Of the estimated 21,000 patients who will receive a new diagnosis of chronic lymphocytic leukemia (CLL) this year in the United States, approximately 80% will have early-stage disease. Patients with early-stage disease do not meet the criteria in the 2018 International Workshop on CLL guidelines for the initiation of therapy, and therefore they are not routinely offered treatment. The current management of these patients follows a “watch-and-wait” paradigm, which entails a regular follow-up every 3 to 6 months that includes a physical examination and relevant laboratory testing to evaluate for disease progression. These recommendations are based on decades of careful observations showing that treatment in early-stage CLL does not improve overall survival. With the advent of better prognostic tools to identify patients at high risk, in addition to the recent approval of several novel oral agents with impressive efficacy, the time is ripe to re-examine this question. This review (1) summarizes the results of studies of early intervention in CLL that led to the current consensus for “watch and wait” in early-stage CLL, (2) discusses the role of contemporary risk stratification in early-stage CLL, (3) describes the adverse clinical complications of untreated CLL, and (4) presents the results of ongoing clinical trials of novel agents used in patients with early-stage CLL.
