This study aims to assess the efficacy and safety of the chemotherapy-light combination of glofitamab, polatuzumab vedotin and zanubrutinib (GPZ) in elderly patients with previously untreated diffuse large B-cell lymphoma.

This study is a prospective, single-center, interventional, phase 2 study. Each patient screend eligible for this study will receive a combination therapy of glofitamab, zanubrutinib and polatuzumab vedotin.

Inclusion Criteria:

Subjects will only be included in the study if they meet all the following criteria:

1. Written informed consent.

2. Aged 70 years old or above.

3. ECOG performance status of 0-3.

4. Histologically confirmed CD20 positive DLBCL.

5. At least one measurable site of disease.

6. Patient did not receive any prior lymphoma therapy.

7. Patient has a life expectancy (in the opinion of the investigator) of at least 12 weeks.

8. Patient has adequate liver function:

   • Total bilirubin ≤1.5 x ULN (≤3 x ULN in patients with Gilbert's syndrome).
   • AST (aspartate aminotransferase) and ALT (alanine aminotransferase) ≤3 x ULN. o Patients with documented liver involvement: AST and/or ALT ≤5 x ULN.

9. Patient as adequate hematological function, unless due to lymphoma:

   • Hemoglobin ≥9.0 g/dL within 7 days before the first treatment.
   • Absolute neutrophil count of ≥1.0 x 109 cells/L (1,000/μL).
   • Platelet count of ≥75 x 109 cells/L (75,000/μL). Note: Transfusion of RBCs and platelets is allowed to reach the inclusion criteria. In case screening procedures are leading to situations that would exclude the patient from study participation (such as Hb value below entry criteria), the patient may still be enrolled into the trial after consultation with the principal investigator.

10. Patient has adequate renal function:

    • Creatinine ≤ 1.5 x ULN, or
    • Creatinine clearance (CrCl) calculated by Cockcroft-Gault formula of ≥ 30 mL/min for patients in whom, in the Investigator's judgment, serum creatinine levels do not adequately reflect renal function.

Exclusion Criteria:

Subjects will not be included in the study if any of the following criteria apply:

1. History of severe cardiac disease: New York Heart Association (NYHA) grade 3-4, congestive heart failure, myocardial infarction or cerebrovascular accident within the past 3 months, unstable arrhythmias, or unstable angina or history of multiple cardiovascular events) or significant pulmonary disease (including obstructive pulmonary disease and history of bronchospasm).

   Note: Congestive heart failure NYHA II patients can be included if they provide an LVEF >40%.;

2. Patient with current or history of CNS lymphoma.

3. Patient with uncontrolled severe infection, whether bacterial (e.g., tuberculosis), viral (including, but not limited to severe pneumonia, COVID-19, Epstein-Barr virus [EBV], cytomegalovirus [CMV], hepatitis B, hepatitis C, and HIV], fungal, mycobacterial, or other pathogens (excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics (for IV antibiotics this pertains to completion of last course of antibiotic treatment) within 4 weeks prior to study enrollment.

   Note: Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.

4. Patient with current > Grade 1 peripheral neuropathy.

5. Any other prior malignancy than non-melanoma skin cancer or stage 0 (in situ) cervical carcinoma, unless treated with curative intent, and without relapse since 2 years, or low grade prostate cancer, not in need of treatment

6. Psychiatric illness or condition which could interfere with their ability to understand the requirements of the study.

7. Known hypersensitivity to Chinese hamster ovary (CHO) cell products or to any component of the zanubrutinib, polatuzumab vedotin, obinutuzumab, or glofitamab and/or to the contrast agents used in the study.

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All IPD that underlie results in a publication

starting 6 months after publication

IPD could be requested by contacting the corresponding author via email after publication.