Treatment and Natural History Study of Lymphomatoid Granulomatosis
NCT ID: NCT00001379
Last Updated: 2025-06-19
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE2
94 participants
INTERVENTIONAL
1995-05-05
2025-01-17
Brief Summary
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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 etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH)-rituximab (EPOCH-R) chemotherapy (each letter representing a drug). If patients have grade 1 or 2 disease, they 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 cluster of differentiation 20 (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 patient's 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 maximum. 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. Granulocyte colony-stimulating factor (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.
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Detailed Description
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* 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 Epstein-Barr virus (EBV) related lymphoproliferative disorders (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)-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin rituximab (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, National Cancer Institute (NCI).
* Patients with any stage of disease will be eligible.
* Previously untreated and treated patients are eligible.
* Patients aged 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 complete remission (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.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Arm 1-Interferon
Interferon starting at 7.5 million Units subcutaneous (subQ) 3 times a week and increasing on the designated schedule, as tolerated. Patients continue taking interferon for 1 year beyond complete remission (CR). Patients who progress may crossover to receive etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R).
Interferon
For lymphomatoid granulomatosis (LYG) Grade 1 and 2: Interferon starting at 7.5 million Units subcutaneous (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 complete remission (CR).
Tumor biopsy
Baseline (optional).
Bone marrow biopsy
Baseline.
Bone marrow aspirate
Baseline.
Lumber puncture
Baseline.
CT
Arm 1: At baseline, then every 4 weeks until on stable dose of interferon or a maximum of 6 monthly scans, then every 3 months while receiving interferon, and following completion of interferon. In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years. Arm 2: At baseline, following cycle 4, and following cycle 6 of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years.
Brain MRI
Arm 1: At baseline, then every 4 weeks until on stable dose of interferon or a maximum of 6 monthly scans, then every 3 months while receiving interferon, and following completion of interferon. In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years (patients with central nervous system (CNS) disease only).
Arm 2: At baseline, following cycle 4, and following cycle 6 of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years (patients with CNS disease only).
Echocardiogram
For participants receiving \> 450 mg/m\^2 doxorubicin.
FDG-PET
Arm 1: Baseline and following completion of interferon. Arm 2: Baseline and following completion of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R).
Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)
Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R) every 3 weeks for up to 6 cycles, based on response. Participants who relapse or progress may crossover to receive interferon.
Rituxan and EPOCH
For lymphomatoid granulomatosis (LYG) Grade 3: EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) every 3 weeks for 6 cycles.
Tumor biopsy
Baseline (optional).
Bone marrow biopsy
Baseline.
Bone marrow aspirate
Baseline.
Lumber puncture
Baseline.
CT
Arm 1: At baseline, then every 4 weeks until on stable dose of interferon or a maximum of 6 monthly scans, then every 3 months while receiving interferon, and following completion of interferon. In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years. Arm 2: At baseline, following cycle 4, and following cycle 6 of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years.
Brain MRI
Arm 1: At baseline, then every 4 weeks until on stable dose of interferon or a maximum of 6 monthly scans, then every 3 months while receiving interferon, and following completion of interferon. In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years (patients with central nervous system (CNS) disease only).
Arm 2: At baseline, following cycle 4, and following cycle 6 of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years (patients with CNS disease only).
Echocardiogram
For participants receiving \> 450 mg/m\^2 doxorubicin.
FDG-PET
Arm 1: Baseline and following completion of interferon. Arm 2: Baseline and following completion of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R).
Interventions
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Interferon
For lymphomatoid granulomatosis (LYG) Grade 1 and 2: Interferon starting at 7.5 million Units subcutaneous (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 complete remission (CR).
Rituxan and EPOCH
For lymphomatoid granulomatosis (LYG) Grade 3: EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) every 3 weeks for 6 cycles.
Tumor biopsy
Baseline (optional).
Bone marrow biopsy
Baseline.
Bone marrow aspirate
Baseline.
Lumber puncture
Baseline.
CT
Arm 1: At baseline, then every 4 weeks until on stable dose of interferon or a maximum of 6 monthly scans, then every 3 months while receiving interferon, and following completion of interferon. In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years. Arm 2: At baseline, following cycle 4, and following cycle 6 of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years.
Brain MRI
Arm 1: At baseline, then every 4 weeks until on stable dose of interferon or a maximum of 6 monthly scans, then every 3 months while receiving interferon, and following completion of interferon. In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years (patients with central nervous system (CNS) disease only).
Arm 2: At baseline, following cycle 4, and following cycle 6 of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years (patients with CNS disease only).
Echocardiogram
For participants receiving \> 450 mg/m\^2 doxorubicin.
FDG-PET
Arm 1: Baseline and following completion of interferon. Arm 2: Baseline and following completion of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R).
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
Patients with any stage of disease will be eligible.
Previously untreated and treated patients are eligible.
Patients aged 12 or older will be eligible.
Exclusion Criteria
Patients with significant renal (serum creatinine (Cr.) greater than 1.5 mg/dl or creatinine clearance less than 40 cc/min) or hepatic (bilirubin greater than 2.5 x upper limit of normal (ULN) 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 principal investigator are poor psychiatric or medical risk are not eligible.
Patients who received \> 450 mg/m\^2 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 hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels below the World Health Organizations cutoff of 100 IU/mL prior to starting therapy.
12 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
Responsible Party
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Christopher Melani, MD
Principal Investigator
Principal Investigators
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Christopher J Melani, M.D.
Role: PRINCIPAL_INVESTIGATOR
National Cancer Institute (NCI)
Locations
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National Institutes of Health Clinical Center
Bethesda, Maryland, United States
Countries
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References
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Melani C, Dowdell K, Pittaluga S, Dunleavy K, Roschewski M, Song JY, Calattini S, Kawada JI, Price DA, Chattopadhyay PK, Roederer M, Lucas AN, Steinberg SM, Jaffe ES, Cohen JI, Wilson WH. Interferon alfa-2b in patients with low-grade lymphomatoid granulomatosis and chemotherapy with DA-EPOCH-R in patients with high-grade lymphomatoid granulomatosis: an open-label, single-centre, phase 2 trial. Lancet Haematol. 2023 May;10(5):e346-e358. doi: 10.1016/S2352-3026(23)00029-7. Epub 2023 Mar 31.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form
Related Links
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NIH Clinical Center Detailed Web Page
Other Identifiers
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94-C-0074
Identifier Type: -
Identifier Source: secondary_id
940074
Identifier Type: -
Identifier Source: org_study_id
NCT00018993
Identifier Type: -
Identifier Source: nct_alias
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