父子同患急性白血病且父亲为三重癌的临床分析

Clinical analysis of father and son both with acute leukemia and father with triple primary malignancies

目的探讨家族性白血病的发病机制及临床特征。方法选择2012年10月及2018年12月泰州市人民医院血液科收治的2例急性白血病(AL)患者为研究对象。2例患者的就诊年龄分别为34、65岁,2例患者为父子关系。对2例患者行血常规检查、骨髓细胞形态学检查、染色体核型分析、白血病细胞免疫分型、微小残留病(MRD)检测及融合基因检测等。回顾性分析2例患者的临床特征、诊断及治疗经过。本研究遵循的程序符合2013年修订版《世界医学协会赫尔辛基宣言》的要求。结果①患者1(儿子)因"头晕乏力、盗汗3个月"于2012年10月23日就诊于泰州市人民医院血液科。入院骨髓细胞形态学检查结果示,有核细胞增生活跃,原始、幼稚淋巴细胞比例为38.5%。白血病细胞免疫分型结果示,CD34、人类白细胞抗原(HLA)-DR、CD10、CD20、CD19均呈阳性;染色体核型分析结果示正常,考虑为B系淋巴瘤/白血病。随后,行R+Hyper-CVAD(利妥昔单抗+环磷酰胺+长春地辛+表柔比星+地塞米松)/R+MA(利妥昔单抗+甲氨蝶呤+阿糖胞苷)方案交替化疗4次,联合8次鞘内注射(甲氨蝶呤+地塞米松或者阿糖胞苷)。其间复查骨髓细胞形态学检查结果示,完全缓解(CR),并且MRD呈阴性。2013年4月26日行自体造血干细胞移植(auto-HSCT),移植后行利妥昔单抗巩固治疗2次。2013年11月8日复查骨髓细胞形态学检查结果示,骨髓增生活跃,淋巴瘤细胞比例为35.0%,考虑疾病复发。随后予VDCLP(长春地辛+柔红霉素+环磷酰胺+培门冬酶+泼尼松)与CA(环磷酰胺+阿糖胞苷)方案进行诱导与巩固化疗,患者获得CR后再次复发。2014年3月12日行挽救性单倍体相合造血干细胞移植(haplo-HSCT)后获得CR。2015年4月3日复查骨髓形态学检查结果示,骨髓有核细胞增生活跃,幼稚淋巴细胞比例为22.0%;白血病细胞免疫分型结果示,CD34、CD22、CD19、CD33、HLA-DR均呈阳性;染色体核型正常。根据患者临床特征及相关检查结果诊断为急性B淋巴细胞白血病(B-ALL)。于2015年4月7日给予挽救性地西他滨+VLP(长春地辛+培门冬酶+地塞米松)方案化疗后获得CR,MRD比例为0.13%。随后给予患者多种方案化疗后再次复发。于2016年1月27日给予CIOLP(环磷酰胺+长春地辛+米托蒽醌+地塞米松+培门冬酶)方案化疗,化疗后患者出现Ⅳ级骨髓抑制合并重症感染,给予对症治疗后无效,患者于2016年2月20日死亡。②患者2(父亲)于2001年7月因"腹胀不适"于泰州市人民医院行胃镜检查、活组织检查,结果示低分化腺癌,遂行全胃切除术。2018年4月患者出现无痛性肉眼血尿于江苏省人民医院查CT结果示膀胱占位,行根治性膀胱全切除术+原位回肠代膀胱术。术后病理学检查结果示,膀胱高级别乳头状尿路上皮癌。2018年11月患者行膀胱癌术后随访,血常规检查结果见幼稚粒细胞。遂就诊于泰州市人民医院血液科,骨髓细胞形态学检查结果示,粒系增生活跃,其中原始粒细胞比例为19.0%,诊断为骨髓增生异常综合征(MDS)-伴原始细胞增多(EB)2。于2018年12月26日复查骨髓细胞形态学检查结果示,原始粒细胞比例为26.0%;白血病细胞免疫分型结果示,CD7、CD34、CD13、CD33、CD117、CD15、CD64、髓过氧化物酶(MPO)、HLA-DR均呈阳性;染色体核型分析结果示复杂核型;荧光原位杂交(FISH)检测结果示,cen8三体阳性比例为86%,TP53缺失阳性比例为85%。诊断为急性髓细胞白血病(AML)-M2,于2018年12月28日给予地西他滨+HA(高三尖杉酯碱+阿糖胞苷)方案诱导化疗。2019年1月30日骨髓细胞形态学检查结果示,原始粒细胞比例为7.0%,考虑为部分缓解(PR)。于2019年2月13日给予地西他滨+IA(去甲氧柔红霉素+阿糖胞苷)方案再次诱导化疗。2019年3月23日骨髓细胞形态学检查结果示,骨髓有核细胞增生程度稍减低,原始粒细胞比例为1.0%,提示CR。分别于2019年3月25日、2019年4月27日行IAG(去甲氧柔红霉素+阿糖胞苷+粒细胞集落刺激因子)方案巩固化疗。期间多次复查骨髓细胞形态学检查提示CR,并且MRD呈阴性。2019年6月10日行HA方案化疗。2019年7月19日复查骨髓细胞形态学检查结果示,原始粒细胞比例为25.0%,提示疾病复发。于2019年7月20日行地西他滨+HA方案再次诱导化疗。截至2019年8月8日,尚未复查化疗后骨髓细胞形态学检查。结论家族性白血病的发病机制以遗传因素为主,常规化疗难缓解、易复发,生存期短。但是该结论仅限于对2例病例的临床分析,尚需要扩大样本量,进一步研究、验证。

Objective To investigate the pathogenesis and clinical characteristics of familial leukemia.Methods In October 2012 and December 2018,2 patients with acute leukemia(AL)admitted to the Department of Hematology,Taizhou People′s Hospital were included in this study.Two patients were 34 and 65 years old,respectively.Routine blood examination,bone marrow cell morphology examination,chromosome karyotype analysis,leukemia cell immunotyping,minimal residual disease(MRD)detection and fusion gene detection were performed on the 2 patients.The clinical features,diagnosis and treatment of the patients were analyzed retrospectively.The procedure