A Pilot Study of Rituximab (RTX) and Third Party Latent Membrane Protein (LMP)-Specific Cytotoxic T-Lymphocytes (LMP-TC) in Pediatric Solid Organ Recipients (SOT) With EBV-Positive CD20-Positive Post-Transplant Lymphoproliferative Disease (PTLD)
Phase: PHASE2
Conditions: EBV-Related Post-Transplant Lymphoproliferative Disorder, Monomorphic Post-Transplant Lymphoproliferative Disorder, Polymorphic Post-Transplant Lymphoproliferative Disorder, Recurrent Monomorphic Post-Transplant Lymphoproliferative Disorder, Recurrent Polymorphic Post-Transplant Lymphoproliferative Disorder, Refractory Monomorphic Post-Transplant Lymphoproliferative Disorder, Refractory Polymorphic Post-Transplant Lymphoproliferative Disorder
Sponsor: Children's Oncology Group

 
 
 
ANHL1522 
 
Version date: 03-23-2020 
 
Page 1 
LE PAGE 
 
Activated: 
03/06/2017 
Version Date: 
03-23-2020 
Closed: 
12/21/2020
 
Amendment #: 
6 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
ANHL1522 
 
A Pilot Study of Rituximab (RTX) and Third Party Latent Membrane Protein (LMP)-specific 
Cytotoxic T-Lymphocytes (LMP-TC, 
) in Pediatric Solid Organ Recipients (SOT) 
with EBV-Positive CD20-Positive Post-Transplant Lymphoproliferative Disease (PTLD) 
 
 
 
Phase 2 Study  
Limited to U.S. and Canada COG-accredited BMT Programs 
 
CETI at CNMC Supplied Agent:  
LMP-specific T cells (LMP-TC, 
, NSC# 782666)  
IND sponsor for LMP-specific T cells: COG 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY 
OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO 
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH MEANS A 
SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO 
DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED 
BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY 
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE 
INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  THE PROCEDURES IN 
THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, 
AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL 
CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST 
LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
  
 
   
  
 

 
 
 
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CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
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. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave. Please see 
the Data Submission 
Schedule in the CRF 
packet for further 
instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded from 
the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Access to 
the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity 
and Access Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM 
username and password. 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.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
 
 

 
 
 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
TABLE OF CONTENTS 
3 
STUDY COMMITTEE 
6 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA: COHORT A (UNTREATED NEWLY DIAGNOSED 
PATIENTS) AND COHORT B (RELAPSED PATIENTS) 
10 
EXPERIMENTAL DESIGN SCHEMA: COHORT C (REFRACTORY PATIENTS) 
11 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
12 
1.1 
Primary Aim 
12 
1.2 
Secondary Aims 
12 
1.3 
Exploratory Aims 
12 
2.0 
BACKGROUND 
13 
2.1 
Introduction 
13 
2.2 
Rationale for Development 
13 
2.3 
PTLD after SOT 
14 
2.4 
Previous Studies in PTLD 
16 
2.5 
EBV-specific T-Lymphocytes 
17 
2.6 
EBV-specific T cells and Immune Reconstitution 
22 
2.7 
EBV Viremia, Disease Activity and EBV-specific T cells 
23 
2.8 
Correlative Biology Studies 
23 
2.9 
Future Development of Third Party LMP-specific T cells 
24 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
25 
3.1 
Study Enrollment 
25 
3.2 
Patient Eligibility Criteria 
28 
4.0 
TREATMENT PROGRAM 
32 
4.1 
Overview of Treatment Plan 
32 
4.2 
COHORT A & B: Induction-Rituximab (RTX1) for Untreated Newly Diagnosed 
or Relapsed Patients 
35 
4.3 
Arm RTX: Course 2 of Rituximab (RTX2) 
38 
4.4 
Arm LMP-TC: Course LMP-TC1 
41 
4.5 
Arm LMP-TC: Course LMP-TC2 
45 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
49 
5.1 
Modifications Due to Hepatitis B or C Infection 
49 
5.2 
Management of Rituximab (or biosimilar) Infusion-related reactions 
49 
5.3 
Management of LMP-specific T Cells Infusion-related Reactions 
49 
6.0 
AGENT INFORMATION 
50 
6.1 
ALLOGENEIC 
LATENT 
MEMBRANE 
PROTEIN 
SPECIFIC 
T-
LYMPHOCYTES 
50 
6.2 
RITUXIMAB, RITUXIMAB-ABBS 
54 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
57 
7.1 
End of Therapy & Follow-up 
57 

 
 
 
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7.2 
Biology Research Studies 
58 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
59 
8.1 
Criteria for Removal from Protocol Therapy 
59 
8.2 
Off Study Criteria 
59 
9.0 
STATISTICAL CONSIDERATIONS 
60 
9.1 
Sample Size and Study Duration 
60 
9.2 
Study Design 
61 
9.3 
Methods of Analysis 
61 
9.4 
Evaluability for Response 
64 
9.5 
Evaluability for Toxicity 
64 
9.6 
Gender and Minority Accrual Estimates 
64 
9.7 
Correlative Studies 
65 
10.0 
EVALUATION CRITERIA 
66 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
66 
10.2 
Response Criteria 
66 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
71 
11.1 
Purpose 
71 
11.2 
Determination of Reporting Requirements 
71 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
71 
11.4 
Specific Examples for Expedited Reporting 
72 
11.5 
Reporting Requirements for Specialized AEs 
74 
11.6 
Exceptions to Expedited Reporting 
75 
11.7 
Reporting Requirements - Investigator Responsibility 
75 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
75 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
76 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
77 
11.11 Reporting of Adverse Events for Commercial Agents – CTEP-AERS Abbreviated 
Pathway 
77 
11.12 Routine Adverse Event Reporting 
78 
12.0 
STUDY REPORTING AND MONITORING 
79 
12.1 
CDUS 
79 
12.2 
Data and Safety Monitoring Committee 
79 
13.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
80 
13.1 
Pathology Goals 
80 
13.2 
Requirements for Handling Tissue or Cytology Specimens at Primary 
Institutions 
80 
13.3 
Immunophenotyping Recommendations for Primary Institutions 
80 
13.4 
Morphology 
80 
13.5 
Study Pathologist 
80 
14.0 
SPECIMENS TO SUBMIT FOR CENTRAL PATHOLOGY REVIEW 
82 
14.1 
List of Specimen Types 
82 
14.2 
Pathology Reports and Transmittal Form 
82 
14.3 
Submission of Pathology Review Materials 
82 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
83 

 
 
 
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15.1 
Table of Specimens 
83 
15.2 Blood Sample Collection 
83 
15.3 
Blood Specimen Shipping 
84 
15.4 
Rationale and Methods for Biology Aims 
85 
15.5 
Specimen Disposition 
85 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
86 
16.1 
Computed Tomography (CT) with Contrast 
86 
16.2 
CT during PET/CT 
86 
16.3 
[18F] Fluorodeoxyglucose (FDG) PET 
87 
17.0 
RADIATION THERAPY GUIDELINES 
87 
APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
88 
APPENDIX II: RITUXIMAB OR BIOSIMILAR INFUSION GUIDELINES 
91 
APPENDIX III: GUIDELINES FOR LMP-SPECIFIC T CELL PRODUCT 
93 
APPENDIX IV: CORRELATIVE BIOLOGY STUDIES 
98 
APPENDIX V: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR 
ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT 
VERSUS HOST DISEASE (GVHD) 
100 
APPENDIX VI: POSSIBLE DRUG INTERACTIONS 
106 
APPENDIX VII: YOUTH INFORMATION SHEETS 
107 
REFERENCES 
109 
 
 
 

  
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INVESTIGATIONAL SUPPLIED AGENT 
 
LMP-TC 
NSC# 782666 
 
 
IND Sponsor: COG 
 
 
 
OTHER AGENTS:  
 
Rituximab 
NSC# 687451 
Commercial 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTION 15 FOR SPECIMEN SHIPPING ADDRESS 
 
 

  
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies.  
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings.  However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances.  For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our 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 mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others 
 
 
ABSTRACT 
This is a pilot study of Rituximab (RTX) with or without Third Party Latent Membrane Protein (LMP)-
specific Cytotoxic T-Lymphocytes (LMP-specific T cells or LMP-TC) in pediatric and young adult solid 
organ transplant recipients (SOT) with newly diagnosed, relapsed or refractory EBV-Positive CD20-
Positive Post-Transplant Lymphoproliferative Disease (PTLD). EBV-positive PTLD has become the most 
common form of lymphoproliferation in childhood with an estimated annual incidence of > 100 newly 
diagnosed patients < 18 years of age in the US. Reduction of immunosuppression with the goal to restore 
the immunological function of cytotoxic T cells is the first-line therapy with response rates between 20-
80% but carries the risk of rejection. Patients who do not respond to reduction of immunosuppression 
require further therapy and addressing the underlying immunological defect is the next logical step. 
Preliminary studies have shown that EBV-specific T cells can repair the underlying immunological defect, 
are well tolerated and have efficacy in PTLD. This pilot study is testing the hypothesis that it is feasible to 
use Third Party LMP-specific T cells in a cooperative group setting. The production of LMP-specific T 
cells has become a reproducible procedure with standardized SOPs to generate Good Manufacturing 
Practice (GMP)-grade LMP-specific T cells. Third Party LMP-specific T cells are readily produced from 
healthy donors, HLA typed and cryopreserved in cell banks. A Third Party LMP-specific T cells bank, 
mostly derived from healthy donors, has been established at the Program for Cell Enhancement and 
Technologies for Immunotherapy (CETI) at Children’s National Medical Center and will supply LMP-
specific T cells for this study. Untreated newly diagnosed (Cohort A) and relapsed (Cohort B) patients will 
receive three weekly doses of rituximab followed by a response assessment. Newly diagnosed patients who 
have a complete response (CR) to rituximab will receive an additional three doses of rituximab because 
they are predicted to have an excellent outcome. Newly diagnosed patients who do not achieve a CR to 3 
doses of rituximab and all relapsed PTLD patients regardless of response will receive LMP-specific T cells. 
Patients with refractory and/or persistent disease after rituximab according to institutional guidelines are 
eligible for Cohort C and will proceed straight to LMP-T cell therapy. The closest HLA matched LMP-
specific T-cell product will be identified for each patient. At least a 1/6 HLA match with activity through 
the shared alleles is required. Based on previous experience, it is expected that about 30 different HLA 
characterized products will cover > 90% of the eligible patients. Participating institutions in this limited 
institution study will have FACT accredited cell processing and storage facilities and have to adhere to 
SOPs about dispensing and infusing LMP-specific T cells. 
 
 
 
 

  
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EXPERIMENTAL DESIGN SCHEMA: COHORT A (UNTREATED NEWLY DIAGNOSED 
PATIENTS) AND COHORT B (RELAPSED PATIENTS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
INDUCTION   
Course RTX1: Rituximab 375 mg/m2 Days 1, 8, 15 
 
ARM RTX 
Course RTX2: Rituximab 375 mg/m2 Days 1, 8, 15 
 
ARM LMP-TC 
Courses LMP-TC1 and LMP-TC2: Partially HLA matched Third Party LMP-specific  
T cells 2 x 107/m2 Days 0 and 7 
 
CR: Complete Response 
PR: Partial Response 
SD: Stable Disease  
PD: Progressive Disease 
 
*  HLA TYPING results must be submitted by Day 14 of protocol therapy. 
^  FIRST LMP-SPECIFIC T CELL ADMINISTRATION (Day 0 LMP-TC1) must be within 2 weeks of Callback date 
#  OFF PROTOCOL THERAPY: chemotherapy is recommended as per institutional guidelines 
%  END OF PROTOCOL THERAPY: delayed response to RTX and LMP-specific T cells have been described. However, 
chemotherapy is recommended for patients with PD or SD as per institutional guidelines 

  
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EXPERIMENTAL DESIGN SCHEMA: COHORT C (REFRACTORY PATIENTS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COHORT C 
 
ARM LMP-TC 
Courses LMP-TC1 and LMP-TC2: Partially HLA matched Third Party LMP-specific  
T cells 2 x 107/m2 given on Days 1 and 8 
 
CR: Complete Response 
PR: Partial Response 
SD: Stable Disease 
 
PD: Progressive Disease 
 
*  HLA TYPING RESULTS MUST BE AVAILABLE AT STUDY ENTRY 
^  First LMP-T CELL ADMINISTRATION (Day 1) must be within 14 days of study enrollment 
#  OFF PROTOCOL TREATMENT: Chemotherapy is strongly recommended as per institutional 
guidelines 
% Delayed response to RTX and/or LMP-specific T cells have been described. However, chemotherapy 
is strongly recommended for patients with PD or SD as per institutional guidelines 

  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aim 
The primary objective of this study is to determine the feasibility of treating pediatric and 
young adult solid organ transplant recipients who have newly diagnosed, relapsed or 
refractory EBV-Positive CD20-Positive Post-Transplant Lymphoproliferative Disease 
(PTLD) with a novel T-cell therapeutic, Third Party Latent Membrane Protein (LMP)-
specific T cells, in a cooperative group setting. Feasibility will be based on the percentage 
of patients assigned to Arm LMP-TC that have a suitable match and receive both T-cell 
infusions within the prescribed timeframe. 
 
1.2 
Secondary Aims 
1.2.1 
To determine the percentage of eligible patients for whom a suitable LMP-specific 
T-cell product derived from a Third Party LMP-specific T-cell bank is available. 
 
1.2.2 
To estimate the response rate (RR) to three doses of RTX as single agent in 
children and young adults with newly diagnosed or relapsed EBV-Positive CD20-
Positive PTLD after solid organ transplantation (SOT). 
 
1.2.3 
To estimate the 2-year event-free survival (EFS) of children and young adults with 
newly diagnosed, refractory or relapsed EBV-Positive CD20-Positive PTLD after 
SOT treated with RTX and/or LMP-specific T cells. 
 
1.2.4 
To estimate overall survival (OS) of children and young adults with newly 
diagnosed, refractory or relapsed EBV-Positive CD20-Positive PTLD after SOT 
treated with RTX and/or LMP-specific T cells. 
 
1.2.5 
To estimate the RR to LMP-specific T cells of newly diagnosed (without complete 
response to Course RTX1), refractory, and relapsed children and young adults with 
EBV-Positive CD20-Positive PTLD. 
 
1.2.6 
To estimate progression-free survival (PFS) of children and young adults with 
newly diagnosed, refractory or relapsed EBV-Positive CD20-Positive PTLD after 
SOT treated with RTX and/or LMP-specific T cells. 
 
1.2.7 
To describe the toxicity of Third Party LMP-specific T cells in children and young 
adults with newly diagnosed, refractory or relapsed EBV-Positive CD20-Positive 
PTLD after SOT treated with RTX and/or LMP-specific T cells. 
 
1.2.8 
To validate that absence of EBV viremia correlates with RR, EFS and OS. 
 
1.3 
Exploratory Aims 
1.3.1 
To determine whether Third Party LMP-specific T cells promote autologous 
immune reconstitution of EBV-specific T cells. 
 
1.3.2 
To determine whether EBV viremia is inversely correlated with an increase in 
EBV-specific T cells in vivo.  
 
1.3.3 
To determine whether plasma cytokine profile and changes in cytokines over time 
correlate with treatment response or toxicity (e.g. cytokine release syndrome). 
 

  
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2.0 
BACKGROUND 
 
2.1 
Introduction 
As solid organ transplantation is becoming more common and transplant mortality has 
decreased, PTLD has quickly become the most prominent form of childhood 
lymphoproliferative disorder. The estimated incidence of PTLD in pediatric SOT 
recipients is greater than 100 cases per year in the US.  
 
PTLD has been approached as an infectious problem with EBV as the responsible 
pathogen, an oncological problem caused by monoclonal proliferation of EBV 
transformed B cells, and as an immunological problem caused by defective immune 
surveillance of EBV transformed B cells. The standard first-line approach to PTLD 
consists of reduction of immunosuppression to restore T-cell function, which repairs the 
immunological defect.1 Reduction of immunosuppression leads to resolution in less than 
50% of patients and is not always feasible because of increased risk of organ rejection. 
Thus, > 50% of patients require further therapy beyond reduction of immunosuppression. 
Other therapeutic approaches have included rituximab as single agent ± chemotherapy or 
chemotherapy alone with reported EFS rates of only 70% for all approaches. 
 
2.2 
Rationale for Development 
The outcome for pediatric patients with PTLD after solid organ transplant who do not 
achieve a complete remission after 3 doses of rituximab are unacceptable with 1-year 
event-free survival of 53% with rituximab as a single agent reported by the German Ped-
PTLD-2005.2 While the established first-line treatment approach is reduction of 
immunosuppression to augment an autologous EBV-specific T-cell response,1 the optimal 
therapy for patients who do not respond after reduction of immunosuppression remains to 
be determined.3 Since the pathogenesis of this tumor is a defective adaptive immune 
response to EBV, utilizing a therapy to enhance EBV-specific T-cell immunity is a logical 
treatment approach and the use of EBV-specific T-cell therapies in single centers has been 
promising.4,5 Exploring a treatment modality such as LMP-specific T cells, which is not 
tied to the expression of CD20, may expand the scope of disease controlling therapy 
beyond other potential therapeutic strategies. Unlike rituximab, chemotherapy, 
bidirectional T-cell engagers (e.g. blinatumomab) or chimeric antigen receptor T cells, 
LMP-specific T cells have been shown to: (i) specifically recognize and kill the 
proliferating EBV-infected B cells and NOT healthy B cells; and (ii) have the potential to 
repair the underlying immune defect that leads to the development of PTLD, (iii) and do 
not add to the immune suppression. Repairing this immune defect is critical for achieving 
a durable treatment response 
 
This protocol tests the hypothesis that targeting the underlying pathologic defect of PTLD 
with EBV/LMP-specific T cells is feasible in a multi-institution cooperative group setting. 
In addition, the study will monitor the toxicity of this novel therapy as well as the event-
free survival, overall survival, response rate and progression-free survival of pediatric SOT 
recipients with EBV positive PTLD receiving rituximab with or without LMP-specific T 
cells.  
 
Cellular therapies including EBV/LMP-specific T cells and chimeric antigen receptor 
(CAR) T cells are currently in clinical trials and have shown impressive results in B-cell 
leukemias and lymphomas, but are not yet widely available.4-6 In PTLD, the proliferating 
cell population expresses EBV viral proteins found in latency stage III including LMP1 

  
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and LMP2 that can be easily targeted using cellular therapy such as EBV-directed T cells 
(e.g. LMP-specific T cells). In single center pilot studies, administration of Third Party 
EBV-specific T cells as a single agent therapy led to an overall response rate (CR+PR) of 
64% at 5 weeks and 52% at six months without significant toxicities or increased risk of 
rejection in 33 pediatric and adult SOT recipients, including 13 patients who were 
refractory to or recurred after prior therapy with rituximab and/or chemotherapy.5 These 
results are comparable to the German Ped-PTLD-2005 study, which showed that 
rituximab as single agent resulted in an EFS of 53%.  
 
ANHL1522 will pilot the use of cellular therapies in the cooperative group setting to 
assess whether these therapies are feasible in multi-institutional studies. LMP-specific T-
cell therapies have the potential to: (i) increase the rate of disease control, (ii) reduce the 
fraction of patients receiving chemotherapy, (iii) improve the host’s adaptive immune 
response (iv) potentially reduce the dose of rituximab required to achieve a durable CR 
thereby limiting the use of IVIG and (v) offer a treatment option with potential economic 
advantages.  
 
If the administration of cellular therapy is proven feasible in a cooperative group setting 
it will enable future randomized studies evaluating rituximab plus LMP-specific T cells 
versus “standard of care” (e.g. rituximab alone) with the goal of increasing the patient 
population treated without chemotherapy from 53% to at least 70%. Additional efforts 
will include extending the use of LMP-specific T cells to other EBV-associated cancers 
such as EBV-associated Hodgkin Lymphoma and Diffuse Large B-cell Lymphoma 
(DLBCL). Further, the success of this study may open the pathway for utilizing Third 
Party “off-the-shelf” products for other cellular therapy studies in a cooperative group 
setting. In summary, demonstrating feasibility will greatly expand patients’ access to this 
and other novel cell therapies in the future. 
 
2.3 
PTLD after SOT  
 
2.3.1 
Incidence  
The association of EBV infection, compromised T-cell immunity and B-cell 
lymphoproliferative disease in patients following transplantation has been known 
for over 20 years1. A cohort study of solid organ transplant recipients from the US 
Scientific Registry of Transplant Recipients from 1987-2008 including almost 
14,000 children showed an overall 2-fold increased risk of cancer compared to the 
general population but a 7.5-fold excess risk for Non-Hodgkin Lymphoma 
(NHL).7 There is a 10-fold increased risk of developing PTLD in the 0-34 years 
age group compared to the > 50 years age group. In the United States the annual 
incidence of SOT in pediatric patients rose from 1,397 solid organ transplants in 
children between the ages of 0-18 in 1990 to 1,825 cases in 2010 based on data 
from the Organ Procurement and Transplantation Network (OPTN).8 With the 
rising incidence of solid organ transplantation in childhood and better long-term 
survival of the recipients, PTLD has become one of the most common forms of 
lymphoproliferative disease in childhood. It is estimated based on OPTN data that 
there are more than 100 newly diagnosed cases each year in the U.S.8 The 
incidence ranges from 1-5% in renal transplants to 10-30% in the pediatric lung, 
small bowel and multiple organ transplants.1  
 

  
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2.3.2 
Pathology 
The most recent WHO classification from 2008 divides PTLD into four groups: 
mononucleosis-like early lesion (or reactive plasmacytic hyperplasia), 
polymorphic PTLD, monomorphic PTLD, and Hodgkin-like PTLD.9 Several 
single-institution studies and one multi-institution study show an almost equal 
incidence of mono- and polymorphic PTLD in the pediatric SOT population.3 
More than 90% of pediatric PTLD cases are of B-cell origin, CD20 positive and 
associated with Epstein Barr virus (EBV) infection. Contrary to bone marrow 
transplant (BMT) recipients where PTLD is usually of donor origin, PTLD after 
SOT generally originates in recipient cells.1 
 
2.3.3 
The Role of EBV in Childhood PTLD 
About 80-90% of people will be infected with EBV during their lifetime and the 
virus persists in latently infected B cells lifelong. An estimated 20-25% of children 
in developed countries will have acquired EBV by 5 years of age.10 Since the 
majority of childhood transplantations occur in the preschool age, the majority of 
pediatric SOT recipients are EBV naïve at the time of transplant. 60-80% of 
patients who are EBV naïve at the time of transplant will convert to EBV positivity 
within three months of transplant either from primary EBV infection or from 
infection via EBV positive “passenger” donor lymphocytes present in the 
transplanted organ.10 In de novo infections, EBV enters the body through the 
oropharyngeal mucosa by transmission through infected saliva.11 B cells transiting 
through the oropharynx pick up the virus and disseminate it to the liver, spleen, 
bone marrow and lymph nodes. The EBV infected B cells progress through several 
phases of latency that are characterized by differential expression of viral antigens. 
 
