Clinical trial NCT01092182
Conditions: Burkitt Lymphoma Diffuse Large B-cell Lymphoma, c-MYC Positive Plasmablastic Lymphoma
Keywords: Microarray Toxicity Therapeutic Index HIV Positive HIV Negative HIV Infections
Sponsor: National Cancer Institute (NCI)
Start date: 2010-03-25; Completion date: 2023-02-16
Enrollment: 194 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

* Burkitt lymphoma/leukemia (BL) is highly treatable, but most of the standard therapies require multiple doses of intensive chemotherapy that may require long hospital stays and frequently have severe side effects. In addition, BL is a fairly common type of cancer in patients who also have human immunodeficiency virus (HIV), but treatment outcomes are poor because standard treatments do not work very well in HIV-positive patients and the more intense treatment regimens are highly toxic. New approaches are needed that expand the ways to treat BL with the same efficiency but with reduced side effects.
* Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) is a standard chemotherapy treatment that consists of the drugs etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab. It may be able to treat BL with similar effectiveness but with fewer side effects. Researchers are interested in confirming the results of previous studies that investigated the effectiveness of DA-EPOCH-R in treating BL.

Objectives:

\- To determine the safety and effectiveness of DA-EPOCH-R in treating Burkitt lymphoma.

Eligibility:

\- Individuals at least 18 years of age who have been diagnosed with Burkitt lymphoma and have not had any prior chemotherapy treatments.

Design:

* Individuals will have a series of blood and other tests to determine their suitability for participating in the study. Eligible participants will be divided into high-risk and low-risk groups based on their disease prognosis and the possibility that the BL may or already has spread into the central nervous system.
* Participants will receive intravenous infusion of the six chemotherapy drugs in DA-EPOCH-R in 21-day treatment cycles. The exact doses will be adjusted depending on participants white blood cell counts and other tests.
* High-risk participants will receive six cycles of DA-EPOCH-R. To treat BL that may have entered the central nervous system, high-risk participants will also receive infusions of other chemotherapy drugs into their spinal fluid.
* Low-risk participants will receive up to six cycles of DA-EPOCH-R, with an additional dose of rituximab during each cycle.
* Frequent blood and urine tests will be performed during treatment, as well as body imaging scans and other tests of cancer progression as directed by the study doctors. Participants will receive additional medicines to help prevent possible adverse side effects of DA-EPOCH-R.
* Participants who respond successfully to the treatment will be asked to return for follow-up exams every 3 months for the first 18 months, then every year for the next 3 years. Participants who do not respond successfully to the treatment will be given the opportunity to participate in additional research and treatment protocols, if any are available.

Detailed description:
Background:

* Burkitt lymphoma/leukemia (BL) is highly curable. Standard treatment employs dose intense multi-agent chemotherapy and though effective is associated with high morbidity. Therefore, novel approaches are needed that improve the therapeutic index of BL while maintaining or improving efficacy. In human immunodeficiency virus (HIV)+ BL, outcome has been poor, mainly due to the use of cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone (CHOP) based regimens in this disease.
* Two National Cancer Institute (NCI) phase II trials have used etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH) chemotherapy with 1 or 2 doses of rituximab (R) per cycle in untreated BL. (Dose-adjusted) etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH)-Rituximab has been used in16 HIV negative BL, and 8 HIV positive patients have received 3 to 4 cycles of EPOCHRR to minimize toxicity and risk of opportunistic infections. All patients remain in continuous remission. Treatment was very well tolerated and represents a novel therapeutic strategy in BL.
* This trial seeks to assess the effectiveness of a risk adaptive approach with DA-EPOCHR in untreated BL (HIV+/-). Because this treatment represents a major conceptual departure from standard treatment, it is important to obtain additional Phase II results in limited/advanced stage BL
* c-MYC positive Diffuse large B cell (DLBCL) is a rare variant of Diffuse Large B-Cell Lymphoma (DLBCL). There is very little data on the biology of this disease and what the optimal therapeutic approach should be has not been defined. Therefore, based on our impression that this behaves aggressively and is likely characterized by a high tumor proliferation rate, we plan to accrue patients with this disease in addition to BL patients.
* Plasmablastic lymphoma, another variant of DLBCL is frequently characterized by the activation of MYC and has had a poor outcome historically with standard treatment. We plan to include these patients in the study also. As they are cluster of differentiation 20 (CD20) negative, they will receive DA-EPOCH without Rituximab.

Objectives:

* Determine progression free survival (PFS), event free survival (EFS) and overall survival (OS) of risk adaptive DA-EPOCH-R in untreated BL and c-MYC + DLBCL and DA-EPOCH in c-MYC+ plasmablastic lymphoma.
* Assess predictive value of early fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans on PFS.
* Obtain pilot comparative molecular profiling in HIV negative and positive BL and c- MYC + DLBCL, including c-MYC+ plasmablastic lymphoma.

Eligibility:

* Burkitt lymphoma, c-MYC + DLBCL and c-MYC + plasmablastic lymphoma age greater than or equal to 18 years.
* No prior treatment except limited-field radiotherapy, short course of glucocorticoids and/or cyclophosphamide for an urgent problem at diagnosis.
* Adequate major organ function unless impairment due to lymphoma.

Study Design:

* Phase II Study of risk adapted DA-EPOCH-R in BL, c-MYC + DLBCL and DA-EPOCH in c-MYC+ plasmablastic lymphoma
* Low risk: DA-EPOCH-RR x 3 cycles.
* High risk , c-MYC + DLBCL and c-MYC+ plasmablastic lymphoma : DA-EPOCH (+/-) R x 6 cycles or 8 cycles in select patients.
* Cerebrospinal fluid (CSF) cytology and flow cytometry for analysis of BL.
* High Risk CSF negative - Prophylactic intrathecal treatment
* CSF positive - Active intrathecal treatment
* FDG-PET/CT pre- and post-cycle 2 in all patients.
* A total of 194 patients will be enrolled in the protocol.

Arms: arm 1: Burkitt lymphoma Low Risk Arm Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) every 21 days for 6 cycles arm 2: Burkitt lymphoma High Risk Arm Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) every 21 days for 6 cycles arm 3: Diffuse large B-cell lymphoma (DLBCL) high risk arm Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) every 21 days for 6 cycles
Interventions: intervention 1: EPOCH-R intervention 2: EPOCH-RR
Intervention descriptions: intervention 1: Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) every 21 days for 6 cycles intervention 2: Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) every 21 days for 3 cycles

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
NCI CC Protocol #:10C0052 N 
 NCI CTEP Protocol #: 9177 
 NCI CC Version Date: 09/20/2019 
 
Abbreviated Title: DA-EPOCH-R in BL 
 
NCT Number: NCT01092182 
 
Phase II Study of Dose-Adjusted EPOCH+/- Rituximab in Adults 
With Untreated Burkitt Lymphoma, C-Myc Positive Diffuse Large B-Cell Lymphoma and 
Plasmablastic Lymphoma 
 
 
Coordinating Center:  National Cancer Institute Lymphoid Malignancies Branch 
(NCILYMB)  
 
 
NCI Principal Investigator: Mark Roschewski, M.D.A-F 
Lymphoid Malignancies Branch, CCR, NCI 
Building 10 Room 4N115 
Bethesda, MD 20892 
Phone: 240-760-6183 
Email:  mark.roschewski@nih.gov 
 
NCI Associate Investigators: Wyndham Wilson, M.D., Ph.D.A-F 
Louis M. Staudt, M.D., LYMB, NCI B,E-F 
Seth M. Steinberg Ph.D., BDMS, NCI E-F 
Andrea Nicole Lucas, R.N., OCD, NCI A-B 
Lydia Chou, FNP-BC, OCD, CCR, NCI A-C 
Jagan Muppidi, M.D., Ph.D A-F 
 
Referral Contact: Andrea Nicole Lucas, R.N., OCD, NCI A-B 
Phone: 240-760-6252 
Email:  Lucasan2@mail.nih.gov 
 
 
Responsible Research Nurse/ 
 
Study Coordinator:  Andrea Nicole Lucas, R.N. A-B 
Phone:  240-760-6252 
Email:  Lucasan2@mail.nih.gov 
 
Accountable Investigator:  
Wyndham H. Wilson, M.D., Ph.D. 
 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Investigator Roles: 
A. Obtain information by intervening or interacting with living individuals for research purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes 
F. Studying, interpreting, or analyzing coded, linked data or specimens for research purposes 
G. Some/all research activities performed outside NIH 
Commercial Products:  
EPOCH-R = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Participants**: 
The University of Texas MD Anderson Cancer Center 
Principal Investigator: Michelle Fanale, MD 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd. FC6. 2000 
Houston, TX 77030-4009 
Tel: 713.792.0492 
Fax: 713.794.5656 
mfanale@mdanderson.org  
Dana Farber Cancer Institute (DFCI)  
Principal Investigator: Ann LaCasce, MD 
Dana Farber Cancer Institute 
450 Brookline Ave Room D1B- 30 
Boston, MA 02215 
Tel: 617-632-5959 
Fax: 617-632-5890 
alacasce@partners.org  
Fax: 617.632.4616 
Massachusetts General Hospital (MGH) 
Principal Investigator: Jeremy Abramson, MD 
Study Coordinator: Christine Connolly 
MGH Cancer Center Protocol Office  
326 Cambridge Street, 3rd Floor, 314  
Boston, MA 0211 
617-726-5131 
cconnolly1@partners.org 
Beth Israel Deaconess Medical Center (BIDMC) 
Principal Investigator: Robin Joyce, MD 
Study Coordinator: Nawal Ali 
330 Brookline Avenue 
Boston, MA 02215 
Ph: 617-667-1964 
Fax: 617-667-9922 
nali1@bidmc.harvard.edu 
ECOG-ACRIN / ECOG-ACRIN Medical Research Foundation, Inc. 
Study Chair: Samir Parekh  
Albert Einstein College of Medicine 
Jack and Pearl Resnick Campus 
1300 Morris Park Avenue 
Chanin Building, Room 302 
Bronx, NY 10461 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Tel: (718) 430-4136 Ext: 4143 
samir.parekh@einstein.yu.edu 
AIDS Malignancies Consortium (AMC) 
Study Chair: Ariela Noy, MD 
Lymphoma Working Group Chair 
AIDS Malignancy Consortium 
www.aidscancer.org 
1275 York Avenue   
New York, NY 10065    
Phone: 212-639-7423 
Fax: 646-422-2284 
noya@mskcc.org   
SWOG (formerly Southwest Oncology Group)  
Study Chair: Michelle Fanale, MD 
Group Chair's Office 
24 Frank Lloyd Wright Drive 
PO Box 483 
Ann Arbor, MI 48106-0483 
Phone: 734-998-7130 
Fax: 734-998-7118 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
Study Chair: Brian Link, MD 
Department of Internal Medicine 
University of Iowa 
200 Hawkins Dr. 
Iowa City, IA 52242 
Phone: (319) 353-8504 
Fax: (319) 353-8383 
brian-link@uiowa.edu 
 
**Roster of NCTN sites with study activation in APPENDIX E 
 
This trial is supported by the NCI Cancer Trials Support Unit (CTSU).  Participation is 
limited to the Lymphoid Malignancies Branch, Center for Cancer Research, NCI 
(NCILYMB, CCR, NCI); and the NCI-supported Participants and Special Member sites .  
All will participate through the CTSU mechanism as outlined below and detailed in the 
protocol. 
• Access and communications: To participate in this trial, enroll patients via the Oncology 
Patient Enrollment Network (OPEN), and access the Medidata Rave Clinical Data 
Management System (CDMS), investigators and research staff must be registered members 
of the CTSU and have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam).  
Instructions on obtaining a CTEP IAM account are outlined in the Registration Procedures 
section of this protocol.  The CTSU Web site and CTSU Bi-Monthly Broadcast will be the 
primary vehicle for communicating study-related updates to clinical sites.  In addition, each 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
site must identify at least one Site Administrator and one Data Administrator to facilitate 
communications with the CTSU, and at least one Registrar to facilitate patient enrollments, 
and designate at least one person as a Rave CRA to facilitate data entry. 
• The study protocol and all related forms and documents may be downloaded from the 
9177 Web page of the CTSU Web site (https://www.ctsu.org).Refer to the Registration 
Procedures section of this protocol for details. 
• Send site registration documents to the CTSU Regulatory Office in Philadelphia as outlined 
in the Registration Procedures section of this protocol.  The CTSU Regulatory Office will 
track documents in the CTSU Regulatory Support System (RSS) and transmit approval data 
to CTEP.   
• Patient registration will be conducted by sites using the Oncology Patient Enrollment 
Network (OPEN) as outlined in the Registration Procedures section of this protocol. To 
perform an enrollment, the site user must have been assigned the 'Registrar' role on the 
relevant Organization roster. OPEN can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ or https://OPEN.ctsu.org. 
• Data management activities will be performed by CTSU Data Operations and all sites will 
submit data and respond to all queries electronically using the Medidata Rave Clinical Data 
Management System (CDMS).  Details are provided in the Data Collection section of this 
protocol.  The Rave CDMS application is available to those individuals assigned the Rave 
CRA role on the relevant Organization roster and who have completed their Rave eLearning 
assignments. Required trainings will be assigned as eLearnings to site staff within Rave as 
staff are invited to the study.  
The treating PI will be expected to review patient data and to document at Off Study certifying 
the data is accurate and complete. If documenting directly in Rave, the PI will need to be 
assigned a PI role on the relevant roster and will need to obtain a Rave account.  For additional 
information about Rave, login to the CTSU members’ website and access the Rave tab.   
• 
Contact Information: 
 
Regulatory documentation must be submitted to the CTSU via the Regulatory 
Submission Portal: 
Regulatory Submission Portal (Sign in at www.ctsu.org, and select the Regulatory 
Submission sub-tab under the Regulatory tab.)  
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 to receive further 
instruction and support. 
     Contact the CTSU Regulatory Help Desk at 1-866-651-2878 for regulatory  
     assistance. 
 
For answers to patient eligibility or treatment-related questions: 
Please contact the Responsible Research Nurse listed on the protocol cover page or 
Dr. Mark Roschewski. 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
All other questions (including OPEN and form-specific and remote data capture 
system questions) should be communicated by phone or e-mail to the CTSU Help 
Desk at:  
CTSU General Information Line 1-888-823-5923, or ctsucontact@westat.com.  All 
calls and correspondence will be triaged to the appropriate CTSU representative.  
CTSU Help Desk hours are 9:00 am – 6:00 pm. E.T. Mon-Fri (excluding holidays). 
 
The CTSU Public Web site is located at www.ctsu.org.  A CTEP-IAM username 
and password is required to access the members’ section of the Web site as well as 
the OPEN and Rave applications. 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
PRÉCIS 
Background: 
• Burkitt lymphoma/leukemia (BL) is highly curable. Standard treatment employs dose-
intense multi-agent chemotherapy and though effective is associated with high morbidity. 
Therefore, novel approaches are needed that improve the therapeutic index of BL while 
maintaining or improving efficacy. In HIV+ BL, outcome has been poor, mainly due to 
the use of CHOP-based regimens in this disease.  
• Two NCI phase II trials have used EPOCH chemotherapy with 1 or 2 doses of rituximab 
(R) per cycle in untreated BL. (Dose-adjusted) DA-EPOCH-Rituximab has been used in 
16 HIV negative BL, and 8 HIV positive patients have received 3 to 4 cycles of EPOCH-
RR to minimize toxicity and risk of opportunistic infections. All patients remain in 
continuous remission. Treatment was very well tolerated and represents a novel 
therapeutic strategy in BL.  
• This trial seeks to assess the effectiveness of a risk adaptive approach with DA-EPOCH-
R in untreated BL (HIV+/-). Because this treatment represents a major conceptual 
departure from standard treatment, it is important to obtain additional Phase II results in 
limited/advanced stage BL 
• c-MYC positive DLBCL is a rare variant of DLBCL. There is very little data on the 
biology of this disease and what the optimal therapeutic approach should be has not been 
defined. Therefore, based on our impression that this behaves aggressively and is likely 
characterized by a high tumor proliferation rate, we plan to accrue patients with this 
disease in addition to BL patients.  
• Plasmablastic lymphoma, another variant of DLBCL is frequently characterized by the 
activation of MYC and has had a poor outcome historically with standard treatment.  We 
plan to include these patients in the study also. As they are CD20 negative, they will 
receive DA-EPOCH without Rituximab. 
 
Objectives: 
• Determine PFS, EFS and OS of risk adaptive DA-EPOCH-R in untreated BL and c-MYC 
+ DLBCL and DA-EPOCH in c-MYC+ plasmablastic lymphoma  
• Assess predictive value of early FDG-PET/CT scans on PFS 
• Obtain pilot comparative molecular profiling in HIV negative and positive BL and c-
MYC + DLBCL, including c-MYC+ plasmablastic lymphoma. 
 
Eligibility: 
• Burkitt lymphoma, c-MYC + DLBCL and c-MYC + plasmablastic lymphoma  age ≥ 18 
years.  
• No prior treatment except limited-field radiotherapy, short course of glucocorticoids 
and/or cyclophosphamide for an urgent problem at diagnosis. 
• Adequate major organ function unless impairment due to lymphoma. 
 
Study Design: 
• Phase II Study of risk adapted DA-EPOCH-R in BL, c-MYC + DLBCL and DA-EPOCH 
in c-MYC+ plasmablastic lymphoma  


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
• Low risk: DA-EPOCH-RR x 3 cycles.  
• High risk, c-MYC + DLBCL and c-MYC+ plasmablastic lymphoma: DA-EPOCH (+/-) 
R x 6 cycles or 8 cycles in select patients. 
• CSF cytology and flow cytometry for analysis of BL. 
• High Risk CSF negative  Prophylactic intrathecal treatment 
• CSF positive  Active intrathecal treatment 
• FDG-PET/CT pre- and post-cycle 2 in all patients.  
• A total of 194 patients will be enrolled in the protocol. 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
TABLE OF CONTENTS 
PRÉCIS .......................................................................................................................................... 7 
TABLE OF CONTENTS ............................................................................................................. 9 
1 
INTRODUCTION............................................................................................................... 12 
1.1 
Primary Objectives ........................................................................................................ 12 
1.2 
Secondary Objectives .................................................................................................... 12 
2 
BACKGROUND ................................................................................................................. 12 
2.1 
Burkitt Lymphoma (BL) ............................................................................................... 12 
2.2 
Rationale ....................................................................................................................... 14 
3 
ELIGIBILITY ASSESSMENT AND ENROLLMENT .................................................. 26 
3.1 
Eligibility Criteria ......................................................................................................... 26 
3.2 
Exclusion Criteria ......................................................................................................... 27 
3.3 
Screening Evaluation .................................................................................................... 28 
3.4 
Baseline Studies ............................................................................................................ 28 
3.5 
Inclusion of Women and Minorities ............................................................................. 28 
4 
REGISTRATION PROCEDURES ................................................................................... 28 
4.1 
Investigator and Research Associate Registration with CTEP ..................................... 28 
4.2 
Site Registration (Applies to all participating sites, including NCILYMB) ................. 29 
4.3 
Patient Registration ....................................................................................................... 31 
4.4 
Access requirements for OPEN: ................................................................................... 31 
4.5 
On-study Procedure for NIH Clinical Center Only ...................................................... 32 
5 
TREATMENT PLAN ......................................................................................................... 32 
5.1 
Agent Administration .................................................................................................... 32 
5.2 
Study Design ................................................................................................................. 33 
5.3 
Study Drug Administration (Dose-Adjusted-EPOCH-Rituximab) .............................. 34 
5.4 
DA-EPOCH-R “Dose Adjustment” .............................................................................. 36 
5.5 
Adverse Event Management (Dose Modification Guidelines) ..................................... 37 
5.6 
Study Calendar .............................................................................................................. 39 
5.7 
Correlative Studies ........................................................................................................ 40 
5.8 
Criteria for Removal from Protocol Therapy and Off-Study Criteria .......................... 43 
5.9 
Post-Treatment Evaluation............................................................................................ 43 
6 
SUPPORTIVE CARE ........................................................................................................ 44 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
6.1 
Prophylaxis of Pneumocystis jiroveci (previously known as Pneumocystis carinii) ... 44 
6.2 
Prophylaxis for hepatitis B reactivation ........................................................................ 44 
6.3 
Additional Prophylaxis for HIV positive patients ........................................................ 44 
6.4 
Tumor Lysis Syndrome................................................................................................. 45 
6.5 
Antiretroviral therapy for HIV infection ....................................................................... 45 
7 
BIOSPECIMEN COLLECTION ...................................................................................... 45 
7.1 
Sample Storage, Tracking and Disposition ................................................................... 45 
7.2 
Samples for Genetic/ Genomic Analysis ...................................................................... 49 
8 
DATA COLLECTION AND EVALUATION ................................................................. 50 
8.1 
Data Collection ............................................................................................................. 50 
8.2 
Accessing Case Report Forms and Related Documents ............................................... 52 
8.3 
Data Submission ........................................................................................................... 52 
8.4 
Data Submission Questions .......................................................................................... 53 
8.5 
Toxicity Criteria ............................................................................................................ 53 
8.6 
Response Criteria .......................................................................................................... 53 
8.7 
Genomic Data Sharing Plan .......................................................................................... 54 
9 
STATISTICAL CONSIDERATIONS .............................................................................. 54 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................ 57 
10.1 
Rationale for subject selection ...................................................................................... 57 
10.2 
Participation of Children ............................................................................................... 58 
10.3 
Evaluation of benefits and risks/ discomforts ............................................................... 58 
10.4 
Risks Benefit Analysis .................................................................................................. 58 
10.5 
Consent Processes and Documentation ........................................................................ 58 
11 NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
60 
11.1 
Definitions (NIH only) .................................................................................................. 60 
11.2 
OHSRP Office Of Compliance And Training / IRB Reporting (NIH Only) ................ 60 
11.3 
NCI Clinical Director (CD) Reporting (NIH Only) ...................................................... 60 
11.4 
NIH Required Data And Safety Monitoring Plan ......................................................... 60 
12 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ......................... 60 
12.1 
Definitions..................................................................................................................... 60 
12.2 
Expedited Adverse Event Reporting ............................................................................. 63 
12.3 
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials ....... 65 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
13 MULTI-INSTITUTIONAL GUIDELINES ..................................................................... 65 
13.1 
IRB Approvals .............................................................................................................. 65 
13.2 
CTEP Multicenter Guidelines ....................................................................................... 66 
14 PHARMACEUTICAL INFORMATION ......................................................................... 67 
14.1 
Rituximab ...................................................................................................................... 67 
14.2 
Cyclophosphamide ........................................................................................................ 71 
14.3 
Doxorubicin .................................................................................................................. 72 
14.4 
Vincristine ..................................................................................................................... 72 
14.5 
Etoposide....................................................................................................................... 72 
14.6 
Administration of vincristine/doxorubicin/etoposide ................................................... 72 
14.7 
Prednisone ..................................................................................................................... 73 
14.8 
Filgrastim ...................................................................................................................... 74 
14.9 
Pegfilgrastim ................................................................................................................. 74 
14.10 
Methotrexate ............................................................................................................. 74 
14.11 
Cytarabine ................................................................................................................. 75 
15 REFERENCES .................................................................................................................... 76 
16 APPENDIX A: EPOCH Admixtures: Preparation and Administration NCI CC only 78 
17 APPENDIX B: Performance Status Criteria ................................................................... 80 
18 APPENDIX C:  NIH IRB form for participating sites Reporting of Deviations Non-
compliance and Unanticipated problems .................................................................................. 81 
19 APPENDIX D: Tumor Biopsy Submission Form ............................................................ 83 
20 APPENDIX E: Roster of NCTN Sites with Study Activation ......................................... 84 
21 APPENDIX F: Burkitt Lymphoma Genome Sequencing Project (BLGSP) ................. 85 
22 APPENDIX G: BLGSP Enrollment Case Report Form ................................................. 92 
23 APPENDIX H:  BLGSP Follow-Up Case Report Form................................................ 111 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
1 
 INTRODUCTION 
1.1 
Primary Objectives 
• Determine PFS, EFS and OS of risk adaptive DA-EPOCH-R in newly diagnosed Burkitt 
Lymphoma, c-MYC + DLBCL and DA-EPOCH in c-MYC+ plasmablastic lymphoma  ≥ 
18 years 
1.2 
Secondary Objectives 
• Assess predictive value of early FDG-PET/CT scans on PFS 
• Obtain pilot comparative molecular profiling of HIV negative and positive BL, c-MYC + 
DLBCL and c-MYC+ plasmablastic lymphoma 
• Assess the toxicity of risk adaptive DA-EPOCH-R in newly diagnosed Burkitt 
Lymphoma, c-MYC + DLBCL and DA-EPOCH in c-MYC+ plasmablastic lymphoma  ≥ 
18 years 
2 
BACKGROUND 
2.1 
Burkitt Lymphoma (BL)  
Burkitt Lymphoma mostly occurs in the first two decades of life and accounts for 1-2% of all 
lymphomas. Three clinical variants are recognized: Endemic BL which is primarily found in 
equatorial Africa[1]; Sporadic BL which presents worldwide but is the most common type in 
Western countries [2] and; Immunodeficiency associated BL which occurs in the setting of HIV 
infection. [3] There are important clinical differences in these variants (Table 1) with endemic 
BL involving the jaw, orbit, and paraspinal regions in half of the cases as well as the mesentery 
and gonads, while sporadic BL mostly involves the distal ileum, cecum and/or mesentery, and 
rarely the jaw. When bulky or disseminated disease is present, extranodal involvement of the 
ovaries, kidney, breasts, and/or CNS may be seen. Clinical presentation in a Berlin-Frankfurt-
Munster Group (BFM) series of 152 pediatric patients included advanced stage (III/IV) disease 
in 38%, bone marrow involvement in 33% and central nervous system (CNS) disease in 4%.[4] 
Overall, 27% of the patients in this series presented as acute leukemia and are usually referred to 
as the L3 subtype of acute lymphoblastic leukemia (ALL) within the French-American-British 
(FAB) classification.[5] BL infrequently presents in adults, but does occur with increased 
frequency in patients with HIV infection.  
 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Table 1. Comparison of Endemic, Sporadic, and HIV-associated Burkitt Lymphoma 
 
ENDEMIC 
SPORADIC 
HIV-ASSOCIATED 
Epidemiology 
Equatorial Africa and Papua, 
New Guinea. Geographic 
association with malaria. 
United States and Europe 
United States and 
Europe 
Incidence 
5-10 cases per 100,000 
2-3 cases per million 
6 per 1,000 AIDS 
cases 
 
Age and 
Gender  
Malignancy of childhood 
Peak Incidence: 4-7 years 
Male: Female of 2: 1 
Malignancy of childhood and 
young adults. 
Median age: 30 years 
Male: Female of 2-3:1  
Malignancy of adults.  
Associated with higher 
CD4 counts > 
100/mm3  
Clinical 
Presentation 
Jaw and facial bones in ≈ 50%. 
Also involves mesentery and 
gonads. Increased risk of CNS 
dissemination.  
Abdomen most common 
presentation often involving the 
ileo-cecal region. Other 
extranodal sites include bone 
marrow, ovaries, kidneys, and 
breasts. Increased risk of CNS 
dissemination. 
Nodal presentation 
most common with 
occasional bone 
marrow. Increased risk 
of CNS dissemination. 
 
 
2.1.1 Staging  
Staging is a critical component of treatment for lymphomas. In particular, the recognition that 
early stage BL requires less treatment than advanced stage disease has led to risk adaptive 
strategies that are dependent on the accuracy of the staging classification systems. The Ann 
Arbor staging system, which is the most commonly used system for lymphomas, was initially 
developed for radiation treatment of Hodgkin lymphoma. As such, it is relatively useful for 
identifying nodal and extranodal regions involved by disease but much less so for disease bulk or 
specific disease sites. The occurrence of BL and LBL in pediatrics led to the St Jude staging 
system [6]  which was developed to more accurately reflect tumor bulk and high risk disease 
sites (Table 2). Overall, the Ann Arbor system is the staging system most commonly used for 
Burkitt lymphoma and this is the system to be used in this study. A table of both the Ann Arbor 
and St. Jude systems is provided.  


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Table 2. Staging Systems  
 
Stage 
St. Jude Staging 
Ann Arbor Staging  
I 
Single site (excluding abdomen or  
 mediastinum) 
Single node region or extranodal site (IE) 
II 
Single extranodal site with regional  
 nodes 
 > 2 nodal sites, same side of diaphragm 
2 extranodal sites, same side of diaphragm 
Primary GI, completely resected (IIR) 
> 2 node regions, same side of diaphragm +/- 
Localized contiguous extranodal site (IIE) 
 
III 
2 extranodal sites, both sides of diaphragm 
> 2 nodal sites, both sides of diaphragm 
Primary thoracic 
Primary GI, extensive 
Paraspinal, epidural 
 > 2 node regions, both sides of diaphragm +/- 
Localized contiguous extranodal site (IIIE) 
Spleen (IIIS) or  
Both (IIIES) 
 
IV 
 CNS and/or bone marrow (< 25%) 
 Bone Marrow or Liver  
Diffuse extranodal disease not encompassed  
in a single radiation field.  
 
 
E: Single extranodal site contiguous with a 
known nodal site 
A: No symptoms 
B: Fever, weight loss, night sweats  
 
2.2 
Rationale 
2.2.1 Standard Treatment of Burkitt Lymphoma  
BL is a systemic disease and requires chemotherapy for all disease stages. Importantly, 
locoregional radiation does not improve survival and should be avoided. While older studies 
showed that surgical resection of abdominal disease improves outcome, indicating the 
importance of tumor volume, more effective and risk adapted treatments have made surgical 
resection unnecessary except for specific complications like obstruction, perforation, fistula or 
bleeding. 
Early treatment strategies for BL were modeled on ALL regimens which employed dose intense 
and prolonged treatment with induction, consolidation and maintenance phases. These 
approaches stand in contrast to the significantly less dose intense regimens used in adults with 
“intermediate-grade” lymphoma, such as CHOP and CHOP-based regimens, that only produced 
a 50-60% EFS. While dose intensity and dose density are important treatment components for 
BL, later studies indicated that shorter treatment durations were equally effective. Furthermore, 
the recognition that tumor volume is an important prognostic feature led to the use of risk 
adaptive approaches and a further reduction in treatment for early stage patients. Several 
biological characteristics of BL have helped guide treatment strategies including its high 
proliferative fraction. It has been recognized for years that BL is sensitive to multiple 
chemotherapy classes and in endemic BL, cures were occasionally achieved with single agent 
cyclophosphamide. Despite initial sensitivity, however, patients frequently relapsed, particularly 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
those with higher volume disease. This apparent dichotomy can potentially be explained by the 
high tumor proliferation rate. The role of tumor cell kinetics was raised some 30 years ago by 
Skipper et al [7] who observed that the fraction of cells undergoing DNA replication, termed the 
"growth fraction," greatly influenced drug sensitivity; a finding that likely reflects the greater 
sensitivity during S phase to many drug classes. Although a high growth fraction would predict 
greater drug sensitivity, it could also lead to greater tumor proliferation between cycles. 
Depending on the relative impact of these two effects, cure rates might increase due to higher 
fractional cell kill or decrease if tumor proliferation between cycles leads to a “kinetic” failure. 
One strategy to overcome “kinetic” failure is to increase dose density through frequent 
chemotherapy administration, a strategy employed in most current BL regimens. Another 
strategy is to increase the fractional cell kill or efficacy of chemotherapy, thereby reducing the 
number of tumor cells which can survive and proliferate between cycles. Hence, BL regimens 
commonly employ multiple chemotherapy agents in high doses and alternating cycles. They 
typically include anthracylines, epipodophyllotoxins, vinca alkaloids, and alkylators, as well as 
methotrexate and cytarabine which are cell cycle active agents and take advantage of the high 
tumor proliferation. These agents, however, are administered in a variety of combinations and 
schedule, indicating the empiric nature of the actual combinations (Table 3). Indeed, the optimal 
dose and schedule of cyclophosphamide, methotrexate and cytarabine remain unknown and vary 
among the major regimens (Table 3). 
The risks of tumor lysis syndrome and propensity for CNS dissemination in BL also have 
important treatment implications. To reduce tumor lysis, which can produce life threatening 
electrolyte imbalances and renal failure, many regimens employ a pre-phase whereby relatively 
low dose cyclophosphamide and prednisone are administered. This strategy has been 
incorporated into the regimens of the French Society of Pediatric Oncology (SFOP), German 
Multicenter ALL Group (GMALL), and BFM, but not CODOX-M or Hyper-CVAD (Table 4). 
The high risk of CNS involvement is handled by the use of relatively high dose intravenous 
methotrexate and cytarabine, both of which have CNS penetration, and intrathecal 
administration. An important advance has been to reduce intrathecal treatment and eliminate 
whole brain radiation for prophylaxis, which has significantly reduced CNS toxicity. A recently 
published FAB/LMB study demonstrated that patients with early stage Burkitt lymphoma had a 
high cure rate and very low rate of CNS relapse without the use of intrathecal chemotherapy[8].  


