本文關(guān)鍵詞：急性早幼粒細(xì)胞白血病誘導(dǎo)治療優(yōu)化策略的探討　出處：《南方醫(yī)科大學(xué)》2015年博士論文　論文類(lèi)型：學(xué)位論文

  更多相關(guān)文章： 急性早幼粒細(xì)胞白血病 誘導(dǎo) 治療 早期死亡 預(yù)后 優(yōu)化

【摘要】：研究背景和目的急性早幼粒細(xì)胞白血病(acute promyelocytic leukemia, APL)是以外周血、骨髓中異常早幼粒細(xì)胞增多、凝血功能異常、出現(xiàn)特異性染色體易位即t(15；17)(q22；q21)為特征的一類(lèi)特殊類(lèi)型急性白血病。隨著全反式維甲酸(all-trans retinoic acid, ATRA)及砷劑的引入,APL已由一類(lèi)高致死性疾病發(fā)展為可獲得較高治愈率的惡性血液腫瘤。APL患者的預(yù)后與轉(zhuǎn)歸受多重因素的影響,歸納起來(lái)早期死亡、復(fù)發(fā)、長(zhǎng)期并發(fā)癥三個(gè)方面的因素決定了患者的總體生存(overall survival, OS)、無(wú)病生存(disease free survival, DFS)、無(wú)事件生存(event free survival, EFS)。盡管ATRA合并砷劑所帶來(lái)的革命性治療使得APL成為一種可被治愈的腫瘤性疾病,然而研究表明：其早期病死率(early death, ED)并沒(méi)因此得以降低。甚至有研究者認(rèn)為,治療的革命性進(jìn)展并未對(duì)降低早期病死率發(fā)揮作用。McClellan等的研究認(rèn)為部分患者在入組試驗(yàn)之前、尚未獲得充分的誘導(dǎo)化療就已死于出血所導(dǎo)致的未能入組大型臨床試驗(yàn)是早期病死率被低估的主要原因。總之,出血、高白細(xì)胞(white blood cells, WBC)、分化綜合征(differentiation syndrome, DS)仍是APL早期死亡的幾大主要原因。NCCN推薦ATRA、蒽環(huán)類(lèi)藥物、三氧化二砷(arsenic trioxide, ATO)為APL誘導(dǎo)治療的一線藥物,但并未對(duì)蒽環(huán)類(lèi)毒性藥物的給藥時(shí)機(jī)、不同危險(xiǎn)度分層下的細(xì)胞毒性藥物選擇予以明確說(shuō)明。因此,本課題擬就APL早期死亡病例臨床特征、細(xì)胞毒性藥物的治療時(shí)機(jī)、細(xì)胞毒性藥物化療方案的選擇、APL預(yù)后相關(guān)的免疫表型予以分析探討,以期達(dá)到優(yōu)化APL誘導(dǎo)治療的目的。1)APL早期死亡病例的特征：一般認(rèn)為嚴(yán)重的出血是APL早期死亡的主要原因,而診斷及治療的延誤可能進(jìn)一步促進(jìn)APL早期死亡。為了更好地區(qū)分APL不同類(lèi)型的早期死亡,為降低早期死亡率提供策略、依據(jù),本研究擬對(duì)不同時(shí)間段的早期死亡、不同危險(xiǎn)度分層下的早期死亡予以比較分析。2)低中危APL誘導(dǎo)化療期間的細(xì)胞毒性藥物化療時(shí)機(jī)：低中危APL經(jīng)ATRA或ATO誘導(dǎo)治療后均存在早幼粒細(xì)胞向后階段細(xì)胞的進(jìn)一步分化,白細(xì)胞總數(shù)增高,并發(fā)高白細(xì)胞血癥、分化綜合征(differentiation syndrome, DS)的高風(fēng)險(xiǎn)；據(jù)報(bào)道化療則可能加重凝血功能障礙；因此有必要在ATRA或ATO誘導(dǎo)治療期間合適的時(shí)機(jī)下加用蒽環(huán)類(lèi)或其他細(xì)胞毒性藥物,以控制高白細(xì)胞帶來(lái)的早期死亡風(fēng)險(xiǎn)。3)高危APL誘導(dǎo)化療期間的細(xì)胞毒性藥物化療時(shí)機(jī)：高危APL起病之初即面臨高白細(xì)胞、顱內(nèi)出血的早期死亡風(fēng)險(xiǎn),存在ATRA誘導(dǎo)分化致白細(xì)胞進(jìn)一步增高、需蒽環(huán)類(lèi)為主的細(xì)胞毒性藥物化療快速控制高白細(xì)胞與可能加重出血、增加腫瘤細(xì)胞溶解綜合征風(fēng)險(xiǎn)的治療矛盾,因此治療困難。而NCCN旨南未就細(xì)胞毒性藥物的化療時(shí)機(jī)給出明確指導(dǎo)意見(jiàn)。4)細(xì)胞毒性藥物的種類(lèi)選擇：基于AIDA、LPA等大型多中心臨床試驗(yàn)的結(jié)果,NCCN推薦誘導(dǎo)治療期間予以蒽環(huán)類(lèi)藥物為主的細(xì)胞毒性藥物化療。在國(guó)內(nèi)高三尖杉酯堿(Homoharringto nine, HHT)、羥基脲同樣被廣泛應(yīng)用于急性髓系白血病的誘導(dǎo)、鞏固治療。為進(jìn)一步說(shuō)明不同蒽環(huán)類(lèi)化療藥物、HHT、羥基脲在APL誘導(dǎo)治療中的早期死亡相關(guān)不良反應(yīng)及近期療效,本研究予以了探討。