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      A rare case of acute promyelocytic leukemia with ider(17)(q10)t(15;17)(q22;q21) and favorable outcome

      case-report

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          Abstract

          Background

          Chromosomal rearrangements in addition to t(15;17) have been reported in 25-40% of APL patients, with a large predominance of trisomy 8. Other abnormalities are far less frequent, particularly as ider(17), and the prognostic significance is still unclear.

          Case presentation

          We present the case of a patient with t(15;17)(q22;q21), der(15)t(15;17) and ider(17)(q10)t(15;17)(q22;q21). In particular, the RT-PCR result for PML-RARA of this patient was a false negative and mutational analysis of AML-related genes showed SNP rs2454206 in the TET2 gene and yielded negative findings in other genes including AML1, ASXL1, CEBPA, DNMT3A, FLT3, KIT, NPM1, TP53, and U2AF1. After the early usage of arsenic trioxide combinated with ATRA and vigorous supportive treatment to maintain PLT ≥30×10 9/L and FIB >1500 mg/L, this patient was under MMR and HCR without any clinical symptoms or signs until now.

          Conclusion

          False negative reslults of RT-PCR analysis for PML-RARA are rare in APL and ider(17) is even more infrequent. To our knowledge, this is the first reported case of APL with ider(17) and false negative RT-PCR analysis results. The role of ider(17) in APL is still an ongoing investigation and limited by the small number of published cases. The patient reported here benefited from vigorous supportive treatment during the combination of ATRA and arsenic trioxide in induction chemotherapy and the clinical outcome was favorable.

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          Most cited references15

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          Acute promyelocytic leukemia: where did we start, where are we now, and the future

          Historically, acute promyelocytic leukemia (APL) was considered to be one of the most fatal forms of acute leukemia with poor outcomes before the introduction of the vitamin A derivative all-trans retinoic acid (ATRA). With considerable advances in therapy, including the introduction of ATRA initially as a single agent and then in combination with anthracyclines, and more recently by development of arsenic trioxide (ATO)-containing regimens, APL is now characterized by complete remission rates of 90% and cure rates of ∼80%, even higher among low-risk patients. Furthermore, with ATRA–ATO combinations, chemotherapy may safely be omitted in low-risk patients. The disease is now considered to be the most curable subtype of acute myeloid leukemia (AML) in adults. Nevertheless, APL remains associated with a significant incidence of early death related to the characteristic bleeding diathesis. Early death, rather than resistant disease so common in all other subtypes of AML, has emerged as the major cause of treatment failure.
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            Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients.

            All trans retinoic acid (ATRA) has revolutionized the therapy of acute promyelocytic leukemia (APL). Treatment of this leukemia with ATRA in combination with chemotherapy has resulted in complete remission rates >90 % and long-term remission rates above 80 %. Furthermore, the combination of ATRA and arsenic trioxide (ATO) was shown to be safe and effective in frontline treatment and, for patients with low and intermediate risk disease, possibly superior to the standard ATRA and anthracycline-based regimen. However, in spite of this tremendous progress, APL still remains associated with a high incidence of early death due to the frequent occurrence of an abrupt bleeding diathesis. This hemorrhagic syndrome more frequently develops in high-risk APL patients, currently defined as those exhibiting >10 × 10(9)/L WBC at presentation. In addition to high WBC count, other molecular and immunophenotypic features have been associated with high-risk APL. Among them, the expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2 help to identify a subset of patients at higher risk of relapse and often the expression of these markers is associated with high WBC count. At the molecular level, the short PML/RARA isoform and FLT3-internal tandem duplication (ITD) mutations have been associated with increased relapse risk. These observations indicate that extended immunophenotypic and molecular characterization of APL at diagnosis including evaluation of CD2, CD56, and CD34 antigens and of FLT3 mutations may help to better design risk-adapted treatment in this disease.
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              中国急性早幼粒细胞白血病诊疗指南(2018年版)

