Conditions: Lymphomatoid Granulomatosis Granulomatosis, Lymphomatoid Non-Hodgkins Lymphoma Lymphoproliferative Disorder
Keywords: Epstein-Barr Virus Lymphoproliferative Disorder Viral Immunosuppression Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 94
Healthy volunteers: no

Brief summary:
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.

...

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.

Arms:
arm 1: 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). arm 2: 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.

Interventions: intervention 1: Interferon intervention 2: Rituxan and EPOCH intervention 3: Tumor biopsy intervention 4: Bone marrow biopsy intervention 5: Bone marrow aspirate intervention 6: Lumber puncture intervention 7: CT intervention 8: Brain MRI intervention 9: Echocardiogram intervention 10: FDG-PET
Intervention descriptions: intervention 1: 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). intervention 2: For lymphomatoid granulomatosis (LYG) Grade 3: EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) every 3 weeks for 6 cycles. intervention 3: Baseline (optional). intervention 4: Baseline. intervention 5: Baseline. intervention 6: Baseline. intervention 7: 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. intervention 8: 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). intervention 9: For participants receiving \> 450 mg/m\^2 doxorubicin. intervention 10: 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).

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title:  Treatment and Nat. Hx. LYG
Version Date:  01/27/2021
1
Abbreviated Title: Treatment and Nat. Hx. LYG 
NIH Protocol #: 94-C-0074 
Version Date: 01/27/2021
NCT Number: NCT00001379
Treatment and Natural History Study of Lymphomatoid Granulomatosis
NCI Principal Investigator: Christopher Melani, M.D.
Lymphoid Malignancies Branch (LYMB) 
Center for Cancer Research (CCR)
National Cancer Institute (NCI)
National Institutes of Health (NIH)
Building 10, Room 4N115
9000 Rockville Pike
Bethesda, MD  20892
Phone: 240-760-6057
Email:  christopher.melani@nih.gov 
Investigational Agents:  None
Commercial Agents: 
alpha-Interferon
EPOCH-R = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab


Abbreviated Title:  Treatment and Nat. Hx. LYG
Version Date:  01/27/2021
2
PRECIS
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.


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TABLE OF CONTENTS 
PRECIS............................................................................................................................................2
TABLE OF CONTENTS ................................................................................................................3
STATEMENT OF COMPLIANCE ................................................................................................6
1
INTRODUCTION....................................................................................................................6
1.1
Objectives..........................................................................................................................6
1.2
Background and Rationale................................................................................................6
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT ..........................................................9
2.1
Eligibility Criteria .............................................................................................................9
2.2
Recruitment Strategies ......................................................................................................9
2.3
Screening Evaluation ........................................................................................................9
2.4
Participant Registration and Status Update Procedures..................................................10
2.5
Baseline Evaluation.........................................................................................................11
3
STUDY IMPLEMENTATION..............................................................................................12
3.1
Treatment with Alpha Interferon ....................................................................................12
3.2
Treatment with DA-EPOCH-R.......................................................................................12
3.3
Progression while on Treatment .....................................................................................13
3.4
Dose Adjustments ...........................................................................................................13
3.5
Hematologic Dose-Adjustment Paradigm ......................................................................13
3.6
Neurologic and Hepatic dose adjustment paradigm .......................................................14
3.7
Studies During and After Therapy..................................................................................15
3.8
Cost and Compensation ..................................................................................................16
3.9
Criteria for Removal from Protocol Therapy and Off Study Criteria.............................17
4
CONCOMITANT MEDICATIONS/MEASURES ...............................................................17
4.1
Prophylaxis of Pneumocystis Jiroveci (formerly pneumocystis carinii) ........................17
4.2
CNS Treatment Guidelines .............................................................................................17
4.3
Monitoring and Treatment to PreventHepatitis B Reactivation......................................18
5
CORRELATIVE STUDIES FOR RESEARCH ....................................................................19
5.1
Summary .........................................................................................................................19
5.2
Blood sample collection and processing.........................................................................19
5.3
TUMOR BIOPSY SAMPLES........................................................................................20
5.4
Sample Storage, Tracking and Disposition.....................................................................21
6
DATA COLLECTION AND EVALUATION ......................................................................22


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6.1
Data Collection ...............................................................................................................22
6.2
Response Criteria ............................................................................................................23
6.3
Toxicity Criteria..............................................................................................................24
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .....24
7.1
Definitions.......................................................................................................................24
7.2
OHSRP Office of Compliance and Training / IRB Reporting........................................24
7.3
NCI Clinical Director Reporting.....................................................................................24
7.4
NIH Required Data and Safety Monitoring Plan............................................................24
8
STATISTICAL CONSIDERATIONS...................................................................................25
9
COLLABORATIVE AGREEMENTS...................................................................................26
10
HUMAN SUBJECTS PROTECTIONS.............................................................................26
10.1
Rationale for Subject Selection ...................................................................................26
10.2
Participation of Children .............................................................................................26
10.3
Participation of Subjects Unable to Give Consent ......................................................26
10.4
Evaluation of Benefits and Risks/Discomforts: ..........................................................26
10.5
Consent and Assent Process and Documentation........................................................28
11
REGULATORY AND OPERATIONAL CONSIDERATIONS.......................................29
11.1
Study Discontinuation and Closure.............................................................................29
11.2
Quality Assurance and Quality Control ......................................................................30
11.3
Conflict of Interest Policy ...........................................................................................30
11.4
Confidentiality and Privacy.........................................................................................30
12
PHARMACEUTICAL INFORMATION ..........................................................................31
12.1
Interferon Alpha 2-B ...................................................................................................31
12.2
Cyclophosphamide ......................................................................................................31
12.3
Doxorubicin.................................................................................................................32
12.4
Vincristine ...................................................................................................................32
12.5
Etoposide.....................................................................................................................33
12.6
Administration of Vincristine/Doxorubicin/Etoposide ...............................................33
12.7
Prednisone ...................................................................................................................33
12.8
Filgrastim.....................................................................................................................34
12.9
Methotrexate................................................................................................................34
12.10
Cytarabine ...................................................................................................................34
12.11
Rituximab ....................................................................................................................35


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12.12
Trimethoprim/Sulfamethoxazole.................................................................................37
13
REFERENCES ...................................................................................................................37
14
APPENDIX 1:  EPOCH ADMIXTURES: PREPARATION AND ADMINISTRATION
39


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6
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.
1
INTRODUCTION
1.1
OBJECTIVES
1.1.1
Primary Objective

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 DA-EPOCH-R chemotherapy in 
patients with grade 3 LYG or in patients who have failed interferon
1.1.2
Secondary Objective

To obtain tissue and blood to examine the immunologic phenotype, EBV viral loads and 
molecular markers of clonality in patients with LYG

To assess overall survival (OS)
1.2
BACKGROUND AND RATIONALE
Lymphomatoid granulomatosis (LYG) is an angiocentric destructive proliferation of lymphoid 
cells predominantly involving the lungs, skin, kidneys, and central nervous system (1).  Although 
the disease has been considered to be a reactive or vasculitic disease and not a neoplastic 
process, the 5-year survival of the initial series of patients was less than 50% with the use of 
corticosteroids and other conservative treatment approaches. Lethal midline granuloma (LMG) 
or midline malignant reticulosis is another angiocentric destructive lymphoproliferative process 
usually involving the sinuses or upper respiratory tract (2).  Some 10 years ago DeRemee, et al. 
noted similarities between LYG and LMG and hypothesized that they were the same disease 
(3).  Jaffe proposed a common pathological description for both lesions, and called them 
angiocentric immunoproliferative lesions (AIL) (4).
Clinical experience with AIL has identified a spectrum of natural histories for the disease and 
recently, histopathological correlations have emerged (5,6).  Cytologic and architectural features, 
based on the degree of cell atypia, extent of the inflammatory background and cellular necrosis, 


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have been used to divide AIL into three histological grades (6).  Grade I lesions are composed of 
angiocentric infiltrates of lymphocytes, plasma cells, and histiocytes with or without 
eosinophils.  Large lymphoid cells are rare and when present show no cellular atypia.  Necrosis 
is uncommon and the lymphocytes are nearly normal in appearance.  In grade II lesions, 
cytologic atypia of the small infiltrating lymphocytes is more prominent, large lymphoid cells 
without atypia are common, and necrosis is frequently present.  Grade III lesions are actual 
angiocentric lymphomas based on the monomorphism of the infiltrate, cytologic atypia in both 
the small and large lymphocytes, appreciable necrosis, and significantly less apparent 
background polymorphous inflammatory infiltrate.
Immunophenotypic examination of AIL shows the predominant cell to be a mature, post-thymic 
T cell with CD4 expressed on the cell surface.  In grade I and II lesions, clonal rearrangement of 
the T-cell receptor gene is essentially never seen, and has only rarely been reported in grade III 
lesions (6,7).  The lack of clonal T-cell gene rearrangements in grade III lesions is paradoxical 
because cytologically, they are malignant T-cell lymphomas.  A number of explanations have 
been proposed for this, including hypotheses that the malignant T-cells may have rearrangements 
of some other, as yet unidentified, T-cell receptor, or that the truly malignant cells comprise a 
small percentage of the total cellular infiltrate.  However, analyses of EBV in biopsies suggest 
that it may play a role in the progression of grade I and II to grade III AIL (malignant 
lymphoma) (8).  In biopsies from 7 patients with grade I and II AIL, EBV-positive cells were 
rare or absent, while all 5 patients with grade III AIL had large numbers of cells containing EBV 
RNA.  Furthermore, EBV was clonally integrated in two patients in whom it was checked (7).   
More recently, there is evidence that LMG and LYG are patho-physiologically distinct diseases 
which involve different cell types.  In LMG, immunohistochemical analysis shows expression of 
peripheral T cell antigens with occasionally coexpression of the natural killer (NK) cell marker, 
CD56 in the malignant cells (9).  This disease is now felt to be a T-cell lymphoma derived from 
peripheral T cells expressing gamma-delta chains or from NK cells.  In contrast, there is 
evidence that LYG is a disease of B cells.  Immunohistochemical and PCR analysis of biopsies 
from 3 patients with LYG demonstrated that EBV was integrated into B-cells but not the T-cells, 
suggesting that LYG is an EBV-positive B cell lymphoproliferative disorder (Jaffe, unpublished 
observation).  
Jaffe, et al. examined the clinical course of patients presenting to the National Institutes of 
Health with AIL of various histologic grades (6).  Patients with grade I/II lesions were usually 
managed with cyclophosphamide/ prednisone, and patients with grade III lesions were treated 
with aggressive combination chemotherapy.  Twenty-three patients were included in this report, 
nine with grade I, six with grade II, and eight with grade III lesions.  The eight patients with 
grade III lesions were further categorized according to the Working Formulation for lymphomas: 
six diffuse mixed (DML), one diffuse large cell (DL), and one diffuse large cell immunoblastic 
(IBL).  Lung was the most common site of involvement (13 of 23 patients) and there were no 
differences in anatomical distribution among the three histologic grades. Seven of nine grade I 
patients achieved CR with cyclophosphamide/ prednisone and 5/7 required no further 
therapy.  The two patients who failed to achieve CR rapidly progressed and died of their disease, 
while 2/7 responders progressed to lymphoma from 2-4 years after diagnosis and died.  Thus, 
cyclophosphamide/prednisone was curative in only 55% of patients with grade I AIL.  Of the six 
patients with grade II AIL, 3 achieved an initial CR with cyclophosphamide/prednisone, but 4 of 
the 6 developed malignant lymphoma within a median of 12 months from diagnosis; only one of 


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8
the four lymphomas responded to combination chemotherapy.  In contrast, 7 of 8 patients with 
grade III patients are in CR after combination chemotherapy + radiation therapy at a median of 7 
years.  Thus, this study suggests that patients with grade III AIL (lymphoma) benefit from 
aggressive combination chemotherapy, while patients with grade I or II do not benefit from less 
aggressive chemotherapy.  
Because the treatment of grade I/II AIL with cyclophosphamide/ prednisone has been 
disappointing, some investigators have advocated the use of aggressive combination 
chemotherapy.  However, there are several concerns with this approach.  First, there are no 
controlled studies of the use of aggressive combination chemotherapy in grade I/II AIL.  
Furthermore, patients with grade II AIL who progressed to grade III disease had a poor response 
to aggressive chemotherapy.  Second, grade I/II AIL is not a clonal disease and is associated with 
immuno-suppression (low CD-4 counts), which may be exacerbated by aggressive 
chemotherapy.  
A major shortcoming of these studies is that they did not distinguish LMG from LYG.  
Pathologically, LMG is a malignant lymphoma of T cell or NK cell origin and should be treated 
with combination chemotherapy.  In contrast, preliminary evidence suggests that LYG is an EBV 
positive B cell lymphoproliferative disorder which occurs in a partially immunocompromised 
host. Interferon offers a rational treatment approach for LYG because it has both anti-
proliferative and anti-viral activity.  Recently, we have had anecdotal experience with the 
treatment of grades I/II LYG with alpha-interferon.  Eighteen months ago, a 21-year-old man 
with grade II LYG developed progressive pulmonary nodules 2 months after completing CHOP 
(cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy.   The patient 
entered a complete remission after 6 months of interferon therapy (10 x 106 units 3 x week) and 
continues in remission on interferon.  Three additional patients with grade II LYG are receiving 
interferon for 7, 6 and 1 months and all show continuing disease resolution.    
In this protocol, we plan to treat all patients with Grade 1 and 2 LYG with interferon.  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).  
Extensive experience with EPOCH in relapsed and refractory non-Hodgkin’s lymphoma has 
shown it to be very well tolerated and effective (10).  Patients who relapse after DA-EPOCH-R 
may be treated with interferon providing they do not relapse with an aggressive large B-cell 
lymphoma.  
The recent approval of rituximab (humanized monoclonal antibody for treatment of CD20 
positive B-cell malignancies) provides a potential new treatment for LYG.  Early experience 
with this agent in post-transplant LPD has shown anecdotal responses (11-13).  For patients who 
fail interferon, rituximab may provide an important new treatment. Furthermore, it has been 
shown in vitro, that rituximab may increase the efficacy of chemotherapy, and clinical data 
suggests high activity and reversal of clinical drug resistance with the addition of rituximab to 
EPOCH (14-15).  We currently have a protocol of DA-EPOCH, as administered in the present 
trial, with rituximab administered on the first day of each cycle, prior to beginning the infusions.  
Preliminary data in relapsed patients has shown this to be an effective regimen (14-15).  For 
patients who fail to achieve a durable remission with interferon and chemotherapy, there are no 
clearly effective treatments. Thus, we wish to be able to treat such patients with rituximab alone 
or with interferon, as clinically appropriate.  In some of these cases, the patients will have 