In the healthy host, EBV-specific T cells recognize viral antigens expressed by 
infected B cells and control the infection. EBV persists in a latent stage by down-
regulating the expression of viral antigens in infected B cells, thereby rendering 
the virus invisible to the immune system. Re-expression of viral antigens on the 
surface of infected dividing B cells leads to periodic expansion of EBV-specific T 
cells that prevent uncontrolled proliferation of the EBV infected B-cell population 
to proliferate. In the immunocompromised host, the lack of a robust T-cell immune 
response permits the uncontrolled proliferation of infected B cells with highest risk 
of developing PTLD at the time of primary seroconversion.12 The majority of 
PTLDs in children derive from EBV infected B cells in latency type III with 
expression of all viral antigens including the immunogenic EBNA1, 2, 3, LMP 1 
and 2 proteins.4  
 
Because the prevailing problem in PTLD after SOT consists of the imbalance 
between EBV infected B cells and EBV-specific T cells, reduction of 
immunosuppression to restore the immunological function of the cytotoxic T cells 
is the accepted first line of therapy. This usually leads to resolution in early 
mononucleosis-like PTLD but is not always feasible because of threat of graft 
rejection and/or failure and reported success rates in polymorphic and 
monomorphic PTLD range from only 20-80%.1 Numerous second-line therapeutic 
approaches for refractory PTLD in pediatric patients have been explored but 
generally there has been a paucity of multicenter collaborative studies for this 
disease. These are generally highly immunogenic tumors that express viral proteins 
of latency type 3 making them potentially amenable to immune based therapies. 

  
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2.4 
Previous Studies in PTLD 
 
2.4.1 
Cyclophosphamide/Prednisone/Rituximab (CPR) Therapy 
The Children’s Oncology Group (COG) conducted a phase 2 study of low dose 
cyclophosphamide (600 mg/m2, day 1), prednisone (1mg/kg/dose twice daily, days 
1-5) and RTX (375 mg/m2, days 1,8,15 in Cycles 1-2 only) for six cycles in 55 
pediatric patients with EBV positive CD20 positive PTLD from 23 centers.13 73% 
of patients had monomorphic disease and 20% had polymorphic disease. Three 
patients (7.5%) who had more than one site biopsied were found to have both 
mono- and polymorphic disease in separate locations. Early treatment response 
rate (CR or PR after the first two cycles of chemotherapy) was 72%. 29 patients 
achieved a CR by the end of therapy and an additional eight patients of twelve 
patients with residual disease at the end of therapy achieved a CR post-therapy 
without any further therapy. The two year event-free survival was 71% and the 
two-year overall survival was 83%. Ten patients died, seven due to PTLD and three 
due to infection during therapy. 
 
2.4.2 
Rituximab (RTX) in PTLD 
Therapy with single agent RTX is the standard of care in PTLD after hematopoietic 
stem cell transplantation (HSCT) and has rapidly become the most commonly used 
form of therapy in PTLD after SOT in pediatric patients.14 RTX as single therapy 
is widely used in adult solid organ recipients with PTLD with reported CR rate of 
60.5%.15 Preliminary data of a phase 2 study in 40 pediatric SOT recipients with 
refractory PTLD showed a 69% CR and 16% PR rate for an overall response rate 
of 85%.16 Histologies consisted of 17 polymorphic PTLD, 7 monomorphic PTLD, 
1 Hodgkin-like, and 1 unspecified histology. A French review reported twenty-six 
SOT recipients with PTLD between the ages of 3-67 years treated with single agent 
RTX. There were 10 cases of polymorphic PTLD and 15 cases of monomorphic 
disease. The overall response rate was 65% (15 CR and 2 PR). Of 15 CRs, 11 
patients remained in CR with a median follow-up of 8 months. The United 
Kingdom Children’s Cancer Study Group (UKCCSG) published a retrospective 
review of rituximab in childhood immunosuppression related lymphoproliferative 
disease that included 10 SOT recipients and 8 HSCT recipients with PTLD out of 
22 patients.17 The other patients had either primary immunodeficiencies (n=2) or 
other prolonged acquired immunodeficiency states (n=2). Of the 19 patients with 
PTLD, 15 patients were treated with single agent rituximab and 5 achieved a CR 
and 2 a PR for a total response rate of 46.7%. The German Pediatric PTLD phase 
2 protocol (“Ped-PTLD2005-Pilot”) tested response stratified therapy with patients 
receiving three weekly doses of RTX at 375 mg/m2.18 Patients with CR or PR after 
three doses of RTX continue with RTX monotherapy while non-responders (NR) 
are assigned chemotherapy. The one-year EFS using RTX monotherapy for this 
entire study overall was 53% confirming that much improvement is required for 
the treatment of this disease beyond using RTX as a single agent therapy. The 
group of responders (64% of total study population) that was treated with RTX 
alone had an overall EFS of 81% (Table 1). Long term follow-up data is available 
on 40 patients. Among the 14 patients who had achieved a CR after three doses of 
RTX there was only one relapse, confirming that this group of patients has an 
excellent prognosis. However, in the group of 17 patients who achieved a PR after 
three doses of rituximab only 11 patients (22.5% of the total study population) 

  
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achieved a lasting CR and did not require any chemotherapy. Six patients 
developed progressive disease and required subsequent chemotherapy (verbal 
communication by Dr. Maecker-Kohlhoff). 
 
Table 1: Published Data of Chemotherapy and Rituximab in PTLD 
Author 
Study 
Size (n) Therapy 
Type of Transplant 
Pathology 
EBV 
Status 
Outcome 
Gross et al., 
2002 
36 
Cyclophosphamide, 
Prednisone 
Liver (17) 
Liver/small bowel (5) 
Liver/small 
bowel/pancreas (1) 
Small Bowel (3) 
Kidney (5) 
Heart (3) 
Lung (2) 
Not reported 
positive 
CR 75% 
PR 8% 
2-year EFS 69% 
Webber et 
al. 
40 
Rituximab 
Heart (15) 
Kidney (11) 
Lung (9) 
Other (5) 
Polymorphic (27) 
Monomorphic (10) 
Hodgkin like (2) 
Nonspecific (1) 
38/40 
positive 
CR 71%, 
76% alive at 1.5 
year follow-up 
Messahel et 
al. 
18 
Rituximab 
HSCT (8) 
Liver (5) 
Heart (4) 
Kidney (1) 
Polymorphic(13) 
Monomorphic (9) 
18/18 
positive 
CR 8  
PR 2 
Gross et al. 
55 
Rituximab, 
Cyclophosphamide, 
Prednisone 
Heart (11) 
Liver (17) 
Kidney (17) 
Lung (5) 
Small Bowel (2) 
Multiple (2) 
Polymorphic (8) 
Monomorphic (29) 
Mono-and 
polymorphic (3) 
55/55 
positive 
CR 69% 
2-year EFS 71% 
Maecker- 
Kohlhoff et 
al. 
 
49 
Rituximab 
induction followed 
by Rituximab only 
for CR and PR(32) 
Or 
Rituximab + 
mCOMP for SD 
and PD (17) 
 
Kidney  (18) 
Liver (11) 
Heart or Lung (20) 
 
Polymorphic (12) 
Monomorphic 
B-cell (30) 
Burkitt (7) 
 
44/49 
positive 
 
64% rituximab 
responders: 81% 
(53% of total 
study population) 
CR with 4.9 year 
median follow-up; 
mCOMP: 66% CR 
rate 
Estimated 5-EFS 
of entire study 
population: 67% 
 
2.5 
EBV-specific T-Lymphocytes 
The ideal therapy for PTLD would be one that is not toxic and enhances cytotoxicity to 
B-cell proliferation, but does not increase the risk of allograft rejection and minimizes the 
inhibition of immune responses required to control EBV driven B-cell proliferation. EBV 
reactive T cells (EBV-specific T cells) are the primary cellular effector cell population in 
controlling EBV driven B-cell proliferation but are also targeted by immunosuppression.12 
Suppression of T cells, particularly autologous EBV-specific T cells, is associated with a 
high risk of developing PTLD. Recent studies in healthy individuals have shown that 

  
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primary EBV infection is associated with a CD8+ cytotoxic T-cell response to viral lytic 
antigens, followed by a CD8+ effector/memory T-cell response against latent viral antigens 
that persists thereafter and presumably provides lifetime immunosurveillance and 
protection against EBV B-cell proliferation.19  
 
2.5.1 
Production of LMP-specific T-Lymphocytes 
The production of LMP-specific T cells has become a reproducible and 
standardized technology.20  
In brief, peripheral blood mononuclear cells (PBMCs) are exposed to a laboratory 
strain of EBV and grown over a period of several weeks into an EBV-infected 
lymphoblastoid cell line (LCL) that is subsequently transduced with a replication-
incompetent adenoviral vector expressing LMP1 and LMP2. In addition, PBMC-
derived monocytes are transduced with the same vector to be used as antigen 
presenting cells (APCs). The genetically modified monocytes are co-cultured with 
T cells to activate and expand the LMP-specific T cells. The LMP-specific T cells 
are further expanded through a second stimulation with the genetically modified 
LCL. The LMP-specific T cells include both CD8- and CD4-positive T cells.21 The 
majority of the expanded LMP-specific T cells express an effector memory 
phenotype (CCR7-/CD62L-), which is important because normal EBV 
seropositive patients have persistent central and effector memory LMP-specific T 
 
Figure 1: LMP-specific T Cell Production  
DC: Dendritic Cells, EBV: Epstein-Barr-Virus, LMP: Latent Membrane Protein,  
PBMC: peripheral blood mononuclear cells.  

  
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cells subsets, and it is now believed that long-term persistent adoptively transferred 
virus-specific T cells are derived from central memory T-cell components.21-23 At 
the time of cryopreservation of LMP-specific T cells, aliquots undergo extensive 
quality assurance and control testing including testing for sterility, HLA typing, 
testing for cytotoxic specificity to avoid allo- and autoreactivity as well as 
confirmation of absence of genetically modified B cells, monocytes or dendritic 
cells. This process (including SOPs) has been published by Bollard et al. and has 
been standardized to manufacture GMP-grade LMP-specific T cells.20 
 
2.5.2 
Donor-Derived EBV-specific T-Lymphocytes in Allogeneic Hematopoietic Stem 
Cell transplantation (HSCT) 
The most experience using EBV-specific T cells exists in HSCT recipients using 
donor-derived EBV-specific T cells. T-cell infusions are generally well tolerated 
by the recipients without any serious side effects, especially without any increase 
in graft-versus-host disease (GvHD). Used prophylactically, none of the patients 
developed PTLD. When used therapeutically as single agent, a complete response 
(CR) was reported in 10/14 patients in the Memorial Sloan Kettering series 6 and 
11/13 patients in the Baylor series 24. 
 
2.5.3 
EBV-Specific or LMP-Specific T Cells in SOT 
Because of the overwhelming use of cadaveric organs, the organ donor does not 
remain available in the majority of SOTs for the generation of LMP-specific 
T cells. But even if the donor is available, donor derived LMP-specific T cells are 
unlikely to be efficacious because PTLD in SOT patients is almost always of 
recipient origin, and donor and recipient are usually not closely HLA matched. 
Alternate strategies include the use of autologous EBV-specific T cells and Third 
Party EBV-specific T cells. Comoli et al. treated three kidney transplant patients 
with monomorphic PTLD with autologous EBV-specific T cells following 
polychemotherapy and/or rituximab all of whom achieved complete response and 
retained allograft function.25 The use of autologous LMP-specific T cells is limited 
since the manufacturing is technically challenging. In a study from Baylor College 
of Medicine, SOT recipients at high risk for PTLD, or with active disease, received 
autologous T-cell infusions without toxicity. None of the 10 “high risk” patients 
treated with LMP-specific T cells for high EBV viral loads progressed to PTLD. 
Two patients received LMP-specific T cells for active disease. One patient with 
liver PTLD showed a complete response, and one with ocular disease had a partial 
response stable for over one year.26 Finally, in another study using LMP-specific 
T cells, two out of two patients with PTLD went into a durable CR for > 2 years 
after LMP-specific T-cell therapy without toxicity. One of these patients received 
LMP-specific T cells as single agent therapy and the other received LMP-specific 
T cells for persistent disease after chemotherapy and rituximab. A third patient 
who achieved a CR after rituximab and chemotherapy received LMP-specific T 
cells and remains in remission for > 2 years.27 
 
2.5.4 
Third Party EBV-specific T cells 
Third Party EBV-specific T cells are readily produced from healthy donors with 
known HLA phenotypes. The advantages of a cell bank containing HLA-typed 
EBV-specific T cells are obvious; these cells would be readily available and can 
be quickly dispensed to matched recipients. Potential downsides may be that less 
common HLA types may be difficult to match. Third party EBV-specific T cells 

  
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have been used in several clinical protocols in SOT recipients with PTLD. They 
were well tolerated without increased risk of GvHD or graft failure. Response rates 
vary but are generally favorable. The largest series, a multicenter phase 2 study of 
33 SOT and HSCT recipients with PTLD, 13 of whom had failed prior rituximab 
and/or chemotherapy showed an overall response rate of 64% at 5 weeks and 52% 
at six months.5 Better outcomes were observed the closer the EBV-specific T cells 
were matched to the recipient but generally a match in at least 1-2 antigens is 
sufficient for activity. In this study, patients received 4 doses of 2 × 106 T cells/kg 
at weekly intervals. Products were selected for matching by low resolution typing 
and screened for high level killing of autologous LCLs and low level killing of 
patient PHA blasts. The degree of HLA matching ranged from 2/6 to 5/6 antigens, 
and there was a statistically significant trend towards a better outcome at 6 months 
with better matching. Importantly, no patient developed significant toxicity or 
GvHD post EBV-specific T cells administration.5 Based on this data, a suitable 
match for this study will be defined as at least a 1/6 match as long as the activity 
is going through the shared allele. 
 
Table 2: Published Data on the Use of EBV-specific T cells in PTLD in SOT recipients  
T Cell 
Source 
Study 
n 
Type of 
transplant Side effects 
Antiviral Effects 
Donor 
Baylor/St 
Jude/Great 
Ormond 
Street 
113 
HSCT 
Local 
inflammation 
during therapeutic 
responses 
Prophylaxis: 
no PTLD 
Treatment: 
11/13 CR’s 
Donor 
MSKCC 
14 
HSCT 
None 
10 CR 
4 PD 
Autologous 
Comoli et al. 
7 
SOT 
None 
Prophylaxis:  
no PTLD 
Autologous 
Comoli et al. 
5 
SOT 
None 
Therapy: CR 
Autologous 
Savoldo et 
al. 
12 
SOT 
None 
Prophylaxis: 
no PTLD 
Therapy: 1/2 CR 
Third party 
Haque et al. 
33 
HSCT and 
SOT 
None 
14 CR, 3 PR,  
16 NR 
Third party 
Gandi et al. 
3 
SOT 
None 
2/3 CR 
Third party 
Sun et al. 
2 
SOT 
None 
2 CR 
Adapted from Bollard et al.24 
 
2.5.5 
Preliminary Data Using LMP-specific T-cells 
The LMP T-cell product that will be used in this study has been developed at 
Baylor University and Children’s National Medical Center.28 The production 
process has been previously published.4 
 

  
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Patients with EBV-positive non-Hodgkin or Hodgkin lymphoma who either had 
relapsed after standard therapy or were at high risk for relapse received autologous 
LMP-TCs at a dose of 2 x 107 cells/m2/week x 2 weeks.27 Patients with a partial 
response (PR) or stable disease (SD) were eligible to receive additional doses 8 
weeks later. In the patient cohort with relapsed disease, 11 out of 21 patients 
achieved a CR and an additional 2 patients achieved a PR.29 One patient suffered 
CNS deterioration due to disease progression and another patient developed 
respiratory complications from an intercurrent infection. In both patients, an 
inflammatory component from LMP-TCs could not be excluded.  
 
Tri-virus specific third party cytotoxic T-lymphocytes (VSTs) with specificity 
against adenovirus, CMV and EBV were administered at a dose of up to 2 x 107 
cells/m2 with additional infusions at an interval of at least 2 weeks in patients who 
achieved a PR.29 In 50 recipients, the cumulative rate of CR and PR was 74%. 
Infusions were well tolerated without any immediate reaction. All patients had 
been recipients of allogeneic stem cell transplantation. Two developed Grade I de 
novo GvHD after VSTs. Six patients had a flare of previously diagnosed acute 
GvHD and one patient had a flare of previously diagnosed chronic GvHD. 
 
2.5.6 
Risks of Administering Third Party LMP-specific T cells 
Over 65 patients have been treated on the Baylor College of Medicine (BCM) 
adoptive immunotherapy protocol in which allogeneic donor derived EBV-specific 
T cells were administered after bone marrow transplantation. The only significant 
complication was an inflammatory response (cytokine release syndrome) in a 
patient with bulky EBV lymphoma. In addition, 18 patients have received 
polyclonal trivirus-specific T cells (i.e. T cells that were selected for EBV, 
adenoviral, and CMV-reactivity), and 12 patients received adenovirus- and EBV-
specific T cells without developing significant adverse events. 
 
None of the patients treated in any of these studies developed significant de novo 
graft-versus-host disease (GvHD). In other reported studies, none of the patients 
treated with CMV-specific T cells by Walter et al. developed GvHD.30 In the 
cohort of HSCT recipients treated by Peggs et al., 3/13 patients developed mild 
(grade 1) GvHD; since immunosuppression had been withdrawn early in this 
study, it is unclear if this side effect was due to T-cell infusion.31 Although there is 
theoretically an increased risk of GvHD due to greater mismatch with partially 
matched T cells, no GvHD was reported in a phase 2 study of closely matched 
allogeneic T cells in 35 patients or in several case reports using matched T cells.5,32 
 
A recent review of the BCM clinical experience with adoptive transfer of 
allogeneic donor-derived virus-specific T cells in 153 recipients, including 73 
instances where there was an HLA mismatch, showed that there was no de novo 
acute GvHD after infusion, and that the incidence of reactivation of pre-existing 
GvHD was low and not significantly different in recipients of matched or 
mismatched virus-specific T cells.4 These data indicate that the adoptive transfer 
of partially HLA-mismatched virus-specific T cells is safe, even if virus-specific 
T cells have some cross-reactivity with HLA-mismatched targets in vitro.33  
 
In the BCM studies with donor-derived virus-specific T cells, T-cell products were 
screened for reactivity against other host tissues, such as fibroblasts, PHA blasts 

  
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or both, as a release criterion. However, performing such an assay in the current 
protocol would be difficult for two reasons. First, many recipients may not have 
pre-treatment lymphocytes available to make PHA blasts. Second, it would add 10 
days to the release time, which would adversely affect feasibility and perhaps 
outcome. Therefore, we will use killing against third party allogeneic PHA blasts 
rather than patient-derived PHA blasts as a release criterion. 
 
Another potential hazard is the infusion of EBV transformed B cells, which have 
been co-cultured with the T cells during generation of the T-cell products. This is 
unlikely to constitute an additional risk to the recipient for several reasons. First, 
the LCLs are not viable because they have been irradiated with 4,000 cGy and co-
cultured with known effectors. In addition, acyclovir is added to the LCL cultures 
to ensure that no productive virus is present in cultures. Finally, EBV DNA levels 
will be monitored in peripheral blood by PCR before and after T-cell infusions. 
The laboratory strain of EBV used for LCL production has not been detected in 
over 200 patients who have received EBV-specific T cells so far. In addition, the 
LMP-specific T-cell products are phenotyped prior to infusion and all products 
have to meet release criteria (< 2% CD19+ B cells in the LMP-specific T-cell 
product for infusion). 
 
Infusion of cells infected with the adenoviral vector (Ad5f35pp65), could 
theoretically lead to an inflammatory response due to infectious virus or viral 
antigens. This is unlikely for several reasons. Firstly, the adenoviral vector is RCA 
negative. Secondly, in this study we are initially using the adenoviral vector to 
infect peripheral blood mononuclear cells to stimulate the T cells. We have shown 
that only CD14-positive cells (monocytes) and not T cells or B cells become 
infected with the adenoviral vector at the multiplicity of infection (MOI) we use. 
Subsequent stimulations of the T cells will be with lethally irradiated monocytes 
and then with EBV-LCL lines transduced with the Ad5f35 vector. Prior to 
stimulation, the irradiated LCL and monocytes will be washed 4 times which we 
have shown eliminates 4 logs of free adenovirus from the cultures. Thirdly, 
adenoviral-specific T cells will be cultured for at least 7 days after the final 
stimulation with LCL infected with the Ad5f35 vector since pre-clinical studies 
have shown that this ensures no adenovirus-infected LCL remain alive to be 
administered to the patients. Finally, we will not infuse any LMP-specific T-cell 
products that contain > 2% CD19 positive cells (B cells) or > 2% CD14 positive 
cells (monocytes). 
 
