This is a study incorporating brentuximab vedotin and dose attenuated rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) into initial therapy for elderly patients with DLBCL. Vincristine will be omitted from the standard R-CHOP regimen given the overlapping toxicities with brentuximab vedotin.

This is a multicenter, single-arm pilot study incorporating brentuximab vedotin and dose attenuated rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) into initial therapy for elderly patients with DLBCL. Vincristine will be omitted from the standard R-CHOP regimen given the overlapping toxicities with brentuximab vedotin. CD30 positivity will be determined at enrollment and patients will be enrolled into a CD30 positive and negative group in equal numbers. Additionally, a Comprehensive Geriatric Assessment (CGA) will be performed on all patients, but this will not be used to guide treatment decisions.

Inclusion Criteria:

• Voluntary written informed consent before performance of any study-specific procedure not part of routine medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. Subjects must be able to understand and be willing to sign the written informed consent form.

• Men and women aged greater than or equal to 75 years of age

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-3

• Histologically-confirmed DLBCL by World Health Organization classification by site hematopathologist

  • Histologic transformation (HT) will be included on the study. This must be confirmed with a biopsy. Patients with HT must not have received an anthracycline-containing regimen in the past.
  • Composite lymphoma containing both indolent and large cell features will be included

• Has received no prior therapy for DLBCL or HT with the exception of a course of prednisone of less than or equal to 7 days given for lymphoma related symptoms; prior therapy for follicular lymphoma is accepted, but no prior anthracycline-containing therapy.

• Carriers of hepatitis B virus should be closely monitored for clinical and laboratory signs of active hepatitis B virus infection and for signs of hepatitis throughout study participation.

• Total bilirubin must be less than 1.5 times the upper limit of normal (ULN) unless the elevation is known to be due to Gilbert syndrome.

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be less than 3 times the upper limit of the normal range. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of DLBCL in liver.

Exclusion Criteria:

• Patient has a platelet count of ≤50,000/mm3 within 14 days before enrollment.

• Patient has an absolute neutrophil count of < 1,000/mm3 within 14 days before enrollment.

• Patient has a calculated or measured creatinine clearance of <30 mL/minute within 14 days before enrollment.

• Patient is receiving peritoneal dialysis or hemodialysis

• Patient has ≥Grade 2 peripheral neuropathy within 14 days before enrollment.

• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

• New York Heart Association class III heart failure or ejection fraction of less than 30% on echocardiogram or Multi Gated Acquisition Scan (MUGA)

• Patient has received other investigational drugs with 14 days before enrollment

• Prior exposure to anthracycline

• Patient has concomitant active malignancy that the treating physician or PI feels may interfere with the ability to measure the primary or secondary outcomes

  • Patients with a history of curative, surgically treated basal or squamous cell carcinoma or stage 1 melanoma of the skin or in situ carcinoma of the cervix are eligible.
  • Patients with a malignancy that has been treated with surgery alone with curative intent will also be excluded, unless the malignancy has been in documented remission without treatment for ≥ 3 years prior to enrollment.

• Patient is known to be HIV positive (test result not required for enrollment).

• History of solid organ transplantation, or post-transplant lymphoproliferative disorder

• Patient has history of allogeneic stem cell transplantation.

• History of, or clinically apparent central nervous system (CNS) lymphoma

• Any clinically significant abnormality in screening blood chemistry, hematology, or urinalysis results that, in the judgment of the investigator, would impede adequate evaluation of adverse events and/or response to treatment, or that requires aggressive intervention