This is a single-center, phase 2, open-label clinical trial of a novel combination of polatuzumab vedotin, glofitamab, and tafasitamab (TPG) as first-line treatment of patients with diffuse large B cell lymphoma (DLBCL) or high-grade B cell lymphoma (HGBL).

Inclusion Criteria:

1. Ability to understand and the willingness to sign a written informed consent document and to comply with the study protocol procedures.

2. Age ≥18 years.

3. Histologically confirmed diagnosis of DLBCL, or HGBL, according to 5th edition WHO classification. Eligible WHO entities include:

   • Diffuse large B-cell lymphoma, not otherwise specified (NOS)
   • T-cell/histiocyte-rich large B-cell lymphoma
   • DLBCL/HGBL with MYC and BCL2 rearrangements
   • Large B-cell lymphoma with IRF4 rearrangement
   • HGBL with 11q aberration
   • EBV-positive diffuse large B-cell lymphoma
   • DLBCL associated with chronic inflammation
   • Primary large B-cell lymphoma of immune-privileged sites
   • Primary cutaneous DLBCL, leg type
   • Intravascular large B-cell lymphoma
   • Primary mediastinal large B-cell lymphoma
   • HGBL, NOS
   • Grade 3B follicular lymphoma.

4. FDG-avid disease by PET-CT Lugano criteria.

5. No prior systemic therapy for B-cell lymphoma, except for:

   • corticosteroids;
   • a single cycle of chemotherapy administered prior to enrollment (to facilitate enrolling patients who require emergent initiation of therapy for rapidly progressive or symptomatic lymphoma);
   • prior local radiation therapy;
   • prior treatment for indolent lymphoma.

6. Performance status ECOG 0, 1, or 2.

7. Ability to receive one of the standard chemotherapy regimens for DLBCL/HGBL including attenuated versions, where clinically appropriate

8. Required initial laboratory values: (unless due to underlying lymphoma):

   • absolute neutrophil count ≥1.0 x 109/L,
   • platelet count ≥75 x 109/L.
   • creatinine ≤ 1.5 mg/dL or glomerular filtration rate (GFR) ≥40 mL/min/1.73m2 using the Mayo Quadratic Formula
   • total bilirubin ≤ 1.5 × institution upper limit of normal (ULN) unless attributable to Gilbert's disease
   • AST and ALT ≤ 3 × institution ULN.
   • Negative antigen or PCR test for SARS-CoV-2.

9. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) and refrain from donating eggs or sperm throughout the treatment and for 3 months after the last dose of trial therapy.

Exclusion Criteria:

1. Pregnancy, breast-feeding, or prisoner status.

2. Central nervous system involvement by the lymphoma.

3. Prior solid organ transplantation or allogeneic stem cell transplantation.

4. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products.

5. Known NYHA class 3/4 congestive heart failure, left ventricular ejection fraction (LVEF) <30%, or active ischemic heart disease.

6. Chronic obstructive pulmonary disease (COPD) requiring continuous oral corticosteroids or chronic oxygen.

7. Grade >1 peripheral neuropathy.

8. Use of systemic immunosuppressive medications (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor agents), within 2 weeks prior to first dose of study treatment (except as allowed in the inclusion criteria for the management of lymphoma).

9. Any of the following conditions:

   • active bacterial infection requiring antibiotics
   • chronic active Epstein Barr virus (CAEBV) infection
   • history of hemophagocytic lymphohistiocytosis (HLH)
   • history of Stevens-Johnson syndrome or toxic epidermal necrolysis
   • progressive multifocal leukoencephalopathy (PML)
   • known active EBV or CMV viremia
   • autoimmune disease requiring systemic immunosuppressive therapy
   • active myasthenia gravis, myositis, autoimmune hepatitis, idiopathic pulmonary fibrosis, systemic lupus erythematosus, inflammatory bowel disease, granulomatosis with polyangiitis, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
   • active hepatitis B (HBV) or hepatitis C (HCV) infection. Patients with a positive total/IgG HBV core antibody (HBcAb) are eligible if (1) HBV DNA is documented at screening, (2) they agree to take entecavir or tenofovir, and (3) they agree to undergo periodic DNA testing. Patients with a positive HCV antibody are eligible if a negative polymerase chain reaction (PCR) for HCV is documented.
   • HIV infection with a detectable viral load or a CD4 count <200 cells/mm3. Patients (1) with an undetectable viral load and CD4 count >200 cells/mm3 within 6 months prior to enrollment, and (2) on antiretroviral therapy are eligible.

10. Administration of a live, attenuated vaccine within 4 weeks before first treatment or anticipation that such a live, attenuated vaccine will be required during the study.

11. History of other malignancy that could affect compliance with the protocol or interpretation of the primary endpoint in the judgement of the investigator.

12. Any major surgery within 4 weeks before the first dose of treatment.

13. Evidence of other significant or uncontrolled medical or psychiatric conditions that could affect compliance with the protocol, in the judgement of the investigator.

IPD are protected by applicable US laws. Summary data can be provided by the principal investigator to qualified researchers with adequate human subject protection committee approval and data use agreement.