The purpose of the research study is to learn whether external beam radiation can be used as a safe and effective treatment for patients with bulky (≥ 5cm) sites of non-Hodgkin's lymphoma prior to treatment with 90Y-ibritumomab tiuxetan (Zevalin).

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoid malignancies that represent the 6th leading cause of cancer death and the 2nd fastest growing cancer in the United States. NHLs can be divided into two prognostic groups: aggressive and indolent lymphomas. Aggressive NHLs grow rapidly and present as disseminated disease in 70% of cases, yet can be cured in a significant number of patients with intensive combination chemotherapy regimens. Indolent (low-grade) NHLs are slow growing malignancies with long natural histories that are incurable when disseminated. Early stage low-grade NHL (stage I and II) has the potential for cure with radiotherapy, but only 10-20% of patients with low-grade NHL present with early stage disease. The vast majority of patients with low-grade NHL present with advanced disseminated disease. While indolent B-cell NHLs have initial sensitivity to chemotherapy and radiotherapy, they frequently relapse and become increasingly resistant to therapy with each successive relapse, eventually transforming to aggressive lymphomas in most patients. Fifty percent of patients presenting with advanced indolent NHL die within 5 years of their first relapse. Only modest improvement has been made in the last 25 years in increasing the survival of patients with indolent NHL with current median survival of 7-10 years.

Recent advances in the field of immunotherapy have proved to benefit patients with relapsed or refractory B-cell NHL. In 1997, rituximab became the first FDA-approved monoclonal antibody (mAb) for the treatment of cancer. Rituximab, a chimeric IgG1 kappa monoclonal antibody, specifically recognizes and binds to the CD20 antigen found on the cell surface of most normal B-cells and malignant B-cell lymphomas. Rituximab binds human complement and lyses B-cell lines through complement dependent cytotoxicity and antibody dependent cellular toxicity. A multi-center Phase II trial of 166 patients with relapsed indolent B-cell lymphoma treated with rituximab found an overall response in 50% of patients with 6% having a complete response and 44% having a partial response. Time to progression was a median of 13 months in patients who responded.

The introduction of radioimmunotherapy (RIT) has exploited the tumor cell targeting ability of mAbs to deliver doses of radiation to the tumor and limited surrounding tissue. This is especially useful in the treatment of NHL because lymphomas are highly sensitive to radiotherapy. 90Yttrium-ibritumomab tiuxetan (Zevalin) is a unique compound composed of the murine IgG1 anti-CD20 antibody ibritumomab, the linker chelator tiuxetan, and the radioisotope 90Y chelated via the linker. 90Y-ibritumomab tiuxetan can be described as providing a double hit therapeutic approach by having the CD20+ antibody properties of rituximab combined with radiation therapy.

90Yttrium-ibritumomab tiuxetan appears to be effective in the treatment of patients refractory to treatment with rituximab, but response rates decrease with increasing tumor size. 90Y-ibritumomab tiuxetan was approved by the FDA in 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or CD20+ transformed B-cell non-Hodgkin's lymphoma (NHL), and rituximab-refractory follicular NHL.

A preliminary survey of 20 patients treated with 90Y-ibritumomab tiuxetan at the Cleveland Clinic Foundation from 1998-2003 detailed patterns of NHL recurrence after treatment. The results of this survey were presented in part by Dr. Macklis at the 2004 annual meeting of the American Society of Therapeutic Radiation Oncology (ASTRO) in Atlanta and recently accepted for publication in the International Journal of Radiation Oncology, Biology, Physics. Based on preliminary data, a hypothesis can be made that some likely sites of disease recurrence/progression after RIT can be predicted by the volume of disease at a specific site prior to RIT. In short, pre-RIT bulky sites of disease are the most likely locations of disease recurrence after RIT followed by gross, but non-bulky, pre-RIT sites followed by entirely new sites. Based on this hypothesis, it might be beneficial to pre-treat bulky sites of NHL with external beam radiotherapy prior to RIT in order to promote a more durable response. Doses of external beam radiation required to consolidate these bulky disease sites are unclear.

In this study, we plan to utilize a dose of EBRT of 2,400cGy to bulky sites of disease followed by RIT. Though the combined effects of 2,400cGy of EBRT and RIT are likely to be well tolerated, such a combination has not been sufficiently studied. Therefore, the primary goal of this study is to determine if the combination of EBRT and RIT has an acceptable toxicity profile with regard to long-term myelosuppression and other non-hematological toxicities.

Inclusion Criteria:

• B-cell non-Hodgkin's lymphoma of one of the following types as defined by the WHO classification:
• Small lymphocytic lymphoma/Chronic lymphocytic leukemia
• Nodal marginal zone B-cell lymphoma
• Extranodal marginal zone B-cell lymphoma
• Splenic marginal zone lymphoma
• Lymphoplasmacytic lymphoma
• Follicular lymphoma
• Diffuse large B-cell lymphoma which has transformed from one of the previously listed types of lymphomas
• At least one site of lymphoma greater than or equal to 5 cm in any dimension
• Received at least one prior therapy
• Should show evidence of symptomatology as a result of their disease and/or evidence of progression of their disease.
• Measurable disease using Cheson criteria [23] for Non-Hodgkin's Lymphoma: a lymph node that is greater than 1 cm in its longest transverse diameter by CT scan should be considered compatible with involvement by NHL
• No anti-cancer therapy for four weeks (six weeks if rituximab, nitrosourea or Mitomycin C) prior to study initiation, and fully recovered from all toxicities associated with prior surgery, radiation treatments, chemotherapy, or immunotherapy
• An IRB-approved signed informed consent
• Age greater than or equal to 18
• Expected survival greater than or equal to 3 months
• Prestudy performance status of 0, 1, or 2 according to WHO
• Absolute neutrophil count ([segmented neutrophils + bands] x total WBC) > 1500/mm3 within two weeks prior to first dose of external beam radiation and also documented again two weeks prior to 90Y-ibritumomab tiuxetan treatment
• Platelet counts greater than or equal to 100,000 within two weeks prior to first dose of external beam radiation and also documented again two weeks prior to 90Y-ibritumomab tiuxetan treatment
• Bone marrow involvement by NHL less than 26% within six weeks of treatment with 90Y-ibritumomab tiuxetan
• Cellularity of bone marrow > 15% within 6 weeks of study
• Female patients who are not pregnant or lactating
• Men and women of reproductive potential who are following accepted birth control methods (as determined by the treating physician, abstinence is an acceptable method)

Exclusion Criteria:

• Prior radioimmunotherapy
• Presence of CNS lymphoma
• Absolute lymphocyte count ≥ 5000
• HIV or AIDS-related lymphoma
• Large pleural effusions or ascites
• Total bilirubin > 2.0 mg/dL
• Serum creatinine > 2.0 mg/dL
• Patients who, in the opinion of their oncology team, have prior external beam radiation therapy to > 25% of active skeletal marrow (either involved field or regional)
• Patients who have received G-CSF or GM-CSF therapy within two weeks or pegfilgrastim within 4 weeks prior to treatment
• Serious nonmalignant disease or infection which, in the opinion of the investigator, would compromise other protocol objectives
• Major surgery, other than diagnostic surgery, within four weeks
• Pregnant women or women of child-bearing age who refuse pregnancy tests
• Patients who have had prior myeloablative autologous or allogenic stem cell transplantation