【作者】 王冰；

【导师】 赵文博；

【作者基本信息】 山东大学 ， 内科学（血液病）（专业学位）， 2023， 硕士

【摘要】 背景:一直以来费城染色体阳性急性淋巴细胞白血病(Philadelphia chromosome positive acute lymphoblastic leukemia,Ph+ALL)由于常规化疗效果不佳,被认为是预后最差的急性白血病。随着靶向药物研究的不断深入,研究人员发现酪氨酸激酶抑制剂(Tyrosine kinase inhibitors,TKIs)可抑制其癌细胞增殖。第一代TKI伊马替尼能够给患者带来更持续的分子学缓解,并能让接受异基因造血干细胞移植(Allogeneic hematopoietic stem cell transplantation,allo-HSCT)的患者获得更久的生存。近年来,由于伊马替尼耐药性的不断报道,第二代TKIs在Ph+ALL的治疗中发挥着愈加重要的作用。然而,当前的相关研究存在研究对象较少、探索角度不够全面的问题,且有一些学者提出,鉴于越来越多的患者可获得持续深度分子学缓解,allo-HSCT是否仍有必要。因此,我们提出能否从真实世界的研究中汇总样本量,研究第二代TKIs融入Ph+ALL化疗序贯allo-HSCT的疗效和长期结局,并对allo-HSCT的必要性进行探讨。目的:从诱导治疗后血液学和分子学反应、复发和死亡风险、长期生存等在内的17个有效事件指标,系统评价第二代TKIs融入Ph+ALL化疗序贯allo-HSCT的疗效和长期结局,并比较移植组患者和化疗组患者之间的生存结局差异,以期为临床用药提供参考。方法:检索中国知网、维普数据库、万方数据库、PubMed、Embase、Cochrane Library、Clinical trials.gov数据库,检索2022年11月前发表的研究,采用非随机干预研究偏倚风险评估工具ROBINS-I对纳入研究进行偏倚评价。使用STATA 14.0软件对数据进行效应量合并、偏倚分析和敏感性分析,效应量合并过程均采用随机效应模型。结果:共纳入20篇文献、1171例患者。Meta分析显示:第二代TKIs在Ph+ALL化疗序贯allo-HSCT的治疗过程中,诱导化疗4周完全缓解(Complete remission,CR)率为97.3%(94.5%～99.3%),主要分子学缓解(Major molecular remission,MMR)率为 31.1%(20.8%～42.4%),完全分子学缓解(Complete molecular remission,CMR)率为 35.5%(23.1%～48.9%);诱导治疗 3 个月 MMR 率为 61.8%(32.8%～86.9%),CMR 率为 52.6%(35.6%～69.4%);累积CMR率为74.0%(54.3%～89.8%);诱导治疗过程中死亡率3.4%(1.7%～5.5%);移植组复发率18.7%(13.4%～24.5%)移植组死亡率18.9%(10.7%～28.4%);化疗组复发率50.0%(35.7%～64.3%),化疗组死亡率36.9%(18.1%～57.7%);急性移植物抗宿主病(Acute graft versus host disease,a-GVHD)发生率 50.5%(43.5%～57.4%),慢性移植物抗宿主病(Chronic graft versus host disease,c-GVHD)发生率 41.6%(29.8%～53.8%);移植组3年总生存(Overall survival,OS)率78.8%(66.3%～89.0%),移植组3年无事件生存(Event-free survival,EFS)率 69.3%(61.9%～76.2%),整体队列 3 年 OS 率 67.5%(55.0%～79.0%),整体队列 3 年 EFS 率 59.7%(46.3%～72.4%)。结论:1.本研究从确诊至长期结局的角度描述性分析了第二代TKIs联合化疗治疗Ph+ALL的真实获益。这种联合治疗表现出较高的首次CR率和累积CMR率(97.3%;74.0%),不区分是否接受allo-HSCT,整体患者3年OS率可达到67.5%(55.0%～79.0%)。本研究分析结果为临床实践提供了较为精确的数据支撑。2.移植组患者的复发率和死亡率均明显低于化疗组(18.7%vs 50%;18.9%vs 36.9%),移植组3年OS率和3年EFS率均优于整体队列(78.8%vs 67.5%;69.3%vs 59.7%),在一线使用第二代TKIs时,allo-HSCT仍具有显著优势。此项分析结论支持allo-HSCT在TKI时代的必要性。更多还原