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Table 3. Comparison of Dose and Dose Intensity among Burkitt Lymphoma Regimens 
 
 
CODOX-M/ 
IVAC 
CODOX-M/ 
IVAC [9] 
LMB 89 LMB 89 
[10] 
BFM 90 BFM 90 
[11] 
Dose 
Range 
Doxorubicin 
 Dose, 
Dose intensity, 
 
40 
13 
 
60 
20 
 
50 
25 
 
40-50 
13-25 
Cyclophosphamide 
Dose 
Dose intensity 
 
1600 
533 
 
1500 
500 
 
1000 
500 
 
1000-1600 
500-533 
Vincristine 
Dose 
Dose intensity 
 
3 
1.0 
 
2 
0.63 
 
1.5 
0.75 
 
1.4-2 
0.63-0.93 
Etoposide 
Dose 
Dose intensity 
 
300 
100 
 
800 
266 
 
200 
100 
 
200-800 
100-266 
Methotrexate 
Dose 
Dose intensity 
 
6720 
2240 
 
8000 
2666 
 
5000 
2500 
 
5000-8000 
2240-2666 
Cytarabine 
Dose 
Dose intensity 
 
8000 
2666 
 
9000 
3000 
 
600 
200 
 
600-9000 
200-3000 
Ifosfamide 
Dose 
Dose intensity 
 
7500 
2500 
 
NA 
NA 
 
4000 
2000 
 
7500-4000 
2500-2000 
Other drugs 
NA 
Prednisone 
Dexamethasone 
NA 
 Dose is expressed as mg/m2. Dose intensity is expressed as planned dose intensity and 
calculated as mg/m2/week. 
 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Table 4. Selected Regimens for Burkitt Lymphoma  
Regimen 
No. of 
Patients 
Histology 
(No.) 
Median age 
yrs (Range) 
Stage 
(%) 
CR 
(%) 
EFS 
(%) 
OS 
(%) 
LMB 89 
LMB 89 
[12] 
561 
Burkitt and 
L3 ALL (420) 
8 (0.17-18) 
III-IV 
79% 
97
% 
92% @ 5 yrs 
92% @ 5 yrs  
Modified 
LMB 
Modified 
LMB [13] 
72 
Burkitt and  
L3 ALL 
33 (18-76) 
III-IV 
67% 
72
% 
65% @ 2 yrs 
70% @ 2 yrs 
GMALL 
B-NHL 86 
B-NHL 86 
[14] 
35 
L3 ALL 
36 (18-65) 
N/A 
74
% 
71% @ 4 yrs 
for DFS 
51% @ 4 yrs 
Modified 
GMALL  
92 
Burkitt and  
L3 ALL 
47 (17-78) 
III-IV 
89% 
74
% 
45-52% @ 3 
yrs 
50-54% @ 3 
yrs 
BFM 90 
BFM 90 [4] 
413 
Burkitt and  
L3 ALL (322) 
9 (1.2-
17.9) 
III-IV 
60% 
N/A  
 
89% @ 6 yrs 
14 deaths 
CODOX-
M/ IVAC 
21 peds 
20 
adult 
Burkitt 
12 (3-17) 
25 (18-59) 
III-IV 
78% 
95
% 
85% (peds) 
and 
100% (adults) 
@ 2 yrs 
2 deaths 
CODOX-
M/ 
IVAC 
IVAC [9] 
52 
Burkitt 
35 (15-60) 
III-IV 
61% 
77
% 
65% @ 2 yrs 
73% @ 2 yrs 
Hyper-
CVAD 
Hyper-
CVAD [15] 
26 
L3 ALL  
58 (17-79) 
N/A 
81
% 
61% @ 3 yrs 
for DFS 
49% @ 3 yrs 
Intensive 
sequential 
and SCT 
Intensive 
sequential 
and SCT 
[16] 
27 
Burkitt 
36 (15-64) 
III-IV 
44% 
81
% 
73% @ 5 yrs 
81% @ 5 yrs  
DA-
EPOCH-R 
25 
Burkitt 
30 (18-66) 
III-IV 
54% 
100
% 
96% @ 28 mos 100% 
@28mos 
  
There are multiple highly effective regimens for BL and L3 B-ALL, most of which have been 
based on leukemia platforms (Table 4). Due to high toxicity and the recognition that some 
patients require less treatment, risk adaptive strategies were tested. The SFOP conducted a series 
of protocols to refine the treatment of BL and L3 ALL (LMB). These studies demonstrated that 
short dose intense treatment was effective in patients without CNS involvement, and that dose 


Abbreviated Title:  DA-EPOCH-R in BL 
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intensification of methotrexate, cytarabine and etoposide with cranial irradiation improved the 
EFS of patients with CNS involvement to 75%. Based on these findings, a risk adapted protocol 
(LMB 89 protocol) was developed in which treatment was based on tumor burden and early 
response to chemotherapy (Table 4). Using the St Jude (Table 1) staging, group A included stage 
I or II with abdominal resection; group B included unresected stage I, non-abdominal stage II, 
any stage III or IV disease and/or L3 ALL (CNS negative and < 70% marrow blasts); and group 
C patients had CNS involvement and/or > 70% marrow blasts. Based on these risks, group A 
only received induction, group B received pre-phase, induction, consolidation and limited 
maintenance and group C also received extended maintenance and cranial irradiation if the CNS 
was involved. If a CR was not achieved in groups B and C after the third or fourth induction-
consolidation course, patients underwent high dose therapy with autologous stem cell transplant. 
This strategy was highly successful in pediatric patients with 5 year event-free and overall 
survivals of 92% (Table 4). The success of LMB 89 in pediatrics led to its testing in adults with 
minor modifications (Table 4). The outcome in 72 adult patients, mostly with advanced disease, 
was favorable with EFS and OS of 65% and 70%, respectively, at 2 years.[13] Toxicity remains 
a problem for advanced stage patients due to the treatment intensity. Treatment-related deaths 
from infection were higher in adults compared to pediatrics with incidences of 5% and 1.6%, 
respectively, among patients in groups B and C. Myelosuppression was the primary treatment 
complication with over 40% of adults experiencing febrile neutropenia. Tumor lysis syndrome 
requiring dialysis was prevented by the pre-phase treatment and associated supportive care. 
The GMALL reported excellent results with an intensive 18 week regimen in adult patients with 
L3 ALL. In an effort to reduce CNS toxicity, the Cancer and Leukemia Group B (CALGB) 
studied a modified version in which intrathecal methotrexate was reduced and cranial radiation 
was only administered to high risk patients (Table 4). These patients were compared to another 
cohort who received the standard CNS prophylaxis. Overall 92 patients enrolled on the two 
cohorts. There were no differences in outcome with EFS and OS of 45-52% and 50-54%, 
respectively, at 3 years. This study suggested that short-duration treatment with less intensive 
CNS prophylaxis was equally effective to more aggressive prophylaxis and with significantly 
less neurotoxicity. 
Another highly effective regimen for BL was developed by the BFM (Table 4). Like other 
regimens for BL, the BFM approach was based on short, intensive cycles and over the course of 
several protocols led to a reduction in the number of cycles based on risk stratification. The BFM 
90 protocol continued to further refine the risk stratification and to improve the outcome of 
patients who had an incomplete initial response with further treatment intensification. Among 
322 pediatric patients with BL or L3 ALL treated with the BFM 90 regimen, the overall EFS was 
89% at 6 years. Importantly, this represented a significant improvement for advanced stage 
patients compared to the previous BFM 86 protocol.  
Two clinical trials conducted at the National Cancer Institute (NCI protocols 77-04 and 89-C-41) 
diverged from the leukemia model of treatment and investigated the role of more limited 
treatment (Table 4). In the 77-04 protocol, 3 cycles of intravenous cyclophosphamide, 
vincristine, doxorubicin, methotrexate and leucovorin rescue with cytarabine intrathecal 
prophylaxis (CODOX-M) showed that intensive combination chemotherapy produced an event-
free survival (EFS) of 66% in patients with low risk disease. However, patients with high risk 
disease (i.e., St. Jude Stage IV) fared poorly with a 19% EFS. Based on the observation that 
some patients were salvaged with combination ifosfamide, etoposide, and cytarabine (IVAC), a 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
successor protocol 89-C-41 was developed in which CODOX-M was alternated with IVAC and 
administered for 4 cycles in high risk patients. This approach yielded an overall EFS of 85% 
compared to 55% for all patients treated on CODOX-M alone with no difference in low and high 
risk disease. When the CODOX-M/IVAC regimen was tested in an adult cooperative group trial, 
however, they only achieved an EFS of 65% at two years.[9]  
The Hyper-CVAD regimen was based on a modification of a regimen developed by Murphy et al 
for pediatric L3 ALL (Table 4). In this regimen, hyperfractionated cyclophosphamide, 
vincristine, doxorubicin and dexamethasone were alternated with methotrexate and cytarabine 
for a total of 8 cycles. The results in 26 adults with L3 ALL were quite favorable with EFS of 
73% at five years. Based on these results in L3 ALL, this regimen has also been used for BL.  
DA-EPOCH-R has been investigated in a pilot study in untreated Burkitt lymphoma based on the 
efficacy of the regimen in DLBCL and the ability of the regimen to overcome tumors with a high 
proliferation rate. Recently reported results demonstrated an EFS and OS of 96% and 100% 
respectively at a median follow-up time of 28 months in a group of 25 patients treated with the 
regimen. This strategy and the results of this pilot study, which have led to this study, are 
discussed in the next section. 
While current treatments are quite effective in BL, improvements are needed in patients with 
high risk disease. Furthermore, toxicity of the regimens for high risk disease is particularly 
problematic for older adults, and treatment related mortality is excessive. Indeed, the high dose 
methotrexate and cytarabine in standard BL regimens has led to significant toxicity as illustrated 
by the CODOX-M/IVAC regimen (Figure 1 and 2). With this regimen, myelosuppression is 
severe and tumor lysis syndrome is high.  Hence, new strategies are needed to improve the 
therapeutic index of treatment and to increase efficacy. The success of rituximab in diffuse large 
B-cell lymphoma has prompted its testing in BL. Rituximab has been incorporated in the Hyper-
CVAD regimen with a three year disease free survival of 88% in 31 patients, most of whom had 
advanced stage disease.[17, 18] Rituximab has also been incorporated into ongoing CALGB 
(Phase II study of rituximab and short-duration, high-intensity chemotherapy with GCSF support 
in previously untreated patients with Burkitt lymphoma/leukemia – P.I. John Byrd – 
NCT00039310) and COG (rituximab, rasburicase, and combination chemotherapy in treating 
young patients with newly diagnosed advanced B-cell leukemia or lymphoma – Study Chair: 
Michael S.Cairo - NCT00057811) protocols for BL.  
 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
 
Figure 1: Percent of patients with Grade 3 or 4 WHO toxicity on CODOX-M for low risk BL. 
 
 
 
Figure 2: Percent of patients with Grade 3 or 4 WHO toxicity on CODOX-M/IVAC for high risk 
BL. 
2.2.2 c-MYC Positive Diffuse Large B-Cell Lymphoma 
Approximately 5% of DLBCLs are c-MYC positive .Though the presence of a MYC break has 
been linked with a very unfavorable prognosis, there has been very little published on this 
subtype of DLBCL and there are have not been clinical trials done to investigate how patients 
with this subtype do. These tumors are usually associated with a high proliferation index and in 
this respect may preferentially benefit from regimens that can overcome high tumor proliferation 
like DA-EPOCH-R. We are therefore very interested in investigating these diseases and also 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
performing gene expression profiling of these tumors, as this has not been well described and 
this is the reason for their inclusion.  
Plasmablastic lymphoma, which is a variant of DLBCL, is associated with a very high rate of c-
MYC activation. The outcome for patients with plasmablastic lymphoma has been poor with 
standard therapies. Plasmablastic lymphomas that are c-MYC + are included in this study. As 
they are CD20 negative, they will receive DA-EPOCH alone (no rituximab). As they historically 
have had a poor outcome with standard therapy, they will be treated on the high risk arm (i.e. 6 
cycles of DA-EPOCH).  
2.2.3 DA-EPOCH-R Background   
DA-EPOCH-R is a pharmacodynamic-based infusional regimen with etoposide, prednisone, 
vincristine, cyclophosphamide, doxorubicin and rituximab. DA-EPOCH was designed to 
improve the therapeutic index of chemotherapy by taking advantage of increased sensitivity of 
highly proliferative tumors to prolonged exposure to low concentrations of chemotherapy. A 
prospective multi-institutional study of DA-EPOCH in 50 patients with previously untreated 
large B-cell lymphomas showed that highly proliferative tumors were sensitive to treatment, 
unlike CHOP-based treatments[19]. A Phase II study of DA-EPOCH-R in 72 patients with 
untreated DLBCL has also been completed. Patients had a median age of 50 years (range, 20-
88 years) and 40% had high-intermediate or high risk disease according to International 
Prognostic Index (IPI) criteria. At 5 years, the progression-free and overall survivals are 79% and 
80% respectively (figure 3) with a median follow-up time of 54 months (in press). As seen with 
DA-EPOCH, high tumor proliferation was not an adverse biomarker.  A CALGB multicenter 
study of 75 patients at 18 centers has also reported similar results (W. Wilson, personal 
communication). Based on these studies, DA-EPOCH-R is currently being compared to CHOP-
R in a phase III multicenter CALGB trial. 
DA-EPOCH-R NCI Clinical Trial Results: figure 3  
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2.4 DA-EPOCH-R in Burkitt Lymphoma 
Based on the hypothesis that DA-EPOCH-R may be effective in BL, given its established 
efficacy in DLBCL and its ability to overcome highly proliferative tumors, we assessed in a pilot 
fashion if DA-EPOCH-R could maintain the high cure rates of standard therapy in BL while 
minimizing treatment related toxicity in HIV negative patients. We also treated a cohort of HIV 
positive patients with Burkitt lymphoma employing a modified version of DA-EPOCH-R. All 
0
1
2
3
4
5
6
7
20
100
80
60
40
Years on Study 
Progression-Free Survival 
8
Survival (%) 
** * * * *** ** *
**
*
*
oo oooo
oo
oo
oo o
o
Overall Survival 
Median 
F/up 54  
months 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
patients had untreated BL of which 8 were HIV positive and 17 ere HIV negative.  HIV negative 
patients received standard DA-EPOCH-R for 6-8 cycles (median 6 cycles) and HIV positive 
patients received 3-6 cycles of DA-EPOCH-RR for 1 cycle beyond CR for a minimum of 3 
cycles (median 3 cycles). All patients received intrathecal methotrexate prophylaxis. A total of 
25 patients with BL have been treated at the NCI on two protocols using EPOCH and rituximab 
(#93-C-0133 (DA-EPOCH-R in untreated DLBCL and BL), #01-C-0030 (DA-EPOCH-RR in 
untreated ARL)). Characteristics of all 25 patients (see table) included median age (range) 30 
(18-66); male sex 20 (80%); median (range) ECOG PS 1 (1-3); stage III/IV 54%; LDH > N 56%; 
extranodal sites 79% and ileocecal disease 54%. 8/25 (32%) had low-risk disease and 17/25 
(68%) had high-risk disease. No patients had CNS involvement at diagnosis. All patients 
achieved a CR/CRu with one patient receiving consolidative radiation to a site of residual 
disease. OS and PFS are both 100% and EFS 96% at a median potential follow-up of 28 months. 
Significant toxicities included tumor lysis syndrome (TLS) in only one patient and 
fever/neutropenia in 16% of cycles. There were no treatment related deaths. These pilot results 
suggest that DA-EPOCH-R is effective regimen in newly diagnosed BL and is associated with 
low toxicity and low rates of TLS compared to “standard” high dose regimens used in BL. 
Hence, these results suggest that DA-EPOCH-R may significantly advance the therapeutic index 
in the treatment of BL[20].  
2.2.5 Rationale for Short-Course Treatment in Low-Risk Patients 
We investigated reduced cycle EPOCH-RR in 10 patients with newly diagnosed HIV-associated 
Burkitt lymphoma, 80% of whom had advanced stage III or IV disease. In this study, we 
administered short-course chemotherapy (minimum of 3 cycles with at least 1 cycle beyond CR) 
in an attempt to reduce treatment duration and toxicity. We demonstrated that most patients 
(79%) required 3 cycles of chemotherapy. The efficacy of this approach was outstanding with 
100% of patients progression-free at 5 years. Based on these results and the current standard to 
employ risk adapted therapy, we plan to treat patients with early stage disease with reduced 
chemotherapy. To increase safety, patients who do not achieve a CR in 2 cycles will be crossed 
over to receive 6 cycles of treatment and an early stopping rule has been incorporated in the 
study design. 
DA-EPOCH-R in Burkitt Lymphoma: Patient Characteristics 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
 
 
DA-EPOCH-R Results in Burkitt Lymphoma: figures 4a and 4b 
2.2.6 DA-EPOCH Pharmacokinetics 
The pharmacokinetics (PK) of DA-EPOCH has been studied in adults with DLBCL (Balis and 
Wilson, et al, personal communication). Age-related clearance was demonstrated for doxorubicin 
and etoposide. In 12 patients studied, the mean coefficient of variation of doxorubicin across the 
6 cycles of therapy was 34% (range, 13-76%). There was no difference in doxorubicin clearance, 
but there was a trend toward lower clearance with advancing age (rho=-0.54, p=0.08). We also 
measured steady state total and free plasma etoposide concentration in 33 patients, ages 22-69, 
over 164 cycles of EPOCH. Free etoposide clearance gradually increased over the course of 
therapy. While the mean clearance for total and free etoposide was similar in males and females, 
there was significantly lower clearance with advancing age (r=-0.45; p=0.034). Pharmacokinetics 
50%
56%
54%
Ileo-caecal disease
79%
56%
54%
25%
30 (18-66)
4:1
25
All Patients
8
17
Total Patients
5:1
3:1
Gender (M/F)
75%
44%
Stage III or IV
87%
37%
LDH > Normal*
87%
75%
Extranodal sites
50%
12%
ECOG PS > 1
40 (24-60)
25 (18-66)
Median age, y (range)
HIV +
HIV -
Characteristics
Overall Survival (%)
0
20
100
80
60
40
3
5
Years
2
1
4
Overall Survival
6
7
Median follow
up 28 months
OS 100%
25 patients
Manuscript in preparation
Overall Survival (%)
0
20
100
80
60
40
3
5
Years
2
1
4
6
7
*
Event-free Survival 
EFS 96%
Median follow
up 28 months
25 patients
Manuscript in preparation


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
and tolerance of doxorubicin and etoposide during treatment of aggressive B-cell lymphomas 
indicate doses need not be routinely reduced for hepatic dysfunction[21]. 
2.2.7 PET Scans in Lymphoma 
PET scans are used in NHL to evaluate residual masses detected on CT after completion of 
chemotherapy, with the positive and negative predictive values for outcome of 80% to 100%. 
[22]   PET after one cycle of chemotherapy was superior to PET at completion of chemotherapy 
in predicting PFS in NHL and HD.[23] In Hodgkin’s lymphoma (HL) positive predictive value 
of a PET-2 (PET after 2 cycles) was 90% and the negative predictive value was 97%. The 
sensitivity, specificity and overall accuracy of PET-2 were 86%, 98% and 95%, respectively.[24] 
There is limited experience with PET scans in BL but it is known that this high grade, chemo-
sensitive malignancy is generally PET positive at diagnosis and negative at completion of 
chemotherapy. Early PET scanning in BL may identify a population of poor prognosis chemo-
resistant patients who could benefit from alternative treatment. Additionally, it may identify 
patients who should not receive limited chemotherapy.  
2.2.8 FISH and Microarray Profiling 
BL is characterized by translocations of the myc-oncogene on chromosome 8 to the IgH locus on 
chromosome 14 although other myc translocations and activating mutations have been reported. 
BL has recently been characterized by microarray profiling. [25, 26] It is possible to differentiate 
between DLBCL and BL using microarray. This study may provide pilot predictive and 
prognostic data and to investigate whether BL in HIV positive and negative patients have 
differences in their gene expression profiles. We aim to perform gene expression profiling on 
Affymetrix whole genome arrays in pre-treatment biopsies from patients enrolled in the study. 
Gene expression profiling provides a comprehensive and highly quantitative overview of tumor 
biology and can be carried out even from small amounts of tissue.  Gene expression signatures 
that relate to specific cellular functions or to the activity of distinct signaling pathways can be 
reproducibly monitored and can identify subsets of patients with distinct tumor biology, different 
prognosis or differential response to therapy.  
2.2.9 Burkitt Lymphoma Genome Sequencing Project (BLGSP) 
In Amendment I  (version date 03/14/14), we added the Burkitt Lymphoma Genome Sequencing 
Project (BLGSP) protocol to this study to allow us to contribute samples from Burkitt 
Lymphoma patients to the Genomic Databank for Burkitt Lymphoma being created by the 
Foundation for Burkitt Lymphoma Research (FFBLR) (APPENDIX F). The effort will be 
coordinated through the Foundation for the National Institutes of Health (FNIH). The NCI, 
through the Office of Cancer Genomics (OCG), will provide the administrative, physical and 
analytical infrastructure in order to carry out this project. This will enable the FFBLR to utilize 
existing Standard Operating Procedures (SOPs) developed by OCG, as well as relationships 
OCG has established with other organizations, in order to carry out this project. This effort will 
enhance the scientific integrity and credibility of the BLGSP, and be consistent with the conduct 
and methodologies used in other NCI sponsored cancer sequencing projects. 
2.2.10 Study Rationale and Design 
The DA-EPOCH-R regimen represents a major paradigm shift for the treatment of BL. Whereas 
standard treatment relies on dose density and intensity based on methotrexate and cytarabine to 
achieve adequate cell kill, DA-EPOCH-R relies on a pharmacodynamic based infusional 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
schedule to improve the therapeutic index of chemotherapy. Based on our pilot results, DA-
EPOCH-R appears to provide a high rate of cure with significantly lower treatment toxicity and 
tumor lysis syndrome compared to standard treatment. As such, DA-EPOCH-R may provide a 
major treatment advance in BL by lowering morbidity, mortality and cost, while maintaining or 
possibly improving efficacy. The current protocol is written to confirm our pilot results of DA-
EPOCH-R in BL and in particular to obtain further results in patients with advanced stage 
disease.  We also plan to obtain pilot information on potential differences in the microarray of 
BL in HIV positive and negative patients. 
Regarding the toxicity of DA-EPOCH-R compared to other treatments for Burkitt lymphoma: In 
the UK Lymphoma Group LY06 study (Mead et al. Annals of Oncology 13: 1264-1274, 2002) - 
which was a very large multicenter study comparing CODOX-M and CODOX-M-IVAC in 52 
patients, the major toxicities were as follows: there were 6 toxic deaths in total: 5 of these were 
in patients receiving CODOX-M-IVAC and 1 was in patients receiving CODOX-M. This is an 
overall treatment related mortality of 12%. This study accrued patients from 16 years to 60 years. 
While appreciating that toxicity may be somewhat less overall in a pediatric population, this 
treatment-related mortality with these regimens is very significant. Thus far, in treating 27 
Burkitt lymphoma patients with DA-EPOCH-R, we have encountered 0% mortality and have 
included patients older than 50 years some with immunodeficiency. Overall hematological 
toxicities and notably mucositis (grade 3 or 43%) are significantly higher for CODOX-M and 
CODOX-M-IVAC than for DA-EPOCH-R but our principal concern with these regimens is 
treatment related mortality. It is also notable that across several studies that have looked at 
toxicity with CODOX-M and CODOX-M-IVAC, dose reductions, particularly of methotrexate, 
have been required and in our study of DA-EPOCH-R in Burkitt lymphoma, we have not needed 
to make any dose reductions. The concern of dose reductions in curable lymphomas is that they 
may compromise cure rates. 
Based on our excellent albeit limited results with short-course (median 3 cycles) DA-EPOCH-
RR (Rituximab day 1 and 5) in HIV associated BL, we hypothesize that low risk BL may only 
require 3 cycles of treatment. Thus far, in our Burkitt lymphoma study, of  HIV positive patients 
with Burkitt lymphoma, most just required 3 cycles of therapy. We administered one cycle of 
therapy beyond CR. There is much literature that patients with low-risk Burkitt lymphoma can 
be cured with shorter courses of therapy (and of course this is associated with less toxicity)  and 
based on this and our excellent results with short-course therapy in the HIV positive population, 
we are confident that 3 cycles of therapy should be adequate for patients with low risk disease. 
Of course patients will be closely monitored and if they have not achieved a CR after 3 cycles of 
therapy, they will receive further courses. Hence, we have developed a risk adaptive paradigm in 
which low risk patients will receive 3 cycles of DA-EPOCH-RR and high risk patients and 
patients with c-MYC+ DLBCL will receive 6 cycles of DA-EPOCH-R (Rituximab day 1). Thus, 
all patients will receive the same amount of rituximab, but the treatment duration will be shorter 
for low risk patients. We used this approach (the administration of 2 doses of rituximab on days 
1 and 5 of the EPOCH cycle) empirically in our study of abbreviated EPOCH-R in ARL, as we 
wanted all patients to receive at least 6 doses of the drug – at this point in time, we do not have 
any data to show that fewer than 6 cycles are as effective as 6. In addition, we hypothesized that 
levels of the drug would rise higher and be sustained over a longer period of time (potentially 
improving tumor cell kill) when 2 doses were given compared to 1 and this strategy, with PK 


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studies, is being investigated by the German High-Grade NHL group and initial PK results 
demonstrate higher levels over a longer period of time. 
To provide a measure of safety in patients with low risk disease, and to assess the predictive 
value of PET/CT scans, all patients will undergo a clinical PET/CT scan after two cycles of 
treatment. Low risk patients who respond with a negative PET/CT scan will receive 3 cycles of 
treatment whereas low risk patients with persistently positive PET/CT scan after 2 cycles will 
cross over to the high risk arm to receive a total 6 cycles of treatment. All patients with a positive 
PET/CT scan after 2 cycles will have a repeat PET/CT scan after treatment completion. Low risk 
patients with a negative CSF by cytology and flow cytometry will not receive prophylactic IT 
chemotherapy, as we deem the risk of CNS dissemination in this group to be extremely 
negligible based on the recent FAB/LMB study; high risk patients with a negative CSF by 
cytology/flow cytometry will receive prophylactic treatment of the CSF with IT methotrexate 
and/or cytarabine and patients with a positive CSF by cytology/flow cytometry will receive 
active treatment of the CSF with IT/Intraventricular methotrexate/cytarabine.  
For patients who receive prophylactic intrathecal chemotherapy, this therapy is commenced on 
Cycle 3. The rationale for this is as follows: in previous studies using the EPOCH regimen in 
aggressive lymphomas, we have noted increased toxicity from the EPOCH drugs on the cycles 
when intrathecal therapy is administered. In treating Burkitt and other aggressive B-cell 
lymphomas, dose intensity on the initial cycles (and dose adjustment potentially) are critical (in 
avoiding kinetic failures).  Adding intrathecal therapy early may enhance cytotoxicity and limit 
the doses of EPOCH drugs that can be administered on these cycles. We feel that this approach is 
safe in view of the fact that every patient’s CSF is analyzed by flow cytometry at diagnosis and 
this detects very small volumes of tumor cells.  
3 
 ELIGIBILITY ASSESSMENT AND ENROLLMENT 
3.1 
Eligibility Criteria  
3.1.1 Patients must have Burkitt Lymphoma. Effective with Amendment J (version date: 
06/24/2014), the following histologies were removed as the maximum number allowed 
for these sub-groups has been reached: B-cell lymphoma: unclassifiable with features 
intermediate between Diffuse Large B–cell lymphoma and Burkitt Lymphoma; c-MYC + 
DLBCL and c-MYC+ plasmablastic lymphoma. 
If questions arise related to diagnosis, please contact the NCI Principal Investigator, Dr. 
Mark Roschewski or the NCI study coordinator, A. Nicole Lucas. 
3.1.2 Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of EPOCH-R in patients <18 years of age, children are excluded from this study, but 
may be eligible for future pediatric trials. 
3.1.3 Pathology confirmed by treating institution’s Pathology Department.   
3.1.4 No prior treatment except patients may be entered if they have had prior limited-field 
radiotherapy, a short course of glucocorticoids, cyclophosphamide for an urgent problem 
at diagnosis (e.g. epidural cord compression, superior vena cava syndrome) and/or a 
single dose of intrathecal methotrexate (MTX) at the time of the pre-treatment diagnostic 
lumbar puncture.  


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3.1.5 All disease stages  
3.1.6 HIV negative or positive 
3.1.7 HIV positive patients on antiretroviral therapy regimen must be willing to suspend all 
Highly Active Antiretroviral Therapy (HAART) except in circumstances described in 
Section 6.5. 
3.1.8 ECOG 0-4  
3.1.9 Ability of patient or durable power of attorney (DPA) for healthcare to give informed 
consent 
3.1.10 Hepatitis B + patients may be enrolled at the discretion of the investigator. 
3.2 
Exclusion Criteria 
3.2.1 Patients with Primary CNS Lymphoma.  
3.2.2 Inadequate renal function, defined as serum Cr > 1.5 mg/dL or creatinine clearance < 50 
ml/min/1.73m2 unless lymphoma related.  
3.2.3 Inadequate hepatic or hematological function, as follows, unless lymphoma-/disease-
related: bilirubin > 2 mg/dl (total) except > 5 mg/dl in patients with Gilbert’s syndrome 
as defined by > 80% unconjugated, ANC < 1000 and platelets < 75,000. 
3.2.4 The effects of EPOCH-R on the developing human fetus are unknown.  For this reason 
and because chemotherapy agents are known to be teratogenic, female subject of child-
bearing potential not willing to use an acceptable method of birth control (i.e., a 
hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with 
spermicide, or abstinence) for the duration of the study and one year beyond treatment 
completion will not be eligible to participate in the study. 
3.2.5 Female subject pregnant or breast-feeding.  Confirmation that the subject is not pregnant 
must be established by a negative serum -human chorionic gonadotropin (-hCG) 
pregnancy test result obtained during screening.  Pregnancy testing is not required for 
women without child-bearing potential. 
3.2.6 The effects of EPOCH-R on the developing human fetus are unknown.  For this reason 
and because chemotherapy agents are known to be teratogenic, male subject unwilling to 
use an acceptable method for contraception for the duration of the study and one year 
beyond treatment completion, will not be eligible to participate in the study. 
3.2.7 History of a prior invasive malignancy in past 5 years 
3.2.8 Active symptomatic ischemic heart disease, myocardial infarction or congestive heart 
failure within the past year. If echo is obtained the LVEF should exceed 40%. 
3.2.9 Serious concomitant medical illnesses that would jeopardize the patient's ability to 
receive the regimen with reasonable safety. 
3.2.10  HIV positive patients with advanced immune suppression and evidence of HIV resistant 
to all combinations of antiretroviral therapy considered at high risk of non-lymphoma 
related death within 12-months due to other AIDS complications should not be enrolled 
on the study.  


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3.3 
Screening Evaluation  
Evaluation pre-treatment (within 4 weeks of treatment except 3.3.2.1and 3.3.2.6 must be done 
within 72 hours of treatment):  
3.3.1 Clinical evaluation 
3.3.1.1 Complete History and Physical examination 
3.3.1.2 Height, weight and performance status 
3.3.1.3 CT scan of chest, abdomen and pelvis  
3.3.1.4 Clinical PET/CT (fluorine 18-FDG) scan.  This PET/CT scan is optional, but it is 
strongly encouraged that it be obtained if possible. 
3.3.1.5 Magnetic Resonance Imaging of head and/or spine if clinically indicated 
3.3.1.6 Unilateral Bone marrow biopsy and aspirate 
3.3.1.7 Lumbar Puncture for flow cytometry, glucose, protein, cell count and cytology. 
3.3.2 Laboratory Evaluation 
3.3.2.1 CBC, differential, PT, PTT, AST, ALT, LDH, alkaline phosphatase, bilirubin, albumin, 
calcium, phosphate, uric acid, creatinine (24 hour creatinine clearance if serum 
creatinine > 1.5 mg/dL), electrolytes, glucose, urinalysis. 
3.3.2.2 HIV antibody, Anti-HCV antibody, & hepatitis B surface antigen. 
3.3.2.3 Serum EBV viral load by PCR (NIH Clinical Center only). 
3.3.2.4 Lymphocyte enumeration (TBNK) for HIV + patients only  
3.3.2.5  HIV viral load for HIV + patients only 
3.3.2.6 Serum HCG in females of childbearing potential. 
3.3.2.7 Peripheral blood flow cytometry  
3.3.2.8 All patients (except Burkitt Lymphoma patients) must have confirmation of cMYC 
rearrangement [(8,14) translocation by FISH or cytogenetics] prior to enrollment.  
3.4 
Baseline Studies 
3.4.1 A fresh tissue biopsy of accessible lymph node will be obtained in patients who consent 
to the optional biopsy where possible and if it does not delay the initiation of treatment 
significantly, as judged by the PI or designee. These biopsies are optional but highly 
encouraged. 
3.5 
Inclusion of Women and Minorities 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
4 
REGISTRATION PROCEDURES 
4.1 
Investigator and Research Associate Registration with CTEP 


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Food and Drug Administration (FDA) regulations require IND sponsors to select qualified 
investigators.  NCI policy requires all persons participating in any NCI-sponsored clinical trial to 
register and renew their registration annually.  To register, all individuals must obtain a CTEP 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to Oncology Patient Enrollment 
Network (OPEN) or Rave or acting as a primary site contact) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined 
in the table below. 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
 
HSP/GCP training 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
• Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL) 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
4.2 
Site Registration (Applies to all participating sites, including NCILYMB) 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 


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before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to the following: 
• An active Federalwide Assurance (FWA) number 
• An active roster affiliation with the Lead Network or a participating organization 
• A valid IRB approval 
• Compliance with all protocol specific requirements 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office.  For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
4.2.1 Downloading Regulatory Documents 
Permission to view and download this protocol and its supporting documents is restricted and is 
based on person and site roster assignment housed in the CTSU RSS. 
Site registration.  Permission to view and download this protocol is restricted and is based on 
person and site roster data housed in the CTSU RSS.  To participate, Investigators and 
Associates must be associated with the Corresponding or Participating protocol organization in 
the RSS.  forms can be downloaded from the 9177 protocol page located on the CTSU Web site.   
• Go to https://www.ctsu.org 
• Log in to the members’ section on the left side of the page using your CTEP IAM 
username and password 
• Click on the Protocols tab in the upper left portion of your screen; enter “9177” in 
the search box, then click the Go button. 
• Click on the LPO Documents tab and scroll down the page to the Site Registration 
Documents links. 
• Download and complete the following forms: 
• CTSU IRB/Regulatory Transmittal 
• CTSU IRB Certification Form 
4.2.2 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal, where they will be entered and tracked in the CTSU RSS. 


