A Phase II Trial of Mosunetuzumab, Polatuzumab, Tafasitamab, and Lenalidomide in Patients With Relapsed B-cell NHL

To learn if giving mosunetuzumab in combination with polatuzumab vedotin, tafasitamab, and lenalidomide can help to control relapsed/refractory FL and DLBCL.

Inclusion criteria: Patients in safety run in must meet the following criteria for study entry: * A diagnosis of relapsed CD20+ Follicular Lymphoma grade 1-3a * A diagnosis of relapsed CD20+ diffuse large B-cell lymphoma Patients in dose expansion must meet the following criteria for study entry: • A diagnosis of relapsed CD20+ diffuse large B-cell lymphoma Patients in each component (safety run in and dose expansion) must meet the following criteria for study entry: 1. Evidence of progression or lack of response following at least 1 prior treatment 2. Able and willing to provide written informed consent and to comply with the study protocol 3. Age ≥ 18 years as these drugs have not yet established safety and efficacy in pediatric patients 4. At least 1 site of measurable disease greater than 1.5cm 5. Adequate hematologic function (unless abnormalities are related to NHL), defined as follows: * Hemoglobin ≥ 9.0 g/dL * Absolute neutrophil count ≥ 1.0 x 109/L * Platelet count ≥ 75 x 109/L 6. Serum bilirubin \ 80% unconjugated bilirubin who must have a serum bilirubin of \ 480 msec at screening, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, COPD, LVEF less than 40%, renal failure, uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura active infection, history of invasive fungal infection, moderate to severe hepatic disease (Child Pugh Class B or C), active hemorrhage, laboratory abnormality, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form. Patients with history of cardiac arrhythmias should have cardiac evaluation and clearance. 16. Known or suspected history of hemophagocytic lymphohistiocytosis 17. History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. Patients with a history of disease-related immune thrombocytopenic purpura, autoimmune hemolytic anemia, or other stable autoimmune diseases may be eligible after review and approval by the Medical Monitor. 18. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics, except if for tumor fever) within 2 weeks prior to the start of cycle 1 19. Patients with suspected active or latent tuberculosis (latent tuberculosis needs to be confirmed by positive Interferon-gamma release assay) 20. Known or suspected chronic active Epstein-Barr virus (EBV) infection 21. Known HIV infection. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative DNA polymerase chain reaction (PCR) and must be willing to undergo DNA PCR testing during the study to be eligible. Those who are HBsAg positive or hepatitis B DNA PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative DNA PCR result to be eligible. Those who are hepatitis C DNA PCR positive will be excluded. 22. Vaccination with live vaccines within 28 days prior to start of treatment 23. No peripheral neuropathy ≥ grade 2 or = grade 2 with pain 24. Pregnant or lactating females. 25. Women of childbearing potential must have a negative serum (-human chorionic gonadotropin \[-hCG\]) at screening and must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program. 26. All patients with known central nervous system involvement with lymphoma. 27. Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis not due to lymphoma. 28. Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment). 29. Major surgery within 4 weeks of study entry, or wound that is not healed from prior surgery or trauma. 30. History of stroke or intracranial hemorrhage within 6 months prior to study entry. 31. Active bleeding or history of bleeding diathesis (eg, hemophilia or von Willebrand disease). 32. Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura). 33. Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) \>2x ULN. 34. Concurrent participation in another therapeutic clinical trial.