2.6 
EBV-specific T cells and Immune Reconstitution 
Reduction of immunosuppression leads to resolution of PTLD in some patients by allowing 
an endogenous immune response to EBV. The German PED-PTLD-2005 showed that 
chemotherapy suppressed the endogenous EBV T-cell response but rituximab as single 
agent did not.18 In addition, Leen et al.29 showed that Third Party trivirus-specific T cells 
aided in the immune reconstitution. In that study, deep sequencing of T-cell TCR νβ chains 
was performed to track T-cell clones over time. Further, in a study of patients who received 
either donor-derived or Third Party EBV-specific T cells for PTLD after HSCT, a decrease 
in EBV viremia and an increase in the frequency of EBV-specific T cells was noted in 
responders.6 Patients with EBV-associated lymphoma who attained durable clinical 
responses after receiving autologous LMP-specific T cells demonstrated an increase in the 
frequency of endogenous T cells specific for non-viral tumor antigens through epitope 

  
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spreading.27 Hence, EBV-specific T cells may have both direct and indirect antitumor 
activity. 
 
2.7 
EBV Viremia, Disease Activity and EBV-specific T cells 
It is standard of care to monitor serial EBV PCRs in EBV-naïve patients for at least the 
first two years post solid organ transplant to detect EBV viremia (as an indication of either 
primary seroconversion or EBV reactivation) early and be able to intervene with reduction 
of immunosuppression to prevent PTLD. Reduction in immunosuppression leads to 
autologous EBV specific immune reconstitution. EBV viremia inversely correlates with 
the presence of EBV-specific T cells and can predict risk for relapse as shown in previous 
publications using autologous EBV-specific T cells.26,27 In addition, Wilsdorf et al. showed 
in 11 pediatric SOT recipients who had been treated for PTLD that a strong autologous 
EBV-specific T-cell expansion in response to EBV viremia is capable of preventing relapse 
and of controlling EBV viremia.18. A secondary aim on this study is to further characterize 
the correlation of EBV viremia, EBV-specific T cells and risk of relapse. 
 
2.7.1 
EBV PCR 
There is no standardization of quantitative EBV PCR in the US. Each laboratory 
typically develops an individual cut-off of significant copy numbers, and results 
are not easily compared between laboratories due to different denominators used. 
EBV copy numbers have been expressed per plasma volume, amount of total DNA 
or per lymphocytes making comparison between laboratories virtually impossible. 
Efforts for standardization are underway, but significant interlab variation is 
reported according to the WHO international standard.34 
 
For that reason, EBV qPCR will be performed centrally at BCM using a cell-based 
assay which is one of the most sensitive and validated methods.35 
 
2.8 
Correlative Biology Studies 
The goal of the correlative biology studies is to test the hypothesis that LMP-specific 
T cells aid in the immune reconstitution in patients with EBV positive PTLD. An additional 
hypothesis is that Third Party LMP-specific T cells may aid in autologous immune 
reconstitution that persists once the Third Party LMP-specific T cells have been cleared 
and that EBV viremia as measured by EBV PCR is inversely correlated with absence of 
EBV-specific T cells.26,27 If autologous immune reconstitution in response to Third Party 
LMP-specific T cells occurs it would be expected to reduce the risk of future EBV related 
lymphoproliferation without the need for persistence of the Third Party LMP-specific T 
cells or repeated LMP-specific T cells administrations. Both efficacy and toxicity of Third 
Party LMP-specific T cells will be measured by cytokines directly or indirectly induced 
through activation of LMP-specific T cells.36 Variability in specimen quality (e.g. PBMC 
quantity) is expected so the number of studies performed for each specimen will be 
adjusted according to feasibility. Correlative biology studies will evaluate: 
 
2.8.1 
General Immune Reconstitution and Persistence of LMP-specific T Cells 
EBV positive PTLD is caused by a defective immune system. The purpose of these 
studies is to assess whether Third Party LMP-specific T cells are aiding in the 
immune reconstitution of the recipients by functioning as a bridge to autologous 
EBV specific immune reconstitution. Monitoring occurrence and persistence of 
this immune reconstitution may be able to predict response and/or risk of 
recurrence of PTLD. To explore this possibility, T-cell immunophenotyping, 

  
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cytokine receptor expression and measurement of cytokine releases will be 
performed. These results will be correlated with serial EBV qPCR. 
 
2.8.2 
Persistence of LMP-specific T cells and Immunity to EBV 
EBV lymphoproliferation is controlled by the presence of EBV-specific T cells. 
Persistent absence of EBV viremia as measured by EBV PCR in the blood is able 
to predict the presence of EBV-specific T cells which reduces the risk of 
recurrence. The rationale behind this correlative study is that it is currently 
unknown what the adequate post-therapy monitoring is for this patient population 
that receives ongoing immune suppression. Serial CT and/or PET scans carry 
significant radiation exposure. Developing reliable biomarkers would be of 
significant clinical importance to avoid unnecessary radiation exposure and/or 
invasive procedures. For this purpose, HLA-tetramer assays to assess T-cell 
frequencies and EBV PCRs will be performed serially. 
 
2.8.3 
Dynamic Production of Inflammatory Cytokines as a Measure of Efficacy and 
Toxicity. 
Plasma inflammatory proteins reflect the cumulative elaboration of cytokines and 
chemokines produced by effector T cells as well as by host immune responses.  We 
hypothesize that specific patterns of cytokine/chemokine expression will predict 
response to therapy as well as toxicity in patients with PTLD treated with Third 
Party LPM-specific T cells. 
 
2.9 
Future Development of Third Party LMP-specific T cells 
Third Party LMP-specific T cells can be produced from healthy donors, and can be stored 
and made readily available without delay when needed. If found that they also aid in 
autologous immune reconstitution without the need of persistence, further clinical 
development of third party cellular therapy would be indicated because they could be 
widely and easily available without the need and delays of “custom-made” cellular 
therapies and without the unknown risks of persistence of modified cells in the host. Future 
plans include extending their use in the cooperative group setting to other EBV positive 
malignancies such as Hodgkin Disease. In addition, if the use of Third Party “off the shelf” 
cellular products is shown to be efficacious this may be studied in other cellular products 
as such chimeric antigen receptor T cells and lead to a much wider availability of those 
products as well. 
 
 

  
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3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
Prior to patient enrollment on ANHL1522, sites must ensure FACT accreditation and COG 
approval as a transplant center. (See COG member website Administration page under the 
Membership tab for the link to the list of Approved COG Transplant Centers.) 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN 
following authorization for the release of protected health information (PHI). The 
COG patient ID number is used to identify the patient in all future interactions with 
COG. If you have problems with the registration, please refer to the online help. 
For additional help or information, please contact the CTSU Help Desk at 1-888-
823-5923 or ctsucontact@westat.com.   
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol.  
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
NOTE: In order for an institution to maintain COG membership requirements, every 
patient with a known or suspected neoplasm needs to be offered participation in 
APEC14B1, Project:EveryChild A Registry, Eligibility Screening, Biology and 
Outcome Study. 
 
3.1.2 
IRB Approval 
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 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 Federal Wide 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. 

  
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For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I.  
 
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. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. 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. Other site registration 
requirements 
(e.g., 
laboratory 
certifications, 
protocol-specific 
training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.3 
Reservation Requirements 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system.  
 
Cohort A: Newly Diagnosed 
Cohort B: Relapsed 
Cohort C: Refractory  
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in OPEN. Prior to discussing 
protocol entry with the patient, site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available for the patient. 
Once a slot-reservation confirmation is obtained, site staff may then proceed to 
enroll the patient to this study.  
 
If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and 
password.  
2) In order to make a reservation, the patient must have an OPEN patient number. 
Click on the ‘Slot Reservation’ tab to create an OPEN patient number, under 
‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient.  

  
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4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the 
COG Patient ID, and choose the required stratum (if applicable) in order to 
obtain a reservation. 
 
Refer to the ‘SITE – Slot Reservation Quick Reference’ guide posted under 
the ‘Help’ tab in OPEN for detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_Q
uickReference_SiteUserGuide_102612.pdf&ftype=PDF  
 
3.1.4 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at  https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the lead 
protocol organization (LPO) or participating organization roster. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval.  If a DTL is required for the study, 
the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• All eligibility criteria have been met within the protocol stated timeframes. 
• All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
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 or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.1.5 
Timing 
Patients must be enrolled before treatment begins. The projected start date of  
protocol therapy for Cohorts A and B must be no later than five (5) calendar days 
after the date of study enrollment. For patients in Cohort C, the first dose of LMP-
TC must be administered within 14 days of study enrollment. Patients who are 
started on protocol therapy prior to study enrollment will be considered 
ineligible.  
 

  
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All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below.  
 
Cohorts A and B: HLA typing must be sent at study enrollment and results 
must be available by Day 14 for identification of available matched LMP-
specific T cell product in time for treatment assignment. 
 
Cohort C: HLA typing must be AVAILABLE at study enrollment for 
identification of available matched LMP-specific T cell product in time for 
treatment to be administered within two weeks from study enrollment. 
Patients without HLA typing available at the time of enrollment are ineligible. 
 
3.1.6 
Cohorts A and B: Callback by Day 22 for Post Induction Treatment Assignment 
Response evaluation followed by a Callback, which is performed in OPEN as a 
Step 2 Registration, should be submitted by Day 22 or as soon as a patient is 
medically stable to proceed to the next cycle. Reasons for delays in submitting 
Callback should be documented in the medical chart. Assignment to Arm RTX or 
Arm LMP-TC (LMP-specific T cells) will be based on the patient’s response to 
Induction. 
 
If HLA typing is not available by the Callback: patients assigned to 
Arm LMP-TC will immediately be taken off protocol therapy (patients 
assigned to Arm RTX proceed with protocol therapy). 
 
Timing is Critical: For patients assigned to Arm LMP-TC who have a suitably 
matched LMP-specific T-cell product, Course LMP-TC1 therapy must begin 
within 2 weeks of the date of the Callback.  
 
3.1.7 
Post Course LMP-TC1 Evaluation and Treatment Assignment  
For patients on Arm LMP-TC, a response evaluation and Callback must be 
submitted by Day 42 of Course LMP-TC1. Patients with PR or SD after LMP-TC1 
and available suitably matched LMP-specific T-cell product will proceed to 
Course LMP-TC2. Patients with CR or PD after LMP-TC1 will go off protocol 
therapy. 
 
3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived. All clinical and laboratory data required for determining eligibility 
of a patient enrolled on this trial must be available in the patient's medical/research 
record which will serve as the source document for verification at the time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 

  
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differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy. Radiographic imaging, endoscopic exams with 
biopsies, lumbar punctures, and bone marrow exams do not need to be repeated if 
done within 14 days prior to study entry.  
 
Immunosuppression: Patients and their treating physician must agree to maintain 
adequate immunosuppression during LMP TC cycles following guidelines to at least 
maintain minimal levels of either a calcineurin and/or a MTOR inhibitor as outlined 
in Section 4.4.5. 
 
 
For Cohort A & B: See Section 4.2.2 for required studies to be obtained at baseline prior 
to starting protocol therapy. 
For Cohort C: See Section 4.4.2 for required studies to be obtained at baseline prior to 
starting protocol therapy.  
 
3.2.1 
Age 
Patients must be < 30 years of age at the time of enrollment. 
 
3.2.2 
Diagnosis  
 
3.2.2.1 
Patient must have a history of solid organ transplantation. 
 
3.2.2.2 
Patients must have biopsy-proven newly diagnosed, relapsed or 
refractory polymorphic or monomorphic PTLD using the WHO 
classification and that is: 
 
3.2.2.2.1 CD20 positive 
 
3.2.2.2.2 EBV positive by EBER in situ hybridization (preferred) 
and/or LMP immunoperoxidase staining.  
 
3.2.2.3 
There must be evaluable disease at study entry either by imaging or by 
serial endoscopic biopsies.   
Note: as indicated in Section 10.2.5.1 a measurable node must have an 
LDi (longest diameter) greater than 1.5 cm. A measurable extranodal 
lesion should have an LDi greater than 1.0 cm. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). 
 
3.2.2.4 
Patients must be considered medically refractory to decreased 
immunosuppression (50% or greater reduction) for at least 1 week or 
there must be documentation in the medical chart that decreased 
immunosuppression would be associated with an unacceptable risk of 
rejection. 
 
3.2.3 
Performance Level  
Patients must have a performance status corresponding to ECOG scores of 0 or 1. 
Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of 
age. See  

  
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https://cogmembers.org/site/pages/default.aspx?page=Prot_reference_materials  
under Standard Sections for Protocols.  
 
3.2.4 
Life Expectancy 
Patients must have a life expectancy of ≥ 8 weeks. 
 
3.2.5 
Prior Therapy 
Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to entering this study. 
a. Myelosuppressive chemotherapy: Must not have received within 2 weeks of 
entry onto this study. 
b. Biologic (anti-neoplastic agent):  
• 
Cohort A and B: Patient must not have received therapy with anti-CD20 
monoclonal antibodies within 90 days of entry onto this study.  
• 
Cohort C: Patient must have received Rituximab at 375 mg/m2 weekly for 
at least 3 doses within the last 90 days prior to study enrollment.  
c. Radiation therapy (RT): Must not have received any prior radiation to any sites 
of measurable disease. 
d. Stem Cell Transplant (SCT): Must not have received any prior stem cell 
transplant.  
e. Investigational Therapy: Must not have received investigational therapy 
within 30 days of entry onto this study. 
f. Cellular Therapy: Must not have received prior EBV or LMP-specific T cells 
within 90 days of entry onto this study. 
g. T-cell Antibodies: Must not have received alemtuzumab or other anti-T-cell 
antibody therapy within 28 days of entry onto this study. 
 
Please see Section 4.1.3 for the concomitant therapy restrictions for patients during 
treatment. 
 
3.2.6 
Cohort C Only: HLA typing is available and will be submitted at the time of 
enrollment.  
\ 
3.2.7 
Exclusion Criteria 
 
3.2.7.1 
Burkitt morphology.  
 
3.2.7.2 
CNS involvement.  
CNS status must be confirmed by lumbar puncture.  
Note: Lumbar puncture can be performed at the time of diagnosis and 
does not need to be repeated unless there is a change in neurological 
status or it was performed more than 14 days prior to study entry. 
 

  
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3.2.7.3 
Bone marrow involvement (>25%).  
Note: Bone marrow aspiration/biopsy can be performed at the time of 
diagnosis and does not need to be repeated unless there is a change in 
peripheral blood counts or it was performed more than 14 days prior to 
study entry. 
 
3.2.7.4 
Fulminant PTLD defined as: 
Fever > 38°C, hypotension, and evidence of multi-organ 
involvement/failure including two or more of the following:  
1) Bone marrow (including pancytopenia without any detectable B-cell 
proliferation)  
2) Liver (coagulopathy, transaminitis and/or hyperbilirubinemia) 
3) Lungs (interstitial pneumonitis with or without pleural effusions)  
4) Gastrointestinal hemorrhage  
 
3.2.7.5 
Any documented donor-derived PTLD. 
 
3.2.7.6 
Infections: 
 
3.2.7.6.1 Hepatitis B or C serologies consistent with past or current 
infections because of the risk of reactivation with rituximab. 
 
3.2.7.6.2 Severe and/or symptomatic refractory concurrent infection 
other than EBV. 
 
3.2.7.7 
Pregnancy and Breast Feeding. 
 
3.2.7.7.1 Pregnant females are ineligible since there is no available 
information regarding human fetal or teratogenic toxicities. 
 
3.2.7.7.2 Lactating females are not eligible unless they have agreed not 
to breastfeed their infants. 
 
3.2.7.7.3 Female patients of childbearing potential are not eligible 
unless a negative pregnancy test result has been obtained. 
 
3.2.7.7.4 Sexually active patients of reproductive potential are not 
eligible unless they have agreed to use an effective 
contraceptive method for the duration of their study 
participation and for 12 months following completion of study 
therapy. 
 
3.2.8 
Regulatory Requirements 
 
3.2.8.1 
All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.8.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 

  
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4.0 
TREATMENT PROGRAM 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except 
where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
 
4.1.1 
Cohorts A & B Induction: Rituximab 
All patients will receive a 21-day course of rituximab or biosimilar at 375 
mg/m2/dose on Days 1, 8, 15. Results of HLA typing must be available by the 
end of Week 2 (Day 14) of Induction for determination of availability of a 
suitable LMP-specific T-cell product. 
 
The HLA typing must be performed at an ASHI accredited laboratory and 
needs to include at a minimum low resolution typing at A, B and DR. Previous 
typing (e.g. HLA typing done for transplant evaluation) is acceptable. 
 
See Section 16.0 for imaging guidelines. A response evaluation during Week 3 
(Days 18-21) of Induction will be followed by a Callback (see Section 3.1.6), 
which must be completed by Day 22 or as soon as a patient is medically stable to 
proceed to the next cycle. Reasons for delays in submitting Callback should be 
documented in the medical chart.  
 
If HLA typing is not available by the Callback: patients assigned to 
Arm LMP-TC will immediately be taken off protocol therapy (patients 
assigned to Arm RTX continue on therapy). 
 
4.1.2 
Assignment to Arm RTX or Arm LMP-TC 
Based on response to Induction therapy, patients will be assigned to either Arm 
RTX or Arm LMP-TC as outlined below. 
 
4.1.2.1 
Arm RTX 
Cohort A: Newly diagnosed patients who achieve a complete response 
(CR) after Induction will be assigned to Arm RTX to receive a second 
21-day course of rituximab or biosimilar (Course RTX2).  
 
4.1.2.2 
Arm LMP-TC 
Cohort A: Newly diagnosed patients who do not achieve a complete 
response (CR) after Induction will be assigned to Arm LMP-TC. 
 
Cohort B: All relapsed patients will be assigned to Arm LMP-TC after 
induction regardless of response.  
 
Cohort C: All  patients with refractory disease who have received 
rituximab (or biosimilar) within 90 days according to institutional 
guidelines are assigned to Cohort C and proceed directly to Arm LMP-

  
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TC at enrollment. 
 
Patients assigned to Arm LMP-TC without a suitable LMP-specific 
T-cell product will go off protocol therapy. Further treatment with 
chemotherapy is at the discretion of the treating physician. 
 
IMMUNOSUPPRESSION 
Patients assigned to Arm LMP-TC are required to have minimum 
levels of either calcineurin inhibitors and/or MTOR inhibitors at the 
start of the course and must maintain these minimum levels 
throughout the course, as follows: 
 
Calcineurin Inhibitors 
Tacrolimus (dose range per institutional guidelines) to achieve 
minimum level of 4 ng/ml 
or 
Cyclosporine (dose range per institutional guidelines) to achieve 
minimum level of 100 ng/ml 
 
and/or 
MTOR Inhibitors 
Sirolimus (dose range per institutional guidelines) to achieve minimum 
level of 4 ng/ml 
or 
Everolimus (dose range per institutional guidelines) to achieve 
minimum level of 3 ng/ml 
 
For patients on combination therapy, the minimum level needs to be 
maintained at least for the calcineurin inhibitors. 
 
Close monitoring of immunosuppression as per institutional 
guidelines is required. Calcineurin inhibitor and/or MTOR 
inhibitor levels are required weekly. If levels are subtherapeutic, 
adjust dose(s) as per institutional guidelines and repeat levels 
approximately every 48-72 hours until the therapeutic range has 
been reached. See Section 4.4.5 
 
Course LMP-TC1 (42 days): Patients with a suitable LMP-specific 
T-cell product will receive the closest HLA matched product at a dose 
of 2 x 107cells/m2/dose on Days 0 and 7 followed by a response 
evaluation completed during Days 36-41 and submitted via the Callback 
form by Day 42 (see Section 3.1.7). Patients with CR at the end of LMP-
TC1 have completed protocol therapy. Patients with PD at the end of 
LMP-TC1 go off protocol therapy with a recommendation to receive 
further chemotherapy per institutional guidelines. 
 
 
Course LMP-TC2 (42 days): Patients with PR or SD after LMP-TC1 
and with a suitable product available will be assigned to Course 
LMP-TC2 to receive two additional doses of LMP-specific T cells.  

  
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1. If the patient had a PR and a sufficient number of vials of cells 
remain, the LMP-TC2 doses should come from the same product 
used in LMP-TC1. 
2. If the patient had SD and/or insufficient cells remain in the original 
product, the LMP-TC2 doses may be selected from another product 
if an additional suitably matched product is available.  
 
Except for the Induction course (RTX1) up to the start of Arm LMP-TC or Arm RTX, all 
patients with progressive disease during protocol therapy will be taken off protocol therapy 
to receive chemotherapy according to institutional guidelines. 
 
4.1.3 
 Concomitant Medications 
 
4.1.3.1 
Concurrent 
immunosuppression 
(e.g., 
calcineurin 
inhibitors, 
mycophenolate mofetil, sirolimus, azathioprine, etc.) to prevent organ 
rejection is allowed. 
 
4.1.3.2 
Corticosteroids are not allowed in excess of 0.5 mg/kg/day in prednisone 
equivalents within 7 days of LMP-specific T-cell administration or 
during Courses LMP-TC1 or LMP-TC2 because the activity of LMP-
specific T cells are inhibited by high dose corticosteroids. The only 
exception is for emergency treatment of allergic/anaphylactic reactions 
as outlined in Appendix III. 
 
4.1.3.3 
Alemtuzumab or other anti-T-cell antibody therapies are not allowed 
during protocol therapy. 
 
4.1.3.4 
Investigational drugs or therapies are not allowed during protocol 
therapy. 
 
4.1.4 
Supportive Care 
 
4.1.4.1 
Anaphylaxis: 
Because of the risk of allergic and/or anaphylactic reaction, rituximab 
and LMP-specific T-cell infusions should be given in a monitored 
setting with resuscitation equipment, diphenhydramine, epinephrine and 
corticosteroids 
(hydrocortisone 
or 
methylprednisolone) 
readily 
available. 
 
4.1.4.2 
Management of other adverse events possibly, probably or definitely 
related to LMP-specific T cells:  
Please refer to Appendix III for detailed management instructions of 
early and late reactions to LMP specific T cells. 
 
4.1.4.3 
Immunoglobulins: 
Patients who develop hypogammaglobulinemia (defined as IgG levels 
below the institutional lower limit of normal for age) should receive 
IVIG replacement every 3-4 weeks until normal values are maintained. 
 
For COG Supportive Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines . 
 

