Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis

Abstract

Minimal residual disease prior to allogeneic hematopoietic cell transplantation has been associated with increased risk of relapse and death in patients with acute myeloid leukemia, but detection methodologies and results vary widely. We performed a systematic review and meta-analysis evaluating the prognostic role of minimal residual disease detected by polymerase chain reaction or multiparametric flow cytometry before transplant. We identified 19 articles published between January 2005 and June 2016 and extracted hazard ratios for leukemia-free survival, overall survival, and cumulative incidences of relapse and non-relapse mortality. Pre-transplant minimal residual disease was associated with worse leukemia-free survival (hazard ratio=2.76 [1.90-4.00]), overall survival (hazard ratio=2.36 [1.73-3.22]), and cumulative incidence of relapse (hazard ratio=3.65 [2.53-5.27]), but not non-relapse mortality (hazard ratio=1.12 [0.81-1.55]). These associations held regardless of detection method, conditioning intensity, and patient age. Adverse cytogenetics was not an independent risk factor for death or relapse. There was more heterogeneity among studies using flow cytometry-based than WT1 polymerase chain reaction-based detection (I²=75.1% vs. <0.1% for leukemia-free survival, 67.8% vs. <0.1% for overall survival, and 22.1% vs. <0.1% for cumulative incidence of relapse). These results demonstrate a strong relationship between pre-transplant minimal residual disease and post-transplant relapse and survival. Outcome heterogeneity among studies using flow-based methods may underscore site-specific methodological differences or differences in test performance and interpretation.

Figure 1.

PRISMA flow diagram for study selection. HCT: hematopoietic cell transplantation; MRD: minimal residual disease.

Figure 2.

Risk of bias assessment illustrating review authors’ judgments about each risk of bias item for each included study.

Figure 3.

Forest plot showing hazard ratio (effect size, ES) for leukemia-free survival with pooling of results for each minimal residual disease detection method. Columns indicate study size (N) and whether each study carries a high risk of bias (Bias Risk). Within groups, studies are listed by year of publication. CI: confidence interval; MFC: multi-parametric flow cytometry; PCR: polymerase chain reaction; MRD: minimal residual disease.

Figure 4.

Figure 4. Meta-regression analysis showing the effect of the ratio of the percentage of MRD^pos patients with adverse cytogenetics to the percentage of MRD^neg patients with adverse cytogenetics on log-hazard for leukemia-free survival. A flat line indicates no relationship, and this is shown for all studies (A) and after excluding studies with a high risk of bias (B). MRD: minimal residual disease; HR: hazard ratio.

Figure 5.

Funnel plot analysis for survival outcomes. Shown are (A) leukemia-free survival (LFS), (B) overall survival (OS), (C) cumulative incidence of relapse (CIR), (D) non-relapse mortality (NRM). HR: hazard ratio.