5)有助于快速診斷及預(yù)后判斷的APL免疫表型模式：相較于染色體檢查、PCR、FISH檢測(cè)的耗時(shí)性,流式細(xì)胞檢測(cè)有助于初治APL的快速診斷。研究表明,CD2.CD56以及CD34與APL的總體生存(overall survival,OS)降低、緩解期縮短、緩解率下降、早期死亡率(early death,ED)的上升有關(guān),但彼此間的關(guān)系鮮有研究。本研究旨在通過(guò)單因素、多因素分析,探討CD2、CD56及CD34對(duì)APL早期死亡及長(zhǎng)期預(yù)后的影響及其彼此間的相互作用。病人與方法2003年1月至2013年12月南方醫(yī)院血液科病房收治初發(fā)急性早幼粒細(xì)胞白血病212例。49例在誘導(dǎo)治療開(kāi)始前或誘導(dǎo)期間死亡,其中男性34例,女性15例,年齡15-84歲,中位年齡32歲。163例患者在誘導(dǎo)治療期間,接受ATRA聯(lián)合蒽環(huán)類(lèi)藥物或高三尖杉酯堿為基礎(chǔ)的聯(lián)合化療。其中低中危APL患者96例,男性47例,女性49例,年齡15-66歲,中位年齡32歲。高危APL患者73例,男性54例,女性19例,年齡15-67歲,中位年齡32歲。所有患者均經(jīng)骨髓涂片檢查明確為急性早幼粒細(xì)胞白血病,染色體檢查提示存在t(15；17),FISH檢測(cè)證實(shí)PML-RARa融合基因陽(yáng)性。所有患者治療前均簽署治療知情同意書(shū)。誘導(dǎo)化療：患者一旦疑診APL,盡快應(yīng)用ATRA(25mg/m2/d),并維持治療直至獲得完全血液學(xué)緩解。細(xì)胞毒性藥物化療方案包括：去甲氧柔紅霉素37例(8mg/m2/d,d1-3);柔紅霉素36例(45 mg/m2/d,d1-3);高三尖杉酯堿23例(2 mg/m2/d,d1-5);阿糖胞苷聯(lián)用劑量(100 mg/m2/d,d1-7)。化療后WBC計(jì)數(shù)仍高于正常的患者予以羥基脲治療,并根據(jù)WBC調(diào)整羥基脲用量。36例患者接受三氧化二砷聯(lián)合治療(0.15g/kg,d1-14)。誘導(dǎo)化療期間的支持治療目標(biāo)：維持血小板在30×109/L以上；維持血紅蛋白在70g/L以上；輸注新鮮冰凍血漿或冷沉淀糾正凝血功能,維持纖維蛋白原在1.5g/L以上。1.不同類(lèi)型APL早期死亡臨床特征的比較分析：將早期死亡病例按照死亡時(shí)間分為超早期死亡組(ATRA誘導(dǎo)治療前及開(kāi)始3天內(nèi)發(fā)生的ED一定程度上可視為ATRA未能完全起效而由自然病程進(jìn)展導(dǎo)致的死亡),治療后早期死亡組(ATRA誘導(dǎo)開(kāi)始3天后、且發(fā)生于誘導(dǎo)治療期間的早期死亡)。根據(jù)Sanz's危險(xiǎn)評(píng)分標(biāo)準(zhǔn)分為低中危組、高危組。分別比較超早期死亡組與治療后早期死亡組,低中危組與高危組的臨床特征。2.低中危APL細(xì)胞毒性藥物化療時(shí)機(jī)的優(yōu)化選擇：低中危APL經(jīng)ATRA誘導(dǎo)后WBC將不同程度上升,根據(jù)予以細(xì)胞毒性藥物化療時(shí)WBC水平分為：≤4×109/L、4～15×109/L、15×109/L三組。根據(jù)低中危APL細(xì)胞毒性藥物化療距離ATRA誘導(dǎo)開(kāi)始時(shí)間分為7天內(nèi)化療、7天后化療兩組。不同分組情況下,分別比較各組臨床基線水平、DS發(fā)生率、3-4級(jí)感染、3-4級(jí)骨髓抑制、化療相關(guān)出血發(fā)生率、CR率(complete remission, CR)、CR所需事件、早期死亡率等臨床療效參數(shù)。二分類(lèi)logistic回歸分析細(xì)胞毒性藥物化療的不同給藥時(shí)機(jī)對(duì)早期死亡相關(guān)事件的影響。3.高危APL細(xì)胞毒性藥物化療時(shí)機(jī)的優(yōu)化選擇將73例高危APL分為小劑量化療組(25例開(kāi)始ATRA誘導(dǎo)治療同時(shí)予以羥基脲聯(lián)合小劑量阿糖胞苷治療)、早期聯(lián)合化療組(35例在ATRA誘導(dǎo)開(kāi)始3天內(nèi)予以蒽環(huán)或高三尖酯堿為基礎(chǔ)的細(xì)胞毒性藥物化療)、晚期聯(lián)合化療組(13例在ATRA+羥基脲(3 g/d)/小劑量阿糖胞苷(25mg q12h)治療3天后予以聯(lián)合化療)。并就臨床基線水平、DS發(fā)生率、3-4級(jí)感染、3-4級(jí)骨髓抑制、化療相關(guān)出血發(fā)生率、CR率、CR所需事件、早期死亡率等予以比較。4.細(xì)胞毒性藥物的種類(lèi)選擇比較2009年10月之前以HA(高三尖杉酯堿±阿糖胞苷3+7方案)、DA(柔紅霉素+阿糖胞苷3+7方案)或單用羥基脲作為誘導(dǎo)治療期間聯(lián)合化療的71例APL的臨床療效。