Suggested definitions and corresponding treatment algorithms for patients with ultra high-risk CLL. Three groups are defined: 1) patients with the 17p deletion or the TP53 mutation and treatment indication, 2) patients with F-refractory CLL, and 3) patients with short PFS after intense therapy (e.g. FCR). Treatment results with current “standard” chemo(immuno)therapy are poor, and therefore these patients are prime candidates for clinical trials evaluating novel agents (that would ideally be comparative). The choice of agent/trial should be based on evidence for efficacy available in the specific situation (i.e., the TP53 mutation). In addition, these patients are prime candidates for consolidation with reduced intensity allo-SCT (fit patients) or experimental approaches in clinical trials. These suggestions are rarely based on comparative trial data because these are scarce.