of this study is accordance with the requirement of the revised World Medical Association Declaration of Helsinki in 2013.Results①Case 1(the son)was admitted to the Department of Hematology,Taizhou People′s Hospital on October 23,2012,due to"dizziness,fatigue,and sleep hyperhidrosis for 3 months".After admission,the result of bone marrow cell morphology revealed hyper-cellularity with 38.5%of lymphoblasts and prolymphocytes,and immunophenotype analysis of leukemia blasts showed that the neoplastic cells were positive for CD34,human leukocyte antigen(HLA)-DR,CD10,CD20 and CD19.No abnormal karyotype was observed in cytogenetic analysis.The patient was diagnosed with B-cell lymphoma/leukemia.Subsequently,4 cycles of R+hyper-CVAD(rituximab+cyclophosphamide+vindesine+epirubicin+dexamethasone)/R+MA(rituximab+methotrexate+cytarabine)chemotherapy were performed,combined with 8 intrathecal injections(methotrexate combined with dexamethasone or cytarabine).Bone marrow cell morphology revealed complete remission(CR),and MRD were negative during this period of time.On April 26,2013,autologous hematopoietic stem cell transplantation(auto-HSCT)was performed,and rituximab was used for consolidation treatment twice since then.On November 8,2013,the result of bone marrow cell morphology reported hypercellularity with 35.0%lymphoma cells,which indicated relapse of the disease.The patient achieved CR again after VDCLP(vindazine+daunorubicin+cyclophosphamide+papeurase+prednisone)and CA(cyclophosphamide+cytarabine)chemotherapy,but still relapsed.On March 12,2014,the patient received haploid hematopoietic stem cell transplantation(haplo-HSCT)and then achieved CR.On April 3,2015,the result of bone marrow cell morphology showed obviously proliferation of karyote cells with 22.0%of prolymphocyte,and immunophenotype of leukemia blasts was positive for CD34,CD22,CD19,CD33 and HLA-DR.No abnormal karyotype was observed in cytogenetic analysis.These findings led to the diagnosis of B-cell acute lymphocytic leukemia(B-ALL).The patient was then given salvage treatment of decitabine combined with VLP(vintelide+pemetrex+dexamethasone)chemotherapy,and CR was achieved with the MRD ratio of 0.13%.Multiple regimens of chemotherapy were given subsequently.On January 27,2016,the patient was treated with CIOLP(cyclophosphamide+vindesine+mitoxantrone+dexamethasone+pemetrexase)chemotherapy,which caused gradeⅣmyelosuppression and led to severe infection afterwards.Efficacy was poor despite of supportive care,and the patient died on February 20,2016.