Polatuzumab Vedotin, Venetoclax, and Rituximab and Hyaluronidase Human for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma

PRIMARY OBJECTIVE: I. To evaluate the end of induction (EOI) complete response rate (CR) for treatment with the regimen of rituximab and hyaluronidase human + polatuzumab vedotin + venetoclax (RSc + Pola + Ven) in relapsed/refractory mantle cell lymphoma (MCL). SECONDARY OBJECTIVES: I. To evaluate the EOI overall response rate (ORR) for the combination of RSc + Pola + Ven in relapsed/refractory MCL. II. To evaluate the best response (CR, partial response \[PR\]) in patients who continue on to maintenance therapy and evaluate the improvement in the depth of response. III. To evaluate the progression free survival (PFS) and overall survival (OS) for the combination of RSc + Pola + Ven) in relapsed/ refractory MCL. IV. To compare the ORR, CR, PFS, and OS in ibrutinib refractory compared to ibrutinib naive patients. V. To evaluate regimen-related toxicity for patients treated with RSc + Pola + Ven. CORRELATIVE RESEARCH OBJECTIVES: I. To evaluate changes in minimal residual disease (MRD) status in both responding and non-responding patients at EOI and end of maintenance and compared to baseline as well as correlate MRD status with PFS and OS. II. To evaluate changes in systemic immune profiles and T cell activation induced by treatment with RSc + Pola + Ven. III. To evaluate the prognostic importance of high risk cytogenetic alterations, and other risk stratification scores in patients with relapsed/refractory MCL receiving RSc + Pola + Ven. IV. To evaluate features of the tumor microenvironment in patients with relapsed/refractory MCL receiving RSc +Pola+Ven. V. To evaluate molecular features associated with response in PDX models from patients with relapsed/refractory MCL receiving RSc +Pola+Ven. OUTLINE: INDUCTION: Patients receive rituximab intravenously (IV) on day 1 of cycle 1 and rituximab and hyaluronidase human subcutaneously (SC) over 5 minutes on day 1 of cycles 2-6. Patients also receive polatuzumab vedotin IV over 30-90 minutes on day 1 and venetoclax orally (PO) daily on days 1-21. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive venetoclax PO daily on days 1-21 and rituximab and hyaluronidase human SC over 5 minutes every 60 days for up to 1 year in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 90 days for up to 5 years.