PRIMARY OBJECTIVE:~I. To determine the complete response rate of the ibrutinib plus rituximab combination followed by venetoclax in newly diagnosed young mantle cell lymphoma (MCL) patients.~SECONDARY OBJECTIVES:~I. To determine the safety profile of the ibrutinib plus rituximab combination followed by venetoclax in newly diagnosed young MCL patients.~II. To evaluate the progression-free survival and overall survival time of the ibrutinib plus rituximab combination followed by venetoclax and hyper-fractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) in newly diagnosed young MCL patients.~EXPLORATORY OBJECTIVE:~I. Developing a novel biomarker for minimal residual disease (MRD) assay using the circulating tumor deoxyribonucleic acid (DNA) (ctDNA) assay on a customized capture sequencing gene panel for MCL using serial plasma samples collected in this trial.~OUTLINE:~PART I: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 and receive rituximab intravenously (IV) over 4-8 hours on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 3-12. Patients also receive venetoclax PO QD on days 1-28 of cycles 5-12. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.~PART II: Patients are assigned to 1 of 3 groups depending on risk status.~GROUP I:~COMBINATION CHEMOTHERAPY: Patients receive rituximab IV over 6 hours on day 1, dexamethasone PO or IV on days 1-4, cyclophosphamide IV over 3 hours twice daily (BID) on days 2-4, and doxorubicin hydrochloride IV over 24 hours and vincristine sulfate IV over 15-30 minutes on day 5 of odd-numbered cycles (1 and 3). Patients also receive rituximab IV over 6 hours on day 1, methotrexate IV over 24 hours on day 2, and cytarabine IV over 2 hours BID on days 3-4 of even-numbered cycles (2 and 4). Treatment repeats every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.~MAINTENANCE THERAPY: Patients receive ibrutinib and venetoclax PO QD on days 1-28, and rituximab IV over 4-8 hours on day 1 of every other month. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.~GROUP II: Patients receive combination chemotherapy as in group I. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive maintenance therapy as in group I.~GROUP III: Patients receive maintenance therapy as in group I.~After completion of study treatment, patients are followed up at 30 days, every 4 months for 2 years, every 6 months for 2 years, and then annually for up to 5 years.
This phase II trial studies how well ibrutinib and rituximab given together with venetoclax and combination chemotherapy work in treating patients with newly diagnosed mantle cell lymphoma. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Drugs used in chemotherapy such as, cyclophosphamide, vincristine, doxorubicin, and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ibrutinib, rituximab, and venetoclax together with combination chemotherapy may work better in treating patients with mantle cell lymphoma.