The purpose of this study is to determine whether a blood test can accurately detect whether if the participant's lymphoma has come back after completion of initial chemotherapy treatment for their aggressive B-cell Non-Hodgkin lymphoma. The purpose of the study is to see if MRD in blood samples can potentially replace CT scans after completion of chemotherapy in the future.

Inclusion Criteria:

• 18 years of age at time of signing informed consent

• Histology-confirmed aggressive B-cell Non-Hodgkin lymphoma

  • De novo diffuse large B-cell lymphoma (including all subtypes such as primary mediastinal B-cell lymphoma and T-cell rich B-cell lymphoma). According to the 2008 WHO Classification of Hematopoietic and Lymphoid Tumors. These would include double or triple-hit diffuse large B-cell lymphomas with MYC/BCL2 and/or BCL6 gene rearrangements. These cases may be classified as high grade B-cell lymphomas according to the 2017 revision of the WHO Classification of Hematopoietic and Lymphoid Tumors.

• Recipient of frontline multi-agent chemotherapy (for example, RCHOP, dose adjusted-REPOCH, RCHOP/RICE, RCHOP+investigational agent, etc). Eligible patients will have recently received (≤ 4 months from end of treatment assessment), be actively receiving, or planned to receive frontline chemotherapy in near future (within 3 months of signing consent). A frontline therapy program can include different sequential phases of treatment, including high-dose therapy and autologous stem cell transplantation.

• Required pre-treatment test specimen from bone marrow, blood, lymph node, or alternate site to identify tumor-specific clonotype.

• Ability to adhere to the study visit schedule and all the protocol requirements, including surveillance imaging and MRD test specimen collection at specified time points.

Exclusion Criteria:

• Patients receiving 2nd or greater line of therapy.
• Stage I or II disease.
• Primary mediastinal B-cell lymphoma.
• Transformation from antecedent or coincident indolent B-cell Non-Hodgkin lymphoma.

Potential research subjects will be identified by a member of the patient's treatment team, the protocol investigator, or research team.