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Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab → Regulatory 
Submission  
When applicable original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
4.2.3 Checking Your Site’s Registration Status 
You can verify your site registration status on the members’ section of the CTSU website. 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
Note:  The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network.  It does not 
reflect compliance with protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks. 
4.3 
Patient Registration 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
All site staff (including NCILYMB) will use OPEN.  OPEN is a web-based registration system 
available on a 24/7 basis. It is integrated with the CTSU Enterprise System for regulatory and 
roster interchange and with the Theradex Interactive Web Response System (IWRS) for retrieval 
of patient registration/randomization assignment.  Patient enrollment data entered by Registrars 
in OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
Prior to accessing OPEN site staff should verify the following: 
4.3.1 All eligibility criteria have been met within the protocol stated timeframes.  
4.3.2 If applicable, all patients have signed an appropriate consent form and Health Insurance 
Portability and Accountability Act (HIPAA)  authorization form. 
4.4 
Access requirements for OPEN: 
4.4.1 Site staff will need to be registered with CTEP and have a valid and active CTEP-IAM 
account. This is the same account (user id and password) used for the CTSU members' 
web site.  
4.4.2 To perform registrations, the site user must have been assigned the 'Registrar' role on the 
relevant Organization roster. Role assignments are handled through the Groups in which 


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you are a member  
4.4.3 Site and/or Data Administrators can manage roster roles (including assignment of the 
Registrar role) within the Regulatory tab/Site Roles sub-tab of the CTSU members' web 
site.  
Note:  The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
Further instructional information is provided on the CTSU members' web site OPEN tab  at 
https://www.ctsu.org or at https://open.ctsu.org.  For any additional questions contact the CTSU 
Help Desk at 1-888-823-5923 or ctsucontact@westat.com.  
A PDF version of the Eligibility Checklist is available on the CTSU web site under the patient 
enrollment documents link for the protocol.  If a paper EC is used for source documentation it 
must be signed and dated. 
4.5 
On-study Procedure for NIH Clinical Center Only 
In addition to registering patients through the OPEN system, authorized staff at the NCI must 
register an eligible candidate with NCI Central Registration Office (CRO) within 24 hours of 
signing consent. A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to: NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents. Verification of Registration will be forwarded electronically via e-mail to 
the research team.  A recorder is available during non-working hours.  
5 
TREATMENT PLAN 
Effective with Amendment L (version date: 11/21/2016) this protocol is no longer on 
Administrative Hold. The investigators at the Clinical Center may resume patient enrollment. 
Effective with Amendment K (version date: 10/18/2016) this protocol is on Administrative Hold 
at the Clinical Center only. No new patients will be enrolled at the NIH Clinical Center; 
however, patients currently on-study will continue to be followed per protocol. Enrollment will 
continue at Participating Sites with current IRB Approval.  
5.1 
Agent Administration 
Treatment will be administered on an outpatient basis, as a general rule. At times, it may be 
necessary to administer the treatment on an inpatient basis.  Reported adverse events and 
potential risks are described in Section 14.  Appropriate dose modifications are described in 
Section 5.4.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the patient's malignancy. 
 


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5.2 
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2.1 Definition of Low and High Risk Patients 
5.2.1.1 Low Risk (LR) Patients must meet all of the following criteria: 
• Normal LDH 
• ECOG PS 0-1 or Karnofsky 100%-70% 
• Ann Arbor stage I-II 
• No tumor mass ≥ 7 cm  
 
5.2.1.2 High Risk (HR) Patients   
All patients not considered low risk (LR) and all patients with c-MYC + DLBCL. Note that 
patients with c-MYC + plasmablastic lymphoma (who are CD20 negative) will NOT receive 
rituximab and will receive 6 (or 8 if applicable) cycles of DA-EPOCH. 
5.2.2 Systemic Treatment  
Systemic treatment is determined by risk as described in Section 5.2.1. The treatment paradigm 
is described in Section 5.3.  
5.2.3 Central Nervous System (CNS) Treatment  
CNS treatment is determined by disease status as described in Section 5.2.1. 
 
Include c-MYC 
+ DLBCL and 
plasmablastic 
lymphoma in 
High Risk 
c-MYC + 
plasmablastic 
lymphoma will 
not receive 
rituximab  


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Patients with low risk disease will not receive prophylactic intrathecal chemotherapy. 
If initial CSF flow cytometry and cytology and brain scan negative, high risk patients (including 
patients with c-MYC+ DLBCL and c-MYC+ plasmablastic lymphoma) will receive prophylactic 
intrathecal chemotherapy beginning on cycle 3.  
If initial CSF flow cytometry or cytology is positive, patients will receive active intrathecal 
chemotherapy beginning on cycle 1.  At the discretion of the Principal Investigator or lead 
associate investigator, patients with abnormal clinical neurological findings, or suspicious flow 
cytometry or cytology may receive active intrathecal chemotherapy beginning on cycle 1.  
5.3 
Study Drug Administration (Dose-Adjusted-EPOCH-Rituximab)  
5.3.1 Low Risk Patients 
LR patients will receive 3 cycles of DA-EPOCH-RR (two doses of rituximab per cycle). As a 
safety measure and secondary endpoint, FDG-PET/CT will be performed after cycle 2 
completion. If the FDG-PET/CT is positive, the patient will complete treatment as outlined for 
high risk patients (i.e. receive 4 additional cycles of DA-EPOCH-R), with a repeat FDG-PET/CT 
after completion of cycle 6.   
 
Dose-Adjusted-EPOCH-RR 
 
Drugs 
Dose/Schedule 
Rituximab 
375  mg/m2 IV day 1 (before infusions) and day 5 (before 
cyclophosphamide); see Section 14.1.5 for administration 
instructions 
Etoposide 
50 mg/m2/day CIV days 1- 4 (96 hour infusion) 
Doxorubicin 
10 mg/m2/day CIV days 1-4 (96 hour infusion) 
Vincristine 
0.4 mg/m2/day CIV days 1-4 (96 hour infusion) 
Cyclophosphamide 
750 mg/m2 IV day 5 over 30 minutes. 
Prednisone* 
60 mg/m2 PO BID days 1-5; (first dose should be given at 
least 60 minutes before starting day 1 rituximab) 
Filgrastim** 
 
480 mcg/day SC days 6-15 or ANC > 5000/µl past the nadir.  
 
 
 
Cycle Length 
Repeat cycle every 21 days  
 
Delay cycle until ANC > 1000/l and platelets >75,000/l.  Use filgrastim to increase ANC and 
begin next cycle as soon as ANC recovers.  If no recovery after 2 weeks, contact Dr. Roschewski 
for guidance.  
*For patients who cannot tolerate oral steroids, please contact the Hospital Pharmacist for 
guidance on dosing equivalents of other steroid preparations. 
** In circumstances where it is not feasible to use filgrastim, pegfilgrastim may be substituted 
but using filgrastim is encouraged if at all possible. If pegfilgrastim is used, the dose is 6 mg SC 
on Day 6 (as close as possible to 24 hours after completion of chemotherapy). 


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5.3.2 High Risk Patients including Patients with c-MYC+ DLBCL and c-MYC+ plasmablastic 
lymphoma   
HR patients will receive 6 cycles of DA-EPOCH-R (one dose of rituximab per cycle).  Patients 
with c-MYC+ plasmablastic lymphoma will receive 6 cycles of DA-EPOCH (no rituximab). As 
a secondary endpoint, FDG-PET/CT will be performed after cycle 2 completion. If that FDG-
PET/CT is positive, it will be repeated after completion of cycle 6.   High risk patients who have 
achieved only a Partial Response at the completion of cycle 6 may receive up to 2 additional 
cycles of DA-EPOCH-R at the discretion of the PI. FDG-PET/CT will be repeated after cycle 8, 
for those patients who receive 8 cycles of therapy.  
 
Dose-Adjusted-EPOCH-R 
 
Drugs 
Dose/Schedule 
Rituximab 
375  mg/m2 IV day 1 (before infusions); see Section 14.1.5 
for administration instructions  
Etoposide 
50 mg/m2/day CIV days 1- 4 (96 hour infusion) 
Doxorubicin 
10 mg/m2/day CIV days 1-4 (96 hour infusion) 
Vincristine 
0.4 mg/m2/day CIV days 1-4 (96 hour infusion) 
Cyclophosphamide 
750 mg/m2 IV day 5 over 30 minutes. 
Prednisone* 
60 mg/m2 PO BID days 1-5; (first dose should be given at 
least 60 minutes before starting day 1 rituximab) 
Filgrastim** 
480 mcg/day SC days 6-15 or ANC > 5000/µl past the nadir. 
 
 
  
Cycle Length 
Repeat cycle every 21 days  
 
Delay cycle until ANC > 1000/l and platelets >75,000/l.  Use filgrastim to increase ANC and 
begin next cycle as soon as ANC recovers.  If no recovery after 2 weeks, contact Dr. Roschewski 
for guidance.   
*For patients who cannot tolerate oral steroids, please contact the Hospital Pharmacist for 
guidance on dosing equivalents of other steroid preparations.  
**In circumstances where it is not feasible to use filgrastim, pegfilgrastim may be substituted but 
using filgrastim is encouraged if at all possible. If pegfilgrastim is used, the dose is 6 mg SC on 
Day 6 (as close as possible to 24 hours after completion of chemotherapy). 
5.3.3 CNS Treatment 
5.3.3.1 Prophylactic CSF treatment:  High risk CSF negative patients (including patients with 
c-MYC+ DLBCL and c-MYC+ plasmablastic lymphoma) will receive prophylactic 
CNS treatment with intrathecal methotrexate (MTX) on the following schedule: 
methotrexate 12 mg IT on days 1 and 5 of cycles 3, 4, 5 and 6 (total of 8 treatments). 
The days of treatment may be adjusted +/- 3 days to accommodate scheduling issues 
such as holidays, etc.  


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5.3.3.2 Active Meningeal Lymphoma treatment:  If the CSF is positive for malignant cells by 
flow cytometry/cytology, or the patient has neurological or radiological evidence 
consistent with leptomeningeal lymphoma, the CSF should be treated with methotrexate 
as follows:   
Induction: MTX (12 mg by lumbar or 6 mg by Ommaya route) twice a week for 2 
weeks past negative cytology with a minimum of 4 weeks treatment. Patients will then 
receive consolidation with MTX weekly x 6 doses and maintenance with MTX monthly 
x 6 doses.  
The above therapy may be modified as clinically indicated.  In some cases, it may be 
necessary to administer radiation to the head and/or spine and/or to substitute cytarabine 
(70 mg by lumbar or 30 mg by Ommaya route) for MTX.  Patients who fail to clear or 
relapse in the CSF will be considered for alternative intraventricular therapy and/or 
radiation. 
The methods of IT administration should be performed according to institutional 
procedures. 
Patients should remain in prone or Trendelenburg position for 1 hour post LP to 
facilitate drug circulation throughout the CNS. 
5.3.3.3 Parenchymal CNS lymphoma: Patients with evidence of a parenchymal mass may be 
treated with radiation.  
5.3.3.4 Chemical Arachnoiditis:  If signs or symptoms of chemical arachnoiditis occur, 
administer 15 mg hydrocortisone (HDC) with the methotrexate or cytarabine as per the 
institutional standard. Cytarabine (Ara-C). Cytarabine may be used in place of 
methotrexate after discussion with the local principal investigator if methotrexate is 
contraindicated.   
5.4 
DA-EPOCH-R “Dose Adjustment” 
Doses for doxorubicin, etoposide and cyclophosphamide will be based on measurements of the 
previous cycle ANC or platelet nadir whichever is lower. Dose adjustment is based on 
measurements of twice weekly CBC only, even if additional CBCs are obtained. Twice weekly 
CBCs must be at least 3 days apart.  
 
**Please Note: This does not apply to patients who have low platelets at baseline due to 
lymphoma or immune-mediated mechanism caused by lymphoma. In those cases, no delay 
or dose reduction is required. The dose adjustments for these patients will be based solely 
on the ANC nadir and the PI or designee’s clinical judgment. 
 
When moving to a higher dose level, adjustments apply only to etoposide, doxorubicin and 
• If Nadir ANC  500/µl on all measurements: 
 One level above last cycle 
 •If Nadir ANC  500/µl on 1 or 2 measurements: 
   Same level as last cycle 
• If Nadir ANC  500/µl  3 measurements: 
 One level below last cycle 
Or 
 
• If nadir platelet  25,000/µl ** on  1 measurement: 
 One level below last cycle 


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cyclophosphamide. When moving to dose levels below dose level 1, adjustments apply only to 
cyclophosphamide and involve 20% reductions in cyclophosphamide. 
 
 Drugs 
      Drug Doses per Dose Levels  
-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 
5.5 
Adverse Event Management (Dose Modification Guidelines) 
5.5.1 Ileus and Constipation  
Symptomatic ileus/constipation may occur. Because the severity of constipation is dose related, 
it is usually unnecessary to stop the vincristine altogether. Every effort should be made to not 
unnecessarily reduce vincristine doses.  Ileus/constipation is usually worse on the first cycle, so 
prophylactic bowel care is essential.  If vincristine dose is reduced for this toxicity, it can often 
be increased to full dose on subsequent cycles without recurrence of severe ileus/constipation. If 
ileus or constipation requires hospitalization, reduce vincristine 25% on the subsequent cycle. If 
symptoms resolve after vincristine reduction, increase dose to previous level on subsequent 
cycles.  
Recommended Bowel Regimen – goal of at least one soft bowel motion every 24 hours while on 
study 
Adults: Sodium Docusate 100mg capsule; take one to two capsules once a day Days 1-7 of each 
cycle. If needed can double the frequency to two capsules every 12 hours. If needed add oral 
lactulose 15-30 ml prn/ every 6 hours. 
5.5.2 Neurological Adverse Events 
5.5.2.1 Sensory neuropathy  
Grade  % Dose of Vincristine 
   2 
100 
   3 
50 
   4 
0 
 
5.5.2.2 Motor neuropathy 
Grade 
% Dose of Vincristine 
    1 
100 
    2 
75 
    3 
25 
    4 
0 
 


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If neuropathy resolves to a lower grade, doses for that lower grade may be reinstituted at 
investigator discretion.  If the grade of neuropathy increases after being re-escalated, doses must 
be reduced for the appropriate toxicity grade and may not be re-escalated, even if neuropathy 
resolves again to a lower grade.  
5.5.3 Hepatic and Renal Dysfunction  
No dose modifications are required for hepatic dysfunction. Specifically, our results have shown 
no clinically significant changes in doxorubicin or vincristine drug clearance.  
Etoposide should be reduced 25% on cycle one for creatinine clearance < 50 cc/min. If the 
creatinine clearance remains low on subsequent cycles, etoposide should remain at the reduced 
level as in the previous cycle.   Etoposide should be returned to full dose (or escalated if 
indicated) once creatinine clearance > 50 cc/min. No other dose modifications for abnormal renal 
indices will be made for enrolled patients.  
5.5.4 Dose Modification for Obese Patients 
All dosing is based on the patient’s BSA as calculated from actual weight. There is no clearly 
documented adverse impact of treatment of obese patients when dosing is performed according 
to actual body weight.  Failure to use actual body weight in the calculation of drug dosages will 
be considered a major protocol deviation. 
5.5.5 Rituximab Infusional related Adverse Events 
Pretreatment for rituximab with diphenhydramine and acetaminophen using standard medical 
practice will be used in all patients. 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. Rituximab will be discontinued for the duration of the cycles in patients with 
grade 4 allergic reactions.  At the discretion of the local PI, rituximab may be administered on 
the following cycles using slower infusion rates. 
5.5.6 Supportive Therapies 
Supportive therapies, such as blood and/or platelet transfusion and medications to prevent nausea 
and vomiting are permitted as clinically indicated. 
 
 


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5.6 
Study Calendar 
 
StudiesA 
Pre-
therapyA 
Pre- 
Cycles 
1-6E 
BIW 
Cycles 
1-6E     
Pre- 
Cycle 
3 
Post 
Cycle 3 
(Low 
Risk) 
Post- Cycle 
6 and Post-
Cycle 8, if 
applicable 
(High risk) 
Follow 
Up (see 
5.9) 
Hx; PE; VS  
x 
x 
 
x 
x 
x 
x 
Height 
x 
 
 
 
 
 
 
*PS and weight 
x 
x 
 
 
 
 
 
Tumor Measurement 
x 
 
 
x 
x 
x 
x 
*CBC/diff 
x 
x 
x 
x 
x 
x 
x 
*PT/PTT 
x 
x 
 
 
 
 
 
*Electrolytes, glucose, 
BUN, Creatinine, 
ALT, AST, Bilirubin, 
Alk Phos, LDH, Ca++, 
Albumin, Phos, Mg, 
uric acid 
x 
x 
 
x 
x 
x 
x 
*Urinalysis 
x 
 
 
 
 
 
 
HIV and Hepatitis B 
and C serology, 
Pregnancy Test 
(serum)* 
x 
 
 
 
 
 
 
Lymphocyte 
enumeration (TBNK) 
HIV + patients only 
x 
 
 
 
x 
x 
xF 
HIV viral load for 
HIV + patients only 
x 
 
 
 
x 
x 
xF 
EBV viral load  
(NIH Clinical Center 
only) 
x 
 
 
x 
x 
x 
x 
CT chest/abd/pelvis  
x 
 
 
x 
xG 
x 
x  
MRI Brain and/or 
spine if clinically 
indicated 
x 
 
 
 
 
 
 
PET/CT scanB 
x 
 
 
x 
 
If positive 
after Cycle 2  
Bone marrow biopsy 
& aspirate, peripheral 
blood flow cytometryC 
x 
 
 
x 
 
x 
 
 
 
 


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StudiesA 
Pre-
therapyA 
Pre- 
Cycles 
1-6E 
BIW 
Cycles 
1-6E     
Pre- 
Cycle 
3 
Post 
Cycle 3 
(Low 
Risk) 
Post- Cycle 
6 and Post-
Cycle 8, if 
applicable 
(High risk) 
Follow 
Up (see 
5.9) 
Lumbar puncture with 
chemistries, cell count, 
cytology and flow 
cytometry 
x 
 
 
xD 
 
 
 
10 cc red top for 
serum storage ( NIH 
Clinical Center only) 
x 
 
 
x 
x 
x 
x 
Tumor Biopsy 
Optional 
x 
 
 
 
 
 
 
Adverse Events, 
Symptoms/Toxicity 
Assessment 
x 
x ..................................................... xH 
xH 
• A—Initial assessment is to be performed within 4 weeks prior to starting treatment, 
except as marked with * which must be performed within 72 hours of treatment. 
• B—Clinical PET/CT scans may be performed at other time points throughout this 
protocol if the investigator deems it medically necessary. If obtaining PET/CT scan will 
delay initiation of treatment, pre-treatment PET/CT scan may be waived. PET/CT scan 
will be obtained after cycle 2 in all patients. If PET/CT scan post cycle 2 is positive, a 
post cycle 6 (and post cycle 8, if applicable) PET/CT scan will be obtained. 
• C—If flow cytometry or bone marrow positive, repeat test as indicated until negative. 
• D—High Risk patients only. 
• E—also applies to Cycle 7 and 8, if applicable. 
• F—To be performed one year after end of treatment and as clinically indicated.  
• G—CT scan may be delayed for up to 2 weeks after Low Risk patients complete Cycle 3. 
• H—Every effort must be made to have all subjects complete a safety visit approximately 
30 days following the last dose of study therapy; this may be completed by phone if the 
subject is not seen in the clinic. 
5.7 
Correlative Studies 
5.7.1 In Amendment I (version date 03/14/2014), the Burkitt Lymphoma Genome Sequencing 
Project (BLGSP) protocol was added to this study to allow for contribution of samples 
from Burkitt Lymphoma patients to the Genomic Databank for Burkitt Lymphoma that 
was created by the Foundation for Burkitt Lymphoma Research (FFBLR). Details related 
to the BLGSP protocol are described in APPENDIX F and for the samples to be collected 
in APPENDIX D. 
Biopsies may be obtained for cytogenetics, immunophenotype, molecular analyses including 
Fluorescent In Situ Hybridization for myc and polymerase chain reaction for Immunoglobulin 
gene rearrangement. Tissue will be frozen for microarray analysis. Laparotomy, thoracotomy, or 


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biopsy of relatively inaccessible lymph nodes (i.e. high axillary nodes) will only be performed if 
needed for definitive diagnosis and not for research purposes alone.  
Standard techniques will be used for biopsies which may include CT and/or ultrasound guided 
biopsy. In some cases, such biopsies may be expedited and facilitated with the use of navigation 
tools such as an automated laser angle selector connected to CT scan, or a standard needle guide 
connected to a protractor to determine which exact angle the biopsy needle will be inserted.  
These guiding techniques may occur as maneuvers to facilitate the biopsy, which will take place 
in the usual conventional fashion, with standard, disposable, conventional spring-loaded biopsy 
equipment. Accurate spatial tissue acquisition may lead to more reliable, accurate and precise 
tissue characterization, which in turn should be more reproducible. Please See Section 7.1 for 
details of sample handling. 
5.7.2 Structural and Functional Genomics of Tumor Cells 
The present study proposes to perform a comprehensive analysis of somatic alterations to the 
tumor genome. Included in this analysis will be DNA sequencing of all or part of the tumor, 
which can be achieved by classical DNA sequencing of individual genes or by utilizing high-
throughput DNA sequencing technologies.  Recently, in diffuse large B cell lymphoma 
(DLBCL), a number of recurrent oncogenic abnormalities have been uncovered by DNA 
sequencing.  These abnormalities track with known molecular subtypes of this disease.  For 
example, in the ABC subtype of DLBCL, recurrent mutations in CARD11, CD79B and MYD88 
have been described. 
The activity of the tumor genome will be assessed by profiling the expression levels of mRNAs 
and microRNAs in a tumor biopsy sample using microarray and multiplexed PCR methods.  The 
mRNA expression profiling of samples on CALGB 50303 have been used to identify molecular 
subtypes of DLBCL and to predict therapeutic responses.  In addition, new methods have been 
developed recently to identify new RNA species that are expressed from the genome.  For 
example, digital gene expression is based on the high-throughput resequencing of mRNA, an 
effort that can uncover previously unannotated genes and new alternatively spliced isoforms of 
known genes.  This effort would be exploratory, aiming to identify new aspects of the biology of 
aggressive B cell tumors that are related to therapeutic response.  In addition, microRNAs have 
the capacity to identify molecular subtypes of DLBCL and can yield additional functional 
information because of their ability to regulate the expression of a large repertoire of 
5.7.3 Methods 
The technology platforms that are able to interrogate genomic structure and function are 
constantly in flux.  Therefore, the exact nature of the methodologies that will be employed will 
be assessed at the time that the samples are collected and ready for analysis. The following are 
technologies in use for each task at the time of protocol writing/amendment:   
5.7.3.1 DNA/RNA sequencing 
Genomic DNA and total RNA will be extracted from tumor samples using a Qiagen All-prep kit. 
MicroRNAs will be extracted from the samples using a QiagenmiRNeasy Mini Kit. 
For investigating individual target genes, classical Sanger sequencing will be performed on PCR 
amplicons, using primers surrounding the known sites of mutation in DLBCL. 


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A related technology, RNA-Seq, utilizes RNA from the tumor specimen to create a cDNA 
library for high-throughput sequencing.  RNA-seq will be performed using Illumina kits 
followed by high-throughput sequencing on an Illumina HighSeq 2000 machine.  The cutoffs for 
coverage and percent mutant calls mentioned above will also be used to identify putative SNVs.  
RNA sequencing will also be used to read out digital gene expression across the genome as 
described60. 
MicroRNAs will be profiled using an Illumina kit to construct a library from tumor RNA 
samples and will be sequenced using the Illumina HighSeq 2000 platform. 
5.7.3.2 Molecular Analyses  
Molecular analyses using fluorescent In Situ Hybridization and polymerase chain reaction may 
be performed on tissue samples.  
5.7.3.3 Flow Cytometric Analysis 
FACS analysis is a standard methodology for studying hematologic malignancy cell phenotype 
and biology.  A variety of standard and new flow cytometric techniques will be applied in 
attempt to improve understanding of cancer biology, investigate mechanisms of chemotherapy 
resistance, and identify new potential therapeutic targets. 
5.7.4 Certificate of Confidentiality 
As part of study efforts to provide confidentiality of subject information, this study will obtain a 
Certificate of Confidentiality which helps to protect personally identifiable research information.  
The Certificate of Confidentiality allows investigators on this trial to refuse to disclose 
identifying information related to the research participants, should such disclosure have adverse 
consequences for subjects or damage their financial standing, employability, insurability or 
reputation.  The informed consent includes the appropriate coverage and restrictions of the 
Certificate of Confidentiality. 
5.7.5 Management of Results 
The analyses that we perform in our laboratory are for research purposes only; they are not 
nearly as sensitive as the tests that are performed in a laboratory that is certified to perform 
genetic testing. Changes that we observe unrelated to our research may or may not be valid.  
Therefore, we do not plan to inform participants of the results of testing on the tissue and blood 
that is performed in our research lab.  However, in the unlikely event that we discover a finding 
during the course of the study that could be clinically relevant, we will contact the participant if 
he/she agrees to be contacted.  We will ask if he/she would like to meet with a genetic healthcare 
provider and have an additional tube of blood drawn to verify the findings we have seen in our 
lab.  If the health history, family history, or tumor diagnosis from the Laboratory of Pathology at 
the NIH Clinical Center suggests that the participant might benefit from genetic testing, we will 
discuss this with him/her.   
 
Note: incidental findings that may be considered clinically relevant will be discussed at the NCI 
Lymphoid Malignancies Branch monthly conference and determined as significant or not by the 
Senior Staff.  It is anticipated that this study will be ongoing for at least 10 years; incidental 
findings will only be reported to the patient while the study is on-going.    


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This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis. 
5.7.6 Genetic counseling  
Should any incidental findings be discovered, the NCI CCR Genetics Branch will be asked to 
provide genetic counseling. 
Subjects will be contacted with a request to provide a blood sample to be sent to a CLIA certified 
laboratory.  If the research findings are verified in the CLIA certified lab, the subject will be 
offered the opportunity to come to NIH to have genetic education and counseling to explain this 
result; at the time of any such event(s), these activities will be funded by the NCI/CCR in 
consideration of the specific circumstances.  If the subject does not want to come to NIH, a 
referral to a local genetic healthcare provider will be provided (at the patient’s expense). 
5.8 
Criteria for Removal from Protocol Therapy and Off-Study Criteria 
Every effort must be made to have all subjects complete a safety visit approximately 30 days 
following the last dose of study therapy for reporting of toxicities; this may be done by phone if 
the subject is not seen in the clinic. 
5.8.1 Criteria for removal from protocol therapy 
• Patient completes therapy as outlined in section 5.3 
• Voluntary withdrawal from treatment  
• Progressive disease  
• Intercurrent illness that prevents further administration of treatment 
• General or specific changes in a patient’s condition that render the patient unacceptable 
for further treatment as determined by that principal investigator 
5.8.2 Off-Study Criteria 
• Voluntary withdrawal from the protocol and follow-up 
• Death 
• Non-compliance which affects safety or endpoints of the study. 
• Physician’s determination that withdrawal is in the patient’s best interest.    
5.8.3 Off Protocol Therapy and Off-Study Procedure for NIH Clinical Center Only 
Authorized staff must notify Central Registration Office (CRO) when a patient is taken off 
protocol therapy and when a subject is taken off-study. A  Participant Status Updates Form from 
the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to: NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov.  
5.9 
Post-Treatment Evaluation  
5.9.1 Patients in complete remission (CR), complete remission-unconfirmed (CRu), partial 
remission (PR) or stable disease (SD) at the end of treatment will proceed to follow up. 
CT scans will be performed every 4 months for the first two years after the completion of 
therapy.  


Abbreviated Title:  DA-EPOCH-R in BL 
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• At the two year post-treatment visit, patients with Burkitt lymphoma whose scans are 
negative will return yearly. At these yearly follow up visits, patients will undergo a 
physical examination and laboratory testing but will not undergo a CT scan unless 
this is clinically indicated.  
• At the two year post-treatment visit, patients with other than Burkitt lymphoma 
whose scans are negative will return yearly. At these yearly follow up visits, patients 
will undergo a physical examination and laboratory testing and a CT scan for up to 5 
years post treatment. After the five years post-treatment visit, these patients will 
continue to have yearly visits; at which time, they will undergo a physical 
examination and laboratory testing but will not undergo a CT scan unless this is 
clinically indicated.  
NOTE:  Following Amendment N, follow-up will stop at 3 years. 
5.9.2 If patients have progressive disease, they will be followed for survival and any further 
therapy for their lymphoma, which should be documented by regimen name and dates of 
treatment only. This follow-up may be done via telephone contact with the patient and/or 
the patient’s local physician.  
Burkitt lymphoma and very aggressive B-cell lymphomas are characterized by early relapses if 
they occur and given the concern for radiation exposure, the PI does not believe that is justified 
to perform routine CTs in this population beyond 2 years. Adverse event data that occurs during 
the follow-up period that is unrelated to study treatment will not be reported.  
6 
SUPPORTIVE CARE  
6.1 
Prophylaxis of Pneumocystis jiroveci (previously known as Pneumocystis carinii) 
All patients will receive prophylaxis for Pneumocystis during EPOCH chemotherapy.  
• Adult Dosing: trimethoprim/sulfamethoxazole 1 DS P.O. QD for three days each week. 
• Patients allergic to either component may receive other standard treatments.   
6.2 
Prophylaxis for hepatitis B reactivation 
Patients who receive chemotherapy and/or rituximab may undergo hepatitis B virus (HBV) 
reactivation. Patients who are hepatitis B Core Ab+ but hepatitis B s Ag Ab- may have low 
levels of hepatitis B viremia and should undergo a blood PCR test for hepatitis B viral load. All 
patients at risk of reactivation will have a PCR analysis of blood for viral loads performed 
pretreatment and after cycles 2, 4 and 6 of chemotherapy treatment.  Additionally, these patients 
will receive appropriate treatment for hepatitis B reactivation prophylaxis.  
Please note: HBV prophylaxis for HIV positive patients should not include tenofovir or 
lamivudine. Other HBV agents must be used in those patients.  
6.3 
Additional Prophylaxis for HIV positive patients 
6.3.1 MAC prophylaxis 


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Initiate in all patients with CD4 cells ≤ 100/mm3 and for patients whose CD4 cells fall below 
this level while on study. Recommend azithromycin 1200 mg once weekly, but other agents are 
acceptable.   
6.3.2  Fungal Infections 
Oral Candidiasis – if asymptomatic, recommend clotrimazole troches.  If symptomatic, 
recommend oral fluconazole.  Fluconazole interacts with many drugs, and can alter EPOCH 
pharmacokinetics and therefore must be held during chemotherapy infusions. 
Esophageal Candidiasis – recommend oral fluconazole, but if no response, consider 
amphotericin B. Fluconazole interacts with many drugs, and can alter EPOCH pharmacokinetics 
and therefore must be held during chemotherapy infusions. 
6.4 
Tumor Lysis Syndrome 
All patients with BL will receive allopurinol starting 24 hours prior to the initiation of therapy 
and continued for the first week of the initial cycle of therapy. Adult dosing: 600 mg x 1 dose 
followed by 300 mg daily PO. The 600 mg dose may be omitted if the patient is already 
receiving allopurinol. Additional measures such as hospitalization with aggressive IV hydration 
will be used at the discretion of the investigator. 
6.5 
Antiretroviral therapy for HIV infection 
It is recommended that antiretroviral therapy be suspended until the completion of 
systemic chemotherapy treatment for Lymphoma.  If antiretroviral therapy is used 
concurrently, the following conditions should be met: 
1. The patient does not have renal or hepatic abnormalities 
2. The patient is already on a stable regimen of antiretroviral therapy that does not include 
ritonavir, zidovudine, or stavudine. 
3. For patients who are not already on antiretroviral therapy, they may begin antiretroviral 
therapy (exclusive of the agents in #2 above) after completion of cycle 2 infusions 
provided there were no treatment related events in cycle one such as mucositis that would 
impair oral intake, and there are no hepatic or renal abnormalities. 
4. If the patient develops renal or hepatic abnormalities at any time, antiretroviral therapy 
must be suspended until completion of all therapy for lymphoma.  
7 
BIOSPECIMEN COLLECTION 
7.1 
Sample Storage, Tracking and Disposition 
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. 
7.1.1  Procedures for stored serum specimens  
• The Clinical Support Laboratory, Leidos Biomedical Research Inc., processes and 
cryopreserves samples in support of IRB-approved, NCI clinical trials.  All laboratory 


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personnel with access to patient information annually complete the NIH online course in 
Protection of Human Subjects.  The laboratory is CLIA certified for anti-IL 15 and 
certain cytokine measurements,  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 
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,  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.   


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• It is the responsibility of the Source Code holder (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.  At a minimum, the lab 
needs confirmation that one has been executed or an exception was granted from an 
office authorized to make such exceptions, e.g. NCI Technical Transfer Center. 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.   
7.1.2 Procedures for Collecting, Processing and Storing of Tumor Biopsies  
• Orders for tumor biopsies and research blood samples collections should be placed in 
CRIS (Clinical Research Information System, Clinical Research Center, NIH, Bethesda, 
MD) 
• 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 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.  
• Tumor can be further processed. Additional purification may be carried out by selection 
with magnetic beads binding to appropriate surface molecules, typically CD19. For 
analysis cells may be lysed to obtain RNA (using Qiagen manufactured kits are similar) 
or proteins (salt and/or triton containing buffers with addition of protease and 
phosphatase inhibitors). Integrity of RNA is monitored by gel electrophoresis and 
concentration of RNA or protein is measured spectrophotometrically.  
• Research sample inventory and storage: All research samples are assigned a unique 
number and cataloged. Tumor biopsies and processed biologic material (RNA, protein) is 
stored at -80C in a temperature controlled, alarm secured -80C freezer.  
• Tumor tissue may be stored by the NCI Department of Hematopathology for future 
research assays which are related to this study and do not pose an increase in patient risk.  


