Key Eligibility:

1. Diagnosed & confirmed CD20+ marginal zone lymphoma (MZL), including splenic, nodal, and extranodal subtypes, but excluding gastrointestinal-only MZL and cutaneous-only MZL
2. Measurable disease by PET-CT or CT scans per protocol details
3. At least one of the following criteria per Investigator: (a) progressive or bulky disease symptoms, (b) progressive disease which compromises or may compromise normal organ function, (c) systemic B symptoms (fevers, weight loss, night sweats), (d) symptomatic extranodal disease, (e) cytopenias from bone marrow infiltration or hypersplenism, or (f) increased disease progression tempo
4. No known or suspected disease transformation to diffuse large OR high-grade B-cell lymphoma. Subjects with prior transformed disease but now in relapse with MZL only are permitted to enroll
5. If central nervous system (CNS) involvement, subjects are eligible if no evidence of progression on follow-up evaluation, or if Investigator determines CNS specific treatment is not required or not likely required during first 6 months of study therapy
6. Must have relapsed/refractory MZL after at least 1 line of CD20 systemic therapy; antibiotic and radiation therapy for local MZL is allowed but does not count as 1 line of systemic therapy
7. If treated with any of the following: (a) BTKi or CD3/CD20 therapies, must be completed at least 180 days prior to enrollment, (b) strong/moderate CYP3A4 therapy, complete or off therapy at least 14 days prior to enrollment, (c) chimeric antigen receptor T-cells (CAR-T), must be completed at least 28 days prior to enrollment, (d) autologous stem cell transplant, completed at least 100 days prior to enrollment, (e) allogenic stem cell transplant, completed at least 180 days prior to enrollment, or (f) primary or booster vaccination either live or attenuated, must be received at least 28 days prior to registration
8. Must have recovered from any side effects of prior therapy, except for alopecia and lymphopenia
9. No active graft versus host disease or any other condition requiring corticosteroid treatment / immunosuppression therapies, except for replacement therapy for adrenal or pituitary insufficiency, or treatment for allergy/hypersensitivity
10. No past treatment with polatuzumab vedotin
11. No known or active post-transplant lymphoproliferative disorder
12. No known history of severe allergy to study drugs or any similar components
13. Zubrod Performance Status between 0-2
14. Complete medical history and physical exam within 28 days of registration
15. Adequate organ function as defined by protocol
16. If known history or current symptoms of cardiac disease, or treated with cardiotoxic agents, must have clinical risk assessment of cardiac function within 28 days of enrollment
17. If known history of HIV, must be on effective treatment at enrollment and must have tested undetectable viral load within 180 days of enrollment
18. If known history of chronic Hepatitis B, must have undetectable viral load while on therapy within 180 days of enrollment. If positive Hep B core antibody, must receive prophylactic therapy before and during treatment with study drug
19. If known history of Hepatitis C, must be treated and cured. If currently on treatment, must have undetectable viral load within 180 days of enrollment.
20. No uncontrolled illness which may jeopardize a subject's safety
21. Must not be using or require any anticoagulation drugs within 7 days of enrollment
22. No history of bleeding disorders or history of requiring medical treatment for spontaneous bleeding
23. No history of stroke or brain bleeding within 180 days prior to enrollment
24. No history of progressive multifocal leukoencephalopathy
25. No prior or concurrent malignancy which may interfere with safety or assessment
26. Not pregnant or nursing. Subjects of reproductive potential must agree to use effective contraceptive method(s)