發(fā)布時間：2018-03-20 13:42

  本文選題：急性髓系白血病　切入點：大劑量阿糖胞苷　出處：《山東大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：背景:急性髓系白血病(acute myeloid leukemia,AML)是起源于髓系造血干/祖細(xì)胞的惡性克隆性疾病,也是成人急性白血病中最常見的類型。在全世界范圍內(nèi),每年都有大約30萬的患者被確診為AML。AML具有起病急、病情重、易復(fù)發(fā)等特點,預(yù)后較差。因此,如何在AML確診后及時有效地控制病情并預(yù)防疾病復(fù)發(fā)是目前臨床AML治療過程中面臨的一項嚴(yán)峻挑戰(zhàn)。根據(jù)NCCN指南,目前AML治療策略主要包括:誘導(dǎo)緩解治療、緩解后的鞏固治療、挽救治療、中樞神經(jīng)系統(tǒng)白血病的預(yù)防以及監(jiān)測、支持治療、造血干細(xì)胞移植等。近幾十年來,國際上普遍認(rèn)可的AML的誘導(dǎo)緩解治療始終以"3+7"方案為主,即標(biāo)準(zhǔn)劑量的阿糖胞苷(Ara-c,d1-7)聯(lián)合蒽環(huán)或蒽醌類的藥物(d1-3)。隨著AML治療水平的提高,約60%-80%的患者經(jīng)誘導(dǎo)緩解階段的治療后可達(dá)到完全緩解(complete remission,CR)。然而,絕大多數(shù)完全緩解后的患者若未行后續(xù)的鞏固治療,病情將會在6-12月以內(nèi)復(fù)發(fā)。而一旦復(fù)發(fā),病人的耐藥性會顯著增加,預(yù)后極差。因此,AML完全緩解后的鞏固治療始終是AML治療當(dāng)中不可忽視的環(huán)節(jié)。國內(nèi)外各項臨床試驗以及大樣本的數(shù)據(jù)顯示,含有大劑量阿糖胞苷(High Dose Ara-c,HDAra-c)的化療方案是目前臨床上AML鞏固治療階段最主要的治療方案。然而,阿糖胞苷(Ara-c)具有多種不良反應(yīng),包括血液學(xué)毒性、胃腸道不良反應(yīng)、皮疹、結(jié)膜炎、發(fā)熱、腎毒性、口腔潰瘍等等。大劑量阿糖胞苷應(yīng)用時會引起嚴(yán)重的骨髓抑制,表現(xiàn)為貧血、粒細(xì)胞缺乏、血小板減少等,從而造成一系列的不良反應(yīng)。國內(nèi)外目前針對不同劑量、不同療程Ara-c在AML鞏固治療階段療效和不良反應(yīng)的報道很多,但尚未有一個統(tǒng)一的結(jié)論。因此關(guān)于阿糖胞苷在AML患者鞏固治療階段應(yīng)用劑量、療程的選擇尚未達(dá)成完全統(tǒng)一的共識,還有許多問題有待探索和解決。目的:本研究旨在分析山東大學(xué)齊魯醫(yī)院85例初診AML(非M3型)患者鞏固化療階段采用不同劑量、不同療程的阿糖胞苷的療效和不良反應(yīng),以期探索出阿糖胞苷鞏固化療的最佳方案,從而對AML的臨床治療具有借鑒和參考價值。方法:收集山東大學(xué)齊魯醫(yī)院自2010年1月至2016年12月期間收治的初診的急性髓系白血病AML病例85例,均經(jīng)MICM標(biāo)準(zhǔn)確診為AML(非M3型)。所有的患者經(jīng)誘導(dǎo)緩解治療后均達(dá)到CR,鞏固治療階段分別應(yīng)用含有不同劑量、不同療程Ara-c單藥或聯(lián)合的方案化療。收集患者的年齡、性別、初診時血常規(guī)(白細(xì)胞、血紅蛋白、血小板)、骨髓原始細(xì)胞、染色體、融合基因等各項臨床資料,并通過電話、門診等方式對患者進(jìn)行隨訪。根據(jù)鞏固治療階段應(yīng)用Ara-c劑量、療程的不同對患者進(jìn)行分組:(1)根據(jù)Ara-c單次劑量不同將85例患者分為 2 組,HDAra-c 組(2-3g/m2q12h,d1-3)和非 HDAra-c 組(中、標(biāo)準(zhǔn)劑量);(2)HDAra-c組根據(jù)總累積劑量不同分為3組,HDAra-c-1組(累積劑量18 g/m2),HDAra-c-2 組(累積劑量 18-36g/m2)和 HDAra-c-3 組(累積劑量≥36g/m2);(3)HDAra-c組根據(jù)療程的不同分為2組,HDAra-c療程1組(1-2個療程)和HDAra-c療程2組(3-4個療程)(4)非HDAra-c組根據(jù)總累積劑量不同分為3組,非HDAra-c-1組(累積劑量9g/m2),非HDAra-c-2組(累積劑量9-18g/m2)以及非HDAra-c-3組(累積劑量≥18g/m2)。對上述各個分組的患者的無復(fù)發(fā)生存率(relapse-free survival,RFS)和總生存率(overall survival,OS)等指標(biāo)進(jìn)行對比評估,并分析HDAra-c組化療期間的不良事件。結(jié)果:1.本研究共收集85例初診AML患者,年齡在14-60歲,中位年齡38歲。隨訪時間為83個月,中位隨訪時間42個月。患者總體1年的RFS率和OS率分別為83.2%和84.7%;2年的RFS率和OS率分別為59.7%和78.6%。患者總體未達(dá)到中位總體生存期(OS)。2.各分組之間療效對比(1)按 Ara-c 單次劑量不同分為 2 組,HDAra-c 組(2-3g/m2q12h,d1-3)53例患者,非HDAra-c組(中、標(biāo)準(zhǔn)劑量)有32例患者。HDAra-c組與非HDAra-c組RFS率和OS率相對比:HDAra-c組患者1年的RFS率為87.6%,2年的RFS率為66.6%;非HDAra-c組1年的RFS率為67.3%,2年的RFS率為50.5%。兩組對比,HDAra-c組在2年RFS率上有顯著優(yōu)勢(66.6%vs50.5%.P=0.006)。