂量阿糖胞苷或者维奈克拉,患者1达持续CR。患者1因个人原因未接受异基因造血干细胞移植(allo-HSCT)。2022年2月18日,患者1疾病复发,再次采取阿扎胞苷+维奈克拉+西达苯胺联合治疗后达部分缓解(PR)。2022年7月20日,患者1疾病进展,采取挽救性化疗措施,病情短暂缓解后疾病持续进展。患者1于2022年11月12日因APMF进展及多器官功能衰竭死亡。③按照本研究设定的文献检索策略,共筛选出2篇英文文献,报道2例APMF患者(患者2和3),加上患者1,共3例患者被纳入以下研究。3例患者(患者1~3)临床特征均表现为外周血细胞减少、骨髓原始细胞增多伴MF,并且均无脾大。患者2接受达那唑、来那度胺治疗6个月后脱离输血,骨髓活组织病理学检查结果提示,骨髓细胞增生程度及细胞形态均已恢复正常。患者3接受IA(伊达比星+阿糖胞苷)方案化疗后,复查骨髓活组织病理学检查结果示,原始细胞比例<5%,骨髓病理网状纤维染色结果示MF-1级,并且症状持续缓解。结论APMF发病率低,临床上常因忽略骨髓病理学检查而使患者无法被明确诊断,并且该疾病进展迅速,患者预后极差。目前,APMF尚无标准治疗方案,新型靶向药物或可作为潜在的治疗选择。

ObjectiveTo investigate clinical characteristics,diagnostic and treatment strategies,and prognosis of patients with acute panmyelosis with myelofibrosis(APMF),and review relevant literature.MethodsOn May 11,2020,a case of 62 year-old male with APMF admitted to Hematology Department of First Affiliated Hospital of Nanjing Medical University was selected as research subject(patient 1).Using a retrospective analysis approach,the medical history,clinical features,laboratory results,additional diagnostic findings,diagnosis,and treatment of patients 1 were analyzed.Patient 1 was followed up until November 12,2022.China National Knowledge Infrastructure database and PubMed database were searched by keywords"acute panmyelosis with myelofibrosis""APMF"in Chinese and English.Literature related to APMF was summarized.Time for literature retrieval was set from established to May 1,2023.Procedure followed in this study was in line with requirements of World Medical Association Declaration of Helsinki revised in 2013,and informed consent of clinical research was obtained from patient 1 and his family.Results①Patient 1 was admitted due to"abnormal blood test results for 1 week".After admitted,blood test results showed white blood cell count(WBC),neutrophil count,platelet count,hemoglobin(Hb)value,and red blood cell count were 5.89×10^(9)/L,4.01×10^(9)/L,276×10^(9)/L,70 g/L and 3.52×10^(12)/L,respectively.Serum lactate dehydrogenase and ferritin levels were elevated.Bone marrow blast cells revealed 8.8%,and reduced hematopoiesis in all three cell lines with marked dysplasia.Results of peroxidase staining and glycogen staining both showed that the blast cells were negative.And it indicated the possibility of APMF.Bone marrow biopsy showed highly active marrow,and small clusters of prokaryotic cells proliferated,accounting for about 20%of nuclear cells,and the proportion of proto-early red cells was significantly increased.Megakaryocytes were mainly megakaryocytes with small cell body and little lobulation.Diffuse hyperplasia of fibrous tissue and myeloid fibrosis(MF)grade 3 suggested APMF.Immunophenotyping of bone marrow cells revealed a CD34+cell proportion of 1.1%and expressed myeloid markers.Proportion of mature granulocytes was significantly reduced with slightly abnormal differentiation,the proportion of erythroid was abnormally increased,and the proportion of monocytes was decreased.Chromosome karyotype analysis showed 46,XY[11].Results of second-generation sequencing(NGS)indicated that the primary mutations were U2AF1 and RUNX1 mutation,and the secondary mutations were PHF6,SETBP and TET2 mutation.②Patient 1 was diagnosed with APMF and received induction therapy with azacitidine and IAG(idarubicin+cytarabine+granulocyte colony-stimulating factor)regimen in combination with ruxolitinib,and achieved complete remission(CR).Subsequently,during consolidation,patient 1 experienced gradeⅣbone marrow suppression and infection,and the treatment regimen was adjusted to azacitidine in combination with low-dose cytarabine or venetoclax.Patient 1 maintained CR,and due to personal reasons,allogeneic hematopoietic stem cell transplantation(allo-HSCT)was not considered.However,on February 18,2022,the disease relapsed,and partial remission(PR)was achieved after treatment with azacitidine,venetoclax,and idarubicin.On July 20,2022,the disease progressed,and after salvage chemotherapy,patient 1′s condition briefly improved but then continued to worsen.Patient 1 died on November 12,2022 due to APMF progression and multi-organ failure.③According to literature search strategy set in this study,two English articles were selected,collectively reporting 2 cases of APMF,numbered as patient 2 and 3.There were 3 cases of APMF patients,including patient 1.Clinical characteristics in all cases were characterized by peripheral blood cytopenias,increased blast cells in the bone marrow with concurrent myelofibrosis,and notably,no splenomegaly.Patient 2 underwent treatment with danazol and lenalidomide for 6 months and achieved detachment from blood transfusion,the pathological examination results of bone marrow biopsy indicated that the degree of cell proliferation and cell morphology restored.Patient 3 received chemotherapy with a combination of idarubicin and cytarabine,the reexamination of bone marrow routine showed that the number of primitive cells was less than 5%,and the bone marrow pathological reticular fiber staining showed MF-1 grade,and the symptoms continued to improve.ConclusionsIncidence of APMF is low,and the diagnosis cannot be made clearly due to the oversight of bone marrow pathological examination in clinical practice.Moreover,the disease progresses rapidly and the prognosis is very poor.Currently,there is no standard treatment plan,and new targeted drugs may be a potential treatment option.