其中HA組31例,DA組22例,單用羥基脲組18例患者。比較2009年9月至2013年12月期間,54例單用去甲氧柔紅霉素(idarubincin,Ida)、27例DA方案聯(lián)合誘導(dǎo)治療的APL病例的臨床療效。5.有助于快速診斷及預(yù)后判斷的APL免疫表型模式以132例有可評(píng)價(jià)的流式細(xì)胞檢測(cè)資料的初發(fā)APL為研究對(duì)象,分析其免疫表型特征；分析比較CD2陽(yáng)性、CD2陰性APL臨床特征及預(yù)后關(guān)系；二分類(lèi)Logistc回歸模型分析CD2、CD3、CD56、發(fā)病時(shí)WBC計(jì)數(shù)與APL早期預(yù)后的關(guān)系。統(tǒng)計(jì)方法分類(lèi)變量采用率表示,連續(xù)性變量采用x±s表示,等級(jí)變量采用平均秩次表示。兩組比較的計(jì)量資料采用t檢驗(yàn),三組比較的計(jì)量資料采用方差分析,分類(lèi)變量采用χ2檢驗(yàn),等級(jí)資料的采用秩和檢驗(yàn)。多因素分析采用二分類(lèi)Logistic回歸模型。P0.05認(rèn)為無(wú)統(tǒng)計(jì)學(xué)差異,P0.05認(rèn)為有統(tǒng)計(jì)學(xué)差異。所有統(tǒng)計(jì)均于SPSS17.0軟件中完成。以10%作為CD34、CD56表達(dá)陽(yáng)性的界定值,其余免疫標(biāo)記均以20%作為陽(yáng)性界定值。結(jié)果1.不同類(lèi)型APL早期死亡臨床特征的比較分析：24/49的早期死亡發(fā)生于治療開(kāi)始前及治療開(kāi)始3天內(nèi),其中12/49例患者早期死亡發(fā)生時(shí)未經(jīng)任何治療。30/49的早期死亡病例為高危APL。6/49例患者系老年,47/49例患者就診時(shí)ECOG評(píng)級(jí)為3-4級(jí)。超早期死亡組與治療后早期死亡組比較,有統(tǒng)計(jì)學(xué)差異的是：治療前的WBC計(jì)數(shù)(53.88±64.49 vs24.53±29.59×109/L,P=0.012),治療前3-4級(jí)出血發(fā)生率(91.7%vs60.90%,P=0.005),發(fā)病至就診時(shí)間(中位7vs10天,Z=186.50,P=0.022),就診至死亡時(shí)間(中位1vs13天,Z=17.060,P=0.000),發(fā)病至死亡時(shí)間(中位9vs24天,Z=67.50,P=0.000)。兩早期死亡組(超早期死亡組與治療后早期死亡組)分別與CR組比較,有統(tǒng)計(jì)學(xué)差異的是：肌酐水平均高于CR組(P=0.000,0.002), LDH水平均高于CR組(P=0.000,0.001),PT延長(zhǎng)率均高于CR組(P=0.000,0.004), ISTH積分均高于CR組(P=0.000,0.000),治療前3-4級(jí)出血發(fā)生率均高于CR組(P=0.000,0.003)。僅超早期死亡組與CR組比較有統(tǒng)計(jì)學(xué)差異的是：超早期死亡組高危患者比例更高(P=0.001),發(fā)病時(shí)WBC計(jì)數(shù)超早期死亡組更高(P=0.012),PLT計(jì)數(shù)超早期死亡組更低(P=0.041), APTT延長(zhǎng)發(fā)生率超早期死亡組更高(P=0.015),顯性DIC發(fā)生率超早期死亡組更高(P=0.000)。低中危ED組與高危ED組比較：高危組LDH水平更高(P=0.002)；高危早期死亡組患者發(fā)病至就診中位時(shí)間8天,低中危組10天,兩組比較有統(tǒng)計(jì)學(xué)差異(χ2=184.50,P=0.037)。發(fā)病至死亡時(shí)間中位時(shí)間高危組11天,低中危早期死亡組24天(χ2=145.50,P=0.004)。2.低中危APL聯(lián)合化療時(shí)機(jī)的優(yōu)化選擇96例低中危APL分別在WBC≤4×109/L、4～15×109/L、≥15×109/L時(shí)接受細(xì)胞毒性藥物化療。三組DS發(fā)生率分別為0%、11.10%、40.00%,三組比較有統(tǒng)計(jì)學(xué)差異(Χ2=186.50,P=0.000),WBC≥15×109/L化療組DS發(fā)生率高于其他兩組(P=0.001,0.003)。三組3-4級(jí)骨髓抑制率的比較無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)；3-4級(jí)感染發(fā)生率分別為71.40%、33.30%、43.30%,三組比較有統(tǒng)計(jì)學(xué)差異(Χ2=8.440,P=0.015),WBC≤4×109/L組化療后3-4級(jí)感染發(fā)生率高于WBC4～15×109/L組(P=0.004)。