              (2018)
              急性早幼粒细胞白血病(APL)是一种特殊类型的急性髓系白血病(AML),绝大多数患者具有特异性染色体易位t(15;17)(q22;q12),形成PML-RARα融合基因,其蛋白产物导致细胞分化阻滞和凋亡不足,是APL发生的主要分子机制[1]–[2]。APL易见于中青年人,平均发病年龄为44岁,APL占同期AML的10%~15%,发病率约0.23/10万[1]。APL临床表现凶险,起病及诱导治疗过程中容易发生出血和栓塞而引起死亡。近三十年来,由于全反式维甲酸(ATRA)及砷剂的规范化临床应用,APL已成为基本不用进行造血干细胞移植即可治愈的白血病[3]–[4]。 一、初诊患者入院评估 1.病史和体检 2.血液检查:血常规、血型,外周血涂片,生化,DIC相关指标检查,输血前有关传染性病原学检查。 3.骨髓检查: (1)细胞形态学和组织化学:以异常的颗粒增多的早幼粒细胞增生为主,且细胞形态较一致,胞质中有大小不均的颗粒,常见呈柴梱状的Auer小体。FAB分型根据颗粒的大小将APL分为:①M3a(粗颗粒型);②M3b(细颗粒型);③M3c(微颗粒型):较少见,易与其他类型AML混淆。细胞化学:APL的典型特征表现为过氧化酶强阳性、非特异性酯酶强阳性且不被氟化钠抑制、碱性磷酸酶和糖原染色(PAS)呈阴性或弱阳性。 (2)免疫分型:免疫分型在APL诊断中起到辅助作用。其典型表现:表达CD13、CD33、CD117和MPO,不表达或弱表达CD34、HLA-DR、CD11b、CD14、CD64、CD56。少数表达CD56患者提示预后较差。 (3)细胞遗传学:典型APL表现为t(15;17)(q22;q12)。变异型APL占2%,如t(11;17)(11q23;q12)、t(5;17)(5q35;q12)、t(11;17)(q13;q21)、der(17)、t(17;17)(q24;q12)、t(4;17)(q12;q21)、t(X;17)(p11;q21)、t(2;17)(q32;q21)、t(3;17)(q26;q21)、t(7;17)(q11;q21)、t(1;17)(q42;q21)等。5%的APL患者核型正常。常规染色体检测有时还可发现除t(15;17)以外的附加染色体异常。 (4)分子生物学:①PML-RARα融合基因:98%以上的APL患者存在PML-RARα融合基因,另有低于2%的APL患者为其他类型融合基因(见以下变异型APL诊断标准),检测PML-RARα融合基因是诊断APL的最特异、敏感的方法之一,也是APL治疗方案选择、疗效评价、预后分析和复发预测最可靠的指标。实时定量PCR(RQ-PCR)可在99%的典型APL患者中检出PML-RARα融合基因,但仍有1%的APL患者可出现假阴性。②基因突变:部分APL患者可伴有FLT3-ITD突变。 4.其他检查:心电图,超声心动图(必要时),胸片,腹部B超或CT(必要时)。 5.如外周血血小板计数及纤维蛋白原定量明显下降,存在严重出血倾向时,则不建议行PICC插管。 二、诊断和分层 (一)诊断 1.FAB分型为AML-M3。 2.WHO 2016年分型为伴重现性遗传学异常急性髓系白血病亚型下的APL伴PML-RARα阳性。 3.t(15;17)APL的诊断标准:PML-RARα融合基因阳性或染色体/FISH证实t(15;17)(q22;q12)时可确诊。 4.变异型APL的诊断标准:具有APL的临床特征、细胞形态学表现,细胞遗传学或分子生物学检测发现t(11;17)(11q23;q12)/PLZF-RARα、t(5;17)(5q35;q12)/NPM-RARα、t(11;17)(q13;q21)/NuMA-RARα、der(17)/STAT5b-RARα、t(17;17)(q24;q12)/PRKAR1A-RARα、t(4;17)(q12;q21)/FIP1L1-RARα、t(X;17)(p11;q21)/BCOR-RARα、t(2;17)(q32;q21)/OBFC2A-RARα、t(3;17)(q26;q21)/TBLR1-RARα、t(7;17)(q11;q21)/GTF2I-RARα、t(1;17)(q42;q21)/IRF2BP2-RARα、t(17;17)(17q21;q12)/STAT3-RARα[5]–[7]。 (二)预后分层 1.ATRA联合化疗作为一线治疗模式下的预后分层[8]: (1)低危:WBC 4×109/L时加羟基脲1.0 g,每日3次,口服,应用天数按白细胞计数而定;治疗中WBC>10×109/L时,酌情加用蒽环类药物或阿糖胞苷(Ara-C)]。 (2)巩固治疗:ATRA 25 mg·m−2·d−1×2周,间歇2周,为1个疗程,共7个疗程。亚砷酸0.16 mg·kg−1·d−1或者复方黄黛片60 mg·kg−1·d−1×4周,间歇4周,为1个疗程,共4个疗程。总计约7个月。 (3)维持治疗(可用或不用):流程见图2。每3个月为1个周期。第1个月:ATRA 25 mg·m−2·d−1×2周,间歇2周;第2个月和第3个月亚砷酸0.16 mg·kg−1·d−1或复方黄黛片60 mg·kg−1·d−1×2周,间歇2周。完成3个周期,维持治疗期共计约9个月。 图2 全反式维甲酸(ATRA)+砷剂治疗方案维持治疗流程 本文中亚砷酸均为静脉滴注。复方黄黛片(主要含四硫化四砷的复方制剂)及ATRA均为口服。 2.ATRA+砷剂+其他化疗治疗方案【备选】[14]:流程见图3。 图3 全反式维甲酸(ATRA)+砷剂+其他化疗治疗方案流程 (1)诱导治疗:ATRA 25 mg·m−2·d−1联合亚砷酸0.16 mg·kg−1·d−1或复方黄黛片60 mg·kg−1·d−1,直到CR;蒽环类或者蒽醌类药物控制白细胞增高。 (2)巩固治疗(2~3个疗程):可选方案: ①HA方案:高三尖杉酯碱(HHT)2 mg·m−2·d−1,第1~7天;Ara-C 100 mg·m−2·d−1,第1~5天。 ②MA方案:米托蒽醌(MIT)6~8 mg·m−2·d−1,第1~3天;Ara-C 100 mg·m−2·d−1,第1~5天。 ③DA方案:柔红霉素(DNR)40 mg·m−2·d−1,第1~3天;Ara-C 100 mg·m−2·d−1,第1~5天。 ④IA方案:去甲氧柔红霉素(IDA)8 mg·m−2·d−1,第1~3天;Ara-C 100 mg·m−2·d−1,第1~5天。 若第3次巩固化疗后未达到分子学转阴,可加用IDA(8 mg·m−2·d−1,第1~3天)和Ara-C(1.0 g/m2,每12 h 1次,第1~3天)。必须达到分子学转阴后方可开始维持治疗。 (3)维持治疗:每3个月为1个周期,第1个月:ATRA 25 mg·m−2·d−1×14 d,间歇14 d;第2个月和第3个月:亚砷酸0.16 mg·m−2·d−1或复方黄黛片60 mg·m−2·d−1×14 d,间歇14 d。完成8个周期,维持治疗期总计约2年。 3.ATRA+其他化疗治疗方案【砷剂不耐受或无砷剂药品时】[2]: (1)诱导治疗:ATRA 25 mg·m−2·d−1直到CR,DNR 45 mg·m−2·d−1静脉注射或IDA 8 mg·m−2·d−1静脉注射,第2、4、6天。 (2)巩固治疗(2个疗程):ATRA 25 mg·m−2·d−1×14 d+ DNR(45 mg·m−2·d−1静脉注射)或IDA(8 mg·m−2·d−1静脉注射)×3 d,间歇28 d,为1个疗程。共2个疗程。 (3)维持治疗:每3个月为1个周期:ATRA 25 mg·m−2·d−1,第1~14天;6-巯基嘌呤(6-MP)50~90 mg·m−2·d−1,第15~90天;甲氨蝶呤(MTX)5~15 mg/m2,每周1次,共11次。共8个周期,维持治疗期总计约2年余。 (二)高危APL患者的治疗 1.ATRA+砷剂+化疗诱导、化疗巩固、ATRA/砷剂交替维持治疗[10]: (1)诱导治疗:ATRA 25 mg·m−2·d−1联合亚砷酸0.16 mg·kg−1·d−1或复方黄黛片60 mg·kg−1·d−1,直到CR;DNR 45 mg·m−2·d−1或IDA 8 mg·m−2·d−1第1~3天。 (2)巩固治疗(3个疗程):可选用以下方案: ①HA方案:HHT 2 mg·m−2·d−1,第1~7天;Ara-C 100 mg·m−2·d−1,第1~5天。 ②MA方案:MIT 6~8 mg·m−2·d−1,第1~3天;Ara-C 100 mg·m−2·d−1,第1~5天。 ③DA方案:DNR 45 mg·m−2·d−1,第1~3天;Ara-C 100 mg·m−2·d−1,第1~5天。 ④IA方案:IDA 8 mg·m−2·d−1,第1~3天;Ara-C 100 mg·m−2·d−1,第1~5天。 若第3次巩固化疗后未达到分子学转阴,可加用IDA(8 mg·m−2·d−1,第1~3天)和Ara-C(1.0 g/m2,每12 h 1次,第1~3天)。必须达到分子学转阴后方可开始维持治疗。 (3)维持治疗:每3个月为1个周期,第1个月:ATRA 25 mg·m−2·d−1×14 d,间歇14 d;第2个月和第3个月:亚砷酸0.16 mg·kg−1·d−1或复方黄黛片60 mg·kg−1·d−1×14 d,间歇14 d。完成8个周期,维持治疗期总计约2年。 2.ATRA+砷剂+化疗诱导、ATRA+砷剂巩固、ATRA/6-MP/MTX维持治疗[2],[15]: (1)诱导治疗:ATRA 25 mg·m−2·d−1,第1~36天;亚砷酸0.16 mg·kg−1·d−1,第9~36天;IDA 6~12 mg·m−2·d−1,静脉注射,第2、4、6、8天。 (2)巩固治疗(2个疗程):①ATRA 25 mg·m−2·d−1,第1~28天+亚砷酸0.16 mg·kg−1·d−1,第1~28天;②ATRA 25 mg·m−2·d−1,第1~7、15~21、29~35天+亚砷酸0.16 mg·kg−1·d−1,第1~5、8~12、15~19、22~26、29~33天。 (3)维持治疗(2年):每3个月为1个周期:ATRA 25 mg·m−2·d−1,第1~14天;6-MP 50~90 mg·m−2·d−1,第15~90天;MTX 5~15 mg/m2,每周1次,共11次。共8个周期,维持治疗期总计约2年余。 (三)首次复发APL患者的治疗 一般采用亚砷酸±ATRA±蒽环类化疗进行再次诱导治疗。诱导缓解后必须进行鞘内注射,预防中枢神经系统白血病(CNSL)。达再次缓解(细胞形态学)者进行PML-RARα融合基因检测,融合基因阴性者行自体造血干细胞移植或亚砷酸巩固治疗(不适合移植者)6个疗程,融合基因阳性者进入临床研究或行异基因造血干细胞移植。再诱导未缓解者可加入临床研究或行异基因造血干细胞移植[1]–[2]。 四、疗效评价和监测 1.诱导阶段评估:ATRA的诱导分化作用可以持续较长时间,在诱导治疗后较早行骨髓评价可能不能反映实际情况。因此,骨髓形态学评价一般在第4~6周、血细胞计数恢复后进行,此时,细胞遗传学一般正常,而PML-RARα或发病时相应异常基因转录本在多数患者仍为阳性。CR标准同其他AML[16]–[17]。 2.微小残留病(MRD)监测:建议采用定量PCR监测骨髓PML-RARα转录本水平[18],治疗期间建议2~3个月进行1次分子学反应评估,持续监测2年。上述融合基因持续阴性者继续维持治疗,融合基因阳性者4周内复查。复查阴性者继续维持治疗,确实阳性者按复发处理。流式细胞术因对于APL的MRD敏感性显著小于定量PCR,因此不建议单纯采用流式细胞术对APL进行MRD监测。 五、支持及其他治疗 1.临床凝血功能障碍和出血症状严重者:首选为原发病的治疗。支持治疗如下:输注单采血小板以维持PLT≥(30~50)×109/L;输注冷沉淀、纤维蛋白原、凝血酶原复合物和冰冻血浆维持纤维蛋白原>1500 mg/L及PT和APTT值接近正常。每日监测DIC相关指标直至凝血功能正常。如有纤溶异常,应快速给予ATRA。如有器官大出血,可应用重组人凝血因子Ⅶa。 2.高白细胞APL患者的治疗:不推荐白细胞分离术。可给予水化及化疗药物。 3.APL分化综合征[19]:临床表现为以下7个表现:不明原因发热、呼吸困难、胸腔或心包积液、肺部浸润、肾脏衰竭、低血压、体重增加5 kg,符合2~3个者属于轻度分化综合征,符合4个或更多个者属于重度分化综合征。分化综合征通常发生于初诊或复发患者,WBC>10×109/L并持续增长者,应考虑停用ATRA或亚砷酸,或者减量,并密切关注体液容量负荷和肺功能状态,尽早使用地塞米松(10 mg,静脉注射,每日2次)直至低氧血症解除。 4.砷剂不良反应监测:治疗前进行心电图(评估有无QT间期延长)检查,外周血的肝功能和肾功能相关检查;同时要注意口服砷剂患者的消化道反应。 5.CNSL的预防和治疗:低中危APL患者,ATRA联合砷剂作为一线治疗方案中建议预防性鞘内治疗;高危APL或复发患者,因发生CNSL的风险增加,对这些患者应进行至少2~6次预防性鞘内治疗。对于已诊断CNSL患者,按照CNSL常规鞘内方案执行。 6.APL诱导治疗期间不主张应用G-CSF。 7.对于有高凝及血栓形成的患者可应用抗凝药物进行治疗。 8.肺功能损害:治疗中应注意肺功能情况。 9.肾功能损害:间断复查肾功能,防止肾功能损害的出现。
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                Author and article information