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Tissue that is given to the technician will be assigned an accession number (HP#) in the 
HP Case Log book.   A Patient background sheet will be filled out and filed with any 
accompanying paperwork in the black notebook.  Final reports and any supplemental 
reports that follow will be added to these notebooks which are located in Room 2N110.  
• Frozen Specimens: Tissue snap frozen or embedded in OCT is wrapped in aluminum foil 
labeled with the patient's name and accession number (HP#), put into a zip-lock bag, and 
stored in liquid nitrogen freezer.  The liquid nitrogen freezers are monitored daily for 
temperature variations. A FileMaker Pro data base called HP Patient Information and 
Specimen Inventory is used for tracking the samples. 
7.1.3 Procedures for shipping Tumor Biopsies from participating sites to NCI  
Contact one of the following individuals to obtain shipping packages: 
 
Andrea Nicole Lucas, RN 
10 Center Drive 
Building 10 Room 4N115 
Bethesda, MD 20892 
240-760-6252 
lucasan2@mail.nih.gov 
Saleema Osman 10 Center 
Drive 
Building 10 Room 4N115 
Bethesda, MD 20892 
240-858-3184 
saleema.osman@nih.gov 
Hong Zhao 
10 Center Drive 
Building 10 Room 6N105 
Bethesda, MD  20892 
240-858-3550 
zhaoho@mail.nih.gov 
 
Shipping packages will be sent to each participating institution. To ensure timely arrival of 
shipping packages, place a request for multiple packages (at least 2 more than is needed) at the 
time of local IRB review. Packages will consist of the following items: 
(1) Fresh (Frozen) Tumor Biopsy Sample Procurement Instructions  
(1) Styrofoam Box 
(1) Cardboard Box 
(1) Biohazard Labeled Ziplock Bag 
(10) 2 mL cryopreservation screw cap tube 
 
Each package should be used to mail only one set of samples from a single 
patient. DO NOT CONSOLIDATE SAMPLES FROM MULTIPLE PATIENTS 
INTO A SINGLE BOX. 
• Remove the collection tubes from the styrofoam container.  
• Label all tubes with the CTSU patient ID number, NCI CTEP protocol number, 
institution, date of acquisition, and tissue source.  
• Use the 2 mL cryotubes to collect tumor samples. A minimum of a hundred milligrams 
(100 mg) of tissue should be provided. This corresponds to a minimum of 4 core needle 
biopsy specimens (16 gauge needle at least) or an excisional biopsy that is at least 100 
cubic mm in volume (i.e., the size of a pea). Fill the Nunc tubes 2/3 full and use as many 
Nunc tubes as necessary. 
• REMOVE ALL LIQUID FROM SAMPLE BEFORE FREEZING. Immediately 
preserve by freezing in dry ice or liquid nitrogen and transfer them from the liquid 
nitrogen or dry ice container, to a -70°/-80° C freezer (preferable), or to a -20°C 
freezer for storage until time of shipment. 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Fresh (Frozen) Tumor Biopsy Sample Shipment 
Note: Must have patient identification number before shipping sample.  
• Place all tubes with samples into the styrofoam box filled with at least 2 lbs. of dry ice. 
Position the tubes so that they are roughly in the center of the container (i.e., surrounded 
by dry ice).  
• Remember: ONE PATIENT SAMPLE SET PER “ZIPLOCK” BAG/BOX.  
• Complete the Tumor Biopsy Specimen Submission Form (APPENDIX D: Tumor Biopsy 
Submission Form) and place in the document compartment of the waterproof “Ziplock” 
plastic bag. Place in the styrofoam box.  
• Send a copy of form to Hong Zhao via email: zhaoho@mail.nih.go.  
• Tape the styrofoam box. Put the box inside the provided cardboard box. Close with tape. 
• Affix a FedEx label. Make a note of the air bill number on the FedEx label.  
• Please mail overnight on a Monday through Thursday so shipment will arrive during the 
week.  
• After mailing, send an e-mail to: lucasan2@mail.nih.gov and zhaoho@mail.nih.gov with 
the subject: “URGENT: NCI Protocol 10C0052_9177 Fresh/Frozen Biopsy Sample Sent” 
indicating the DAY, TIME, INSTITUTION, CTSU PATIENT ID NUMBER AND AIR 
BILL NUMBER OF THE PACKAGE in which the sample set was mailed.  
• Mail the samples to: 
Louis M. Staudt, MD, PhD 
Lymphoid Malignancies Branch, CCR, NCI 
Building 10/ Room 6N105 
National Institutes of Health 
9000 Rockville Pike 
Bethesda, MD 20892 
lstaudt@mail.nih.gov 
 
Questions or problems with sample procurement or shipment should be directed to the following 
individuals: 
Hong Zhao, Phone: 240-858-3550 (Primary Contact) 
Louis Staudt, MD, PhD, Phone: 240-781-13394 
Mark Roschewski, MD, Phone: 240-760-6183 
7.1.4 Protocol Completion/Sample Destruction 
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 11.2. 
7.2 
Samples for Genetic/ Genomic Analysis 
7.2.1 Description of the scope of genetic/genomic analysis 
The research correlates for this study are expected to include DNA/RNA sequencing of tumors, 
including circulating tumor (ctDNA)/cell-free (cfDNA) DNA. In addition, whole exome 
sequencing may include evaluation for known lymphoma mutations. For any genetic studies 
performed, the results will be deposited in a database such as dbGaP per NIH requirements. 
Although there is controlled access to such a database, such a submission carries theoretical risks 
of revealing the identity of the subject. This is discussed in the consent. 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
7.2.2 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized 
Confidentiality for genetic samples will be maintained as described (Section 7.1). In addition, a 
Certificate of Confidentiality has been obtained for this study.  
8 
DATA COLLECTION AND EVALUATION 
8.1 
Data Collection 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system.  Access to the trial in Rave is granted through the iMedidata application to 
all persons with the appropriate roles assigned in Regulatory Support System (RSS).  To access 
Rave via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, Site 
Investigator) on either the Lead or Participating Organization roster at the enrolling site.  To hold 
the Rave CRA role or Rave CRA (Lab Admin) role, the user must hold a minimum of an AP 
registration type.  To hold the Rave Investigator role, the individual must be registered as an 
NPIVR or IVR.  Associates can hold read-only roles in Rave.  If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on 
the DTL. 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page.  Please note, site users will not be able to access the study in 
Rave until all required Medidata and study specific trainings are completed.  Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the 
upper right pane of the iMedidata screen.   
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account.  Account activation instructions are located on the CTSU website, Rave 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance).  Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com.   
Data will be directly entered into the Medidata Rave database by each site. Data should be 
entered into the database no later than 2 weeks after the completion of each cycle. Data in section 
3 must be entered within 2 weeks of registration. 
The CTSU will be responsible for data management and abbreviated CDUS reporting.  NCI will 
be responsible for data analysis.   
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
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 11.2.1. 
8.1.1 The following is a list of specific data elements that will be collected and recorded in the 
database: 
1. All data elements of the International Prognostic Index (IPI) at baseline  
2. All transfusions of blood products 
3. All infections 
4. All hospitalizations, regardless of reason and the reason for hospitalization and 
the duration of hospitalization 
5. As patients will potentially remain on protocol until the time they die, the name(s) 
of subsequent regimens and date(s) received if patient has progressive disease. 
6. PET/CT results will be reported as positive or negative. (PET/CT and CT scan 
reports will be loaded into the database).  
7. All Unexpected Grade 2 adverse events 
8. Only the following expected Grade 2 adverse events:  
a. Neuropathy-motor 
b. Neuropathy-sensory 
c. Constipation 
d. Ileus 
e. Allergic Reaction 
f. Hemorrhagic Cystitis 
g. Febrile Neutropenia 
9. All other adverse events grade 3 or higher 
10. Special Note: Record only the highest grade of each adverse event (and the dates 
corresponding to the highest grade) during each cycle of treatment.  
8.1.2 Refer to Section 12.2.5 for a list of adverse events that do not require expedited reporting. 
8.1.3 The following is a list of specific data elements that will not be collected or recorded in 
the database: 
• Grade 1 adverse events 
• Grade 2 expected adverse events, except as listed above 
• Any adverse events which occur during subsequent regimens administered for 
progressive disease.  
• Concomitant medications 
• Results of physical exams 
• Vital Signs 
Complete records must be maintained on each patient including supplementary information 
obtained from outside laboratories, radiology reports, or physician’s records. These records will 
serve as the primary source material that forms the basis for the research record. The primary 
source documentation will assure the following:  
• The patient satisfied each eligibility criterion.  
• Signed informed consent was obtained prior to registration and treatment.  


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
• Treatment was given according to protocol or any protocol violations documented and 
justified.   
• Toxicity and response were assessed according to protocol. 
• Drug accountability records were kept on each patient. 
8.2 
Accessing Case Report Forms and Related Documents 
8.2.1 All clinical case report forms and supporting documentation associated with this study 
will be available through Medidata Rave. Instructions for accessing and using Rave are 
located on the 9177 Web page located on the members’ section of the CTSU Web site. 
• Go to www.ctsu.org 
• Log in to the members’ section on the left side of the page 
• Click on the Protocols tab in the upper left of your screen 
• Click on by Lead Group, then NCILYMB and select trial #9177  
• Click on the 9177 Study Specific RDC Instructions link  
8.3 
Data Submission 
8.3.1 The Medidata Rave Clinical Data Management System (CDMS) 
8.3.1.1 All participating sites will submit patient data via the Medidata Rave Clinical Data 
Management System.  Rave CDMS allows sites to enter patient data into the 9177 
database in Rave over a secure Internet connection.  Rave also allows for data 
correction at the point of entry, and is used to communicate and resolve issues relating 
to discrepant data.  Rave is available to those individuals who have completed their 
assigned eLearnings and are ready to enter actual patient data into the system.  
8.3.1.2 In addition to submitting patient data electronically via Rave, sites may be required to 
submit clinical reports to CTSU. Reports (if required) will be uploaded into the 
applicable Rave CRF. 
8.3.2 The Clinical Data Update System (CDUS) 
8.3.2.1 This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Abbreviated CDUS data will be submitted quarterly to CTEP by electronic means.    
Reports are due January 31, April 30, July 31, and October 31.  Instructions for 
submitting data using the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html).  
8.3.2.2 Responsibility for Data Submission: Study participants are responsible for submitting 
CDUS data and/or data forms to the CTSU quarterly at least 2 weeks before CTEP’s 
due date to allow time for CTSU compilation, Principal Investigator review, and timely 
submission to CTEP (Section 13.2.2). The CTSU is responsible for compiling and 
submitting CDUS data to CTEP for all participants and for providing the data to the 
Principal Investigator for review. 
8.3.3 Rave Training 
8.3.3.1 Required trainings will be assigned as eLearnings to site staff within Medidata as staff 
are invited to the study.    


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
8.4 
Data Submission Questions 
The CTSU help desk is available to answer questions regarding data submission at 1-888-823-
5923 or by email at ctsucontact@westat.com. Hours are between 9:00 A.M. and 6:00 P.M. 
Eastern Time, Monday through Friday (excluding holidays). 
8.5 
Toxicity Criteria 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
8.6 
Response Criteria 
This trial will use the IWC criteria when evaluating primary end points. The IWC+PET criteria 
will be documented and compared with the IWC. 
 
IWC Response criteria for lymphomas: Responses must last for at least 4 weeks off treatment.  
 
For detailed explanations of combined IWC and PET criteria, please refer to J Clin Oncol, 2005. 
23(21): p. 4652-61. 
 
Response 
Category 
Physical Examination 
Lymph Nodes 
Lymph Node 
Masses 
Bone Marrow 
CR 
Normal 
< 1 cm  
< 1 cm  
Normal 
CRu 
Normal 
> 1 cm   
> 75% decrease  
Indeterminate 
PR 
Normal 
Normal 
Normal 
Positive 
Normal 
50% decrease 
50% decrease 
Irrelevant 
Decrease in liver/spleen 
50% decrease 
50% decrease 
Irrelevant 
Progression 
Enlarging liver/spleen; 
new sites 
New or 
increased  
> 50% 
New or increased 
> 50% 
Reappearance
 
 
IWC (International Workshop Criteria)+PET-Based Response Designations Based on the IWC 
Designations and PET Findings [22] 
IWC+PET-Based 
Response 
Designations 
Description 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
CR 
CR by IWC with a completely negative PET 
CRu, PR, or SD by IWC with a completely negative PET and a 
negative BMB if positive prior to therapy 
PD by IWC with a completely negative PET and CT abnormalities 
(new lesion, increasing size of previous lesion) 1.5 cm (  1.0 cm in 
the lungs) and negative BMB if positive prior to therapy 
CRu 
CRu by IWC with a completely negative PET but with an 
indeterminate BMB 
PR 
CR, CRu, or PR by IWC with a positive PET at the site of a 
previously involved node/nodal mass 
CR, CRu, PR, or SD by IWC with a positive PET outside the site of a 
previously involved node/nodal mass 
SD by IWC with a positive PET at the site of a previously involved 
node/nodal mass that regressed to < 1.5 cm if previously > 1.5 cm, or 
< 1 cm if previously 1.1-1.5 cm 
SD 
SD by IWC with a positive PET at the site of a previously involved 
node/nodal mass (i.e., residual mass) 
PD 
PD by IWC with a positive PET finding corresponding to the CT 
abnormality (new lesion, increasing size of previous lesion) 
PD by IWC with a negative PET and a CT abnormality (new lesion, 
increasing size of previous lesion) of < 1.5 cm (< 1.0 cm in the lungs) 
Abbreviations: IWC+PET, International Workshop Criteria plus positron emission tomography; 
CR, complete response; BMB, bone marrow biopsy; CT, computed tomography; CRu, 
unconfirmed complete response; PR, partial response; SD, stable disease; PD, progressive 
disease. 
8.7 
Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
9 
STATISTICAL CONSIDERATIONS 
The primary objective of this trial is to provide DA-EPOCH-R to patients with either high or low 
risk Burkitt lymphoma and to estimate the event free survival (EFS) in both groups.  In addition, 
a cohort of MYC+ patients with large cell lymphoma will be enrolled and treated in the same 
fashion, in order to estimate the event free survival in those patients. 
Secondary objectives are to perform exploratory analyses as they relate to identifying markers or 
molecular characteristics of patients and to determine if they may be related to clinical outcomes 
including response, event free and progression free survival (PFS) and overall survival (OS); to 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
explore whether PET is able to provide an early prediction of clinical outcome; to perform 
microarray analyses to see if there are differences between high and low risk patients. Patients 
with Burkitt lymphoma enrolled prior to amendment F will have their EFS evaluated in a 
secondary analysis in which their data may be reported separately or combined with that of 
patients enrolled subsequent to amendment F, if the results are sufficiently similar to do so. 
Patients with Burkitt lymphoma have been treated on the previous NCI trial of DA-EPOCH-R as 
one of several histologies being evaluated. In this trial, at a 35 month median potential follow-up, 
none of the 25 patients with Burkitt lymphoma enrolled between 2000 and 2008 have 
experienced a disease progression or have died from any cause. There was one event which was 
unrelated to disease progression: one patient required radiation at the completion of 
chemotherapy for localized residual disease.  It is the goal of this trial to continue to offer DA-
EPOCH-R to additional patients with Burkitt lymphoma in order to determine if the results seen 
previously can be replicated. The new results will be used to estimate the EFS to the 
DA_EPOCH-R regimen with reasonable precision. 
Data from a published trial of CODOX-M (low risk) or CODOX-M + alternating IVAC) high 
risk) indicated that the two year EFS was 83.3% for low risk (95% CI: 59.0-99.0%) and 59.5% ( 
43.0-76.0%) for high risk patients (Mead GM, Sydes MR, Walewski et al, Annals of Oncology 
13: 1264-1274, 2002).  In this trial of DA-EPOCH-R, low risk patients will be treated with 3 
cycles of therapy while high risk patients will be treated with 6 cycles of therapy. The goal will 
be to estimate the EFS for patients treated with DA-EPOCH R at 2 years and to informally 
describe the results relative to those found with CODOX-M (alone or with IVAC, as appropriate 
and to report the toxicity profile in this study. 
In the cohort with low risk patients, CODOX-M was associated with an 83.3% two year EFS 
probability with a lower 95% confidence bound of 59.0%. It would be desirable to have 
reasonable precision to estimate the EFS at two years for low risk patients receiving DA-EPOCH 
R.  In this cohort, 55 evaluable patients will be enrolled and followed for EFS for the primary 
analysis. If the fraction of patients who have not had an event by 2 years were similar to that of 
CODOX-M, it would be expected to be approximately 83%. With 55 low-risk patients, the two-
sided 95% confidence interval for the expected proportion of 0.83 without an event will extend 
+/- 0.10. In practice, in addition to determining the number of patients who have not had an event 
by two years, a Kaplan-Meier curve will also be constructed, with 80% and 95% confidence 
intervals determined at 1, 2, and 3 years. The results may also be informally compared with those  
from the published CODOX result in similar patients. 
In the cohort with high risk patients, CODOX-M + IVAC was associated with a 59.5% two year 
EFS probability with a lower 95% confidence bound of 43.0%. It would be desirable to have 
reasonable precision to estimate the EFS at two years for the high risk patients receiving DA-
EPOCH R.  In this cohort, 41 evaluable patients will be enrolled and followed for EFS for the 
primary analysis. If the fraction of patients who have not had an event by 2 years is similar to 
that of CODOX-M+ IVAC, it would be expected to be approximately 60%. With 41 high-risk 
patients, the two-sided 95% confidence interval for the expected proportion of 0.60 without an 
event will extend +/- 0.15. In practice, in addition to determining the number of patients who 
have not had an event by two years, a Kaplan-Meier curve will also be constructed, with 80% 
and 95% confidence intervals determined at 1, 2, and 3 years. The results may be informally 
compared with those from the published CODOX + IVAC result in similar patients. 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
The following stopping rule will apply for patients with low-risk Burkitt lymphoma (HIV 
negative patients only) who receive 3 cycles of therapy. A stopping rule will apply to monitor for 
<90% durable CR (defined as maintaining CR for one year beyond completion of therapy) 
among those with low risk BL who receive only 3 cycles of therapy. The first 10 patients in this 
category will be monitored for this outcome over one year. If < 8/10 has a durable CR, then this 
will be considered insufficient since the upper one sided 90% CI for 7/10 is 88.4%, which would 
indicate that this regimen is likely to not have results which are consistent with a desirable 90% 
CR rate. If this stopping rule is invoked, all patients (regardless of risk) will be treated as in the 
high risk arm.   
In addition, a stopping rule will be implemented for patients who enroll with documented CNS 
disease. If within the first 10 patients enrolled with active CNS disease, there are 4 patients who 
attain a failure in the CNS, the study will not accrue any more patients with documented CNS 
disease. A separate cohort of patients with c-MYC positive DLBCL (including plasmablastic 
subtype) will also be eligible and may be enrolled onto this trial.  A total of 30 patients will be 
enrolled in order to provide an approximate estimate of the EFS for this group of patients being 
treated in a relatively homogeneous fashion. This will allow the trial to determine a preliminary 
estimate of the effect of DA-EPOCH-R in Myc+ DLBCL.  All of these patients will be treated 
using 6 cycles of DA-EPOCH-R (as written for high-risk Burkitt lymphoma). 
Markers and molecular characteristics of the patients will be obtained and evaluated for their 
association with EFS, PFS and OS using Kaplan-Meier curves and two-tailed log-rank tests. 
These evaluations will be done separately for low and high risk patients, and may be evaluated in 
an overall analysis stratified by risk category as well.  Results may also be compared between 
responders and non-responders using a Wilcoxon rank sum test. In general, all secondary 
analyses will be performed with exploratory intent, and any findings which result from these 
analyses will be used to generate hypotheses which can be investigated in later studies. 
This trial will be opened to multiple centers through the CTSU mechanism. When most enrolling 
centers have opened the protocol, it is expected that approximately 27 Burkitt lymphoma and 8 
myc+ DLBCL can be accrued per year. Thus, it is expected that the study will require 3.5 years 
in order to accrue a total of 55 low risk and 41 high risk patients to the trial (total 96), and up to 
30 of the patients with c-MYC positive DLBCL and c-MYC positive plasmablastic lymphoma.  
The patients enrolled on the trial prior to this amendment will be considered a separate cohort for 
evaluation purposes, as required by an external scientific committee. The results from this earlier 
cohort may be examined in combination with those patients enrolled after the present 
amendment if the results are shown to be sufficiently similar. This would be done in an 
exploratory fashion only, in addition to main analyses restricted to newly enrolled patients. 
In order to allow for a very small number of non-evaluable patients, the accrual ceiling will be 
set at 153 (up to 18 from earlier enrollment + 96 low and high risk Burkitt + 30 with c-MYC 
positive DLBCL and c-MYC positive plasmablastic lymphoma, and up to 9 extra to allow for 
inevaluable patients). 
In April 2014, an interim analysis that looked at accrual of the MYC + DLBCL and BL arms 
showed that the accrual ceiling in the MYC + DLBCL arm, which included plasmablastic 
lymphoma and B-cell lymphoma with features intermediate between BL and DLBCL, had been 
exceeded – therefore, accrual to this arm was suspended. At the same time, the analysis revealed 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
that only 35 patients had been accrued to the BL arm which is significantly short of the initial 
accrual goal for this arm (96 patients).  
Effective with Amendment J (version date: 06/24/2014): In order to reach the BL arm initial 
accrual goal, we elected to amend the study to increase the overall accrual goal to 194 – allowing 
for the following breakdown:  
• 31 patients enrolled prior to Amendment F (The patients enrolled on the trial prior to 
Amendment F will be considered a separate cohort for evaluation purposes, as required 
by an external scientific committee (CTEP). 
• 96 Burkitt Lymphoma 
• 47 DLBCL (initially planned for 30; but 47 enrolled after Amendment F—we need to add 
slots for them). No more patients will be enrolled in this subgroup. 
• 20 inevaluable patients  
• Effective with Amendment N, all patients on trial will be followed for PFS for up to 3 
years from the date they sign the consent form. Any future analysis will focus on 
evaluations taking place no more than 3 years after study entry. This will apply both to 
previously enrolled patients as well as to any patients who enroll after this amendment is 
in effect. 
10 HUMAN SUBJECTS PROTECTIONS 
10.1 Rationale for subject selection 
BL affects all races and genders.  However, males are more likely than females to be affected 
and this will be reflected in the gender distribution of our cases.  The incidence of BL is 
increased in HIV positive patients. In the US HIV is more prevalent in ethnic minorities and Men 
who have Sex with Men (MSM). Our experience to date suggests that most of our patients will 
be HIV negative. Some of our HIV positive patients may come from ethnic minorities and/or be 
MSM. Strategies/procedures for recruitment: This trial will be available on the cancer.gov 
website as a dedicated trial for BL. We have excellent relations with medical schools, 
oncologists and infectious disease doctors who refer us patients for second opinions and clinical 
trials. Patients or their physicians contact the lead research nurse who arranges for a medical 
doctor to contact them or to screen them in clinic. Patients who are hospital in-patients with a 
diagnosis of untreated BL can be directly admitted to our in-patient unit for assessment. 
Justification for exclusions: Pregnant or nursing mothers are excluded because of the potential 
teratogenic effects of therapy. These are standard exclusions from clinical trials of 
chemotherapy. There are case reports of pregnant patients with BL being successfully treated in 
the second and third trimester with existing chemotherapy regimens who delivered healthy 
infants. [27] We do not have experience in using EPOCH-R during pregnancy and feel it would 
expose the fetus to unnecessary and unquantifiable risks. The risks of cytotoxic agents being 
excreted in breast milk outweigh the benefits of breastfeeding to the infant. Mothers who are 
willing to stop breastfeeding are eligible for this study. Procedures or practices that will be used 
in the protocol to minimize the susceptibility of children and vulnerable subjects to undue 
influences and unnecessary risks: All patients will be informed that different chemotherapy 
regimens exist to treat their BL and that they are under no obligation to participate in this 
research. This is particularly relevant to HIV negative patients where excellent outcomes are 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
achieved with current regimens. All patients will be given the opportunity to decline research 
biopsies. 
Adults who are unable to consent are included in this protocol because the protocol offers a 
prospect of direct benefit and should therefore exclude participants only when scientifically 
necessary or participants with this condition are at risk of losing capacity at least temporarily and 
enrollment might be compromised without their involvement.  Capacity to consent will be 
evaluated by the Principal or Associate Investigator(s).  For adults whose ability to consent is 
uncertain, The PI or AI will contact the NIH Ability to Consent Assessment Team for 
evaluation.  The PI or AI will obtain permission for decisionally-impaired adults via their 
appointed surrogate decision-maker or another legally authorized representative (such as legal 
guardian or holder of the durable power of attorney) in accordance with NIH Policy and 
Communications Bulletin Number 87-4 (rev.). Procedures described in NIH Policy 87-4 for 
appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed.  The risks 
and benefits of participation for adults unable to consent should be no different than those 
described for less vulnerable patients.  
 
In cases where the patient’s DPA is unable to be present in person at the Clinical Center, the 
procedures described in Section 10.5 and 10.5.2 will be followed. 
10.2 Participation of Children 
Pediatric patients <18 years of age will not be eligible to participate in this protocol.   
10.3 Evaluation of benefits and risks/ discomforts 
The potential benefit of this protocol for patients is cure of life threatening malignancy with 
fewer side effects and shorter duration of chemotherapy than existing regimens for all patients 
enrolled on this protocol. The main danger to participants in this study is drug toxicity. 
Therefore, this protocol involves greater than minimal risk for adults, but presents the potential 
for direct benefit to individual subjects. Patients may or may not obtain direct benefit from 
EPOCH-R or DA-EPOCH. Results from two phase II studies of EPOCH-R show promising 
initial results and acceptable toxicity. In particular toxicity is less than with commonly used 
regimens such as CODOX-M/IVAC and response rates and survival is similar or superior 
especially in HIV positive patients. Adults with HIV BL have very poor outcomes with existing 
chemotherapy regimens which are either too toxic or non-curative.  
10.4 Risks Benefit Analysis 
Patients may derive direct benefit from DA-EPOCH-R or DA-EPOCH based on prior research 
results. The potential toxicity of this combination is reasonable in relation to the potential benefit 
to this group of patients who have treatable diseases. In HIV positive patients the increased risks 
of opportunistic infection and reactivation of Hepatitis B are outweighed by the potential for 
cure. Additionally, the knowledge that will be gained from this trial is potentially important and 
may be of direct benefit to patients. 
10.5 Consent Processes and Documentation 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
All patients will read and sign the informed consent document prior to enrollment.  Members of 
the protocol team will describe the protocol, alternative therapies, and the risks and benefits of 
each to the individual signing the consent.  In cases where the patient is unable to give informed 
consent, an appropriate surrogate, such as a DPA, will be identified as per the NIH Clinical 
Center (CC) Institutional policy. In that case, members of the protocol team will describe the 
protocol, alternative therapies, and the risks and benefits of each to the patient’s DPA for health 
care and the DPA may give informed consent on behalf of the patient.  If possible, verbal assent 
will be obtained from patients unable to give informed consent. As this is potentially curable 
therapy, and a DPA is being used because the patient is unable to understand the consequences 
of their assent or dissent, the Study PI has determined that the designated DPA should be 
allowed to make the decision for the patient to enroll in this protocol. The investigational nature 
and research objectives of this trial, the procedures and treatments involved and their attendant 
risks and discomforts and potential benefits, and alternative therapies will be carefully explained 
to the patient or their DPA. An informed consent document will be obtained prior to entry onto 
the study. In cases where the patient’s DPA is unable to be present in person at the Clinical 
Center, obtaining informed consent via technology and/or electronic processes is permissible. In 
these cases, the informed consent discussion will be carried out over telephone and giving of 
informed consent may be done by phone, fax or email. The informed consent process will be 
documented in the patient’s medical record and on the informed consent document. This process 
will be performed by the local Principal Investigator or designee. 
10.5.1 Subjects who become unable to give consent (NIH Clinical Center) 
Subjects could become decisionally impaired during participation on this study.  For this reason 
and because there is a prospect of direct benefit from research participation (Section Error! 
Reference source not found.), all subjects 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 for evaluation.  For those subjects that become incapacitated and do 
not have pre-determined substitute decision maker, the procedures described in MEC Policy 87-4 
for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, 
and (b) who do not have a legal guardian or durable power of attorney, will be followed. 
10.5.2 Telephone Consent and Re-consent (NIH Clinical Center) 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent.  
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained  via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 
The informed consent process will be documented in the medical record. 
In cases of telephone reconsent of subjects unable to give consent (i.e., those who are 
decisionally impaired upon enrollment or who become decisionally impaired), reconsent may 
take place with the patient’s DPA by phone with verbal assent from the subject, if possible. 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
11 NIH  REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN  
11.1 Definitions (NIH only) 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
11.2 OHSRP Office Of Compliance And Training / IRB Reporting (NIH Only) 
11.2.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here.  
11.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
11.3 NCI Clinical Director (CD) Reporting (NIH Only) 
Problems expeditiously reported to the OHSRP/IRB 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. 
11.4 NIH Required Data And Safety Monitoring Plan  
11.4.1 Principal Investigator/Research Team  
The Coordinating Center research team will meet on a monthly at least weekly when patients are 
being actively treated on the trial to discuss each patient.  
All data will be collected in a timely manner and reviewed by the Coordinating Center principal 
investigator. Events meeting requirements for expedited reporting as described in section 11.2.1 
will be submitted within the appropriate timelines. 
The principal investigator at each site will review adverse event and response data on each 
patient to ensure safety and data accuracy. The principal investigator at each site will personally 
conduct or supervise the investigation and provide appropriate delegation of responsibilities to 
other members of the research staff. 
12 ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following  characteristics of an observed AE (Sections 12.1.1 and 12.2) will determine whether 
the event requires expedited reporting via the CTEP Adverse Event Reporting System (CTEP-
AERS) in addition to routine reporting. 
12.1 Definitions 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
12.1.1 Adverse Event Characteristics 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form.   
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, though 30 days after the last administration of study drug.  AEs 
and serious adverse events (SAEs) that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of at least possibly related to the 
agent/intervention should be recorded and reported as per sections 12.2, Error! Reference source 
not found., and 12.3.   
 
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. 
Attribution of the AE: 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment. 
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
12.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
12.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in or 
consistent with the risk information described in the package insert or is not listed at the 


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specificity or severity that has been observed, or is not consistent with the general investigational 
plan or elsewhere in the current application.  
12.1.4 Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
12.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• Death, 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
12.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
12.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
12.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from IRB-approved research protocol.  
12.1.9 Protocol Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
12.1.10Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to  
• the research risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents, and 
• the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 


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• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
12.1.11Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects she is pregnant while participating in this study, she 
must inform her treating physician immediately and permanently discontinue drug. 
12.2 Expedited Adverse Event Reporting 
12.2.1 CTEP-AERS 
Expedited AE reporting for this study must use CTEP Adverse Event Reporting System (CTEP-
AERS), accessed via the CTEP Web site (http://ctep.cancer.gov).  The reporting procedures to be 
followed are presented in the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP Web site (http://ctep.cancer.gov).   
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
the NCI Study Coordinator, Andrea Nicole Lucas, RN at 240-760-6252 or 
lucasan2@mail.nih.gov.  Once Internet connectivity is restored, the 24-hour notification phoned 
in must be entered electronically into CTEP-AERS by the original submitter at the site. 
12.2.2 Distribution of Adverse Events 
CTEP-AERS is programmed for automatic electronic distribution of reports to the following 
individuals:  Study Coordinator of the Lead Organization, Principal Investigator, and the local 
treating physician.  CTEP-AERS provides a copy feature for other e-mail recipients.  
12.2.3 Expedited Reporting Guidelines  
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note:  A death on study requires BOTH routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
Commercial Agent Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur in a Non-IND/IDE trial within 30 Days of the Last Administration of a Commercial 
Agent 


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NCI CC Version Date:  09/20/2019 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in Section 12.2.4 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
Grade 3 adverse events 
Effective Date:  May 5, 2011 
12.2.4 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
For this protocol only, only events that are both serious and unexpected as defined in section 
12.2.3 should be reported via CTEP-AERS.  Institutes should follow their own Institutional 
guidelines for reporting events to their local IRBs.  
12.2.5 Routine Adverse Event Reporting 
All Adverse Events (AEs) must be recorded in the database, including AEs reported through 
CTEP-AERS .   
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in 


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future studies using similar agents.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the Adverse Event CRF is used for routine 
AE reporting in Rave. 
12.2.6 Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included within the 
NCI Guidelines for Adverse Event Reporting Requirements must be completed and submitted to 
CTEP.  Any pregnancy occurring in a patient or patient’s partner from the time of consent to 90 
days after the last dose of study drug must be reported and then followed for outcome.  Newborn 
infants should be followed until 30 days old.  Please see the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” 
(at http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on how to 
report pregnancy and its outcome to CTEP. 
12.2.7 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event: 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
recorded in the database.  
12.2.8 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY recording in the 
database.  
12.3 NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials 
The site PI must immediately report to the NCI-LYMB PI any serious adverse event as defined 
above in Section 12.2.3; using CTEP Adverse Event Reporting System (CTEP-AERS), accessed 
via the CTEP Web site (http://ctep.cancer.gov).   
Report events to the Reviewing IRB as per its policy. Please also notify the coordinating center 
PI and study coordinator of your submission at the time you make it. 
13 MULTI-INSTITUTIONAL GUIDELINES 
13.1 IRB Approvals 


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NCI CC Version Date:  09/20/2019 
The NIH IRB must approve the addition of each participating institution to the protocol and will 
require a copy of the local IRB approval from each participating institution before NIH IRB 
approval will be granted. The CCR PI will provide the NIH IRB with copies of all consents and 
IRB approvals from each participating institution. The Cancer Trials Support Unit (CTSU) 
Regulatory Office is responsible for collecting and maintaining IRB approvals and informed 
consent documents for all participating institutions and will provide digital copies to the NCI for 
submission to the NIH IRB. 
The PI will provide the NIH IRB with a copy of the participating institution’s approved yearly 
continuing review.  The CTSU Regulatory Office is responsible for collecting and maintaining 
yearly continuing review approvals for all participating institutions and will provide digital 
copies to the NCI for submission to the NIH IRB. Registration will be halted at any participating 
institution in which a current continuing approval is not on file at the NIH IRB.   
13.2 CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. 
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are listed below. The Principal 
Investigator/Coordinating Center is responsible for distributing all Action Letters or Safety 
Reports received from CTEP to all participating institutions for submission to their individual 
IRBs for action as required. 
13.2.1 Responsibility of the Protocol Chair 
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
13.2.2 Responsibilities of the Coordinating Center: 
Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protections (OHRP), HHS. The CTSU is responsible for assuring that each 
participating institution has an OHRP assurance and must maintain copies of IRB approvals from 
each participating site. Prior to the activation of the protocol at each participating institution, 
documentation of initial IRB approval must be submitted to the CTSU Regulatory Office 


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• 
The CTSU is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• 
The Coordinating Center is responsible for ensuring each participating site is accruing a 
representative sample consistent with the estimate of population representation in the 
site's geographical location for race and ethnic groups as determined by the Census 
Bureau to assure overall target goals are met. 
• 
The CTSU is responsible for the preparation of all submitted data for review by the 
Protocol Chair. 
• 
The Coordinating Center will maintain documentation of AE reports. Participating 
institutions will report directly to CTEP with a copy to the Coordinating Center. The 
Coordinating Center will submit AE reports to the Protocol Chair for timely review. 
• 
Audits may be accomplished in one of two ways (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit; or, (2) selected patient records may be audited on-site at participating 
sites. If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
14 PHARMACEUTICAL INFORMATION 
• Qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of chemotherapeutic agents in a self-contained, protective environment. 
• Discard unused portions of injectable chemotherapeutic agents that do not contain a 
bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for 
Injection USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial 
entry to minimize the risk of bacterial contamination. 
• The total administered dose of chemotherapy may be rounded up or down within a range 
of 5% of the actual calculated dose. 
14.1 Rituximab 
Refer to the FDA approved package insert for complete product information. 
14.1.1 Supply 
Genentech/IDEC will supply the agent for this protocol to DFCI, MGH, BIDMC and MD 
Anderson Cancer Center.  It is otherwise commercially available.   
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. 
14.1.2 Storage 
Rituximab for clinical use should be stored in a secure refrigerator at 2º to 8°C.  


