常曉麗，董征，劉莎，姚波，滿秋紅，劉鐵強，李玉芳，劉志強，劉廣賢，艾輝勝，郭梅

伴t(11;17)(q23;q21)易位的急性早幼粒細胞白血病1例并文獻復習

常曉麗，董征，劉莎，姚波，滿秋紅，劉鐵強，李玉芳，劉志強，劉廣賢，艾輝勝，郭梅

目的探討伴t(11;17)(q23;q21)易位的急性早幼粒細胞白血病(APL)的臨床特點、治療及預后情況。方法報告1例APL伴t(11;17) (q23;21)，分析其細胞形態(tài)學、免疫學、細胞遺傳學及分子遺傳學特點，并對近20年國內(nèi)外相關(guān)文獻進行復習。結(jié)果本例患者為男性，35歲，白細胞計數(shù)38.17×109/L，骨髓早幼粒細胞88.5%，細胞核規(guī)則，無Auer's小體，PLZF-RARA融合基因陽性。染色體核型：46，XY，t(11;17)(q23;q21)。診斷：APL伴t(11;17)(q23;q21)。治療采用亞砷酸、全反式維甲酸(ATRA)和大劑量阿糖胞苷(2g/m2，總量24g，3個療程)聯(lián)合化療，隨訪至2013年2月，患者完全緩解已10個月。國內(nèi)外文獻已報道伴t(11;17)(q23;q21)易位的APL患者20例，年齡23～75(48.9±16.3)歲，其中男性占90%。3例單用維甲酸治療的患者中2例死于早期并發(fā)癥，應用維甲酸聯(lián)合誘導化療的10例患者中6例在11～56個月死于復發(fā)，1例死于早期膿毒血癥，提示大多數(shù)病例對維甲酸治療療效欠佳。結(jié)論伴t(11;17)(q23;q21)易位的APL是一種少見變異型，具有重要的形態(tài)學和臨床特點。延長亞砷酸治療時間，采用亞砷酸、全反式維甲酸和大劑量阿糖胞苷聯(lián)合化療方案可能對緩解病情和患者存活有益。

白血病，前髓細胞性，急性；易位，遺傳；抗腫瘤聯(lián)合化療方案

急性早幼粒細胞白血病(acute promyelocytic leukemia，APL)的典型特征是伴有t(15;17)(q22;21)染色體易位，并形成特征性PML/RARA融合基因，其多數(shù)對維甲酸及砷劑治療敏感[1-4]。但有5%～10%的APL患者缺乏這種典型的染色體改變[2-6]，伴t(11;17)(q23;q21)易位的APL就是其中一種罕見而獨特的變異類型，其基因?qū)W特點是11號染色體上的早幼粒細胞白血病鋅指基因(promyelocytic leukemia zinc finger，PLZF)與位于17號染色體的RARA基因發(fā)生融合，而且此類患者對全反式維甲酸(ATRA)不敏感，對砷劑及化療的反應目前亦無統(tǒng)一的報道[7-12]。軍事醫(yī)學科學院附屬醫(yī)院血液科經(jīng)治1例伴t(11;17)(q23;q21)易位的APL患者，經(jīng)亞砷酸、維甲酸聯(lián)合化療治療取得較好療效，已達持續(xù)完全緩解(complete response，CR)期，現(xiàn)就其臨床和實驗室特點并結(jié)合文獻討論報道如下。

