Safety and Feasibility Study for CNS-Relapse Prevention in High-Risk Diffuse Large B-cell Lymphoma With Thiotepa-based Autologous Stem Cell Transplant (CNS-PHLAT)

Screening Inclusion Criteria: * Newly diagnosed diffuse large B-cell lymphoma, large B-cell lymphoma transformed from underlying indolent lymphoma, or high-grade B-cell lymphoma. Patients with secondary CNS lymphoma are eligible. Patients with Richter's transformation are NOT eligible. * At high risk for CNS relapse prior to start of induction as defined by at least one of the criteria below: * CNS-IPI ≥ 4 * Kidney or adrenal involvement * Testicular involvement * Breast involvement * Ovarian involvement * Uterine involvement * Skin involvement * Double hit lymphoma as defined by containing translocations of MYC gene together with rearrangement of BCL2 and/or BCL6. * Bone marrow involvement * Myocardium involvement * CNS adjacent * Secondary CNS involvement * Intend to receive a full course of curative-intent anthracycline-based induction treatment and has not yet received more than 2 cycles at the time of screening. Can receive induction chemotherapy outside of Siteman if still compliant with study eligibility, laboratory studies, lumbar punctures, imaging, and other events. * Ages 18 to 75. * Ability to understand and willingness to sign an IRB-approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants if patient is otherwise unable to sign for themselves or unable to understand consent document. Treatment Eligibility Criteria: * Currently undergoing anthracycline-based induction treatment. Dose modifications and/or delays during induction therapy may be made at the discretion of the treating physician and will not affect eligibility for continuation in the study. * ECOG performance status ≤ 2. * PET/CT assessment performed between the end of induction Cycle #2 and end of induction Cycle #4 demonstrates no evidence of progressive disease, and patient is eligible for autologous stem cell transplant as determined by the treating physician. * Has signed treatment consent form following mid-induction PET/CT and prior to conditioning treatment with thiotepa/carmustine. * Thiotepa and carmustine can cause fetal harm when administered to a pregnant person. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study treatment, and for 6 months following receipt of thiotepa and/or carmustine (for women) and 12 months following receipt of thiotepa and/or carmustine (or 3 months following receipt of carmustine if discontinuing before thiotepa) (for men). Should a woman become pregnant or suspect she is pregnant during treatment or within 6 months of the last dose of either thiotepa or carmustine or should a man suspect he has fathered a child, s/he must inform the treating physician immediately. Exclusion Criteria (applies at both screening and treatment) * Relapsed or refractory diffuse large B-cell lymphoma or high-grade B-cell lymphoma. Prior treatment for underlying indolent lymphoma is permitted. * Diagnosis of primary CNS lymphoma. * Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen as determined by the PI. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial. * Currently receiving any other investigational agents. * A history of allergic reactions attributed to compounds of similar chemical or biologic composition to thiotepa, carmustine, or other agents used in the study. * Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days prior to start of induction (for people enrolling prior to induction) or within 7 days of enrollment (for people enrolling after the start of induction).