The goal of this clinical study is to compare the study drug, axicabtagene ciloleucel, versus standard of care (SOC) in first-line therapy in participants with high-risk large B-cell lymphoma.

Five years after randomization, participants who have received axicabtagene ciloleucel will transition to a separate long-term follow-up study (study KT-US-982-5968) to complete the remainder of the 15-year follow-up assessments.

Key Inclusion Criteria:

• Histologically confirmed large B cell lymphoma (LBCL) based on 2016 World Health Organization (WHO) classification by local pathology lab assessment, including of the following:

  • Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS)
  • High-grade B-cell lymphoma (HGBL)

• Note: Transformed DLBCL from follicular lymphoma or from marginal zone lymphoma is eligible if no prior treatment with anthracycline-containing regimen.

• High-risk disease defined as an International Prognostic Index (IPI) score of 4 or 5 at initial diagnosis.

• Have received only 1 cycle of rituximab plus chemotherapy (R-chemotherapy).

• Adequate bone marrow, renal, hepatic, pulmonary, and cardiac function.

• Females of childbearing potential must have a negative serum or urine pregnancy test.

Key Exclusion Criteria:

• The following WHO 2016 subcategories by local assessment:

  • T-cell/histiocyte-rich LBCL
  • Primary DLBCL of the central nervous system (CNS)
  • Primary mediastinal (thymic) LBCL
  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
  • Burkitt lymphoma
  • History of Richter's transformation of chronic lymphocytic leukemia

• Presence of detectable cerebrospinal fluid (CSF)-malignant cells, brain metastases, or a history of CNS involvement of lymphoma.

• Presence of cardiac lymphoma involvement.

• Any prior treatment for LBCL other than the 1 cycle of R-chemotherapy.

• History of severe immediate hypersensitivity reaction to any of the agents used in this study.

• Presence of CNS disorder. History of stroke, transient ischemic attack, or posterior reversible encephalopathy syndrome (PRES) within 12 months prior to enrollment.

• History of acute or chronic active hepatitis B or C infection.

• Positive for human immunodeficiency virus (HIV) unless taking appropriate anti-HIV medications, with an undetectable viral load by PCR and with a cluster of differentiation 4 (CD4) count > 200 cells/uL.

• Medical conditions or residual toxicities from prior therapies likely to interfere with assessment of safety or efficacy of study treatment. Please refer to protocol for further details.

• History of clinically significant cardiac disease within 12 months before enrollment.

• History of any medical condition requiring maintenance systemic immunosuppression/systemic disease modifying agents within the last 2 years.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.