三組化療后出血發(fā)生率分別為9.50%、29.30%、42.90%,三組比較有統(tǒng)計(jì)學(xué)差異(χ2=5.817,P=0.039)。CR率分別為90.5%,100%；73.3%,三組比較有統(tǒng)計(jì)學(xué)差異(χ2=13.740,P=0.000)；三組CR所需時(shí)間無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)；三組早期死亡率分別為4.8%、0.0%、26.70%,三組比較有統(tǒng)計(jì)學(xué)差異(χ2=15.739,P=0.000),兩兩比較WBC4～15×109/L組早期死亡率低于WBC≥15×109/L組(P=0.001)。96例患者按聯(lián)合化療距離ATRA的時(shí)間分為：誘導(dǎo)開(kāi)始3天內(nèi)及3天以上接受細(xì)胞毒性化療兩組。2組間DS發(fā)生率、3-4級(jí)骨髓抑制率、3-4級(jí)感染率、CR率、早期死亡發(fā)生率均無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。但3天以上接受化療組出血事件發(fā)生率高于3天內(nèi)接受化療組,分別為33.3%、7.4%,兩組比較有統(tǒng)計(jì)學(xué)差異(χ2=6.773,P=0.009)；此外3天以上化療組獲得CR所需時(shí)間更長(zhǎng),兩組比較有統(tǒng)計(jì)學(xué)差異(t=-1.924,P=0.004)。二分類(lèi)logistic回歸分析顯示：給予細(xì)胞毒性藥物化療時(shí)的WBC計(jì)數(shù)是DS發(fā)生、早期死亡的獨(dú)立危險(xiǎn)因素,有統(tǒng)計(jì)學(xué)差異(P0.05)。化療距離ATRA開(kāi)始時(shí)間、初診WBC、初診PLT均非DS發(fā)生、早期死亡、完全緩解失敗的獨(dú)立危險(xiǎn)因素(P0.05)。3.高危APL細(xì)胞毒性藥物化療時(shí)機(jī)的優(yōu)化選擇小劑量化療組、早期聯(lián)合化療組、晚期聯(lián)合化療三組間DS發(fā)生率、3-4級(jí)骨髓抑制率、化療后出血事件發(fā)生率無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。三組3-4級(jí)感染發(fā)生率分別為13.00%、57.10%、69.20%,三組比較有統(tǒng)計(jì)學(xué)差異(χ2=14.655,P=0.001),小劑量化療組低于早期聯(lián)合化療組及晚期聯(lián)合化療組(P=0.000,0.001)。三組獲得CR所需時(shí)間分別為29.27+6.78,28.54+8.08,50.00+21.75天,三組比較有統(tǒng)計(jì)學(xué)差異(F=11.851,P=0.000),晚期聯(lián)合化療組長(zhǎng)于其他兩組,P=0.000。三組CR率分別為40.0%,68.6%,84.6%,三組比較有統(tǒng)計(jì)學(xué)差異(χ2=8.605,P=0.014),小劑量化療組低于晚期聯(lián)合化療組。三組早期死亡率分別為56.0%,25.7%,15.4%,三組比較有統(tǒng)計(jì)學(xué)差異(χ2=8.439,P=0.015),小劑量化療組早期死亡率高于早期聯(lián)合化療組及晚期聯(lián)合化療組(P=0.017,0.016)。4.細(xì)胞毒性藥物的種類(lèi)選擇DA、HA、單用羥基脲分別聯(lián)合ATRA誘導(dǎo)治療APL,各組DS發(fā)生率分別為22.7%、25.8%、38.9%；3-4級(jí)感染發(fā)生率分別為40.9%、45.2%、16.7%；3-4級(jí)出血發(fā)生率分別為6.7%、7.1%、0.0%。三組間DS發(fā)生率、3-4級(jí)感染發(fā)生率、3-4級(jí)出血發(fā)生率的比較均無(wú)統(tǒng)計(jì)學(xué)差異,P0.05。化療后三組3-4級(jí)骨髓抑制率分別為90.5%、90.3%、29.4%,三組比較有統(tǒng)計(jì)學(xué)差異(χ2=14.655,P=0.000),單用羥基脲組3-4級(jí)骨髓抑制程度低于DA、HA組(P=0.000,0.000)。誘導(dǎo)治療療效方面,DA、HA、單用羥基脲三組CR率分別為86.4%、90.30%、88.9%；CR所需中位時(shí)間分別為37.76±13.67、38.54±12.62、33.17±10.95天；早期誘導(dǎo)治療期間死亡率分別為9.1%、3.2%、5.6%,均無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。