A b brevi ate d Title:   D A -E P O C H -R i n B L  
N CI C C Versi o n D ate:   0 9/ 2 0/ 2 0 1 9  
1 4. 1. 3  Pre parati o n  
Rit u xi ma b will be dil ute d wit h 0. 9 % S o di u m C hl ori de or 5 % De xtr ose I njecti o n t o pre pare a 
sta n dar d pr o d uct wit h c o nce ntrati o n of 2 m g/ ml.  Ca uti o n s h o ul d be ta ke n d uri n g t he pre parati o n 
of t he dr u g, as s ha ki n g ca n ca use a g gre gati o n a n d preci pitati o n of t he a nti b o d y  
1 4. 1. 4  Sta bilit y  
After dil uti o n, rit u xi ma b is sta ble at  2 -8 de grees C ( 3 6 -4 6 de grees F) f or 2 4 h o urs a n d at r o o m 
te m perat ure f or a n a d diti o nal 2 4  h o urs.  
1 4. 1. 5  A d mi nistrati o n  
A peri p heral or ce ntral i ntra ve n o us li ne will be esta blis he d. D uri n g rit u xi ma b i nf usi o n, a patie nt's 
vital si g ns ( bl o o d press ure, p ulse, res pir ati o n, te m perat ure) s h o ul d be m o nit ore d acc or di n g t o t he 
sta n dar d of care. Me dicati o ns rea dil y a vaila ble f or t he e mer ge nc y ma na ge me nt of a na p h ylact oi d 
reacti o ns s h o ul d i ncl u de: e pi ne p hri ne ( 1: 1 0 0 0, 1 m g/ m L) f or s u bc uta ne o us i njecti o n, 
di p he n h y dra mi ne h y dr o c hl ori de f or i ntra ve n o us i njecti o n, a n d res uscitati o n e q ui p me nt.  
Pr o p h yla xis a gai nst h y perse nsiti vit y a n d i nf usi o n -relate d reacti o ns ass ociate d wit h rit u xi ma b will 
i ncl u de aceta mi n o p he n 6 5 0 m g a n d di p he n h y dra mi ne h y dr oc hl ori de 5 0-1 0 0 m g a d mi nistere d 3 0 
t o 6 0 mi n utes pri or t o starti n g rit u xi ma b. Patie nts will als o recei ve t heir first d ose of pre d nis o ne 
6 0 m g/ m 2 ( or a gl uc oc ortic oi d e q ui vale nt d ose of a n alter nati ve ster oi d) at least 6 0 mi n utes 
bef ore rit u xi ma b treat me nt c o m me nces.  
Rit u xi ma b will be a d mi niste re d as a n i ntra ve n o us i nf usi o n at 3 7 5 m g/ m 2 o n da y 1 of eac h c ycle 
of E P O C H, i m me diatel y pri or t o starti n g et o p osi de + d o x or u bici n + vi ncristi ne a d mi nistrati o n. 
F or L o w Ris k Patie nts recei vi n g E P O C H -R R, Rit u xi ma b will als o be a d mi nistere d o n da y 5 of 
eac h c ycle, f oll o wi n g et o p osi de + d o x or u bici n + vi ncristi ne b ut pri or t o c ycl o p h os p ha mi de 
a d mi nistrati o n . Rit u xi ma b i nf usi o ns will be a d mi nistere d t o patie nts pri maril y i n a n o ut patie nt 
cli nic setti n g.   
First d ose : 
T he i nitial d ose rate at t he ti me of t he firs t rit u xi ma b i nf usi o n s h o ul d be 5 0 m g/ h o ur ( 2 5 m L/ hr) 
f or t he first 3 0 mi n utes. If n o t o xicit y is see n, t he d ose rate ma y be escalate d gra d uall y i n 5 0 
m g/ h o ur ( 2 5 m L/ h) i ncre me nts at 3 0 mi n ute i nter vals) t o a ma xi m u m of 4 0 0 m g/ h o ur ( ma xi m u m 
rate = 2 0 0 m L/ h).  
Sec o n d a n d S u bse q ue nt D oses (select t he a p pr o pri ate a d mi nistr ati o n ti mi n g):  
9 0 -mi n ute A d mi nistr ati o n  
If t he first d ose of rit u xi ma b was well t olerate d, s u bse q ue nt d oses ma y be a d mi nistere d o ver 9 0 
mi n utes wit h 2 0 % of t he t otal d ose gi ve n i n t he first 3 0 mi n utes, a n d re mai ni n g 8 0 % of t he t otal 
d ose a d mi nistere d o ver t he s u bse q ue nt 6 0 mi n utes; e. g.:  
 
T w o -Ste p Rate Escalati o n  
V ol u me t o a d mi nister ( X  m L)  
1st p orti o n ( 0 –  3 0  mi n utes)  
T otal D ose ( m g)
2
´ 0. 2 = X m L ( o ver 3 0  mi n)
 


A b brevi ate d Title:   D A -E P O C H -R i n B L  
N CI C C Versi o n D ate:   0 9/ 2 0/ 2 0 1 9  
2 n d p orti o n ( 3 0 –  9 0  mi n utes)  
T otal D ose ( m g)
2
´ 0. 8 = X m L ( o ver 6 0  mi n)
 
S peci al N ote : T he 9 0-mi n ute i nf usi o n sc he me is n ot rec o m me n de d f or patie nts wit h cli nicall y 
si g nifica nt car di o vasc ular disease or hi g h circ ulati n g l y m p h oc yte c o u nts (≥5 0 0 0/ mc L).  
St a n d ar d A d mi nistr ati o n f or Sec o n d & S u bse q ue nt I nf usi o ns  
Patie nts w h o t olerate i nitial treat me nt wit h o ut e x perie nci n g i nf usi o n -relate d a d verse effects b ut 
f or w h o m t he 9 0-mi n ute i nf usi o n sc he me d uri n g s u bse q ue nt treat me nts is c o nsi dere d 
i na p pr o priate, ma y recei ve s u bse q ue nt rit u xi ma b d oses at t he Sta n dar d Rate for S u bse q ue nt 
I nf usi o ns, w hic h is as f oll o ws: 
Be gi n at a n i nitial rate of 1 0 0 m g/ h o ur ( 5 0 m L/ h) f or 3 0 mi n utes. If a d mi nistrati o n is well 
t olerate d, t he a d mi nistrati o n rate ma y be escalate d gra d uall y i n 1 0 0-m g/ h o ur ( 5 0 -m L/ h) at 3 0 -
mi n ute i nter vals t o a ma x i m u m rate of 4 0 0 m g/ h o ur ( ma xi m u m rate = 2 0 0 m L/ h). 
C A U TI O N:  D O N O T A D MI NI S T E R A S A N I N T R A V E N O U S P U S H O R B O L U S.   
1 4. 1. 6  Safet y Pr ofile  
N o d ose -li miti n g effects were o bser ve d i n t he P hase I/II st u dies.  Re p orte d a d verse e ve nts 
i ncl u di n g fe ver, c hills, hea dac he, na usea, v o miti n g, r hi nitis, ast he nia, a n d h y p ote nsi o n, occ urre d 
pri maril y d uri n g rit u xi ma b i nf usi o ns a n d t y picall y res p o n de d t o a n  i nterr u pti o n of t he i nf usi o n 
a n d res u m pti o n at a sl o wer rate.   
Fatal I nf usi o n Reacti o ns:  Se vere a n d fatal car di o p ul m o nar y e ve nts, i ncl u di n g a n gi oe de ma, 
h y p o xia, p ul m o nar y i nfiltrates, ac ute res pirat or y distress s y n dr o me, m y ocar dial i nfarcti o n, a n d 
car dio ge nic s h oc k, ha ve bee n re p orte d.  T hese se vere reacti o ns t y picall y occ urre d d uri n g t he first 
i nf usi o n wit h ti me t o o nset of 3 0-1 2 0 mi n utes.  
Car diac E ve nts:  Patie nts wit h pree xisti n g car diac c o n diti o ns, i ncl u di n g arr h yt h mia a n d a n gi na, 
ha ve ha d rec urre nce s of t hese car diac e ve nts d uri n g rit u xi ma b i nf usi o ns. 
T u m or L ysis S y n dr o me:  T u m or l ysis s y n dr o me, s o me wit h fatal o utc o me,  has bee n re p orte d 
a n d is c haracterize d i n patie nts wit h a hi g h n u m ber of circ ulati n g mali g na nt cells ( ≥2 5, 0 0 0 ul) b y 
ra pi d re d ucti on i n t u m or v ol u me, re nal i ns ufficie nc y, h y per kale mia, h y p ocalce mia, 
h y per urice mia, a n d h y per p h os p hate mia.  
Re nal E ve nts:  Rit u xi ma b has bee n ass ociate d wit h se vere re nal t o xicit y i ncl u di n g ac ute re nal 
fail ure re q uiri n g dial ysis, a n d i n s o me cases has le d t o deat h.  Re nal t o xicit y has occ urre d i n 
patie nts wit h hi g h n u m bers of circ ulati n g mali g na nt cells ( ≥2 5, 0 0 0/ m m 2 ) or hi g h t u m or b ur de n 
w h o e x perie nce t u m or l ysis s y n dr o me a n d i n patie nts a d mi nistere d c o nc o mita nt cis plati n.  
M uc oc uta ne o us Reacti o ns:  Se vere b ull o us s ki n reacti o ns, i ncl u di n g fatal cases of t o xic 
e pi der mal necr ol ysis a n d para ne o plastic pe m p hi g us, ha ve bee n re p orte d i n patie nts treate d wit h 
rit u xi ma b.  T he o nset of reacti o n has varie d fr o m 1 t o 1 3 wee ks f oll o wi n g rit u xi ma b e x p os ure. 
He mat ol o gic E ve nts:  I n cli nical trials, Gra de 3 a n d 4 c yt o pe nias were re p orte d i n 4 8 % of 
patie nts treate d wit h rit u xi ma b; t hese i ncl u de: l y m p h o pe nia ( 4 0 %), ne utr o pe nia ( 6 %), le u k o pe nia 
( 4 %), a ne mia ( 3 %), a n d t hr o m b oc yt o pe nia ( 2 %).  T he me dia n d urati o n of l y m p h o pe nia was 1 4 
da ys (ra n ge, 1 t o 5 8 8 da ys) a n d of ne utr o pe nia was 1 3 da ys (ra n ge, 2 t o 1 1 6 da ys).  A si n gle 


Abbreviated Title:  DA-EPOCH-R in BL 
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occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic 
anemia following Rituximab therapy were reported.  
In addition, there have been a limited number of post-marketing reports of prolonged 
pancytopenia, marrow hypoplasia, and late onset neutropenia.  
Infectious Events:  Rituxan induced B-cell depletion in 70% to 80% of patients with NHL and 
was associated with decreased serum immunoglobulins in a minority of patients; the 
lymphopenia lasted a median of 14 days (range, 1-588 days).  Infectious events occurred in 31% 
of patients: 19% of patients had bacterial infections, 10% had viral infections, 1% had fungal 
infections, and 6% were unknown infections.  Serious infectious events (Grade 3 or 4), including 
sepsis, occurred in 2% of patients. 
Hepatitis B Reactivation:  Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic 
failure, and death has been reported in some patients with hematologic malignancies treated with 
rituximab.  The majority of patients received rituximab in combination with chemotherapy.  The 
median time to the diagnosis of hepatitis was approximately four months after the initiation of 
rituximab and approximately one month after the last dose. 
Other Serious Viral Infections:  The following additional serious viral infections, either new, 
reactivated or exacerbated, have been identified in clinical studies or post-marketing reports. The 
majority of patients received Rituxan in combination with chemotherapy or as part of a 
hematopoietic stem cell transplant. These viral infections included JC virus (progressive 
multifocal leukoencephalopathy [PML]), cytomegalovirus, herpes simplex virus, parvovirus 
B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections 
occurred up to one year following discontinuation of Rituxan and have resulted in death. 
Progressive multifocal leukoencephalopathy (PML) 
PML is a rare disease caused by the reactivation of latent JC virus in the 
brain.  Immunosuppression allows reactivation of the JC virus which causes demyelination and 
destruction of oligodendrocytes resulting in death or severe disability.  Rare cases of PML, some 
resulting in death, have been reported in patients with hematologic malignancies who have 
received rituximab.  The majority of these patients had received rituximab in combination with 
chemotherapy or as part of a hematopoietic stem cell transplant.  Cases of PML resulting in 
death have also been reported following the use of rituximab for the treatment of autoimmune 
diseases. The reported cases had multiple risk factors for PML, including the underlying disease 
and long-term immunosuppressive therapy or chemotherapy.  Most cases of PML were 
diagnosed within 12 months of their last infusion of rituximab.  
Physicians should consider PML in any patient presenting with new onset neurologic 
manifestations. Consultation with a neurologist, brain MRI, and lumbar puncture should be 
considered as clinically indicated.  In patients who develop PML, rituximab should be 
discontinued and reductions or discontinuation of any concomitant chemotherapy or 
immunosuppressive therapy should be considered. 
Bowel Obstruction and Perforation:  Abdominal pain, bowel obstruction and perforation, in some 
cases leading to death, were observed in patients receiving Rituxan in combination with 
chemotherapy for DLBCL. In post-marketing reports, which include both patients with low-
grade or follicular NHL and DLBCL, the mean time to onset of symptoms was 6 days (range 
1−77) in patients with documented gastro-intestinal perforation. Complaints of abdominal pain, 


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especially early in the course of treatment, should prompt a thorough diagnostic evaluation and 
appropriate treatment. 
Immunogenicity:  Patients may develop a human anti-chimeric antibody (HACA) response with 
rituximab treatment.  The clinical significance of this is unclear. 
Pregnancy:  B-cell lymphocytopenia generally lasting less than 6 months can occur in infants 
exposed to rituximab in utero. 
Immunization:  Response rates may be reduced with non live vaccines. 
Additional Safety Signals:  The following serious adverse events have been reported to occur in 
patients following completion of rituximab infusions: arthritis, disorders of blood vessels 
(vasculitis, serum sickness and lupus-like syndrome), eye disorders (uveitis and optic neuritis), 
lung disorders including pleuritis and scarring of the lung (bronchiolitis obliterans), that may 
result in fatal outcomes, and fatal cardiac failure. 
See the rituximab Investigator Brochure for additional details regarding safety experience with 
rituximab. 
14.2 Cyclophosphamide 
Refer to the FDA approved package insert for complete product information. 
14.2.1 Supply 
Commercially available as a lyophilized powder for reconstitution, in 100 mg, 200 mg, 500 mg, 
1gm, and 2 gm vials.  
14.2.2 Storage and preparation 
Intact vials should be stored at room temperature (not to exceed 30oC). Reconstituted solution is 
stable up to 6 days if refrigerated (2-8oC).  Discard solution after storage for 24 hours at room 
temperature.  
14.2.3 Administration 
Cyclophosphamide will be diluted in 100 mL of D5W or 0.9% NaCl and infused over 30 
minutes or according to institutional standard.  Patients will be instructed to drink an adequate 
amount of fluids and empty their bladders frequently during cyclophosphamide administration.  
14.2.4 Toxicities  
Myelosuppression, nausea and vomiting, hemorrhagic cystitis, and 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.  Please refer to the package insert for a complete listing 
of all toxicities.   
14.2.5 Hydration Guidelines 
All patients should receive 0.9%NS at the following volumes (based on cyclophosphamide dose 
levels) and rates with half the specified volume given before starting cyclophosphamide 
administration and half the volume given after completion of the cyclophosphamide 
administration.   
 


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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 
14.3 Doxorubicin 
Refer to the FDA approved package insert for complete product information. 
14.3.1 Supply 
Commercially available as a lyophilized powder for reconstitution in 10, 20, 50 and 100 mg 
vials. Also available as a 2 mg/mL solution for injection in 10, 20, 50, and 200mg vials. 
14.3.2 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. Please refer to the package insert for a complete listing of all toxicities.   
14.4 Vincristine 
Refer to the FDA approved package insert for complete product information. 
14.4.1 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 2º-8oC and should be protected from light.  
14.4.2 Toxicities 
Peripheral neuropathy, autonomic neuropathy, and alopecia. Local necrosis if injected 
subcutaneously. Please refer to the package insert for a complete listing of all toxicities. 
14.5 Etoposide 
Refer to the FDA approved package insert for complete product information. 
14.5.1 Supply 
Commercially available as a 20 mg/mL solution for injection in 5, 25, and 50 mL vials.   Each ml 
contains, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg polysorbate 80, 650 mg of polyethylene 
glycol 300, and 30.5% alcohol.  
14.5.2 Toxicities 
Myelosuppression, nausea, vomiting, anaphylactoid reactions, alopecia, and hypotension if 
infusion is too rapid. Please refer to the package insert for a complete listing of all toxicities. 
14.6 Administration of vincristine/doxorubicin/etoposide 


Abbreviated Title:  DA-EPOCH-R in BL 
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Stability studies conducted by the Pharmaceutical Development Service, Pharmacy Department, 
NIH Clinical Center, have demonstrated that admixtures of vincristine, doxorubicin, and 
etoposide in 0.9% Sodium Chloride Injection, USP 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 and 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 degrees 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. 
For NIH Clinical Center Only: Please see APPENDIX A for further details.  
Each participating site is encouraged to mix the vincristine, doxorubicin and etoposide in one 
bag. If that is not feasible due to institutional constraints, then a site should prepare the 
continuous infusion of vincristine, doxorubicin and etoposide according to institutional 
procedures. 
14.7 Prednisone 
Refer to the FDA approved package insert for complete product information. 
14.7.1 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 may 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 (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 
 
14.7.2 Toxicities 


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Proximal muscle weakness, glucose intolerance, thinning of skin, redistribution of body fat, 
Cushingoid facies, immunosuppression, and propensity to gastrointestinal ulceration. Please refer 
to the package insert for a complete listing of all toxicities.  
14.8 Filgrastim  
Refer to the FDA approved package insert for complete product information. 
14.8.1 Supply 
Commercially available in single use vials containing 480 mcg/vial (300 mcg/ml, 1.6 mlvial). 
Should be stored at 2º-8oC (do not freeze and do not shake) and is stable for at least 1 year at this 
temperature. Filgrastim will be given by subcutaneous injection; patient or other caregiver will 
be instructed on proper injection technique. 
14.8.2 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. Please 
refer to the package insert for a complete listing of all toxicities. 
14.9 Pegfilgrastim  
Refer to the FDA approved package insert for complete product information. 
14.9.1 Supply 
Commercially available in a prefilled single use syringe containing 6 mg pegfilgrastim, supplied 
with a 27-gauge, 1/2-inch needle with an UltraSafe® The needle cover of the prefilled syringe 
contains dry natural rubber (a derivative of latex).  
Should be stored at 2° to 8°C (36° to 46°F) in the carton to protected from light. Do not shake. 
Discard syringes stored at room temperature for more than 48 hours. Avoid freezing; if frozen, 
thaw in the refrigerator before administration. Discard syringe if frozen more than once. 
14.9.2 Toxicities 
The most common adverse reactions are bone pain and pain in extremity. Please refer to the 
package insert for a complete listing of all toxicities. 
14.10 Methotrexate  
Refer to the FDA approved package insert for complete product information 
14.10.1Supply 
Commercially available folic acid antagonist, and only the preservative-free preparation may be 
used for intrathecal injection. 
14.10.2Storage 
It should be stored at 15-30C and protected from light. Prior to intrathecal or intraventricular 
injection, the prescribed dose of methotrexate should be reconstituted/diluted with preservative-
free 0.9% sodium chloride to a total volume of 3 to 5 mL.  Prepared methotrexate doses should 
be utilized within 4 hours of preparation. 


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14.10.3Toxicities 
It can cause leukopenia, and as such leucovorin may 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. Please refer to 
the package insert for a complete listing of all toxicities. 
14.11 Cytarabine 
Refer to the FDA approved package insert for complete product information 
14.11.1Supply 
A commercially available pyrimidine nucleoside antimetabolite. 
14.11.2Storage 
Cytarabine should be stored at –15-30C, and used within 2 years of the date of manufacture.  
Prior to intrathecal injection it is reconstituted with preservative free 0.9% sodium chloride, and 
should be utilized within 4 hours of preparation.  Prior to intrathecal or intraventricular injection, 
the prescribed dose of cytarabine should be reconstituted/diluted with preservative-free 0.9% 
sodium chloride to a total volume of 3 to 5 mL. 
14.11.3Toxicities 
It can cause myelosuppression, fever, dizziness, somnolence, and arachnoiditis. Please refer to 
the package insert for a complete listing of all toxicities. 
 


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15 REFERENCES 
1. 
Burkitt, D., A sarcoma involving the jaws in African children. Br J Surg, 1958. 46: p. 
218-223. 
2. 
Diebold, J., et al., Burkitt lymphoma. World Health Organisation Classification of 
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2001: p. 181-184. 
3. 
Jaffe, E.S., et al., World Health Organization classification of tumours. Pathology and 
Genetics of Tumours of Haematopoietic and Lymphoid Tissues, 2001. 
4. 
Reiter, A., et al., Improved treatment results in childhood B-cell neoplasms with tailored 
intensification of therapy: A report of the Berlin-Frankfurt-Munster group trial NHL-
BFM 90. Blood, 1999. 94(10): p. 3294-3306. 
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Bennett, J.M., et al., Proposed revised criteria for the classification of acute myeloid 
leukemia. A report of the French-American-British Cooperative Group. Annals of 
Internal Medicine, 1985. 103(4): p. 620-625. 
6. 
Murphy, S.B., et al., Non-Hodgkin's lymphomas of childhood: An analysis of the 
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of Clinical Oncology, 1989. 7(2): p. 186-193. 
7. 
Skipper, H.E., F.M. Schabel, Jr., and W.S. Wilcox, Experimental Evaluation of Potential 
Anticancer Agents. Xiii. On the Criteria and Kinetics Associated with "Curability" of 
Experimental Leukemia. Cancer Chemother Rep, 1964. 35: p. 1-111. 
8. 
Gerrard, M., et al., Excellent survival following two courses of COPAD chemotherapy in 
children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results 
of the FAB/LMB 96 international study. Br J Haematol, 2008. 141(6): p. 840-7. 
9. 
Mead, G.M., et al., An international evaluation of CODOX-M and CODOX-M 
alternating with IVAC in adult Burkitt's lymphoma: Results of United Kingdom 
Lymphoma Group LY06 study. Annals of Oncology, 2002. 13(8): p. 1264-1274. 
10. 
Philip, T., et al., Treatment of poor prognosis Burkitt's lymphoma in adults with the 
Societe Francaise d'Oncologie Pediatrique LMB Protocol - A study of the Federation 
Nationale des Centres de Lutte Contre le Cancer (FNLCC). European Journal of Cancer 
Part A: General Topics, 1992. 28(12): p. 1954-1959. 
11. 
Pees, H.W., et al., The BFM-protocol for HIV-negative Burkitt's lymphomas and L3 ALL 
in adult patients: A high chance for cure. Annals of Hematology, 1992. 65(5): p. 201-
205. 
12. 
Patte, C., et al., The Societe Francaise d'Oncologie Pediatrique LMB89 protocol: Highly 
effective multiagent chemotherapy tailored to the tumor burden and initial response in 
561 unselected children with B-cell lymphomas and L3 leukemia. Blood, 2001. 97(11): p. 
3370-3379. 
13. 
Divine, M., et al., Burkitt lymphoma in adults: A prospective study of 72 patients treated 
with an adapted pediatric LMB protocol. Annals of Oncology, 2005. 16(12): p. 1928-
1935. 
14. 
Lerede, T., et al., Therapeutic impact of adult-type acute lymphoblastic leukemia 
regimens in B-cell/L3 acute leukemia and advanced-stage Burkitt'S lymphoma. 
Haematologica, 1996. 81(5): p. 442-449. 
15. 
Thomas, D.A., et al., Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic 
leukemia. Journal of Clinical Oncology, 1999. 17(8): p. 2461-2470. 


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16. 
van Imhoff, G.W., et al., Short intensive sequential therapy followed by autologous stem 
cell transplantation in adult Burkitt, Burkitt-like and lymphoblastic lymphoma. 
Leukemia, 2005. 19(6): p. 945-952. 
17. 
Thomas, D.A., et al., Rituximab and hyper-CVAD for adult Burkitt's (BL) or Burkitt's-like 
(BLL) leukemia or lymphoma. Blood, 2001. 98(11 PART I). 
18. 
Thomas, D.A., et al., Chemoimmunotherapy with hyper-CVAD plus rituximab for the 
treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. 
Cancer, 2006. 106(7): p. 1569-1580. 
19. 
Wilson, W.H., et al., Dose-adjusted EPOCH chemotherapy for untreated large B-cell 
lymphomas: a pharmacodynamic approach with high efficacy. Blood, 2002. 99(8): p. 
2685-2693. 
20. 
Dunleavy, K., et al., Novel treatment of Burkitt lymphoma with dose-adjusted EPOCH-
Rituximab: Preliminary results showing excellent outcome. Blood (ASH annual meeting 
abstracts), 2006. 108. 
21. 
Cole DE, B.F., Lowe ES, et al., Pharmacokinetics (pk) and tolerance of doxorubicin 
(dox) and etoposide (etop) during treatment of aggressive B-cell lymphomas indicate 
doses need not be routinely reduced for hepatic dysfunction. Proc Am Soc Clin Oncol, 
2005. 24. 
22. 
Juweid, M.E., et al., Response assessment of aggressive non-Hodgkin's lymphoma by 
integrated International Workshop Criteria and fluorine-18-fluorodeoxyglucose positron 
emission tomography. J Clin Oncol, 2005. 23(21): p. 4652-61. 
23. 
Kostakoglu, L., et al., PET Predicts Prognosis After 1 Cycle of Chemotherapy in 
Aggressive Lymphoma and Hodgkin's Disease. J Nucl Med, 2002. 43(8): p. 1018-1027. 
24. 
Gallamini, A., et al., The predictive value of positron emission tomography scanning 
performed after two courses of standard therapy on treatment outcome in advanced stage 
Hodgkin's disease. Haematologica, 2006. 91(4): p. 475-81. 
25. 
Yusuf, S., et al., Effect of enalapril on mortality and the development of heart failure in 
asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med, 
1992. 327(10): p. 685-691. 
26. 
Hummel, M., et al., A Biologic Definition of Burkitt's Lymphoma from Transcriptional 
and Genomic Profiling. N Engl J Med, 2006. 354(23): p. 2419-2430. 
27. 
Magloire, L.K., et al., Burkitt's lymphoma of the ovary in pregnancy. Obstet Gynecol, 
2006. 108(3 Pt 2): p. 743-5. 
 
 


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16 APPENDIX A: EPOCH Admixtures: Preparation and Administration NCI CC only 
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. 


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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). 
 
 


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17 APPENDIX B: Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 


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18 APPENDIX C:  NIH IRB form for participating sites Reporting of Deviations Non-
compliance and Unanticipated problems  
Participating sites should contact Nicole Lucas, RN at lucasan2@mail.nih.gov or 240-760-6252 
and request a WORD version of this form to be completed and returned to NCI. 
NIH PROBLEM REPORT FORM 
NCI Protocol #: 10-C-0052_9177 
Protocol Title: Phase II Study of Dose-Adjusted 
Epoch+/- Rituximab in Adults with Untreated Burkitt 
Lymphoma, C-Myc Positive Diffuse Large B-Cell 
Lymphoma and Plasmablastic Lymphoma 
 
Report version: (select one) 
____Initial Report  
____Revised Report 
____Follow-up  
Site Principal Investigator: 
 
  
Date of problem:     
Location of problem: (e.g.,  patient’s home, doctor’s 
office ) 
 
Who identified the problem? (provide role (not name of person): nurse, investigator, monitor, 
etc…) 
Brief Description of Subject (if 
applicable)  
(Do NOT include personal 
identifiers)  
Sex:  ___ Male  ___ Female 
Age:   
 ___ Not applicable (more than subject is involved) 
 
Diagnosis under study:   
Name the problem: (select all that apply)   
[  ] Adverse drug reaction   
[  ] Abnormal lab value   
[  ] Death   
[  ] Cardiac Arrest/ code  
[  ] Anaphylaxis  
[  ] Sepsis/Infection   
[  ] Blood product reaction 
[  ] Unanticipated surgery/procedure   
[  ] Change in status (e.g. increased level of care required)    
[  ] Allergy (non-medication)  
[  ] Fall  
[  ] Injury/Accident (not fall)  
[  ] Specimen collection issue   
[  ] Informed consent issue   


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[  ] Ineligible for enrollment   
[  ] Breach of PII  
[  ] Tests/procedures not performed on schedule  
[  ]  Other, brief  1-2 word description: _________________________ 
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent 
history): 
 
 
*Is this problem unexpected? (see the definition of unexpected in the protocol))  __YES __NO  
Please explain: 
 
 *Is this problem related or possibly related to participation in the research?  __YES __NO  
Please explain: 
 
*Does the problem suggest the research places subjects or others at a greater risk of 
harm than was previously known or recognized?    __YES __NO      Please explain: 
 
 
Is this problem? (select all that apply) 
[  ] An Unanticipated Problem* that is:       [  ] Serious        [  ] Not Serious  
[  ] A Protocol Deviation that is:                [  ] Serious        [  ] Not Serious 
[  ] Non-compliance 
*Note if the 3 criteria starred above are answered, “YES”, then this event is also a UP. 
Is the problem also (select one)  [  ] AE  [  ] Non-AE 
Have similar problems occurred on this protocol at your site? __YES __NO       
If “Yes”, how many? ____      Please describe: 
Describe what steps you have already taken as a result of this problem: 
 
 
In addition to the NIH IRB, this problem is also being reported to: (select all that apply) 
[  ] Local IRB 
[  ] Study Sponsor 
[  ] Manufacturer : ____________________  
[  ] Institutional Biosafety Committee  
[  ] Data Safety Monitoring Board 
[  ] Other: ____________________________________  
[  ] None of the above, not applicable 
INVESTIGATOR’S SIGNATURE:  
DATE:   
 
 


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19 APPENDIX D: Tumor Biopsy Submission Form  
9177 Tumor Biopsy Specimen Submission Form 
 
9177 Patient ID: _______________  Date form submitted: ___/__/____  
Patient Initials: ___________  
Participating Group Study No.: ___________ 
Patient Hospital No: _________  
Participating Group Patient ID: ___________  
Institution/Affiliate: ______________________ 
 
TO BE COMPLETED BY SUBMITTING INSTITUTION  
 
Does specimen accompany this form?  
(NOTE: Core needle biopsy specimens for each patient should be submitted with this form.  If 
specimens will not be submitted, specify the reason and submit the form as required by 
protocol.)  
 
No, specify reason: _______________________________ 
 
Institution error: ____ Sample lost or destroyed:  ____ Other, specify: __________  
 
Yes: Date specimen collected: ____/____/______  
 
Number of core needle biopsy specimens sent with this form: ________ 
 
Sample period: Pre-treatment:  Y:____ N: ____ 
 
Submitted by: ______________________ Phone number: ____________________  
 
Institution/Affiliate: ________________ NCI institution code: ________________  
 
 
TO BE COMPLETED BY RECEIVING INSTITUTION  
Date Specimen received: ________________ Specimen ID number: _________________ 
Specimen condition (Mark one with an X)  
_____Usable         ____ No specimen received              _____ Insufficient amount  
_____ Damaged or unusable          _____Thawed          ____ Clotted  
Received by: __________________ Phone number: ___________________ 
 
 


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20 APPENDIX E: Roster of NCTN Sites with Study Activation 
NOTE:  Effective with Amendment M, the Roster of NCTN Sites has been removed from the 
protocol document.  This information will be reported within the NIH IRB application.   
Participating sites may find this information on the CTSU and ClinicalTrial.gov websites.   
 
 
 
 


Abbreviated Title:  DA-EPOCH-R in BL 
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21 APPENDIX F: Burkitt Lymphoma Genome Sequencing Project (BLGSP) 
FOUNDATION FOR BURKITT LYMPHOMA RESEARCH 
BURKITT LYMPHOMA GENOME SEQUENCING PROJECT (BLGSP) 04/17/13 
 
EXECUTIVE SUMMARY 
The Foundation for Burkitt Lymphoma Research (FFBLR) has established a collaborative effort 
with the National Cancer Institute (NCI), in order to develop a genomic databank for Burkitt 
Lymphoma (BL).  The BLGSP will compile genetic changes present in BL tumors, analyze the 
data to identify diagnostic, prognostic, or therapeutic markers or targets, and publish the results. 
As with other cancer sequencing projects, the goal is to identify potential genetic changes in 
patients with BL that could lead to better prevention, detection and treatment of the cancer. 
The effort will be coordinated through the Foundation for the National Institutes of Health 
(FNIH).  The NCI, through the Office of Cancer Genomics (OCG), will provide the 
administrative, physical and analytical infrastructure in order to carry out this project.  This will 
enable the FFBLR to utilize existing Standard Operating Procedures (SOPs) developed by OCG, 
as well as relationships OCG has established with other organizations, in order to carry out this 
project.  This effort will enhance the scientific integrity and credibility of the BLGSP, and be 
consistent with the conduct and methodologies used in other NCI sponsored cancer sequencing 
projects. 
The FFBLR will assist in the accrual of the tissues by identifying sites in the US, Europe and 
Africa, making the initial contacts and providing administrative support.  NCI will establish the 
contracts and protocols for accrual and quality control that are already in place as part of ongoing 
projects, such as the Cancer Genomic Characterization Initiative 
(http://cgap.nci.nih.gov/cgci.html).  The FFBLR will participate in the scientific leadership of the 
BLGSP, including having members of its Scientific Advisory Board review the data from the 
project; provide the biologic context for publication and dissemination within the appropriate 
scientific communities.   
It is anticipated that the project timeline will be 3-4 years; approximately 2 years to identify and 
collect appropriate tissue and data from approximately 120 qualifying patients with BL (Phase I), 
about 6-12 months to complete the sequencing and analysis (Phase II), 6 months for validation 
studies (Phase III), and another 3-6 months to publish the data (Phase IV). 