  
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Induction: RTX1 
 
4.2 
COHORT A & B: Induction-Rituximab (RTX1) for Untreated Newly 
Diagnosed or Relapsed Patients 
 
4.2.1 
Therapy Delivery Map – Induction: RTX1 
Rituximab (RTX) 
Induction lasts 21 days and begins on Day 1. 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
 
This TDM is on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Rituximab or 
biosimilar 
(RTX) 
IV 
375 mg/m2/dose 
1, 8, 15 
Please refer to Appendix II for detailed 
rituximab (or biosimilar) administration 
guidelines, including recommended 
premedication and monitoring during infusion.  
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date Given 
Day 
RTX or biosimilar 
______mg 
Studies 
 
 
 
Enter calculated dose above and actual dose 
administered below 
 
 
 
1 
______mg 
a-d, f-m 
 
 
 
 
 
 
 
8 
______mg 
f-k 
 
 
 
 
 
 
 
15 
______mg 
f-k  
 
 
 
 
 
 
 
18 
 
l 
 
 
 
 
 
 
 
21 
 
e-k, m 
 
Complete Callback (Section 3.1.6) by Day 22 (or as soon as a patient is medically stable to proceed to 
the next cycle) for treatment assignment to Arm RTX (Section 4.3) or Arm LMP-TC (Section 4.4). 
 
 
 
See Section 5.0 for Dose Modifications including management of infusion-related reactions, and see 
Section 4.1.4 for Supportive Care Guidelines. 
 
 
Page 1 of 2 

  
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Induction: RTX1 
Page 2 of 2 
 
4.2.2 
Required Observations in Induction 
All baseline studies must be performed prior to starting protocol therapy. 
Unless otherwise indicated, observations a-m can be performed up to 7 days 
prior to the start of therapy. Radiographic imaging and/or endoscopy with 
biopsies, bone marrows, or lumbar punctures do not need to be repeated as 
long as they were obtained within 14 days prior to enrollment.  
 
a. HLA Typing from ASHI-accredited laboratory. Results required by Day 14. Must be at minimum 
low resolution typing at A, B and DR. Previous typing done for transplant evaluation is acceptable. 
b. Height/ BSA. 
c. Hepatitis B and C serologies. 
d. Pregnancy Test: Female patients of childbearing potential require a negative pregnancy test prior 
to starting Induction. 
e. Repeat bone marrow aspiration and biopsy on Day 21 is required only for patients with a positive 
BM at diagnosis. 
f. History and Physical Exam, Vital Signs, Performance Status, Weight. 
g. CBC, diff. 
h. Electrolytes, BUN, creatinine: for all patients at Baseline and Day 21. Note: interim weekly 
evaluations are required only for patients with renal transplant.  
i. AST, ALT, total and direct bilirubin, albumin, total protein, LDH: for all patients at Baseline and 
Day 21. Note: interim weekly evaluations are required only for patients with liver transplant. 
j. Documentation of immunosuppressive medication. 
k. If applicable: tacrolimus, sirolimus, cyclosporine level. If levels are subtherapeutic, adjust dose(s) 
as per institutional guidelines and repeat levels approximately every 48-72 hours until the 
therapeutic range has been reached. 
l. CT with contrast of involved areas: Baseline scan and response evaluation between Days 18-21. 
See Section 10.2 specifics for use of MRI or PET in addition to or as an alternative modality to 
CT. Patients with GI tract involvement require endoscopy with biopsies if they do not have 
measurable disease by imaging.  
m. EBV PCR: 5 mL whole Blood in EDTA (purple top). Submission to BCM for centralized assay. 
See Section 15 for specimen collection and shipment instructions. 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 

  
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Induction: RTX1 
 
4.2.3 
Induction (RTX1): Newly Diagnosed and Relapsed Patients 
See Appendix II for rituximab infusion guidelines and Section 4.1.4 for supportive 
care guidelines. Premedication with acetaminophen and diphenhydramine prior to 
each dose of rituximab (or biosimilar) is strongly recommended. 
 
Rituximab or biosimilar (RTX): IV infusion 
Days: 1, 8, 15 
Dose: 375 mg/m2/dose 
 
Special precautions: Due to the risk of hypotension, it is recommended to hold 
antihypertensive medications 12 hours prior to infusion. 
 
See Section 5.0 for management of allergic and anaphylactic reactions to 
rituximab. Patients who cannot receive any further rituximab due to 
anaphylaxis or hepatitis will be taken off protocol therapy. 
 
4.2.4 
Callback (see Section 3.1.6): 
A Callback must be completed by Day 22 or as soon as a patient is medically stable 
to proceed to the next cycle. Reasons for delays in submitting Callback should be 
documented in the medical chart. Patients assigned to Arm LMP-TC must start the 
next course of therapy within 2 weeks of the Callback.  
 
4.2.5 
Post-Induction Treatment Arm Assignment 
Patients newly diagnosed with PTLD who achieve a CR after induction (RTX1) 
will be assigned to Arm RTX (see Section 4.3). 
 
Patients with newly diagnosed PTLD who have a PR, SD or PD at the end of 
Induction (RTX1) will be assigned to Arm LMP-TC. If no suitable LMP-specific 
T-cell product is available, these patients will immediately be taken off protocol 
therapy. Chemotherapy is strongly recommended. Further therapy is as per 
institutional guidelines. 
 
Following completion of Induction, the next course of therapy starts on Day 28 for 
Arm RTX, or within 2 weeks of the Callback for Arm LMP-TC.  
 
 

  
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Arm RTX: Course RTX2 
Page 1 of 2 
 
4.3 
Arm RTX: Course 2 of Rituximab (RTX2)  
 
4.3.1 
Course RTX2  
For newly diagnosed patients in CR after Induction. 
 
Course RTX2 lasts 21 days and begins on Day 1. 
____________________________ 
Patient COG ID number 
________________________ 
DOB 
 
This TDM is on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Rituximab or 
biosimilar 
(RTX) 
IV 
375 mg/m2/dose 
1, 8, 15 
Please refer to Appendix II for detailed 
rituximab (or biosimilar) administration 
guidelines including recommended 
premedication and monitoring during infusion. 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
 
Date Due 
Date Given 
Day 
RTX or biosimilar 
______mg 
Studies 
 
 
 
Enter calculated dose above and 
actual dose administered below 
 
 
 
1 
______mg 
a-h, j, k 
 
 
 
 
 
 
 
8 
______mg 
d-h, k 
 
 
 
 
 
 
 
15 
______mg 
d-h, k 
 
 
 
 
 
 
 
21 
 
d-k 
 
End of protocol therapy is after the final evaluation.  
 
 
See Section 5.0 for Dose Modifications including management of infusion-related reactions, and see 
Section 4.1.4 for Supportive Care Guidelines. 
 
 

  
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Page 39 
Arm RTX: Course RTX2 
Page 2 of 2 
 
4.3.2 
Required Observations in Course RTX2 
 
a. Height/ BSA. 
b. Pregnancy Test: Female patients of childbearing potential require a negative 
pregnancy test prior to starting RTX2. 
c. History and Physical Exam, Vital Signs, Performance Status, Weight. 
d. CBC, diff. 
e. Electrolytes, BUN, creatinine: for all patients on Days 1 and 21. Note: interim 
weekly evaluations are required only for patients with renal transplant.  
f. AST, ALT, total and direct bilirubin, albumin, total protein, LDH: for all patients 
on Days 1 and 21. Note: interim weekly evaluations are required only for patients 
with liver transplant. 
g. Documentation of immunosuppressive medication. 
h. If applicable: tacrolimus, sirolimus, cyclosporine level. If levels are 
subtherapeutic, adjust dose(s) as per institutional guidelines and repeat levels 
approximately every 48-72 hours until the therapeutic range has been reached. 
i. CT with contrast of involved areas. See Section 10.2 specifics for use of MRI or 
PET in addition to or as an alternative modality to CT. Patients with GI tract 
involvement require endoscopy with biopsies if they do not have measurable 
disease by imaging.  
j. EBV PCR: 5 mL whole blood in EDTA (purple top). Submit specimen to BCM. 
See Section 15 for specimen collection and shipment instructions. 
k. Correlative Biology Studies: Submission to BCM required for patients who 
consent for the optional studies. See Section 15 for timing and shipping 
instructions. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 

  
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Arm RTX: Course RTX2 
 
4.3.3 
Course RTX2 Treatment Details 
See Appendix II for rituximab infusion and Section 4.1.4 for supportive care 
guidelines. Premedication with acetaminophen and diphenhydramine prior to each 
dose of rituximab is strongly recommended. 
 
Rituximab or biosimilar (RTX): IV infusion 
Days: 1, 8, 15 
Dose: 375 mg/m2/dose 
 
Special precaution: due to the risk of hypotension, it is recommended to hold 
antihypertensive medications 12 hours prior to infusion. 
 
See Section 5.0 for management of allergic and anaphylactic reactions to 
rituximab. Patients who cannot receive any further rituximab due to 
anaphylaxis or hepatitis will be taken off protocol therapy. 
 
4.3.4 
Post RTX2 Response Assessment 
Evaluation by CT with contrast should be completed during Week 3 of 
Course RTX2. See Section 10.2 for specific instances in which MRI or PET are 
recommended in addition to or as an alternative modality to CT. 
 
Following completion of RTX2, patients have completed protocol therapy. 
 
For patients who develop PD, chemotherapy as per institutional guidelines is 
strongly recommended.  
 
 
 

Course LMP-TC1 
  
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Page 1 of 2 
4.4 
Arm LMP-TC: Course LMP-TC1 
4.4.1 
Course LMP-TC1 
Cohort A: For newly diagnosed patients with PR, SD or PD response to 
Induction. 
Cohort B: For all relapsed patients regardless of response to rituximab. 
Cohort C: For all patients with refractory disease.  
 
Course LMP-TC1 therapy lasts 6 weeks and begins on Day 0 
 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
To start this course, patients require adequate immunosuppression: Tacrolimus level must be > 4ng/ml OR 
cyclosporine level must be > 100ng/ml OR sirolimus level must be > 4ng/ml OR everolimus level must > 
3ng/ml. This levels MUST be maintained throughout the course. 
This TDM is on 2 pages.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
LMP-specific T cells 
(IND: 17068) 
IV over 1-2 
minutes 
2 x 107 cells/m2/dose 
0, 7 
Please refer to Appendix III for detailed 
administration guidelines including 
recommended premedication and monitoring 
during and after infusion. 
Immuno-suppression: 
_________ 
Specify Medication 
IV/PO 
______ 
Specify dose  
 
________ 
Specify target level 
Days 0- 
47 
See below Section 4.4.5 
Immuno-suppression: 
_________ 
Specify Medication 
IV/PO 
______ 
Specify dose  
 
________ 
Specify target level 
Days 0- 
47 
See below Section 4.4.5 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
LMP-specific T Cells 
______ /m2 
Immunosuppression: 
Drug:___________________ 
Dose:______       mg/dose 
Frequency: ________ 
Immunosuppression: 
Drug: ___________ 
Dose:________mg/dose_ 
Frequency: ________ 
Studies 
 
 
 
Enter calculated dose 
above and  
actual dose 
administered below 
Enter medication, dose & frequency (total daily dose may be 
divided into one or more doses) 
 
 
 
0 
___________cells 
______ 
______ 
a-i, k, l 
 
 
 
 
 
 
 
 
 
7 
_______________cells 
______ 
______ 
d-i, l 
 
 
 
 
 
 
 
 
 
14 
 
______ 
______ 
d-i, k, l 
 
 
 
 
 
 
 
 
 
21 
 
______ 
______ 
d-i,  
 
 
 
 
 
 
 
 
 
28 
 
______ 
______ 
d-i, l 
 
 
 
 
 
 
 
 
 
35 
 
______ 
______ 
d-i  
 
 
36 
 
______ 
______ 
j 
 
 
 
 
 
 
 
 
 
41 
 
______ 
______ 
d-i, k, l 
LMP-TC1 Confirmation CRF must be submitted within 24 hours of the 2nd dose (i.e. on Day 8), OR as soon as 
possible after determination is made that the patient will not receive the 2nd dose. 
 
The end of Course LMP-TC1 response evaluation and Callback must be submitted by Day 42 (see Section 3.1.6). 
 
See Section 5.0 for Dose Modifications including management of infusion-related reactions, and see Section 
4.1.4 for Supportive Care Guidelines. 
 

Course LMP-TC1 
  
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Page 2 of 2 
 
4.4.2 
Required Observations in Course LMP-TC1 
For Cohort C patients: All baseline studies must be performed prior to 
starting protocol therapy. Unless otherwise indicated, observations a-i can be 
performed up to 7 days prior to the start of therapy. Radiographic imaging 
and/or endoscopy with biopsies, bone marrows, or lumbar punctures do not 
need to be repeated as long as they were obtained within 14 days prior to 
enrollment.  
 
a. Height/ BSA. 
b. Pregnancy Test: Female patients of childbearing potential require a negative 
pregnancy test prior to starting LMP-TC1. 
c. O2-saturation. 
d. History and Physical Exam, Vital Signs, Performance Status, Weight. 
e. CBC, diff. 
f. Electrolytes, BUN, creatinine: for all patients at Days 0 and 41. Note: interim weekly 
evaluations are required only for patients with renal transplant.  
g. AST, ALT, total and direct bilirubin, albumin, total protein, LDH: for all patients at 
Days 0 and 41. Note: interim weekly evaluations are required only for patients with 
liver transplant. 
h. Documentation of immunosuppressive medication. 
i. As applicable: tacrolimus, cyclosporine, sirolimus and/or everolimus levels weekly. If 
levels are subtherapeutic as outlined above, adjust dose(s) as per institutional 
guidelines and repeat levels approximately every 48-72 hours until the therapeutic 
range has been reached. See Section 4.4.5 
j. CT with contrast of involved areas: Response evaluation between Days 36-41 of 
Course LMP-TC1. See Section 10.2 specifics for use of MRI or PET in addition to or 
as an alternative modality to CT. Patients with GI tract involvement require endoscopy 
with biopsies if they do not have measurable disease by imaging.  
k. EBV PCR: 5 mL whole Blood in EDTA (purple top). Submission to BCM required for 
centralized assay. See Section 15 for instructions. 
l. Correlative Biology Studies: Submission to BCM required for patients who consent 
for the optional studies. See Section 15 for instructions. 
 
This listing only includes evaluations necessary to answer the primary and secondary 
aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications)  
 
 
 

Course LMP-TC1 
  
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Page 43 
4.4.3 
Course LMP-TC1 Treatment Details 
Refer to Appendix III for detailed instructions for the preparation and 
administration of the LMP-specific T-cell product.  
 
LMP-specific T cells: IV infusion over 1-2 minutes 
Days: 0, 7 
Dose: 2 x 107 cells/m2/dose  
 
4.4.3.1 
Premedication  
30-60 minutes prior to LMP-specific T-cell infusion, premedication with 
acetaminophen and diphenhydramine is strongly recommended unless 
contraindicated. 
 
Acetaminophen 10-15 mg/kg; max 650 mg PO 30-60 minutes prior to 
LMP-specific T cells. (May be given IV in exceptional circumstances.) 
 
Diphenhydramine 1 mg/kg; max 50 mg PO 30-60 minutes prior to LMP-
specific T cells (may be given IV). 
 
4.4.3.2 
LMP-specific T Cell Product Preparation and Thawing 
LMP-specific T cells (2x107cells/m2) will be thawed according to the 
SOP (see Appendix III) and administered IV 30-60 minutes after pre-
medication, if applicable. 
 
4.4.4 
Post LMP-CT1 Response Evaluation 
CT scan with contrast of all involved areas must be completed during Week 6 of 
LMP-TC1 and the Callback must be submitted by Day 42. See Section 10.2 
specifics for use of MRI or PET in addition to or as an alternative modality to CT. 
1) Patients with CR at the end of LMP-TC1 have completed protocol therapy and 
will transition to follow-up. 
2) Patients with PR or SD at the end of LMP-TC1 who have a suitable LMP-
specific T-cell product available are eligible for Course LMP-TC2.  
3) Patients with PR and SD who do not have a suitable LMP-specific T-cell 
product available, or patients with PD at the end of LMP-TC1 will go off 
protocol therapy. Chemotherapy is strongly recommended. Further treatment 
is according to institutional guidelines. 
4.4.5 
Immunosuppression  
Unlike chemotherapy, LMP T cells do NOT provide any immunosuppression. 
Patients assigned to Arm LMP-TC are required to have minimum levels of either 
calcineurin inhibitors and/or MTOR inhibitors at the start of the course and must 
maintain these minimum levels throughout the course. To prevent organ rejection, 
compliance with the below guidelines is required. 
 
MINIMUM Levels for Calcineurin inhibitors: 
Tacrolimus  4 ng/ml 
Cyclosporine 100 ng/ml 
 
MINIMUM Levels for MTOR Inhibitors: 
Sirolimus 4 ng/ml 

Course LMP-TC1 
  
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Page 44 
Everolimus 3 ng/ml 
For patients on combination therapy, the minimum level needs to be maintained at 
least for the calcineurin inhibitors. 
 
 
Course LMP-TC2 will start as soon as a suitable LMP-specific T-cell product is 
available but no later than 21 days from the end of LMP-TC1.  
 
See Section 5.0 for Dose Modifications including management of infusion-
related reactions. 
 

  
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Page 45 
Course LMP-TC2 
Page 1 of 2 
4.5 
Arm LMP-TC: Course LMP-TC2 
4.5.1 
Course LMP-TC2 
For patients with PR or SD following Course LMP-TC1. 
 
Course LMP-TC1 therapy lasts 6 weeks and begins on Day 
0. 
 
____________________________ 
Patient COG ID number 
________________________ 
DOB  
Course LMP-TC2 will start as soon as a suitable LMP-specific T-cell product is available but no later than 21 days from the end of LMP-TC1. 
To start this course, patients require adequate immunosuppression: Tacrolimus level must be > 4ng/ml OR cyclosporine level must be > 
100ng/ml OR sirolimus level must be > 4ng/ml OR everolimus level must > 3ng/ml. This levels MUST be maintained throughout the course. 
This TDM is on 2 pages.  
DRUG 
ROUTE 
DOSAGE 
DAYS IMPORTANT NOTES 
LMP-specific T 
cells 
(IND: 17068) 
IV over 1-2 
minutes 
2 x 107 cells/m2/dose 
0, 7 
Please refer to Appendix III for detailed administration guidelines 
including recommended premedication and monitoring during and after 
infusion.  
Immuno-
suppression: 
_________ 
_________ 
Specify 
Medication 
IV/PO 
______ 
Specify dose  
 
________ 
Specify target level  
Days 0- 
47 
See below Section 4.5.5 
 
Immuno-
suppression: 
_________ 
Specify 
Medication 
IV/PO 
______ 
Specify dose  
 
________ 
Specify target level 
Days 0- 
47 
See below Section 4.4.5 
 
Ht _________cm 
Wt _________kg 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
LMP-specific T Cells 
______ /m2 
Immunosuppression: 
Drug:___________________ 
Dose:______       mg/dose 
Frequency: ________ 
Immunosuppression: 
Drug:___________________ 
Dose:______       mg/dose 
Frequency: ________ 
Studies 
 
 
 
Enter calculated 
dose above and  
actual dose 
administered below 
Enter medication, dose & frequency (total dose may be divided into 
one or more daily doses) 
 
 
 
0 
_____________ cells 
________ 
________ 
a-i, k ,l 
 
 
 
 
 
 
 
 
 
7 
_____________ cells 
________ 
________ 
d-i 
 
 
 
 
 
 
 
 
 
14 
 
________ 
________ 
d-i, k 
 
 
 
 
 
 
 
 
 
21 
 
________ 
________ 
d-i 
 
 
 
 
 
 
 
 
 
28 
 
________ 
________ 
d-i 
 
 
 
 
 
 
 
 
 
35 
 
________ 
________ 
d-i 
 
 
 
 
 
 
 
 
 
41 
 
________ 
________ 
d-k 
*After LMP-TC1 Correlative Biology Study dates are calculated from LMP-TC1 Day 0. The Week 8 and Month 3 time 
points are likely to occur during Course LMP-TC2. Day may vary. See Section 15.3.3 for additional detail. 
End of protocol therapy is after the final evaluation. 
 
See Section 5.0 for Dose Modifications including management of infusion-related reactions, and see Section 4.1.4 
for Supportive Care Guidelines.  
 

  
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Course LMP-TC2 
Page 2 of 2 
4.5.2 
Required Observations in Course LMP-TC2 
 
a. Height/ BSA. 
b. Pregnancy Test: Female patients of childbearing potential require a negative 
pregnancy test prior to starting LMP-TC2. 
c. O2-saturation. 
d. History and Physical Exam, Vital Signs, Performance Status, Weight. 
e. CBC, diff. 
f. Electrolytes, BUN, creatinine: for all patients at Days 0 and 41. Note: interim weekly 
evaluations are required only for patients with renal transplant.  
g. AST, ALT, total and direct bilirubin, albumin, total protein, LDH: for all patients at 
Days 0 and 41. Note: interim weekly evaluations are required only for patients with 
liver transplant. 
h. Documentation of immunosuppressive medication. 
i. As applicable: tacrolimus, cyclosporine, sirolimus and/or everolimus levels weekly. If 
levels are subtherapeutic, adjust dose(s) as per institutional guidelines and repeat 
levels approximately every 48-72 hours until the therapeutic range has been reached. 
See Section 4.5.5 
j. CT with contrast of involved areas: response evaluation between Days 36-41 of LMP 
CTL2. See Section 10.2 specifics for use of MRI or PET in addition to or as an 
alternative modality to CT. Patients with GI tract involvement require endoscopy with 
biopsies if they do not have measurable disease by imaging.  
k. EBV PCR: 5 mL whole Blood in EDTA (purple top). Submission to BCM required 
for centralized assay. See Section 15 instructions. 
l. Correlative Biology Studies: Submission to BCM required for patients who consent 
for the optional studies. See Section 15 for instructions.  
 
This listing only includes evaluations necessary to answer the primary and secondary 
aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
(Include any held doses, or dose modifications) 
 
 
 
 
 
 
 

  
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Page 47 
Course LMP-TC2 
 
4.5.3 
Course LMP-TC2 Treatment Details 
Refer to Appendix III for detailed instructions for the preparation and 
administration of LMP-specific T cells. 
 
