【作者】 赵翔宇；

【导师】 成娟；

【作者基本信息】 兰州大学 ， 临床医学·内科学（专业学位）， 2023， 硕士

【摘要】 目的:评估阿扎胞苷(azacitidine,AZA)在急性髓系白血病(acute myeloid leukemia,AML)维持治疗中的疗效及安全性,并分析影响患者疗效及生存预后的相关因素。方法:回顾性收集2019年1月至2022年12月期间就诊于兰州大学第一医院血液科的98例初治AML患者的临床资料,根据诱导巩固治疗或造血干细胞移植后是否接受AZA维持治疗分为维持治疗组(n=41)及对照组(n=57)。维持治疗组给药方案为AZA总量(36-75)mg/m~2×7d,皮下注射,每4周为一个疗程。主要研究终点为无复发生存(relapse-free survival,RFS)率及总体生存(overall survival,OS)率,次要终点为治疗相关不良反应的发生情况,从而评估该方案的疗效及安全性,并通过单因素及多因素Cox回归分析影响患者预后的相关因素。结果:1.疗效评估:本研究共收集98例初治AML患者,维持治疗组41例,对照组57例。中位随访时间为26.0(20.1-31.5)个月,共有38例患者复发,31例死亡。维持治疗组患者接受AZA维持的中位疗程数为5(2-13),其中7例复发,5例死亡。维持治疗组和对照组的2年RFS分别为84.4%和34.5%,2年OS分别为85.9%和47.4%,且差异均有统计学意义(P<0.05)。通过对各亚组患者进行生存分析,在未接受造血干细胞移植、预后不良、M2型及MRD阴性AML患者亚组中,维持治疗组的2年RFS和OS均高于对照组,差异有统计学意义(P<0.05)。预后中等、M5型及MRD阳性患者,维持治疗组与对照组RFS之间的差异有统计学意义,OS差异无统计学意义(P>0.05)。AZA维持治疗组预防治疗和抢先治疗的2年RFS分别为100%与50.9%,2年OS分别为96.2%与55.6%,差异均有统计学意义(P<0.05)。维持疗程数>5的患者2年RFS及OS更高,均达到100%,疗程数≤5的患者2年RFS和OS分别为66.6%和67.7%,差异有统计学意义(P<0.05)。移植和未移植患者的2年RFS分别为100%和70.6%,差异有统计学意义(P=0.007),2年OS分别为94.7%和79.1%,差异无统计学意义(P>0.05)。2.预后影响因素分析:维持治疗患者,单因素分析显示初诊白细胞计数、诱导巩固阶段有无AZA用药史及维持治疗的疗程数对RFS的影响具有统计学意义,维持治疗前MRD状态对OS的影响具有统计学意义(P<0.05)。将上述因素与筛选的其他相关因素纳入多因素Cox回归模型,结果表明维持治疗的疗程数(HR=0.561,95%CI 0.323-0.974,P=0.040)对RFS的影响有统计学意义,初诊骨髓原始细胞比例<30%较骨髓原始细胞比例≥30%,对RFS的影响有统计学意义(HR=13.945,95%CI 1.642-118.408,P=0.016)。所有变量对OS的影响均无统计学意义(P>0.05)。3.安全性分析:发生不同程度不良事件的患者为84.7%(83/98)。维持治疗组最常见的血液学不良事件为中性粒细胞减少(75.6%)和血小板减少(43.9%),最常见的非血液学不良事件为恶心(63.4%)、呕吐(43.9%)、疲劳(34.1%)及注射部位反应/红斑(31.7%),且主要为1-2级,多发生在维持治疗的前2个疗程,随着疗程数增加,不良反应常减轻或消失。维持治疗组与对照组相比,中性粒细胞减少、恶心、呕吐及便秘等不良事件的发生率更高,且差异有统计学意义(P<0.05)。随着AZA剂量的增加,中性粒细胞减少、血小板减少、贫血等血液学不良事件和恶心、便秘、肝脏毒性及注射部位反应/红斑等非血液学不良事件的发生率有增加的趋势。结论:1.AZA维持治疗可以延长AML患者的缓解期,改善RFS及OS。未接受造血干细胞移植、预后不良、M2型及MRD阴性等患者亚组获益更明显。2.维持治疗组,预防治疗较抢先治疗有更好的RFS和OS,移植患者较未移植患者有更好的RFS。维持治疗疗程数及初诊骨髓原始细胞比例<30%是影响维持治疗患者RFS的独立危险因素。3.AZA维持治疗安全性及耐受性良好,最常见血液学不良事件为中性粒细胞减少和血小板减少,最常见非血液学不良事件为恶心、呕吐、疲劳及注射部位反应/红斑,随着疗程数增加常减轻或消失。更多还原

