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 thanWT1polymerase 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.

Anthony Nolan Research Institute London UK Royal Marsden Hospital London UK

Biostatistics and Bioinformatics Core Masonic Cancer Center University of Minnesota Minneapolis MN USA

Clinical Research Division Fred Hutchinson Cancer Research Center Seattle WA USA Department of Medicine Division of Hematology University of Washington Seattle WA USA Department of Epidemiology University of Washington Seattle WA USA

Department of Hematology Fondazione Policlinico Tor Vergata Rome Italy

Department of Pediatrics Jena University Hospital Germany

Division of Hematology Oncology and Transplantation Department of Medicine University of Minnesota Minneapolis MN USA

Division of Hematopathology Department of Laboratory Medicine and Pathology University of Minnesota Minneapolis MN USA

Division of Hematopathology Department of Laboratory Medicine University of Washington Seattle WA USA

Hematology Branch National Heart Lung and Blood Institute National Institutes of Health Bethesda MD USA

Hematology Oncology Fellowship Program University of Washington Seattle WA USA

Institute of Haematology and Blood Transfusion Prague Czech Republic

Pharmaceutical Outcomes Research and Policy Program University of Washington Seattle WA USA Department of Health Services University of Washington Seattle WA USA Department of Biomedical Informatics University of Washington Seattle WA USA

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA

Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore MD USA Experimental Transplantation and Immunology Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD USA

Unit of Blood Diseases and Stem Cell Transplantation University of Brescia A O Spedali Civili Italy

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