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Version Date:  01/27/2021
9
relapsed following EPOCH-R or interferon and may benefit from additional intervention with 
rituximab.  Furthermore, in patients who fail to achieve a remission with EPOCH-R, rituximab 
alone may provide disease control.  This has been seen in unpublished experience in indolent 
lymphomas. Because these patients have a rare disorder, we believe that we may obtain 
important pilot information through the treatment of these relapsed patients with these standard 
agents.  
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
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 Stefania 
Pittaluga, M.D. or her designee. 
2.1.2
Patients with any stage of disease will be eligible.
2.1.3
Previously untreated and treated patients are eligible.
2.1.4
Patients age 12 or older will be eligible.
2.1.5
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.  
2.1.6
Patients with significant renal (Cr. > 1.5 mg/dl or creatinine clearance< 40 cc/min) or 
hepatic (bilirubin > 2.5 u) dysfunction not due to tumor involvement will not be eligible 
to receive DA-EPOCH-R chemotherapy.  
2.1.7
Informed consent must be obtained.
2.1.8
Patients who in the opinion of the principal investigator are poor psychiatric or medical 
risks are not eligible.  
2.1.9
Patients who received > 450 mg/m2 doxorubicin and have a cardiac ejection fraction on 
echocardiogram < 40% on protocol entry are not eligible to received DA-EPOCH-R.  
2.1.10 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.
2.2
RECRUITMENT STRATEGIES
This study will be posted on NIH websites and NIH Social Media forums.  
Study participants will be recruited from the population of patients screened in the lymphoid 
malignancy clinics of the National Institutes of Health. These will include both referrals from 
outside physicians as well as patient self-referrals. In addition, we participate in a locoregional 
consortium of eight academic institutions within the mid-Atlantic region that shares information 
regarding active clinical protocols and aims to enhance patient recruitment across the region.
2.3
SCREENING EVALUATION
2.3.1
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for study 


Abbreviated Title:  Treatment and Nat. Hx. LYG
Version Date:  01/27/2021
10
01C0129, on which screening activities will be performed. 
NOTE: Results from outside NIH or on another NIH protocol are accepted.  Other body areas 
may be imaged if clinically indicated. 
NOTE: Assessments and procedures to confirm study eligibility should be completed within 28 
days prior to registration (unless otherwise noted).  
2.3.2
Clinical Evaluations

Complete history and physical examination with measurement of all palpable peripheral 
lymph nodes, skin, liver, spleen and other measurable lesions. 

Biopsy of tumor may be performed when possible by needle or peripheral biopsy to 
confirm the diagnosis. Biopsies requiring laparotomy or thoracotomy will only be 
performed if necessary for patient care and not for research purposes alone
2.3.3
Laboratory Evaluations

Chemistry Studies: Acute Care Panel (sodium, potassium, chloride, CO2, glucose, BUN, 
creatinine); Hepatic panel (alkaline phosphatase, ALT, AST, total and direct bilirubin), 
and 24-hour creatinine clearance if creatinine > 1.5 mg/dl and beta-HCG. HBV DNA 
Levels (for participants with prior exposure to Hepatitis B).  

Serum or urine pregnancy test in women of childbearing potential.
2.3.4
Imaging Studies:

CT Scan (Site varies on disease).

Head CT scan or brain MRI.  
2.3.5
Other Procedures

Echocardiogram for patients receiving > 450 mg/m2 doxorubicin.
2.4
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here. 
2.4.1
Treatment Assignment and Randomization/Stratification Procedures 
2.4.1.1
Cohorts
Number
Name
Description
1
Patients with lymphomatoid 
granulomatosis (LYG)
Patients with grades 1, 2 or 3 LYG


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2.4.1.2
Arms
Number
Name
Description
1
Interferon 
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.
2
EPOCH-R
EPOCH-R every 3 weeks for up to 6 cycles, based on response. 
2.4.1.3
Arm Assignment 
Subjects in Cohort 1 directly assigned to Arm 1 or Arm 2 based upon grade and stage of disease, 
at investigator’s discretion (treatment is non-randomized and open-label).  Subjects initially 
assigned to Arm 1, and who progress, may crossover to Arm 2.  
2.5
BASELINE EVALUATION
2.5.1
Hematology Studies: CBC with differential, ESR, PT, PTT, fibrinogen, Coomb’s test.
2.5.2
Serology Studies: Anti-EBV Antibody Panel, HIV 1/2 Antibody/Antigen Combo, 
Hepatitis B Core Antibody, Hepatitis B Surface Antibody, Hepatitis B Surface Antigen, 
and Hepatitis C Antibody. 
2.5.3
Acute care panel (Sodium (NA), Potassium (K), Chloride (CL) Total CO2 (Bicarbonate), 
Creatinine, Glucose, Urea nitrogen, eGFR, Anion Gap), Hepatic panel (Alkaline 
Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin), Total protein, 
Mineral panel (serum calcium, phosphate, magnesium and albumin), LDH, CK, uric acid, 
serum protein electrophoresis, quantitative immunoglobulin levels, TSH and free 
thyroxine if TSH is abnormal, and urinalysis.
2.5.4
FACS analysis for lymphocyte subsets including Total T and B cells, CD4, CD8, CD19 
or CD56 (NK).
2.5.5
CMV/EBV PCR
2.5.6
Pregnancy test (Female patients only)  
2.5.7
Lumbar puncture with CSF for cytology, flow cytometry, cell count and chemistry in all 
patients.
2.5.8
FDG-PET Scan 
2.5.9
Bone marrow biopsy and aspirate to determine if bone marrow has disease involvement. 
2.5.10 Optional biopsy of tumor may be performed when possible by needle or peripheral 
biopsy for research purposes. Biopsies requiring laparotomy or thoracotomy will only be 
performed if necessary for patient care and not for research purposes alone. These 
biopsies may be done by CT guidance.
2.5.11 Analysis of fresh tissue and/or paraffin blocks for in-situ hybridization for EBV; 
immunohistochemistry for B and T cell antigens; and isolate DNA for T-cell receptor and 
immunoglobulin gene rearrangements by PCR if available.   
2.5.12 Obtain up to 50 cc blood for storage and analysis of EBV viral loads and T-cell responses 
to EBV.   


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Note:  Biopsies for experimental purposes will not be done on children.
3
STUDY IMPLEMENTATION
Please note that this protocol was on Administrative Hold from October 17, 2016 through 
February 8, 2017. Amendment AA serves as the formal notification to the IRB of the 
Administrative Hold. During the time the protocol was on Administrative Hold, no new patients 
were enrolled; however, patients who were on-study were followed per protocol. 
3.1
TREATMENT WITH ALPHA INTERFERON 
Grade 1 and 2 LYG will be initially treated with interferon-2b.  However, in rare 
circumstances, patients with advanced and symptomatic grade 2 LYG may be treated with DA-
EPOCH-R, at the discretion of the PI, if they require a rapid clinical response.   Interferon will be 
started at 7.5 x 106 Units subcutaneously (sc) three times per week (TIW).  Interferon dose can 
be escalated every 1-2 weeks, if no grade 3 or 4 toxicity (excluding fever) is observed and it is 
clinically tolerated (i.e. fatigue), on the following schedule: 10 x 106 U; 15 x 106 U; 20 x 106 U; 
25 x 106; and increased in 5 x 106 U increments as clinically indicated, thereafter.  If a patient 
develops grade 3 toxicity (except hematological and fever) or has intolerable fatigue, the dose 
will be reduced one to two dose levels.  If a patient develops grade 4 toxicity (except 
hematological), interferon will be stopped until toxicity recovers to < grade 2 and then interferon 
may be restarted at 50% of the last dose.  If patient develops grade 4 neutropenia, standard 
treatment with filgrastim (e.g. 300 ug TIW) may be used to increase neutrophil count.  Patients 
with thrombocytopenia or anemia may be supported as clinically indicated with transfusions. If 
the toxicity does not resolve to < grade 2 (except hematological) within 4 weeks, interferon will 
be permanently discontinued.  
Interferon treatment duration: Patients who enter a complete remission/stable residual 
abnormalities will receive interferon for 12 months beyond reaching this state.  Patients with 
progressive disease will cross-over to receive DA-EPOCH-R chemotherapy as outlined in 
Section 3.2. 
3.2
TREATMENT WITH DA-EPOCH-R 
Patients with grade 3 LYG and patients who progress on interferon will be treated with: DA-
EPOCH-R chemotherapy.  However, in rare circumstances, patients with advanced and 
symptomatic grade 2 LYG may be treated with DA-EPOCH-R at the discretion of the PI as 
initial therapy if they require a rapid clinical response. Patients who achieve a CR/stable residual 
abnormalities will be followed.  However, patients who achieve a PR (clear disease present) with 
DA-EPOCH-R will receive interferon beginning 4 weeks after the last dose of chemotherapy 
according to the algorithm in Section 3.1.   
3.2.1
DA-EPOCH-R treatment duration
Patients will receive DA-EPOCH-R for 2 cycles beyond CR, for a maximum of 6 cycles.   
3.2.2
DA-EPOCH-R Starting Dose Level (Level 1)
Drug
Dose
Route
Treatment Days
Infused Agents 
   Etoposide 
50 mg/m2/day
CIV
1,2,3,4 (96 hours)
   Doxorubicin
10 mg/m2/day 
CIV
1,2,3,4 (96 hours)


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Drug
Dose
Route
Treatment Days
   Vincristine
 0.4 mg/m2/day
CIV
1,2,3,4 (96 hours)
Bolus Agents            
  Cyclophosphamide
750 mg/m2/day 
IV
day 5
  Prednisone 
60 mg/m2/bid 
PO
day 1-5
  Rituximab
375 mg/m2/day
IV
day 1
Neupogen®     
300 mcg/day (if < 75 kg) or 
480 mcg/day (if ≥ 75 kg)
SC
day 6 until ANC>5000
3.2.3
Administration

Begin the infusional agents immediately after rituximab is completed.

Administer cyclophosphamide immediately after infusion is completed on day 5. 

Repeat cycles every 3 weeks (21 days). 

NOTE:  DA-EPOCH-R infusional drugs should be administered through a central venous 
access device.
3.3
PROGRESSION WHILE ON TREATMENT
Patients who progress on the protocol treatment with interferon and/or DA-EPOCH-R or another 
doxorubicin-based regimen may be treated with standard therapy to include rituximab.  Patients 
who receive rituximab will be treated with a standard dose of 375 mg/m2 IV.  When given 
without chemotherapy, 4 doses are given over 1- 4 weeks for each treatment cycle.  The 
treatment of such patients will depend on their prior treatment history.  Consent for treatment 
with these standard agents will be individually obtained because the treatment is using standard 
agents and is not systematically studied on this protocol.  However, patients will remain enrolled 
on this study as the vehicle for this treatment so that we can obtain pilot information on these 
treatment approaches.
3.4
DOSE ADJUSTMENTS
Goals and General Strategy:  The aim is to maximize DA-EPOCH-R dose-intensity while 
minimizing toxicity. Drug doses may be modified for severe toxicity either manifests on day 1 or 
occurring during the previous cycle and resolved by day 1 of the next cycle. The rules for either 
eventuality are described separately below. When two different rules give different answers for a 
particular dose decision, use the lower of the two dose options. The rules are for events that 
occur during the preceding cycle.
3.5
HEMATOLOGIC DOSE-ADJUSTMENT PARADIGM

Dose adjustments above starting dose level (level 1) apply to etoposide, doxorubicin and 
cyclophosphamide

Dose adjustments below starting dose level (level 1) apply to cyclophosphamide only.  

Drug Doses based on previous cycle ANC nadir:

If Nadir ANC  500/l on all measurements:           1 dose level above last cycle 

If Nadir ANC  500/l on 1 or 2 measurements:        Same dose level as last cycle  

If Nadir ANC  500/l  3 measurements:               1 dose level below last cycle

Or


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
If nadir platelet  25,000/l on 1 measurement:        1 dose level below last cycle. 

If ANC  1000/l and platelets  100,000/l on day 21, begin treatment.

