Older patients with diffuse large B- cell lymphoma (DLBCL) do not have the same rates of disease control as younger patients and are at risk for toxicity. Identifying which patients might benefit from more therapy at the end of first-line treatment is important. The ability to measure small amounts of persistent lymphoma (circulating tumor DNA or ctDNA) might allow the investigators to risk stratify patients. If older patients have detectable ctDNA in the blood at the end of six cycles of polatuzumab vedotin, rituximab and dose-attentuated CHP chemotherapy, patients will receive a bispecific antibody called mosunetuzumab. The investigators hypothesize this will result in "clearing" the ctDNA from the blood and result in better disease control and outcomes for patients. The study will also measure the safety of this regimen and the impact on the function of these older patients utilizing a tool called the geriatric assessment.

Inclusion Criteria

1. Patients aged greater than or equal to 70 years of age who are ineligible for full-intensity chemoimmunotherapy at the discretion of the treating investigator. If between the ages of 70-79, the reason for ineligibility should be documented in a clinical note. If 80 or older, the reason for dose-attenuated chemoimmunotherapy is assumed to be age.
2. ECOG performance status of 0-2.
3. Histologically-confirmed DLBCL, NOS, high grade B-cell lymphoma with MYC and BCL2 rearrangements, high grade B-cell lymphoma, NOS, and grade 3b follicular lymphoma
4. Histologic transformation (HT) will be included on the study. This must be confirmed with a biopsy. Patients with HT may have received prior treatment for indolent lymphoma including chemoimmunotherapy but must not have received an anthracycline-containing regimen in the past.
5. Composite and discordant lymphomas containing both indolent and large cell features will be included.
6. Has received no prior therapy for aggressive B-cell lymphoma or HT with the following exceptions: a course of corticosteroids given for lymphoma related symptoms or one cycle of anthracycline containing chemotherapy prior to enrollment on the clinical trial. Pre-phase treatment with polatuzumab vedotin and steroids is allowable at the treating investigator's discretion.
7. Ejection fraction of ≥ 45% on echocardiogram or MUGA
8. Patient has a platelet count of ≥75,000/µL within the screening period unless inadequate function is due to bone marrow infiltration with aggressive B-cell lymphoma in which case the platelet count should be ≥ 30,000/µL
9. Patient has an absolute neutrophil count of ≥1,500/ µL within the screening period unless inadequate function is due to bone marrow infiltration with aggressive B-cell lymphoma in which case the neutrophil count should be ≥500/ µL
10. Patient has a calculated or measured creatinine clearance of >40 mL/minute within the screening period.
11. Total bilirubin must be less than 1.5 times the upper limit of normal (ULN) unless the elevation is known to be due to Gilbert syndrome or hepatic involvement with aggressive B-cell lymphoma in which case it can be ≤ 3.0 times the ULN. ALT or AST must be ≤ 2.5 times the ULN.
12. Patient has, with treatment in the opinion of the treating investigator, a life expectancy of at least 12 weeks.
13. Signed Informed Consent Form
14. Ability to comply with the study protocol

Exclusion Criteria

Patients who meet any of the following exclusion criteria are not to be enrolled to this study:

1. History of, or clinically apparent central nervous system (CNS) lymphoma
2. Primary mediastinal B-cell lymphoma
3. Patient is receiving peritoneal dialysis or hemodialysis
4. Patient has > Grade 1 peripheral neuropathy.
5. EF <45% or significant or extensive history of cardiovascular disease such as New York Heart Association Class III or IV cardiac disease or Objective Assessment Class C or D, myocardial infarction within the last 6 months prior to the start of Cycle 1, unstable arrhythmias, or unstable angina
6. Patient has received other investigational drugs within 28 days before enrollment.
7. Prior exposure to anthracycline
8. Patient has concomitant active malignancy that the treating physician or PI feels may interfere with the ability to measure the primary or secondary outcomes. Patients with stage 1 cancers are eligible after definitive treatment. Patients with low grade prostate cancer who are managed with observation are eligible. Patients with other malignancies that have been treated with curative intent may be included after discussion with the study PI.
9. Participants who have a positive HIV test at screening, with the following exception: Individuals with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy for at least 4 weeks, have a CD4 count >/= 200/uL, have an undetectable viral load, and have not had a history of opportunistic infection attributable to AIDS within the last 12 months.
10. Patient has active hepatitis B with a positive surface antigen or viral load. Carriers of hepatitis B virus should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis throughout study participation according to national and local guidelines. Those at high risk of reactivation should be placed on appropriate antiviral therapy as per national guidelines.
11. History of solid organ transplantation, or post-transplant lymphoproliferative disorder.
12. Patient has history of allogeneic stem cell transplantation.
13. Serious medical or psychiatric illness likely to interfere with participation in this clinical study including clinically significant CNS disease, active infections, or autoimmune disease that in the opinion of the treating investigator impacts their ability to safely participate in the clinical trial.
14. Any clinically significant abnormality in screening blood chemistry, hematology, or urinalysis results that, in the judgment of the investigator, would impede adequate evaluation of adverse events and/or response to treatment, or that requires aggressive intervention.
15. Treatment with systemic immunosuppressive medications, including, but not limited to, prednisone (>20 mg), azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents within 2 weeks prior to Day 1 of the first cycle of mosunetuzumab. The use of inhaled corticosteroids is permitted, as is the use of mineralocorticoids for management of orthostatic hypotension and a dose of dexamethasone 20mg or less for nausea or B symptoms.

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At time of publication

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