This phase III trial tests whether continuous or intermittent zanubrutinib after achieving a complete remission (CR) with rituximab works in older adult patients with mantle cell lymphoma (MCL) who have not received treatment in the past (previously untreated).

Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Zanubrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. When zanubrutinib is used in MCL, the current standard of care is to continue administering the drug indefinitely until disease progression. This continuous treatment comes with clinical as well as financial toxicity, which could be especially detrimental in older patients. For patients who achieve a CR after initial zanubrutinib plus rituximab therapy, it may be safe and equally effective to stop treatment and restart zanubrutinib upon disease progression rather than continuing indefinitely in previously untreated older adult patients with MCL.

Zanubrutinib is considered investigational which means it has not been approved by the U.S. Food and Drug Administration. Rituximab is FDA-approved.

Participants will be randomized into one of two treatment groups. There is a 50/50 chance of being assigned to either group.

Group 1 will receive rituximab (or rituximab biosimilar) through a vein in the arm or an injection under the skin on Day 1 of each cycle and take zanubrutinib by mouth on days 1-28 of each cycle for six 28-day cycles. After completing 6 cycles, participants will continue to take zanubrutinib by mouth every day until the disease gets worse.

Group 2 will receive rituximab (or rituximab biosimilar) through a vein in the arm or an injection under the skin on Day 1 of each cycle and take zanubrutinib by mouth on days 1-28 of each cycle for six 28-day cycles. After completing 6 cycles, participants will go into observation (clinic visits every 3 months) until their disease gets worse. Then, they will take zanubrutinib by mouth every day until the disease gets worse again. 

Participants in both groups will be asked to complete a medication diary for zanubrutinib and will be followed every 6 months for 10 years following study treatment.