Association of hematologic response and assay sensitivity on the prognostic impact of measurable residual disease in acute myeloid leukemia: a systematic review and meta-analysis

Abstract

Measurable residual disease (MRD) is associated with relapse and survival in acute myeloid leukemia (AML). We aimed to quantify the impact of MRD on outcomes across clinical contexts, including its association with hematologic response and MRD assay sensitivity. We performed systematic literature review and meta-analysis of 48 studies that reported the association between MRD and overall survival (OS) or disease-free survival (DFS) in AML and provided information on the MRD threshold used and the hematologic response of the study population. Among studies limited to patients in complete remission (CR), the estimated 5-year OS for the MRD-negative and MRD-positive groups was 67% (95% Bayesian credible interval [CrI], 53-77%) and 31% (95% CrI, 18-44%), respectively. Achievement of an MRD-negative response was associated with superior DFS and OS, regardless of MRD threshold or analytic sensitivity. Among patients in CR, the benefit of MRD negativity was highest in studies using an MRD cutoff less than 0.1%. The beneficial impact of MRD negativity was observed across MRD assays and timing of MRD assessment. In patients with AML in morphological remission, achievement of MRD negativity is associated with superior DFS and OS, irrespective of hematologic response or the MRD threshold used.

Figure 1 –

Flow diagram of the study selection process. Forty-eight articles were ultimately included in this meta-analysis.

Figure 2 -. Estimated survival curves according to MRD response for the entire study population and for only studies reporting patients in CR.

(A) Overall survival for the entire study population (N=35 studies, n=6004 patients), (B) disease-free survival for the entire study population (N=39 studies, n=4663 patients), (C) overall survival for studies only in patients in CR (N=21 studies, n=3427 patients), and (D) disease-free survival for studies only in patients in CR (N=23 studies, n=2939 patients). The curves show the posterior medians of survival probabilities. The shadings of each curve show the 95% Bayesian credible intervals for the survival rates at the corresponding point in time of follow-up.

Figure 3 –. Estimated survival curves according to MRD response for the entire study population, stratified by MRD threshold.

(A) Overall survival using threshold <0.1% (N=14 studies, n=2723 patients), (B) disease-free survival using threshold <0.1% (N=14 studies, n=1265 patients), (C) overall survival using threshold = 0.1% (N=11 studies, n=1139 patients), (D) disease-free survival using threshold = 0.1% (N=13 studies, n=1238 patients), (E) OS using threshold >0.1% (N=10 studies, n=2205 patients), and (F) DFS using threshold >0.1% (N=14 patients, n=2288 studies). The curves show the posterior medians of survival probabilities. The shadings of each curve show the 95% Bayesian credible intervals for the survival rates at the corresponding point in time of follow-up.

Figure 4 –

Hazard ratios (HRs) by MRD threshold for studies that only included patients in CR. Each square shows the posterior median of HR and the horizontal bands demonstrate the corresponding 95% credible intervals (CrI).

Figure 5 –. Hazard ratios (HRs) by subgroups for the entire study population, stratified by MRD threshold.

(A) Overall survival and (B) disease-free survival. Each square shows the posterior median of HR and the horizontal bands demonstrate the corresponding 95% credible intervals (CrI). Abbreviations: MFC, multiparameter flow cytometry; PCR, polymerase chain reaction.

Figure 6 –. Hazard ratios (HRs) by subgroups for the entire study population, stratified by inclusion of only patients in CR versus inclusion of patients with lesser responses.

(A) Overall survival and (B) disease-free survival. Each square shows the posterior median of HR and the horizontal bands demonstrate the corresponding 95% credible intervals (CrI). Abbreviations: MFC, multiparameter flow cytometry; PCR, polymerase chain reaction. “Mixed response” refers to studies including patients in CRi and/or MLFS in the MRD analyses.