COX多因素分析單次劑量分組對患者的RFS來說是獨立的影響因素(P=0.004,HR=0.347.95%CI 0.170-0.708)。HDAra-c 組患者1年的OS率為89.5%,2年的OS率77.2%;非HDAra-c組1年的OS率為78.7%,2年的OS率62.7%。HDAra-c組相對于非HDAra-c組在2年OS率優(yōu)勢也較為明顯(77.2%vs62.7%.P=0.043)。COX多因素分析單次劑量分組對患者的 OS 來說是潛在的影響因素(P=0.093,HR=0.467,95%CI 0.192-1.137)。(2)HDAra-c組按照總累積劑量分為3組:HDAra-c-1組(累積劑量18 g/m2)共16例,HDAra-c-2組(累積劑量18-36g/m2)共18例,HDAra-c-3組(累積劑量≥36g/m2)共19例。對三組之間RFS和OS進(jìn)行對比分析:在RFS上,HDAra-c-3組(累積劑量≥36g/m2)顯著優(yōu)于HDAra-c-1組(累積劑量18 g/m2)(P=0.041);HDAra-c-2 組(累積劑量 18-36g/m2)與 HDAra-c-1 組(累積劑量18 g/m2)相比較,差異雖無顯著統(tǒng)計學(xué)意義,但有改善的趨勢(P=0.069);HDAra-c-3 組(累積劑量≥36g/m2)與 HDAra-c-2 組(累積劑量18-36g/m2)相比在RFS上無顯著優(yōu)勢(P=0.103)。COX多因素分析提示總累積劑量是RFS的潛在影響因素(總P=0.066,HDAra-c-1組vs HDAra-c-3組:P=0.062,HR=4.297,95%CI 0.932-19.808;HDAra-c-2 組 vs HDAra-c-3 組:P=0.020,HR=7.904,95%CI 1.378-45.345)。在 OS 上,HDAra-c-3 組(累積劑量≥36g/m2)與另外兩組相比較差異無顯著統(tǒng)計學(xué)意義(總P=0.772,HDAra-c-1組vs HDAra-c-3 組:P=0.420,HR=1.854,95%CI 0.414-8.306;HDAra-c-2 組 w HDAra-c-3 組:P=0.654,HR=1.443,95%CI 0.290-7.172)。(3)HDAra-c組按照療程分為2組:HDAra-c療程1組(1-2個療程)31例,HDAra-c療程2組(3-4個療程)22例。對比兩個療程組之間RFS和OS,得出結(jié)果:在RFS上,療程2組(3-4個療程)比療程1組(1-2個療程)有顯著優(yōu)勢(P=0.03),差異有統(tǒng)計學(xué)意義。COX多因素分析提示療程分組是RFS的潛在影響因素(P=0.098,HR=0.615,95%CI 0.346-1.093)。在 OS 上,療程 2 組(3-4個療程)相比于療程1組(1-2個療程)無顯著優(yōu)勢(P=0.228)。(4)非HDAra-c組按照總累積劑量分為3組:非HDAra-c-1組(累積劑量9g/m2)17 例,非 HDAra-c-2 組(累積劑量 9-18g/m2)5 例,非 HDAra-c-3 組(累積劑量≥18g/m2)10例。對比3組之間RFS和OS:在RFS上,非HDAra-c-3組(累積劑量≥18g/m2)上與非HDAra-c-1組(累積劑量9g/m2)和非HDAra-c-2組(累積劑量9-18g/m2)之間對比均有顯著優(yōu)勢(非HDAra-c-1組vs非HDAra-c-3組:P=0.002;非HDAra-c-2組vs非HDAra-c-3組:P=0.04),差異有統(tǒng)計學(xué)意義。非HDAra-c-1組(累積劑量9g/m2)和非HDAra-c-2組(累積劑量9-18g/m2)之間在RFS上無顯著優(yōu)勢(P=0.850)。COX多因素分析提示累積劑量分組是RFS的主要影響因素(P=0.047,HR=2.013,95%CI 1.009-4.017)。在OS,非HDAra-c-3組(累積劑量≥18g/m2)相對于非HDAra-c-1組(累積劑量9g/m2)有顯著優(yōu)勢(P=0.027)。非HDAra-c-3組(累積劑量≥18g/m2)與非HDAra-c-2組(累積劑量9-18g/m2)以及非HDAra-c-1組(累積劑量9g/m2)與非HDAra-c-2組(累積劑量9-18g/m2)之間對比差異無顯著統(tǒng)計學(xué)意義。3.HDAra-c組不良反應(yīng)發(fā)生情況:(1)患者HDAra-c鞏固化療后的血液學(xué)不良反應(yīng):Ⅳ度骨髓抑制的發(fā)生率為 84.9%,NEU0.5*109/L、NEU0.2*109/L 以及 PLT20*109/L 的中位持續(xù)時間分別為 7(2-14)d、6(1-12)d 以及 6(2-]3)d。(2)患者HDAra-c鞏固化療后的非血液學(xué)不良反應(yīng):化療后粒缺期感染(上呼吸道感染、肺部感染、肛周感染等)率88.7%,發(fā)熱率81.1%,肝臟毒性的發(fā)生率為32%,Ⅰ～Ⅲ級胃腸道不良反應(yīng)的發(fā)生率為26.4%,皮疹發(fā)生率11.3%,結(jié)膜炎發(fā)生率9.4%。無嚴(yán)重心功能不全以及神經(jīng)系統(tǒng)毒性發(fā)生。結(jié)論:1.鞏固化療階段應(yīng)用HDAra-c相對于非HDAra-c化療方案在提高AML(非M3)患者的RFS率和OS率上有較顯著的優(yōu)勢。2.HDAra-c累積劑量≥36g/m2相對于HDAra-c累積劑量18 g/m2在延長AML(非M3)患者的RFS上有顯著優(yōu)勢;HDAra-c3-4個療程相對于HDAra-c 1-2個療程化療方案在延長RFS上也有顯著優(yōu)勢。3.AML(非M3)患者可耐受HDAra-c鞏固治療。