LMP-specific T cells: IV infusion over 1-2 minutes 
Days: 0, 7 
Dose: 2 x 107 cells/m2/dose 
 
4.5.3.1 
LMP-TC2 LMP-specific T cells  
Course LMP-TC2 doses will come from the original infused product 
used in LMP-TC1 if the patient had a PR and sufficient vials are 
available. 
 
If the patient had SD and/or there are insufficient cells in the original 
product, another LMP-specific T-cell product may be selected and 
shipped (per SOP) for Course LMP-TC2 if an additional suitably 
matched product is available. 
 
4.5.3.2 
Premedication  
30-60 minutes prior to LMP-specific T-cell infusion, premedication with 
acetaminophen and diphenhydramine is strongly recommended unless 
contraindicated. 
 
Acetaminophen 10-15 mg/kg; max 650 mg PO 30-60 minutes prior to 
LMP-specific T cells. (May be given IV in exceptional circumstances.)  
 
Diphenhydramine 1 mg/kg; max 50 mg PO 30-60 minutes prior to 
LMP-specific T cells (may be given IV). 
 
4.5.3.3 
LMP-specific T Cell Product Preparation and Thawing 
LMP-specific T cells (2x107cells/m2) will be thawed according to the 
SOP (see Appendix III) and administered IV 30-60 minutes after pre-
medication, if applicable. 
 
4.5.4 
Post-therapy Response Assessment 
Evaluation by CT scan with contrast of all involved areas should be completed 
during Week 6 of LMP-TC2. See Section 10.2 specifics for MRI or PET in 
addition to or as an alternative modality to CT. Note: for patients with PR, SD or 
PD, chemotherapy is strongly recommended. Further treatment is according to 
institutional guidelines. 
 
 
4.5.5 
Immunosuppression  
Unlike chemotherapy, LMP T cells do NOT provide any immunosuppression. 
Patients assigned to Arm LMP-TC are required to have minimum levels of either 
calcineurin inhibitors and/or MTOR inhibitors at the start of the course and must 
maintain these minimum levels throughout the course. To prevent organ rejection, 
compliance with the below guidelines is required. 
 

  
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Course LMP-TC2 
MINIMUM Levels for Calcineurin inhibitors: 
Tacrolimus  4 ng/ml 
Cyclosporine 100 ng/ml 
 
MINIMUM Levels for MTOR Inhibitors: 
Sirolimus 4 ng/ml 
Everolimus 3 ng/ml 
 
For patients on combination therapy, the minimum level needs to be maintained at 
least for the calcineurin inhibitors. 
 
See Section 5.0 for Dose Modifications including management of infusion-
related reactions. 
 
 

 
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Page 49 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Modifications Due to Hepatitis B or C Infection 
Any patients with evidence of hepatitis B or C infection must have rituximab (or 
biosimilar) discontinued and must be taken off protocol therapy if they are undergoing 
treatment in Induction or Course RTX2. 
 
5.2 
Management of Rituximab (or biosimilar) Infusion-related reactions 
During the infusion of rituximab (or biosimilar), the occurrence of fever and chills and/or 
hypotension is possible as well as other infusion related symptoms. In case of these adverse 
events, the rituximab (or biosimilar) infusion must be interrupted and the patient treated 
appropriately as per institutional guidelines. After the symptoms have subsided, the 
infusion may be restarted at half the initial infusion rate per guidelines in Appendix II. 
 
Patients with repeated allergic or anaphylactic reaction after more than 1 dose of rituximab 
(or biosimilar) should have rituximab (or biosimilar) discontinued at the investigator’s 
discretion according to institutional guidelines. Patients who do not tolerate all doses of 
rituximab (or biosimilar) will be taken off protocol therapy and further therapy is at the 
treating physician’s discretion. 
 
5.3 
Management of LMP-specific T Cells Infusion-related Reactions 
LMP-specific T cells have been well tolerated in preliminary studies but carry the risk of 
causing an allergic or anaphylactic reaction. Emergency medications including 
diphenhydramine, acetaminophen, hydrocortisone or methylprednisolone and epinephrine 
should be readily available during the infusion. Infusion should be monitored by medical 
staff competent in managing anaphylaxis. In case of any adverse events, the LMP-specific 
T-cell infusion must be interrupted and the patient treated appropriately as detailed in 
Appendix III. 
 
Patients who develop allograft rejection and/or failure possibly, probably or definitely 
related to LMP-TC will not receive any further LMP-TC and will be taken off protocol 
therapy. Further therapy is at the treating physician’s discretion. Administration of high 
dose steroids may be considered since steroid doses of > 0.5 mg/kg/day can effectively 
eliminate LMP-specific T cells in vivo. 
 
Patients who develop Grade 3 or higher GvHD will not receive any further LMP-TC 
therapy and will be taken off protocol therapy. 
 
 

 
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Page 50 
6.0 
AGENT INFORMATION  
 
6.1 
ALLOGENEIC LATENT MEMBRANE PROTEIN SPECIFIC T-LYMPHOCYTES 
(LMP-specific T cells) NSC# 782666, 
  
 
 
(04/29/16) 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

 
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Page 53 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participating clinical trial sites should also consult with their local Institutional 
Biosafety Committee (IBC) for site-specific recommendations regarding preparation, 
handling and disposal; healthcare worker precautions; and patient care. 
 
 
 

 
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Page 54 
 
6.2 
RITUXIMAB, RITUXIMAB-ABBS 
 
 
 
 
 (07/30/19) 
(Rituxan®, Truxima®, Biogen-IDEC-C2B8) NSC #687451   
 
 
 
 
 
 
6.2.1 
Source and Pharmacology 
Rituximab is a genetically engineered chimeric murine/human monoclonal 
antibody which binds specifically to the antigen CD20 (human B lymphocyte 
restricted differentiation antigen, Bp35) located on the surface of pre B and mature 
B lymphocytes of both normal and malignant cells. The antibody is an IgG1 kappa 
immunoglobulin containing murine light- and heavy-chain variable region 
sequences and human constant region sequences. Rituximab is composed of two 
heavy chains of 451 amino acids and two light chains of 213 amino acids and has 
an approximate molecular weight of 145 kD. It is produced in mammalian cell 
(Chinese Hamster Ovary) culture.  
 
CD20 regulates an early step(s) in the activation process for cell cycle initiation 
and differentiation, and possibly functions as a calcium ion channel. Rituximab 
binds to the CD20 antigen on B lymphocytes and recruits immune effector 
functions to mediate B-cell lysis. Possible mechanisms of cell lysis include 
complement-dependent cytotoxicity and antibody-dependent cell mediated 
cytotoxicity. The antibody has been shown to induce apoptosis in the DHL-4 
human B-cell lymphoma line.  
 
In 83% of patients, circulating B cells were depleted within the first three doses of 
rituximab with sustained depletion for up to 6 to 9 months post-treatment. Serum 
levels and half-life are proportional to the dose and have ranged from 31.5 to 
152.6 hours after the first infusion and 83.9 to 407 hours after the fourth weekly 
infusion of 375 mg/m2. The wide range of half-lives may reflect the variable tumor 
burden among patients and the changes in CD20-positive (normal and malignant) 
B-cell populations upon repeated administrations. 
 
6.2.2 
Toxicity 
Incidence 
Toxicities 
Common 
(> 20% of patients) 
• 
Infusion reactions 
• 
Infections 
• 
Lymphopenia 
• 
Fever 
• 
Chills 
• 
Fatigue 
• 
Nausea 
Occasional 
(4-20% of patients) 
• 
Diarrhea, vomiting 
• 
Neutropenia 
• 
Leukopenia  
• 
Anemia 
• 
Thrombocytopenia 
• 
Night sweats 
• 
Rash, pruritus, urticaria 
• 
Increased cough 
• 
Rhinitis 

 
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Page 55 
• 
Bronchospasm, dyspnea 
• 
Headache 
• 
Pain 
• 
Myalgia, arthralgia 
• 
Throat irritation 
• 
Flushing 
• 
Hypotension 
• 
Hypertension 
• 
Hypogammaglobulinemia  
Rare 
(≤ 3% of patients) 
• 
Severe mucocutaneous reactions (paraneoplastic pemphigus, Stevens-
Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, 
and toxic epidermal necrolysis)  
• 
Hepatitis B reactivation with fulminant hepatitis  
• 
Tumor lysis syndrome 
• 
Renal toxicity 
• 
Cardiac adverse reactions, including ventricular fibrillation, myocardial 
infarction, and cardiogenic shock  
• 
Antibody formation 
• 
Bowel obstruction and perforation 
• 
Bronchiolitis obliterans, interstitial lung disease 
• 
Posterior Reversible Encephalopathy Syndrome (PRES) / Reversible 
Posterior Leukoencephalopathy Syndrome (RPLS)  
• 
Prolonged pancytopenia, marrow hypoplasia 
Pregnancy 
& 
Lactation 
Based on human data, rituximab products can cause fetal harm due to B-cell 
lymphocytopenia in infants exposed in-utero. Advise pregnant women of the risk 
to a fetus. Females of childbearing potential should use effective contraception 
while receiving rituximab products and for 12 months following the last dose of 
a rituximab product. 
 
It is unknown whether the drug is excreted in breast milk; however, human IgG 
is excreted in human milk. Advise women not to breastfeed during treatment with 
rituximab products and for 6 months after the last dose.  
 
 
 
6.2.3 
Formulation and Stability 
Rituxan® is a sterile, clear, colorless, preservative free liquid concentrate for 
intravenous administration. Rituximab is supplied at a concentration of 10 mg/mL 
in either 100 mg (10 mL) or 500 mg (50 mL) single use vials. The product contains 
9 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL 
polysorbate 80, and SWFI. The pH is adjusted to 6.5. Store refrigerated at 
temperatures of 2°-8°C (36°-46°F). Protect from direct sunlight.  
 
Truxima® is a clear to opalescent, colorless to pale yellow solution for intravenous 
infusion supplied at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 
mg/50 mL single-dose vials. Each mL of solution contains 10 mg rituximab-abbs, 
polysorbate 80 (0.7 mg), sodium chloride (9 mg), tri-sodium citrate dihydrate (7.35 
mg), and Water for Injection, USP. The pH is 6.5. Truxima® solutions do not 
contain a preservative, hence diluted solutions should be stored refrigerated (2°C 

 
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to 8°C). No incompatibilities between Truxima® and polyvinylchloride or 
polyethylene bags have been observed. 
 
 
6.2.4 
Guidelines for Administration 
See Treatment and Dose Modifications sections of the protocol for additional 
detail. See Appendix II for rituximab infusion guidelines.  
 
Dilute to a final concentration of 1 to 4 mg/mL in NS or D5W. Rituximab solutions 
for infusion may be stored at 2º-8°C (36º-46°F) for 24 hours and have been shown 
to be stable for an additional 24 hours at room temperature.  
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. 
Premedications consisting of acetaminophen and H1-receptor antagonist should be 
administered prior to each infusion. Since transient hypotension may occur during 
rituximab infusions, consider withholding antihypertensive medications 12 hours 
prior to infusion.  
 
6.2.5 
Supplier  
Commercially available from various manufacturers. See package insert for further 
information. 
 
 
 

 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care. 
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, 
procedure and/or anesthesia scheduling issues are acceptable (except where explicitly prohibited 
within the protocol). 
 
7.1 
End of Therapy & Follow-up 
 
7.1.1 
Arm RTX  
End of therapy is Day 22 of Course RTX2 after the CT scan to evaluate response. 
 
7.1.2 
Arm LMP-TC 
End of therapy is Day 42 of Course LMP-TC1 for patients with a CR or PD after 
this course and for patients with PR or SD after this course who do not have a 
suitable T-cell product available for Course LMP-TC2. 
 
End of therapy is Day 42 of Course LMP-TC2 for all other patients. 
 
7.1.3 
Observations During Follow-up 
Observations During Follow-up After 
Completion of Therapy 
1 
Months 
2 
Months 
3 
Months 
6 
Months 
9 
Months 
12 
Months 
History and Physical exam 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
Documentation of immunosuppressive 
medication 
X 
X 
X 
X 
X 
X 
If applicable tacrolimus, sirolimus, 
cyclosporine level 
X 
X 
X 
X 
X 
X 
CBC, diff 
X 
X 
X 
X 
X 
X 
Electrolytes, BUN, creatinine 
X 
X 
X 
X 
X 
X 
AST, ALT, total and direct bilirubin, 
albumin, total protein, LDH 
X 
X 
X 
X 
X 
X 
CT* of involved areas 
As needed for clinical symptoms 
Endoscopy of involved areas 
As needed for clinical symptoms 
Specimens for Submission to BCM  
See Section 15 for Details 
EBV PCR (Required for all patients): 
5 mL whole Blood in EDTA (purple top) 
X 
X 
X 
X 
X 
X 
Correlative biology studies  
(for patients consenting for the optional 
studies) 
Arm LMP-TC follow-up time points are calculated from 
Day 0 of LMP-TC1 regardless of LMP-TC2 participation. 
See Section 15  
For a detailed guide to the follow-up sampling time points. 
* And/or MRI, PET. The same method of assessment and the same technique should be used at 
baseline and during follow-up. See Section 10.2. 
 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 

 
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Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 
 
7.2 
Biology Research Studies  
This section is provided as a brief overview of required and optional biology studies. See 
Section 15 for a detailed guide for time points, specimen requirements and shipping 
instructions. 
 
Study 
Before or 
During 
Induction 
During 
Course 
RTX2 
After 
Course 
RTX2 
During 
Course 
LMP-TC1 
After 
Course 
LMP-TC1 
In Case 
of CRS 
In Case  
of Allograft 
Rejection or 
Failure 
Required 
EBV PCR  
X 
X 
X 
X 
X 
 
 
 
 
 
Optional 
General immune 
reconstitution 
 
X 
X 
X 
X 
X 
 
Persistence of  
LMP-specific T cells 
 
X 
X 
X 
X 
 
X* 
 
Immunity to EBV 
 
X 
X 
X 
X 
 
 
*Submission only in case of suspected allograft rejection or failure during Course LMP-TC1 or LMP-TC2. 
Obtain specimen prior to increasing immunosuppression or commencing steroid therapy. 
 
 
 

 
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
 
8.1 
Criteria for Removal from Protocol Therapy 
a) Repeat eligibility studies (if required) are outside the parameters required for eligibility 
(see Section 3.2.). 
b) Pregnancy. 
c) Evidence of Hepatitis B or C infection during any course of treatment with rituximab (or 
biosimilar). 
d) Unacceptable toxicity due to protocol therapy (See Section 5.2 and Section 5.3). 
e) Progressive disease after or during Course RTX2, Course LMP-TC1, Course LMP-TC2. 
f) Assigned to Arm LMP-TC without an available matched LMP-specific T-cell product. 
g) Assigned to Arm LMP-TC without HLA typing available by the Day 22 post-induction 
Callback. 
h) Refusal of further protocol therapy by patient/parent/guardian. 
i) Physician determines it is in the patient’s best interest. 
j) Development of a second malignancy. 
k) Completion of planned protocol therapy. 
l) Inability to attain and maintain therapeutic immunosuppressive drug levels on the LMP 
TC arm 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see 
below). Follow-up data will be required unless patient is taken off study. 
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (e.g., at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of the date the patient was enrolled on this study. 
f) No treatment received.  
 
 
 

 
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9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Sample Size and Study Duration 
Review of patient accrual onto recent phase 2 PTLD studies and personal communication 
from Canadian investigators indicates the following entry rates can be expected: 
 
 
 
 Disease Group 
 
 
Patients/Year 
Post-Transplant Lymphoproliferative Disorder (PTLD) 
   
 19    
 
The study will likely require 3.1 to 4.9 years to enroll sufficient patients to evaluate LMP-
specific T cells in the stated disease group. A maximum of 90 eligible patients is anticipated 
to obtain at least 30 patients evaluable for the primary endpoint. 
 
Patients in Cohort A (newly diagnosed) are assigned to Arm LMP-TC only if they fail to 
achieve a CR after Course RTX1, while patients in Cohorts B (relapsed) and C (refractory) 
are automatically assigned to Arm LMP-TC.  To avoid going too far past the targeted sample 
size of 30 patients evaluable for the primary aim (i.e., assigned to Arm LMP-TC) while 
avoiding the need to repeatedly open and close the trial to enrollments, we will closely monitor 
enrollments when the number of patients assigned to Arm LMP-TC approaches 30. The 
number of available enrollments will be limited to the smallest number such that there is a 
90% chance of reaching 30 patients assigned to Arm LMP-TC assuming each patient in 
Cohort A has a 40% chance of being assigned to Arm LMP-TC and all patients in Cohort B 
and C will be assigned to Arm LMP-TC. If at any time the number of patients enrolled in 
Cohort A but not having reached Callback equals or exceeds this threshold, the study will be 
closed to accrual until all patients currently enrolled have either been assigned to either Arm 
RTX or Arm LMP-TC or have been removed from protocol therapy. If after that there are 
fewer than 30 patients assigned to Arm LMP-TC, the study will be re-opened with the number 
of available slots as in the table below. 
 
The table below displays the maximum number patients that will be allowed to be enroll, the 
probability of reaching 30 patients on Arm LMP-TC if there are exactly that many patients in 
Cohort A pre-Callback, and the probability of exceeding 36 patients on Arm LMP-TC if there 
are exactly that many patients in Cohort A pre-Callback. 
 
Current Cohort A patients 
assigned to Arm LMP-TC 
plus all patients in 
Cohorts B and C 
Maximum number 
of Cohort A patients 
pre-Callback 
Probability of 
reaching 30 patients 
on Arm LMP-TC 
Probability of 
exceeding 36 patients 
on Arm LMP-TC 
21 
30 
90.6% 
  9.7% 
22 
27 
90.5% 
  7.4% 
23 
24 
90.4% 
  5.3% 
24 
21 
90.4% 
  3.5% 
25 
18 
90.6% 
  2.0% 
26 
15 
90.9% 
  0.9% 
27 
12 
91.7% 
  0.3% 
28 
  9 
92.9% 
<0.1% 
29 
  5 
92.2% 
  — 
 

 
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9.2 
Study Design 
The primary endpoint of the study (Aim 1.1.1) is the percentage of patients assigned to Arm 
LMP-TC who had a suitable LMP-specific T-cell product, were treated within two weeks of 
the expected start date (Callback for Cohorts A and B, study enrollment for Cohort C), and 
received both weekly doses in a cooperative multi-institutional setting. All 3 Cohorts will be 
analyzed together for the primary aim.  
 
The main secondary endpoint of the study (Aim 1.2.1) is the percentage of all eligible patients 
who had a suitable LMP-specific T-cell product derived from a Third Party LMP-specific 
T-cell bank available in a cooperative multi-institutional setting.  Additional secondary 
endpoints (Aims 1.2.2-1.2.8) will be the estimation of progression-free survival (PFS), event-
free survival (EFS), overall survival (OS), response rate (RR), and toxicity rates in the study 
population. 
 
At least thirty (30) patients evaluable for the primary endpoint will be enrolled, with a futility 
analysis after 15 patients. The study will be considered successful if 23/30 evaluable patients 
in the trial are matched, are treated within two weeks of the expected start date, and receive 
both weekly doses of LMP-specific T cells. If exactly 23/30 successes occurred, the one-sided 
exact binomial 95% confidence interval (adjusted for the interim analysis by the method of 
Jung and Kim)37 would be p > 60.7%, which would exclude the possibility that the true 
success rate is as low as 60%. If the true success rate in the study population is 80%, then the 
proposed sample size of 30 will give 75.3% power to get at least 23/30 successes. If the true 
success rate in the study population is 60%, then there is a 4.2% chance of getting at least 
23/30 successes. 
 
Since evaluability for the primary endpoint depends on the response to the initial treatment 
with rituximab for patients in Cohort A (newly diagnosed patients), it is possible that more 
than 30 patients will be evaluable for the primary endpoint.  In that case, the trial will be 
considered successful if the one-sided exact binomial 95% confidence interval excludes the 
possibility that the true success rate is as low as 60%. The required number of successes and 
power under various scenarios is displayed below. 
 
Number of  
evaluable patients 
Number of 
successes needed 
Power 
(80% true rate) 
Power  
(60% true rate) 
30 
23 
75.3% 
4.2% 
31 
24 
72.4% 
3.2% 
32 
25 
69.3% 
2.4% 
33 
25 
78.7% 
4.2% 
34 
26 
76.2% 
3.3% 
35 
27 
73.5% 
2.5% 
36 
27 
81.4% 
4.2% 
 
 
9.3 
Methods of Analysis 
For the primary endpoint, the point estimate of the proportion successfully matched and 
treated (among all 3 Cohorts combined) will be the uniformly minimum variance unbiased 
estimator, and an exact one-sided binomial 95% confidence interval (adjusted for the interim 
analysis by the method of Jung and Kim)37 will be used to get a lower bound for the actual 
rate of successful treatments as defined in the primary objective. 
 