If ANC < 1000/l or platelets ≤  100,000/l on day 21, delay up to 1 week.  G-CSF may 
be started for ANC < 1000/l and stopped 24 hours before treatment.  If counts still low 
after 1 week delay,  1 dose level below last cycle. 
Important: Measurement of ANC nadir is based on twice weekly CBC only (3 days 
apart).  Only use twice weekly CBC for dose-adjustment, even if additional CBC’s are 
obtained. 
Table of doses per level for adjusted agents:  
Drug Doses per Dose Levels
Drugs
-2
-1
1
2
3
4
5
6
Doxorubicin (mg/m2/day)
10
10
10
12
14.4
17.3
20.7
24.8
Etoposide (mg/m2/day)
50
50
50
60
72
86.4
103.7
124.4
Cyclophosphamide (mg/m2/day)
480
600
750
900
1080
1296
1555
1866
3.6
NEUROLOGIC AND HEPATIC DOSE ADJUSTMENT PARADIGM
3.6.1
Ileus
Constipation commonly occurs in patients receiving vincristine, so patients should receive stool 
softeners as indicated.  Occasionally, symptomatic ileus may occur, and this should be treated 
with a vincristine dose reduction.  Because the severity of ileus is dose related, it is usually not 
necessary to stop the vincristine altogether.  Furthermore, because the therapy administered in 
this study is potentially curative, every effort should be made to avoid unnecessarily reducing 
vincristine doses.  The following guidelines for symptomatic ileus on a previous cycle should be 
followed:
Clinical ileus < 8 days with abdominal pain requiring narcotics and/or persistent nausea/vomiting 
>2 days: Reduce vincristine dose 25%.
Clinical ileus 8-12 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting > 2 days: Reduce vincristine dose 50%.
Clinical ileus > 12 days with abdominal pain requiring narcotics and/or persistent 
nausea/vomiting > 2 days: Hold vincristine on next cycle.  May restart at 50% reduction on 
subsequent cycle.
3.6.2
Sensory neuropathy 
Grade 
% Dose of Vincristine
2
100
3
50
3.6.3
Motor neuropathy
Grade
% Dose of Vincristine
1
100
2
75
3
25


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4
0
3.6.4
Hepatic dysfunction
Bilirubin on Day 1
%  Dose of Vincristine
1.5-3.0
75
   
>3.0
50
3.6.5
Rituximab toxicity (skin) 
Side effects of rituximab may be infusion rate related and may be reduced by slower 
administration or premedication. Thus, dose reductions of rituximab will not be made for rate 
related reactions. Rituximab will be discontinued in patients with grade 4 allergic reactions.  
Patients who develop significant skin toxicity including mucositis and/or diffuse rash felt 
secondary to rituximab and at risk of toxic epidermal necrolysis will have rituximab discontinued 
and will only receive EPOCH alone for the remainder of cycles. Patients will be given a 
rituximab toxicity reporting sheet for presentation to their local physicians if they develop any 
skin, mouth or bleeding symptoms or signs. 
3.7
STUDIES DURING AND AFTER THERAPY
3.7.1
Patients receiving interferon

CBC/differential and liver panel weekly until stable dose of interferon and then every 
other week while on interferon. 

TSH and free thyroxine if TSH is abnormal q3 months while receiving interferon.  

Clinic visit q4 weeks and appropriate imaging (i.e. CT Scan and MRI in patients with 
CNS disease) until on stable dose of interferon or a maximum of 6 monthly scans.  
Thereafter q3 months while receiving interferon. 

On completion of interferon, approximately 30 days after last dose (by phone or in clinic) 
a toxicity assessment only will be done, followed by clinic visits,  CT Scans (type of scan 
depended on site of disease) and brain MRI if there is CNS involvement for restaging, 
and labs as follows: q3 months x 1 year, q4 months x 1 year, q6 months x 1 year and 
yearly thereafter for 2 years. FDG-PET will be done at the completion of interferon 
therapy or as clinically indicated.  After 5 years of follow-up, we will continue to see you 
in clinic (or contact you by phone) at least yearly; restaging and labs will be done as 
clinically indicated. Restaging of involved sites with appropriate scans/x-rays will be 
done at each scheduled visit. Labs to be collected at each clinic visit during follow-up: 
CBC w/differential, PT, PTT, acute care, mineral and hepatic panels, total protein, LDH, 
TSH and free thyroxine if TSH is abnormal.  

FACS analysis for CD-4/CD-8 cells are to be drawn at the following times: Pre-
treatment; then Q4 weeks until stable interferon dose and then q 3 months during 
treatment and with each surveillance follow-up visit. FACS analysis will also be 
performed at each restaging visit during follow-up.The FACS analysis for CD4/CD8 cells 
will be performed in the Clinical Center Laboratory. 

EBV Viral Loads: EBV viral loads are to be drawn at the following times: Pre-treatment; 
then Q4 weeks until stable interferon dose and then q 3 months during treatment and at 
each surveillance follow-up visit . EBV viral loads will be performed in the Clinical 


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Center Laboratory.
3.7.2
Patients receiving DA-EPOCH-R

Patients will be seen in clinic q3 weeks for DA-EPOCH-R chemotherapy.  Labs to be 
collected: CBC w/differential, PT, PTT, acute care, mineral, hepatic panels, total protein, 
and LDH q3 weeks.  Restaging of all involved sites will be performed after cycles 4 and 
6.  CBC w/differential 2 x week, three days apart, will be performed while receiving DA-
EPOCH-R therapy.  

When DA-EPOCH-R is completed, approximately 30 days after last dose (by phone or in 
clinic) a toxicity assessment only will be done, followed by clinic visits, restaging, and 
labs as follows:  q3 months x 1 year, q4 months x 1 year, q6 months x 1 year and yearly 
thereafter for 2 years.  After 5 years of follow-up, we will continue to see you in clinic (or 
contact you by phone) at least yearly; restaging and labs will be done as clinically 
indicated.  Restaging of involved sites with appropriate CT scans will be done at each 
scheduled visit (type of scan depended on site of disease) and brain MRI if there is CNS 
involvement as well as PET Scans (at the completion of therapy). Labs to be collected at 
each clinic visit during follow-up: CBC w/differential, PT, PTT, acute care, mineral and 
hepatic panels, total protein, and LDH.

FACS analysis for CD4/CD8 cells performed at the following time-points: 1. Pre-
treatment; 2. Patients on DA-EPOCH-R: prior to each cycle of therapy, and at the end of 
treatment. When patients have completed therapy, obtain FACS analysis at each 
restaging visit during follow-up.  The FACS analysis will be performed in the Clinical 
Center Laboratory.

EBV Viral Loads: EBV viral loads are to be drawn at the following times: 1. Pre-
treatment; 2. Patients on DA-EPOCH-R: prior to each cycle of therapy, and at the end of 
treatment. When patients have completed therapy, obtain EBV viral loads at each 
restaging visit during follow-up. EBV viral loads will be performed in the Clinical Center 
Laboratory.
3.7.3
Research Samples
Note:  See Section 5 for additional information
3.8
COST AND COMPENSATION 
3.8.1
Costs
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company.  Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center.    
3.8.2
Compensation
Participants will not be compensated on this study.
3.8.3
Reimbursement 
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 


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these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.
3.9
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
3.9.1
Criteria for removal from protocol therapy

A patient will no longer receive study agents (DA-EPOCH-R or interferon) if he/she 
develops a serious medical condition (irreversible > grade 3 or 4 non-hematologic 
toxicity) which makes their administration life-threatening.  However, the patient may 
continue to be followed on study. 

If a woman becomes pregnant while on this study, treatment will be stopped. 

Patient voluntary withdrawal: Patient may withdraw from treatment and continue to be 
followed on-study.

Investigator discretion.
3.9.2
Criteria for removal from study

Participant requests to be withdrawn from study.

Patient non-compliance; that is, the patient does not follow the instructions provided by 
the research team.

Pregnancy 

Death.
4
CONCOMITANT MEDICATIONS/MEASURES
4.1
PROPHYLAXIS OF PNEUMOCYSTIS JIROVECI (FORMERLY PNEUMOCYSTIS CARINII) 

Adult patients will receive prophylaxis for Pneumocystis Jiroveci during EPOCH 
chemotherapy. Trimethoprim/sulfamethoxazole 1 DS P.O. QD for three days each 
week. Monday, Wednesday, Friday is the preferred schedule. Children ages 12-17 
receive the same Trimethoprim/sulfamethoxazole dose as adults.

Patients allergic to either component may receive inhaled pentamidine 300 mg once a 
month or other standard treatments.
4.2
CNS TREATMENT GUIDELINES
Patients with Grade 1, 2 or 3 leptomeningeal LYG without transformation to a large B-cell 
lymphoma who are receiving interferon will be monitored every 2-4 weeks after the start of 
interferon by CSF analysis and/or brain scan until evidence of resolving disease.  If there are no 
progressive neurological signs or symptoms and evidence of resolving CNS disease, patients 
may be followed without intrathecal chemotherapy or radiation as appropriate.  Intrathecal 
chemotherapy and/or radiation will be used in patients receiving interferon with evidence of 
disease progression in the CNS, patients receiving interferon who at the investigators discretion 
are felt to have neurological symptoms (based on severity and duration of symptoms) warranting 
cytotoxic/radiation treatment, patients with evidence of aggressive lymphoma in the CNS and 


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patients receiving DA-EPOCH-R chemotherapy.
4.2.1
Guidelines for intrathecal treatment: Patients will initially receive monotherapy with 
methotrexate and/or cytarabine.  

Doses for IT therapy are methotrexate 12 mg or cytarabine 70 mg. 

Doses for Ommaya therapy are methotrexate 6 mg or cytarabine 70 mg. 
4.2.2
Due to unforeseeable events, the above therapy may be modified as clinically indicated.  
All decisions should be discussed with the PI or protocol chairperson. 
4.2.3
Treatment Schedule: Induction: Twice weekly for 2 weeks beyond negative cytology or 
FACS, for a minimum of 4 weeks (obtain CSF for cytology and flow cytometry weekly); 
Consolidation- Weekly for 6 weeks (obtain CSF for cytology weekly); Maintenance- 
Monthly for 6 months (obtain CSF for cytology and flow cytometry monthly).
4.2.4
Radiation treatment: Patients who have progressive disease on intrathecal chemotherapy 
and/or have parenchymal lesions may receive radiation treatment.  
4.3
MONITORING AND TREATMENT TO PREVENTHEPATITIS B REACTIVATION
Patients who are positive for either Hepatitis B core antibody (anti-HBc) or Hepatitis B surface 
antigen (HBsAg) and not acutely infected are at varying risk for reactivation of Hepatitis B when 
treated with 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. These patients will be treated with entecavir (or equivalent) 
to prevent hepatitis B reactivation and should have HBV DNA levels obtained monthly for at 
least 12 months after the last cycle of therapy by means of real-time PCR with the use of an 
assay that has a sensitivity of at least 10 IU/mL.
If the HBV DNA assay becomes positive during DA-EPOCH-R, study treatment should be held, 
and the patient should be immediately referred to a gastroenterologist or hepatologist for 
management recommendations.
If a patient’s HBV DNA level exceeds 100 IU/mL while the patient is receiving antiviral 


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medication, study treatment must be permanently discontinued.  
5
CORRELATIVE STUDIES FOR RESEARCH
5.1
SUMMARY
Sample
Collection Details
Time Points
Laboratory
Blood Samples
EBV Analysis
4 x 8.5 mL yellow top
Pre-treatment
Each Clinic Visit 
First 4 follow-up visits after treatment ends
CSL
(Leidos)
Serum Storage
1 x 10 mL red top
Pre-treatment
Every 3-6 months during treatment
Each re-staging visit during follow-up
CSL 
(Leidos)
Tissue Samples
Archival Tissue
FFPE or other, as 
available
Baseline
Tumor Biopsy 
(optional)
Excision (single or 
multiple nodes) or 
core (4-6 passes); 
placed in media per 
routine practice
Baseline
NCI LP
NOTE:  

Tubes/media may be adjusted at the time of collection based upon materials available and/or to ensure the 
best viable samples are collected for planned routine and/or research analysis at the time of procedure.