DA、Ida分別聯(lián)合ATRA誘導(dǎo)治療初治APL,兩組比較,DA、單用Ida組DS發(fā)生率分別為37%、24.1%；3-4級(jí)骨髓抑制率分別為77.8%、90.7%；3-4級(jí)感染發(fā)生率分別為40.7%、53.7%；3-4級(jí)出血發(fā)生率分別為8.3%、4.3%。兩組間DS發(fā)生率、3-4級(jí)骨髓抑制率、3-4級(jí)感染發(fā)生率、3-4級(jí)出血發(fā)生率的比較均無(wú)統(tǒng)計(jì)學(xué)差異,P0.05。DA組、單用Ida組CR率分別為70.4%、85.2%,兩組比較無(wú)統(tǒng)計(jì)學(xué)差異。早期死亡率分別為29.6%、14.8%,t=2.492,P=0.114。兩組獲得CR所需中位時(shí)間分別為33.25±15.21、31.33±11.51天,兩組比較無(wú)統(tǒng)計(jì)學(xué)差異,P0.05。5.有助于快速診斷及預(yù)后判斷的APL免疫表型模式單核巨噬系統(tǒng)相關(guān)抗原CD64表達(dá)陽(yáng)性率為78.4%,熒光強(qiáng)度呈弱至中度。CD9陽(yáng)性率為96.6%,熒光強(qiáng)度呈弱至強(qiáng)度均有分布。此外,預(yù)后相關(guān)抗原CD2陽(yáng)性率為11.9%,CD56陽(yáng)性率為9.3%。101例獲得CD2資料的初診APL,89例CD2陰性,12例陽(yáng)性。初診時(shí)WBC計(jì)數(shù)的比較兩組之間有統(tǒng)計(jì)學(xué)差異,CD2陽(yáng)性組WBC計(jì)數(shù)高于CD2陰性的APL[(15.06+22.49)×x109/L vs(34.97+57.6)×109/L,t=-2.263, P=0.028]。CD2陽(yáng)性APL其CD34陽(yáng)性率高于CD2陰性組(13.74%vs3.63%,χ2=-2.055,P=0.006),而CD56的表達(dá)兩組間無(wú)統(tǒng)計(jì)學(xué)差異(P0.05)。與CD2陰性的APL相比,CD2陽(yáng)性APL早期死亡率更高(50%vs15.7%, X2=5.741, P=0.016),完全緩解率更低(50%vs91.1%, X2=5.741, P=0.042),5年的總體生存更低(41.7%vs74.2%,χ2=5.346,P=0.018),均有統(tǒng)計(jì)學(xué)差異。但DS發(fā)生率及5年復(fù)發(fā)率兩者間無(wú)統(tǒng)計(jì)學(xué)差異。將APL初診時(shí)WBC計(jì)數(shù)、CD2、CD34、CD56一同納入自變量,分別分析其對(duì)APL患者DS的發(fā)生、早期死亡、CR、5年總體生存、5年復(fù)發(fā)率的影響,結(jié)果顯示,CD2陽(yáng)性對(duì)早期死亡的風(fēng)險(xiǎn)預(yù)測(cè)因初診時(shí)WBC計(jì)數(shù)納入自變量而被抵消。CD2、CD34、CD56均不是發(fā)生DS、早期死亡、緩解失敗、5年內(nèi)死亡、5年復(fù)發(fā)的獨(dú)立危險(xiǎn)因素(P0.05)。而初診時(shí)WBC計(jì)數(shù)是早期死亡、完全緩解失敗、5年長(zhǎng)期生存的獨(dú)立危險(xiǎn)因素(P0.05)。結(jié)論1.初治APL的超早期死亡不同于治療后早期死亡。高白細(xì)胞所代表的高腫瘤負(fù)荷、疾病的迅速進(jìn)展是APL超早期死亡區(qū)別于治療后早期死亡的主要特征。PT延長(zhǎng)、ISTH積分更高、嚴(yán)重出血發(fā)生率更高是早期死亡病例不同于CR病例的特征。高LDH水平、PT的顯著延長(zhǎng)、3-4級(jí)出血是ED病例中高危APL區(qū)別于低中危APL的主要特征。疾病自身性質(zhì)及快速進(jìn)展可能是超早期死亡的主要原因。高白細(xì)胞加重出血是超早期死亡發(fā)生的重要因素。當(dāng)前的治療尚不足以降低早期死亡發(fā)生率,尤其是超早期死亡率,APL起始治療有待于改進(jìn)。2.對(duì)于低中危APL,當(dāng)ATRA誘導(dǎo)分化治療至WBC計(jì)數(shù)介于4～15×109/L之間時(shí)予以細(xì)胞毒性藥物化療,APL患者可能獲得更佳的早期生存受益。對(duì)于持續(xù)WBC減少的低中危APL,是否仍需聯(lián)合強(qiáng)烈的細(xì)胞毒性藥物化療值得進(jìn)一步探討。3.與低中危APL不同,高危APL推薦在ATRA誘導(dǎo)治療開(kāi)始3天內(nèi)予以盡快的聯(lián)合細(xì)胞毒性藥物化療,以有效控制高白細(xì)胞血癥、降低致死性顱內(nèi)出血風(fēng)險(xiǎn)、從而降低早期死亡4.對(duì)于那些不宜接受標(biāo)準(zhǔn)劑量毒性藥物化療的患者,羥基脲為主的小劑量化療仍是治療的選擇之一,但不宜首選推薦；作為一個(gè)經(jīng)濟(jì)的化療藥物,HA方案在APL誘導(dǎo)治療中,在短期、長(zhǎng)期療效方面與蒽環(huán)類(lèi)藥物相當(dāng),價(jià)格低廉,值得推薦。5.CD64各個(gè)范圍熒光強(qiáng)度的高表達(dá)、CD9中等至強(qiáng)熒光強(qiáng)度的高表達(dá)是對(duì)APLCD13+CD33+HLA-DR-CD34-經(jīng)典免疫表型的補(bǔ)充,有助于APL的快速診斷。雖然單因素分析提示CD2陽(yáng)性APL早期死亡高于CD2陰性APL,但多因素分析顯示W(wǎng)BC計(jì)數(shù)仍是APL預(yù)后的唯一獨(dú)立危險(xiǎn)因素。