                Contributors
                719112295@qq.com
                719112295@qq.com
                719112295@qq.com
                719112295@qq.com
                719112295@qq.com
                719112295@qq.com
                719112295@qq.com
                719112295@qq.com
                719112295@qq.com
                719112295@qq.com
                Journal
                Mol Cytogenet
                Mol Cytogenet
                Molecular Cytogenetics
                BioMed Central (London )
                1755-8166
                10 April 2020
                10 April 2020
                2020
                : 13
                : 13
                Affiliations
                [1 ]GRID grid.440323.2, Clinical Laboratory, Qindao University Medical College Affiliated Yantai Yuhuangding Hospital, ; No. 20, Yuhuangding East Road, Yan Tai, 264000 China
                [2 ]GRID grid.440323.2, Department of Hematological, Qindao University Medical College Affiliated Yantai Yuhuangding Hospital, ; No. 20, Yuhuangding East Road, Yan Tai, 264000 China
                Article
                479
                10.1186/s13039-020-00479-1
                7149855
                76ee1314-7895-4c49-8096-361cda9b98a5
                © The Author(s) 2020

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                History
                : 7 January 2020
                : 9 March 2020
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                Case Report
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                © The Author(s) 2020

                Genetics
                fish,rt-pcr,apl,pml-rara,ider(17)(q10)t(15,17)(q22,q21)
                Genetics
                fish, rt-pcr, apl, pml-rara, ider(17)(q10)t(15, 17)(q22, q21)

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