完全缓解急性白血病患者微小残留病的监测及其临床意义

发布时间：2018-05-11 03:10

本文选题：急性白血病 + 完全缓解　；参考：《青岛大学》2016年博士论文

【摘要】：研究背景:白血病(Leukemia)是血液系统的恶性疾病。临床上将白血病分为急性和慢性两大类。急性白血病(Acute Leukemia,AL)患者骨髓内主要以原始细胞及早期的幼稚细胞为主,短期内细胞分化迅速,病情凶险发展迅速,其自然病程可几天到几个月左右。慢性白血病(Chronic Leukemia,CL)的细胞多为较成熟的幼稚细胞,病情发展相对缓慢,部分自然病程可达数年甚则数十年。急性白血病通常会在短期内严重威胁着患者的生命,因此积极探索一种监测急性白血病的治疗效果和预后的方法来指导临床合理治疗就显得极为重要。目前临床上通过以下指标来判断白血病是否达到理想的治疗效果即完全缓解(complete remission,CR):患者无发热、乏力等临床不适;血常规基本正常,白细胞分类中无白血病细胞;骨髓中幼稚细胞≤5%,无Auer小体,余红系和巨核系正常,髓外没有发现恶性细胞。经过诱导缓解治疗达CR后患者体内仍会残留一小部分恶性细胞,这些恶性细胞用常规显微镜是检测不到的,我们称这部分经治疗后仍患者体内仍存在的恶性细胞为微小残留病(minimal residul disease,MRD)。微小残留病是急性白血病日后复发和难治的根源,降低患者体内的微小残留病也是诸多学者孜孜研究和不断渴求攻破的难题,以期为患者带来长久的无病生存。在未来的几年、十几年甚则几十年,白血病疗效的提高可能主要依赖于两个方面的进展,一个是靶向药物的临床应用,另一个就是根据微量残留病动态评价患者的预后进行个体化治疗。目前,MRD的监测已经成为APL和CML治疗方案的一部分。对于急性淋巴细胞白血病,国内外都有正在进行的大系列多中心临床试验,研究应用微小残留病监测进一步提高疗效,也许三五年以后,微小残留病监测也会成为急性淋巴细胞白血病治疗方案的一部分。对于其他疾病如急性髓系白血病、慢性淋巴细胞白血病和非霍奇金氏淋巴瘤等,微小残留病监测在治疗中的作用和意义也在研究中。近年来,白血病干细胞成为白血病研究领域的一个热点;目前,MRD监测的概念和方法与白血病干细胞相结合,可以实现更加准确的疗效判断。目前,急性白血病联合化疗的完全缓解率已达到60%-70%,治疗后无病生存率已达25%-40%。但白血病的复发仍是当前白血病治疗的主要障碍。当今,急性白血病微小残留病的检测和治疗研究已成为国内外的一个热点,这一课题的提出和研究,标志着白血病的研究已进入了一个新的阶段,即白血病的治疗,不仅是如何提高完全缓解率和延长患者的生存时间,还包括如何控制微量残留白血病,最终治愈白血病。我们把MRD作为一个独立的预后因素,在分子水平上评价白血病的缓解程度,相信会为白血病的临床治疗提供更深层次的指导。中国医学科学院天津血液病研究院以王建祥所长为中心的白血病治疗团队提出,建议越来越多的学者在白血病的诱导治疗结束、早期强化结束、晚期巩固结束、维持治疗结疗阶段每3个月进行MRD的监测,可以更详细地检测MRD的情况,以期更早的发现白血病的复发和监测白血病缓解的深度。研究目的:将不同白血病进行分类汇总,通过动态监测不同类型不同时期急性白血病患者完全缓解后微小残留病的变化情况结合患者治疗情况和预后,进一步探讨和研究白血病微小残留病变在临床治疗中的使用和指导价值。研究方法:随机选择在青大医疗集团商业医院(青岛市商业职工医院)血液科住院的急性白血病(Acute leukemia,AL)病人共146人,其中急性淋巴细胞白血病49人,急性非淋巴细胞白血病(急性髓系白血病)97人;对49例成年人急性淋巴细胞白血病(Acute lymphoblastic leukemia,ALL)完全缓解(CR)患者(男性30例,女性19例)和97例成年人急性髓系白血病(Acute myeloid leukemia,AML)完全缓解患者(男性53例,女性44例),采用多参数流式细胞术(flow cytometery,FCM)检测骨髓中微小残留病,同时检测骨髓细胞形态学、遗传学的变化。平均跟踪随访22个月(3个月-42个月),得出完全缓解病人微小残留病的平均值,观察不同患者不同节点的MRD值与患者预后之间的关系,探讨MRD在临床治疗中的价值和指导作用。研究结果:在所统计的49例ALL患者中,测得的完全缓解时B-ALL MRD平均数为0.202%,最大检测值为7.79%,均数0.616%,T-ALL最大值1.81%,。所统计97例AML患者,MRD平均数0.997%,最大值11.65%,最小值0.006%。ALL患者复发26例,AML患者复发29例,均可见当MRD≥0.1%时复发率明显升高。结论:用流式细胞术的方法检测急性白血病微小残留病值可以作为评价预后的敏感性指标用于指导临床合理的个体化的治疗;10-4是MRD检测值的一个明显的分水岭,MRD值10-4时,骨髓是缓解的,10-4时需密切注意未缓解或复发的风险加大。当MRD检测值≥0.1%时白血病复发可能性大。6个月内复发的情况多发生在MRD检测值≥1%;流式细胞术的方法检测急性白血病MRD值波动范围较大,在10-5—10-2之间,将MRD作为白血病完全缓解的单一指标不够充分,需要临床医师根据缓解指标综合判断是否完全缓解。
[Abstract]:Background: leukemia (Leukemia) is a malignant disease of the blood system. Leukemia is divided into two major categories: acute and chronic. The bone marrow of Acute Leukemia (AL) is mainly composed of primitive cells and early immature cells. In the short term, the cell differentiation is fast and the disease is dangerous and rapid. The natural course can be several days to several days. For a month or so, the cells of Chronic Leukemia (CL) are more mature and immature cells, and the development of the disease is relatively slow and some natural course can reach several years. Methods to guide clinical rational treatment is very important. At present, the following indicators are used to determine whether leukaemia has reached an ideal therapeutic effect: complete remission (complete remission, CR): patients without fever, fatigue and other clinical discomfort; blood routine is basically normal, leukocyte classification of leukaemia cells; immature