[Abstract]:Background and objective of acute promyelocytic leukemia (acute promyelocytic, leukemia, APL) is the peripheral blood and bone marrow abnormal promyelocyte cells increased, abnormal blood coagulation, specific chromosome translocation t (15; 17) (q22; q21) is characterized by a special type of acute leukemia. With all trans retinoic acid (all-trans retinoic acid, ATRA and APL) introduced the arsenic, has a class of highly fatal disease development for malignant tumors can obtain higher cure rate. The prognosis of APL patients and the prognosis is affected by multiple factors, summed up the three factors of early death, recurrence and long-term complications determines the overall survival of patients with (overall survival, OS), disease-free survival (disease free, survival, DFS), event free survival (event free, survival, EFS). Although ATRA with revolutionary treatment caused by arsenic makes APL become a neoplastic disease can be cured, but the study shows that the early mortality rate (early death, ED) and therefore did not be reduced. Even some researchers believe that the revolutionary progress of treatment does not play a role in reducing early mortality. McClellan and other studies believe that some patients who had not received sufficient induction chemotherapy before the admission test were dead due to hemorrhage and failed to enter the large clinical trial, which is the main reason for the early mortality rate being underestimated. In conclusion, bleeding, high leukocyte (white blood cells, WBC) and differentiation syndrome (differentiation syndrome, DS) are still a major cause of the early death of APL. NCCN recommended ATRA, anthracycline, and arsenic trioxide (ATO) as first-line drugs for APL induction treatment, but it did not specify the timing of anthracycline toxicity and the choice of cytotoxic drugs under different risk stratification. Therefore, the aim of this study is to analyze the clinical characteristics, the timing of cytotoxic drugs, the choice of cytotoxic drugs and the immunophenotype of APL related prognosis in the early stage of APL death, so as to achieve the goal of optimizing APL induction therapy. 