PURPOSE: Although most patients with follicular lymphoma (FL) can expect an indolent course, progressive lymphoma remains the primary cause of death during the first decade after diagnosis. Progression of disease within 24 months (POD24) of starting first-line (1L) immunochemotherapy defines a high-risk population with poor survival, but better risk stratification at diagnosis is needed. METHODS: The FLIPI24 model was developed and internally validated to predict 24-month event rates using individual data from 4,485 patients treated with 1L immunochemotherapy from 10 observational cohorts of FL. Overall and cause-specific survival was further evaluated in FLIPI24 risk groups. External validation in the 1L immunochemotherapy setting was performed using the prospective observational Lymphoma Epidemiology of Outcomes (LEO) cohort (N = 565) and three randomized phase III trials (N = 3,192); extension to all patients with FL (any 1L therapy) was performed in the LEO cohort (N = 1,445) and its Molecular Epidemiology Resource subcohort (N = 1,074). RESULTS: The FLIPI24 model uses age and four blood-based variables (hemoglobin, lactate dehydrogenase, beta-2 microglobulin, and WBC count). FLIPI24 showed consistent performance across validation and extension data sets, which was superior to existing prognostic tools. Across the four external immunochemotherapy validation data sets, patients with high-risk FLIPI24 (23%-32% of patients) had significantly higher 24-month event rates (22%-35%) and inferior 5-year overall survival (77%-83%) compared with patients with low-risk FLIPI24 (29%-31% of patients, 24-month event rates: 10%-12%; 5-year OS: 96%-97%). Results were consistent when evaluating lymphoma-related death and when extended to all patients with FL. CONCLUSION: The FLIPI24 model robustly stratifies, at diagnosis, patients with FL at increased risk of lymphoma-related death versus patients with very low lymphoma-related mortality during the first decade after diagnosis. FLIPI24 can be used to enrich future clinical trial designs in newly diagnosed FL.

1st Faculty of Medicine Charles University General Hospital Prague Czech Republic

4th Department of Internal Medicine Haematology University Hospital and Faculty of Medicine Hradec Kralove Czech Republic

BC Cancer Centre for Lymphoid Cancer and University of British Columbia Vancouver BC Canada

Cancer Sciences Division Somers Cancer Research Building Faculty of Medicine University of Southampton Southampton United Kingdom

Department of Biometry Lymphoma Study Association Clinical Research Hopital Lyon Sud Pierre Benite France

Department of Blood and Marrow Transplantation and Cellular Immunotherapy H Lee Moffitt Cancer Center and Research Institute Tampa FL

Department of Haematology Sir Charles Gairdner Hospital Perth Australia

Department of Hemato Oncology Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Olomouc Czech Republic

Department of Hematology Aalborg University Hospital Aalborg Denmark

Department of Hematology and Medical Oncology Emory University School of Medicine Winship Cancer Institute Atlanta GA

Department of Hematology and U1245 Centre Henri Becquerel Rouen France

Department of Hematology Centre Hospitalier Universitaire de Lille Groupe de Recherche sur les Formes Injectables et les Technologies Associées Lille France

Department of Hematology Clinical Cancer Research Center Aalborg University Hospital Aalborg Denmark

Department of Hematology Hopital Lyon Sud Claude Bernard Lyon 1 University Pierre Benite France

Department of Hematology Karolinska University Hospital Stockholm Sweden

Department of Hematology Lyon Sud Hospital Lyon France

Department of Hematology Odense University Hospital Odense Denmark

Department of Hematology; Nancy University Hospital Vandoeuvre les nancy France

Department of Lymphoma and Myeloma The University of Texas MD Anderson Cancer Center Houston TX

Department of Lymphoma and Myeloma University of Texas MD Anderson Cancer Center Houston TX

Department of Medicine Vejle Hospital Vejle Denmark

Division of Clinical Epidemiology Department of Medicine Solna Karolinska Institutet Stockholm Sweden

Division of Clinical Epidemiology Dept of Medicine Solna Karolinska Institutet Stockholm Sweden

Division of Clinical Trials and Biostatistics Department of Quantitative Health Sciences Mayo Clinic Rochester MN

Division of Epidemiology Department of Quantitative Health Sciences Mayo Clinic Rochester MN

Division of Hematology Department of Internal Medicine Mayo Clinic Rochester MN

Division of Hematology Oncology and Bone and Marrow Transplantation Department of Internal Medicine University of Iowa Iowa City IA

Division of Hematology Oncology Weill Cornell Medicine New York NY

Faculty of Medicine Masaryk University Brno Czech Republic

Faculty of Science Palacky University Olomouc Olomouc Czech Republic

Fakultni nemocnice Kralovske Vinohrady Department of Haematology and 3rd Faculty of Medicine Charles University Prague Czech Republic

Hematology Department University Hospital UMR CNRS553 Montpellier France

Institution for Medicine at Huddinge Karolinska Institutet and Medical Unit Hematology at Solna Cancer Karolinska University Hospital Stockholm Sweden

Lymphoid Malignancies Unit Assistante Publique Hôpitaux de Paris APHP Hopital Henri Mondor Creteil France

Lymphoma Section University of Miami Sylvester Comprehensive Cancer Center Miami FL

Mater Research Institute University of Queensland Translational Research Institute Brisbane Queensland Australia

Medical School University of Western Australia Perth Australia

Memorial Sloan Kettering Cancer Center New York NY

Olivia Newton John Cancer Research Institute at Austin Health Melbourne Australia

Peter MacCallum Cancer Centre Royal Melbourne Hospital and University of Melbourne Melbourne Australia

Princess Margaret Cancer Centre UHN Toronto Ontario Canada

Rigshospitalet Department of Hematology Copenhagen Denmark

Southwest Oncology CommonSpirit Mercy Durango CO

University of Rochester Medical Center Department of Pathology and Laboratory Medicine Rochester NY

Washington University School of Medicine St Louis MO

Weill Cornell Medical College New York NY

Wilmot Cancer Institute University of Rochester Rochester NY

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