Abbreviated Title:  DA-EPOCH-R in BL 
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INTRODUCTION 
Dr. Jean Paul Martin and Dr. Marie Reine Martin have established a Foundation for Burkitt 
Lymphoma (BL) Research in Geneva, Switzerland to further the understanding and the treatment 
of BL.  They made this decision because their son Xavier was diagnosed in July 2009 with BL 
and passed away from a relapse of the disease in May 2010. 
Burkitt Lymphoma, first described by Dr. Denis Parsons Burkitt in 1956, is an uncommon type 
of Non-Hodgkin Lymphoma, often but not exclusively affecting children.  It is a highly 
aggressive type of B-cell lymphoma and often involves body parts other than lymph nodes.  The 
disease is associated with a chromosomal translocation of the MYC gene.  The tumor consists of 
sheets of a monotonous (similar in size and morphology) population of medium size lymphoid 
cells with high proliferative activity and apoptotic activity described as a “starry sky” appearance 
under low power magnification. 
Currently BL is divided into three main clinical variants:  1.  Endemic: This BL variant occurs 
mainly in equatorial Africa, where the disease was first described and is the most common 
malignancy in children. In 95% of cases, the children are infected with Epstein-Barr virus, which 
is presumably key to its etiology.  The disease involves children much more than adults.  The 
disease characteristically involves the jaw or other facial bone, and may involve the distal ileum, 
cecum, ovaries, kidney or the breast.  2.  Sporadic: This BL variant is found outside of Africa 
and is usually not associated with Epstein-Barr virus infection, but has morphological and 
molecular features in common with endemic BL.  The jaw is less commonly involved, whereas 
the ileo-cecal region is the most common site of involvement.  3.  Immunodeficiency-associated: 


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This variant is usually associated with HIV infection and can be associated with the initial 
manifestations of AIDS, but can also occur in post-transplant patients who are taking 
immunosuppressive drugs. 
Current chemotherapy regimens are effective in approximately 40-90% of patients depending on 
age, stage of the disease, treatment regimen, and site of the treatment facility.  Hence, new 
treatments are needed to improve the efficacy of current regiments and potentially to substitute 
less toxic agents for the high intensity chemotherapeutic drugs that are currently given. 
With this as a brief background of BL, the vision of the Foundation is to provide monetary 
support of prioritized, key pre-clinical and clinical research activities that will provide a better 
understanding of the mechanisms of the disease and lead to more effective treatment algorithms.  
The Foundation has a renowned international Advisory Board including Professor Jane 
Apperley, Professor Riccardo Dalla-Favera, Professor Gerard Evan, Dr. Stephen Friend, 
Professor John Gribben, Dr. Ariela Noy, and Dr. Louis Staudt.  The Executive Director of the 
Foundation is Dr. John D. Irvin. 
The Foundation’s first key research project is to establish a comprehensive databank of genomic 
and clinical data in patients with BL.  The purpose of this document is to outline and describe the 
activities associated with developing the database. 
AIM 
This project will establish a comprehensive databank of genomic sequence from patients with 
BL, utilizing tumor DNA and matched normal DNA as well as tumor RNA.  Clinical data will 
also be collected so that associations between clinical parameters and genetic abnormalities can 
be discovered.   
SIGNIFICANCE 
Since the discovery in 1983 of MYC translocations in BL, little progress has been made in 
understanding the molecular pathogenesis of the disease.  MYC, the defining oncogene for this 
cancer, is itself insufficient to transform primary cells and actually induces apoptosis unless 
growth factors are provided or cooperating oncogenes are activated.  Loss of p53 function by 
mutation or by inactivation of INK4aARF may contribute to cell survival in a fraction of cases.  
However, there has yet to be a comprehensive effort to discover new genetic aberrations 
associated with BL using high throughput methods. 
There are several major unmet needs in the clinical management of BL that require urgent 
attention.  First, current chemotherapy is ineffective in roughly 20% of cases, and is associated 
with therapy induced toxicity and death.  Because of the toxicity, patients with BL over the age 
of 70 are ineligible for this potentially curative therapy.  Second, young individuals exposed to 
these intensive regimens face the real possibility of secondary malignancies years later.  Finally, 
children with endemic BL in Africa in general do not receive these curative chemotherapy 
regimens because of the lack of hospital support for the management of post-treatment 
infections, and consequently most will die of their disease. 
What is needed, therefore, are new approaches to the therapy of BL that are based on an 
understanding of its molecular pathogenesis and the regulatory pathways that it utilizes for 
proliferation and survival.  Currently, we have no insight into the possible involvement of 
kinases and signaling pathways that might promote the high rate of proliferation that 


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characterizes these tumors.  Likewise, mechanisms that prevent apoptosis of BL cells, besides 
p53 inactivation, have yet to be discovered. 
Burkitt Lymphoma is derived from the germinal center stage of B cell differentiation, and as 
such expresses a professional mutator, activation-induced cytosine deaminase (AID).  AID is 
likely involved in generating the breakpoints that lead to MYC translocations in sporadic BL and 
almost certainly targets many cellular genes for mutation.  Hence, BL may utilize AID-generated 
mutations to modulate oncogene and tumor suppressor pathways.  This BL comprehensive 
genome characterization project will shed considerable light on the oncogenic capacity of AID 
and identify other potential disease-causing candidates. 
An additional fascinating question is whether genetic alterations in the BL genome may 
influence the symbiotic relationship with the Epstein-Barr virus in the endemic variant in a 
proportion of the sporadic and immunodeficiency-related cases.  EBV viral proteins can mimic 
Notch signaling (EBNA2), CD40 signaling (LMP1), and B cell receptor signaling (LMP2).  It 
may be necessary for the BLs to acquire mutations in these pathways to shape the cellular 
response to these virally derived signals. 
Many key clinical questions may be illuminated by knowledge of genomic abnormalities in BL.  
Why do approximately 10-60% of patients treated with potentially curative chemotherapy 
nonetheless succumb to their disease?  How do the genomic alterations in the BL variants 
(endemic, sporadic, immunodeficiency-related) differ, and how do these differences affect their 
response to therapy?  What new therapeutic options may be available to augment or supplant 
high-dose chemotherapy? 
STUDY POPULATION 
The study population should include fresh tissue samples (case-matched tumor and normal) from 
60 adult patients with sporadic BL; and tissue from approximately 20 patients of each of the 
other three variants, pediatric sporadic, endemic and HIV-associated BL.  It is anticipated that 
about double that number of cases will need to be collected as there is about a 50% failure rate at 
the pathology and molecular processing stages. 
STUDY CONDUCT AND STANDARD OPERATING PROCEDURES 
In order to enhance the scientific integrity and credibility of the Burkitt Lymphoma Genome 
Sequencing Project (BLGSP), the project will be carried out utilizing SOPs developed by the 
OCG at the NCI.  The BLGSP-specific SOPs can be found in the OCG Tumor Molecular 
Characterization Projects Standard Operating Procedures manual 
(http://cgap.nci.nih.gov/files/OCG_SOP_Manual.pdf) and are consistent with those currently 
utilized in the NCI-sponsored HIV+ Tumor Molecular Characterization Project (HTMCP). 
Using the SOPs, the tissues will be accrued by collaborators (referred to as Tissue Source Sites 
[TSS]) with access to BL patients.  Each TSS will need to obtain an institutional review board 
(IRB)-approved study protocol that allows for collection of human tumor tissue and matched 
normal tissue (preferably blood). Upon approval, all TSS will be required to collect and store the 
tissues, perform site-capable pathology analysis to determine the BL diagnosis, and provide the 
BLGSP-required clinical data.  The above-referenced OCG Tumor Molecular Characterization 
Projects SOP Manual includes templates of an informed consent and an institutional certification 
letter, which can be adapted by each TSS for their use.  Every patient studied in the BLGSP must 
be enrolled in a site-specific protocol, and agree to participate by signing an informed consent.  


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The institutional certification letter states that the IRB understands that the data generated will be 
made publicly available with the appropriate patient protection procedures 
(http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/about.html). 
TISSUE COLLECTION AND PREPARATION 
Procedures for tissue collection, preparation, pathology review and shipment in the BLGSP are 
detailed in the OCG Tumor Molecular Characterization SOP Manual.  Adherence to the SOPs is 
essential to ensure that the quality of the tissues collected meet the technical requirements of the 
methods of analysis.  The protocols include information on tissue collection and preservation by 
freezing, pathology review, collection of blood samples for molecular characterization, shipping 
cryoports containing frozen biosamples for processing and extraction of nucleic acids, sample 
shipping guidelines, sample identifier standards, and disposition form for remaining 
macromolecules/tissues that are contributed to the project.  Templates for suggested language for 
prospective tissue collection and the data release policy are also included within the SOPs.   
TISSUE REQUIREMENTS 
Following is a summary of the tissue requirements for the BLGSP.  The specific detailed 
requirements are included in the above referenced SOPs. 
• Paired tumor and matched normal (non-involved tissue or blood) of untreated cases must 
be available in sufficient quantities.   
• If blood is the normal tissue, documentation of normal peripheral white blood cell counts 
and smears must be provided since in rare instances, BL cells can be in the peripheral 
blood.  There are 2 ways of getting normal tissue without tumors: a) Granulocytes can be 
separated from lymphocytes with Ficoll.  b) Also with Ficoll separation, flow cytometry 
analysis can be performed with CD10, a BL surface marker.  
• Pre-treatment blood sample is preferred as the source of normal tissue.  However, if a 
tumor specimen is pre-existing and the patient is alive and can be re-consented following 
treatment for the collection of a post-treatment blood sample, then that will be acceptable.   
• Tissues (both normal and tumor) need to be snap frozen.  Currently the project anticipates 
that ~100 mg of tumor tissue and 10 ml of blood is required, but this may change as the 
sequencing characterization technology improves. 
• A portion of tumor adjacent to the snap frozen sample will be assessed to estimate % 
tumor cells, with additional immunohistochemical (IHC) stains and FISH to be 
performed to validate the diagnosis, as needed (see below).  Tumors need to have 
minimum 70-80% tumor nuclei as assessed on the H&E section from the frozen tissue 
with ~80% viable cells. 
• Standard World Health Organization diagnostic criteria for BL must be fulfilled.  
Specifically, the tumor cells have the “starry-sky” appearance, be positive for CD10 
and/or BCL6 by IHC and >90% of the cells need be Ki67 positive.  It would be optimal if 
the presence of MYC to immunoglobulin locus translocation was confirmed by 
fluorescent in situ hybridization (FISH).  At least 12 paraffin-embedded slides, or even 
better a block, have to be provided, from each case for pathology review by the project 
pathologists.   
• Clinical data (see SOPs) has to be collected at the time of diagnosis, updated after 


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treatment, and then every year for the next 2 years 
If tumor tissue or blood/constitutional tissue is not available, but clinical information and 
paraffin-embedded slides or block(s) are, we would consider accepting nucleic acids from 
pathology review-confirmed cases that meet the following criteria: 
• At least 10 µg of RNA with RNA Integrity Number (RIN) > 7 as determined on an 
Agilent Bioanalyzer or similar system 
• At least 20 µg each of tumor and normal high molecular weight (>80% of the molecules 
are >10 kb) DNA  
The tissues will be processed in a single biospecimen-processing center using standard protocols 
developed for and validated in Therapeutically Applicable Research to Generate Effective 
Treatments (TARGET) and The Cancer Genome Atlas (TCGA).  The RNA and DNA will be 
quality controlled and the match of the tumor and normal DNA confirmed.  As part of the 
processing, the DNA will be whole genome amplified by the method considered the most 
optimal for genomic characterization at the time when this project will be ready to do so.  One of 
the BLGSP’s outcomes will be the availability of the DNA and/or RNA for other projects. 
PATHOLOGY REVIEW/VERIFICATION 
The review of all tissues by a central pathology review panel of three board-certified hematology 
pathologists will ensure that the samples that are molecularly characterized are BL, and remove 
the subjectivity encountered in standard pathology practice.  The pathology criteria for BL 
diagnosis include: 1) characteristic histological appearance; 2) Ki67 immunohistochemical 
staining in >90% of tumor nuclei; 3) CD10+ and/or BCL6+ by immunohistochemistry; 4) 
MYC/Ig translocation by FISH analysis; BCL2 staining by IHC and those cases which are 
positive, will by analyzed by MYC/BCL2 FISH.  A SOP for this review and verification has been 
established and is available in the BLGSP section of the OCG SOP manual. 
SEQUENCING, ANALYSIS AND VALIDATION 
One of the major objectives of the BLGSP will be to generate genomic-scale DNA and/or RNA 
sequence from case-matched tumor-normal pairs from patients with BL.  For DNA as well as 
RNA sequencing, normal DNA needs to be sequenced to define which novel sequence variants 
are germline and which are somatic changes.  The plan is to initiate sequencing once a critical 
number of cases (12-20) have been collected and continue sequencing in batches throughout the 
term of this project.  We anticipate that the cost of whole genome sequence will be decreasing, 
though the exact cost cannot be estimated.  The analysis of the genomic DNA sequence will 
provide information of single-nucleotide polymorphisms (SNPs) for loss of heterozygosity, 
somatic mutations, genomic rearrangements and copy number. 
We anticipate that sufficient funds will be available for whole transcriptome sequencing 
(mRNA-seq and miRNA-seq).  The analysis of that data results in digital gene expression 
profile, identification of alternative spliced variants, discovery of fusion transcripts created by 
genomic rearrangements, RNA editing (in comparison with the genomic sequence), confirmation 
of mutation calls, and if mutant or wild type alleles are expressed as mRNA (either due to loss of 
heterozygosity or imprinting). 
While the cost and quality of sequencing (2nd, 3rd generation) in two years is impossible to 
predict (currently the costs are decreasing rapidly and the quality of the sequence is improving as 


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well), there is every reason to anticipate that it will be the norm to sequence the genome more 
than the current 30X (50-100X?) and include the transcriptome as well.   
The current proposal does not include epigenetic characterization, however whatever materials 
will be left over could be used in the future to do genome-wide characterization of the 
methylation profile. 
The NCI project team will develop an analytical protocol for the data generated, including: 
• Analysis of the copy number alternations with integration with digital gene expression 
• Identification of somatic mutations 
• Identification of translocations   
Taken together, these analyses will look for recurrent lesions within BL as a whole and within 
the BL variants.  Genetic changes will be placed into biological pathways and integrated using 
available methods.  The findings will be validated in a new population cohort via high-
throughput evaluation of gene alterations in BL as a whole and within the BL variants. The 
validation cohort will include up to 200 patients; the proportion of subtype cases will be selected 
based on the results obtained in the discovery phase (II). Validation studies performed in this 
new cohort will allow for mutations uncovered in Phase II to be verified as true and increase the 
power to estimate the frequency with which they occur. Moreover, validation will enable 
evaluation of the clinical relevancy of the genetic changes found.  
GOVERNANCE 
The tissue contributors will be co-authors on the first manuscript and may collaborate in the 
future in others.  The project will have a steering committee (SC) whose membership includes 
members of the FFBLR’s scientific advisory board (Dr. Louis Staudt, Professor Riccardo Dalla-
Favera, Dr. Stephen Friend, Dr. Ariela Noy, and Dr. John Irvin, Executive Director FFBLR), one 
representative each from the contractor(s) doing the sequencing and tissue processing, the 
members of the pathology review board and 1-2 representatives from OCG as needed.  During 
the first 2 years of the project, the SC will meet by teleconference quarterly, and face-to-face 
annually to assess the progress in tissue accrual and any issues, which may arise in the process to 
isolation of the molecular analytes.  The sequencing will be performed by contractors, which will 
be put in place by OCG.  Once sequencing starts, the SC needs to meet monthly through 
teleconferencing and face to face every 6 months. 
DATA RELEASE POLICY AND PUBLICATION  
The data that are generated will be submitted to publicly accessible databases developed for 
HTMCP and other projects.  The NCI database is called the Data Coordinating Center and it 
allows an easy access to all data generated (TARGET, CGCI and TCGA) as well as analytical 
tools developed for other large-scale sequencing projects.  The BLGSP will be listed on the 
CGCI web page and the Foundation acknowledged as a collaborator.  The procedures developed 
for the other projects include submission of the sequence generated to publicly accessible 
databases (currently called sequence-read archive), which are an NCI-defined resource used by 
all NCI projects.  The BLGSP agrees to abide by the data release policy formulated for the 
HTMCP (http://cgap.nci.nih.gov/files/H_TMCP_Data_Release_Policy.pdf).  Every effort will 
be made to rapidly, and not later than in 3-6 months after validation, publish the first manuscript 
describing the data and including a high-level analysis.  
 


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22 APPENDIX G: BLGSP Enrollment Case Report Form 
 
 
 
 
 
 
 
 
 
Tissue Source Site (TSS): ____________________________TSS Identifier: _____________ TSS Unique Patient 
Identifier: _______________________________  
Completed By (Interviewer Name in OpenClinica): __________________________________________Completed 
Date: ___________________________________ 
Instructions: The Clinical Data needed to complete this Enrollment Form should be collected for each patient in the 
Burkitt Lymphoma Genome Sequencing Project (BLGSP) prior to acquisition of tissues. Upon qualification notice 
from the Office of Cancer Genomics (OCG), the Tissue Source Site (TSS) should complete this Enrollment form for 
each qualified case within 60 days.  
Questions regarding this form should be directed to the Nationwide Children’s Hospital (NCH) or OCG. 
Please note the following definitions for the “Unknown” and “Not Evaluated” answer options on this form. 
Unknown: This answer option should only be selected if the TSS does not know this information after all efforts to 
obtain the data have been exhausted.  If this answer option is selected for a question that is part of the BLGSP 
required data set, the TSS must complete a discrepancy note providing a reason why the answer is unknown. 
Not Evaluated: This answer option should only be selected by the TSS if it is known that the information being 
requested cannot be obtained. This could be because the test in question was never performed on the patient or the 
TSS knows that the information requested was never disclosed.  


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# 
Data Element 
Entry Alternatives 
Working Instructions 
General Information 
BLGSP  Project ID: 
 
*1 
Is this a prospective 
tissue collection? 
 Yes 
 No 
Indicate whether the TSS providing tissue is 
contracted for prospective tissue collection. If 
the submitted tissue was collected after the date 
the BLGSP contract was executed, the tissue 
has been collected prospectively. 
3088492 
*2 
Is this a 
retrospective tissue 
collection? 
 Yes 
 No 
Indicate whether the TSS providing tissue is 
contracted for retrospective tissue collection. If 
the submitted tissue was collected prior to the 
date the BLGSP contract was executed, the 
tissue has been collected retrospectively. 
3088528 
Patient Information 
Demographic Information 
*3 
Date of Birth 
_____ _____ / 
(month) 
_____ _____ / 
(day) 
___ ___ ___ ___ 
(year) 
Provide the date the patient was born. 
2896950 (month), 2896952 (day), 2896954 
(year) 
Note: The day of Birth is not required. 
*4 
Gender 
 Female 
 Male 
Provide the patient's gender using the provided 
categories.  
2200604 
*5 
Race 
(check all that 
apply) 
 American Indian or Alaska Native 
 Asian/East Indian 
 White 
 Black/African American 
 Native Hawaiian or other Pacific Islander 
 Other (please specify) 
 Unknown 
Provide the patient's race using the defined 
categories. 
3009519 
American Indian or Alaska Native: A person 
having origins in any of the original peoples of 
North and South America (including Central 
America), and who maintains tribal affiliation 
or community attachment. 
Asian: A person having origins in any of the 
original peoples of the far East, Southeast Asia, 
or in the Indian subcontinent including, for 
example, Cambodia, China, India, Japan, Korea, 
Malaysia, Pakistan, the Philippine Islands, 
Thailand, and Vietnam. 
White: A person having origins in any of the 
original peoples of the four Europe, the Middle 
East, or North Africa. 
Black or African American: A person having 
origins in any of any of the black racial groups 
of Africa. Terms such as “Haitian” or “Negro” 
can be used in addition to “Black or African 
American.” 
Native Hawaiian or other Pacific Islander: A 
person having origins in any of the original 
peoples of Hawaii, Guam, Samoa, or other 
Pacific Islands. 
Unknown: Could not be determined or unsure 
*6 
Other Race 
____________________________ 
If the patient’s race was not defined in the 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
# 
Data Element 
Entry Alternatives 
Working Instructions 
Only complete if 
“other” is selected in 
#5. 
previous question, provide the patient’s race. 
2192205 
7 
Ethnicity 
 Not Hispanic or Latino 
 Hispanic or Latino 
 Not Reported 
 Unknown 
Provide the patient's ethnicity using the defined 
categories.  
2192217 
Not Hispanic or Latino: A person not meeting 
the definition of Hispanic or Latino. 
Hispanic or Latino: A person of Mexican, 
Puerto Rican, Cuban, Central or South 
American, or other Spanish culture or origin, 
regardless of race. 
Not Reported: Not provided or available 
Unknown: Could not be determined or unsure 
8 
Height 
(at time of 
diagnosis) 
_____________________________(cm) 
Provide the patient’s height (centimeters) at the 
time the patient was diagnosed with the tumor 
submitted for BLGSP. 
649 
9 
Weight 
(at time of 
diagnosis) 
_____________________________(kg) 
Provide the patient’s weight (kilograms) at the 
time the patient was diagnosed with the tumor 
submitted for BLGSP. 
651 
 
 
Survival Information 
*10 
Vital Status 
(at date of last 
contact) 
 Alive 
 Dead 
The survival state of the person registered on 
the protocol. 
5 
*11 Date of Last Contact 
____ _____ / 
(month) 
_____ _____ / 
(day) 
___ ___ ___ ___ 
(year) 
If the patient is living, provide the date of last 
contact with the patient (as reported by the 
patient, medical provider, family member, or 
caregiver).  
2897020 (month), 2897022 (day), 
2897024 (year) 
Note: The day of Last Contact is not required. 
*12 Date of Last Known 
Alive 
____ _____ / 
(month) 
____ ____ / 
(day) 
__ ___ ___ ___ 
(year) 
Indicate the last date the patient was known to 
be alive, regardless of whether the patient, 
medical provider, family member or caregiver 
was contacted. 
2975722 (month), 2975724 (day), 
2975726 (year) 
Note: The day of Last Known Alive is not 
required. 
*13 Date of Death 
____ ____ / 
(month) 
____ ____ / 
(day) 
___ ___ ___ ___ 
(year) 
If the patient is deceased, provide the month of 
death.  
2897026, (month) 2897028 (day), 
2897030 (year) 
Note: The day of Death is not required. 
6 
Cause of Death 
Only complete if 
patient is deceased. 
 Cancer Related         Non-Cancer Related 
 Unknown                  Other (please specify) 
 
Indicate the patient’s cause of death. 
2554674 
7 
Other Cause of 
____________________________________ 
If the patient’s cause of death was not included 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Death 
Only complete if 
“other” is selected in 
#6. 
in the provided list, specify the patient’s cause 
of death. 
2004150 
Patient Status (Regarding Submitted Tumor) 
*14 
Did the patient 
receive neo-adjuvant 
therapy for the 
tumor submitted for 
BLGSP? 
 Yes (exclusion criterion) 
 No 
Indicate whether the patient received treatment 
(radiation, pharmaceutical, or both) prior to the 
procurement of the sample submitted for 
BLGSP. 
3382737 
If the answer to this question is “yes”, the 
submitted case is excluded. 
*15 
Tumor Status 
(at time of last 
contact or death) 
 Tumor free 
 With tumor 
 Unknown  
Indicate whether the patient was tumor/disease 
free (i.e. free of the malignancy that yielded the 
sample submitted for the BLGSP study) at the 
date of last contact or death.  
2759550 
16 
Performance Status: 
Eastern Cooperative 
Oncology Group  
 0: Fully active, able to carry on all pre-disease 
performance without restriction.   
 1:  Restricted in physically strenuous activity 
but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light 
housework, office work. 
 2: Ambulatory and capable of all selfcare but 
unable to carry out any work activities. Up 
and about more than 50% of waking hours. 
 3: Capable of only limited selfcare, confined 
to bed or chair more than 50% of waking 
hours.  
 4: Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair. 
 Unknown 
 Not Evaluated 
Provide the Eastern Cooperative Oncology 
Group (ECOG) performance status of the 
patient at the time selected in the “timing” 
question below. 
88 
17 
Performance Status: 
Karnofsky Score  
 100: Normal, no complaints, no evidence of 
disease 
 90:  Able to carry on normal activity; minor 
signs or symptoms of disease 
 80: Normal activity with effort; some signs or 
symptoms of disease 
 70: Cares for self, unable to carry on normal 
activity or to do active work 
 60: Requires occasional assistance, but is able 
to care for most of his/her needs. 
 50: Requires considerable assistance and 
frequent medical care 
 40:  Disabled, requires special care and 
assistance 
 30: Severely disabled, hospitalization 
indicated. Death not imminent.  
 20: Very sick, hospitalization indicated. Death 
not imminent. 
 10: Moribund, fatal processes progressing 
rapidly 
 0: Dead 
 Unknown 
Provide the Karnofsky score for the patient at 
the time selected in the “timing” question 
below. 
2003853 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
 Not Evaluated 
18 
Performance Status 
Score: Timing 
 Preoperative 
 Pre-adjuvant Therapy 
 Adjuvant Therapy 
 Post-adjuvant Therapy 
 Unknown 
Indicate the timing of the performance 
status(es) provided in the previous question(s). 
2792763 
18 
Tumor Response 
 Progressive Disease 
 Stable Disease 
 Partial Response 
 Complete Response 
Indicate the patient’s measure of success after 
their primary treatment for the tumor submitted 
for HTMCP. Treatment includes surgery and 
adjuvant therapies. 
2786727 
Treatment 
*19 
Indication of 
Regimen 
 Initial 
 Adjuvant 
 Progression after initial 
 Recurrence 
 Palliative 
 Unknown 
Text term to identify the reason for the 
administration of a treatment regimen.  
2793511 
*20 
Lymphoma 
Treatment Type 
 Chemotherapy 
 Radiation 
 Radiation and Chemotherapy 
 Stem Cell Transplant 
 Surgery 
 No Treatment 
 Other Treatment 
Text term that describes the kind of treatment 
that was given for the primary lymphoma. 
3284925 
*21 
If other, specify 
____________________________________ 
Indicate the other treatment type for the 
lymphoma. 
2861111 
Chemotherapy 
22 
Chemotherapy 
Start Date 
 
__ __ / __ __ / __ __ __ __ 
 
 
Date chemotherapy started. 
2897050 (month), 2897052 (day), 2897054 
(year) 
23 
Did 
chemotherapy 
end during this 
reporting 
period? 
 Yes 
 No 
 
Indicate whether chemotherapy administration 
ended during this reporting period. 
2188260 
24 
Chemotherapy 
End Date 
 
__ __ / __ __ / __ __ __ __ 
 
Date chemotherapy ended. 
2897056 (month), 2897058 (day), 2897060 
(year) 
*25 
Pharmaceutical 
Regimen 
  BACOP 
  C-MOPP 
  CAP-BOP 
  CHOP + Bleomycin 
  CHOP + Etoposide 
  CHOP-14 
  CHOP-14 + Rituximab 
  CHOP-21 
  CHOP-21 + Rituximab 
  CNOP 
  CODOX + Rituximab 
  CVP 
  DA-EPOCH 
  DA-EPOCH + Rituxumab 
Text term or code to represent the name of a 
pharmaceutical regimen containing two or more 
agents which are given together or separately to 
treat a patient with malignant lymphoma. 
3366758 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
  F-MACHOP 
  High Dose Methotrexate w/Leucovorin 
  HyperCVAD-Mtx/AraC + Rituximab 
  ICE 
  ICE + Rituxumab 
  LNH-84 
  LNH-87 
  M-BACOP 
  MACOP-B 
  ProMace-CytaBOM 
  ProMace-MOPP 
  VACOP-B 
  Vanderbilt regimen + Rituximab 
  Single Agent Therapy (please specify) 
  Other Pharmaceutical  Regimen (please 
specify) 
  Unknown 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
26 
If Other 
Pharmaceutical 
Regimen, 
specify 
 
 
 
 
Text term or abbreviation to represent another 
name of a pharmaceutical regimen containing 
two or more agents which are given together or 
separately to treat a patient with malignant 
lymphoma that was not already mentioned or 
specified. 
3366930 
27 
If Single-Agent 
Therapy, 
specify 
 
 
 
Text name for agent used without other agents 
in a treatment regimen or study. 
3590022 
28 
Number of 
Cycles 
 
 
 
 
The total number of cycles administered to the 
patient of a protocol specified drug or therapy 
agent as of the current report. 
62590  
Radiation Therapy  
29 
Radiation 
Therapy Start 
Date 
 
__ __ / __ __ / __ __ __ __ 
 
Date radiation therapy started. 
2897100 (month), 2897102 (day), 2897104 
(year) 
30 
Did radiation 
therapy end 
during this 
reporting 
period? 
 Yes 
 No 
 
Indicate whether radiation therapy ended during 
this reporting period. 
 
31 
Radiation 
Therapy End 
Date 
 
__ __ / __ __ / __ __ __ __ 
 
Date radiation therapy ended. 
2897106 (month), 2897108 (day), 2897110 
(year) 
32 
Total Dose of 
Radiation 
Therapy 
 
__________________________ (Gy) 
A numeric value for the total dose volume of 
radiation therapy given to a patient, in Gray. 
36 
33 
Radiation 
Field, 
extranodal  
 Abdomen, total 
 Arm 
 Body, total 
 Bone, non-spine 
 Brain, focal 
 Brain, whole 
 Breast 
 Chest wall 
 Eye 
 Gastrointestinal, colon 
 Gastrointestinal, gallbladder 
 Gastrointestinal, intestine 
 Gastrointestinal, Liver 
 Gastrointestinal, NOS 
 Gastrointestinal, Pancreas 
 Gastrointestinal, Stomach 
 Genitourinary, Bladder 
 Genitourinary, Kidney 
 Genitourinary, NOS 
 Head, Face, 
or Neck 
 Leg 
 Lung 
 Lymph node, 
distant (specify 
site) 
 Lymph node, 
locoregional 
(specify site) 
 Lymph 
Nodes 
 Mantle 
 Mediastinum 
 Parametrium 
 Pelvis 
 Shoulder 
 Skin, lower 
extremity, local 
 Skin, total 
 Skin, trunk, 
local 
 Skin, upper 
extremity, local 
 Spine 
 
Text term to identify anatomically-specified 
areas or fields that are targeted for radiation 
therapy. 
2416537 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Supraclavicular 
 Thorax 
 Trunk 
 
 Other 
 Unknown 
 
34 
Nodal Regions 
Targeted 
 Axillary  
 Cervical  
 Epitrochlear  
 Femoral  
 Hilar  
 Iliac-common  
 Iliac-external  
 Inguinal  
 Mediastinal  
 Mesenteric  
 Occipital  
 Paraaortic  
 Parotid  
 Popliteal  
 Retroperitoneal  
 Splenic  
 Submandibular  
 Supraclavicular  
Identify lymph node sites targeted for radiation 
therapy. 
3762198 
35 
Other, specify 
_________________________  
Specify other field of radiation 
62999 
Stem Cell Transplantation  
36 
Type of Stem 
Cell 
Transplantation 
 Autologous 
 Syngeneic/Allogeneic related donor 
 Allogeneic, unrelated donor 
Indicate the hematopoietic stem cell source 
type. 
2957417 
37 
Date of Stem 
Cell 
Transplantation 
__ __ / __ __ / __ __ __ __ 
Indicate the date of the hematopoietic stem 
cell transplant. 
3718671 
Surgery 
38 
Date of cancer 
debulking 
surgery 
 
__ __ / __ __ / __ __ __ __ 
Indicate the date related to the procedure of 
surgically removing as much of the tumor as 
possible being executed. 
2839523 
39 
Measure of 
Success of 
Outcome at the 
Completion of 
Initial First 
Course 
Treatment 
 Progressive Disease 
 Persistent Disease 
 Stable Disease 
 Partial Remission/ Response 
 Complete 
Remission/Resp
onse  
 Unknown 
 Not 
Applicable 
(treatment 
ongoing) 
Indicate the patient’s measure of success after 
the initial first course of treatment. 
2786727 
Patient History of Disease 
 
HIV Status 
*40 HIV antibody status 
 Positive 
 Negative 
 Unknown 
Indicate whether the patient is HIV positive. 
2180464 
41 
Date of HIV 
_____ _____ 
_____ _____ / 
___
Provide the month the patient was diagnosed 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Diagnosis (if 
known) 
/ 
(month) 
(day) 
__ 
___
__ 
___
__ 
___
__ 
(y
ea
r) 
with HIV. 
3579640 (month), 3579644 (day), 
3579643 (year) 
Note: The day of HIV Diagnosis is not required. 
42 
Nadir CD4 Counts 
(at time of last 
contact) 
____________________________ (cells/mm3) 
Provide the patient’s Nadir CD4 counts, which 
are the lowest CD4 counts the patient has had. 
2684395 
43 
CD4 Counts at 
Diagnosis of the 
Submitted 
Malignancy 
____________________________ (cells/mm3) 
Provide the patient’s CD4 Counts at the time 
the patient was diagnosed with the malignancy 
submitted for the BLGSP study. 
2922654 
44 
HIV RNA load at 
Diagnosis of 
Submitted 
Malignancy 
____________________________ (counts/mL) 
Provide the HIV RNA load (also known as the 
“viral load”) at the time the patient was 
diagnosed with the malignancy submitted for 
the BLGSP study. 
2922674 
45 
Prior AIDS 
Defining Conditions 
 Candidiasis of bronchi, trachea or lungs 
 Candidiasis, esophageal 
 CMV other than liver, spleen or nodes, onset 
at age >1month 
 CMV retinitis 
 Coccidioidomycosis, disseminated or 
extrapulmonary 
 Cryptococcosis, extrapulmonary 
 Cryptosporidiosis, chronic intestinal 
 Encephalopathy, HIV-related 
 Herpes simplex: chronic ulcers (> 1 month's 
duration) or bronchitis, pneumonitis or 
esophagitis (onset at age > 1 month) 
 Histoplasmosis, disseminated or 
extrapulmonary 
 Isosporiasis, chronic intestinal (> 1 mon) 
 Mycobacterium avium complex or 
Mycobacterium kansasii disseminated or 
extrapulmonary 
 Mycobacterium tuberculosis of any site, 
pulmonary, disseminated or extrapulmonary 
 Mycobacterium, other species or unidentified 
species, disseminated or extrapulmonary 
 Nocardiosis 
 Pneumocystis jirovecii pneumonia 
 Pneumonia, recurrent 
 Progressive multifocal leukoencephalopathy 
 Salmonella septicemia, recurrent 
 Toxoplasmosis of the brain, onset at age 
>1month 
 Wasting syndrome, due to HIV 
Prior to the malignancy submitted for the 
BLGSP study, provide any AIDS defining 
conditions. 
2679581 
v46 Co-Infections  
Test 
Positive 
Negative 
Inconclusive 
Not 
Tested 
Using the list 
provided, 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
indicate whether 
the patient had 
any co-
infections by 
providing the 
results of each 
of the tests 
listed. 
HBV 
 
 
 
 
2180456 
HCV 
 
 
 
