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 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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Study Overview

• Status: Completed
• Conditions: Lymphomatoid Granulomatosis; Non-Hodgkins Lymphoma; Lymphoproliferative Disorder; Granulomatosis, Lymphomatoid
• Intervention / Treatment: Biological: Interferon; Procedure: Tumor biopsy; Procedure: Bone marrow biopsy; Biological: Bone marrow aspirate; Procedure: Lumber puncture; Diagnostic test: CT; Diagnostic test: Brain MRI; Diagnostic test: Echocardiogram; Diagnostic test: FDG-PET; Drug: Rituxan and EPOCH

Detailed Description

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 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.

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

Patients must have a tissue-diagnosis of grade 1, 2 and/or 3 lymphomatoid granulomatosis (LYG) (or a diagnosis consistent with LYG) confirmed by the Laboratory of Pathology, National Cancer Institute (NCI). Final histopathologic classification and pathologic grade will be determined by Stephania Pittaluga, medical doctor (M.D.) or her designee.

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 a history of coronary artery disease with angina pectoris, or a history of congestive heart failure will not be eligible to receive. etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) chemotherapy.

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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).	Biological: 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).; Other Names: IFN; Procedure: Tumor biopsy; Baseline (optional).; Other Names: Tumor bx; Procedure: Bone marrow biopsy; Baseline.; Other Names: BM biopsy; Biological: Bone marrow aspirate; Baseline.; Other Names: BM aspirate; Procedure: Lumber puncture; Baseline.; Other Names: LP; Diagnostic test: 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.; Other Names: Computed tomography; Diagnostic test: 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).; Other Names: Brain magnetic resonance imaging; Diagnostic test: Echocardiogram; For participants receiving > 450 mg/m^2 doxorubicin.; Other Names: Echo; Diagnostic test: 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 Names: Fluorodeoxyglucose positron emission tomography
Experimental: 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.	Procedure: Tumor biopsy; Baseline (optional).; Other Names: Tumor bx; Procedure: Bone marrow biopsy; Baseline.; Other Names: BM biopsy; Biological: Bone marrow aspirate; Baseline.; Other Names: BM aspirate; Procedure: Lumber puncture; Baseline.; Other Names: LP; Diagnostic test: 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.; Other Names: Computed tomography; Diagnostic test: 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).; Other Names: Brain magnetic resonance imaging; Diagnostic test: Echocardiogram; For participants receiving > 450 mg/m^2 doxorubicin.; Other Names: Echo; Diagnostic test: 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 Names: Fluorodeoxyglucose positron emission tomography; Drug: Rituxan and EPOCH; For lymphomatoid granulomatosis (LYG) Grade 3: EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) every 3 weeks for 6 cycles.; Other Names: Rituximab; etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Overall response rate will be classified as the following: complete remission (CR), partial remission (PR), disease progression or disease stabilization measured by the Response Criteria. CR is no evidence of active disease on restaging for at least 2 months duration. All lesions must have decreased by > 75%, be gallium or positron emission tomography (PET) negative (if obtained) and be stable for > 3 months without new lesions appearing. PR is 50% or greater decrease in the sum of the products of the diameters of all measurable lesions for at least one month. Disease progression is 25% or greater progression in the sum of the products of the diameter of any measurable lesion over one month or the appearance or any new lesion consistent with metastatic disease. Disease stabilization is no change in the sum of the products of the diameters of all measurable lesions over two months and no new lesions consistent with disease.	From study enrollment and throughout treatment, up to a maximum of 40 months for the 2 interferon groups and 8 months for the 2 EPOCH-R groups.
Progression Free Survival (PFS)	PFS is defined as the duration of time from the date of study enrollment until the date of disease relapse, disease progression, death, or last follow-up, whichever occurs first, using the Kaplan-Meier method. Response was assessed by the Lugano Classification Response Criteria for Non-Hodgkin lymphoma (NHL). Disease progression is defined as an increase of ≥ 50% from the product of the perpendicular diameter (PPD) nadir and an increase in longest transverse diameter of a lesion (LDi) or shortest axis perpendicular diameter (SDi) from nadir of >0.5 cm for lesions <2 cm or >1.0 cm for lesions >2 cm.	Assessed from date of study enrollment until time of disease relapse, disease progression, death, or last follow-up, whichever comes first, up to a maximum of 27 years for the 2 interferon groups and 20 years for the 2 EPOCH-R groups.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is defined as the time from treatment start date until date of death or date last known alive. The median OS will be determined and reported along with a 95% confidence interval.	Assessed from date of study enrollment until time of death or last follow-up, whichever comes first, up to a maximum of 27 years.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Toxicity Criteria (CTC v2.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Toxicity Criteria (CTC v2.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Adverse Events were monitored/assessed from the first study intervention, Study Day 1 of Cycle 1 through 30 days after the study agent (s) was/were administered, up to a maximum of 49 months.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Christopher J Melani, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 1995
• Primary Completion (Actual): January 17, 2025
• Study Completion (Actual): January 17, 2025

Study Registration Dates

• First Submitted: November 3, 1999
• First Submitted That Met QC Criteria: November 3, 1999
• First Posted (Estimated): November 4, 1999

Study Record Updates

• Last Update Posted (Actual): June 19, 2025
• Last Update Submitted That Met QC Criteria: June 9, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Immunosuppression; Lymphoma; Epstein-Barr Virus; Lymphoproliferative Disorder; Viral
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Precancerous Conditions; Lymphoma, B-Cell; Lymphoma; Lymphoproliferative Disorders; Lymphomatoid Granulomatosis; Antineoplastic Agents, Immunological; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Antirheumatic Agents; Antiviral Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Topoisomerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Rituximab; Prednisone; Cyclophosphamide; Etoposide; Doxorubicin; Vincristine; Interferons
• Other Study ID Numbers: 940074; 94-C-0074

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.
• IPD Sharing Time Frame: Clinical data will be available during the study and indefinitely.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No