Monitoring active disease or progressive disease under therapy in chronic lymphocytic leukemia (CLL) represents a challenge to earlier and better adapt therapeutic strategy, notably in the era of targeted therapies in which minimal residual detection or mutations are sometimes not associated to poor clinical outcome. By following CLL patients before treatment (Binet stages A and B/C) or during targeted therapy, the Inventors developed a new flow cytometric method, based on CD69, CD49d, CD20 and CD279 expression at the surface of CD19+/CD5+ B leukemic cells. Analyses of these markers alone or in combination show that CD69/CD49d/CD20/CD279 co-expression (quadruple population, QP) > 0.5% is the best criterion predicting CLL active disease or progression under therapy. This new flow cytometry immunophenotyping could help clinicians to monitor CLL evolution and quickly adapt their therapeutic strategy. Accordingly, the present invention relates to an ex vivo method for predicting active Chronic Lymphocytic Leukemia (CLL) or progressive CLL under therapy in a subject suffering from CLL, comprising the step of quantifying a population of CD69+/CD49d+/CD20+/CD279+ cells in a sample obtained from the subject.