Background: Currently, asymptomatic patients with CLL/SLL are observed without treatment until development of symptoms or cytopenias. Historically, early intervention studies with chemoimmunotherapy have not resulted in an overall survival (OS) benefit and have resulted in toxicity. The introduction of targeted therapies, such as venetoclax and obinutuzumab (VO), have provided tolerable/efficacious options for CLL patients. In the CLL14 study, symptomatic CLL patients receiving frontline therapy with VO had longer progression-free survival (PFS) and deeper remissions [more minimal residual disease-undetectable (MRDu)] compared with those receiving chlorambucil and obinutuzumab (Fischer 2019). The CLL-International Prognostic Index (CLL-IPI; Table) is a validated prognostic model to predict which patients are highest risk for a shorter time to first therapy and shorter OS. We aim to use VO as early intervention in asymptomatic, high-risk patients with CLL to potentially lengthen OS and thus alter the natural history of the disease. Methods: On 12/14/20, we activated the S1925 study for adult patients with CLL or SLL, who were diagnosed within 12 months of enrollment. Eligible patients have a CLL-IPI score ≥ 4 (Table) or complex cytogenetics (≥3 cytogenetic abnormalities) and do not meet any criteria for initiation of treatment by the International Working Group for CLL (IWCLL; Hallek 2018) guidelines. Enrolled patients are randomized in a 2:1 manner to early versus delayed (at the time IWCLL indication for treatment is met) therapy with VO. VO is administered for a fixed duration of 12 months as previously described (Fischer 2019). The primary endpoint is OS. We hypothesize that early intervention with VO will improve the rate of 6-year OS from 60% to 80%. This design requires 222 eligible patients for 88% power (2-sided α=0.05) for the primary comparison. To allow for 10% ineligibility, we will enroll 247 patients. Estimated accrual time is 4 years. Secondary endpoints include: rates of response, PFS, and relapse-free survival; safety; time to 2nd CLL-directed therapy; and quality of life (FACT-Leukemia total score). The primary translational objective is to evaluate the prognostic association between OS and peripheral blood MRD status at 15 months after treatment initiation by flow cytometry. Additional exploratory objectives include the association of other clinical outcomes, baseline prognostic factors, and IWCLL-defined response with MRD status at multiple timepoints. Currently, enrollment is open. Clinical trial information: NCT04269902