[Abstract]:Background: acute myeloid leukemia (acute myeloid, leukemia, AML) is originated from myeloid hematopoietic stem / progenitor cells of malignant clonal disease, is also the most common type of adult acute leukemia. In the whole world, every year there are about 300 thousand of the patients were diagnosed as AML.AML with acute onset, severe illness. So easy to relapse, poor prognosis. Therefore, how to AML after diagnosis timely and effectively control the disease and prevent the recurrence of the disease is a severe challenge currently faced in the process of clinical treatment of AML. According to the NCCN guidelines, the AML treatment strategies include: induction therapy, post remission consolidation therapy, salvage therapy, central nervous the system of leukemia prevention and monitoring, supportive therapy, hematopoietic stem cell transplantation. In recent decades, internationally recognized AML induction therapy are always dominated by the "3+7" program, which is a standard dose of Ara Glycosides (Ara-c, D1-7) combined with anthracycline or anthraquinone drugs (D1-3) with AML. The improvement of treatment, about 60%-80% of patients after induction of remission stage after treatment can achieve complete remission (complete, remission, CR). However, most of the patients after complete remission without subsequent consolidation therapy. The illness will be recurred in 6-12 months. But once patients relapse, drug resistance will increase significantly, the prognosis is poor. Therefore, the consolidation treatment of AML after complete remission is always a part that can not be ignored. AML treatment at home and abroad of the clinical trials and large sample data show that with high dose cytarabine (High Dose Ara-c HDAra-c), chemotherapy regimen is currently in clinical stage AML consolidation therapy is the most important. However, cytarabine (Ara-c) with a variety of adverse reactions, including hematological toxicity, gastrointestinal adverse reactions, skin rash, conjunctivitis, fever, Renal toxicity, oral ulcer and so on. High dose cytarabine application can cause severe bone marrow suppression, manifested as anemia, neutropenia, thrombocytopenia, resulting in a series of adverse reactions at home and abroad. According to different dosage, different courses of Ara-c consolidation phase of treatment efficacy and adverse reactions of AML in many reports but there is not a unified conclusion. Therefore a cytarabine consolidation stage application dose treatment in patients