【Abstract】 Background:Philadelphia chromosome positive acute lymphoblastic leukemia(Ph+ALL)has long been regarded as the most acute leukemia with the worst prognosis due to the poor effect of conventional chemotherapy.With the development of targeted drugs,researchers found that Tyrosine kinase inhibitors(TKIs)could inhibit the proliferation of cancer cells.First-generation TKI Imatinib provides patients with more sustained molecular remission and enables longer survival in patients undergoing Allogeneic hematopoietic stem cell transplantation(allo-HSCT).In recent years,due to reports of imatinib resistance,second-generation TKIs are playing an increasingly important role in the treatment of Ph+ALL.However,current studies have been characterized by a small number of subjects and an insufficiently comprehensive approach,and some scholars have asked whether allo-HSCT is still necessary given that more and more patients are able to achieve sustained deep molecular remission.Therefore,we ask whether sample sizes can be pooled from real world studies to study the efficacy and long-term outcome of second generation TKIs integrated into Ph+ALL chemotherapy sequenced allo-HSCT,and discuss the necessity of allo-HSCT.Objective:Based on 17 effective event indexes including hematological and molecular responses after induction therapy,risk of recurrence and death,long-term survival,etc.,the efficacy and long-term outcome of second generation TKIs integrated into Ph+ALL chemotherapy sequentially allo-HSCT were systematically evaluated,and the difference in survival outcome between the transplant group and the chemotherapy group was compared,in order to provide reference for clinical drug use.Method:China National Knowledge Network,VIP database,Wanfang Database,PubMed,Embase,Cochrane Library,Clinical trials.gov database were searched for studies published before November 2022.ROBINS-I,a non-randomized intervention study bias risk assessment tool,was used to assess bias in the included studies.STATA 14.0 software was used to perform effect index merging,bias analysis and sensitivity analysis.The random effects model was used in the process of effect index merging.Results:A total of 20 literature with 1171 patients were included.Meta-analysis showed that:In the period of second generation of TKIs in Ph+ALL chemotherapy followed by allo-HSCT treatment course,The rates of Complete remission(CR),Major molecular remission(MMR)and Complete molecular remission(CMR)after 4 weeks of induction therapy were 97.3%(94.5%～99.3%),31.1(20.8%-42.4%)and 35.5%(23.1%-48.9%).The rates of MMR and CMR after 3 months of induction therapy respectively were 61.8%(32.8%-86.9%)and 52.6%(35.6%-69.4%).The cumulative CMR rate was 74.0%(54.3%-89.8%).The mortality rate during induction therapy was 3.4%(1.7%～5.5%).The recurrence rate was 18.7%(13.4%-24.5%)and the mortality rate was 18.9%(10.7%-28.4%)in the transplant group.The recurrence rate is 50.0%(35.7%-64.3%)and the mortality rate was 36.9%(18.1%-57.7%)in the chemotherapy group.The incidence of Acute graft versus host disease(a-GVHD)was 50.5%(43.5%to 57.4%).The incidence of Chronic graft versus host disease(c-GVHD)was 41.6%(29.8%-53.8%).The 3-year Overall survival(OS)rate of the transplant group was 78.8%(66.3%-89.0%),and the 3-year Event-free survival(EFS)rate was 69.3%(61.9%-76.2%).The 3-year OS rate of the whole cohort was 67.5%(55.0%～79.0%),and the 3-year EFS rate was 59.7%(46.3%～72.4%).Conclusion:1.This study described the true benefit of second-generation TKIs in combination with chemotherapy for Ph+ALL from diagnosis to long-term outcome.This combination therapy showed higher rates of first-time CR and cumulative CMR(97.3%;74.0%),regardless of whether allo-HSCT was received,the overall 3-year OS rate was 67.50(55.0%～79.0%).The analysis results of this study provide more accurate data support for clinical practice.2.The recurrence rate and mortality of patients in the transplant group were significantly lower than those in the chemotherapy group(18.7%vs 50%;18.9%vs 36.9%),the 3-year OS rate and 3-year EFS rate of the transplant group were better than those of the whole cohort(78.8%vs 67.5%;69.3%vs 59.7%),allo-HSCT still has a significant advantage in first-line use of second-generation TKIs.This conclusion supports the necessity of allo-HSCT in the era of TKI.更多还原