 
2695021 
HPV 
 
 
 
 
2230033 
KSHV/HHV8 
 
 
 
 
3335773 
47 
HAART Treatment 
Prior to Diagnosis of 
Submitted 
Malignancy 
 Yes 
 No 
 Unknown 
Indicate whether the patient received Highly 
Active Antiretroviral Therapy (HAART) 
treatment prior to the diagnosis of the 
malignancy submitted for the BLGSP study. 
3335156 
48 
HAART Treatment 
at Time of 
Diagnosis of 
Submitted 
Malignancy 
 Yes 
 No 
 Unknown 
Indicate whether the patient received Highly 
Active Antiretroviral Therapy (HAART) 
treatment at the time of the diagnosis of the 
malignancy submitted for the BLGSP study. 
2922679 
49 
CDC HIV Risk 
Group(s) 
 Homosexual or bisexual contact 
 Heterosexual contact 
 IV drug user 
 Transfusion recipient 
 Hemophiliac 
 Unknown 
 
Indicate whether the patient has a history of any 
of the listed HIV Risk Groups as defined by the 
Center for Disease Control (CDC). 
2542215 
Prior Malignancies 
*50 History of other 
malignancy  
 Yes (exclusion criterion) 
 No 
Indicate whether the patient has a history of 
malignancies, including synchronous or 
bilateral malignancies.  
3382736 
If the answer to this question is “yes”, the 
submitted case is excluded. This exclusion does 
not apply if the patient only has a history of 
non-melanoma skin cancer OR cervical in situ 
carcinoma. 
Prior Immunological Disease 
51 
Patient History of 
Prior Immunological 
Disease 
 Rheumatoid Arthritis 
 Sjogren’s Syndrome 
 Systemic Lupus Erythematous 
 Crohn's Disease 
 Ulcerative Colitis 
 Hasimoto's Thyroiditis 
 Other 
 Unknown 
Indicate whether the patient has a history of any 
of the listed immunological diseases. 
3233628 
52 
Other Specified 
Patient History of 
Immunological 
Disease 
Only complete if 
______________________________ 
Indicate whether the patient has a history of any 
of the listed immunological diseases. 
3233629 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
“other” is selected in 
#5. 
53 
Patient History of 
Prior 
Immunosuppressive 
Therapy  for 
Immunological 
Disease  
 Methotrexate 
 Cyclophosphamide 
 Azathioprine 
 Anti-TNF therapy 
 None 
 Other 
 Unknown 
If the patient received immunosuppressive 
therapy for the immunological disease selected 
in the previous question, provide the type of 
immunosuppressive therapy given. 
3233638 
54 
Other Prior 
Immunosuppressive 
Therapy 
Administered 
Specify Text 
Only complete if 
“other” is selected in 
#5. 
___________________________ 
What was the other immunosuppressive therapy 
administered?  
2873928 
Prior Infectious Disease 
55 
Patient History of 
Relevant Prior 
Infectious Disease 
 Hepatitis B 
 Hepatitis C 
 H. Pylori 
 Malaria 
 Other 
 Unknown 
Indicate whether the patient has a history of any 
of the listed  infectious disease. 
3233642 
 
56 
Patient History of 
Other Relevant 
Infectious Disease 
Only complete if 
“other” is selected in 
#5. 
____________________________ 
If the patient has a history of relevant prior 
disease that was not included in the list, provide 
the infectious disease. 
3233643 
Pathologic Information 
*57 Histological 
Subtype 
 Burkitt Lymphoma (BL), classic morphology 
 Burkitt Lymphoma (BL), atypical morphology 
 Other, specify 
 Unknown  
Using the patient's final diagnostic pathology 
report, provide the most detailed histological 
subtype available.  
3081934 
58 
Other Neoplasm 
Histologic Type, 
Specify 
Only complete if 
“other” is selected in 
#5. 
_____________________________ 
Free text field to specify the structural pattern 
of cancer cells used to define a microscopic 
diagnosis that is not already specified or 
mentioned. 
3294805 
*59 Percent Follicular 
Component 
 <=10% 
 > 10% (exclusionary) 
 Unknown 
Using the pathology report, indicate the 
percentage of the follicular component within 
the Burkitt  lymphoma sample that was 
removed from the patient. 
 3770422 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
*60 
Site(s) of Nodal 
Involvement at 
Diagnosis 
(Please check all 
that apply) 
 
 Axillary 
 Cervical 
 Epitrochlear 
 Femoral 
 Hilar 
 Iliac 
 Iliac-common 
 Iliac-external 
 Mediastinal 
 Mesenteric 
 
 
 Occipital 
 Paraaortic 
 Parotid 
 Popliteal 
 Retroperitoneal 
 Splenic 
 Supraclavicular 
 Submandibular 
 
 No known nodal 
involvement 
 
Using the patient’s medical record check all 
applicable boxes to identify the lymph node 
chain(s) that were involved by Burkitt 
lymphoma at the time of initial diagnosis. 
2180591 
To select multiple sites of involvement, press 
the control button and select the sites of 
involvement. Your selections should be 
highlighted after you’ve selected. 
*61 
Site(s) of Extranodal 
Involvement 
At Diagnosis 
(Please check all 
that apply) 
 Adrenal Gland 
 Bone 
 Bone Marrow 
 Breast 
 Peripheral Blood 
 Skin 
 Soft Tissue (muscle, 
ligaments, subcutaneous) 
ENT & Eye 
 Eye 
 Larynx 
 Mandible 
 Maxilla 
 Nasal Soft Tissue 
 Nasopharynx 
 Ocular orbits 
 Oropharynx 
 Parotid Gland 
 Peri-orbital Soft Tissue 
 Salivary Gland 
 Sinus(es) 
 Thyroid gland 
Central Nervous System 
 Brain 
 Epidural space 
 Leptomeninges 
Gastrointestinal/ 
Abdominal 
 Ascites 
 Appendix 
 Colon 
 Esophagus 
 Gallbladder 
 Liver 
 Pancreas 
 Rectum 
 Small Intestine 
 Stomach 
Genito-urinary 
Tract 
 Bladder 
 Epididymis 
 Kidney 
 Ovary 
 Prostate 
 Testicle 
 Uterus 
Mediastinal/ Intra-
thoracic 
 Heart 
 Lung 
 Mediastinal Soft 
Tissue 
 Pericardium 
 Pleura 
 
 Not applicable 
 Other, please 
specify 
 
Using the patient’s medical record check all 
applicable boxes to identify the anatomic 
location of all site(s) of extranodal involvement 
by Burkitt lymphoma at the time of initial 
diagnosis. 
2735776 
To select multiple sites of involvement, press 
the control button and select the sites of 
involvement. Your selections should be 
highlighted after you’ve selected. 
62 
Other Specified Site 
of Extranodal 
Involvement at 
Diagnosis 
(For Primary 
Clinical 
Involvement) 
____________________________ 
If all extranodal sites of involvement are not 
included in the list provided, please indicate 
any sites of extranodal involvement. 
3234303 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
63 
Number of 
Extranodal Sites of 
Involvement Above  
(to calculate the IPI) 
____________________________ 
Provide the total number of extranodal sites 
with lymphoma involvement. Use the previous 
three questions to determine this number.  This 
information, along with other data provided, 
will be used by the Analysis Working Group 
(AWG) to calculate the International Prognostic 
Index (IPI).   
3233242 
64 
Maximum Tumor 
Bulk 
(Dimension) 
____________________________ (cm) 
After review of the entire medical record, 
record the length of the largest dimension/ 
diameter of a tumor, regardless of anatomical 
plane. 
64215 
*65 
Anatomic Site of 
Maximum Tumor 
Bulk 
(Select one 
anatomic site from 
listing above) 
 Adrenal 
 Bone 
 Bone Marrow 
 Brest 
 Peripheral Blood 
 Skin 
 Soft Tissue (muscle, 
ligaments, subcutaneous) 
Genito-urinary Tract 
 Epididymis 
 Kidney 
 Ovary 
 Prostate 
 Testes 
 Uterus  
ENT & Eye 
 Intraocular 
 Larynx 
 Nasal Soft Tissue 
 Nasopharynx 
 Oropharynx 
 Parotid Gland 
 Peri-orbital Soft Tissue 
 Salivary Gland 
 Sinus 
 Thyroid 
Mediastinal/ Intra-thoracic 
 Heart 
 Lung 
 Mediastinal Soft Tissue 
 Pericardium 
 Pleura 
 Other, please specify 
 No Known Extranodal 
Involvement 
Gastrointestina
l/ Abdominal 
 Ascites/ 
Peritoneum 
 Appendix 
 Colon 
 Esophagus 
 Liver 
 Pancreas 
 Rectum 
 Small 
Intestine 
 Stomach 
Central 
Nervous 
System 
 Brain 
 Epidural 
 
Lepomeninges 
Lymph Nodes 
 Axillary 
 Cervical 
 Epitrochlear 
 Femoral 
 Ililac 
 Iliac-
common 
 Iliac-external 
 Mediastinal 
 Mesenteric  
 Occipital 
 Paraaortic 
 Parotid 
 Popliteal 
 
Retroperitoneal 
 Splenic 
 
Supraclavicular 
 
Submandibular 
Using the list of sites in numbers 39 and 40, 
provide the anatomic site of the maximum 
tumor bulk. 
3233300 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
 No Known 
Nodal 
Involvement 
Pathologic Diagnosis and Surgical Resection 
*66 
Date of Initial 
Pathologic 
Diagnosis 
____ ____ / 
(month) 
____ ____ / 
(day) 
___ ___ ___ ___ 
(year) 
Provide the date the patient was initially 
diagnosed with the malignancy submitted for 
BLGSP. This may or may not be the date of the 
surgical resection that yielded the tumor sample 
submitted for BLGSP. 
2896956 (month), 2896958 (day), 
2896960 (year) 
Note: The day of Initial Pathologic Diagnosis is 
not required. 
67 
Initial Pathologic 
Diagnosis 
Acquisition Method  
 
 Incisional Biopsy 
 Excisional Biopsy  
 Core Biopsy 
 Blood Draw 
 Bone Marrow Aspirate 
 Other (please specify) 
 Unknown 
 
Provide the method of the initial pathologic 
diagnosis. This is the method used on the date 
provided above. 
2757941 
68 
Other Method of 
Initial Pathologic 
Diagnosis 
____________________________ 
If the method of initial pathologic diagnosis is 
not included in the list above, provide the 
method used. 
2757948 
69 
Date of Tumor 
Collection 
____ ____ / 
(month) 
____ ____ / 
(day) 
___ ___ ___ ___ 
(year) 
Provide the date of the surgical resection that 
yielded the tumor sample submitted for 
BLGSP. 
3008197 (month), 3008195 (day), 
3008199 (year) 
Staging and Histology of Bone Marrow 
*70 Tumor Stage 
 
 Stage IA 
 Stage IB 
 Stage IE 
 Stage IIA 
 Stage IIB 
 Stage IIE 
 
 
 Stage IIIA 
 Stage IIIB 
 Stage IIIE 
 Stage IVA 
 Stage IVB 
 Stage IVE 
 
Using the Ann Arbor criteria, provide the stage 
that was used to treat the patient. 
2902417 
A: Absence of the Ann Arbor staging system 
symptoms including fevers, night sweats, and 
weight loss. 
B: Presence of the Ann Arbor staging system 
symptoms including fevers, night sweats, and 
weight loss. 
E: Presence of lymphoma in extranodal sites. 
71 
Presence of 
Malignant Cells in 
Bone Marrow by 
Histology 
 
 Yes 
 No 
 Unknown 
 
Indicate if malignant cells are histologically 
confirmed in the patient’s bone marrow. 
2180550 
72 
Histology of Bone 
Marrow Samples 
 Concordant Histology 
 Discordant Histology 
 Unknown 
If malignant cells are present in the bone 
marrow at the time of initial staging workup, 
determine if the histologic diagnosis of the 
bone marrow is concordant with the diagnosis 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
of BL. 
3233401 
Tests Performed 
LDH Level (at the time of staging) 
*73 LDH Level 
____________________________(IU) 
Record the result of the LDH lab test performed 
during the staging workup. 
2798766 
*74 
LDH Level Upper 
Limit for Normal at 
Facility 
____________________________(IU) 
Record the upper limit of the normal range of 
the LDH lab test performed at the reporting 
facility. 
2953115 
Genetic Testing 
75 
Immunophenotypin
g 
 
(+) 
(-) 
Indeterminate 
Indicate all tests 
performed for 
immunophenotypic 
analysis in order to 
classify clonal subgroups. 
3234614, 3234626 
Ki-67 > 90% 
 
 
 
CD10 > 30% 
 
 
 
BCL2 
 
 
 
CD20 
 
 
 
BCL6 > 30% 
 
 
 
CD3 
 
 
 
76 
Other 
Immunophenotypin
g (please specify) 
 
Indicate all tests performed for 
immunophenotypic analysis in order to classify 
clonal subgroups. 
3234626, 2516429 
77 
B-cell 
Immunophenotype 
Methodology 
 Immunohistochemistry 
 Flow Cytometry, not otherwise specified 
 Immunofluorescence 
 Other 
If B-cell genotype was performed, indicate the 
testing method used. 
64540 
Genetic Abnormalities 
78 
Genetic 
Abnormalities 
 
N 
T 
G 
A 
L 
O 
Indicate all genetic 
abnormalities for which 
the patient was tested. 
3234675, 3234680 
 
N = Normal 
T = Translocation 
G = Gain 
L = Loss 
A = Amplification 
O = Other 
C-MYC 
 
 
 
 
 
 
BCL2 
 
 
 
 
 
 
BCL6 
 
 
 
 
 
 
79 
Other Genetic 
Abnormalities  
(please specify) 
 
N 
T 
G 
A 
L 
O 
Specify any other genetic 
abnormalities not in the 
provided list for which the 
patient was tested. 
3234685, 3234680 
________ 
 
 
 
 
 
 
________ 
 
 
 
 
 
 
________ 
 
 
 
 
 
 
________ 
 
 
 
 
 
 
80 
Methodology Used 
to Identify Genetic 
Abnormalities 
 
1 
2 
3 
4 
If the patient was tested 
for a specific genetic 
abnormality, indicate the 
testing method used to 
perform each analysis. 
3234684 
C-MYC 
 
 
 
 
BCL2 
 
 
 
 
BCL6 
 
 
 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
 
Methodology Code: 
1 = PCR 
2 = Southern Blot 
3 = FISH 
4 = Cytogenetic 
81 
Methodology Used 
to Identify Other 
Genetic 
Abnormalities 
 
If the patient was tested for a specific genetic abnormality, 
indicate the testing method used to perform each analysis. 
3234684 
 
Methodology Code: 
1 = PCR 
2 = Southern Blot 
3 = FISH 
4 = Cytogenetic 
82 
EBV Status of 
Malignant Cells 
 Positive 
 Negative 
 Unknown 
Provide the result of the lab test to detect the presence of 
Epstein/Barr Virus antibody in the patient. 
2003961 
83 
If EBV status is 
positive, provide the 
percent positive. 
(does not include 
background 
positives) 
________________________(%) 
If the patient’s EBV status was positive, provide the 
percentage of EBV positive malignant cells.  Do not include 
the number of background positives. 
3233649 
84 
Methodology Used 
to Determine EBV 
Status of Malignant 
Cells 
 EBER in situ Hybridization 
 LMP Immunohistochemistry 
 EBV PCR 
 Unknown 
If the patient’s EBV status was positive, provide the testing 
method used to determine the EBV status of the malignant 
cells. 
3233656 
New Tumor Event Information Complete this section if the patient had a new tumor event.  If the patient did not have a new 
tumor event (or if the TSS does not know) indicate this in the question below, and the 
remainder of this section can be skipped. 
Note: The New Tumor Event section on OpenClinica can be completed multiple times, if the patient had multiple New Tumor 
Events. 
First Recurrence or Progression 
85* 
Has the patient 
developed a 
first relapse or 
progression 
that has not 
been 
previously 
reported? 
 Yes 
 No 
 Unknown 
Indicate whether the patient has been diagnosed 
with a first recurrence or progression. 
2002502 
86 
Date of First 
Recurrence or 
Progression 
__ __ / __ __ / __ __ __ __ 
Provide the date documenting the initial 
identification of reappearance or advancement 
in extent or severity of cancer.  
62998 
87 
Type of New 
Tumor Event 
 Locoregional Recurrence  
 Locoregional Disease 
 Distant Metastasis 
 Recurrence 
 New Primary Tumor 
Indicate whether the patient’s new tumor event 
was a locoregional recurrence, a distant 
metastasis, or a new primary tumor. 
3119721 
88 
Site of First 
Malignant 
Lymphoma 
 Adrenal  
 Appendix 
 Ascites/ Peritoneum 
 Nasal Soft 
Tissue 
 Nasopharynx 
Description of the anatomic location of 
progression of disease for malignant 
lymphoma.  


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
Progression 
 Axillary lymph nodes 
 Bone 
 Bone Marrow 
 Brain 
 Breast 
 Cervical lymph nodes 
 Colon 
 Conjunctiva 
 Epididymis 
 Epidural 
 Epitrochlear lymph nodes 
 Esophagus 
 Femoral lymph nodes 
 Gastrointestinal/ Abdominal 
 Heart 
 Hilar lymph nodes 
 Iliac-common lymph nodes 
 Iliac-external lymph nodes 
 Inguinal lymph nodes 
 Intraocular 
 Kidney 
 Large intestine 
 Larynx 
 Leptomeninges 
 Liver 
 Lung 
 Mandible 
 Maxilla 
 Mediastinal/ Intrathoracic 
 Mediastinal lymph nodes 
 Mediastinal soft tissue 
 Mesenteric lymph nodes 
 Occipital 
lymph nodes 
 Orbit 
 Oropharynx 
 Ovary 
 Pancreas 
 Paraaortic 
lymph nodes 
 Parotid 
Gland 
 Parotid 
lymph nodes 
 Peri-orbital 
Soft Tissue 
 Pericardium 
 Peripheral 
Blood 
 Pleura/ 
Pleural 
Effusion 
 Popliteal 
lymph nodes 
 Prostate 
 Rectum 
 
Retroperiton
eal lymph 
nodes 
 Salivary 
Gland 
 Sinus 
 Skin 
 Small 
Intestine 
 Soft Tissue 
(muscle, 
ligaments, 
subcutaneous
) 
 Splenic 
lymph nodes 
 Stomach 
 
Submandibul
ar lymph 
nodes 
 
Supraclavicu
lar lymph 
nodes 
 Testes 
 Thyroid 
 Uterus 
 No known 
extranodal 
3282650 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
involvement 
 Other 
Extranodal 
Site 
89 
Other Specified 
Extranodal Site 
of First 
Malignant 
Lymphoma 
Progression 
____________________________________ 
If the patient had a new tumor event and the 
site of this tumor was not included in the 
provided list, describe the site.   
3282651 
90 
Was Site of 
First 
Progression 
Biopsied? 
 Yes 
 No 
 Unknown 
If the patient has had progression of disease, 
indicate whether the site of first progression 
was biopsied. 
2716366 
*91 
If biopsied, 
what was the 
Histological 
Subtype? 
 Burkitt lymphoma, classic morphology 
 Burkitt lymphoma, atypical morphology 
 Other Histological Type, specify 
 Unknown  
Using the patient's final diagnostic pathology 
report, provide the most detailed histological 
subtype available.  
3282652 
92 
Other Specified 
Histologic 
Type 
_____________________________ 
Specify the structural pattern of malignant 
lymphoma cells at the time of biopsy for first 
progression of malignant lymphoma different 
from those already specified or mentioned. 
3282653 
Additional New Tumor Events 
*93 
Has the patient 
developed a 
second 
progression or 
relapse that has 
not been 
previously 
reported? 
 Yes 
 No 
 Unknown 
Indicate whether the patient had a second 
progression or relapse that has not been 
previously reported.  
3137510 
94 
Type of New 
Tumor Event 
 Locoregional Recurrence  
 Locoregional Disease 
 Distant Metastasis 
 Recurrence 
 New Primary Tumor 
 No new Tumor Event 
 Not applicable 
Indicate whether the patient’s new tumor event 
was a locoregional recurrence, a distant 
metastasis, or a new primary tumor. 
3119721 
*95 
Date of New 
Tumor Event 
____ ____ / 
(month) 
____ ____ / 
(day) 
__ ___ ___ __ 
(year) 
If the patient had a new tumor event, provide 
the date of diagnosis for this new tumor event. 
3104044 (month), 3104042 (day), 
3104046 (year) 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
*96 
Patient Vital 
Status 
(at date of last 
contact) 
 Alive 
 Dead 
 Lost to follow-up 
Indicate whether the patient was living or 
deceased at the date of last contact, or has been 
lost to follow-up as defined by the ACoS 
Commission on Cancer. This only includes 
cases where updated follow-up information has 
not been collected within the past 15 months 
and all efforts to contact the patient have been 
exhausted (this includes reviewing death 
records). If the patient is lost to follow-up, the 
remaining questions can be left unanswered.  
If the patient is deceased and a BLGSP follow-
up form has not yet been completed, the 
remaining applicable questions should be 
completed. 
5 
General Comments 
 
 
_____________________________________/________________________________________ 
Principal Investigator (Printed Name) 
Principal Investigator (Signature) 
  Date 
I acknowledge that the above information provided by my institution is true and correct and has been 
quality controlled. 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
23 APPENDIX H:  BLGSP Follow-Up Case Report Form  
 
 
 
 
 
 
 
 
 
 
 
 
 
Tissue Source Site (TSS): ________________________TSS Identifier: ____________ TSS Unique Patient 
Identifier: _________  
Completed By (Interviewer Name in OpenClinica): __________________________________________Completed 
Date: ___________________________________ 
Instructions: The Clinical Data needed to complete this Follow-up Form should be collected for each qualified case in 
the Burkitt Lymphoma Genome Sequencing Project (BLGSP) at 12 and 24 months after the date of patient consent. The 
Tissue Source Site (TSS) should complete this Follow-up Form within 60 days after the 12 and 24 month patient consent 
anniversary for all qualified cases indicated by the Office of Cancer Genomics (OCG). Questions regarding this form 
should be sent to Nationwide Children’s Hospital or OCG. 
Please note the following definitions for the “Unknown” and “Not Evaluated” answer options on this form. 
Unknown: This answer option should only be selected if the TSS does not know this information after all efforts to obtain the data 
have been exhausted.  If this answer option is selected for a question that is part of the BLGSP required data set, the TSS must 
complete a discrepancy note providing a reason why the answer is unknown. 
Not Evaluated: This answer option should only be selected by the TSS if it is known that the information being requested cannot be 
obtained. This could be because the test in question was never performed on the patient or the TSS knows that the information 
requested was never disclosed.  


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
# 
Data Element 
Entry Alternatives 
Working Instructions 
Patient Information 
Survival Information 
*1 
Patient Vital 
Status 
(at date of last 
contact) 
 Alive 
 Dead 
 Lost to follow-up 
Indicate whether the patient was living or deceased at 
the date of last contact, or has been lost to follow-up 
as defined by the ACoS Commission on Cancer. This 
only includes cases where updated follow-up 
information has not been collected within the past 15 
months and all efforts to contact the patient have 
been exhausted (this includes reviewing death 
records). If the patient is lost to follow-up, the 
remaining questions can be left unanswered.  
If the patient is deceased and a BLGSP follow-up 
form has not yet been completed, the remaining 
applicable questions should be completed. 
5 
*2 
Date of Last 
Contact 
____ ____ / 
(month) 
____ ____ / 
(day) 
___ ___ ___ ___ 
(year) 
If the patient is living, provide the date of last contact 
with the patient (as reported by the patient, medical 
provider, family member, or caregiver).  
2897020 (month), 2897022 (day), 2897024 
(year) 
Do not answer if patient is deceased. 
Note: The day of Last Contact is not required. 
*3 
Date Last 
Known Alive 
____ ____ / 
(month) 
____ ____ / 
(day) 
___ ___ ___ ____ 
(year) 
Indicate the last date the patient was known to be 
alive, regardless of whether the patient, medical 
provider, family member or caregiver was contacted. 
2975722 (month), 2975724 (day), 2975726 
(year) 
Note: The day of Last Known Alive is not required. 
*4 
Date of Death 
_____ _____ / 
(month) 
_____ _____ / 
(day) 
_____ _____ 
_____ _____ 
(year) 
If the patient is deceased, provide the date of death.  
2897026, (month) 2897028 (day), 2897030 
(year) 
Note: The day of Death is not required. 
Patient Status (Regarding Submitted Tumor) 
*5 
Tumor Status 
(at time of last 
contact) 
 Tumor free 
 With tumor 
 Unknown tumor status 
Indicate whether the patient was tumor/disease free 
(i.e. free of the malignancy that yielded the sample 
submitted for the BLGSP study) at the date of last 
contact or death.  
2759550 
6 
Performance 
Status: Eastern 
Cooperative 
Oncology 
Group  
(at time of last 
contact) 
 0: Fully active, able to carry on all pre-disease 
performance without restriction.   
 1:  Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work. 
 2: Ambulatory and capable of all selfcare but unable to 
carry out any work activities. Up and about more than 
50% of waking hours. 
 3: Capable of only limited selfcare, confined to bed or 
chair more than 50% of waking hours.  
 4: Completely disabled. Cannot carry on any selfcare. 
Totally confined to bed or chair. 
 Unknown 
 Not Evaluated 
Provide the Eastern Cooperative Oncology Group 
(ECOG) performance status of the patient at the time 
selected in the “timing” question below. 
88 
7 
Performance 
Status: 
Karnofsky 
Score  
(at time of last 
contact) 
 100: Normal, no complaints, no evidence of disease 
 90:  Able to carry on normal activity; minor signs or 
symptoms of disease 
 80: Normal activity with effort; some signs or symptoms 
of disease 
 70: Cares for self, unable to carry on normal activity or to 
do active work 
 60: Requires occasional assistance, but is able to care for 
most of his/her needs. 
 50: Requires considerable assistance and frequent medical 
care 
 40:  Disabled, requires special care and assistance 
Provide the Karnofsky score for the patient at the 
time selected in the “timing” question below. 
2003853 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
# 
Data Element 
Entry Alternatives 
Working Instructions 
 30: Severely disabled, hospitalization indicated. Death not 
imminent.  
 20: Very sick, hospitalization indicated. Death not 
imminent. 
 10: Moribund, fatal processes progressing rapidly 
 0: Dead 
 Unknown 
 Not Evaluated 
*8 
Measure of 
Success of 
Outcome at the 
Completion of 
this Follow-up 
Submission 
(at time of last 
contact) 
  Complete Remission/Response 
  Partial Remission/Response  
  Stable disease 
  Progressive disease 
  Persistent disease 
  Unknown 
Text term to describe the overall outcome of 
treatment up to the point of the current data 
submission. 
3104050 
 
HIV Status 
*9 
HIV antibody 
status 
 Positive 
 Negative 
 Unknown 
Indicate whether the patient is HIV positive. 
2180464 
10 
Date of HIV 
Diagnosis (if 
known) 
__ __ / __ __ / __ __ __ __  
Provide the date the patient was diagnosed with HIV. 
3579640 (month), 3579644 (day), 3579643 
(year) 
Note: The day of HIV Diagnosis is not required. 
11 
Nadir CD4 
Counts 
____________________________ (cells/mm3) 
Provide the patient’s Nadir CD4 counts, which are 
the lowest CD4 counts the patient has had. 
2684395 
Treatment 
*12 
Indication of 
Regimen 
 Initial 
 Adjuvant 
 Progression after initial 
 Recurrence 
 Palliative 
 Unknown 
Text term to identify the reason for the 
administration of a treatment regimen.  
2793511 
*13 
Lymphoma 
Treatment 
Type 
 Chemotherapy 
 Radiation 
 Radiation and Chemotherapy 
 Stem Cell Transplant 
 Surgery 
 No Treatment 
 Other Treatment 
Text term that describes the kind of treatment that 
was given for the primary lymphoma. 
3284925 
*14 
If other, 
specify 
____________________________________ 
Indicate the other treatment type for the lymphoma. 
2861111 
Chemotherapy 
15 
Chemotherapy 
Start Date 
 
__ __ / __ __ / __ __ __ __ 
 
 
Date chemotherapy started. 
2897050 (month), 2897052 (day), 2897054 (year) 
16 
Did 
chemotherapy 
end during this 
reporting 
period? 
 Yes 
 No 
 
Indicate whether chemotherapy administration ended 
during this reporting period. 
2188260 
17 
Chemotherapy 
End Date 
 
__ __ / __ __ / __ __ __ __ 
 
Date chemotherapy ended. 
2897056 (month), 2897058 (day), 2897060 (year) 
*18 
Pharmaceutical 
Regimen 
  BACOP 
  C-MOPP 
  CAP-BOP 
  CHOP + Bleomycin 
  CHOP + Etoposide 
Text term or code to represent the name of a 
pharmaceutical regimen containing two or more 
agents which are given together or separately to treat 
a patient with malignant lymphoma. 
3366758 
 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
# 
Data Element 
Entry Alternatives 
Working Instructions 
  CHOP-14 
  CHOP-14 + Rituximab 
  CHOP-21 
  CHOP-21 + Rituximab 
  CNOP 
  CODOX + Rituximab 
  CVP 
  DA-EPOCH 
  DA-EPOCH + Rituxumab 
  F-MACHOP 
  High Dose Methotrexate w/Leucovorin 
  HyperCVAD-Mtx/AraC + Rituximab 
  ICE 
  ICE + Rituxumab 
  LNH-84 
  LNH-87 
  M-BACOP 
  MACOP-B 
  ProMace-CytaBOM 
  ProMace-MOPP 
  VACOP-B 
  Vanderbilt regimen + Rituximab 
  Single Agent Therapy (please specify) 
  Other Pharmaceutical  Regimen (please specify) 
  Unknown 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
# 
Data Element 
Entry Alternatives 
Working Instructions 
19 
If Other 
Pharmaceutical 
Regimen, 
specify 
 
 
 
 
Text term or abbreviation to represent another name 
of a pharmaceutical regimen containing two or more 
agents which are given together or separately to treat 
a patient with malignant lymphoma that was not 
already mentioned or specified. 
3366930 
20 
If Single-Agent 
Therapy, 
specify 
 
 
 
Text name for agent used without other agents in a 
treatment regimen or study. 
3590022 
21 
Number of 
Cycles 
 
 
 
 
The total number of cycles administered to the 
patient of a protocol specified drug or therapy agent 
as of the current report. 
62590  
Radiation Therapy  
22 
Radiation 
Therapy Start 
Date 
 
__ __ / __ __ / __ __ __ __ 
 
Date radiation therapy started. 
2897100 (month), 2897102 (day), 2897104 (year) 
23 
Did radiation 
therapy end 
during this 
reporting 
period? 
 Yes 
 No 
 
Indicate whether radiation therapy ended during this 
reporting period. 
 
