• Patients must have a histo-pathologically confirmed aggressive B-cell NHL intended for or currently undergoing standard of care ASCT or CAR T-cell therapy.

‣ Note: Patients should have met the Food and Drug Administration (FDA) approved indications for the respective CAR T cell construct being used. Standard of care/FDA approved CAR-Ts for this population include axicabtagene ciloleucel, tisagenlecleucel or lisocabtagene maraleucel, any of which may have been used for this patients and is provider dependent. Out of specification products of these respective CAR Ts may also be utilized if intended for FDA approved indication by way of expanded access if the provider feels that the product offers similar efficacy and safety as compared to commercial product per guidance provided by manufacturer. For the purpose of this study, aggressive B-cell NHL histologies should conform to the label indications for the respective CAR-T being utilized. Accordingly, CAR-T eligible histologies include the following groups according to the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements

⁃ High-grade B-cell lymphoma, Not Otherwise Specified (NOS)

⁃ Diffuse large B-cell lymphoma (DLBCL), NOS

⁃ Diffuse large B-cell lymphoma (DLBCL), NOS; Germinal center B-cell type\*\* \[Refer note below\]

⁃ Diffuse large B-cell lymphoma (DLBCL), NOS; Non-germinal center B cell type\*\* \[Refer note below\]

⁃ Large B-cell lymphoma with IRF4 rearrangement (subtype of DLCBL)

⁃ T-cell/histiocyte-rich large B-cell lymphoma (subtype of DLCBL)

⁃ Primary cutaneous DLBCL, leg type (subtype of DLCBL)

⁃ Epstein Barr Virus (EBV)+ DLBCL, NOS (subtype of DLCBL)

⁃ DLBCL associated with chronic inflammation (subtype of DLCBL)

⁃ Primary mediastinal (thymic) large B-cell lymphoma

⁃ Intravascular large B-cell lymphoma (subtype of DLCBL)

⁃ Transformed indolent B-cell lymphoma; composite lymphomas with aggressive B-cell NHL as outlined above and indolent lymphomas are also allowable if felt to represent transformation.

∙ NOTE: \* Cell of origin will be determined by Hans criteria (immuno histochemistry). We have therefore updated criteria to indicate non-germinal center B-cell type to reflect this (rather than activated B-cell \[ABC\] subtype which implies use of molecular testing)

• For CAR T-cell therapy, patients must have metabolically active disease on PET/CT prior to therapy; For ASCT therapy, patients must be in complete remission

• Patients must be age ≥ 18 years on the day of signing informed consent

• Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

• Patients must have a life expectancy of greater than 12 weeks

• Absolute neutrophil count (ANC)\* ≥ 500/μL neutrophil count prior to either admission for ASCT or CAR T-cell apheresis Note: \* Use of growth factor is allowable if deemed clinically appropriate by the treating physician up to the day prior to LDC/conditioning chemotherapy (i.e. if felt to be disease related) Patients must meet the parameter at screening if intended for ASCT or CAR-T treatment but have not yet received the cellular therapeutic. For patients enrolled after receiving ASCT or CAR T-cell therapy, patients will be eligible if they meet the criteria on day 1 of either conditioning chemotherapy (ASCT) or lymphodepleting chemotherapy (LDC) (CAR-T)

• Platelets (PLT) ≥ 50,000/μL within 14 days prior to either admission for ASCT or CAR T-cell apheresis, unless deemed to be related to disease (transfusion not permitted within 7 days) Minimum platelet count requirement in those with bone marrow involvement will be ≥ 25,000 Patients must meet the parameter at screening if intended for ASCT or CAR-T treatment but have not yet received the cellular therapeutic. For patients enrolled after receiving ASCT or CAR T-cell therapy, patients will be eligible if they meet the criteria on day 1 of either conditioning chemotherapy (ASCT) or lymphodepleting chemotherapy (LDC) (CAR-T)

