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NCT Number: NCT00001379

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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Key information

Conditions

Lymphomatoid Granulomatosis DNA Virus Infections Epstein-Barr Virus Infections Granulomatosis, Lymphomatoid Hemic and Lymphatic Diseases Herpesviridae Infections Immune System Diseases Immunoproliferative Disorders Infections Lymphatic Diseases Lymphoma Lymphoma, B-Cell Lymphoma, Non-Hodgkin Lymphoproliferative Disorder Lymphoproliferative Disorders Neoplasms Neoplasms by Histologic Type Non-Hodgkins Lymphoma Precancerous Conditions Tumor Virus Infections Virus Diseases

Age range

12 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

  • 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.

Treatment and study plan

Interferon

Biological

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

Rituxan and EPOCH

Drug

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

Tumor Biopsy

Procedure

Baseline (optional).

Other names: Tumor bx

Bone Marrow Biopsy

Procedure

Baseline.

Other names: BM biopsy

Bone marrow aspirate

Biological

Baseline.

Other names: BM aspirate

Lumber puncture

Procedure

Baseline.

Other names: LP

CT

Diagnostic Test

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

Brain MRI

Diagnostic Test

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

Echocardiogram

Diagnostic Test

For participants receiving > 450 mg/m^2 doxorubicin.

Other names: Echo

FDG-PET

Diagnostic Test

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

Primary outcomes

  1. Overall Response Rate (ORR)

    Time frame: 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.

    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.

  2. Progression Free Survival (PFS)

    Time frame: 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.

    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.

Secondary outcomes

  1. Overall Survival (OS)

    Time frame: Assessed from date of study enrollment until time of death or last follow-up, whichever comes first, up to a maximum of 27 years.

    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.

Other outcomes

  1. Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Toxicity Criteria (CTC v2.0)

    Time frame: 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.

    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.

Sponsors and collaborators

Lead sponsor

National Cancer Institute (NCI)

Nih

Registry information

Important dates

Study start
1995
Primary completion
2025
Study completion
2025
First posted
Nov 4, 1999
Registry last updated
Jun 19, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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