 
T HI S P R O T O C O L I S F O R R E S E A R C H P U R P O S E S O N L Y , S E E P A G E 1  F O R U S A G E P O LI C Y  
A N H L 1 5 2 2  
 
 
 
 
Versi o n date: 0 3- 2 3- 2 0 2 0 
 
Pa ge 6 2 
 
F or t he sec o n dar y e n d p oi nts:  
• T he pr o p orti o n of eli gi ble patie nts w h o are s uccessf ull y matc he d will be assesse d usi n g t he 
u nif or ml y mi ni m u m varia nce u n biase d esti mat or f or t he pr o p orti o n a n d  a n e xact o ne-si de d 
bi n o mial 9 5 % c o nfi de nce i nter val (a dj uste d f or t he i nteri m a nal ysis b y t he met h o d of J u n g 
a n d Ki m) 3 7 t o get a l o wer b o u n d f or t he act ual rate. 
• P F S ( defi ne d as ti me t o first occ urre nce of pr o gressi o n or  deat h (e ve nts) or l oss t o f oll o w -
u p or s ur vi val t o a nal ysis date ( n o n -e ve nts)), E F S ( defi ne d as ti me t o first occ urre nce of 
rela pse, sec o n d/sec o n dar y mali g na nt ne o plas m ( S M N), deat h (e ve nts) or l oss t o f oll o w-u p 
or s ur vi val t o a nal ysis date ( n o n -e ve nts)), a n d O S ( defi ne d as ti me t o deat h (e ve nt) or l oss 
t o f oll o w-u p or s ur vi val t o a nal ysis date ( n o n -e ve nts)) will be assesse d usi n g Ka pla n -Meier 
esti mates, b ot h f or all patie nts c o m bi ne d a n d als o se paratel y i n eac h C o h ort. Ai m 1. 2. 8 will 
be  assesse d  usi n g  t he  L o g-Ra n k  test  f or  E F S  a n d  O S  a n d  t he  e xact  c o n diti o nal  test  of 
pr o p orti o ns  ( Fis her’s E xact test) f or R R, b ot h f or all patie nts c o m bi ne d a n d stratifie d b y 
C o h ort . 
• Res p o nse rates will be assesse d usi n g e xact t w o -si de d bi n o mial 9 5 % c o nfi de nce i nter vals 
t o get esti mates of t he res p o nse rate. Ai m 1. 2. 2  will be e val uate d i n C o h orts A a n d B o nl y 
(c o m bi ne d a n d se paratel y), wit h res p o nse classifie d b y co m pari n g disease e val uati o n at t he 
Wee k 3 e val uati o n t o t he baseli ne of disease e val uati o n at st u d y e ntr y usi n g  t he criteria i n 
Secti o n 1 0. 2.  Patie nts wit h C R will be c o nsi dere d res p o n ders . F or Ai m 1. 2. 5, res p o nse will 
be classifie d b y c o m pari n g disease e val uati o n at t he Wee k 6 of L M P -C T 1 e val uati o n t o 
t he baseli ne of disease e val uati o n at t he Wee k 3 e val uati o n usi n g t he criteria i n Secti o n 
1 0. 2 , b ot h i n all C o h orts c o m bi ne d a n d i n eac h C o h ort se paratel y.  Patie nts wit h C R or P R 
will be c o nsi dere d res p o n ders.  
• T o xicities will be descri be d usi n g descri pti ve statistics. T o xicit y m o nit ori n g a n d a nal ysis 
will be perf or me d base d o n “as treate d”.  
 
We will assess t he pr o p orti o n of s uccesses f or t he pri mar y ai m o n t he first  1 5 patie nts assi g ne d 
t o Ar m L M P-T C  as a n i nteri m f utilit y m o nit ori n g r ule . If fe wer t ha n 1 0 of t he first 1 5 patie nts 
are s uccesses f or t he pri mar y ai m ( matc he d a n d treate d wit hi n t he prescri be d ti mefra me), t he 
St u d y C o m mittee will assess t he reas o ns f or fail ure a n d ma y c h o ose t o cl ose t he st u d y if it is 
felt t hat the reas o ns are n ot c orrecta ble.  If t he tr ue s uccess rate is 6 0 %, t his r ule will be i n v o ke d 
w it h  pr o ba bilit y  5 9. 7 %;  if  t he  tr ue  s uccess  rate  is  8 0 %,  t he  r ule  will  be  i n v o ke d  wit h 
pr o ba bilit y 6. 1 %.  
We will d o real -ti me m o nit ori n g f or pr o gressi o n rate at wee k 1 0 a n d f or certai n pr ot oc ol-
s pecific t o xicities, na mel y : all o graft fail ure, all o graft rejecti o n, c yt o ki ne release s y n dr o me 
gra de 3 or hi g her, a n d graft vers us h ost disease  (see A p pe n di x V ). T he m o nit ori n g will be 
d o ne usi n g Ba yesia n r ules wit h beta pri ors. 3 8 ,3 9  T he f o ur para meters f or eac h sce nari o are 
t he t w o beta distri b uti o n para meters (α , β ), t he u nacce pta ble pr o ba bilit y rate f or t he e ve nt 
we are m o nit ori n g ( p 0), a n d t he p osteri or pr o ba bilit y t hat t he act ual rate e xcee ds p 0 (P (p  > 
p 0 | Data)), w hic h is calc ulate d usi n g t he sta n dar d Ba yesia n p osteri or pr o ba bilit y f or m ula  
 
( 
)
( 
)
( ) ( )
( 
)
( 
)
( 
)
( ) ( )
( 
)
0
1
1
1
0
1
1
1
0
Γ
1
1
 
Γ
Γ
(  
Data)
 ,
Γ
1
1
 
Γ
Γ
n
x
x
p
n
x
x
d
n
p
p
 
p
 
p
x
P p  
p
n
q
q
 
q
 
q
p
x
d q
β
α
β
α
α
β
α
β
α
β
α
β
−
−
−
−
−
−
+


−
−




>
=
+


−
−




∫
∫
∣
 

 
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Page 63 
where n is the number of observations and x is the number of events among those n 
observations. 
 
We will suspend enrollment to the study if any patient suffers or is suspected to suffer 
allograft failure or allograft rejection to review the circumstances of the failure or rejection. 
A recommendation to re-open enrollment might be made if causes other than study therapy 
were thought to be the primary cause of failure or rejection. 
 
For cytokine release syndrome and graft versus host disease, the analytic unit for 
monitoring for protocol-specific toxicities will be the patient-course. Each course where 
the patient receives the agent or where a protocol-specific toxicity event is observed will 
be considered in the analysis. We will assume a beta prior distribution with α = 0.6 and β 
= 1.4 and an unacceptable toxicity rate of p0 = 30%. At least once per month, we will 
calculate the posterior probability (given the data) that the probability of protocol-specific 
toxicity exceeds the 30% threshold, i.e., P(p > 0.3 | Data). If there is a posterior probability 
of 80% that the toxicity rate is at least 30%, then accrual will be suspended pending review 
by DSMC. Examples of situations in which this rule will indicate protocol-specific 
toxicities have been noted and are presented below: 
 
Number of failures Number of patient-cycles 
2 
3 
3 
6 
4 
8 
5 
11 
6 
14 
7 
17 
8 
20 
9 
23 
10 
26 
11 
29 
12 
32 
13 
35 
14 
38 
 
Interim monitoring will also be performed to watch for a 20% progression rate at week 10 in 
newly-diagnosed patients and a 40% progression rate at week 10 for relapsed and refractory 
patients. For newly-diagnosed patients, the beta parameters will be α = 0.52 and β = 2.08; and 
for relapsed and refractory patients the beta parameters will be α = 1.04 and β = 1.56; if there 
is a posterior probability of 80% that the progression rate at week 10 is at least 20% for newly-
diagnosed patients or 40% for relapsed/refractory patients, then accrual for the respective 
cohort or cohorts will be suspended pending review by the DSMC. The stopping rule will be 
triggered as described in the following table: 
 
Number 
of failures 
Number of 
newly-diagnosed 
patients 
Number of 
relapsed/refractory 
patients 
2 
4 
2 
3 
8 
4 
4 
12 
6 
5 
16 
8 

 
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6 
20 
11 
7 
24 
13 
8 
29 
15 
9 
33 
17 
10 
38 
19 
 
 
9.4 
Evaluability for Response  
Eligible patients assigned to Arm LMP-TC will be considered evaluable for the primary 
endpoint (percentage successfully matched and treated). All 3 Cohorts will be combined into 
a single set of patients for the analysis.  
 
All eligible patients will be evaluable for Aims 1.2.1, 1.2.8, and 1.3.2. For Aim 1.2.1, all 
patients who submit HLA typing by the end of the trial will be evaluable, regardless of the 
timing of the submission. 
 
Any eligible patient who receives at least one dose of RTX will be considered evaluable for 
Aims 1.2.2–1.2.4 and 1.2.6. 
 
Any eligible patient who receives at least one dose of LMP-specific T cells will be considered 
evaluable for Aims 1.2.5, 1.2.7, 1.3.1, and 1.3.3. 
 
9.5 
Evaluability for Toxicity  
A patient will be considered for toxicity monitoring if the patient is eligible, receives at 
least one dose of protocol therapy, and one of the following occurs: (1) completes a full 
cycle of therapy with no toxicities; (2) dies on protocol therapy for a reason considered 
possibly, probably, or likely related to protocol therapy; or (3) experiences an adverse 
experience possibly, probably, or likely related to one of the agents. A toxicity-evaluable 
patient will be considered in the analysis during the interval from study enrollment until 
protocol therapy is terminated or a toxicity-event is observed, whichever occurs first. A 
toxicity-evaluable patient will be considered to have experienced a protocol-specific 
toxicity event if: (1) the patient dies on protocol therapy for a reason considered possibly, 
probably, or likely related to protocol therapy; or (2) experiences a dose-limiting toxicity. 
 
 
9.6 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
1 
0 
0 
1 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
7 
3 
0 
0 
10 
White 
16 
32 
3 
3 
54 
More Than One Race 
0 
0 
0 
0 
0 
Total 
23 
36 
3 
3 
65 
 
 

 
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INTERNATIONAL (including Canadian participants) PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ Alaska Native 
0 
1 
0 
0 
1 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
3 
1 
0 
0 
4 
White 
6 
12 
1 
1 
20 
More Than One Race 
0 
0 
0 
0 
0 
Total 
9 
14 
1 
1 
25 
 
This distribution was derived from patients enrolled on ANHL0221, the most recent COG 
study of PTLD. 
 
9.7 
Correlative Studies 
We will summarize the in vivo measurements of virus-specific T cells over the pre-LMP-
specific T cells to the post-LMP-specific T cells monitoring period in patients who receive 
LMP-specific T cells versus patients who do not to assess the pattern and magnitude of 
T-cell expansion and persistence for EBV and response to LMP-specific T cells 
administration using plots generated for each patient to graphically illustrate the pattern 
and duration of LMP-specific T-cell persistence and expansion. The area under the curve 
(AUC) will be calculated for each subject by the trapezoidal rule. The AUCs will be 
summarized, and after logarithmic transformation, will be analyzed by a two-sample t-test. 
Measurements of immunity, tetramer analysis and functional assays will be evaluated by 
descriptive statistics (means, standard deviations, medians and ranges) at each time point 
and analyzed by paired t-tests to compare changes from pre- to post-infusion.  
 
 
 

 
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10.0 
EVALUATION CRITERIA 
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 5.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting. A copy of the CTCAE version 5.0 can be downloaded 
from the CTEP website  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v5.0’ is understood to represent the most current version of CTCAE 
v5.0 as referenced on the CTEP website (i.e., v5.02 and all subsequent iterations prior to 
version 6.0). 
 
10.2 Response Criteria  
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Pediatric Non-Hodgkin 
Lymphoma Criteria40, with modification from the Lugano classification for all patients 
with measurable disease.41 Patients with evaluable disease of the GI tract will have to be 
evaluated by endoscopy and biopsies. 
 
10.2.1 Induction: RTX for all non-refractory patients 
For the purposes of this study, patients will be evaluated for response Week 3 of 
Induction (RTX1).  
 
10.2.2 Arm RTX 
In addition to a baseline scan or endoscopy with biopsies, confirmatory scans 
and/or endoscopy with biopsies should also be obtained at the end of Course 
RTX2.  
 
10.2.3 Arm LMP-TC 
In addition to a baseline scan and/or endoscopy with biopsies, additional scans 
and/or endoscopy with biopsies to document response need to be obtained at the 
end of Course LMP-TC1 during Week 6 of that course. For patients assigned to 
Course LMP-TC2, there will be an additional evaluation time point with scans 
scheduled at week 6 of LMP-TC2. 
 
For patients found to have progressive disease (PD) at either one of those 
evaluations, it is recommended to repeat scans in a 2-4 week time frame as per the 
Lugano classification41 to confirm progressive disease prior to changing therapy 
because inflammatory responses to LMP-specific T cells have been reported with 
a corresponding initial increase in size and metabolic uptake of involved lymph 
nodes. 
 
10.2.4 Definitions 
 
10.2.4.1 Evaluable for toxicity: A patient will be considered for toxicity 
monitoring if the patient is eligible and one of the following occurs: (1) 
completes one course of protocol therapy; (2) dies on protocol therapy 
for a reason considered possibly, probably, or likely related to protocol 
therapy; or (3) is removed from protocol therapy because of an adverse 

 
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experience possibly, probably, or likely related to one of the agents. 
 
10.2.4.2 Evaluable for objective response: Only those patients who have 
measurable disease present at baseline and have received at least one 
dose of protocol therapy will be considered evaluable for response. 
These patients will have their response classified according to the 
definitions stated below. (Note: Patients who exhibit objective disease 
progression prior to the end of Course 1 will also be considered 
evaluable.) 
 
10.2.5 Disease Parameters 
 
10.2.5.1 Measurable disease: A measurable node must have an LDi (longest 
diameter) greater than 1.5 cm. A measurable extranodal lesion should 
have an LDi greater than 1.0 cm. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
10.2.5.2 Non-measured disease: All other lesions (including nodal, extranodal, 
and assessable disease) should be followed as nonmeasured disease (e.g., 
cutaneous, GI, bone, spleen, liver, kidneys, pleural or pericardial 
effusions, ascites).   
 
10.2.5.3 Target lesions: For patients staged with CT, up to six of the largest target 
nodes, nodal masses, or other lymphomatous lesions that are measurable 
in two diameters (longest diameter [LDi] and shortest diameter) should 
be identified from different body regions representative of the patient’s 
overall disease burden and include mediastinal and retroperitoneal 
disease, if involved. 
 
10.2.6 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 2 weeks prior to the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
10.2.6.1 Clinical lesions: Clinical lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes) 
and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
10.2.6.2 Conventional CT and MRI: The major response designations will be 
established by CT or MRI of involved sites in conjunction with 
morphologic evaluation of bone marrow (BM) if involved at diagnosis. 
With growing concerns about the risks of cumulative ionizing radiation 
exposure to children from CT, MRI could be considered as an alternative 

 
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to CT for evaluating non-pulmonary disease sites. e.g., assessment of 
abdominal/pelvic disease. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be 
optimized for the evaluation of the type and site of disease. Furthermore, 
as with CT, the modality used at follow-up should be the same as was 
used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the response guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible 
to prior scans. Pulse sequences should include at a minimum, axial and 
coronal fat-saturated FRFSE-T2, coronal T1 and axial and coronal post-
gadolinium fat-saturated T1 weighted imaging. Body scans should be 
performed with breath-hold scanning techniques, if possible. 
 
10.2.6.3 PET-CT: At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality. 
However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV 
and oral contrast), then the CT portion of the PET-CT can be used for 
International Pediatric Non-Hodgkin Lymphoma Response Criteria 
measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the 
PET portion of the CT introduces additional data, which may bias an 
investigator if it is not routinely or serially performed.   
 
10.2.6.4 Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. Ultrasound 
examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken 
from one assessment to the next. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
10.2.6.5 Endoscopy, Laparoscopy: Endoscopy may be used in patients with 
evaluable disease of the GI tract to confirm complete pathological 
response by obtaining biopsies.  
 
10.2.6.6 Tumor markers: There will be no use of tumor markers to assess response 
in the protocol. EBV qPCR of peripheral blood PBMCs will be 
performed centrally to measure the presence of active viral replication 
and disease activity but results will not be used to stratify assignment to 
treatment arms. 
 
10.2.6.7 FDG-PET: For patients with a positive PET scan at diagnosis, PET can 
be used to follow response in addition to a CT scan using the 
International Pediatric Non-Hodgkin Lymphoma Response Criteria.40 
 

 
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10.2.7 Response Criteria 
 
10.2.7.1 Evaluation of Measurable Disease 
 
Complete Response (CR): 
Disappearance of all disease. CT or MRI 
should be free of residual mass or evidence 
of new disease. FDG-PET should be 
negative. 
 
CR unconfirmed (Cru):   Residual mass is negative by FDG-PET; no 
new lesions by imaging examination; no 
new and/or progressive disease elsewhere 
 
Partial Response (PR): 
 50% decrease in SPD (the sum of the 
products of the largest diameter and the 
perpendicular diameter for a tumor mass) on 
CT or MRI; FDG-PET may be positive 
(Deauville score or 4 or 5 with reduced 
lesional uptake compared with baseline); no 
new and/or PD; morphologic evidence of 
disease may be present in BM if present at 
diagnosis; however, there should be 50% 
reduction in percentage of lymphoma cells 
 
Progressive Disease (PD): For those with > 25% increase in SPD on CT 
or MRI, Deauville score 4 or 5 on FDG-PET 
with increase in lesional uptake from 
baseline, 
or 
development 
of 
new 
morphologic evidence of disease in BM 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum 
diameters while on study. 
 
10.2.7.2 Evaluation of Non-measured Lesions (CT-based response, PET/CT 
based response not applicable)41 
 
Complete Response (CR): 
Absent non-measured lesions.  
 
Partial response (PR): 
Absent/normal, regressed, lesions, but no 
increase. 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): New or clear progression of preexisting 
non-measured lesions. 
 
 
10.2.7.3 Evaluation of organ enlargement41  
 

 
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Complete Response (CR): 
Regress to normal  
 
Partial response (PR): 
Spleen must have regressed by > 50% in 
length beyond normal 
 
Stable Disease (SD): 
No increase consistent with progression 
 
Progressive Disease (PD): In the setting of splenomegaly, the splenic 
length must increase by 50% of the extent 
of its prior increase beyond baseline. If no 
prior splenomegaly, must increase by at 
least 2 cm from baseline.  
 
New or recurrent splenomegaly 
 
10.2.8 Duration of Response 
 
10.2.8.1 Duration of overall response: The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented. 
 
10.2.8.2 Duration of stable disease: Stable disease is measured from the start of 
the treatment until the criteria for progression are met.  
 
10.2.9 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression 
or death, whichever occurs first. 
 
10.2.10 Response Review 
Response will be as per institutional evaluations. 
 
 
 

 
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11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
  
11.1 
Purpose 
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 future studies using similar agents. Certain adverse events must be reported 
in an expedited manner to allow for timelier monitoring of patient safety and care. The 
following sections provide information about expedited reporting. 
 
11.2 Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was associated 
with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Application (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply. 
• 
Concurrent administration: When an investigational agent is used in combination 
with a commercial agent, the combination is considered to be investigational and 
expedited reporting of adverse events would follow the guidelines for investigational 
agents. 
• 
Sequential administration: When a study includes an investigational agent and a 
commercial agent on the same study arm, but the commercial agent is given for a 
period of time prior to starting the investigational agent, expedited reporting of 
adverse events which occur prior to starting the investigational agent would follow 
the guidelines for commercial agents.  Once therapy with the investigational agent is 
initiated, all expedited reporting of adverse events follow the investigational agent 
reporting guidelines. 
 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, NCI requires that AEs be 
submitted according to the timeframes in the AE reporting tables assigned to the protocol, 
using the CTEP Adverse Event Reporting System (CTEP-AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 

 
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1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
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 a serious adverse drug experience 
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. 
 
11.4 
Specific Examples for Expedited Reporting  
 
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 
possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting tables in this protocol.  
 
11.4.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it 
occurs at any time following treatment with an agent under a NCI, COG, or 
industry sponsor IND/IDE since these are considered to be serious AEs. 
 
11.4.3 Death 
 
Reportable Categories of Death  
o Death attributable to a CTCAE term.  
o Death Neonatal: A disorder characterized by cessation of life during the first 
28 days of life.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o 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.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 
24 hours.  
 

 
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Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.4.4 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 metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via 
CTEP-AERS. Three options are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.4.5 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 routine reporting via CDUS unless otherwise specified. 
 
11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form, available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to (301) 897-7404. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.4.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents that may be teratogenic. For this reason, pregnancy needs 
to be reported in an expedited manner via CTEP-AERS as Grade 3 
“Pregnancy, 
puerperium 
and 
perinatal 
conditions 
- 
Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
 
Pregnancy needs to be followed until the outcome is known. If the baby 
is born with a birth defect or anomaly, then a second CTEP-AERS report 
is required. 
 
11.4.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any 
Pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 

 
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conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 
11.4.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring during 
the first 28 days after birth” should be reported expeditiously as Grade 
4 “Death neonatal” under the “General disorders and administration” 
SOC when the death is the result of a patient pregnancy or 
pregnancy in partners of men on study. Do NOT report a neonatal 
death resulting from a patient pregnancy or pregnancy in partners of men 
on study as a Grade 5 event since CTEP-AERS recognizes any Grade 5 
event as a patient death.  
 
11.5 
Reporting Requirements for Specialized AEs  
 
11.5.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (e.g., elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must reassess 
the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event to 
determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities existing 
at baseline. 
 
11.5.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
11.5.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 

 
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11.6 Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is listed as 
expected. The exception or acceptable reporting procedures will be specified in the 
protocol. The protocol specific guidelines supersede the NCI Adverse Event Reporting 
Guidelines. These special situations are listed under the CTEP-AERS reporting Table A 
for this protocol. 
 
11.7 Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database.   
 
11.8 General Instructions for Expedited Reporting via CTEP-AERS  
 
The reporting methods described below are specific for clinical trials evaluating 
agents for which the IND is held by COG, an investigator, or a pharmaceutical 
company. It is important to note that these procedures differ slightly from those used 
for reporting AEs for clinical trials for which CTEP holds the IND. 
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting.  
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
An expedited AE report must be submitted electronically via CTEP-AERS at:  
https://eapps-ctep.nci.nih.gov/ctepaers 
 
• 
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 event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth defect, 
or is an IME, which based upon the medical judgment of the investigator may 
jeopardize the patient and require intervention to prevent a serious AE, must be 
reported via CTEP-AERS if the event occurs following investigational agent 
administration.  
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention requires expedited reporting within 24 hours via e-mail to the 
COG CTEP-AERS Coordinator and Study Chair.   
 

 
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• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention requires expedited reporting 
within 24 hours via e-mail to the COG CTEP-AERS Coordinator and Study Chair. 
 
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 
Fax or email supporting documentation for AEs related to investigational agents to 
COG: Fax # (310) 640-9193; email: COGAERS@childrensoncologygroup.org; Attention: 
COG AERS Coordinator.  
 
• 
ALWAYS include the ticket number on all faxed documents. 
• 
Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (COG) 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) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours. This  does not include hospitalizations that are part of routine medical practice. 
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 
 
7 Calendar Days 
 
 
24-Hour Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 Calendar Days 

 
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NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Additional Special 
Situations as Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“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 
notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of 
learning of the AE.  
 