All blood/ tubes should remain at ambient temperature after collection and until processing, do not place 
samples on ice.  Processing windows; SST/red top tubes should be processed same day, whenever possible.
5.2
BLOOD SAMPLE COLLECTION AND PROCESSING
5.2.1
EBV Analyses
For patients receiving Interferon or EPOCH-R, 4 yellow top tubes should be drawn at the time 
points outlined in Section 5.
These yellow top tube samples should be sent via courier to the Clinical Support Laboratory, 
Leidos Biomedical Research Inc. in Frederick, MD.  The storage for these samples is described 
in Section  5.3.1.  
Studies to be performed on these bloods includes analysis of EBV specific T cells by tetramer 
staining, markers for senescence, clonal exhaustion by flow, and functional activity of virus 
specific T-cells. EBV-transformed B cell lines from select patients may be created which will be 
used as antigen-presenting cells to be used for other studies in the future.   Additional studies 
may be done on these samples that are related to understanding the pathogenesis of LYG and its 
treatment providing those studies are of minimal risk to the patients.  If the studies are not of 


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minimal risk, IRB approval and patient consent will be obtained.
5.2.2
Serum Storage 
For patients receiving Interferon or EPOCH-R, one red top tube for serum storage should be 
drawn at the time points outlined in Section 5. 
These serum samples should be sent to the laboratory of Clinical Support Laboratory, Leidos 
Biomedical Research Inc. in Frederick, MD. Processing and storage procedures are described in 
Section 5.3.1.
5.3
TUMOR BIOPSY SAMPLES
5.3.1
Overview
Excision or core needle biopsy will be performed per routine standard of care, by Surgery 
Consultants or Interventional Radiology, as appropriate.  A procedure-specific consent form will 
be signed by the patient prior to the procedure.  Every attempt will be made to perform 
excisional biopsies to obtain the best quality tissue for translational investigation.  Consideration 
of alternative biopsy methods (e.g., core needle biopsy) will only be made if follow-up 
excisional biopsy is not possible/safe or patient is unwilling to undergo repeat excisional biopsy. 
These biopies may be done by CT guidance.
In the event that a surgical biopsy procedure is performed, more than one lesion and at more than 
one anatomic site may be collected, provided the additional procedures are not unacceptable risk 
to the patient.  In the event of core needle biopsy, these are obtained typically by using a 16-18G 
needle at the discretion of the provider performing the procedure.  Conscious sedation may be 
used, if warranted, and the use and risks are acceptable to the patient.  
Potential site(s) of biopsy include, but are not limited to:  bone marrow lesions, bony lesions, 
extramedullary disease/masses, and lymph nodes.  The type of procedure to be done and manner 
in which it will proceed (e.g., excision/core, single vs. multiple sites of biopsy) will be discussed 
with the patient prior to the biopsy procedure.  The patient will be reminded that all sampling for 
research is voluntary.
If the patient agrees to the optional biopsy, he/she will sign a procedure consent at the time of the 
procedure.  If the patient refuses the optional biopsy, the refusal will be documented in the 
medical record and in the research record.
5.3.2
Processing and Handling
All samples will be handled/processed as per routine processes applicable to the type of sample 
(e.g., formalin fixation, snap frozen, and/or single-cell preparation).  It is anticipated that all 
samples will go through NCI Laboratory of Pathology for review/processing prior to release for 
research analyses.
5.3.3
Analysis 
Analysis of fresh tissue and/or paraffin blocks for in-situ hybridization for EBV; 
immunohistochemistry for B and T cell antigens; and isolate DNA for T-cell receptor and 
immunoglobulin gene rearrangements by PCR if available.   
Immunohistochemical (IHC) analyses will take part in tumor tissue samples, including but not 


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necessarily limited to CD10, CD20, BCL6, and MUM1.
5.4
SAMPLE STORAGE, TRACKING AND DISPOSITION
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside NIH without appropriate approvals and/or agreements, if 
required. 
All specimens obtained in the protocol are used as defined in the protocol.  Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below 
for an indefinite amount of time. The PI will record any loss or unanticipated destruction of 
samples as a deviation. Reporting will be per the requirements of section 7.2.1. 
5.4.1
Procedures for stored blood specimens 

The Clinical Support Laboratory (CSL), Leidos Biomedical Research Inc.-Frederick, 
processes and cryopreserves samples in support of IRB-approved, NCI clinical trials.  All 
laboratory personnel with access to patient information annually complete the NIH online 
course in Protection of Human Subjects.  The laboratory is CLIA certified for CD4 
immunophenotyping and all laboratory areas operate under a Quality Assurance Plan 
with documented Standard Operating Procedures that are reviewed annually.  Laboratory 
personnel are assessed for competency prior to being permitted to work with patient 
samples.  Efforts to ensure protection of patient information include:

The laboratory is located in a controlled access building and laboratory doors are kept 
locked at all times. Visitors to the laboratory are required to be accompanied by 
laboratory staff at all times.  

Hard copy records or electronic copies of documents containing patient information are 
kept in the locked laboratory or other controlled access locations.   

An electronic database is used to store information related to patient samples processed 
by the laboratory.  

The database resides on a dedicated program server that is kept in a central, locked 
computer facility.  

The facility is supported by two IT specialists who maintain up to date security features 
including virus and firewall protection.  

Program access is limited to specified computers as designated by the laboratory 
director.  Each of these computers has a password restricted login screen.  

The database sample entry program itself is accessed through a password protected entry 
screen.  

The database program has different levels of access approval to limit unauthorized 
changes to specimen records and the program maintains a sample history.  

Upon specimen receipt each sample is assigned a unique, sequential laboratory accession 
ID number.  All products generated by the laboratory that will be stored either in the 
laboratory freezers or at a central repository facility are identified by this accession ID.

Inventory information will be stored at the vial level and each vial will be labeled with 


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both a sample ID and a vial sequence number.  

Vial labels do not contain any personal identifier information.   

Samples are stored inventoried in locked laboratory freezers and are routinely transferred 
to the NCI-Frederick repository facilities for long term storage.    

Access to stored clinical samples is restricted.  Investigators establish sample collections 
under “Source Codes” and the investigator responsible for the collections, typically the 
protocol Principal Investigator, specifies who has access to the collection.  Specific 
permissions will be required to view, input or withdraw samples from a collection. 

Sample withdrawal requests submitted to approved laboratory staff by anyone other than 
the repository source code owner are submitted to the source code owner for approval.  
The repository facility will also notify the Source Code holder of any submitted requests 
for sample withdrawal.  

It is the responsibility of the Source Code holder (generally the NCI Principal 
Investigator) to ensure that samples requested and approved for withdrawal are being 
used in a manner consistent with IRB approval.  

The Clinical Support Laboratory does perform testing services that may be requested by 
clinical investigators including, but not limited to, immunophenotyping by flow 
cytometry and cytokine testing using ELISA or multiplex platforms.  

When requests are submitted by the NCI investigator for shipment of samples outside of 
the NIH it is the policy of the laboratory to request documentation that a Material Transfer 
Agreement is in place that covers the specimen transfer.  The laboratory does not provide 
patient identifier information as part of the transfer process but may, at the discretion of 
the NCI investigator, group samples from individual patients when that is critical to the 
testing process.   

The NCI investigator responsible for the sample collection is responsible for ensuring 
appropriate IRB approvals are in place and that a Material Transfer Agreement has been 
executed prior to requesting the laboratory to ship samples outside of the NIH.  
5.4.2
Procedures for storage of tissue specimens
Tumor biopsies will be submitted in native condition to the Department of Pathology, NCI, NIH 
and handled according to routine procedures.  Initial processing of samples for research will 
depend on the size of the tumor biopsy.  For core biopsies the research sample will typically 
consist of 2 cores in a microcentrifuge vial snap frozen on dry ice. Surgical lymph node biopsies 
may in addition be processed for single cell suspension, additional vials of snap frozen tissue and 
OCT embedded tissue.
Tumor samples may be viably frozen, typically at concentrations of 20-100x106/mL in FCS with 
10% DMSO using a temperature controlled freezing process to optimize sample viability.  
Samples will be transferred to Nitrogen tanks for long term storage. 
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 


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with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant.
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention, Study Day 1, through 30 days after the last 
study intervention was administered.  Beyond 30 days after the last intervention, only adverse 
events which are serious and related to the study intervention need to be recorded.
An abnormal laboratory value will only be considered an AE if the laboratory abnormality is 
characterized by any of the following:

Results in discontinuation from the study

Is associated with clinical signs or symptoms 

Requires treatment or any other therapeutic intervention

Is associated with death or another serious adverse event, including hospitalization. 

Is judged by the Investigator to be of significant clinical impact

If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.
6.1.1
Special considerations for data collection/recording:

As the toxicity profile of EPOCH-R is well defined and published, grade 1 clinical 
adverse events will not be recorded in the database.  

All hospitalizations, regardless of reason, will be recorded in the database with the reason 
of hospitalization and the duration of hospitalization noted. 

Only the highest grade of each event during a cycle of treatment during EPOCH-R will 
be recorded in the database. 

All grade 2 events and above that occur while the patient is treated with interferon will be 
recorded. 

In certain circumstances, patients may stay on study and receive non-protocol therapy for 
a diagnosis other than LYG. In these cases, adverse events that are attributed to the non-
protocol therapy will not be collected.  
6.2
RESPONSE CRITERIA
6.2.1
Complete Remission: No evidence of active disease on restaging for at least 2 months 
duration.  Because LYG frequently involves the lungs, residual scar may be present.  To 
be considered in CR, all lesions must have decreased by > 75%, be gallium or PET 


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negative (if obtained) and be stable for > 3 months without new lesions appearing.  If 
lesions can be biopsied, such as the skin, or pleural, peritoneal or CSF fluid collected, 
these must be negative for disease.
6.2.2
Partial Remission: 50% or greater decrease in the sum of the products of the diameters of 
all measurable lesions for at least one month.
6.2.3
Disease Progression: 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. 
6.2.4
 Disease Stabilization: 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. 
6.3
TOXICITY CRITERIA
Adverse events will be documented according to the Common Toxicity Criteria v. 2.0, which can 
be found at http://ctep.cancer.gov/reporting/ctc.html. Serious ( grade 3) which are unexpected 
and reasonably ascribed to treatment drugs and all fatal reactions occurring on this study should 
be reported immediately by phone to Dr. Wyndham Wilson at 240-760-6092.
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found here.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here.
7.2.2
IRB Requirements for PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the 
Clinical Director.
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
7.4.1
Principal Investigator/Research Team 
The clinical research team will meet approximately weekly when patients are being actively 
treated on the trial to discuss each patient. Decisions about dose level enrollment and dose 
escalation if applicable will be made based on the toxicity data from prior patients. 


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All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
8
STATISTICAL CONSIDERATIONS
Initially, 15 patients each with Grade I/II and Grade III LYG may be enrolled in this study.  The 
first 9 patients in each group entering a CR or stable PR will have their remission durations 
observed, and the proportions with durations exceeding 12 months will be noted.  If 9 patients in 
any group of 9 progress with the same disease grade (i.e. grades I/II or III) within 12 months, no 
additional patients beyond 15 will be entered into that group (15 will probably have been 
enrolled by the time nine have had a minimum of 12 months potential follow-up).  This will 
allow us to conclude with 95% confidence and power that the true proportion of patients with 
response durations exceeding 12 months is less than 30%.
If at least one of 9 patients in either group have response durations exceeding 12 months, then up 
to 30 patients will be enrolled in that group. If at least 10 of 29 patients with CR or stable PR 
have remission duration > 12 months, we can conclude that the true proportion with remission 
duration exceeding 12 months is at least 20%, with 95% power and confidence.
In order to have 60 evaluable patients enrolled on this protocol, the accrual ceiling will be 70 
patients to account for 10 non-evaluable patients.
All patients will be followed for survival and disease-free survival (among appropriately 
responding patients), with appropriate life-table analyses performed at the conclusion of the 
study.
Due to the rarity of this disease and its now recognized multiple subtypes (grade I, II and III), we 
wish to increase the number of patients overall in the series to a total of 85 patients.
Effective with Amendment Y (Version Date: 09/16/2014), the accrual ceiling is being increased 
by 5 to a total of 90 patients. This will allow for continuation of our ongoing work with the very 
complex LYG patients until we complete the development of the new protocol, which is in the 
early stages of development.
Effective with Amendment CC (Version Date: 06/10/2019), the accrual ceiling is being 
increased by 15 to a total of 105 patients.   LYG is a rare disease that does not have effective 
treatments.  This increase in accrual for this natural history study allows for continued work on 
the biology and management of a very rare lymphoproliferative process.  We have a new 
protocol testing novel agents that can be offered to these patients, but that protocol does not 


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allow us to perform baseline mutational testing or manage patients who do not active therapy.
9
COLLABORATIVE AGREEMENTS
None/Not applicable.
10 HUMAN SUBJECTS PROTECTIONS
10.1
 RATIONALE FOR SUBJECT SELECTION 
LYG is a rare disorder which affects otherwise normal individuals.  It may be seen in patients of 
all ages and sex, and may be associated with immunodeficiency states such as HIV infection and 
CID. Any patient with a diagnosis of LYG at least 12 years of age, regardless of gender, 
ethnicity, or race will be eligible for this study. Patients who in the opinion of the principal 
investigator are poor psychiatric or medical risks are not eligible. This study is addressing the 
natural history of LYG and testing the efficacy of interferon and/or DA-EPOCH-R treatment in a 
disease in which there is no standard treatment. 
10.2
 PARTICIPATION OF CHILDREN
We wish to include patients who are at least 12 years old because this disease does occasionally 
affect younger age patients and because there is no adequate treatment at this time.  The age 
cutoff is based on the rarity of this disease in younger children.
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally-impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 10.4), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation to assess ongoing capacity of the 
subjects and to identify an LAR,as needed. 
Please see section 10.5.1 for consent procedure.
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS: 
Patients may obtain direct benefit from treatment with interferon and/or DA-EPOCH-R 
chemotherapy.  Preliminary results indicate that interferon may induce durable remissions in 
over 50% of patients.  The risks of interferon and DA-EPOCH-R chemotherapy are well 
described and reasonable in anticipation of expected benefits. 
10.4.1 Hepatitis B Reactivation
Because of the risk hepatitis B reactivation in patients receiving DA-EPOCH-R, patients will be 
closely monitored as per Section 4.3.  Patients who test positive for either hepatitis B surface 
antigen or hepatis B core antibody will receive prophylaxis.  HBV PCR is also closely monitored 


