3007 - Randomized, Phase III Study of Early Intervention with Venetoclax and Obinutuzumab (VO) versus Delayed Therapy with VO in Newly Diagnosed Asymptomatic High-Risk Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): EVOLVE CLL/SLL Study (SWOG S1925; NCT#04269902)

Background: Currently, asymptomatic patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) are observed without treatment until development of CLL/SLL-related symptoms or cytopenias. Historically, early intervention studies in patients with CLL/SLL with non-targeted chemoimmunotherapy agents have not resulted in prolonged overall survival (OS) and have resulted in considerable toxicity. The introduction of targeted therapies, such as venetoclax (an oral BCL2 inhibitor) and obinutuzumab (an intravenous anti-CD20 monoclonal antibody; VO), have provided tolerable and efficacious options for patients with CLL/SLL. In the CLL14 study, symptomatic patients with CLL receiving frontline therapy with VO had longer progression-free survival (PFS) and deeper remissions [more undetectable minimal residual disease (MRDu)] compared with to that seen in patients receiving chlorambucil and obinutuzumab (Fischer 2019). The CLL-International Prognostic Index (CLL-IPI; Table 1) is a validated prognostic model to predict which patients are at highest risk for a shorter time to first therapy and shorter OS. A CLL-IPI score of ≥ 4 is considered high-risk on this scale. We aim to use VO as early intervention in asymptomatic, high-risk patients with CLL/SLL to potentially lengthen OS with the goal to alter the natural history of the disease.

Methods: On 12/14/20, we activated the S1925 study (NCT#04269902) for adult patients with CLL or SLL, diagnosed within 12 months of enrollment. Eligible patients have a CLL-IPI score ≥ 4 (Table 1) 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 (Figure 1). Obinutuzumab is given intravenously on Cycle 1 Day 1 (C1D1; 100mg) and 2 (900mg), and at a dose of 1000mg on C1D8, C1D15, and C2-6 D1. Venetoclax is given daily by mouth starting on C1D21 at a dose of 20mg daily, followed by a weekly ramp up to 50mg (C2D1), 100mg (C2D8), 200mg (C2D15), and 400mg (C2D21) pending no evidence of tumor lysis syndrome. As tolerated, 400mg daily dosing of venetoclax will be continued through the end of Cycle 12. The VO therapy is provided by the study. 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 a=0.05) for the primary comparison. To allow for 10% ineligibility, we will enroll 247 patients. The original estimated accrual time is 4 years. Secondary endpoints include: rates of response, PFS, and relapse-free survival; safety; time to second CLL-directed therapy; and quality of life (assessed by FACT-Leukemia total score). The primary translational objective is to evaluate the association between OS and peripheral blood MRD status by flow cytometry at 15 months after treatment initiation. Additional exploratory objectives include the association of other clinical outcomes, baseline prognostic factors, and IWCLL-defined response with MRD status at multiple timepoints.
Current Status: At the time of submission, 67 patients have been registered and randomized per protocol. Accrual is ongoing.