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Meta-Analysis
. 2017 Jul 13;3(7):e170580.
doi: 10.1001/jamaoncol.2017.0580. Epub 2017 Jul 13.

Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis

Donald A Berry  1 , Shouhao Zhou  1 , Howard Higley  2 , Lata Mukundan  2 , Shuangshuang Fu  3 , Gregory H Reaman  4 , Brent L Wood  5 , Gary J Kelloff  6 , J Milburn Jessup  7 , Jerald P Radich  8
Affiliations
Meta-Analysis

Association of Minimal Residual Disease With Clinical Outcome in Pediatric and Adult Acute Lymphoblastic Leukemia: A Meta-analysis

Donald A Berry et al. JAMA Oncol. .

Abstract

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 mortality may 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Berry is co-owner of Berry Consultants LLC, a company that designs Bayesian and adaptive clinical trials for pharmaceutical and medical device companies, groups funded by the US National Institutes of Health, and consortia funded by international agencies. No other disclosures are reported.

Figures

Figure 1.
Figure 1.. Literature Search Diagram
Figure 2.
Figure 2.. Estimated Survival Curves for Patient Groups With ALL
A, EFS: 3191 patients at time 0 with MRD and 8058 with no MRD. B, OS: 883 patients at time 0 with MRD and 1993 with no MRD. C, EFS: 711 patients at time 0 with MRD and 1354 with no MRD. D, OS: 242 patients at time 0 with MRD and 564 with no MRD. The plots show the means of the Bayesian hierarchical analyses. The shadings associated with each curve show the 95% BCIs for the mean survival proportion at the corresponding point in time of follow-up. All 20 pediatric studies and all 16 studies contributed to the EFS distributions (A and C) whereas only 5 of the studies in each age group contained information about OS (B and D). ALL indicates acute lymphoblastic leukemia; BCI, Bayesian credible intervals, EFS, event-free survival; MRD, minimal residual disease; OS, overall survival.
Figure 3.
Figure 3.. Forest Plot of EFS HRs for Pediatric and Adult ALL Subtypes
Numerical results are in eTable 2 in the Supplement. The dots represent the mean HR for the Bayesian hierarchical analysis. The horizontal lines show the 95% BCIs for the subgroup’s EFS HR. ALL indicates acute lymphoblastic leukemia; EFS, event-free survival; OS, overall survival.
Figure 4.
Figure 4.. Forest Plot of OS HRs for Pediatric and Adult ALL Subtypes
Numerical results are in eTable 2 in the Supplement. The dots represent the mean HR for the Bayesian hierarchical analysis. The horizontal lines show the 95% BCIs for the subgroup’s EFS HR. ALL indicates acute lymphoblastic leukemia; EFS, event-free survival; OS, overall survival.
See this image and copyright information in PMC

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