1SAEs 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 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  
 
 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
 
• Allograft rejection and/or failure requires expedited reporting. 
• GvHD Grade 3 and higher (see Appendix V) requires expedited reporting. 
11.11 Reporting of Adverse Events for Commercial Agents – CTEP-AERS Abbreviated 
Pathway 
The following are expedited reporting requirements for adverse events experienced by 
patients on study who have not received any doses of an investigational agent on this study. 
Commercial reporting requirements are provided in Table B.  
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning 
of the event. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy with a Commercial Agent or Within 30 Days1 
 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or 
Unlikely 
 
 
CTEP-AERS 
Possible, Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial agent, 
regardless of attribution. Any death that occurs more than 30 days after the last dose of 
treatment with a commercial agent that can be attributed (possibly, probably, or definitely) to 
the agent and is not due to cancer recurrence must be reported via CTEP-AERS. 
 

 
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11.12 Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all CTEP-AERS 
reportable events and Grade 3 and higher Adverse Events, and all grades of the following: 
allograft failure, allograft rejection, cytokine release syndrome, and graft versus host 
disease (see Appendix V). 
 
 
 

 
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12.0 
STUDY REPORTING AND MONITORING  
The Case Report Forms and the submission schedule are posted on the COG web site with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted quarterly to CTEP 
by electronic means. Reports are due January 31, April 30, July 31 and October 31. CDUS 
reporting is not a responsibility of institutions participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (e.g., termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified 
in the protocol document. 
 
 
 

 
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13.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
 
13.1 
Pathology Goals 
• 
By retrospective review provide accurate diagnosis and classification of CD20 positive 
and EBV positive Post-Transplant Lymphoproliferative Disease (PTLD) in pediatric 
solid organ recipients included in this treatment protocol. The diagnosis to be based on 
both morphological and immunophenotypic criteria.  As this is a retrospective review, 
results of the review will not be returned to the submitting site. 
 
• 
Employ the World Health Organization Lymphoma Classification to facilitate 
concordance in diagnosis.  
 
• 
Evaluate CD20+ and EBV+ PTLD included in this protocol for immunophenotypic 
and pathologic features that may impact prognosis.  
 
13.2 
Requirements for Handling Tissue or Cytology Specimens at Primary Institutions  
Tissue should, whenever possible, be obtained fresh and delivered immediately to the 
Pathology laboratory for optimal handling and distribution (fixation, snap freezing, 
cytogenetics, etc.) 
 
Representative tissue sections should be submitted for fixation including at least one block 
with 10% buffered formalin. 
 
13.3 
Immunophenotyping Recommendations for Primary Institutions 
For initial determination of cell lineage the methodology and criteria for immunophenotypic 
analysis defined by the submitting institution will be accepted. Recognized methods include 
paraffin section, immunohistochemistry, flow cytometry and cytospin immunocytochemistry. 
 
13.3.1 Required Antibodies/In-Situ Hybridization: 
• 
CD20 
• 
EBER (preferred) and/or LMP-1 
 
13.3.2 Recommended antibodies 
• 
At least one additional anti-B antibody (CD79A, PAX-5)  
• 
At least two anti-T antibodies (CD3 and one other T-cell specific antibody)  
 
13.4 
Morphology 
The following are recognized morphological variants of PTLD that should be diagnosed 
according to the criteria established by the WHO Classification.9 
• 
Mononucleosis-like 
• 
Plasma cell hyperplasia 
• 
Polymorphic 
• 
Monomorphic 
• 
Classical Hodgkin-like 
 
13.5 
Study Pathologist 
For any questions regarding the pathology protocol or assistance with immunophenotyping 
studies, contact the pathologist listed below. Difficult cases may also be reviewed in 
consultation prior to enrollment with the pathologists listed below. 

 
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14.0 
SPECIMENS TO SUBMIT FOR CENTRAL PATHOLOGY REVIEW 
14.1 
List of Specimen Types 
Materials to be submitted for retrospective pathology review are not required but strongly 
encouraged. If possible, please submit the following materials to the COG Biopathology 
Center (BPC): 
 
1. Representative sample, (paraffin embedded material, 1 or 2 blocks) from tumor biopsy 
at original diagnosis, time of relapse (if applicable) and time the patient was confirmed 
to be refractory (if applicable).  
a. If blocks are unavailable submit 30 unstained slides from one representative 
block and 2 H&E slides from each available block. For surgical biopsy 
specimens 10% buffered formalin is the preferred fixative. Please submit 
unbaked slides that are air dried at room temperature for the unstained slides.  
Sections should be cut on silane-coated slides (i.e. Fisher Superfrost Plus).   
b. For cytologic specimens, at least 10 unstained cytology slides or (preferably) 
20 slides from a cell block preparation, prepared as outlined for surgical 
specimens above, should be submitted. 
 
14.2 
Pathology Reports and Transmittal Form 
All corresponding pathology reports and ancillary testing (i.e. flow cytometry, 
cytogenetics) for each case must be submitted. These are required even if no blocks or 
slides were sent. Please include reports from original diagnosis, time of relapse (if 
applicable) and time the patient was confirmed to be refractory (if applicable). This should 
include: 
1. Final pathology reports of all diagnostic biopsies, bone marrow specimens, and 
cerebrospinal fluid specimens including all immunophenotyping reports of diagnostic 
biopsy, bone marrow specimens and cerebrospinal fluid specimens (if available);  
2. Results of any genotypic studies (i.e. gene rearrangement or fluorescent in-situ 
hybridization studies); and  
3. Results of any cytogenetic (karyotypic) analysis.  
4. Pathology Data Collection Forms (Institutional Pathology Form). 
A separate pathology data collection form (Institutional Pathology Form) must be 
completed and submitted along with the above materials. Also, indicate the primary 
institution pathology diagnosis utilizing the WHO Classification criteria9 on the data 
collection form. 
5. COG Pathology Transmittal Form along with the Pathology Data Collection Form 
(Institutional Pathology Form).  
 
14.3 
Submission of Pathology Review Materials 
Label all review materials with the patient’s COG patient ID number and the surgical 
pathology identification number and block number from the corresponding pathology 
report. Send a completed COG Pathology Transmittal Form with the pathology review 
materials by U.S. mail or using your institution’s courier account. All material submitted 
for central pathology review should be sent to: 
 
Biopathology Center Nationwide Children’s Hospital  
700 Children’s Drive, WA 1340  
Columbus, OH 43205  
Phone:  (614) 722-2865  
Fax:  
(614) 722-2897 

 
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Email:  BPCParaffinTeam@nationwidechildrens.org  
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
 
15.1 
Table of Specimens 
* Time point calculated from Day 1 of RTX2. 
# Time point calculated from Day 0 of LMP-TC1 regardless of treatment on Course LMP-TC2. 
 
15.2 Blood Sample Collection 
 
15.2.1 Whenever a specimen collection time falls on a treatment infusion day, blood must be 
drawn prior to initiation of the infusion. 
 
15.2.2 The indicated time points in the table above represent the ideal schedule. Flexibility is 
expected in order to coordinate with times of blood draw for regular clinical care: 
Study 
Time points 
Collection Details 
Additional Details 
Mailing 
Destination 
15.1.1 
EBV PCR 
Required from all 
patients 
• 
RTX1: Days 1 & 21 
• 
RTX2: Days 1 & 21 
• 
LMP-TC1: Days 0, 14, & 41 
• 
LMP-TC2: Days 0, 14, & 41 
• 
Follow-up: Months 1, 2, 3, 6, 9 
& 12 
Draw 5 mL of 
whole blood in a 
EDTA (purple top) 
tube. 
Store at room 
temperature. Ship on 
the day of collection. 
Do not freeze 
samples. 
Allen Lab at 
Baylor College 
of Medicine 
(BCM) 
Section 15.3.4 
15.1.2 
General Immune 
Reconstitution 
(Optional patient 
consent required) 
• 
RTX2: Days 1, 8, 15, & 21  
• 
After completing RTX2*: 
Weeks 6, 8, Months 3, 6, 9 & 12 
• 
LMP-TC1: Days 0, 7, 14, 28 & 
41 
• 
After completing LMP-TC1#: 
Week 8, Months 3, 6, 9 & 12 
Draw 6-12 mL of 
whole blood in a 
sodium heparin 
(green top) tube. 
Store at room 
temperature. Ship on 
the day of collection. 
Do not freeze 
samples. 
Allen Lab at 
BCM 
Section 15.3.4 
15.1.3 
Persistence of 
LMP-specific T 
cells; Immunity to 
EBV 
(Optional patient 
consent required) 
• 
RTX2: Days 1, 8, 15 & 21 
• 
After completing RTX2*: 
Weeks 6 & 8 
• 
LMP-TC1: Days 0, 7, 14, 28 & 
41 
• 
After completing LMP-TC1#: 
Week 8 
Draw 6-12 mL of 
whole blood in a 
sodium heparin 
(green top) tube. 
Store at room 
temperature. Ship on 
the day of collection. 
Do not freeze 
samples. 
Allen Lab at 
BCM 
Section 15.3.4 
15.1.4 
Cytokine Release 
Syndrome 
(Optional patient 
consent required) 
In case a late reaction necessitates 
clinical labs to assess for cytokine 
release syndrome 
Draw 6-12 mL of 
whole blood in a 
sodium heparin 
(green top) tube. 
Store at room 
temperature. Ship on 
the day of collection. 
Do not freeze 
samples. 
Allen Lab at 
BCM 
Section 15.3.4 
15.1.5 
Allograft 
Rejection or 
Failure 
(Optional patient 
consent required) 
If allograft rejection or failure occurs 
during LMP-TC1 or LMP-TC2. 
Please draw before initiation of any 
immunosuppression. 
Draw 12-20 mL of 
whole blood in a 
sodium heparin 
(green top) tube. 
Store at room 
temperature. Ship on 
the day of collection. 
Do not freeze 
samples. 
Bollard Lab at 
CNMC 
Section 15.3.5 

 
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• 
After Course LMP-TC1 or RTX2 or during follow-up time points at Week 6, Week 8 
and Months 2 & 3: variations of up to 2 days before/after scheduled dates are 
acceptable.  
• 
For the later time points Months 6, 9, 12: variations of up to 4 weeks are acceptable. 
 
15.2.3 Missed Time Points: If biology specimens are not obtained at any requested time 
point, please send specimens at the next requested time point or at the next clinic visit, 
whichever is sooner. Please note that EBV PCR is a required specimen on this study. 
 
15.3 
Blood Specimen Shipping  
A COG Generic Specimen Transmittal Form should accompany each shipment. 
 
15.3.1 Packing of Peripheral Blood Samples  
Blood should be packaged for shipping according to institutional protocol for the 
packaging and shipping of blood products.  
 
15.3.2 IATA standards  
When shipping blood, please be aware that your institution must comply with 
IATA standards (www.iata.org). 
 
15.3.3 Shipping Conditions  
All samples should be shipped at ambient temperature in a thick Styrofoam 
container to provide temperature stability. Ship overnight Monday to Thursday 
only for Tuesday-Friday arrival. Notify the Lab Contact Person prior to shipment.  
 
Samples will not be accepted on Saturdays.  
 
Blood should be shipped to the BCM and CNMC Labs at the addresses indicated 
below using the COG FedEx account  
https://members.childrensoncologygroup.org/_files/reference/FEDEXmemo.pdf.  
 
15.3.4 Shipping Address at BCM 
 
 
  
 
 
 
  
 
 
  
 
  
 
  
 
 
15.3.5 Shipping Address at CETI at CNMC 
 
 

 
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15.4 
Rationale and Methods for Biology Aims 
In brief, the rationale of the biology studies is that biomarkers reflecting immune response 
may predict efficacy and toxicity of therapy. Methods will depend on available samples. 
Assays to be performed may include: 
 
15.4.1 Evaluation of general immune reconstitution via immunophenotyping and 
cytokine analysis. 
15.4.2 Investigation of persistence of LMP-specific T cells and immunity to EBV via 
HLA-tetramer assays and/or Enzyme-linked Immunospot (ELISPOT) assays 
15.4.3 Evaluation of EBV viral load pre and post T-cell infusions using serial PCR-based 
assays to monitor EBV DNA levels in the peripheral blood. 
 
See Appendix IV for a more detailed overview of the rationale, hypotheses, and methods 
for the Biology Aims. 
 
15.5 
Specimen Disposition  
Specimens will be received at BCM or CNMC, aliquoted and either assayed immediately 
or frozen for subsequent correlative study procedures. After the analyses are completed, 
any remaining sample will be destroyed. 
 
 
 

 
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16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except where 
explicitly prohibited within the protocol). 
 
16.1 
Computed Tomography (CT) with Contrast 
Most, if not all, COG institutions will be using multi-detector helical CT scanners. This is 
preferred in order to decrease scanning time compared to conventional CT, allow image 
acquisition at the time of peak contrast enhancement, reduce/eliminate the need for 
sedation, and reduce image degradation from motion artifact.  The volumetric acquisition 
of helical/spiral CT and the reconstruction of overlapping images increases the conspicuity 
of small lesions and facilitates multi-planar reconstruction for better depiction of certain 
lesions. Sagittal and coronal reconstructed images, as well as images reconstructed using a 
lung algorithm should be submitted where feasible, along with the axial imaging data. CT 
imaging should be performed with intravenous and oral contrast using age and weight-
based adjustments to kVp and mA, in accordance with institutional practice and 
ALARA/Image Gently guidelines. Timing of protocol therapy administration, response 
assessment studies, and surgical interventions are based on schedules derived from the 
experimental design or on established standards of care. Minor unavoidable departures (up 
to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week 
for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable (except where explicitly prohibited within the 
protocol). 
 
MRI may be used as an alternative modality for assessment of non-pulmonary disease sites 
(e.g. abdominal/pelvic disease), provided the institution is able to acquire images using 
phased array surface coils, cardiac gating and respiratory triggering, in order to minimize 
artifacts from cardiac motion, diaphragmatic motion and bowel peristalsis. Pulse sequences 
should include at a minimum axial and coronal fat-saturated FRFSE-T2, coronal T1 and 
axial and coronal post-gadolinium fat-saturated T1 weighted imaging. If MRI is used for 
imaging of the thorax, abdomen and/or pelvis, an unenhanced CT of the chest should still 
be obtained to evaluate the lungs. 
 
16.2 
CT during PET/CT 
Nearly all PET scanners in use today are integrated PET/CT scanners. However, low 
dose CT scans performed on integrated PET/CT scanners for the purpose of 
attenuation correction are of non-diagnostic quality, are usually performed without 
intravenous contrast, and will not be acceptable for staging or response assessment. 
As noted above, staging CT scans should include intravenous and oral contrast. In 
some instances – particularly for staging – a diagnostic quality CT will have been 
performed prior to the PET/CT. In these cases an additional low-dose CT will still be 
required for attenuation correction of the PET images. Provided that the diagnostic quality 
CT scan has been performed within 14 days of the PET/CT, a repeat diagnostic CT 
examination is not necessary at the time of PET/CT. For post-therapy follow-up scans 
limited to the neck and/or thorax the use of IV contrast alone is sufficient, provided the 
scanning parameters are optimized to achieve diagnostic quality images. Some institutions 

 
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perform the low dose attenuation correction CT with intravenous contrast. Please refer to 
Section 10.2.6.3 for the requirements. 
 
16.3 
[18F] Fluorodeoxyglucose (FDG) PET 
The use of PET scans is optional but highly recommended. If there is positive disease by 
PET scan at diagnosis, PET scans have to be performed at repeat evaluation time points 
until the patient has achieved a CR. 
 
 
17.0 
RADIATION THERAPY GUIDELINES 
No radiation therapy is planned for this study. 
 
 
 

 
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APPENDIX I: CTEP AND CTSU REGISTRATION PROCEDURES 
 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their registration 
annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (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 OPEN, RAVE, or TRIAD 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 CTSU (Cancer Trials Support Unit) 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. 
 
 
 

 
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CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the ANHL1522 protocol page located on the 
CTSU members’ website. 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. 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Either enter the protocol # in the search field at the top of the protocol tree, or 
 
Click on the By Lead Organization folder to expand 
 
Click on the COG link to expand, then select trial protocol #ANHL1522 
Click on LPO Documents, select the Site Registration documents link, and download and 
complete the forms provided. 
 
Requirements For ANHL1522 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted ) 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.  
 
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 3000 
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. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office. 
 
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 
 

 
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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. 
 
Data Submission / Data Reporting 
 
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, CRA (Lab 
Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum 
of an AP registration type. To hold the Rave Site 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. 
 
 
 
 

 
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APPENDIX II: RITUXIMAB OR BIOSIMILAR INFUSION GUIDELINES  
 
Special precaution: Due to the risk of hypotension, hold antihypertensive medications 12 hours 
prior to infusion. 
 
Dose = 375 mg/m2 
1. Dilute in NS or D5W to a final concentration of 1-4 mg/mL. Consider 1 mg/mL concentration for 
ease of administration and rate titration. 
2. Administer intravenously through a dedicated line (should not be mixed or diluted with other 
drugs) 
3. Premedication recommended 30-60 minutes prior to each dose with: 
Acetaminophen 10-15 mg/kg PO (max 650 mg) 
Diphenhydramine 1 mg/kg IV or PO (max 50 mg) 
 
FIRST INFUSION: 
 
1. Initial rate: 
• 
In patients < 18 years of age: 
o 0.5 mg/kg/hr (maximum of 50 mg/hr) for the 1st hour, or 
• 
In patients ≥ 18 years of age: 
o 50 mg/hr for the 1st hour. 
 
2. If no hypersensitivity or infusion-related events: 
• 
In patients < 18 years of age: 
o Increase infusion rate by 0.5 mg/kg/hr (maximum 50 mg/hr increase) every 30 minutes, 
to a maximum rate of 400 mg/hr as tolerated, or 
• 
In patients ≥ 18 years of age: 
o Increase infusion rate by 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr as 
tolerated. 
 
3. If a hypersensitivity or infusion related event develops for patients at any age: 
• 
The infusion should be slowed or interrupted 
• 
The infusion can continue at one half the previous rate upon improvement of patient symptoms 
 
SUBSEQUENT INFUSIONS (if the patient tolerated the first infusion well): 
 
1. Initial rate: 
• 
In patients < 18 years of age: 
o 1 mg/kg/hr (maximum 100 mg/hr) for the 1st hour, or 
• 
In patients ≥ 18 years of age: 
o 100 mg/hr for the 1st hour 
 
2. If no hypersensitivity or infusion-related events: 
• 
In patients < 18 years of age: 
o Increase infusion rate by 1 mg/kg/hr (maximum 100 mg/hr) every 30 minutes, to a 
maximum rate of 400 mg/hr as tolerated. 
• 
In patients ≥ 18 years of age: 
o Increase infusion rate by 100 mg/hr every 30 minutes, to a maximum rate of 400 mg/hr as 
tolerated. 

 
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3. If a hypersensitivity or infusion related event develops at any age: 
• 
The infusion should be slowed or interrupted 
• 
The infusion can continue at one half the previous rate upon improvement of patient’s 
symptoms 
 
If the patient did not tolerate the first infusion well subsequent infusions should be given following 
the guidelines under First Infusion. 
 
Nursing Implications: 
 
1. Monitor blood pressure, pulse, respiration and temperature every 15 minutes for the first hour 
or until the patient is stable, then hourly until the infusion is complete. 
2. Have epinephrine, diphenhydramine and corticosteroids available along with resuscitation 
equipment for the emergency management of anaphylactic reactions. 
3. If infusion related events occur, slow the infusion or stop the infusion until resolution, treating 
the patient if necessary. If it is determined that the patient can be safely rechallenged, begin the 
infusion at 50% of the rate at which the infusion was running when stopped. 
4. Verify that the patient has not taken antihypertensive medications within 12 hours of beginning 
the Rituximab infusion. Hypotension may occur during the infusion. 
5. A high number of circulating cancer cells (> 25,000/mm3) in patients may indicate a higher 
risk for tumor lysis syndrome. These patients should receive allopurinol and intravenous 
hydration and should be monitored. 
6. Patients that experience severe infusional symptoms may need to be hospitalized for 
observation. Patients should be counseled to be seen in the emergency room if infusion related 
symptoms occur again after the infusion is complete (i.e. at home at a later time). 
7. Monitor patients during and for a few weeks after receiving Rituximab for the development of 
mucositis with a sore throat or mouth ulcers followed by a diffuse skin rash which can worsen 
rapidly and result in total body skin sloughing and can become life threatening. 
8. See Section 5.0 for criteria for discontinuation of Rituximab. 
 
 
 

 
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APPENDIX III: GUIDELINES FOR LMP-SPECIFIC T CELL PRODUCT  
 
 
I. 
Selection of LMP-specific T Cell Product 
The most appropriate LMP-specific T-cell product will be selected based on degree of HLA 
matching and number of shared alleles with LMP activity. 
 
II. 
Product Storage 
A. The LMP-specific T-cell product will be stored in the vapor phase of liquid nitrogen in a 
continuously monitored cell bank at the Program for Cell Enhancement and Technologies for 
Immunotherapy (CETI) at Children’s National Medical Center. At the time of shipment, the 
product will be removed from inventory following Standard Operating Procedures for product 
release. The cryogenic vial(s) will be placed in a qualified charged liquid nitrogen dry shipper 
equipped with a continuous temperature monitor. The shipper will be labeled to comply with 
FACT and IATA standards and transported by a qualified courier using Priority Overnight 
service. 
B. The receiving institution will be notified of the shipment and the tracking number provided. Upon 
receipt, the integrity of the product and the temperature of the shipper will be documented. The 
temperature recorder will be stopped, and the product transferred to liquid nitrogen storage at the 
site’s Stem Cell Transplantation facility or thawed upon receipt. 
C. The shipper will be returned to CETI at CNMC by a qualified courier, and the data from the 
temperature logger downloaded and printed. The shipping information will be retained at CETI 
and a copy sent to the receiving facility. 
 
III. 
Product Labeling 
These are Third Party donor derived HLA matched LMP-specific T cells and are labeled with the 
coded name (P#), product-specific donor identification number (DIN number), product type 
(LMP-specific T cells), date of manufacture and cell dose. The dose of cells in this study is 
2 x 107/m2. 
 