1) the characteristics of early death in APL: it is generally believed that severe bleeding is the main cause of early death in APL, and the delay in diagnosis and treatment may further promote the early death of APL. In order to better distinguish different types of early death in APL and provide strategies and basis for reducing early mortality, this study will compare and analyze early death in different time periods of early death and different risk stratification. 2) cytotoxic chemotherapy time during induction chemotherapy in low risk APL: there were further differentiation of promyelocytic cells in low back stage risk APL by ATRA or ATO after induction therapy, leukocytosis, concurrent high white blood cell differentiation syndrome (differentiation, syndrome, DS) high risk; according to reports, chemotherapy may aggravate the dysfunction of blood coagulation; therefore it is necessary during the appropriate induction therapy in ATRA or ATO time with anthracycline or other cytotoxic drugs, to control the high white blood cells caused by the risk of early death. 3) the timing of cytotoxic chemotherapy in high-risk APL during induction chemotherapy: high risk APL onset beginning early facing the risk of death, intracranial hemorrhage, high white blood cell, white blood cell, has further increased to anthracycline based cytotoxic chemotherapy control high white blood cells and may increase the bleeding, increase tumor cell lysis the treatment of ATRA syndrome risk contradiction differentiation, which makes it difficult to treat. NCCN, however, does not give a clear guidance to the timing of chemotherapy for cytotoxic drugs. 4) the selection of cytotoxic drugs: Based on the results of large multicenter clinical trials such as AIDA and LPA, NCCN recommended the anthracycline based cytotoxic chemotherapy for induction therapy. In the domestic homoharringtonine (Homoharringto nine, HHT), induction and consolidation therapy of hydroxyurea is also widely used for acute myeloid leukemia. To further illustrate the different anthracyclines, HHT and hydroxyurea related adverse reactions and efficacy of early death in APL induction therapy, this study discussed. 