cells in bone marrow is less than 5%, there is no Auer corpuscle, the residual red system and megakaryocyte are normal. No malignant cells are found outside the medulla. After the induction of remission treatment, a small number of malignant cells still remain in the patient's body after CR. These malignant cells are not detected by the conventional microscope. We call this part of the treatment that the malignant cells still exist in the patient's body after the treatment. (minimal residul disease, MRD). Minimal residual disease is the root cause of relapse and refractory in acute leukemia. Reducing the minimal residual disease in the patient is also a difficult problem that many scholars have studied and craving for a long time. In the next few years, more than ten years and decades, the curative effect of leukemia is raised. High may be mainly dependent on two aspects of progress, one is the clinical application of targeted drugs, and the other is to dynamically evaluate the patient's prognosis according to the trace residual disease. The monitoring of MRD has become part of the APL and CML treatments. A large series of multicenter clinical trials have studied the application of minimal residual disease monitoring to further improve the efficacy. Perhaps 35 years later, minimal residual disease monitoring will also be part of the treatment scheme for acute lymphoblastic leukemia. For other diseases such as acute myeloid leukemia, chronic lymphocytic leukemia and non Hodge's gold's lymphoma, micro The role and significance of small residual disease monitoring in the treatment are also in the study. In recent years, leukemic stem cells have become a hot spot in the field of leukemia research. At present, the concept and method of MRD monitoring with leukemia stem cells can be combined to achieve more accurate results. At present, the complete remission rate of combined chemotherapy in acute leukemia has reached a complete rate. To 60%-70%, the survival rate of the disease has reached 25%-40%. after treatment, but the recurrence of leukemia is still the main obstacle to the treatment of leukaemia. Nowadays, the research on the detection and treatment of acute leukemia has become a hot spot at home and abroad. The research and research of this subject indicate that the study of leukemia has entered a new stage. The treatment of leukaemia is not only how to improve the complete remission rate and prolong the survival time of the patients, but also how to control the trace residual leukemia and ultimately cure the leukemia. We consider MRD as an independent prognostic factor to evaluate the remission of leukemia at the molecular level, and believe that it will provide deeper clinical treatment for leukemia. Level guidance. The Tianjin hematology Institute of the Chinese Academy of Medical Sciences, the leukemia therapy team, centered on Wang Jianxiang's director, suggests that more and more scholars have completed the induction therapy of leukemia, early intensification, late consolidation, and maintenance of the treatment stage for MRD monitoring every 3 months, and more detailed detection of MRD Early detection of leukemia relapse and monitoring of the depth of leukemia remission. Objective: to classify and summarize different leukemia, and to further explore and study the changes of minimal residual disease in patients with acute leukemia after complete remission in different types and different types of leukemia, combined with the treatment and prognosis of patients. The use and guidance value of minimal residual disease of leukemia in clinical treatment. Research methods: 146 patients with acute leukemia (Acute leukemia, AL) hospitalized in the Department of Hematology of Qingda medical group (Qingdao commercial hospital) Department of Hematology, among them, acute lymphoblastic leukemia (acute lymphoblastic leukemia), acute non lymphocytic leukemia (acute lymphoblastic leukemia) Sexual myeloid leukemia) 97 people; 49 adult acute lymphoblastic leukemia (Acute lymphoblastic leukemia, ALL) complete remission (30 men, 19 women) and 97 adult acute myeloid leukemia (Acute myeloid leukemia, AML) completely remission patients (53 men, 44 women), multiparameter flow cytometry (flow CYT) Ometery, FCM) detection of small residual disease in bone marrow, and detection of bone marrow cell morphology and genetic changes. Follow up the average follow-up of 22 months (3 months -42 months), to obtain the mean value of minimal residual disease in the patients, observe the relationship between the MRD value of different nodes and the prognosis of the patients, and explore the value of MRD in the clinical treatment. Results: in the 49 patients with ALL, the average number of B-ALL MRD was 0.202%, the maximum detection value was 7.79%, the average number was 0.616%, and the maximum of T-ALL was 1.81%. The statistics of 97 AML patients, the average MRD number 0.997%, the maximum value 11.65%, the minimum value of 0.006%.ALL patients had 26 cases, and 29 cases of AML patients, all were seen, all were visible, all visible, all visible, all visible AML patients, all visible, can be seen, all can be seen, all visible, all visible, all can be seen, all visible, all visible AML patients can be seen, all can be visible, all visible, all visible, AML patients can be visible, can be seen in 29 cases, all visible, can be visible, all can be seen, all can be seen The recurrence rate was significantly higher when MRD was more than 0.1%. Conclusion: the detection of minimal residual disease in acute leukemia by flow cytometry can be used as a sensitive index for evaluating the prognosis to guide clinical and individualized treatment. 10-4 is a distinct watershed of the value of MRD, and the bone marrow is relieved when the value of MRD is 10-4, and it needs to be closely injected at 10-4. The risk of unremission or recurrence was increased. When the MRD detection value was more than 0.1%, the recurrence of the leukemia relapse was more than 1% in the possibility of recurrence within.6 months. The flow cytometry was used to detect the range of MRD in acute leukemia, between 10-5 and 10-2, and the single indicator of MRD as a complete remission of leukemia was not sufficient. Clinicians are required to determine whether complete remission is based on remission indicators.

【学位授予单位】：青岛大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R733.71

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