【Abstract】 Objective:To evaluate the efficacy and safety of azacitidine in the maintenance treatment of acute myeloid leukemia(AML),and to analyze the related factors affecting the efficacy and prognosis of patients.Methods:Clinical data of 98 AML patients admitted to the Department of Hematology,The First Hospital of Lanzhou University from January 2019 to December 2022 were retrospectively collected.They were divided into maintenance group(n=41)and control group(n=57)according to whether they received azacitidine maintenance therapy after induction and consolidation therapy or hematopoietic stem cell transplantation.The regimen of the maintenance group was(36-75)mg/m~2×7d,subcutaneous injections,every 4 weeks as a course of treatment.The main endpoints were relapse-free survival(RFS)rate and overall survival(OS)rate,and the secondary endpoints were the occurrence of treatment-related adverse reactions,to evaluate the efficacy and safety of the regimen.Univariate and multivariate Cox regression was used to analyze the prognostic factors.Results:1.Efficacy evaluation:A total of 98 patients with newly diagnosed AML were collected in this study,including 41 patients in the maintenance group and 57 patients in the control group.The median follow-up time was 26.0(20.1-31.5)months.A total of 38 patients relapsed and 31 patients died.In the maintenance group,41 patients received a median of 5(2-13)courses of azacitidine maintenance therapy,of which 7relapsed and 5 died.The 2-year RFS of the maintenance group and control group were84.4%and 34.5%,respectively,and the 2-year OS were 85.9%and 47.4%,respectively,and the differences were statistically significant(P<0.05).Survival analysis of patients in each subgroup showed that for patients who did not receive hematopoietic stem cell transplantation,patients in adverse risk,patients with M2,and patients with MRD negative,the 2-year RFS and OS in the maintenance group were higher than those in the control group,and the differences were statistically significant(P<0.05).For patients with intermediate-risk,M5,and MRD-positive,the difference in RFS between the maintenance group and the control group was statistically significant,while the difference in OS was not statistically significant(P>0.05).The2-year RFS of prophylactic therapy and preemptive therapy in the AZA maintenance treatment group were 100%and 50.9%,and the 2-year OS were 96.2%and 55.6%,respectively,and the difference were statistically significant(P<0.05).The 2-year RFS and OS of the patients with maintenance treatment courses>5 were higher,both reaching 100%,while the 2-year RFS and OS of the patients with maintenance treatment courses≤5 were 66.6%and 67.7%,respectively,and the differences were statistically significant(P<0.05).The 2-year RFS of transplant patients and non-transplant patients were 100%and 70.6%,respectively,the difference was statistically significant(P=0.007),and the 2-year OS were 94.7%and 79.1%,respectively,the difference between OS was not statistically significant(P>0.05).2.Analysis of prognostic factors:In the maintenance group,the results of the univariate analysis showed that white blood cell count at initial diagnosis,azacitidine history at induction and consolidation therapy,and the number of maintenance treatment courses had statistically significant effects on RFS,and MRD status before maintenance therapy had statistically significant effects on OS(P<0.05).The above factors and other related factors were included in the multivariate Cox regression model.The results showed that the number of maintenance treatment courses(HR=0.561,95%CI 0.323-0.974,P=0.040)had a statistically significant effect on RFS.Compared with the proportion of bone marrow blast cells≥30%at initial diagnosis,the proportion of bone marrow blast cells<30%had a statistically significant effect on RFS(HR=13.945,95%CI 1.642-118.408,P=0.016).None of the variables had statistically significant effects on OS(P>0.05).3.Safety analysis:84.7%(83/98)of patients experienced at least one adverse event of any grade.In the maintenance group,the most common hematologic toxicities were neutropenia(75.6%),and thrombocytopenia(43.9%),while the most common non-hematologic adverse events were nausea(63.4%),vomiting(43.9%),fatigue(34.1%),and injection site reaction/erythema(31.7%),which were mainly grade 1-2.The above adverse events mainly occurred in the first two courses of maintenance therapy.With the increase in the number of courses,the adverse events were often alleviated or disappeared.Compared with the control group,the incidence of neutropenia,nausea,vomiting,and constipation in the maintenance group was higher,and the difference was statistically significant(P<0.05).The incidence of hematologic adverse events such as neutropenia,thrombocytopenia,anemia,and non-hematologic adverse reactions such as nausea,constipation,hepatotoxicity,and injection site reaction/erythema tended to increase with the increase of azacitidine dose.Conclusions:1.Azacitidine maintenance therapy can prolong the remission period and improve RFS and OS in AML patients.The benefits were more obvious in the subgroup of patients who didn’t receive hematopoietic stem cell transplantation,were at adverse risk,and were M2-type and MRD-negative.2.In the maintenance group,prophylactic therapy had better RFS and OS than preemptive therapy,and the transplant patients had better RFS than the non-transplant patients.The number of treatment courses and the proportion of bone marrow blast cells<30%at initial diagnosis were independent risk factors affecting RFS in maintenance patients.3.Azacitidine maintenance treatment was safe and well tolerated,the most common hematologic adverse events were neutropenia and thrombocytopenia,while the most common non-hematologic adverse events were nausea,vomiting,fatigue,and injection site reaction/erythema,which were often alleviated or disappeared with the increase of the number of courses.更多还原