This phase III trial compares early treatment with venetoclax and obinutuzumab versus delayed treatment with venetoclax and obinutuzumab in patients with newly diagnosed high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Immunotherapy with monoclonal antibodies, such as obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Starting treatment with the venetoclax and obinutuzumab early (before patients have symptoms) may have better outcomes for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma compared to starting treatment with the venetoclax and obinutuzumab after patients show symptoms.
Participants must have a confirmed diagnosis (within the past 12 months) of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Participants must have CLL-International Prognostic Index (CLL-IPI) score >= 4 and/or complex cytogenetics (defined as 3+ chromosomal abnormalities)
Participants must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Participants must not have received or be currently receiving any prior CLL-directed therapy, including non-protocol-related therapy, anti-cancer immunotherapy, experimental therapy (with exception of agents approved for emergency access use for the prevention or treatment of COVID-19), or radiotherapy
Participants must not have current, clinically significant gastrointestinal malabsorption, in the opinion of treating doctor
Participants must not have a history of stroke or intracranial hemorrhage within 6 months prior to enrollment
Patients receive obinutuzumab IV over 4 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-6. Patients also receive venetoclax by moth every day on days 22-28 of cycle 1 and on days 1-28 of cycles 2-12. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT (at pre-treatment, Cycle 1, and 15 months after treatment initiation), collection of blood samples (up to 25 mL at pre-treatment, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, 15 months after treatment initiation, and every 6 months starting 21 months after protocol treatment initiation) and bone marrow aspiration (about 5 mL 15 months after treatment initiation) throughout the trial. After coming off of protocol therapy there is follow-up for 10 years after registration.