Inclusion Criteria:
* Patients must have a pathologically confirmed diagnosis of immunodeficiency-related large B-cell lymphoma as defined by the 5th Edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors 2022 in addition to any of the following:
* Lymphomas arising in immune deficiency which encompass monomorphic post-transplant lymphoproliferative disorder (PTLD) OR
* Polymorphic B-cell lymphoproliferative disorder arising in the setting of immunodeficiency and/or immune dysregulation as seen in 1 or more of the following settings:
* Underlying autoimmune disease
* Iatrogenic or therapy-related immunosuppression
* Conditions arising from inborn errors of immunity
* Immune senescence as seen in patients aged ≥80 years or those ≥ 65 years with CD4 count \< 500 cells/mm\^3
* Epstein-Barr virus (EBV) infection as demonstrated by EBV positivity in the tumor cells
* Patients must have measurable disease (≥ 1 measurable nodal lesion \[long axis \> 1.5 cm\] or ≥ 1 measurable extra-nodal lesion \[long axis \> 1.0 cm\] on CT scan or MRI) per Lugano criteria
* Note; Patients with hepatomegaly /organomegaly deemed to be related to disease will also be eligible if not meeting strict Lugano criteria
* Patients must meet one disease status as follows AND deemed ineligible for chimeric antigen receptor T-cell (CAR-T):
* Primary refractoriness defined as a partial response or less on interim PET-CT during therapy with frontline chemo-immunotherapy (containing anti-CD20 monoclonal antibody)
* Primary refractoriness defined as a partial response or less on interim PET-CT during therapy with rituximab (or any other anti-CD20 monoclonal antibody) monotherapy AND deemed ineligible for escalation to chemotherapy
* Relapse after achieving a complete response with ≥ 1 prior systemic therapy (including CART)
* Patients must be aged ≥ 18 years
* Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Absolute neutrophil count (ANC) ≥ 1000/mcL (the use of growth factor support to attain goal ANC allowed, but not the last 14 days prior to screening laboratory test)
* Platelets (PLT) ≥ 50,000/mcL (transfusions allowed ≥ 7 days prior)
* Total bilirubin ≤ 1.5 Institutional upper limit of normal (ULN) unless attributed to Gilbert's ≤ 3 Institutional ULN if attributed to disease or Gilbert's
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 3 x institutional ULN (\> 3 and ≤ 5 x institutional upper limit of normal (ULN) if deemed related to disease)
* Glomerular filtration rate (GFR) ≥ 45 mL/min/1.73 m2
* Estimated (e)GFR is calculated by the abbreviated Modification of Diet in Renal Disease (MDRD)
* For patients with a known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* The effects of lenalidomide on the developing human fetus are known. For this reason and because lenalidomide as well as other therapeutic agents used in this trial are known to be teratogenic, females of child-bearing potential (FOCBP) must agree to use adequate contraception. Female subjects of reproductive potential must either completely abstain from heterosexual sexual contact or must use 2 effective methods of contraception (at least 1 highly effective method and one effective method) at the same time
* The 2 effective contraceptive methods must be started at least 30 days before lenalidomide therapy, during therapy (including dose interruptions), and for at least 12 months following discontinuation of therapy
* Should a female patient become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
* Females should also refrain from egg donation from the time of informed consent, during the study and for 12 months after the last dose of study drug
* NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
* Has not undergone a hysterectomy or bilateral oophorectomy
* Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months)
* If male, and subject is sexually active with female partner(s) of childbearing potential, he must agree, from 30 days prior to randomization through 12 months after the last dose of study drug, to practice the protocol-specified contraception
* Male who is not considering fathering a child or donating sperm during the study or for 12 months after the last dose of study drug
* FOCBP must have a negative pregnancy test prior to registration on study
* Patients must have no known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
* (If a patient has signs/symptoms suggestive of SARS-CoV-2 infection or have had recent known exposure to someone with SARS-CoV-2 infection, the patient must have a negative molecular (e.g., polymerase chain reaction \[PCR\]) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection)
* Note: SARS-CoV-2 diagnostic tests should be applied following local requirements/recommendations.
* Patients who do not meet SARS-CoV-2 infection eligibility criteria must be screen failed and may only rescreen after they meet the following SARS-CoV-2 infection viral clearance criteria:
* No signs/symptoms suggestive of active SARS-CoV-2 infection
* Negative molecular (e.g., PCR) result or 2 negative antigen test results at least 24 hours apart)
Exclusion Criteria:
* Patients who have received any prior therapy with a bispecific T-cell engager targeting CD3 and CD20
* Patients who have received chemotherapy and/or other antineoplastic agents (except CD20- targeting monoclonal antibodies, steroids and/or radiation) within 1 week or 5 half-lives (whichever is shorter) prior to registration
* Patients who have undergone autologous stem cell transplant (ASCT) within 100 days of registration
* Patients who have undergone CAR-T therapy with refractoriness or relapse within 30 days of registration
* Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to epcoritamab and/or lenalidomide
* Patients with human immunodeficiency virus (HIV) with detectable viral load and CD4 count ≤350 cells/mm3 \& not on treatment for more than 1 year
* Patients with evidence of active disease in the central nervous system (CNS) defined as either the presence of active lesions on MRI or cerebrospinal fluid (CSF) studies obtained within 4 weeks prior to registration or progressive neurological decline, attributable to CNS disease
* Patients who have a seizure disorder that is not controlled (requiring anti-epileptic therapy AND with seizure within 12 months of registration)
* Patients who have had major surgery within 4 weeks prior to registration
* Patients who have clinically significant cardiac disease include the following:
* Myocardial infarction or stroke within 6 months prior to enrollment,
* OR the following conditions within 6 months prior to enrollment: unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV), uncontrolled cardiac arrhythmia, and uncontrolled hypertension),
* OR Other clinically significant electrocardiogram (ECG) abnormalities within 6 months prior to enrollment unless deemed stable and appropriately treated
* OR Left ventricular ejection fraction \< 45% for Echocardiogram
* Patients who are unable to swallow, retain and absorb oral tablet/gel/capsules
* Patients who have received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention.
* Note: Administration of killed vaccines is allowed
* Female patients who are pregnant or nursing.
* Note: Females should refrain from breast feeding from the time of informed consent, during the study and for 12 months after the last dose of study treatment
* Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible:
* Ongoing or active infection requiring IV antimicrobial treatment
* Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints