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while patients are receiving treatment. 
10.4.2 Risks related to CT and PET scans
CT and PET scans often use a contrast agent.  There is a small risk of having a reaction to the 
contrast and most often include nausea, pain in the vein where the contrast is given, headache, 
metallic and/ or bitter taste in the mouth and a warm, flushing feeling.  Rarely, some people have 
more severe allergic reactions to the contrast which may include skins rashes, shortness of 
breath, wheezing or low blood pressure.
10.4.3 Risks from Radiation Exposure
On this study, patients who are given EPOCH-R will receive up to two (2) PET Scans and four 
(4) CT Scans (type of scan varies by disease, max dose possible is from 
Neck/Chest/Abdomin/Pelvis scans) maximum in annual period. Patients who are given 
Interferon will receive up to two (2) PET Scans and eight (8) CT Scans (type of scan varies by 
disease, max dose possible is from Neck/Chest/Abdomin/Pelvis scans) maximum in annual 
period. Participants in both arms will undergo up to one (1) optional CT guided biopsy. The 
procedures for performing the CT and [18F]-FDG PET scans will follow clinical policies, no 
special procedures will apply to these assessments for research purposes.
The total radiation dose for research purposes will be approximately 12.4 rem for patient who 
receive Interferon. The total radiation dose for research purposes will be approximately 7.2 rem 
for patient who receive EPOCH-R. This amount is more than would be expected from everyday 
background radiation. Being exposed to excess radiation can increase the risk of cancer.
10.4.4 Risks of MRI:  
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. 
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the 
scanner is loud enough to damage hearing, especially in people who already have hearing loss. 
There are no known long-term risks of MRI scans.
10.4.5 Risks related to Gadolinium enhanced MRI
During part of the MRI patient will receive gadolinium, a contrast agent, through an intravenous 
(IV) catheter (small tube). It will be done for research purposes. 
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  There is also a risk of kidney damage from the use of gadolinium. 
10.4.6 Blood Sampling
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting.
10.4.7 Lumbar Puncture
Risks of lumbar puncture include headache, dizziness, infection, back discomfort, minor radicular 
numbess and brainstem herniation
10.4.8 Biopsy Collection
The risks associated with biopsies are pain and bleeding at the biopsy site. In order to minimize 
pain, local anesthesia will be used. Rarely, there is a risk of infection at the sampling site. CT 


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guidance may be used in obtaining biopsies (see 10.4.3 for radiation risk). 
10.4.9 Bone Marrow Aspiration/ Biopsy
Bone marrow biopsy is minimally invasive and is typically a very safe procedure. Usually the 
hipbone is numbed with anesthesia. Using a needle, the solid and liquid portion of bone marrow 
is taken out. This procedure causes some pain. Very rarely, infection or bleeding may occur at the 
needle site.
10.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided to the participant or consent designee(s) (e.g., 
the parent/guardian if participant is a minor, legally authorized representative [LAR] if 
participant is an adult unable to consent) for review prior to consenting.  A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the 
designated study investigator and with the agreement of the participant/consent designee(s).  
Whether in person or remote, the privacy of the subject will be maintained. Consenting 
investigators (and participant/consent designee, when in person) will be located in a private area 
(e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee 
will be informed of the private nature of the discussion and will be encouraged to relocate to a 
more private setting if needed.
With regard to the optional biopsy for research in the protocol, the patient will consent at the 
time of the procedure.  If the patient refuses the optional biopsy at that time, the refusal will be 
documented in the medical record and in the research record.
10.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation
For participants addressed in section 10.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 10.5. 
10.5.2 Consent Process for Minors
Consent will be obtained from parent(s)/guardians of minor children as described in Section 
Where deemed appropriate by the clinician and the child’s parent(s) or guardian, the child will 
also be included in all discussions about the trial and age-appropriate language will be used to 
describe the procedures and tests involved in this study, along with the risks, discomforts and 
benefits of participation. The assent process will take place in conjunction with consent; 
therefore, in person and remote assent are permitted under the same circumstances as in person 
and remote consent. Written assent will not be obtained from children as the study holds out the 
prospect of direct benefit that is important to the health and well-being of the child and is 
available only in the context of the research. Verbal assent will be obtained as appropriate for 
children ages 12-17. The consent/assent process will be documented in the child’s medical 


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record, including the assessment of the child’s ability to provide assent (verbal versus written) as 
applicable.
All children will be contacted after they have reached the age of 18 to determine whether they 
wish to continue on the trial and informed consent will be obtained from them at that time.
10.5.3 Consent for minors when they reach the age of majority 
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require that consent be obtained 
from of the now adult with the standard protocol consent document to ensure legally effective 
informed consent has been obtained. We request waiver of informed consent for those 
individuals who become lost to follow-up or who have been take off study prior to reaching the 
age of majority.
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d):
(1) The research involves no more than minimal risk to the subjects.
a.
Analysis of samples and data from this study involves no additional risks to 
subjects.
(2) The waiver or alteration will not adversely affect the rights and welfare of the subjects.
a.
Retention of these samples or data does not affect the welfare of subjects. 
(3) The research could not practicably be carried out without the waiver or alteration.
a.
Considering the length of time between the minor’s last contact with the research 
team and their age of majority, it will likely be very difficult to locate them again. 
A significant reduction in the number of samples analyzed is likely to impact the 
quality of the research. 
(4) Whenever appropriate, the subjects will be provided with additional pertinent information 
after participation.
a.
We only request a waiver of consent for those subjects who have been lost to 
follow-up or who have been taken off study prior to reaching the age of majority.
11 REGULATORY AND OPERATIONAL CONSIDERATIONS 
11.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB) 
and will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

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
Insufficient compliance to protocol requirements

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB.
11.2 QUALITY ASSURANCE AND QUALITY CONTROL
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and inspection by local and regulatory authorities.
11.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
11.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff. This confidentiality is extended to cover testing of biological samples and genetic 
tests in addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. 
All research activities will be conducted in as private a setting as possible.
The study monitor, representatives of the Institutional Review Board (IRB), and/or regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 


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for the participants in this study. The clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by the clinical site(s) and by NCI CCR research staff will be secured and password 
protected. At the end of the study, all study databases will be archived at the NIH.
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.
12 PHARMACEUTICAL INFORMATION 
12.1 INTERFERON ALPHA 2-B
Refer to the FDA approved package insert for complete product information.
12.1.1 Supply
Commercially manufactured by Schering Corporation.  It is supplied as a sterile liquid in vials 
containing 5 MU (million units)/0.5 ml or 10 MU/ml.  Vials should be stored at 2-8oC.  
12.1.2 Toxicities
Acute side effects include fever and flu-like symptoms of headache, myalgias, and chills.  
Chronic toxicities appear to be related to the weekly cumulative dose and are persistent as long 
as treatment is continuing.  Other toxicities include depression, hypothyroidism, severe fatigue, 
hemophagocytic syndrome, gastrointestinal symptoms such as constipation, neurological side 
effects involving both the peripheral and central nervous system such as memory loss, rapidly 
reversible granulocytopenia, and transaminitis.   Clinically significant cardiovascular side effects 
are infrequent.  
12.2 CYCLOPHOSPHAMIDE 
Refer to the FDA approved package insert for complete product information.
12.2.1 Supply
Commercially available in white crystalline formulation for intravenous injection, in vials 
containing 100 mg, 200 mg, 500 mg, 1gm, or 2 gm. Intact vials are stable at room temperature 
storage (not to exceed 30oC). Reconstitute with appropriate amounts of Sodium Chloride 


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Injection (0.9%NS) to produce a solution with final concentration of 20 mg/ml.  Discard solution 
after storage for 24 hours at room temperature. After reconstitution, cyclophosphamide is stable 
for up to 6 days if refrigerated (2-8oC). Cyclophosphamide will be diluted in 100 mL of 5% 
Dextrose Injection or 0.9%NS and infused over 30-60 minutes. 
12.2.2 Toxicities
Myelosuppression, nausea and vomiting, hemorrhagic cystitis, alopecia. Cystitis can be largely 
prevented by maintaining a good state of hydration and good urine flow during and after drug 
administration using the following guidelines. Please refer to the package insert for a complete 
listing of all toxicities.  
12.2.3 Hydration Guidelines
All patients should receive 0.9%NS at the following volumes (based on cyclophosphamide dose 
levels) and rates with half given before and half the specified volume given before starting 
cyclophosphamide administration and half the volume given after completion of the 
cyclophosphamide administration.  
Cyclophosphamide
Dosage Levels
Fluid Volume and Administration Rate
1 & 2
1000 mL 0.9%NS @ 300 – 500 mL/h
Levels 3, 4, & 5
2000 mL 0.9%NS @ 300 – 500 mL/h
Levels  6
2500 mL 0.9%NS @ 300 – 500 mL/h
12.3 DOXORUBICIN
Refer to the FDA approved package insert for complete product information.
12.3.1 Supply
Commercially available in 10, 20, 50, and 150 mg vials with 50 mg, 100 mg, and 250 mg of 
lactose, respectively. 
12.3.2 Toxicities
Myelosuppression, stomatitis, alopecia, nausea and vomiting, and acute and chronic cardiac 
toxicity, manifested as arrhythmias or a congestive cardiomyopathy, the latter uncommon at total 
cumulative doses less than 500 mg/m2. The drug causes local necrosis if infiltrated into 
subcutaneous tissue. 
12.4
 VINCRISTINE
Refer to the FDA approved package insert for complete product information.
12.4.1 Supply
Commercially available in 1 mg, 2 mg, and 5 mg vial sizes. Each ml contains 1 mg of 
vincristine, 100 mg mannitol, 1.3 mg methylparaben, and 0.2 mg propylparaben. Drug should be 
stored at 2-8oC and should be protected from light. 
12.4.2 Toxicities 
Peripheral neuropathy, autonomic neuropathy, alopecia. Local necrosis if injected 


Abbreviated Title:  Treatment and Nat. Hx. LYG
Version Date:  01/27/2021
33
subcutaneously.
12.5
 ETOPOSIDE
Refer to the FDA approved package insert for complete product information.
12.5.1 Supply
Commercially available as a concentrate for parenteral use in 100 mg vials; each ml contains 20 
mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80, 650 mg of 
polyethylene glycol 300, and 30.5% alcohol. 
12.5.2 Toxicities 
Myelosuppression, nausea, vomiting, anaphylactoid reactions, alopecia, and hypotension if 
infusion is too rapid.
12.6 ADMINISTRATION OF VINCRISTINE/DOXORUBICIN/ETOPOSIDE
Stability studies conducted by the Pharmaceutical Development Section, Pharmacy Department, 
NIH Clinical Center, have demonstrated that admixtures of vincristine, doxorubicin, and 
etoposide in 0.9% Sodium Chloride Injection, USP (0.9%NS) at concentrations, respectively, of 
1, 25, and 125 mcg/mL; 1.4, 35, and 175 mcg/mL; 2, 50, and 250 mcg/mL; and 2.8, 70, 350 
mcg/mL are stable for at least 36 hours at room temperature when protected from light. Also, 
admixtures containing vincristine, doxorubicin, and etoposide concentrations of 1.6, 40, and 200 
mcg/mL are stable for at least 30 hours at 32°C.
For this study, etoposide, doxorubicin, and vincristine comprising a daily dose (a 24-hour 
supply) will be diluted in 0.9%NS. Product containers will be replaced every 24 hours to 
complete the planned duration of infusional treatment. Product volumes will be determined by 
the amount of etoposide present in a 24-hour supply of medication. For daily etoposide doses 
≤130 mg, admixtures will be diluted in approximately 500 mL 0.9%NS.  For daily etoposide 
doses >130 mg, admixtures will be diluted in approximately 1000 mL 0.9%NS.
Etoposide + doxorubicin + vincristine admixtures will be administered by continuous IV 
infusion over 96 hours with a suitable rate controller pump via a central venous access device.
12.7 PREDNISONE
Refer to the FDA approved package insert for complete product information.
12.7.1 Supply
Commercially available in a large number of oral dosage strengths including pills and liquid 
formulations. Tablets should be stored in well-closed containers at temperatures between 15-
30oC. 

Doses:  Prednisone utilization will be simplified by using only 20- and 50-mg tablets to 
produce individual doses and by stratifying prednisone doses by a patient’s body surface area 


Abbreviated Title:  Treatment and Nat. Hx. LYG
Version Date:  01/27/2021
34
(BSA), according to the chart below. These are recommendations and not requirements.
BSA (m2)
Each Dose
1.25 – 1.49
80 mg
1.5 – 1.83
100 mg
1.84 – 2.16
120 mg
2.17 – 2.41
140 mg
2.42 – 2.6
150 mg
2.61 – 2.69 
160 mg
2.7 – 3
170 mg
12.7.2 Toxicities
Proximal muscle weakness, glucose intolerance, thinning of skin, redistribution of body fat, 
Cushingoid facies, immunosuppression, propensity to gastrointestinal ulceration.
12.8
 FILGRASTIM 
Refer to the FDA approved package insert for complete product information.
12.8.1 Supply
Commercially available as a clear sterile solution in single use vials containing 300 mcg (1 mL 
vial) and 480 mcg (1.6 mL vial). Filgrastim will be stored at 2-8oC and is stable for at least 1 
year when maintained under refrigeration.  DO NOT FREEZE and DO NOT SHAKE the drug 
product. Final concentration is 300 mcg/ml. Filgrastim will be given by subcutaneous injection; 
patient or other caregiver will be instructed on proper injection technique. 
12.8.2 Toxicities
Rare anaphylactic reactions with the first dose; bone pain at sites of active marrow with 
continued administration. Local reactions at injection sites. Constitutional symptoms, increased 
alkaline phosphatase, LDH, uric acid; worsening of pre-existing inflammatory conditions. 
12.9
 METHOTREXATE
Refer to the FDA approved package insert for complete product information.
12.9.1 Supply
Commercially available folic acid antagonist, and only the preservative-free preparation may be 
used for intrathecal injection.  It should be stored at 15-30C and protected from light. 
12.9.2 Toxicities 
It can cause leukopenia, and as such leucovorin should be administered 24 hours after each dose.  
It can cause headaches, drowsiness, and blurred vision.  It can also cause a transient acute 
neurologic syndrome manifested by confusion, hemiparesis, seizures, and coma.
12.10  CYTARABINE 
Refer to the FDA approved package insert for complete product information.
12.10.1
  Supply
A commercially available pyrimidine nucleoside antimetabolite, and should be stored at 20 - 
25C, and used within 2 years of the date of manufacture.  Prior to intrathecal injection it is 
reconstituted with preservative free 5% dextrose or 0.9% sodium chloride, and should be used as 


Abbreviated Title:  Treatment and Nat. Hx. LYG
Version Date:  01/27/2021
35
soon as possible. 
12.10.2
  Toxicities  
It can cause myelosuppression, fever, dizziness, somnolence, and arachnoiditis.
12.11 RITUXIMAB
Refer to the FDA approved package insert for complete product information.
12.11.1
  Supply
The NIH Clinical Center Pharmacy Dept. will purchase rituximab from commercial sources. 
Rituximab is provided in pharmaceutical grade glass vials containing 10 mL (100 mg) or 50 mL 
(500 mg) at a concentration of 10 mg of protein per milliliter. Please refer to the FDA-approved 
package insert for rituximab for product information, extensive preparation instructions, and a 
comprehensive list of adverse events. 
12.11.2
  Storage
Rituximab for clinical use should be stored in a secure refrigerator at 2 to 8o C. 
12.11.3
  Preparation
Rituximab will be diluted with 0.9% Sodium Chloride or 5% Dextrose Injection to prepare a 
standard product with concentration of 2 mg/ml.  Caution should be taken during the preparation 
of the drug, as shaking can cause aggregation and precipitation of the antibody. 
12.11.4
  Stability
After dilution, rituximab is stable at 2-8 degrees C (36-46 degrees F) for 24 hours and at room 
temperature for an additional 24 hours. 
12.11.5
  Administration
A peripheral or central intravenous line will be established. During rituximab infusion, a patient's 
vital signs (blood pressure, pulse, respiration, temperature) should be monitored according to the 
standard of care. Medications readily available for the emergency management of anaphylactoid 
reactions should include: epinephrine (1:1000, 1 mg/mL) for subcutaneous injection, 
diphenhydramine hydrochloride for intravenous injection, and resuscitation equipment.
Prophylaxis against hypersensitivity and infusion-related reactions associated with rituximab will 
include acetaminophen 650 mg and diphenhydramine hydrochloride 50-100 mg administered 
30 to 60 minutes prior to starting rituximab. Patients will also receive their first dose of 
prednisone 60 mg/m2 (or a glucocorticoid equivalent dose of an alternative steroid) at least 
60 minutes before rituximab treatment commences.
Rituximab will be administered as an intravenous infusion at 375 mg/m2 on day 1 of each cycle 
of EPOCH, immediately prior to starting etoposide + doxorubicin + vincristine administration. 
Rituximab infusions will be administered to patients primarily in an outpatient clinic setting.  
First dose:
The initial dose rate at the time of the first rituximab infusion should be 50mg/hour (25 
mL/hr) for the first 30 minutes. If no toxicity is seen, the dose rate may be escalated 
gradually in 50 mg/hour (25 mL/h) increments at 30 minute intervals) to a maximum of 400 


Abbreviated Title:  Treatment and Nat. Hx. LYG
Version Date:  01/27/2021
36
mg/hour (maximum rate = 200 mL/h). 
Second and Subsequent Doses (select the appropriate administration timing):
90-minute Administration
If the first dose of rituximab was well tolerated, subsequent doses may be administered 
over 90 minutes with 20% of the total dose given in the first 30 minutes, and remaining 
80% of the total dose administered over the subsequent 60 minutes; e.g.:
Two-Step Rate Escalation
Volume to administer (X mL)
1st portion (0 – 30 minutes)
2nd portion (30 – 90 minutes)
Special Note: The 90-minute infusion scheme is not recommended for patients with 
clinically significant cardiovascular disease or high circulating lymphocyte counts 
(≥5000/mcL).
Standard Administration for Second & Subsequent Infusions
Patients who tolerate initial treatment without experiencing infusion-related adverse 
effects but for whom the 90-minute infusion scheme during subsequent treatments is 
considered inappropriate, may receive subsequent rituximab doses at the Standard Rate 
for Subsequent Infusions, which is as follows:
Begin at an initial rate of 100 mg/hour (50 mL/h) for 30 minutes. If administration is well 
tolerated, the administration rate may be escalated gradually in 100-mg/hour (50-mL/h) at 
30-minute intervals to a maximum rate of 400 mg/hour (maximum rate = 200 mL/h).
CAUTION:  DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.  
12.11.6
  Toxicities
Common toxicities include fever, chills, nausea, asthenia, headache, angioedema, pruritis and 
rash.  Leukopenia occurs in approximately 10% but grade 3 or 4 neutropenia is uncommon. 
Hypotension occurred in 10% of patients during rituximab infusion, and serious bronchospasm 
and urticaria associated with rituximab infusion each occurred in fewer than 10% of patients. 
Less common toxicities include abdominal pain, vomiting, thrombocytopenia, anemia, myalgia, 
arthralgia, dizziness, and rhinitis. Bowel obstruction and perforation have been rarely reported. 
Skin reactions, some of them life threatening, have been noted in patients receiving rituximab.  
The FDA currently has a database of 18 patients who have had Stevens-Johnson or toxic 
epidermic necrolysis (TEN) after rituximab and 7 of those patients have died.  The time to onset 
typically was during or within a few weeks of receiving rituximab.  Patients may initially have 
mucositis with sore throat or mouth ulcers followed by diffuse skin rash, which rapidly 
progressed to a total body desquamative rash.  In fatal cases, sloughing of the skin over 80-90% 
of the body surface area was seen, followed by fulminate infection, multi-organ failure and 
death. In addition, hepatitis B virus reactivation with fulminant hepatitis, hepatic failure and 
death has been reported. In patients with Rheumatoid Arthritis, serious cardiac events have 
Total Dose (mg)
2
0.2 X mL (over 30 min)
Total Dose (mg)
2
0.8 X mL (over 60 min)


Abbreviated Title:  Treatment and Nat. Hx. LYG
Version Date:  01/27/2021
37
occurred.
12.12 TRIMETHOPRIM/SULFAMETHOXAZOLE
Refer to the FDA approved package insert for complete product information.
12.12.1
  Supply
Will be given as PCP prophylaxis to patients receiving chemotherapy.  It will be supplied by the 
Clinical Center Pharmacy. 
12.12.2
  Toxicities
The most common side effects are hypersensitivity, rash, nausea, vomiting, diarrhea, GI upset, 
and photosensitivity. Stevens-Johnson syndrome, bone marrow suppression, hepatic toxicity, and 
renal toxicity may occur. This agent should be stopped immediately if rash develops. See 
package insert for additional information. 
13 REFERENCES
1.
Liebow AA, Carrington CB, Friedman RJ.  Lymphomatoid granulomatosis. Human Pathol 
3:457-558 (1972).
2.
Kassel SH, Echevarria RA, Guzzo FP. Midline malignant reticulosis (so called lethal 
midline granuloma). Cancer 23:920-935 (1969).
3.
DeRemee RA, Weiland LH, McDonald TJ. Polymorphic reticulosis, lymphomatoid 
granulomatosis: two diseases or one? Mayo Clin Proc 53:634-640 (1978).
4.
Jaffe ES. Pathologic and clinical spectrum of post-thymic T-cell malignancies. Cancer 
Invest 2:413-426 (1984).
5.
Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid granulomatosis. Prospective clinical 
and therapeutic experience over 10 years. N Engl J Med 306:68-75 (1982).
6.
Jaffe ES, Lipford Jr EH, Margolick JB, et al. Lymphomatoid granulomatosis and 
angiocentric lymphoma: a spectrum of post-thymic T-cell proliferations. Semin Resp Med, 
(1988).
7.
Medeiros, LJ, Peiper, SC, Elwood, L, et al. Angiocentric immunoproliferative lesions: A 
molecular analysis of eight cases. Human Path 22: 1150-1157 (1991). 
8.
Medeiros, LJ, Jaffe, ES, Chen, Y, et al. Localization of Epstein-Barr viral genomes in 
angiocentric immunoproliferative lesions.  Am J Surg Path 16:439-447 (1992).
9.
Borishch, B, Hennig, I, Laeng, H, et al. Association of the subtype 2 of the Epstein-Barr 
virus with T-cell non-Hodgkin’s lymphoma of the midline granuloma type. Blood 82:858-
864 (1993).
10.
Wilson, WH, Bryant, G, Bates, S, et al. EPOCH chemotherapy: Toxicity and efficacy in   
relapsed and refractory non-Hodgkin’s lymphoma. J. Clin Oncol 11:1573, 1993.  
11.
Faye A, Van Den Abeele T, Peuchmaur M, et al: Anti-CD20 monoclonal antibody for post-
transplant lymphoproliferative disorders. Lancet 352:1285, 1998. 
12.
Cook RC, Connors JM, Gascoyne RD, et al: Treatment of post-transplant lympho-
proliferative disease with rituximab antibody after lung transplantation.  Lancet 354:1698, 
1999.
13.
Kuehnle I, Huls MH, Liu Z, et al: CD20 monoclonal antibody (rituximab) for therapy of 
Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation. Blood 95:1502, 
2000.


Abbreviated Title:  Treatment and Nat. Hx. LYG
Version Date:  01/27/2021
38
14.
Gutierrez ME, Grossbard ML, Little RF, et al: Dose-adjusted EPOCH chemotherapy and 
rituximab (EPOCH-R): An effective regimen in poor prognosis aggressive B-cell non-
Hodgkin’s lymphoma.  Proc Am Soc Clin Oncol (Accepted) 2000. 
15.
Little R, Gutierrez ME, Wilson WH: Chemotherapy sensitization by rituximab: 
Presentation of two case studies.  (Submitted).


Abbreviated Title:  Treatment and Nat. Hx. LYG
Version Date:  01/27/2021
39
14 APPENDIX 1:  EPOCH ADMIXTURES: PREPARATION AND ADMINISTRATION 
Preparation: 
All 3-in-1 admixtures dispensed from the Pharmacy will contain a 24-hour supply of etoposide, 
doxorubicin, and vincristine, PLUS 40 mL overfill (excess) fluid and a proportional amount of 
drug to compensate for volume lost in parenteral product containers and administration set 
tubing.
Etoposide Dose
Volume of Fluid 
Containing a Daily Dose
Volume of Overfill
(fluid + drug)
Total Volume in the Product
(including overfill)
< 130 mg
528 mL
40 mL
568 mL
≥ 130 mg
1056 mL
40 mL
1096 mL
Before dispensing 3-in-1 admixtures, Pharmacy staff will:
[1] Purge all air from the drug product container,
[2] Attach an administration set appropriate for use with a portable pump,
[3] The set will be primed close to its distal tip, and
[4] The set will be capped with a Luer-locking cap.
Pre-printed product labeling will identify the ‘Total Volume To Infuse’ and the ‘Volume of 
Overfill (fluid + drug)’.
Bags will be exchanged daily for four consecutive days to complete a 96-hour drug infusion 
(unless treatment is interrupted or discontinued due to un-anticipated events).
Administration: 
Portable pumps used to administer etoposide + doxorubicin + vincristine admixtures will be 
programmed to deliver one of two fixed volumes at one of two corresponding fixed rates based 
on the amount of etoposide and fluid that is ordered (see the table, below).
Etoposide Dose
Total Volume to 
Infuse per 24 hours
Volume of Overfill
(drug-containing fluid)*
Administration Rate
< 130 mg
528 mL
40 mL
22 mL/hour
≥ 130 mg
1056 mL
40 mL
44 mL/hour
*DO NOT attempt to infuse the overfill
At the end of an infusion, some residual fluid is expected because overfill 
(excess fluid and drug) was added; however, nurses are asked to return to the 
Pharmacy for measurement any drug containers that appear to contain a 
greater amount of residual drug than expected.
Example at right:
The amount of fluid remaining in a bag after completing a 24-hour 
infusion (1056 mL delivered).

