The goal of this clinical research study is to find out if the study drug, ONTAK (denileukin diftitox), can shrink or slow the growth of B-cell non-Hodgkin's lymphoma (NHL) in patients whose disease has not responded to prior treatments, or has relapsed after an initial response to prior treatments. The safety of treatment with ONTAK will also be studied. The hypothesis is that patients with relapsed or refractory B-cell NHL and mild to moderate myelosuppression treated with ONTAK at a new dosing regimen will respond sufficiently to warrant further study.

Inclusion Criteria:

• Relapsed or refractory B-Cell NHL
• Histological documentation of diffuse large B-cell lymphoma, follicular lymphoma (grade 1, 2, or 3), small lymphocytic lymphoma or transformed B-Cell lymphoma.
• Bi-dimensionally measurable disease with at least one lymph node or tumor mass measuring > or equal to 4 cm2
• ECOG performance status less than or equal to 2.
• Failure to respond or progression of disease after 2 or more prior treatment regimens; this may include high dose therapy (HDT) with stem cell transplantation (SCT). Patients with prior HDT plus SCT will be considered as having "diminished bone marrow reserve"
• At least 18 years of age
• At least 3 weeks from last anti-lymphoma therapy
• Mild to moderate cytopenia defined as any of the following:
• ANC > or equal to 1,000/microL and < 1,500/microL off growth factors
• WBC counts > or equal to 2,000/microL and < 4,000/microL off growth factors or
• Platelet count > or equal to 40,000/microL (25,000/microL if thrombocytopenia is secondary to marrow involvement by lymphoma) and < 150,000/microL.
• Acceptable organ function defined as all of the following:
• Bilirubin < or equal to 1.5 times the upper limit of normal (ULN)
• SGOT (AST) and SGPT (ALT) < or equal to 2 times the ULN.
• Serum creatinine < 2 times ULN.
• Serum albumin > or equal to 3.0 g/dL
• Female patient of childbearing potential must have a negative pregnancy test within seven days prior to study drug administration, and must agree to use an effective means of contraception throughout the study.
• Life expectancy of at least 16 weeks.
• Patients must have reviewed, signed and dated a witnessed informed consent document that has been approved by the IRB of each participating center.

Exclusion Criteria:

• Less than 6 months from prior allogeneic stem cell transplant and/or patient with active graft versus host disease (GVHD) Grade > or equal to 2.
• Prior history of veno-occlusive disease of the liver.
• Inability to comply with protocol requirements of this study for intravenous administration of ONTAK.
• Pregnant women or lactating women who are breastfeeding or women planning to become pregnant during the treatment period.
• Serious intercurrent medical illnesses or active infections that, in the investigators opinion, might interfere with the interpretation of the study safety data or compromise the patients ability to carry out the treatment program.
• Known history of seropositivity for HIV or chronic hepatitis (testing for HIV is not required).
• Known hypersensitivity to ONTAK or any of its components: diptheria toxin, interleukin-2 or excipients.
• Experimental therapy within 4 weeks prior to study entry.
• Patients diagnosed with congestive heart failure, NYHA Class III or IV, ventricular tachycardia, fibrillation, or a history of myocardial infarction in the 12 months prior to study entry.
• Any prior radiation therapy within four weeks of enrollment, or prior radiation therapy to the only site of evaluable disease unless disease progression has occurred in that site.
• Patients on concurrent corticosteroids as treatment for NHL. The use of tapering doses or low doses of corticosteroids for resolving GVHD, or the use of corticosteroids as premedication prior to ONTAK or as a transient treatment for hypersensitivity reactions is permitted as necessary.
• History of prior malignancy within the preceding 5 years, except for successfully treated cervical carcinoma in situ or basal cell carcinoma.