Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia AMeta-analysis
Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia AMeta-analysis
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DOI：
10.1001/jamaoncol.2017.0580
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发表时间：
2017-07-01
期刊：
影响因子：
28.4
通讯作者：
Radich, Jerald P.
中科院分区：
文献类型：
--
作者：
Berry, Donald A.;Zhou, Shouhao;Radich, Jerald P.
重要性微小残留病（MRD）是指通过常规病理分析认为完全缓解的病例中存在的疾病。评估急性淋巴细胞白血病（ALL）诱导治疗后MRD状态与复发和死亡率的关系可能会提高临床试验的效率，加速药物开发。目的量化无事件生存期（EFS）与总生存期（OS）之间的关系使用临床试验和其他数据库的出版物，对儿童和成人ALL的MRD状态进行分析。MEDLINE和临床试验。研究选择我们的检索和研究筛选过程遵循PRISMA指南。纳入了在ALL患者中通过MRD状态讨论EFS或OS的研究;数据提取和综合研究样本量、患者年龄、随访时间、MRD评估时间（诱导后或巩固），MRD检测方法，表型/基因型（B细胞、T细胞、费城染色体），PubMed和MEDLINE的EFS和OS.临床试验的平行检索。截至2014年，gov发现了67个封闭试验和62个开放试验。合并2次独立检索的结果并进行排除，得到3组患者人群（成人、儿童和混合人群）的39篇出版物。我们对这3个亚群进行了单独的荟萃分析。结果39篇文献包括13637例患者：16项成人研究（2076例患者），20项儿科研究（11249例患者）和3项混合研究（312例患者）。儿科患者达到MRD阴性的EFS风险比（HR）为0.23（95%贝叶斯可信区间[BCI] 0.18-0.28），成人为0.28（95% BCI，0.24-0.33）。OS的HR分别为0.28（95%BCI，0.19-0.41）和0.28（95%BCI，0.20-0.39）。在所有亚组和协变量之间的效果是相似的。结论和相关性已经实现MRD阴性的价值是实质性的，在儿童和成人ALL患者。这些结果在不同治疗、MRD评估方法和时间、临界水平和疾病亚型之间一致。最小残留疾病状态值得考虑作为疾病反应的早期测量，用于评估新疗法，提高临床试验的效率，加速药物开发和监管批准。需要注意的是，使用中间终点（如MRD）加速批准特定新药将需要使用传统疗效终点进行确认。
IMPORTANCE Minimal residual disease (MRD) refers to the presence of disease in cases deemed to be in complete remission by conventional pathologic analysis. Assessing the association of MRD status following induction therapy in patients with acute lymphoblastic leukemia (ALL) with relapse and mortalitymay improve the efficiency of clinical trials and accelerate drug development.OBJECTIVE To quantify the relationships between event-free survival (EFS) and overall survival (OS) with MRD status in pediatric and adult ALL using publications of clinical trials and other databases.DATA SOURCES Clinical studies in ALL identified via searches of PubMed, MEDLINE, and clinicaltrials. gov.STUDY SELECTION Our search and study screening process adhered to the PRISMA Guidelines. Studies that addressed EFS or OS by MRD status in patients with ALL were included; reviews, abstracts, and studies with fewer than 30 patients or insufficient MRD description were excluded.DATA EXTRACTION AND SYNTHESIS Study sample size, patient age, follow-up time, timing of MRD assessment (postinduction or consolidation), MRD detection method, phenotype/genotype (B cell, T cell, Philadelphia chromosome), and EFS and OS. Searches of PubMed and MEDLINE identified 566 articles. A parallel search on clinicaltrials. gov found 67 closed trials and 62 open trials as of 2014. Merging results of 2 independent searches and applying exclusions gave 39 publications in 3 arms of patient populations (adult, pediatric, and mixed). We performed separate meta-analyses for each of these 3 subpopulations.RESULTS The 39 publications comprised 13 637 patients: 16 adult studies (2076 patients), 20 pediatric (11 249 patients), and 3 mixed (312 patients). The EFS hazard ratio (HR) for achieving MRD negativity is 0.23 (95% Bayesian credible interval [BCI] 0.18-0.28) for pediatric patients and 0.28 (95% BCI, 0.24-0.33) for adults. The respective HRs in OS are 0.28 (95% BCI, 0.19-0.41) and 0.28 (95% BCI, 0.20-0.39). The effect was similar across all subgroups and covariates.CONCLUSIONS AND RELEVANCE The value of having achieved MRD negativity is substantial in both pediatric and adult patients with ALL. These results are consistent across therapies, methods of and times of MRD assessment, cutoff levels, and disease subtypes. Minimal residual disease status warrants consideration as an early measure of disease response for evaluating new therapies, improving the efficiency of clinical trials, accelerating drug development, and for regulatory approval. A caveat is that an accelerated approval of a particular new drug using an intermediate end point, such as MRD, would require confirmation using traditional efficacy end points.