In a systematic review and meta-analysis reported in JAMA Oncology, Nicholas J. Short, MD, of The University of Texas MD Anderson Cancer Center, and colleagues, found that measurable residual disease (MRD) negativity is associated with superior disease-free and overall survival in patients with acute myeloid leukemia (AML).1
As stated by the investigators: “In patients with … AML, determining the association of MRD with survival may improve prognostication and inform selection of efficient clinical trial endpoints.”
Nicholas J. Short, MD
The meta-analysis included 81 articles (published between January 2000 and October 2018) that assessed disease-free or overall survival by MRD status in a total of 11,151 patients. Of them, 17 articles (n = 3,118) reported on overall survival alone, 20 (n = 1,783) reported on disease-free survival alone, and 44 (6,250) reported on both. Meta-analyses for disease-free survival and overall survival were performed separately using Bayesian hierarchical modeling with a time-varying hazard ratio effect using 6-month follow-up intervals. Results are expressed as hazard ratio average over time with corresponding 95% credible interval. Analysis of differences in restricted mean survival time (the area under survival curves up to given time points) was performed to provide an additional estimate of treatment effect.
Survival Outcomes in Total Populations
The average hazard ratio for achieving MRD negativity was 0.37 (95% credible interval = 0.34–0.40) for disease-free survival and 0.36 (95% credible interval = 0.33–0.39) for overall survival.
Estimated 5-year disease-free survival was 64% for patients without MRD vs 25% for those with MRD, fot an average hazard ratio of 0.37 (95% credible interval = 0.34–0.40). Estimated 5-year overall survival was 68% for patients without MRD vs 34% for those with MRD, for an average hazard ratio of 0.36 (95% credible interval = 0.33–0.39).
The difference in 5-year restricted mean survival time between the MRD-negative group and the MRD-positive group was 19.6 months (95% credible interval = 17.3–21.9 months) for disease-free survival and 15.4 months (95% credible interval = 13.6–17.2 months) for overall survival.
MRD negativity was associated with superior disease-free and overall survival regardless of age group, MRD assessment time point, AML subtype, or specimen source and for all methods of MRD detection except cytogenetics/fluorescence in situ hybridization (FISH). The prognostic impact of MRD negativity in all subgroups was confirmed by a subsequent multivariate analysis.
For disease-free survival, the average hazard ratios (95% credible intervals) were 0.39 (0.32–0.49) for adults and 0.34 (0.24–0.49) for pediatric patients; 0.39 (0.32–0.49), 0.43 (0.32–0.58), and 0.30 (0.23–0.40) for MRD assessment time point of induction, during consolidation, and after consolidation; 0.39 (0.31–0.50) for MRD detection by multiparameter flow cytometry, 0.34 (0.23–0.51) for polymerase chain reaction (PCR; gene/fusion), 0.41 (0.23–0.72) for next-generation sequencing, and 0.64 (0.34–1.21) for cytogenetics/FISH; 0.23 (0.14–0.36) for core-binding factor AML subtype and 0.41 (0.34–0.52) for non–core-binding factor subtype; and 0.39 (0.32–0.49) for bone marrow and 0.20 (0.13–0.31) for blood as specimen source.
For overall survival, the average hazard ratios (95% credible intervals) were 0.38 (0.33–0.44) for adults and 0.28 (0.19–0.41) for pediatric patients; 0.38 (0.33–0.44), 0.37 (0.29–0.48), and 0.29 (0.22–0.38) for MRD assessment time at point of induction, during consolidation, and after induction; 0.46 (0.37–0.57) for MRD detection by multiparameter flow cytometry, 0.27 (0.21–0.35) for PCR (gene/fusion), 0.40 (0.22–0.70) for next-generation sequencing, and 0.78 (0.38–1.60) for cytogenetics/FISH; 0.31 (0.19–0.49) for core-binding factor AML subtype and 0.38 (0.33–0.45) for non–core-binding factor subtype; and 0.38 (0.33–0.44) for bone marrow and 0.29 (0.18–0.46) for blood as specimen source.
The investigators concluded: “In this large-cohort meta-analysis, achievement of MRD negativity was associated with superior [disease-free survival] and [overall survival] in patients with AML, an association that was observed across ages, disease subtypes, time of assessment, specimen source, and most MRD detection methods. Assessment of MRD in AML in cytomorphologic remission provides important prognostic information. Given the robustness of the association of MRD with long-term outcomes across studies, use of MRD status as an eligibility criterion and/or an endpoint in clinical trial design could lead to more efficient assessment of the efficacy of new drugs and combination therapies in AML.”
DISCLOSURE: The study was supported by grants from the National Cancer Institute and National Institutes of Health. Dr. Short reported no conflicts of interest.
1. Short NJ, Zhou S, Fu C, et al: Association of measurable residual disease with survival outcomes in patients with acute myeloid leukemia: A systematic review and meta-analysis. JAMA Oncol. October 8, 2020 (early release online).
Relapse is the primary obstacle to cure in leukemia. The term minimal residual disease (MRD) was coined in the early 1990s to describe finding a disease-specific marker in the context of a morphologic-appearing remission. The technique first used for MRD detection was the Southern blot (!), but the ...