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/27/2021
Page 1 of 19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
Christopher Melani, M.D.
STUDY TITLE: 
Treatment and Natural History Study of Lymphomatoid 
Granulomatosis
STUDY SITE: 
NIH Clinical Center
Cohort:
Affected patient
Consent Version:
01/27/2021
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Christopher Melani, M.D. 
Phone:  240-760-6057
Email:  christopher.melani@nih.gov 
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being enrolled is a minor then the term “you” refers to “you and/or your child” 
throughout the remainder of this document.
If the individual being asked to participate in this research study is not able to give consent to be 
in this study, you are being asked to give permission for this person as their decision-maker. The 
term “you” refers to you as the decision-maker and/or the individual being asked to participate in 
this research, throughout the remainder of this document.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
You are being asked to take part in this study because you have Lymphomatoid Granulomatosis 
(LYG). The purpose of this study is to learn about LYG and its treatments.
IRB NUMBER: 94C0074
IRB APPROVAL DATE: 04/13/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/27/2021
Page 2 of 19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
A total of 105 people will be enrolled in this study.
DESCRIPTION OF RESEARCH STUDY
This is a study of interferon and/or chemotherapy for the treatment of lymphomatoid 
granulomatosis (LYG).  There is no standard treatment for your disease.  In this study, the selection 
of your therapy will depend on the type of your disease and past treatment.  If you have LYG 
without signs of aggressive LYG, you will receive interferon.  Interferon is an approved drug that 
is being tested as a treatment for your disease.  Interferon is a protein which your body naturally 
produces.  If you do not respond to interferon and/or have aggressive LYG, you will receive 
EPOCH-R chemotherapy (each letter stands for one of the drugs used in the combination).  If you 
have disease after receiving interferon and/or EPOCH-Rituximab (EPOCH-R), you may receive 
rituximab by itself or with interferon.  Your physician may make changes to this treatment 
approach if your disease does not adequately respond.
EPOCH-R is a combination of drugs which seem to have a high degree of effectiveness in patients 
with other types of lymphomas.  Rituximab is a special kind of drug called an antibody which 
binds to a specific molecule (called CD20) present on most B-cell lymphomas. EPOCH-R contains 
drugs which are standard for the treatment of lymphomas.  Because higher doses of chemotherapy 
may increase the benefit, the doses of several drugs in EPOCH-R may be increased on each cycle 
if you tolerated them on the previous cycle.  However, EPOCH-R has not been previously tested 
in patients with LYG.  If you respond to EPOCH-R but still have disease present after its 
completion, you will receive interferon after the chemotherapy is completed.  An important part 
of this study is to understand the features of LYG.  Therefore, to help us understand this disease 
better, we will try to obtain a biopsy of one of your lesions.  Although the results of this biopsy 
may not directly benefit you, it may help in our future understanding of the disease.
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?
In order to determine if you are eligible for this study, several tests need to be done.  This period 
of evaluation may take up to three weeks and may be done on an outpatient basis.  Evaluation may 
include some or all of the following tests: standard blood tests, 24 hour collections of urine, tests 
of lung and heart function, computerized tomography (CT) scans, MRIs if you have disease in 
your central nervous system (CNS), nuclear medicine scans of the body (called a PET scan), bone 
marrow biopsies and biopsies of suspected areas of tumor using CT guidance.  
Interferon treatment
If you receive interferon, you administer this drug to yourself as an injection under the skin three 
times a week.  While you are receiving interferon, you will be followed in the clinic every 2-12 
weeks, depending on how you are tolerating and responding to the interferon.  We will evaluate 
your disease with  CT scans MRI (if you have CNS disease) every month for the first 6 months, 
then every 3 months. In addition, PET scans will be done before you start study therapy and after 
you have completed interferon therapy. The dose will be increased as tolerated over the next 
several months to a dose that is effective and tolerated by you.  You will receive interferon on a 
chronic basis, for a year past the time your disease goes away, depending on your response.
EPOCH-R chemotherapy treatment
IRB NUMBER: 94C0074
IRB APPROVAL DATE: 04/13/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/27/2021
Page 3 of 19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The chemotherapy regimen known as DA-EPOCH-R will be given by intravenous (IV) infusion 
through a “central line,” an IV catheter (or tube) placed in a large vein your arm or chest. Patients 
who receive dose adjusted (DA) EPOCH-R chemotherapy will receive the following drugs: 
etoposide (E), prednisone (P), vincristine (O), cyclophosphamide (C), doxorubicin (H), and 
rituximab (R). The drug rituximab will be given by IV infusion on the first day of treatment over 
several hours. When the rituximab IV infusion is complete, the drugs doxorubicin, etoposide, and 
vincristine will each be given by continuous IV infusion over the next 4 days (that is, continuously 
for a total of 96 hours). Cyclophosphamide will be given by IV infusion on Day 5 after you have 
received the previous chemotherapy drugs. Prednisone will be given by mouth (orally) on each 
day for 5 days. You will receive the drug filgrastim by subcutaneous (under the skin) injection 
starting on Day 6 to increase white blood cell counts. Filgrastim will be continued until your white 
blood counts have reached acceptable levels. The dose of doxorubicin, etoposide, and/or 
cyclophosphamide may be “adjusted” up or down depending on your white blood cell count. You 
will be given a drug commonly known as Bactrim to be taken by mouth (orally) three times a week 
(for example, on a Monday-Wednesday-Friday schedule) to guard against possible infections. You 
will also receive a drug each day to be taken by mouth (orally) to guard against stomach ulcers. In 
addition, you will receive colace, or equivalent, by mouth twice daily to prevent constipation. If 
constipation becomes severe, you may also receive the laxative known as lactulose.
The DA-EPOCH-R therapy will be repeated every twenty-one (21) days, which is known as a 
“cycle” of therapy, for a total of 6 cycles.  Following the fourth and sixth treatment cycles 
(approximately weeks 12 and 18) of DA-EPOCH-R, your doctor will evaluate you with blood 
tests, CT, and  MRI scans (if you have CNS disease). In addition, PET scans will be done before 
you start study therapy and after you have completed study therapy. 
Day of Treatment
1
2
3
4
5
6
7
8
9
10
11
12
13
…
21*
Rituximab
X
Etoposide
X 
Prednisone
X
X
X
X
X
Vincristine
X 
Cyclophosphamide
X
Doxorubicin
X 
Filgrastim
X** 
* This twenty-one day (21) period will be known as a “cycle” of therapy. Therapy will be 
repeated for a total of 6-8 cycles. As described above, during the course of treatment, you 
may also receive the following drugs: methotrexate, Bactrim, omeprazole, and colace.
** Filgrastim will continue to be given to you until your blood counts have reached 
acceptable levels.
Hepatitis B Testing and Prophylaxis:
IRB NUMBER: 94C0074
IRB APPROVAL DATE: 04/13/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/27/2021
Page 4 of 19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
As part of our study, we will test you for infection with Hepatitis B. We will tell you what the 
results mean and if you will require more frequent testing for Hepatitis B and need to take 
medicine to prevent Hepatitis B reactivation while on the study.
If you need to take medicine, you will take one, such as entecavir, by mouth every day until 12 
months after your last chemotherapy.
EBV Testing:
As part of our study, we will test you for infection with Epstein-Barr virus. We will tell you what 
the results mean and if you will require more frequent testing for Epstein-Barr virus. 
OPTIONAL BIOPSY
The biopsy to be performed may be done using CT guidance and is exclusively for research 
purposes and will not benefit you.  It might help other people in the future.  Biopsies for 
experimental purposes will not be done on children. We may request biopsy after you sign consent 
document.
If you agree to have the optional biopsy, you will be asked to sign a separate procedure consent 
before you have the procedure.
Treatment of disease in the nervous system
LYG may spread to the central nervous system (CNS) which includes the brain and spinal cord.  
In some cases, the disease in the CNS will respond to interferon.  However, it may be necessary to 
treat the CNS with chemotherapy which usually includes the instillation of one of chemotherapy 
drugs (methotrexate and cytarabine) directly into the fluid (the cerebrospinal fluid, or CSF) 
surrounding the brain.  This is usually done by first placing a small reservoir (called an Ommaya 
reservoir) under the skin of the scalp; this reservoir is connected to a catheter that is placed through 
the brain itself into the fluid.  This procedure is performed by a neurosurgeon under general 
anesthesia.  These drugs may also be administered through a spinal tap (also called a lumbar 
puncture).  Depending on how you respond to this therapy, it may be necessary to modify it and/or 
to also administer radiation to your brain and/or spinal cord.  Each of these therapies will be 
discussed with you if they are needed.
When you are finished taking the drugs
About 30 days after the last dose of interferon or DA-EPOCH-R, someone will contact you by 
phone if you are not seen in the clinic to see how you are doing and collect information about any 
symptoms or side effects you may be having.  You will then continue to be followed in the clinic 
with visits, scans, and labs about every 3 months during year 1, about every 4 months for year 2, 
about every 6 months for year 3, and then once a year for years 4 and 5.  After 5 years, we will 
continue to see you in the clinic or contact you by phone at least yearly, and you will have scans 
and other tests only as needed.  
BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a woman 
who can become pregnant, or are the partner of a woman who can become pregnant, you will need 
to practice an effective form of birth control before starting study treatment and during study 
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treatment. If you think that you or your partner is pregnant, please contact the study doctor before 
taking any further study treatment or undergoing any imaging scans.  
Effective forms of birth control include:

abstinence 

intrauterine device (IUD)

hormonal [birth control pills, injections, or implants]

tubal ligation

vasectomy
RISKS OR DISCOMFORTS OF PARTICIPATION
You will have a blood drawn from a vein.  This may require a needle stick in your arm or hand, or 
if you already have an IV catheter in place, we may be able to draw through that.  The amount of 
blood we will draw is up to 5 tablespoons of blood may be drawn before treatment, and at 2, 4, 8, 
and 12 weeks and every 3 months thereafter for research studies. Blood draws may cause pain, 
redness, bruising or infection at the site of the needle stick.  Rarely some people faint.  The study 
team member may apply numbing cream to the area so that the needle stick won’t hurt as much 
Biopsies of tumor will be done with local or general anesthesia.  The tumor biopsies are being 
performed for two reasons; first to confirm your diagnosis and second to perform research tests on 
the tumor.  Biopsies requiring major surgery (opening the chest or abdomen) will only be done if 
necessary for medical care and will not be done for experimental purposes.  It is important for you 
to understand that in some cases, biopsies of tumor may be done primarily for experimental 
purposes. Biopsies for experimental purposes will not be done on children, however, biopsies to 
confirm diagnosis may be done.
In order to receive EPOCH-R chemotherapy, you will need to have a central venous catheter.  This 
is catheter is placed under the skin of the chest wall and enters a major vein in the chest.  There 
are several types of catheters including those which must be removed after each cycle of 
chemotherapy (temporary type) and those which may be kept for the duration of therapy 
(permanent type).  These options will be discussed with you.  The risks associated with placing 
some catheters include pain, bleeding, infection and collapsed lung.  The long term risks of the 
catheter include infection, and clotting of your veins.  If these occur, it may be necessary to remove 
the catheter.  These risks will be explained to you in more detail at the time of insertion. 
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don’t know all the side effects that may happen. 
Side effects may be mild or serious. Your health care team may give you medicines to help lessen 
side effects. In some cases, side effects can be serious or long-lasting or may never go away. There 
is also the risk of death from either the treatment or your disease.
You should talk to your doctor about any symptoms that you experience while taking part in the 
study.
Risks and side effects related to the treatment are identified below.
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Side Effects of Interferon
Likely:

Flu-like symptoms with headache, fever, chills, muscle and joint aches

Redness, pain and swelling at the injection sites

Lowered white blood cell count that may lead to infection

Lowered platelets which may lead to an increase in bruising or bleeding

Lowered thyroid function which may require replacement with an oral medication

Increase in the liver enzymes

Gastrointestinal symptoms such as nausea, taste change, and constipation

Weight loss

Change in mood such as depression, agitation, anxiety or short temper

Severe fatigue

Neurological symptoms such as numbness in your hands and feet, and memory loss

Decreased sexual function for men
Rare, but serious:

Fainting

Hemophagocytic syndrome, a process where your body destroys its own blood cells

Increased blood clotting

Heart abnormalities

Seizure

Lung infiltrates
Side Effects of EPOCH-R
Likely:

Lowered white blood cell count that may lead to infection

Lowered platelets which may lead to an increase in bruising or bleeding

Lowered red blood cells which may cause anemia, tiredness, or shortness of breath

Should low counts occur, they can be treated with blood products (transfusions), 
antibiotics, and there may be a reduction in the amount of drug given to you

Constipation

Fatigue or tiredness

Tingling of fingers and/or toes
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
Hair loss

Fever and/or chills

Time away from work

Urine colored red for a day or two after the doxorubicin infusion

Fingernail and toenail changes

Tearing or dry eyes

Runny nose

Bony pain
Less Likely:

Nausea and/or vomiting

Loss of appetite, change in taste and weight loss

Temporary shortness of breath or dizziness while receiving rituximab

Headaches

Muscle aches and muscle weakness

Hoarseness or pain in the jaw

Elevated blood sugar levels

Elevated or decreased blood pressure

Confusion

Mouth & throat sores. Temporary irritation to the mouth may lead to mouth ulcers (similar 
to canker sores). Medications to numb the mouth may ease the mouth discomfort

Stomach ulcers

Skin rashes and/or dry skin

Loss of control of muscles or reflexes

Abnormalities in blood results such as elevated liver enzymes, low blood protein and low 
blood calcium

Mood changes such as agitation or depression

Trouble sleeping
Rare, But Serious:

Severe constipation may result in abdominal pain and cramping

Bladder irritation with painful and bloody urine

Damage to the heart muscle
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
Skin rash that may be serious and life-threatening

Allergic reaction that may be severe or life-threatening. Symptoms may include difficulty 
breathing, low blood pressure, fast heart rate, and sweating.

Severe hepatitis (liver infection) in those patients who are carriers of the hepatitis virus. 
Patients who may have had prior exposure to the hepatitis B and C virus may be at an 
increased risk of recurrence of the virus that may lead to severe liver damage that can be 
life-threatening. You doctor will screen you for the hepatitis virus before beginning 
treatment on this study. If you test positive for the virus, you will be closely monitored for 
signs of the infection, and you will be treated, if appropriate, by your doctor.
Other Risks

Drugs used for the treatment of the nervous system:
o
Methotrexate, when administered into the spinal fluid, may cause low blood counts and 
ulcerations in the mouth, stomach, and intestines.  It can cause acute headache, back 
pain, stiff neck, and /or fever; it can also cause weakness or paralysis of certain muscles.  
It can cause seizures and coma.  Other side effects it can cause are usually associated 
with intravenous administration rather than intrathecal (lumbar puncture 
administration), but these include liver function abnormalities, inflammation and 
scarring of the lungs, inflammation of the tissue covering the heart, and severe skin 
reactions. 
o
Cytarabine given by lumber puncture can cause nausea, vomiting, fever, and 
headaches.  Rarely, it can cause weakness and seizures.  When given into the spinal 
fluid, it does not usually cause systemic toxicity, but we will monitor you for low blood 
counts, and liver function abnormalities, which can occur with cytarabine when given 
by vein.

