Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston.
CCS Associates, Inc.
JAMA Oncol. 2017 Jul 13;3(7):e170580. doi: 10.1001/jamaoncol.2017.0580.
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 mortality may improve the efficiency of clinical trials and accelerate drug development.
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.
Clinical studies in ALL identified via searches of PubMed, MEDLINE, and clinicaltrials.gov.
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.
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.
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.
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.
微小残留病（MRD）是指通过常规病理分析判断为完全缓解的病例中存在疾病。评估急性淋巴细胞白血病（ALL）患者诱导治疗后 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并加速药物开发。
使用临床试验和其他数据库中的出版物，量化儿科和成人 ALL 患者诱导治疗后无事件生存（EFS）和总生存（OS）与 MRD 状态之间的关系。
通过在 PubMed、MEDLINE 和 clinicaltrials.gov 上搜索，确定 ALL 的临床研究。
我们的搜索和研究筛选过程遵循 PRISMA 指南。纳入了评估 ALL 患者 MRD 状态与 EFS 或 OS 关系的研究；排除了综述、摘要和患者数量少于 30 例或 MRD 描述不足的研究。
研究样本量、患者年龄、随访时间、MRD 评估时间（诱导后或巩固后）、MRD 检测方法、表型/基因型（B 细胞、T 细胞、费城染色体）以及 EFS 和 OS。在 PubMed 和 MEDLINE 上的搜索共确定了 566 篇文章。在 clinicaltrials.gov 上进行的平行搜索发现，截至 2014 年，有 67 项已关闭试验和 62 项开放试验。合并两次独立搜索的结果，并进行排除，得到 39 篇来自成人、儿科和混合人群（3 个患者群体亚组）的出版物。我们对这 3 个亚组分别进行了单独的荟萃分析。
39 篇出版物共纳入 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]为 0.18-0.28），而成人患者为 0.28（95%BCI 为 0.24-0.33）。OS 中的相应 HR 分别为 0.28（95%BCI 为 0.19-0.41）和 0.28（95%BCI 为 0.20-0.39）。在所有亚组和协变量中，效果相似。
对于儿科和成人 ALL 患者，达到 MRD 阴性的价值是巨大的。这些结果在治疗方法、MRD 评估的时间、截点水平和疾病亚型上都是一致的。MRD 状态应作为评估新疗法的疾病反应的早期指标进行考虑，以提高临床试验的效率、加速药物开发，并获得监管机构的批准。需要注意的是，使用中间终点（如 MRD）加速批准特定新药，需要使用传统的疗效终点进行确认。
