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Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid LeukemiaA Systematic Review and Meta-analysis

Educational Objective
To learn the association of measurable residual disease (MRD) with survival outcomes in patients with acute myeloid leukemia (AML).
1 Credit CME
Key Points

Question  What is the association between measurable residual disease (MRD) and survival outcomes in patients with acute myeloid leukemia?

Findings  In a systematic review and meta-analysis of 81 publications reporting on 11 151 patients with acute myeloid leukemia, the estimated 5-year disease-free survival was 64% for patients without MRD and 25% for those with MRD. The estimated overall survival was 68% for patients without MRD and 34% for those with MRD.

Meaning  The findings of this study suggest that, in patients with acute myeloid leukemia, achievement of MRD negativity is associated with superior long-term survival and warrants consideration as a clinical trial end point that may allow for more rapid evaluation of the efficacy of novel therapies.


Importance  Measurable residual disease (MRD) refers to neoplastic cells that cannot be detected by standard cytomorphologic analysis. In patients with acute myeloid leukemia (AML), determining the association of MRD with survival may improve prognostication and inform selection of efficient clinical trial end points.

Objective  To examine the association between MRD status and disease-free survival (DFS) and overall survival (OS) in patients with AML using scientific literature.

Data Sources  Clinical studies on AML published between January 1, 2000, and October 1, 2018, were identified via searches of PubMed, Embase, and MEDLINE.

Study Selection  Literature search and study screening were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies that assessed DFS or OS by MRD status in patients with AML were included. Reviews, non–English-language articles, and studies reporting only outcomes after hematopoietic cell transplantation or those with insufficient description of MRD information were excluded.

Data Extraction and Synthesis  Study sample size, median patient age, median follow-up time, MRD detection method, MRD assessment time points, AML subtype, specimen source, and survival outcomes were extracted. Meta-analyses were performed separately for DFS and OS using bayesian hierarchical modeling.

Main Outcomes and Measures  Meta-analyses of survival probabilities and hazard ratios (HRs) were conducted for OS and DFS according to MRD status.

Results  Eighty-one publications reporting on 11 151 patients were included. The average HR for achieving MRD negativity was 0.36 (95% bayesian credible interval [CrI], 0.33-0.39) for OS and 0.37 (95% CrI, 0.34-0.40) for DFS. The estimated 5-year DFS was 64% for patients without MRD and 25% for those with MRD, and the estimated OS was 68% for patients without MRD and 34% for those with MRD. The association of MRD negativity with DFS and OS was significant for all subgroups, with the exception of MRD assessed by cytogenetics or fluorescent in situ hybridization.

Conclusions and Relevance  The findings of this meta-analysis suggest that achievement of MRD negativity is associated with superior DFS and OS in patients with AML. The value of MRD negativity appears to be consistent across age groups, AML subtypes, time of MRD assessment, specimen source, and MRD detection methods. These results support MRD status as an end point that may allow for accelerated evaluation of novel therapies in AML.

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Article Information

Accepted for Publication: July 20, 2020.

Corresponding Author: Farhad Ravandi, MD, Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (fravandi@mdanderson.org).

Published Online: October 8, 2020. doi:10.1001/jamaoncol.2020.4600

Author Contributions: Dr Ravandi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Short and Zhou contributed equally to this work.

Concept and design: Short, Zhou, Berry, Freeman, Hourigan, Kantarjian, Ravandi.

Acquisition, analysis, or interpretation of data: Short, Zhou, Fu, Berry, Walter, Freeman, Huang, Nogueras Gonzalez, Hwang, Qi, Ravandi.

Drafting of the manuscript: Short, Zhou, Fu, Huang, Hwang, Qi, Ravandi.

Critical revision of the manuscript for important intellectual content: Short, Berry, Walter, Freeman, Hourigan, Nogueras Gonzalez, Kantarjian, Ravandi.

Statistical analysis: Short, Zhou, Fu, Berry, Huang, Nogueras Gonzalez, Hwang, Qi, Kantarjian.

Obtained funding: Ravandi.

Administrative, technical, or material support: Ravandi.

Supervision: Kantarjian, Ravandi.

Conflict of Interest Disclosures: Dr Berry is co-owner of Berry Consultants LLC, a company that designs bayesian and adaptive clinical trials. Dr Freeman reported receiving personal fees from JAZZ outside the submitted work. Dr Hourigan reported receiving research funding from Sellas and Merck during the conduct of the study. No other disclosures were reported.

Funding/Support: The study was supported by MD Anderson Cancer Center support grant CA016672 and Specialized Programs of Research Excellence. Dr Short is supported by the K12 Paul Calabresi Clinical Oncology Scholar Award and the American Society of Hematology Junior Faculty Scholar Award in Clinical Research. This study was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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