②Case 2(the father)was admitted to Taizhou People′s Hospital for"abdominal bloating"in July 2001.Endoscopic biopsy was performed,which indicated poorly differentiated adenocarcinoma.A total gastrectomy was performed subsequently.In April 2018,the patient was admitted to Jiangsu Province Hospital for"painless gross hematuria".Bladder occupied lesions was observed in CT.Then the patient underwent radical cystectomy with orthotopic ileal neobladder,in which the pathological examination showed high grade papillary urothelial carcinoma of the bladder.In November 2018,the patient received postoperative examinations,including a blood routine test in which myeloblasts were inspected,therefore the patient was transfered to the Department of Hematology,Taizhou People′s Hospital for further diagnosis.Proliferation of granulocyte with 19.0%of myeloblasts was observed in bone marrow cell morphology,and the diagnosis of myelodysplastic syndrome(MDS)-excess blasts(EB)2 was made.On December 26,2018,the result of bone marrow cell morphology revealed 26.0%of myeloblasts,and these primitive cells were positive for CD7,CD34,CD13,CD33,CD117,CD15,CD64,myeloperoxidase(MPO),HLA-DR by immunophenotype analysis.Normal karyotype was indicated through cytogenetic analysis,and results of fluorescence in situ hybridization(FISH)showed 86%of trisomy cen8 and 85%of TP53 deletion.Thus,the patient was diagnosed as acute myeloid leukemia(AML)-M2.Induction chemotherapy of decitabine combined with HA(homoharringtonine+cytarabine)was given on December 28,2018.On January 30,2019,the result of bone marrow cell morphology showed 7.0%of myeloblasts which suggested partial remission(PR).On February 13,2019,the patient was treated with an additional induction therapy of decitabine combined with IA(demethoxydaunorubicin+cytarabine).It is indicated that CR was achieved based on the result of bone marrow cell morphology,performed on March 23,2019,which showed slightly reduced proliferation of karyote cells with 1.0%of myeloblasts.Thereafter,consolidation chemotherapy of IAG(demethoxydaunorubicin+cytarabine+granulocyte colony-stimulating factor)was performed on March 25,2019,and April 27,2019,respectively.Result of bone marrow cell morphology indicated CR and negative MRD during this stage.HA chemotherapy was implemented on June 10,2019,followed by relapse of the disease on July 19,2019,which was manifested by 25.0%of myeloblasts observed in bone marrow cell morphology.Re-induction chemotherapy of decitabine combined with IA was given on July 20,2019,and by August 8,2019,bone marrow cell morphology hasn′t been reexamined.Conclusions Familial leukemia is mainly induced by genetic factors.Patients usually suffer from low remission rate,as well as high probability of relapse.The overall survival is generally short.This conclusion is limited to the clinical analysis of 2 cases,and it requires to expand sample size for further study and verification.