Prognostic markers and standard management of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is usually diagnosed in early stage, asymptomatic patients, and, although a wealth of prognostic parameters have been identified, the standard approach is a "watch and wait" strategy irrespective of risk factors. Therapy is only indicated if "active disease" criteria (International Workshop on Chronic Lymphocytic Leukemia guidelines) are met, and the routine upfront treatment is a combination of CD20 antibody (rituximab, ofatumumab or obinutuzumab) and chemotherapy (fludarabine /cyclophosphamide, bendamustine, chlorambucil), with the choice mainly determined by physical fitness of the patient. The major subgroup in which this approach does not result into satisfactory efficacy is in CLL with 17p deletion (17p-) or TP53 mutation (TP53mut). Likewise, patients with a short initial response duration (i.e., <24-26 months) have a dismal outcome with chemoimmunotherapy salvage. Therefore, these patients have been referred to as "ultra high risk," and, in these subgroups, novel agents such as signaling kinase inhibitors (also termed B-cell receptor signaling inhibitors; e.g., ibrutinib targeting Bruton tryosine kinase, idelalisib targeting phosphoinositide 3-kinase) and BCL2 antagonists (venetoclax, formerly ABT-199/GDC-0199) have shown dramatic efficacy. Ibrutinib and idelalisib are currently approved for the treatment of relapsed or refractory CLL or frontline treatment of 17p-/TP53mut CLL regardless of fitness. Therefore, these agents are challenging the concept of adjusting treatment to fitness and TP53 status, because they offer remarkable efficacy combined with exceptional tolerability. Nevertheless, it appears that 17p-/TP53mut retains an adverse prognostic impact, making additional improvement a primary research goal aimed at the development of the best combinations and/or sequences of these new agents, as well as prognostic and predictive markers guiding their use.