1 病例資料

患者，男，35歲，因“周身乏力1年，發(fā)熱16d”于2012-02-14入院。血常規(guī)：白細胞38.17×109/L，血紅蛋白72g/L，血小板100×109/ L；出凝血功能：凝血酶原時間(PT) 15.2s，活動度57%，纖維蛋白原定量(FIB)0.47g/L，部分凝血活酶時間(APTT)不凝，凝血酶時間(TT) 21.3s，纖維蛋白降解產(chǎn)物(FDP)72.8μg/ml，伴全身多發(fā)出血傾向。骨髓形態(tài)學檢查提示：①骨髓異常顆粒增多的早幼粒細胞占88.5%，胞核多規(guī)則，染色質(zhì)固縮；②胞體大，胞質(zhì)豐富，胞質(zhì)粗顆粒型占31%，細顆粒型57.5%；③未見Auer's小體(圖1A)。外周血白細胞分類：早幼粒細胞64%。免疫組化：過氧化物酶(POX)、特異性酯酶(CE)染色陽性率均為100%，非特異性酯酶(NSE)染色陽性率為68%，氟化鈉(NaF)抑制試驗陰性；PLZF-RARA融合基因定性陽性；PLZF-RARA/ABL1=86.78%。FISH分析間期細胞400個，未見含典型PML/RARA融合信號的細胞，而3R2G信號模式(無BCR/ABL融合基因的異常信號模式)細胞364個，占91%；2R1G1Y信號模式(DC-DFFISH融合信號特征)細胞24個，占6%，提示可能是涉及17q21的RARA基因的少見變異型易位(圖1C)。染色體R顯帶核型分析示46，XY，t(11;17)(q23;q21) [3]/46，XY，?del(9q)，t(11;17)[2]/46，XY[9]核型(圖2A)。免疫分型：cMPO 77.7%、CD33 38.8%、CD13 92.8%、CD64 22.6%、CD15 26.1%、CD117 44.8%、CD56 63.4%。診斷為伴t(11;17)(q23;q21)易位的APL。

患者確診當天(2012-02-18)起給予亞砷酸(10mg，1次/d，共55d)誘導化療，亞砷酸治療誘導第6天白細胞36.4×109/L，故輔以MA方案(米托蒽醌10mg，d1-3+阿糖胞苷200mg，d1-7)，亞砷酸化療3周復查骨髓異常早幼粒細胞占74.5%，提示未緩解。為此，化療第24天加用維甲酸60mg，1次/d口服誘導分化治療。第28天白細胞再次升至35.07×109/L，遂加用HA方案(高三尖杉酯堿3mg，d1-7，阿糖胞苷200mg，d1-7)再誘導化療。亞砷酸共用55d，維甲酸共36d。期間患者外周血白細胞、骨髓比例變化見圖3。停用亞砷酸后20d復查見骨髓中原始+早幼粒細胞占3.5%，外周血未見原始及早幼粒細胞，PLZF-RARA/ABL1=2.58%，F(xiàn)ISH分析未見17q21的RARA基因變異(圖1D)，染色體R顯帶核型分析示46，XY(圖2B)，提示達形態(tài)學及遺傳學完全緩解。

圖1 誘導化療前后骨髓形態(tài)學及FISH分析結(jié)果對比Fig.1 Comparison of marrow morphology and FISH analysis before and after induction chemotherapyA. Morphology of bone marrow before induction chemotherapy (Arrows indicate the nuclear in regular shape, cytoplasmic particles and no Auer's bodies in cytoplasm) (Wright's ×100); B. Morphology of bone marrow after induction chemotherapy (Arrows indicate the increased caryolobism and decreased cytoplasmic granules)(Wright's ×100); C. Abnormality of chromosome with 17q21 revealed by FISH analysis before induction chemotherapy (Arrow indicates fracture of chromosome 17 after labeled by PML-RARA probe); D. No abnormality was found of RARA gene with 17q21 by FISH analysis in CR patients after induction chemotherapy

2012-05-13至2012-11-27共給予大劑量阿糖胞苷(阿糖胞苷2g/m2，總量24g)3個療程，以進行緩解后治療。2013年1月復查PLZF-RARA/ABL1=0，提示獲分子生物學完全緩解。隨訪至2013年2月，患者仍處于CR1期，無復發(fā)生存10個月。

2 文獻復習

圖2 誘導化療前后染色體R顯帶核型分析結(jié)果Fig.2 Karyotype analysis of chromosomal R-banding before and after induction chemotherapyA. Chromosome abnormality with t(11;17)(q23;q21) and ?Del(9q) before induction chemotherapy (Arrows indicate the translocation of 11q23 and 17q21 and the doubtful deletion of 9q, respectively); B. Normal karyotype of CR patients after induction chemotherapy

圖3 誘導化療期間骨髓、外周血早幼粒細胞比例及白細胞數(shù)變化Fig. 3 Changes of promyelocytes proportion in bone marrow (BM) and peripheral blood (PB) and counts of white blood cell (WBC) during induction chemotherapyMitoxantrone and Ara-C (MA) was added on the 6th day during the course of As2O3treatment; All Trans retinoic acid (ATRA) was added on the 24th day during the course of As2O3treatment; Homoharringtonine and Ara-C(HA) was added on the 28th day during the course of As2O3treatment

