‣ Patients must meet the following criteria for study entry:

• Age ≥18 years

• Histologically diagnosed

• Diffuse large B-cell lymphoma, not otherwise specified (NOS) or

• High grade B-cell lymphoma (NOS or MYC and BCL2 rearrangements) or

• T cell/histiocyte-rich large B-cell lymphoma

• Have no prior systemic treatment for current lymphoma

• Ineligible for anthracycline-based cytotoxic chemotherapy due to one or more of the following:

• Age ≥80

• Unfit/frail by simplified geriatric assessment4

• The link to calculate simplified geriatric assessment https://redcap.filinf.it/surveys/?s=89AFXML8AK Criteria Fit Unfit Frail ADL ≥ 5 \< 5 6 \< 6 IADL ≥ 6 \< 6 8 \< 8 CIRS-G 0 score = 3-4

• ≤ 8 score = 2 ≥ 1 score = 3-4 8 score = 2 0 score = 3-4 \< 5 score = 2 ≥ 1 score = 3-4

• ≥ 5 score = 2 Age \<80 \< 80 ≥ 80 ≥ 80 Abbreviations: ADL, activities of daily living; IADL, instrumental ADL; CIRS-G, Cumulative Illness Rating Scale for Geriatrics

• Ejection fraction (EF) \<50% but ≥30%

• Needs to be asymptomatic or minimally symptomatic, New York Heart Association (NYHA) class 1 or 2

• Previous cardiotoxic cancer treatment with anthracycline

• Stage II bulky (\>7cm), III or IV disease

• Performance status ≤2 on the ECOG scale (PS ≤3 if attributed to lymphoma and improves to ≤2 by pre-phase treatment prior to enrollment)

• Bi-dimensionally measurable disease, with at least one nodal lesion ≥ 1.5 cm or one extra-nodal lesion \> 1 cm in longest diameter by CT, PET/CT, and/or MRI

• Patients must have adequate organ and marrow function as defined below:

• Absolute neutrophil count (ANC) ≥1.0 × 109/L\*

⁃ -\*Growth factor permitted during screening

• Platelet count ≥75 × 109/L

• Total bilirubin ≤ 3 ULN, unless consistent with Gilbert's (ratio between total and direct bilirubin \> 5)

• AST and ALT ≤ 3x upper limit of normal (ULN)

• Alkaline phosphatase \< 2.5 ULN

• Creatinine clearance \>45 ml/min calculated by modified Cockcroft-Gault formula

• All subjects must

• Agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 12 months following the last dose of study treatment.

• Sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

‣ The investigator is responsible for: ensuring that the patient understands the potential risks and benefits of participating in the study; ensuring that informed consent is given by each patient, this includes obtaining the appropriate signatures and dates on the informed consent document prior to the performance of any study procedures and prior to the administration of study treatment; answering any questions the patient may have throughout the study and sharing in a timely manner any new information that may be relevant to the patient's willingness to continue his or her participant in the trial. Subjects will undergo a brief physical exam including a brief exam to determine cognitive review. No one without capacity to personally consent will be enrolled. Patients have medical decision-making capacity if they can demonstrate understanding of the situation, appreciation of the consequences of their decision, and reasoning in their thought process, and if they can communicate their wishes.

‣ A determination of lack of decision-making capacity shall be made after an appropriate medical evaluation that concludes there is little or no likelihood that the participant will regain decision-making capacity in a reasonable period of time.

• Females must agree to abstain from breastfeeding during study participation and for at least 12 months after epcoritamab discontinuation.

• Females of childbearing potential (FCBP§) must:

• Have one negative pregnancy tests via serum or urine prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, prior to day 1 of each cycle, and after end of study therapy. This applies even if the subject practices true abstinence\* from heterosexual contact.

• Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice. Otherwise, she must agree to use, and be able to comply with two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting epcoritamab, during the study treatment (including dose interruptions), and for at least 12 months after the last dose of epcoritamab.

• Male subjects must:

• A male subject who is sexually active with a female with reproductive potential must agree to use a barrier method of birth control, eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ suppository (including dose interruptions), even if they have undergone a successful vasectomy, from the time of signing consent and for at least 12 months after the last dose of epcoritamab. A male subject must agree not to donate sperm or semen, while taking epcoritamab, during breaks (dose interruptions), and for at least 12 months after the last dose of epcoritamab.