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

Abstract

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.

Figure 1.. Flow Diagram of the Study Selection Process

ALL indicates acute lymphoblastic leukemia; MRD, measurable residual disease.

Figure 2.. Estimated Survival Curves, Stratified by Measurable Residual Disease (MRD) Status

Overall survival (OS) (A) and disease-free survival (DFS) (B). The curves show the posterior means of survival distribution in the bayesian hierarchical analysis. The shadings of each curve show the 95% bayesian credible intervals (CrIs) for the survival proportion at the corresponding point in time of follow-up. The 5-year OS was 68% (95% CrI, 63%-73%) for the MRD-negative group and 34% (95% CrI, 28%-40%) for the MRD-positive group. The average hazard ratio for OS was 0.36 (95% CrI, 0.33-0.39), with a 5-year restricted mean survival time difference of 15.37 months (95% CrI, 13.58-17.19 months). The 5-year DFS was 64% (95% CrI, 59%-70%) for the MRD-negative group and 25% (95% CrI, 20%-32%) for the MRD-positive group. The average hazard ratio for DFS was 0.37 (95% CrI, 0.34-0.40), with a 5-year restricted mean survival time difference of 19.61 months (95% CrI, 17.33-21.92 months).

Figure 3.. Hazard Ratios (HRs) for Subgroups

Overall survival (A) and disease-free survival (B). Each square represents the mean HR from bayesian hierarchical analysis, and the horizontal lines represent the 95% bayesian credible interval (CrI) for the subgroup’s HR. AML indicates acute myeloid leukemia; CBF, core-binding factor; FISH, fluorescence in situ hybridization; MA, meta-analysis; MFC, multiparameter flow cytometry; MRD, measurable residual disease; NGS, next-generation sequencing; PCR, polymerase chain reaction; and WT1, Wilms tumor 1.