目前已報道的20例伴t(11;17)(q23;q21)易位的APL患者(表1)中，年齡分布在23～75歲(48.9±16.3歲)，其中男性占90%，提示中老年男性可能為好發(fā)人群。所有患者均伴PLZF-RARA融合基因異常。20例患者中彌散性血管內(nèi)凝血(DIC)的發(fā)生率達60%，與傳統(tǒng)APL患者相當。既往報道的文獻中，3例患者單用維甲酸治療，其中2例死于早期并發(fā)癥，10例采用維甲酸聯(lián)合誘導化療，其中6例在11～56個月死于復發(fā)，1例死于早期膿毒血癥[13-24]，提示大多數(shù)病例對維甲酸治療效果欠佳。

3 討 論

自上海報道世界首例伴t(11;17)(q23;q21)易位的APL以來[6]，國外陸續(xù)報道并證實該型染色體易位的APL已接近20例。APL的特征性改變是產(chǎn)生了X/RARA融合基因，目前已報道與RARA基因融合的有PML、PLZF、NuMA、NPM1、FIP1L1、PRKAR1A、STAT5b及BCOR，其中以PML最多見，占90%～95%。而由t(11;17)(q23;q21)易位所形成的PLZF/RARA融合基因則是其中一種較為罕見的變異類型，占APL的0.80%～1.08%[24-25]。文獻報道，PLZF/RARA與RARA/PLZF融合蛋白幾乎同時表達于t(11;17)(q23;q21)APL患者中，RARA/PLZF作為一種癌基因，會干擾正常造血，可通過不同機制與PLZF/RARA共同作用導致t(11;17)(q23;q21)APL的患者發(fā)病，而且對ATRA及傳統(tǒng)化療耐藥[6,26]。PLZF/RARA能阻斷髓系分化中起重要作用基因的表達，從而使髓系細胞停滯在早期階段，尤其是早幼粒細胞階段，而RARA/PLZF可激活細胞周期關(guān)鍵調(diào)控因子如cyclinA2等，使停滯分化的早幼粒細胞生長加速，且不受正常調(diào)控，從而導致對ATRA耐藥t(11;17)(q23;q21)APL的產(chǎn)生[6]。

不同于傳統(tǒng)的PML/RARA重排，伴PLZF/ RARA基因重排的APL多表現(xiàn)為以下形態(tài)學特征：①細胞核規(guī)則；Pelger–Hu?t細胞增多，染色質(zhì)固縮；②胞體大，胞質(zhì)豐富，胞質(zhì)內(nèi)多為細顆粒；③多無Auer's小體[2,24,27]。Sainty等[2]的研究表明，規(guī)則核的出現(xiàn)是伴t(11;17)(q23;q21)APL的關(guān)鍵形態(tài)學特征，且這種形態(tài)學表現(xiàn)可直接受到RARA/PLZF融合蛋白的影響，提示RARA/PLZF與PLZF/RARA基因一樣在該型APL的形成中不可或缺。另外，免疫表型方面也有一定特征有助于與傳統(tǒng)APL進行鑒別，即CD56高表達[24]。有文獻報道，CD56的高表達表明，與t(15;17)APL相比，t(11;17)APL可能來源于起源更早的白血病前體細胞[2]。

表1 國內(nèi)外已報道的20例伴t(11;17)(q23;q21)APL患者的臨床特征Tab. 1 Clinical features of 20 patients with APL accompanied by t(11;17)(q23;q21) reported domestically and aboard

目前，國內(nèi)外對伴有t(11;17)(q23;q21)易位的APL的治療尚無統(tǒng)一的方案，但大多數(shù)文獻報道，其早期緩解率較低、易復發(fā)，治療效果不佳，對單純ATRA或亞砷酸治療不敏感，聯(lián)合化療的療效尚不明確；文獻[13-24]報道，3例此類患者單用維甲酸治療，其中2例死于早期并發(fā)癥，10例采用維甲酸聯(lián)合誘導化療，其中6例在11～56個月死于復發(fā)，1例死于早期膿毒血癥，提示大多數(shù)病例對維甲酸治療療效欠佳。但Petti等[8]曾報道過3例單用ATRA或聯(lián)合G-CSF治療達到完全緩解的病例。分析原因如下：該患者白血病細胞未表達RARA/PLZF融合蛋白，而后者被認為在APL形成及ATRA耐藥機制中發(fā)揮重要作用；延長的ATRA治療可能有助于取得更好療效。尚有Kitamura等[11]報道2例通過ATRA聯(lián)合G-CSF治療達到完全緩解的病例。