• Total bilirubin ≤ 1.5 x Institutional upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL), OR direct bilirubin ≤ ULN for patients with total bilirubin \> 1.5 x ULN Patients must meet the parameter at screening if intended for ASCT or CAR-T treatment but have not yet received the cellular therapeutic. For patients enrolled after receiving ASCT or CAR T-cell therapy, patients will be eligible if they meet the criteria on day 1 of either conditioning chemotherapy (ASCT) or lymphodepleting chemotherapy (LDC) (CAR-T)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) ≤ 2.5 x institutional ULN Patients must meet the parameter at screening if intended for ASCT or CAR-T treatment but have not yet received the cellular therapeutic. For patients enrolled after receiving ASCT or CAR T-cell therapy, patients will be eligible if they meet the criteria on day 1 of either conditioning chemotherapy (ASCT) or lymphodepleting chemotherapy (LDC) (CAR-T)

• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 x institutional ULN Patients must meet the parameter at screening if intended for ASCT or CAR-T treatment but have not yet received the cellular therapeutic. For patients enrolled after receiving ASCT or CAR T-cell therapy, patients will be eligible if they meet the criteria on day 1 of either conditioning chemotherapy (ASCT) or lymphodepleting chemotherapy (LDC) (CAR-T)

• Creatinine clearance ≥ 30 mL/min estimated by the Cockcroft-Gault equation Patients must meet the parameter at screening if intended for ASCT or CAR-T treatment but have not yet received the cellular therapeutic. For patients enrolled after receiving ASCT or CAR T-cell therapy, patients will be eligible if they meet the criteria on day 1 of either conditioning chemotherapy (ASCT) or lymphodepleting chemotherapy (LDC) (CAR-T)

• International normalized ratio (INR) activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN, unless participant is receiving anticoagulant therapy as long as INR or aPTT is within therapeutic range of intended use of anticoagulants Patients must meet the parameter at screening if intended for ASCT or CAR-T treatment but have not yet received the cellular therapeutic. For patients enrolled after receiving ASCT or CAR T-cell therapy, patients will be eligible if they meet the criteria on day 1 of either conditioning chemotherapy (ASCT) or lymphodepleting chemotherapy (LDC) (CAR-T)

• Patients with a known history of hepatitis C virus (HCV) infection who have undetectable HCV viral load at screening

‣ Note: Patients must have completed curative anti-viral therapy at least 4 weeks prior to registration

• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification

‣ Note: To be eligible for this trial, patients should be class 2 or better

• Patients must have the ability to understand and the willingness to sign a written informed consent document

• Females of child-bearing potential (FOCBP) either practice complete abstinence or agree to use two reliable methods of contraception simultaneously. This includes ONE effective method of contraception and ONE additional effective contraceptive method. Women should use effective contraceptive methods beginning ≥ 28 days prior to initiating, study treatment, for the duration of study participation, and for at least 6 months following completion of therapy. As tazemetostat may interfere with hormonal contraception and render it ineffective, adequate contraception in this case would consist of a barrier method of birth control or abstinence.

• 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.

• Men treated or enrolled on this protocol must also agree to either practice complete abstinence or agree to use a latex or synthetic condom, even with a successful vasectomy (medically confirmed azoospermia), during sexual contact with a FOCBP from time of informed consent, for the duration of study participation (including during dose interruptions), and atleast 6 months after study drug discontinuation.

• Male subjects must not donate semen or sperm from first dose of tazemetostat, during study treatment (including during dose interruptions), and for 6 months after discontinuation of study drugs.

• 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 or bilateral salpingectomy

• Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months)

‣ FOCBP must have a negative pregnancy test prior to registration on study

• Note: Serum or urine pregnancy test for females of childbearing potential. This should be performed within 28 days prior to registration. A pregnancy test will need to be repeated if cycle 1 day 1 is \> 3 days after registration. Pregnancy test will also be done during maintenance phase with each cycle, for females of childbearing potential