This is a single-arm, Phase II study designed to enroll and treat up to 64 patients. All patients in this study will receive ofatumumab and bendamustine as an IV infusion for 6 cycles (a cycle is defined as 21 days in length). Patients will receive as an IV infusion bendamustine Days 1 and 2 of Cycles 1 through 6 and ofatumumab Days 1 and 8 during Cycle 1 only and on Day 1 of Cycles 2 through 6.

While R-CHOP has improved survival and is considered standard of care for patients with DLBCL, the toxicities associated with R-CHOP are substantial in the elderly population. This is one of several reasons the outcome of older patients is worse than the corresponding younger patients. Bendamustine is an alkylating agent which causes intra- and inter-strand cross-links between DNA bases. Ofatumumab is a fully human anti-CD 20 antibody well tolerated by elderly patients. Ofatumumab targets a novel epitope of the CD20 molecule on B cells and remains on the cell surface twice as long as rituximab. The combination of both agents allows for a potentially efficacious, less toxic regimen.

Inclusion Criteria:

1. Histologically confirmed CD20-positive DLBCL.

2. Newly diagnosed, stage III-IV DLBCL considered poor candidates for R-CHOP.

3. Age >=70 years

4. At least one of the following criteria:

   • ECOG PS 2
   • Cardiac compromise precluding anthracycline therapy
   • Previous anthracycline therapy for other malignancy precluding further anthracycline therapy.
   • Severe coexisting medical problems
   • General frailty

5. ECOG 0-2

6. Measurable disease with at least one bidimensional lymph node or tumor mass >1.5 cm in the longest diameter that can be followed for response as a target lesion as measured by CT

7. Patients must be HBV sAg and HBV cAb negative within 6 weeks of screening.

8. Patient must understand and voluntarily sign the IRB-approved informed consent.

9. Life expectancy >= 3 months

10. Laboratory parameters:

    • Absolute neutrophil count >=1,000 cells/mm3
    • Platelet count >=75,000 cells/mm3
    • Hemoglobin >=8 g/dL
    • Creatinine <=2.0 mg/dL or Creatinine Clearance >= 40 mL/min (calculated or 24 hour urine sample)
    • AST/SGOT <=2.0 x ULN (<=5.0 x ULN if secondary to lymphoma)
    • ALT/SGPT <=2.0 x ULN (<=5.0 x ULN if secondary to lymphoma)
    • Bilirubin level of <2.0 mg/dL unless secondary to Gilbert's disease (or pattern consistent with Gilbert's)

Exclusion Criteria:

1. Patients with active/symptomatic central nervous system (CNS) involvement based on clinical evaluation by lumbar puncture, PET, CT or MRI.
2. Known sensitivity to bendamustine or any component of bendamustine.
3. Known anaphylaxis or sensitivity to ofatumumab.
4. Major surgery within 28 days of Cycle 1, Day 1. Patients undergoing minor surgery within 7 days of Cycle 1, Day 1. (no wait needed for port placement)
5. Prior chemotherapy, immunotherapy, or irradiation for lymphoma.
6. Prior use of investigational anti-cancer agents for lymphoma.
7. HIV-related lymphoma.
8. Known active HIV or HCV infection, or known seropositivity for HIV, or current or chronic HBV or HCV infection. HBV test required at screening or a negative result within 6 weeks of screening.
9. Concurrent active or history of other malignancies, except non-melanoma skin cancer or carcinoma in situ of cervix or breast. Patients with previous malignancies are eligible provided they have been treated with curative intent and disease free for >= 1 year.
10. Serious (grade 3-4), active, intercurrent infection requiring therapy, or deep seated or systemic mycotic infections.
11. Myocardial infarction within 6 months prior to registration or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or significant conduction system abnormalities, in the judgment of the Investigator.
12. Concurrent uncontrolled serious medical or psychiatric conditions likely to interfere with participation in this clinical study, in the judgment of the Investigator
13. Patients who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
14. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study.
15. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.
16. Male patients unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.