本研究報道1例APL患者伴t(11;17)(q23;q21)，發(fā)病早期合并DIC，其形態(tài)學特點符合前述典型特征的改變，并可見CD56高表達，經(jīng)以亞砷酸為基礎(chǔ)的聯(lián)合化療取得較好療效。分析原因如下：本例在誘導治療中延長了亞砷酸的療程，并同時聯(lián)合化療和ATRA治療，提高了完全緩解的可能性；本例治療過程中采用了大劑量阿糖胞苷作為完全緩解后治療，該舉措可能對殺滅殘留白血病細胞、維持緩解狀態(tài)有重要作用。

綜上，伴t(11;17)(q23;q21)易位的APL是一種罕見的變異型，具有重要的形態(tài)學、免疫學和臨床特點，延長亞砷酸治療時間、聯(lián)合化療及ATRA治療有可能對其早期緩解及較長的無病生存有益。

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Acute promyelocytic leukaemia with translocation of t(11;17)(q23;q21): a case report and review of literature

CHANG Xiao-li1, DONG Zheng2, LIU Sha2, YAO Bo2, MAN Qiu-hong2, LIU Tie-qiang2, LI Yu-fang2, LIU Zhi-qiang2, LIU Guang-xian2, AI Hui-sheng2, GUO Mei2*
1Postgraduate Medical School of PLA, Beijing 100853, China
2Department of Hematology, Affiliated Hospital, Academy of Military Medical Sciences, Beijing 100071, China
*

, E-mail: guom196801@yahoo.com.cn

ObjectiveTo study the clinical attributes, treatment and prognosis of acute promyelocytic leukaemia (APL) with translocation of t(11;17)(q23;q21).MethodsA case of APL with t(11;17)(q23;q21) was reported, and the cytomorphology, immunology, cytogenetics and molecular genetics of the patient were analyzed. The related literature published in recent 20 years domestically and abroad was reviewed.ResultsThe case herewith studied was a male patient aged 35 years with leucocyte count (WBC) of 38.17×109in peripheral blood, and 88.5% of promyelocytes in bone marrow. Marrow karyotype analysis showed 46, XY, t(11;17)(q23;q21) and PLZF-RARA rearrangement was detected. The patient was definitely diagnosed as APL with t(11;17) (q23;q21). Complete morphological and genetic remission was achieved after a combined chemotherapy of As2O3and ATRA, then a molecular biological remission was achieved after the treatment of 3 courses of large dose cytarabine. The patient was followed up to February 2013 with disease-free survival of nearly 10 months. Up to date, 20 cases of APL with t(11;17)(q23;q21) have been reported domestically and abroad, and their clinical attributes were reviewed. For the 20 cases, the mean age was 48.9±16.3 years and the male/female ratio was 9:1. Among the patients, males aged over 45 years accounted for 55%, implying that the elderly males may be high-risk population. The incidence of DIC was 60%, most of which got poor curative effect of ATRA.ConclusionAPL with t(11;17)(q23;q21) is a very rare illness with distinct morphological changes and clinical characteristics. Prolonged combined chemotherapy with As2O3and ATRA with large dose cytarabine may be beneficial to attain a remission and prolong survival.

leukemia, promyelocytic, acute; translocation, genetic; antineoplastic combined chemotherapy protocols

R733.712

A

0577-7402(2013)05-0378-05

2013-03-12；

2013-03-20)

(責任編輯：沈?qū)?

國家自然科學基金(30200116)

常曉麗，住院醫(yī)師，碩士研究生。主要從事惡性血液病方面的研究

100853 北京 解放軍醫(yī)學院[常曉麗(現(xiàn)在軍事醫(yī)學科學院附屬醫(yī)院血液科)]；100071 北京 軍事醫(yī)學科學院附屬醫(yī)院血液科(董征、劉莎、姚波、滿秋紅、劉鐵強、李玉芳、劉志強、劉廣賢、艾輝勝、郭梅)

郭梅，E-mail：guom196801@yahoo.com.cn

This work was supported by the National Natural Science Foundation of China(30200116)