Treatment and Natural History Study of Lymphomatoid Granulomatosis

This study will evaluate the response and long-term effects of alpha-interferon in patients with lymphomatoid granulomatosis (LYG). The disease causes proliferation of destructive cells involving the lungs, skin, kidneys, and central nervous system. Patients ages 12 and older who have LYG and who are not pregnant or breast feeding may be eligible for this study. Alpha interferon or chemotherapy, or both, will be used. Alpha interferon is a protein the body naturally produces. If patients have grade 3 disease, they will usually receive EPOCH-rituximab (EPOCH-R) chemotherapy (each letter representing a drug). If patients have grade 1 or 2 disease, the will usually receive alpha interferon. If patients have LYG after receiving alpha interferon and/or EPOCH-R, they may receive rituximab alone or with alpha interferon. Rituximab is an antibody, binding to a specific molecule (CD20) present on most B-cell lymphomas. Doses of several drugs in EPOCH-R may be increased if patients tolerated them in the previous cycle. If patients respond to EPOCH-R but still have low grade LYG, they may receive alpha interferon. Researchers will also try to obtain a biopsy of patients lesions, to help in understanding the disease. Patients self-administer alpha interferon by injection under the skin three times weekly. They will visit the clinic every 2 to 12 weeks for follow-up. Patients will receive alpha interferon for 1 year after LYG goes away, depending on response. EPOCH-R has these drugs: rituximab by vein on Day 1; prednisone by mouth on Days 1 to 5; etoposide, doxorubicin, and vincristine as a continuous intravenous infusion on Days 1 to 5; and cyclophosphamide by intravenous injection over 1 hour on Day 5. Each cycle lasts 3 weeks: 5 days of chemotherapy and 16 days of no chemotherapy. Etoposide, doxorubicin, and vincristine are infused through a small pump worn by patients. The drugs are given over 5 days through a central intravenous catheter. There are two cycles of EPOCH-R beyond a maximum response, with six cycles minimum. To reduce harm to bone marrow, patients receive granulocyte colony stimulating factor (G-CSF), self-administered by injection under the skin daily for approximately 10 days between chemotherapy cycles. If at the end of therapy, patients have a complete response, treatment will stop. If there is residual low grade disease, patients may receive alpha interferon. Alpha interferon can have flu-like side effects of headache, fever, chills, and body aches. EPOCH-R drugs can cause gastrointestinal problems, hair loss, and weakness. G-CSF can cause bone pain, body aches, and hair thinning. Chemotherapy can cause some patients to develop leukemia. This study may or may not have a direct benefit for participants. It is not certain whether the new therapy will help decrease tumors. However, knowledge gained may improve the understanding of and treatment for LYG.

BACKGROUND: Lymphomatoid granulomatosis (LYG) is an angiocentric destructive proliferation of lymphoid cells predominantly involving the lungs, skin, kidneys, and central nervous system. It is divided into three grades, depending on the degree of necrosis and cellular atypia. The grades of disease are histologically-based and do not necessarily correlate with clinical outcome. However, like other EBV related LPD's, LYG can transform into an aggressive large B-cell lymphoma, which would be included within the grade 3 category. It is important to note that not all grade 3 lesions are a large B-cell lymphoma. Current evidence shows that LYG is a disease of B cells. OBJECTIVES: To determine the response and long-term efficacy of alpha-Interferon in patients with lymphomatoid granulomatosis (LYG). To determine the response and long-term efficacy of dose-adjusted (DA)-EPOCH-R chemotherapy in patients with grade 3 LYG or in patients who have failed interferon. ELIGIBILITY: Patients must have a tissue diagnosis of grade 1, 2 and/or 3 LYG (or a diagnosis consistent with LYG) confirmed by the Laboratory of Pathology, NCI. Patients with any stage of disease will be eligible. Previously untreated and treated patients are eligible. Patients age 12 or older will be eligible. DESIGN: Interferon is used as initial treatment in patients with grades 1 and 2 LYG . Patients will receive interferon for one year past CR. Patients who progress after or during interferon, and patients with grade 3 LYG will receive aggressive combination chemotherapy with DA-EPOCH-R (rituximab, etoposide, doxorubicin, vincristine, cyclophosphamide and prednisone). Patients who fail one treatment approach may be crossed over to the other. A total of 105 patients will be enrolled at this single institution.

Lymphomatoid Granulomatosis, Granulomatosis, Lymphomatoid, Non-Hodgkins Lymphoma, Lymphoproliferative Disorder

Interferon starting at 7.5 million Units subQ 3 times a week and increasing on the designated schedule, as tolerated. Patients continue taking interferon for 1 year beyond CR. Patients who progress may crossover to receive EPOCH-R.

For LYG Grade 1 and 2: Interferon starting at 7.5 million Units subQ 3 times a week and increasing on the following schedule: 10 million U; 15 million U; 20 million U; 25 million U; and increased in 5 million U increments, as tolerated. Patients continue taking interferon for 1 year beyond CR.

For LYG Grade 3: EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituxan) every 3 weeks for 6 cycles.

Overall response will be classified as the following: complete remission, partial remission, disease progression or disease stabilization.

Post treatment: every 3 months x 1 year, then every 4 months x 1 year, then every 6 months x 1 year then yearly

INCLUSION CRITERIA: Patients must have a tissue-diagnosis of grade 1, 2 and/or 3 LYG (or a diagnosis consistent with LYG) confirmed by the Laboratory of Pathology, NCI. Final histopathologic classification and pathologic grade will be determined by Stephania Pittaluga, M.D. or her designee. Patients with any stage of disease will be eligible. Previously untreated and treated patients are eligible. Patients age 12 or older will be eligible. EXCLUSION CRITERIA: Patients with a history of coronary artery disease with angina pectoris, or a history of congestive heart failure will not be eligible to receive. DA-Epoch-R chemotherapy. Patients with significant renal (Cr. greater than 1.5 mg/dl or creatinine less than 40 cc/min) or hepatic (bilirubin greater than 2.5 u) dysfunction not due to tumor involvement will not be eligible to receive DA-EPOCH-R chemotherapy. Informed consent must be obtained. Patients who in the opinion of the principle investigator are poor psychiatric or medical risk are not eligible. Patients who received > 450 mg/m2 doxorubicin and have a cardiac ejection fraction on echocardiogram less than or equal to 40% on protocol entry are not eligible to received DA-EPOCH-R. Patients with prior hepatitis B exposure may be included in the study provided that they have HBV DNA levels below the World Health Organization s cutoff of 100 IU/mL prior to starting therapy.

Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.