5) APL immunophenotype mode that helps to diagnose and predict prognosis rapidly. Compared with chromosome examination, time consuming of PCR and FISH detection, flow cytometry is helpful for rapid diagnosis of APL. Studies have shown that CD2.CD56 and CD34 are related to the overall survival (overall survival, OS) of APL, the remission period is shortened, the remission rate is decreased, and the early death rate (early death, ED) is rising, but there is little research on the relationship between them. The purpose of this study was to investigate the effects of CD2, CD56 and CD34 on the early death and long-term prognosis of APL and the interaction between them by single factor and multi factor analysis. Patients and methods 212 cases of early acute promyelocytic leukemia were treated in the Department of Hematology of the southern hospital from January 2003 to December 2013. 49 cases died before or during the induction therapy, of which 34 were male, 15 women, 15-84 years old, and the median age was 32 years. During the induction of treatment, 163 patients received ATRA combined with anthracycline or high APU base combined chemotherapy. Among them, there were 96 patients with low middle risk APL, 47 male, 49 female, 15-66 years old and 32 years old. There were 73 patients with high risk APL, 54 men, 19 women, 15-67 years old, and a median age of 32 years. All patients were diagnosed as acute promyelocytic leukemia by bone marrow smear. Chromosome examination showed the presence of T (15; 17). FISH test confirmed that PML-RARa fusion gene was positive. Informed consent was signed for all patients before treatment. Induction chemotherapy: Patients with suspected APL once, as soon as possible application of ATRA (25mg/m2/d), and maintenance treatment to obtain complete hematologic remission. Chemotherapy regimens for cytotoxic drugs include: 37 cases of dimethoxorubicin (8mg/m2/d, D1)
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R733.71
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本文編號(hào)：1346790