24 
Radiation 
Therapy End 
Date 
 
__ __ / __ __ / __ __ __ __ 
 
Date radiation therapy ended. 
2897106 (month), 2897108 (day), 2897110 (year) 
25 
Total Dose of 
Radiation 
Therapy 
 
__________________________ (Gy) 
A numeric value for the total dose volume of 
radiation therapy given to a patient, in Gray. 
36 
26 
Radiation 
Field, 
extranodal  
 Abdomen, total 
 Arm 
 Body, total 
 Bone, non-spine 
 Brain, focal 
 Brain, whole 
 Breast 
 Chest wall 
 Eye 
 Gastrointestinal, colon 
 Gastrointestinal, gallbladder 
 Gastrointestinal, intestine 
 Gastrointestinal, Liver 
 Gastrointestinal, NOS 
 Gastrointestinal, Pancreas 
 Gastrointestinal, Stomach 
 Genitourinary, Bladder 
 Genitourinary, Kidney 
 Genitourinary, NOS 
 Head, Face, or 
Neck 
 Leg 
 Lung 
 Lymph node, 
distant (specify site) 
 Lymph node, 
locoregional (specify 
site) 
 Lymph Nodes 
 Mantle 
 Mediastinum 
 Parametrium 
 Pelvis 
 Shoulder 
 Skin, lower 
extremity, local 
 Skin, total 
 Skin, trunk, local 
 Skin, upper 
extremity, local 
 Spine 
 Supraclavicular 
 Thorax 
 Trunk 
 
 Other 
 Unknown 
 
Text term to identify anatomically-specified areas or 
fields that are targeted for radiation therapy. 
2416537 
27 
Nodal Regions 
Targeted 
 Axillary  
 Cervical  
 Epitrochlear  
 Femoral  
Identify lymph node sites targeted for radiation 
therapy. 
3762198 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
# 
Data Element 
Entry Alternatives 
Working Instructions 
 Hilar  
 Iliac-common  
 Iliac-external  
 Inguinal  
 Mediastinal  
 Mesenteric  
 Occipital  
 Paraaortic  
 Parotid  
 Popliteal  
 Retroperitoneal  
 Splenic  
 Submandibular  
 Supraclavicular  
28 
Other, specify 
_________________________  
Specify other field of radiation 
62999 
Stem Cell Transplantation  
29 
Type of Stem 
Cell 
Transplantation 
 Autologous 
 Syngeneic/Allogeneic related donor 
 Allogeneic, unrelated donor 
Indicate the hematopoietic stem cell source type. 
2957417 
30 
Date of Stem 
Cell 
Transplantation 
__ __ / __ __ / __ __ __ __ 
Indicate the date of the hematopoietic stem cell 
transplant. 
3718671 
Surgery 
31 
Date of cancer 
debulking 
surgery 
 
__ __ / __ __ / __ __ __ __ 
Indicate the date related to the procedure of 
surgically removing as much of the tumor as possible 
being executed. 
2839523 
32 
Measure of 
Success of 
Outcome at the 
Completion of 
Initial First 
Course 
Treatment 
 Progressive Disease 
 Persistent Disease 
 Stable Disease 
 Partial Remission/ 
Response 
 Complete 
Remission/Response  
 Unknown 
 Not Applicable 
(treatment ongoing) 
Indicate the patient’s measure of success after the 
initial first course of treatment. 
2786727 
New Tumor Event Information Complete this section if the patient had a new tumor event.  If the patient did not have a new 
tumor event (or if the TSS does not know) indicate this in the question below, and the 
remainder of this section can be skipped. 
Note: The New Tumor Event section on OpenClinica can be completed multiple times, if the patient had multiple New Tumor 
Events. 
First Recurrence or Progression 
33* 
Has the patient 
developed a 
first relapse or 
progression 
that has not 
been 
previously 
reported? 
 Yes 
 No 
 Unknown 
Indicate whether the patient has been diagnosed with 
a first recurrence or progression. 
2002502 
34 
Date of First 
Recurrence or 
Progression 
__ __ / __ __ / __ __ __ __ 
Provide the date documenting the initial 
identification of reappearance or advancement in 
extent or severity of cancer.  
62998 
35 
Type of New 
Tumor Event 
 Locoregional Recurrence  
 Locoregional Disease 
 Distant Metastasis 
 Recurrence 
 New Primary Tumor 
Indicate whether the patient’s new tumor event was a 
locoregional recurrence, a distant metastasis, or a 
new primary tumor. 
3119721 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
# 
Data Element 
Entry Alternatives 
Working Instructions 
36 
Site of First 
Malignant 
Lymphoma 
Progression 
 Adrenal  
 Appendix 
 Ascites/ Peritoneum 
 Axillary lymph nodes 
 Bone 
 Bone Marrow 
 Brain 
 Breast 
 Cervical lymph nodes 
 Colon 
 Conjunctiva 
 Epididymis 
 Epidural 
 Epitrochlear lymph nodes 
 Esophagus 
 Femoral lymph nodes 
 Gastrointestinal/ 
Abdominal 
 Heart 
 Hilar lymph nodes 
 Iliac-common lymph 
nodes 
 Iliac-external lymph nodes 
 Inguinal lymph nodes 
 Intraocular 
 Kidney 
 Large intestine 
 Larynx 
 Leptomeninges 
 Liver 
 Lung 
 Mandible 
 Maxilla 
 Mediastinal/ Intrathoracic 
 Mediastinal lymph nodes 
 Mediastinal soft tissue 
 Mesenteric lymph 
nodes 
 Nasal Soft Tissue 
 Nasopharynx 
 Occipital lymph 
nodes 
 Orbit 
 Oropharynx 
 Ovary 
 Pancreas 
 Paraaortic lymph 
nodes 
 Parotid Gland 
 Parotid lymph nodes 
 Peri-orbital Soft 
Tissue 
 Pericardium 
 Peripheral Blood 
 Pleura/ Pleural 
Effusion 
 Popliteal lymph 
nodes 
 Prostate 
 Rectum 
 Retroperitoneal 
lymph nodes 
 Salivary Gland 
 Sinus 
 Skin 
 Small Intestine 
 Soft Tissue (muscle, 
ligaments, subcutaneous) 
 Splenic lymph nodes 
 Stomach 
 Submandibular 
lymph nodes 
 Supraclavicular 
lymph nodes 
 Testes 
 Thyroid 
 Uterus 
 
 No known 
extranodal involvement 
 Other Extranodal 
Site 
Description of the anatomic location of progression 
of disease for malignant lymphoma.  
3282650 
37 
Other 
Specified 
Extranodal Site 
of First 
Malignant 
Lymphoma 
Progression 
____________________________________ 
If the patient had a new tumor event and the site of 
this tumor was not included in the provided list, 
describe the site.   
3282651 
38 
Was Site of 
First 
Progression 
Biopsied? 
 Yes 
 No 
 Unknown 
If the patient has had progression of disease, indicate 
whether the site of first progression was biopsied. 
2716366 


Abbreviated Title:  DA-EPOCH-R in BL 
NCI CC Version Date:  09/20/2019 
# 
Data Element 
Entry Alternatives 
Working Instructions 
*39 
If biopsied, 
what was the 
Histological 
Subtype? 
 Burkitt lymphoma, classic morphology 
 Burkitt lymphoma, atypical morphology 
 Other Histological Type, specify 
 Unknown  
Using the patient's final diagnostic pathology report, 
provide the most detailed histological subtype 
available.  
3282652 
40 
Other 
Specified 
Histologic 
Type 
_____________________________ 
Specify the structural pattern of malignant lymphoma 
cells at the time of biopsy for first progression of 
malignant lymphoma different from those already 
specified or mentioned. 
3282653 
Additional New Tumor Events 
*41 
Has the patient 
developed a 
second 
progression or 
relapse that has 
not been 
previously 
reported? 
 Yes 
 No 
 Unknown 
Indicate whether the patient had a second progression 
or relapse that has not been previously reported.  
3137510 
42 
Type of New 
Tumor Event 
 Locoregional Recurrence  
 Locoregional Disease 
 Distant Metastasis 
 Recurrence 
 New Primary Tumor 
 No new Tumor Event 
 Not applicable 
Indicate whether the patient’s new tumor event was a 
locoregional recurrence, a distant metastasis, or a 
new primary tumor. 
3119721 
*43 
Date of New 
Tumor Event 
____ ____ / 
(month) 
____ ____ / 
(day) 
___ ___ ___ ____ 
(year) 
If the patient had a new tumor event, provide the date 
of diagnosis for this new tumor event. 
3104044 (month), 3104042 (day), 3104046 
(year) 
General Comments 
 
 
 
 
 
Principal Investigator (Printed Name) 
 
Principal Investigator (Signature) 
 
 
 
 
 
     Date 
 
I acknowledge that the above information provided by my institution is true and correct and has been quality 
controlled. 
 
 

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: 09/20/2019
Page 1 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Mark Roschewski, M.D.
STUDY TITLE: Phase II Study of Dose- Adjusted EPOCH+/-Rituximab in Adults with 
Untreated Burkitt Lymphoma, c-MYC+ Diffuse Large B-Cell Lymphoma and Plasmablastic 
Lymphoma
STUDY SITE: NIH CC
Cohort: Affected Patient
Consent Version:  09/20/2019
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator: Mark Roschewski, M.D. 
Phone:  240-760-6183
Email:  mark.roschewski@nih.gov
    
Study Coordinator: A. Nicole Lucas, R.N.
Phone:  240-760-6252
Email:  andrea.lucas@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 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 an aggressive B-cell lymphoma. 
The purpose of this study is to compare the good and/or bad effects of an experimental approach 
IRB NUMBER: 10C0052
IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/20/2019
Page 2 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
to treating your disease and to analyze your tumor using new scientific laboratory studies. Many 
of the standard treatments for Burkitt lymphoma can cause severe side effects that may require 
long stays in the hospital. Our experience using this treatment, Dose-Adjusted EPOCH +/- 
Rituximab (DA-EPOCH-R) has been that it has not been associated with the same severity of 
side effects or long durations in the hospital. In addition, studies so far using DA-EPOCH-R in 
patients with your disease appear to be promising. We hope to confirm these very good results in 
this study. 
Before being enrolled in the study, you will undergo a series of tests to determine if you are 
eligible for the study and to determine the extent (called stage) of your lymphoma.  It is likely 
that you will be asked to undergo another biopsy of your tumor to obtain fresh tissue to help us 
gain a better understanding of this disease. If you are found not to be eligible for the study, you 
will be referred back to your home physician. If you are eligible and agree to participate, you 
will receive DA-EPOCH-R chemotherapy, an experimental treatment for lymphomas developed 
over the last 14 years. If you have plasmablastic lymphoma, you will receive DA-EPOCH 
without the rituximab. In addition, your tumor will be analyzed using new scientific laboratory 
studies to better understand how to develop even more effective treatments.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
A total of 194 people will be enrolled in this study.
DESCRIPTION OF RESEARCH STUDY
What will happen if you take part in this research study?  
Based on the disease that you have and the tests that are performed before you start treatment, 
your doctor will determine if you have “high risk” or “low risk” disease.
High risk disease 
If you have “high risk” disease 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 the large 
vein in your arm or in your chest. Participants will receive DA-EPOCH-R chemotherapy which 
consists of the following drugs: etoposide (E), prednisone (P), vincristine (O), cyclophosphamide 
(C), doxorubicin (H), and rituximab (R). If you have plasmablastic lymphoma, you will not receive 
the rituximab. 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 each cycle depending on your white blood cell 
count (WBC) and/or platelet count. At the beginning of each cycle, your doctors will evaluate how 
low your WBC and platelets went during the previous cycle and decide if your doses of 
doxorubicin, etoposide, and/or cyclophosphamide need to be adjusted.  The DA-EPOCH-R 
therapy will be repeated every twenty-one (21) days, which is known as a “cycle” of therapy. Most 
IRB NUMBER: 10C0052
IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/20/2019
Page 3 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
people will receive a total of 6 cycles (18 weeks) of treatment. It is possible you will receive a total 
of 8 cycles (24 weeks) of treatment if the study doctor believes it is in your best interest. A PET 
scan will be performed after you have finished cycle 2.  If the PET scan shows residual disease, 
you will have another PET scan repeated after you have completed cycle 6 or 8.
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.
You may receive other drugs as needed to prevent or treat problems during your treatment. If this 
becomes necessary, your study doctor will explain the drug, its actions and side effects.
If you have high risk disease, you are at high risk of your lymphoma spreading into your central 
nervous system (CNS). To reduce the risk of the lymphoma spreading to your CNS, you will also 
receive eight doses of a drug known as methotrexate injected into the spinal fluid. You will 
receive this treatment on Days 1 and 5 of cycles 3-6 of therapy.
Your lymphoma may have already spread to the CNS, which includes the brain and spinal cord.  
If so, it will be necessary to treat the CNS with chemotherapy which usually includes the 
instillation of chemotherapy drugs (methotrexate and/or 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.  If this applies, you will receive 
this treatment for approximately 8 months and your study doctor or study nurse will explain the 
schedule to you before beginning the treatment.
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** 
IRB NUMBER: 10C0052
IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/20/2019
Page 4 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
* 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. You and/or your caregiver will be taught how to give the Filgrastim 
injections.
Low risk disease 
If you have “low risk” disease (your risk category will be determined by the treating doctor) you 
will receive 3 cycles (9 weeks) of Dose-Adjusted EPOCH + 2 doses of Rituximab (DA-EPOCH-
RR) (two doses of rituximab per cycle). The additional dose of rituximab is given on day 5 of 
each cycle. The DA-EPOCH-RR will be given by intravenous (IV) infusion through a “central 
line,” an IV catheter (or tube) placed in the large vein in your arm or in your chest. Participants 
will receive DA EPOCH-RR chemotherapy which consists of 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). The second dose of rituximab is given again (over several hours) after the 96 
hour infusion ends. Cyclophosphamide will be given by IV infusion on Day 5 after you have 
completed the second rituximab infusion. 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 
each cycle depending on your white blood cell count (WBC) and/or platelet count. At the 
beginning of each cycle, your doctors will evaluate how low your WBC and platelets went 
during the previous cycle and decide if your doses of doxorubicin, etoposide, and/or 
cyclophosphamide need to be adjusted.  The DA-EPOCH-RR therapy will be repeated every 
twenty-one (21) days, which is known as a “cycle” of therapy.
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.
You may receive other drugs as needed to prevent or treat problems during your treatment. If this 
becomes necessary, your study doctor will explain the drug, its actions and side effects.
If you have “low risk’ disease, you will not receive methotrexate injected into the spinal fluid. As 
a safety measure, a PET scan will be performed after you have completed cycle 2. If the PET 
scan shows that you still have lymphoma, you will receive 4 additional cycles of DA-EPOCH-R 
(same treatment as the high risk group), and the PET scan will be repeated after you have 
completed cycle 6.
IRB NUMBER: 10C0052
IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/20/2019
Page 5 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Day of Treatment
1
2
3
4
5
6
7
8
9
10
11
12
13
…
21*
Rituximab
X
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 3 cycles. As described above, during the course of treatment, you 
may also receive the following drugs: Bactrim, omeprazole, and colace.
**Filgrastim will continue to be given to you until your blood counts have reached 
acceptable levels. You and/or your caregiver will be taught how to give the Filgrastim 
injections.
Research tests  
Research studies will be performed on your blood, tumor tissue or other fluids to look at 
different genes and proteins that may be involved in the development of your lymphoma or the 
reaction of the immune system. The blood samples are collected in the beginning of the study 
and at the following time points while you are involved in the study: before Cycle 3, after Cycle 
3 for Low Risk patients, after Cycle 6 (and after Cycle 8 if you receive 8 cycles) and on every 
scheduled follow-up visit.
We will not examine your tissue for anything that could have implications for an inherited gene 
mutation that would affect you and your family without first obtaining additional permission 
from you.  It may be necessary to perform another biopsy of your tumor to perform important 
scientific research studies to better understand the biology of aggressive lymphoma, that is, how 
your type of lymphoma behaves. The special research studies done on this tissue will not be used 
to make any medical decisions, and the results of these tests will not be given to you. 
OPTIONAL BIOPSY 
We plan to do a tissue biopsy to learn more about your disease before you start treatment. Repeat 
biopsies requiring major surgery (e.g., in the chest or the abdomen) will not be performed for 
research purposes alone but only if absolutely necessary for your medical care.  
The biopsy to be performed is exclusively for research purposes and will not benefit you.  It 
might help other people in the future.  Even if you sign "yes" to have the biopsy you can change 
your mind at any time.  Please read each sentence below and think about your choice. After 
reading each sentence, circle and initial the answer that is right for you. The decision to 
participate in this part of the research is optional, and no matter what you decide to do, it will not 
affect your care. 
IRB NUMBER: 10C0052
IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/20/2019
Page 6 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
I agree to have the tumor biopsy for the research tests in this study. 
Yes              No               Initials_________
What happens after treatment is completed?
This depends on how you have responded to the therapy.  If all evidence of disease has 
disappeared, you will be asked to return to the clinic about 30 days after the last treatment to assess 
your symptoms and any side effects (this may be done by phone if you cannot return to clinic), 
and then for follow-up exams every four (4) months for the first 2 years after completion of 
therapy.
If you have Burkitt lymphoma and your scans are negative at the two year post-treatment visit, 
you will return for one more visit at year 3. At these yearly follow up visits, you will undergo a 
physical examination and laboratory testing. You will not undergo a CT scan unless your study 
doctor determines it is clinically indicated.
If you have DLBCL or plasmablastic lymphoma and your scans are negative at the two year post-
treatment visit you will return yearly. At these yearly follow up visits, you will undergo a physical 
examination, laboratory testing and a CT scan for up to 3 years post treatment. 
If the disease does not disappear entirely or if it should recur after having disappeared for a period 
of time, then you may need further therapy.  At that time you will be given the opportunity to 
participate in additional research protocols that may be appropriate for you.  If no such protocols 
are available, you will be returned to the care of your local physician.
RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study?
In order to determine whether this study is suitable for you, a number of tests will have to be done.   
Some or all of these tests will be repeated during and after the chemotherapy at different times.  
Depending on the tests you had before coming here, these may include blood and urine tests, CAT 
or MRI scans, PET scans, and biopsies of tumor tissue, bone marrow, liver, or other sites.  Biopsies 
will, when possible, be done under local anesthesia.  The risks associated with bone marrow or 
any other biopsies include pain, bleeding, and local infection.  General anesthesia itself is generally 
very safe but has a very small risk of major complications such as heart attack or stroke.  The 
surgical and anesthetic risks will be explained to you in more detail at the time of surgery, if this 
is needed.    
In order to receive this therapy you will need to have an intravenous catheter placed. This catheter 
is usually placed in the arm, chest or neck area into a major vein inside your chest.  We usually 
remove the catheter after each cycle but on occasion it can be left in for several cycles.  The catheter 
is necessary for infusion of chemotherapy and for the drawing of blood.  It is usually inserted under 
local anesthesia.  The risks associated with the procedure include pain, bleeding, infection, and 
puncture of the underlying lung.  Lung puncture can result in lung collapse, which might require 
that a chest tube be placed into the chest cavity (usually for a day or two) to help the lung reinflate.  
The long-term risks of the catheter include infection and clotting of the vein in which the catheter 
IRB NUMBER: 10C0052
IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/20/2019
Page 7 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
sits.  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 the 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 side effects that you have while taking part in the study.
Risks and side effects related to the treatment are identified below.
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.

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.
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
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.

A tear in the large or small bowel 

Bladder irritation with painful and bloody urine.

Damage to the heart muscle.

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.
Secondary Malignancy 
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.   
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File in Section 4: Protocol Consent (1)
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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, you will need to practice an effective form of birth control before 
starting study treatment, during study treatment, and for 12months after you finish study treatment. 
If you are male and the partner of a woman who can become pregnant, you and your partner will 
need to practice an effective form of birth control before starting study treatment, during study 
treatment, and for 12 months after you finish study treatment. If you think that you or your partner 
is pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include:
•
abstinence 
•
intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
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 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.
Complications of treatment to the Central Nervous System
Complications of Ommaya insertion are uncommon when done by an experienced physician 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 is necessary for you, the complications of the lumbar puncture or 
Ommaya insertion and chemotherapy instillation will be discussed in more detail.  
Drugs used for the treatment of the Central Nervous System

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.  Rarely, 
it can cause seizures and coma.  
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IRB APPROVAL DATE: 12/03/2019


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File in Section 4: Protocol Consent (1)
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•
Cytarabine given by lumbar puncture can cause nausea, vomiting, fever, and headaches.  
Rarely, it can cause weakness and seizures.  
Psychological or Social Risks Associated with Loss of Privacy:  
The following general points are indirectly related to your participation in the research study.
1. Unanticipated medical information: During the course of this investigation, it is possible 
(although not likely) that we will obtain unanticipated information about your health or 
genetic background.  
2. Release of genetic information:

Your privacy is very important to us, and we use many safety measures to protect your 
privacy. However, despite all of the safety measures that we will use, we cannot 
guarantee that your identity will never become known. Although your genetic 
information is unique to you, you do share some genetic information with your 
children, parents, brothers, sisters, and other relatives. Consequently, it may be possible 
that genetic information from them could be used to help identify you. Similarly, it may 
be possible that genetic information from you could be used to help identify them.

Patterns of genetic variation also can be used by law enforcement agencies to identify 
a person or his/her blood relatives. Therefore, your genetic information potentially 
could be used in ways that could cause you or your family distress, such as by revealing 
that you (or a blood relative) carry a genetic disease.

There also may be other privacy risks that we have not foreseen. 
Since some genetic variations can help to predict future health problems for you and your relatives, 
this information might be of interest to health care providers, life insurance companies, and others.  
However, Federal and State laws provide some protections against discrimination based on genetic 
information. For example, the Genetic Information Nondiscrimination Act (GINA) makes it illegal 
for health insurance companies, group health plans, and most employers to discriminate against 
you based on your genetic information. However, GINA does not prevent companies that sell life 
insurance, disability insurance, or long-term care insurance from using genetic information as a 
reason to deny coverage or set premiums. GINA also does not apply to members of the United 
States military, individuals covered by the Indian Health Service, or veterans obtaining health care 
through the Veteran’s Administration. Lastly, GINA does not forbid insurance medical 
underwriting based on your current health status though the Affordable Care Act limits 
consideration of pre-existing conditions by insurers. 
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study?
Most patients will have tumor shrinkage with chemotherapy. It is possible that you may not 
respond to any of this treatment. Taking part in this study may or may not make your health better. 
We do know that the information from this study will help doctors learn more about DA-EPOCH-R 
as a treatment for aggressive lymphoma. This information could help future patients diagnosed 
with lymphoma.
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IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
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File in Section 4: Protocol Consent (1)
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The possible benefits of taking part in the study are the same as receiving the drugs used in this 
study without being in the study.
RELATED RESEARCH STUDIES – BLGSP
Please note: The following section of the informed consent document is about an additional 
research study that is being done with people who are taking part in the main study. You may take 
part in this additional study if you want to. You can still be part of the main study even if you say 
“no” to taking part in this additional study.
The results of these research studies will not be provided to you or your doctor, nor will the results 
have any effect on your treatment. It is unlikely that what we learn from these studies will have a 
direct benefit to you. However, the information learned from these studies may benefit other 
patients in the future. 
The results from these studies may be published, but individual patients will not be identified in 
these publications.
There will be no charge to you for participating in these research studies. Your samples will only 
be used for research and will not be sold. The research done with your sample may help to develop 
new products in the future.
The greatest risk to you is the release of information from your health records. We will do our best 
to make sure that your personal information will be kept private. The chance that this information 
will be given to someone is very small.
You will be asked to mark your choice by saying “yes” or “no” to several questions later in this 
consent form.
Purpose of the project
The purpose of this extra project, Burkitt Lymphoma Genome Sequencing Project (BLGSP) is 
to discover genetic changes associated with cancer, thus potentially leading to better prevention, 
detection and treatment of cancer, and perhaps other diseases as well. Body tissues are made up of 
cells containing DNA, which is part of the unique genetic material carrying the instructions for 
your body’s development and function. Cancer can result from changes in this genetic material, 
thereby causing cells to divide in an uncontrolled way and possibly to travel to other organs. Some 
of the genetic changes leading to cancer are currently known, however many remain to be 
discovered.
The BLGSP is designed to identify genetic changes that can cause cancer in humans. As such, we 
would like to study the genetic material obtained from your tumor tissue as part of this project. We 
will compare the genetic material from your cancerous tissue with the genetic material from your 
normal tissue to find any differences that may exist. By combining information about genetic 
differences between normal and disease tissues along with information contained in your medical 
records, it may be possible to identify the genetic changes that are associated with your particular 
type of cancer. This same process will be performed with normal and cancerous tissues obtained 
from a number of other people who have agreed to participate in this research project. In this way, 
we expect to identify most of the genetic changes associated with many different kinds of cancer. 
By comparing treatment responses of patients with various cancers (through recorded medical 
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information), this project could also lead to more knowledge about why certain cancers respond 
differently to treatments. With such knowledge, future treatment options could potentially become 
customized to a patient’s unique genetic make-up.
Collection of Samples and Medical Information
Your scheduled surgery (or surgery you already had) is/was part of the medical treatment that you 
agreed upon with your doctor. During surgery, cancerous tissue will be removed. Usually, when 
cancerous tissue is removed, very small amounts of nearby normal tissue are removed as well. 
Your surgery is not part of the BLGSP research project. We will receive some of these cancerous 
and normal tissues following your surgery. 
We will collect a sample of blood (approximately 4 tablespoons), drawn from a vein in your arm, 
as a second type of normal tissue. 
Should you object to having blood drawn, we will instead swab cells from inside of your mouth 
through gentle sweeping of the inner cheeks to obtain a secondary source of normal tissue. 
We will also collect information from your medical records, including your age, ethnic 
background, diagnosis, disease history, medical treatments, and response to treatments. 
Coding of Tissue Samples and Medical Information
Your tissues, blood or buccal (cheek swab) sample, and medical information will be labeled with 
a confidential project-assigned ID. 
Only Dr. Roschewski at the National Cancer Institute and your main study doctor at your local 
hospital will have the information that matches the code to traditionally-used identifying 
information, such as your name, address, phone number, or social security number. Dr. 
Roschewski and your main study doctor will keep the information that matches the confidential 
code to this identifying information in a safeguarded database. Only authorized personnel, who 
have specifically agreed to protect your identity, will have access to this database. All materials 
conveyed to the BLGSP will be labeled with a project-assigned ID, removing traditionally-used 
identifying information, such as your name, address, phone number, or social security number. All 
other researchers and personnel, including those who will be working with your samples and 
medical information, will not have access to any of the traditionally-used identifying information 
about you. 
Storage and Release of Samples and Medical Information
Your coded tissue samples will be sent to a National Cancer Institute (NCI)-sponsored storage 
facility. The facility will process the samples and then send portions of your samples to different 
types of laboratories for analysis as part of this project. One type of laboratory will analyze your 
DNA by a method called sequencing. Other laboratories will study your samples by different 
methods. The remaining tissue from your samples might be stored for an unlimited period of time 
for use in future research related to cancer, or perhaps in other research projects. 
Information obtained from analyses performed on your coded samples and medical information 
will be entered into Internet-accessible databases along with information acquired from the other 
research participants in this project. Anonymous information from the analyses, which is nearly 
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impossible to trace to any individual patient, will be available to anyone in a completely public 
Internet database. 
Information obtained from more detailed analyses, along with your confidential coded medical 
information, will be put into a controlled-access database. The information in this database will be 
available only to researchers who have received approval from an NIH Data Access Committee. 
In gaining access to such information, researchers have to agree to use the data only for research 
projects and not to ever try to use it in order to identify the donor of the material. However, despite 
all of the safety measures that we will use, we cannot guarantee that your identity will never 
become known. 
Please note that traditionally-used identifying information about you, such as your name, address, 
telephone number, or social security number, will NOT be put into either the public or controlled-
access databases for this project.
Recontact
In the future, we may want to obtain additional samples or follow-up information about your health 
or medical care. Should this be needed, a person from the NCI will contact you with an explanation 
of the reasons for any follow-up and to ask whether you would be interested in participating in this 
additional research. 
Financial Compensation/Costs
You will not be paid to participate in this project. Your tissue samples and your medical 
information will be used for research purposes only and will not be sold. It is possible that some 
of the research conducted using your tissue samples or medical information will eventually lead 
to the development of new diagnostic tests, drugs or other commercial products. Should this occur, 
you will not receive any part of the profits generated from such products. 
You will not incur any expenses from participating in this project
Potential Benefits of Participating in the Project
You should not expect to personally benefit from this research, aside from the knowledge that your 
participation will help researchers and health professionals around the world to better understand 
the causes of cancer and other diseases. Research projects such as this lead to better ways to 
prevent, detect, treat, and cure such illnesses.
Potential Risks of Participating in the Project
Physical Risks:  

There are very few physical risks associated with this project. Possible side effects from 
drawing the blood sample include mild pain, bleeding, bruising, and infection at the site of 
the needle insertion. Fainting or light-headedness can sometimes occur, but usually lasts 
only a few minutes. Every precaution will be taken to minimize these effects. 
Psychological or Social Risks Associated with Loss of Privacy:  
Your privacy is very important to us, and we use many safety measures to protect your privacy. 
However, despite all of the safety measures that we will use, we cannot guarantee that your identity 
will never become known. Although your genetic information is unique to you, you do share some 
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IRB APPROVAL DATE: 12/03/2019


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Consent to Participate in a Clinical Research Study
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genetic information with your children, parents, brothers, sisters, and other relatives. 
Consequently, it may be possible that genetic information from them could be used to help identify 
you. Similarly, it may be possible that genetic information from you could be used to help identify 
them.
While neither the public nor the controlled-access databases developed for this project will contain 
information that is traditionally used to identify you (your name, address, telephone number, or 
social security number), technology may be developed in the future that would allow someone to 
link your genetic or medical information in our databases back to you. For example, someone 
could compare information in our databases with information from you (or a relative) in another 
database and be able to identify you (or your relative). It is also possible that there could be 
violations to the security of the computer systems used to store the codes linking your genetic and 
medical information back to you. Because some genetic variations can help to predict the current 
or future health problems of you and your relatives, this information may be of interest to 
employers, health providers, insurance companies, and others. Patterns of genetic variation also 
can be used by law enforcement agencies to identify a person or his/her relatives. Therefore, your 
genetic information could potentially be used in ways that could cause you or your family distress, 
such as by revealing that you (or a relative) carry a genetic disease or by leading to the denial of 
employment or insurance for you (or a relative). 
There also may be other privacy risks that we have not foreseen. 
While we believe that the risks to you and your family are very low, we are unable to tell you 
exactly what all of the risks are. There are some state laws that protect against genetic 
discrimination by employers or insurance companies, but there is currently no federal law that 
prohibits such discrimination. We believe that the benefits of learning more about cancer and other 
diseases outweigh these potential risks.
Confidentiality 
We will make every attempt to protect your confidentiality and to ensure that your personal identity 
remains anonymous. This signed consent form will be stored in a locked file that will be accessible 
only to authorized people involved with this project. We will carefully follow the coding, storage, 
and release plan explained in the Description of the Research section of this document.
Certificate of Confidentiality 
This study has received a Certificate of Confidentiality which helps to protect your research 
information. The researchers involved in this study cannot be forced to disclose the identity or any 
information collected in this study in any legal proceedings at the federal, state, or local level, 
regardless of whether they are criminal, administrative, or legislative proceedings. However, you 
or the researcher may choose to voluntarily disclose the protected information under certain 
circumstances. For example, if you request the release of information in writing, the Certificate 
does not protect against that voluntary disclosure. Furthermore, federal agencies may review your 
records under limited circumstances, such as a DHHS request for information for an audit or 
program evaluation or an FDA request under the Food, Drug and Cosmetics Act. The Certificate 
of Confidentiality will not protect against the required reporting by hospital staff of information 
on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self 
or others.
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Consent to Participate in a Clinical Research Study
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Project Results 
Your individual results from this research project will not be given back to you or put into your 
medical records. If research from this project is published in professional journals, there will be 
no traditionally-used identifying information, such as your name, address, telephone number, or 
social security number, included in the publications. Some publications from this project will be 
found at the BLGSP website. 
Alternatives to Participating in the Project 
The alternative option is not to participate in the BLGSP which is an optional part of your main 
study.
Voluntary Participation 
The choice to participate in the BLGSP by donating your tissues and medical information is 
completely up to you. No matter what you decide, your decision will not affect your medical 
care.
Withdrawal from the Project 
Once your coded samples have been distributed to the participating research laboratories and 
centers, and your information transferred to the appropriate databases, you will not be able to 
withdraw your information from this research project. However, you may be able to request the 
return or destruction of the tissue samples if you so desire.
Contact Information 
If you have any questions about the project or your participation, please contact your main study 
doctor or Dr. Roschewski and 240-760-6183.
Agreeing to Participate in the Project 
You have the right to receive the planned therapy on this study without participating in the optional 
BLGSP research study. Please read the sentence below and think about your choice. After reading 
the sentence, please mark your choice, sign your name, and provide the current date. No matter 
what you decide to do, it will not affect your care.
To participate in this research, you must agree to ALL of the following statements: 
I voluntarily agree to donate cancerous tissue and normal tissue to be used for this and for other 
research projects. 
I agree to release information from my medical records for this and for other research projects. 
I agree to have my coded genetic information and coded medical information placed into Internet-
accessible databases as described in the Storage and Release of Samples and Medical Information 
section of this document. 
I understand that my coded genetic information and coded medical information contained in the 
Internet-accessible databases will be used in this and in other research projects. 
I understand that there is a risk that someone in the future may be able to use information in these 
databases to identify me or possibly my relative(s). 
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PATIENT IDENTIFICATION
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I agree to be contacted in the future about my willingness to provide additional samples or follow-
up information about my health or medical care if it is required. 
Please sign your name here if you agree to the six statements listed above. 
Your signature: ________________________________________________________ 
Date: ________________________________
INCIDENTAL MEDICAL FINDINGS
When we are examining these pieces of your DNA, it is possible that we could identify possible 
changes in other parts of your DNA that are not related to this research.  These are known as 
“incidental medical findings”. 
These include: 

Changes in genes that are related to diseases other than cancer 

Changes in genes that are not known to cause any disease. These are known as normal 
variations. 

Changes in genes that are new and of uncertain clinical importance. This means that we do 
not know if they could cause or contribute to a disease or if they are normal variations. 
However, the analyses that we perform in our laboratory are for research purposes only; they are 
not nearly as sensitive as the tests that are performed in a laboratory that is certified to perform 
genetic testing. Changes that we observe unrelated to our research may or may not be valid.  
Therefore, we do not plan to inform you of the results of testing on your tissue and blood that is 
performed in our research lab.  However, in the unlikely event that we discover a finding during 
the course of this study that could be clinically relevant, we will contact you if you agree.  This 
could be many years in the future.  We will ask you to have an additional tube of blood drawn to 
verify the findings we have seen in our lab.  If the results are verified, you will be re-contacted and 
offered a referral to a genetic healthcare provider.    
______ I DO NOT want to be recontacted if incidental findings with potential health implications 
are discovered. 
______ I DO want to be recontacted if incidental findings with potential health implications are 
discovered. (You will be given a choice to learn or not learn about a genetic change that we find.)
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. Getting treatment or care for your lymphoma without being in a study. For example, such 
treatment may include the same or other commonly-used chemotherapy drugs. 
2.
Participating in another research study.
3. Treatment with single drugs.  This may produce very brief responses but has no beneficial 
effect in long-term control of the disease.
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4. Radiation (X-ray) treatments.  This can stop tumor growth in particular locations, such as bone, 
abdomen, and other sites but is not successful in controlling the disease overall. 
5. Surgery.  As with radiation, surgery can be successful in removing tumor from particular 
locations but cannot be used successfully to remove all lymphoma cells from the body, since 
the disease is almost always present in multiple locations.  Also, surgery cannot be used against 
tumor in some of the organs most commonly involved by lymphoma, such as the liver or the 
lungs.
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
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.  
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We plan to keep some of your specimens and data that we collect and 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 
purposes. 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 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.  
We may share your specimens and data with other researchers. They may be doing research in areas 
similar to this research or in other unrelated areas. These researchers may be at NIH, other research 
centers and institutions, or industry sponsors of research. 
We may put your research data in a large database for broad sharing with the research community. 
These databases are commonly called data repositories. These data repositories might or might not be 
located at the NIH. The information in this database could include but is not limited to genetic 
information, ethnicity and sex. If your individual research data is placed in one of these repositories, 
it will not be labeled with your name or other information that could be used to easily identify you, 
and only qualified researchers will be able to look at your data. These researchers must receive prior 
approval from individuals or committees to access the data. 
Your summary genomic data is being placed in an unrestricted database, so researchers will be able to 
access summary information about all the participants included in the study (including you), or 
summary information combined from multiple studies, without applying for permission. The risk of 
anyone identifying you with this information is very low.
In addition to the use and sharing of your specimens and data described above, we might remove any 
information from your specimens and data that can identify you such as name, address, or medical 
record number, and then use the specimens and data for additional research studies at the NIH or other 
places. If we do this, we might not contact you to ask your permission or otherwise inform you.
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.
How Long Will Your Specimens and Data be Stored by the NIH?
Your specimens and data may be stored by the NIH indefinitely.
Risks of Storage and Sharing of Specimens and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
IRB NUMBER: 10C0052
IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/20/2019
Page 19 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
You will not receive compensation for participation in this 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 performed outside the NIH Clinical Center, 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 NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
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
The study Sponsor, the Cancer Trials Support Unit (CTSU), a service sponsored by the 
National Cancer Institute (NCI) to provide greater access to cancer trials.
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 
IRB NUMBER: 10C0052
IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/20/2019
Page 20 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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. 
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.
IRB NUMBER: 10C0052
IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/20/2019
Page 21 of 22
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
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.
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, Mark 
Roschewski, M.D. at 240-760-6183 or mark.roschewski@nih.gov.  Other researchers you may 
call are: Nicole Lucas, at 240-760-6252. 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: 10C0052
IRB APPROVAL DATE: 12/03/2019


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 09/20/2019
Page 22 of 22
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
Investigator:
Signature of Investigator
Print Name of Investigator
Date
IRB NUMBER: 10C0052
IRB APPROVAL DATE: 12/03/2019