with AML, no consensus course selection, there are many problems need to be solved. Objective: This study aimed to analyze the Qilu Hospital of Shandong University in 85 newly diagnosed AML (non M3) patients with different stages of consolidation chemotherapy dose, efficacy and adverse reactions of different courses of cytarabine, in order to explore the best scheme of cytarabine chemotherapy, and clinical treatment of AML with reference and Reference value. Methods: acute myeloid collected from Qilu Hospital of Shandong University from January 2010 to December 2016 during the newly diagnosed leukemia AML 85 cases were diagnosed as AML by MICM standard (non M3). All of the patients after induction of remission after treatment reached CR, stage of consolidation therapy were applied with different doses, different courses of Ara-c monotherapy or combination chemotherapy were collected. The age, gender, initial blood (white blood cell, hemoglobin, platelet), bone marrow primitive cells, chromosome, fusion gene and other clinical data, and through the way of telephone, outpatient follow-up of patients. According to the consolidation phase of treatment dose of Ara-c, the different course of treatment the patients were divided into two groups: (1) according to the different single dose of Ara-c 85 patients were divided into 2 groups, group HDAra-c (2-3g/m2q12h, D1-3) and non HDAra-c group (in standard dose); (2) according to the HDAra-c group The total cumulative dose were divided into 3 groups, group HDAra-c-1 (cumulative dose of 18 g/m2), group HDAra-c-2 (cumulative dose 18-36g/m2) and group HDAra-c-3 (cumulative dose of more than 36g/m2); (3) HDAra-c group according to different treatment for 2 groups, HDAra-c treatment group 1 (1-2 cycles) and HDAra-c treatment group (2 3-4 course) (4) non HDAra-c group according to the total cumulative dose were divided into 3 groups, HDAra-c-1 group (cumulative dose 9g/m2) and non HDAra-c-2 group (cumulative dose 9-18g/m2) and non HDAra-c-3 group (cumulative dose of more than 18g/m2). The relapse free survival rate for each group of patients (relapse-free survival, RFS the total survival rate (overall) and survival, OS) were compared to assess and analyze the adverse events during HDAra-c chemotherapy group. Results: 1. this study collected 85 cases of newly diagnosed AML patients at the age of 14-60, the median age was 38 years. The follow-up time was 83 months, median follow-up time of 42 June. 鎮(zhèn)ｈ，

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