Secondary malignancy (EPOCH-R):
A number of established chemotherapy agents have an inherent risk of causing another 
cancer (known as a “secondary malignancy”). Certain drugs in use today, not currently 
known to be associated with this risk may be shown at a later time to result in the 
development of these secondary malignancies.

Reproductive risks:
Many of the drugs used in this treatment program are toxic to the cells in the ovary and 
testicle and may produce sterility.  Recovery of normal fertility is not well studied although 
we know that some patients treated with this combination have remained fertile after the 
therapy has been completed.  For this reason, men who are about to receive this treatment 
should, if they wish to have children in the future, consider sperm banking before start of 
the treatment.  These drugs, as well as the scans performed to assess your disease may also 
be very toxic to an unborn child or nursing baby.  Women of childbearing age will have a 
pregnancy test, which must be negative at the time of study entry.  This test requires that 
blood be drawn from a vein one or two days prior to the study.  The results of the pregnancy 
test will be made available to you prior to the initiation of the study. If you are a woman 
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and become pregnant while on this study, treatment will be stopped immediately. A safety 
visit will be completed within 30 days following the stop of treatment and then you will be 
taken off the study.

Infection risks:
It is important to emphasize that when you have a decreased white blood cell count you are 
at risk of infection.  Such infections can be very serious and can even cause death if not 
quickly and properly treated.  If you are receiving EPOCH-R, and if you have a temperature 
greater than 38.3o C (101o F), you must call your doctor immediately. If your temperature 
is higher than 38.0o C (100.4 o F) two times in a 24-hour period, you must call your doctor 
immediately.  Chemotherapy may also cause your platelets to fall; since platelets are the 
blood elements that permit blood to clot, this may place you at increased risk of serious 
bleeding.  It may be necessary to give you transfusions of platelets if your platelet counts 
reach very low levels.  There is a small chance that damage to the normal bone marrow 
may eventually result in bone marrow failure, leading to a serious shortage of one or more 
kinds of cells in the blood, or to leukemia.
Interferon may also cause decreases in WBCs.  However, these are usually not associated 
with severe infections.  Because interferon itself causes fever, you should not be concerned 
if you have a fever after the interferon.  However, if you have a persistent fever (more than 
12 hours after your interferon dose), you should call your doctor. 
Your physicians will watch you closely for side effects and will stop treatment if any side 
effects become a serious threat to your life or well-being.  Your physicians will also stop 
the treatments if it becomes clear that the treatment is not successfully controlling your 
disease. For more information about risks and side effects, ask your study doctor.

Complications of treatment in the Central Nervous System (CNS):
Complications of Ommaya insertion are uncommon when done by an experienced group 
but could include infection and bleeding at the operative site or in the brain itself. 
Complications of lumbar puncture may include pain or bleeding at the site of needle 
insertion (the low back), infection, and headache. Most patients tolerate this treatment 
without serious side effects, although drugs placed into the brain fluid (CSF) may cause 
headache, stiff neck, and confusion that resolve when they are stopped.  With long-term 
treatment, confusion and a slowing of thought processes may occur. If this treatment 
becomes necessary for you, the complications of the lumbar puncture or Ommaya insertion 
and methotrexate instillation will be discussed in more detail.  

Hepatitis B Reactivation
Hepatitis B reactivation has occurred in patients treated with DA-EPOCH-R. Signs of 
hepatitis B reactivation may include: fever, fatigue, loss of appetite, nausea, vomiting, 
abdominal pain, dark urine, clay colored bowl movement, joint pain and yellowing of the 
skin and/or eyes (jaundice).  It may lead to long-term health problems, including liver 
damage, liver failure, liver cancer, and even death.  
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
Risks of Lumbar Puncture:
The lumbar puncture may cause pain at the site where the needle goes in and the spinal 
fluid is taken.  There is a small risk of infection or bleeding.  After the lumbar puncture 
you may get a headache.  About a third of adults report a headache after an LP. To minimize 
the risk of a headache, the doctor will use a small needle and may prescribe bed rest for 
one or more hours after the procedure.  If a headache occurs, it is usually mild and can be 
controlled by bed rest, drinking lots of fluids and a pain pill, such as acetaminophen.  
Rarely, the headache is severe and may require additional treatment with a “blood patch”.  
In this procedure, a small amount of your own blood is injected into the lumbar puncture 
site.  This procedure is generally effective in stopping the headache.  A rare but serious 
complication of a LP, if it is done when the pressure inside the head is higher than normal 
(such as when a brain tumor is present), is known as medullary herniation which can result 
in death.  Increased intracranial pressure is very unlikely to be present.  The LP will not be 
done if there are any clinical indications that you have increased intracranial pressure, a 
skin infection in the lower back area, or bone malformation of the lower back (including 
severe scoliosis) which would make a LP difficult. To minimize these risks, the lumbar 
puncture procedure will be performed by a medical professional specifically trained to do 
this procedure.

Biopsy Risks:
Once treatment is complete as part of follow-up assessments, you may agree to the biopsy 
now and change your mind later. If at any time you do not want to have a biopsy done, 
please tell us, it will not affect your care. If you agree to have the biopsy, you will be asked 
to sign a separate procedure consent before you have the procedure(s). The likely side 
effects include discomfort or pain, redness, swelling, and/or bruising at the site of the 
needle insertion.  Bleeding from the site of the needle insertion is a less likely risk.  Rarely, 
significant infection or bleeding from this procedure, allergic reaction to the anesthetic, or 
formation of a scar at the site of needle entry occurs.  If you will have sedation with the 
procedure, these risks will be discussed with you prior to the procedure.  You will be asked 
to sign a separate consent form prior to any biopsy procedure.

Risks of Bone Marrow Aspiration:
These procedures usually cause only brief discomfort at the site from which the biopsy is 
taken.  Rarely, infection or bleeding may occur at the needle site.  A numbing agent that 
can cause a stinging or burning sensation may be injected at the site of your bone marrow 
biopsy.  The biopsy needle will go through the skin into the bone and may produce a brief, 
sharp pain.  As the bone marrow liquid is taken from the bone, there may be a brief, sharp 
pain.  Since the inside of the bone cannot be numbed, this procedure may cause some 
discomfort, however not all patients experience discomfort.  The possible side effects 
associated with a bone marrow biopsy include pain, bleeding, bruising, and infection, as 
well as a reaction to the numbing agent.  
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
Risks of Radiation Exposure:
If you receive Interferon
During your participation in this research study, you may be exposed to radiation from up to eight 
(8) CT scans and two (2) PET Scans to assess your disease and up to one (1) optional CT guided 
each year.  The amount of radiation exposure from these procedures is equal to approximately 12.4 
rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans that you get in this study will expose you to roughly the same amount of radiation 
as 41.3 years’ worth of background radiation. Being exposed to too much radiation can cause 
harmful side effects such as an increase in the risk of cancer.  The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer 
during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from 
the radiation exposure in this study is 1.2 out of 100 (1.2%) and of getting a fatal cancer is 0.6 out 
of 100 (0.6%). 
If you receive DA-EPOCH
During your participation in this research study, you may be exposed to radiation from up to four 
(4) CT scans and two (2) PET Scans to assess your disease and up to one (1) optional CT guided 
each year.  The amount of radiation exposure from these procedures is equal to approximately 7.2 
rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans that you get in this study will expose you to roughly the same amount of radiation 
as 24 years’ worth of background radiation. Being exposed to too much radiation can cause 
harmful side effects such as an increase in the risk of cancer.  The risk depends on how much 
radiation you are exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer 
during their lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from 
the radiation exposure in this study is 0.7 out of 100 (0.7%) and of getting a fatal cancer is 0.4 out 
of 100 (0.4%). 
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
Risks related to MRIs: 
People are at risk for injury from the MRI magnet if they have some kinds of metal in their 
body. It may be unsafe for you to have an MRI scan if you have pacemakers or other implanted 
electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips 
on the wall of a large artery), metal prostheses (including metal pins and rods, heart valves, 
and cochlear implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel 
fragments. Welders and metal workers may have small metal fragments in the eye. You will 
be screened for these conditions before having any MRI scan. If you have a question about 
metal in your body, you should inform the staff. You will be asked to complete an MRI 
screening form before each MRI scan you have.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner. The noise from the 
scanner is loud enough to damage hearing, especially in people who already have hearing loss. 
Everyone having a research MRI scan will be fitted with hearing protection. If the hearing 
protection comes loose during the scan, you should let us know right away. 
There are no known long-term risks of MRI scans.

Risks related to Gadolinium enhanced MRI
During part of the MRI you will receive gadolinium, a contrast agent, through an intravenous 
(IV) catheter (small tube). It will be done for research purposes. It is not known if MRI with 
contrast is completely safe for a developing fetus.  Therefore, all women of childbearing 
potential will have a pregnancy test performed no more than 24 hours before each MRI scan 
with contrast. The scan will not be done if the pregnancy test is positive.
Risks: The risks of an IV catheter include bleeding, infection, or inflammation of the skin and 
vein with pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, 
a metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, 
hives, and lowering of blood pressure. You should not receive gadolinium if you previously had 
an allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is    
given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”.  This condition always involves the skin and can also 
involve the muscles, joints and internal organs.  NSF has resulted in a very small number of 
deaths. A blood test of your kidney function may be done within the month before an MRI scan 
with gadolinium contrast. You will not receive gadolinium for a   research MRI scan if your 
kidney function is below the safe level. Most of the gadolinium contrast leaves the body in the 
urine.  However, the FDA has issued a safety alert that indicates small amounts of gadolinium 
may remain in the body for months to years. The effects of the retained gadolinium are not 
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clear. At this time, retained gadolinium has not been linked to health risks in people whose 
kidneys work well. Some types of gadolinium contrast drugs are less likely to remain in the 
body than others. In this study, we will use the gadolinium contrast drugs that are less likely to 
remain in the body, whenever possible. We will also give you additional information called a 
“Medication Guide.” Upon request, we will give you individual information about retained 
gadolinium we see on your study.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study?
As a result of participating in this investigational treatment program, you will receive evaluation 
and treatment of your LYG.  We do not know if you will receive personal, medical benefit from 
taking part in this study. These potential benefits could include shrinking of your tumor or 
lessening of your symptoms, such as pain, that are caused by the cancer.  In addition, the 
knowledge gained from this study may help others in the future who have cancer.  
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study?
Instead of being in this study, you have these options:
1. Treatment with other chemotherapy.
2. Radiation treatment may control tumor growth in local areas such as lymph nodes, bones 
and lung.  However, this approach will not effectively treat disease which is outside the 
area that is being irradiated.
3. Surgery can be used to remove disease from local areas but is not useful for long-term 
control when the disease has spread.
4. If you decide to have no therapy for your disease, therapy may be started at a later time.  
However, in general, waiting to start therapy may decrease your potential benefit to 
therapy.
5. If your disease has progressed, you also have the option to receive no further treatment and 
seek only treatments that will make you comfortable.
Please talk to your doctor about these and other options.
STOPPING THERAPY
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you

if you become pregnant
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In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. If you withdraw your consent and leave the trial, 
any samples of yours that have been obtained for the study and stored at the NCI can be destroyed 
upon request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed.
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect, use them for future research and 
share them with other researchers. We will not contact you to ask about each of these future uses.  
These specimens and data will be stripped of identifiers such as name, address or account number, 
so that they may be used for future research on any topic and shared broadly for research purpose.  
Your specimens and data will be used for research purposes only and will not benefit you.  It is 
also possible that the stored specimens and data may never be used.  Results of the research done 
on your specimens and data will not be available to you or your doctor.  It might help people who 
have cancer and other diseases in the future. 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
You will not receive compensation for participation in this study. 
IRB NUMBER: 94C0074
IRB APPROVAL DATE: 04/13/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/27/2021
Page 15 of 19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may 
be paid directly by the NIH and some may be reimbursed after you have paid.  Someone will 
work with you to provide more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the Clinical Center, NIH, you may 
have to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board
When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any 
information about your research involvement without your written permission.  However, if you 
sign a release of information form, for example, for an insurance company, the NIH will give the 
insurance company information from your medical record.  This information might affect (either 
favorably or unfavorably) the willingness of the insurance company to sell you insurance.
If we share your specimens or data with other researchers, in most circumstances we will remove 
your identifiers before sharing your specimens or data. You should be aware that there is a slight 
possibility that someone could figure out the information is about you. 
IRB NUMBER: 94C0074
IRB APPROVAL DATE: 04/13/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/27/2021
Page 16 of 19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting,  to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
IRB NUMBER: 94C0074
IRB APPROVAL DATE: 04/13/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/27/2021
Page 17 of 19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Christopher 
Melani, M.D., 240-760-6057, christopher.melani@nih.gov . You may also call the NIH Clinical 
Center Patient Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-
3713, if you have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 94C0074
IRB APPROVAL DATE: 04/13/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/27/2021
Page 18 of 19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Parent/Guardian of a Minor Participant: I have read the explanation about this study and have been given 
the opportunity to discuss it and to ask questions. I give permission for my child to take part in this study.
Signature of Parent/Guardian
Print Name of Parent/Guardian
Date
Signature of Parent/Guardian (as applicable)
Print Name of Parent/Guardian
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
IRB NUMBER: 94C0074
IRB APPROVAL DATE: 04/13/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 01/27/2021
Page 19 of 19
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 94C0074
IRB APPROVAL DATE: 04/13/2021