IV. 
Product Administration 
The product will be thawed and infused in accordance with the Standard Operating Procedure that 
follows. Prior to administration, premedication is recommended with diphenhydramine 1 mg/kg 
(max 50 mg) P O or  IV and acetaminophen 10-15 mg/kg (max 650 mg) PO 30-60 minutes 
prior to infusion. LMP-specific T cells (2 x 107cells/m2) will be thawed according to the 
instructions below and administered IV 30-60 minutes after diphenhydramine and acetaminophen 
(as applicable). All institutions participating in this study are FACT accredited. 
 
A. Thawing of LMP-specific T Cell Products 
1. LMP-specific T cells are supplied in vial(s) that are transported from liquid nitrogen 
storage at GMP CETI at CNMC to the site of infusion in liquid nitrogen in a suitable 
container. 
2. When the transplant physician/designee is ready, remove the component vial(s) from the 
liquid nitrogen with a pair of hemostats. Two physicians or a physician and nurse must check 
the patient’s name and medical record number on the vial(s) against the patient’s name and 
medical record number on the receipt/storage worksheet supplied with the shipment. Any 
discrepancy MUST be investigated prior to thawing the product. 
3. Place the cryopreserved LMP-specific T-cell vial(s) in a sterile overwrap bag and seal. 
4. Submerse in a 37° C water bath filled with sterile water. 

 
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5. When the product has thawed to a slushy consistency, remove the vial(s) from water bath, 
spray with 70% ethanol and dry with a towel. 
6. The product is to be transferred to a sterile syringe for intravenous administration. The 
physician should only draw up the appropriate volume into the syringe as designated on the 
prescription. The syringe should be labeled with the recipient’s name, medical record 
number, date of thaw and product name (LMP-specific T cells). 
7. The thawed vial(s) should be saved and a sample removed for viability and bacterial 
(aerobic and anaerobic) and fungal culture according to the institution’s standard procedures. 
 
B. Infusion of LMP-specific T Cells 
1. Nursing staff will ensure that patient has IV access and that the line contains a stopcock 
for LMP-specific T-cell infusion. Normal saline should be running through the IV line 
to be accessed. 
2. Nursing staff will prepare for emergency procedure by ensuring that oxygen and suction 
equipment are available in the patient room, according to institution’s SOPs, which include 
availability of emergency drugs and equipment (i.e. epinephrine, diphenhydramine, 
hydrocortisone or methylprednisolone). In addition, baseline vital signs are documented. 
3. The LMP-specific T-cell product will be infused as soon as possible after thawing 
4. Two licensed staff will identify the patient by verifying the information on the patient 
armband and the component with a check of the identification bracelet on the recipient for 
correct name and hospital number, as per institution’s SOP, against the product. 
5. The LMP-specific T-cell product will be given through peripheral or central intravenous line 
over 1 minute and flushed with sterile saline.   
 
V. 
Management of Adverse Reactions to LMP-specific T Cell Infusions 
LMP-specific T cells infusions are typically well tolerated but adverse reactions may occur early 
(within 24 hours of infusion) or late (greater than 24 hours after infusion). Early reactions are 
usually related to the cryopreserved components.   
 
A. Monitoring Post LMP-specific T Cell Infusion  
Medical staff will assess for any adverse effects for 1 hour post-infusion. Vital signs should be 
monitored immediately at end of infusion then at 30 and 60 minutes. Patients should remain on 
continuous pulse oximetry for at least 30 minutes after infusion. 
 
1. Common, mild complications from LMP-specific T-cell infusion include:  
• 
Mild increase in blood pressure not requiring intervention 
• 
Mild headache 
• 
Mild flushing 
• 
Slight slowing of the heart rate 
• 
Bad taste in mouth 
 
2. Severe early reactions from LMP-specific T-cell infusion are rare but may include: 
• 
Acute pulmonary edema and dyspnea 
• 
Persistent nausea and vomiting 
• 
Sustained or significant increase in blood pressure  
• 
Fever 
• 
Anaphylactic shock  

 
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• 
Bradycardia or cardiac arrest 
 
B. Management of Early Reactions 
Most common, mild early reactions do not require intervention. 
  
1. Management of anaphylaxis: Emergency medications should be ordered in advance and 
available at the patient’s bedside at the time of infusion.  Hydrocortisone (or other steroids) 
should not be administered without approval of physician administering LMP-specific T cells. 
• 
Hydrocortisone 5-10 mg/kg IV (maximum 500 mg) or methylprednisolone 1-2 mg/kg IV 
(maximum 125 mg) 
• 
Epinephrine 0.01 mg/kg IM (preferred) or SubQ (maximum 0.5 mg; 0.01 mL/kg of 
1 mg/mL solution, maximum of 0.5 mL) 
2. In the event of a severe reaction, the patient should be immediately transferred to emergency 
room or intensive care unit for intensive monitoring and intervention, which usually includes 
blood pressure support, steroids, and management of anaphylaxis.   
 
C. Monitoring and Management of Late Reactions 
Late reactions to LMP-specific T cells infusion are rare. The following details regarding 
signs/symptoms and management, follow (Source: CETI SOP SCTCP-27 Management of 
Adverse Reactions to T-Lymphocyte Infusions, Version 1.2, Effective Date: 2016-03-21) 
 
1. Late reactions to T-cell infusion may be related to a T-cell engraftment syndrome or cytokine 
release syndrome (CRS), tumor lysis syndrome, and rarely to contamination of the product. 
 
2. Symptoms and signs of late complications from infusion of T-cell products may include: 
 
Systemic 
fever 
malaise, fatigue 
myalgias and arthralgias 
skin rash mimicking acute GvHD 
general feeling of unwellness 
disseminated intravascular coagulation (DIC) +/- bleeding 
macrophage activation syndrome/hemophagocytotic lymphohistiocytosis (HLH) 
anorexia, nausea, vomiting, diarrhea 
Cardiorespiratory 
tachycardia 
blood pressure changes (either hyper- or hypotension) 
acute pulmonary edema, dyspnea, hypoxia 
pulmonary infiltrates 
capillary leak syndrome 
cardiac dysfunction 
stress cardiomyopathy (Takotsubo cardiomyopathy) 
adult respiratory distress syndrome (ARDS) 

 
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Hepatic and Renal 
weight gain 
renal impairment 
azotemia 
hyperuricemia 
hepatic impairment – transaminitis, hyperbilirubinemia 
Neurological 
headache 
mental status changes 
confusion 
delirium 
hallucinations 
altered gait 
seizures 
encephalopathy 
mild encephalopathy with reversible splenial lesion syndrome (MERS) 
 
3. Management of Late Reactions 
 
(1) The development of a severe late reaction necessitates immediate notification of the PI 
and ANHL1522 Study Chair AND (if an outpatient) transfer to the hospital for an 
urgent medical assessment. It is important to evaluate the patient and initiate therapy 
as quickly as possible since rapid deterioration is possible. 
 
(2) Biomarkers: Circulating cytokine levels can serve as biomarkers to diagnose and 
potentially quantify syndrome severity. 
(a) IL-6 signaling is major component of severe cytokine release syndrome 
(b) If possible, cytokine levels should be sent to Viracor prior to starting any anticytokine 
directed therapy. See Section 15 for corresponding optional research specimen 
submission.  
(c) CRP serves as a reliable surrogate for IL-6 bioactivity and levels should be sent pre 
and post therapy to monitor response 
(d) Ferritin may also be used in conjunction with CRP monitoring 
 
(3) The immediate assessment and treatment may also include: 
(a) Intensive monitoring (BP, cardiovascular monitoring, pulse oximetry or ABG) 
(b) CXR or CT of chest 
(c) Steroids – single dose. See #(4) below 
(d) Microbiological studies (especially blood cultures and virus studies) and initiation of 
broad-spectrum antibiotics +/- antivirals should be considered. 
(e) Blood pressure/Cardiovascular support – early institution of inotropic medications. 
Limit fluid resuscitation to the minimum volume needed to support blood pressure, 
no more than 20 mL/kg, (up to 1,000 mL), if possible. 
(f) Fluid management/Renal support – Aggressive diuresis. Institute early involvement 
of the renal service for fluid management especially if evidence of capillary leak 
syndrome. Consider infusion of 25% albumin if serum albumin is < 3 g/dL.  
(g) Respiratory support – supplemental oxygen therapy should be initiated for all 
hypoxemic patients. Patients also may require intubation and mechanical ventilation. 
(h) Management of tumor lysis syndrome if there is laboratory evidence it is occurring. 

 
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(4) Treatment of the cytokine release syndrome or other T-cell associated adverse reactions 
must be discussed with the PI and ANHL1522 Study Chair. If the situation is emergent, 
the first dose of steroids can be given prior to consultation with the PI. 
 
In general, the cytokine release syndrome is managed similarly to engraftment syndrome 
EXCEPT: 
• As the patient received an investigational T-cell agent, steroids may not be considered 
first line therapy and anti-IL-6 directed therapy MAY be given without first starting 
steroids.  
• When managing CRS, anti-IL-6 directed therapy should be initiated before anti-TNFa 
directed therapy. 
• Caution is required when using tocilizumab in the setting of hepatic impairment. 
 
(5) If treatment with a biological agent is necessary, the order of priority will usually be: 
• Tocilizumab 
• Infliximab (anti-TNFa) 
• Etanercept (soluble TNFa receptor inhibitor) 
 
Drug
Dosing
Duration
Tocilizumab 
<30 kg: 12 mg/kg IV 
≥30 kg: 8 mg/kg (maximum 800 mg) IV 
One dose, with repeat dosing if 
no improvement observed within 
24-48 hours. 
Infliximab 
10 mg/kg IV 
One dose, may give second 3-4 
days later 
Etanercept 
0.4 mg/kg (maximum 25 mg) SubQ  
One dose, may give second 3-4 
days later 
 
 
 
 
 

 
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APPENDIX IV: CORRELATIVE BIOLOGY STUDIES 
 
Immune Reconstitution, Persistence of LMP-specific T Cells, and EBV Viremia 
 
1V.1 
Background: 
The goal of the correlative biology studies is to test the hypothesis that LMP-specific T cells aid in 
the immune reconstitution of patients with EBV positive PTLD. In addition, we are testing the 
hypothesis that third party LMP-specific T cells may aid in autologous immune reconstitution that 
persists once the third party LMP-specific T cells have been cleared and that EBV viremia as 
measured by EBV PCR is inversely correlated with absence of EBV-specific T cells and can predict 
risk for relapse as shown in our previous publications using autologous EBV-specific T cells.26,27 
Finally, these studies will determine the ability of plasma cytokine profiles to predict and measure 
response to therapy and toxicity in patients treated with EBV-specific T cells.   
If autologous immune reconstitution in response to third party LMP-specific T cells occurs, it 
would be expected to reduce the risk of future EBV-related lymphoproliferation without the need 
for long-term persistence of the third party LMP-specific T cells or repeated LMP-specific T cells 
administrations. Third party LMP-specific T cells have the main advantage to be readily available 
without delay when needed because they can be produced from healthy donors to cover the most 
prevalent HLA phenotypes and be stored in a cell bank. If they also aid in autologous immune 
reconstitution without the need of persistence, there would be a rationale of further clinical 
development of third party cellular therapy because it could be widely and easily available without 
the need and delays of “custom-made” cellular therapies and without the unknown risks of 
persistence of modified cells in the host. 
 
IV.2 
 
3. 
  
 
 
A. General Immune reconstitution 
Hypothesis and Rationale: Third Party LMP-specific T cells in combination with rituximab 
will be superior in aiding the immune reconstitution of the recipients compared to rituximab 
alone. The rationale behind this correlative study is that EBV positive PTLD is caused by a 
defective immune system and LMP-specific T cells lead to EBV specific immune 
reconstitution. Monitoring occurrence and persistence of this immune reconstitution may be 
able to predict response and/or risk of recurrence of PTLD. Studies to evaluate general immune 
reconstitution will include: 
 
I. Immunophenotyping  
Sample Requirement: 3-6 ml whole blood in sodium heparin (green top) 
 Method: We will first characterize the phenotype of the T cells (gating on EBV tetramer+ 
(tet) T cells if informative tetramers are available) in the PBMCs. General T-cell markers 
including memory markers may be used when sufficient PBMC are available - for example: 
CD4, CD8, CD45RA, CD45RO, CD62L, CD27, CD28, and chemokine receptor 
expression (e.g. CCR7, CCR4 and CXCR3 and CLA) by flow cytometry. 
 

 
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II. Cytokine Analysis 
Sample Requirement: 3-6 ml whole blood in sodium heparin (green top) 
Method: Cytokine release by the T cells will be evaluated luminex assay and/or 
intracellular cytokine assay (e.g. for tet+ IFNg/IL-2 double secreting CM T cells) and/or 
Cytokine Bead Array when sufficient PBMC are available and informative tetramers are 
available.42 
 
B. Persistence of LMP-specific T Cells and Immunity to EBV 
Hypothesis and Rationale: EBV lymphoproliferation is controlled by the presence of EBV-
specific T cells. Persistent absence of EBV viremia as measured by EBV PCR in the blood is 
able to predict the presence of EBV-specific T cells and the risk of recurrence. The rationale 
behind this correlative study is that it is currently unknown what the adequate post-therapy 
monitoring is for this patient population that receives ongoing immune suppression. Serial CT 
and/or PET scans carry significant radiation exposure. Developing reliable biomarkers would 
be of significant clinical importance to avoid unnecessary radiation exposure and/or invasive 
procedures. Studies planned for evaluation of persistence of LMP-specific T Cells and 
Immunity to EBV include: 
 
I. Tetramer Staining 
Sample Requirement: 3-6 ml whole blood in sodium heparin (green top) 
Method: T-cell frequencies may be measured in HLA-tetramer assays when informative 
tetramers are available. These functional analyses MUST be performed on fresh samples 
to ensure consistency of the analysis both intra- and inter- patient.43 
 
II. Enzyme-Linked Immunospot (ELISPOT) Assay  
Sample Requirement: 3-6ml whole blood in sodium heparin (green top) 
Method: ELISPOT assays using third party donor EBV-LCL to stimulate EBV-specific 
T cells in patient PBMC may be utilized to evaluate EBV specific T-cell frequencies. As a 
control, CMV-derived peptides can be used to measure CMV-specific responses.44 A 0.5 
log or greater increment in the frequency of EBV specific T cells from one time point to 
the next will be taken as indicative of a significant expansion of EBV specific T cells in 
vivo.  
 
C. Detection of EBV DNA 
Sample Requirement: 5 ml whole blood in EDTA (purple top) 
Method: Serial blood samples will be used to follow EBV viremia using PCR based assays and 
analyzed with respect to clinical outcomes. Due to the wide variability of results from EBV 
quantification methods using different assays and different blood fractions (e.g. plasma versus 
white blood cells), these studies will be performed with a CLIA-certified assay at Baylor 
College of Medicine. This surveillance will enable establishment of endpoints for correlating 
EBV specific T-cell immune reconstitution with effects on PTLD/EBV viral load.  
 
IV.3 
Justification for collection of fresh samples: 
All correlative biology studies will be performed on peripheral blood samples. The above described 
studies require fresh blood samples shipped overnight because they are largely functional studies 
that require processing prior to freezing and storing. Samples will be batched and testing will be 
performed based on available funding.  
 
IV.4 
Statistical Design 
See Section 9.7.  
 

 
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APPENDIX V: COG STEM CELL COMMITTEE CONSENSUS GUIDELINES FOR 
ESTABLISHING ORGAN STAGE AND OVERALL GRADE OF ACUTE GRAFT VERSUS HOST 
DISEASE (GVHD)  
 
Reporting Requirements for Acute GvHD in COG Studies 
In an attempt to standardize reporting of acute GvHD, the COG Stem Cell Transplantation Committee has 
adopted a modification of guidelines that were originally developed at the University of Michigan. 
 
Table 1 outlines standard criteria for GvHD organ staging. However, confounding clinical syndromes (such 
as non-GvHD causes of hyperbilirubinemia) may make staging GvHD in a given organ difficult. In 
addition, timing of organ specific symptoms affects whether that symptom is more or less likely to be true 
GvHD. Please refer to Tables 2 and 3 to assist you in deciding whether to attribute these clinical findings 
to GvHD, especially in situations where a biopsy is not possible. For additional help, please see the text 
which follows the tables. Table 4 reviews the approach to assessing GvHD as acute, chronic, or the overlap 
between the two. 
 
Finally, engraftment syndrome will be reported separately from the GvHD scoring presented below. 
 
Engraftment Syndrome 
A clinical syndrome of fever, rash, respiratory distress, and diarrhea has been described, just prior 
to engraftment in patients undergoing unrelated cord blood and mismatched transplantation. If, in 
the judgment of the local investigator, a patient experiences this syndrome, details of the event 
should be reported when requested in the study CRFs. 
 
Modified Glucksberg Staging Criteria for Acute Graft versus Host Disease 
 
Table 1 Organ Staging (See tables and text below for details) 
 
Stage  
Skin  
Liver (bilirubin)  
Gut (stool output/day)  
0  
No GvHD rash  
< 2 mg/dL  
Adult: < 500 mL/day  
Child: < 10 mL/kg/day  
1  
Maculopapular rash  
< 25% BSA  
2-3 mg/dL  
Adult: 500–999 mL/day  
Child: 10 -19.9 mL/kg/day 
Or 
persistent 
nausea, 
vomiting, or anorexia, with a 
positive upper GI biopsy.  
2  
Maculopapular rash  
25 – 50% BSA  
3.1-6 mg/dL  
Adult: 1000-1500 mL/day 
Child: 20 – 30 mL/kg/day  
3  
Maculopapular rash 
> 50% BSA  
6.1-15 mg/dL  
Adult: > 1500 mL/day  
Child: > 30 mL/kg/day  
4  
Generalized 
erythroderma 
plus 
bullous formation and 
desquamation > 5% BSA  
>15 mg/dL  
Severe abdominal pain with 
or without ileus, or grossly 
bloody stool (regardless of 
stool volume).  

 
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For GI staging: The “adult” stool output values should be used for patients > 50 kg in weight. Use 
3 day averages for GI staging based on stool output. If stool and urine are mixed, stool output is 
presumed to be 50% of total stool/urine mix (see Section 3.2). 
 
For stage 4 GI: the term “severe abdominal pain” will be defined as: 
(a) Pain control requiring institution of opioid use, or an increase in on-going opioid use, PLUS 
(b) Pain that significantly impacts performance status, as determined by the treating MD. 
 
If colon or rectal biopsy is +, but stool output is < 500 mL/day (< 10 mL/kg/day), then consider as 
GI stage 0.  
 
There is no modification of liver staging for other causes of hyperbilirubinemia 
 
Overall Clinical Grade (based on the highest stage obtained): 
Grade 0: No stage 1-4 of any organ 
Grade I: Stage 1-2 skin and no liver or gut involvement 
Grade II: Stage 3 skin, or Stage 1 liver involvement, or Stage 1 GI 
Grade III: Stage 0-3 skin, with Stage 2-3 liver, or Stage 2-3 GI 
Grade IV: Stage 4 skin, liver or GI involvement 
 
 
Table 2 Evaluating Liver GvHD in the Absence of Biopsy Confirmation (See Table 3.0 below) 
 
Establishing liver GvHD with no skin or GI GvHD 
No Skin/GI GvHD 
Day 0-35 
Assume no liver GvHD, unless proven by biopsy  
No Skin/GI GvHD  
Day 36-100 
If NO other etiology identified, NO 
improvement with stopping 
hepatotoxic medications/TPN: 
Stage as liver GvHD  
If other etiology identified or 
improves with stopping hepatotoxic 
drugs/TPN: 
Do not stage as liver GvHD  
Establishing liver GvHD with skin or GI GvHD and other cause of hyperbilirubinemia 
Skin and/or GI GvHD 
present  
Worsening bilirubin level (includes 
worsening just prior to onset of skin 
or GI tract GvHD) OR stable 
elevated bilirubin despite resolution 
of non-GvHD cause of increased 
bilirubin:  
Stage as liver GvHD  
Stable or improving bilirubin after 
diagnosis of skin or GI GvHD, 
irrespective of treatment:  
Do not stage as liver GvHD 
Changing liver GvHD stage with other cause of hyperbilirubinemia 
Skin and GI GvHD 
stable, improving, or 
absent  
Liver GvHD staging is carried forward without increase in stage until other 
disease process resolves (e.g., if TTP is diagnosed in the presence of stage 2 
liver GvHD, the liver GvHD stage 2 is carried forward despite rising bilirubin 
level until TTP is resolved. If there is no liver GvHD – stage 0 – and new 
onset TTP, the stage 0 is carried forward until TTP is resolved).  

 
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Skin and/or GI GvHD 
worsening  
Liver GvHD is staged according to the Glucksberg criteria. The elevated 
bili is attributed to GvHD alone. 
 
Thus, when skin or GI GvHD is worsening, there is no downgrading of liver 
GvHD staging for other causes of hyperbilirubinemia. (e.g., if TTP is 
diagnosed in the presence of stage 2 liver GvHD and worsening skin or GI 
GvHD, the liver is staged according to the actual bilirubin level even if some 
of the rise in bilirubin is attributed to TTP). 
 
Similarly, even if there is no liver GvHD at onset of a new process, (such as 
TPN cholestasis), but skin or GI GvHD worsen during that process, then liver 
GvHD is diagnosed and staged according to the height of the bilirubin. 
 
There is one exception to this: the diagnosis of TTP, with high LDH and 
unconjugated bilirubin precludes the diagnosis and staging of new liver 
GvHD in the absence of a confirmatory liver biopsy. 
 
 
Table 3 Evaluating GI GvHD in the Absence of Biopsy Confirmation (See Table 4.0 below) 
 
Establishing GI GvHD with new onset diarrhea and no skin or liver GvHD 
No Skin/liver GvHD  
Day 
0 
through 
engraftment 
Assume no GI GvHD, unless proven by biopsy  
 
No Skin/liver GvHD 
Engraftment through day 
100  
NO other etiology of diarrhea 
identified: 
Stage as GI GvHD  
Any other etiology of diarrhea 
identified: 
Do not stage as GI GvHD  
Establishing GI GvHD with pre-existing diarrhea and skin or liver GvHD 
Skin and/or liver GvHD 
present  
Worsening 
diarrhea 
(includes 
worsening just prior to onset of skin 
or liver GvHD) OR persistent 
diarrhea despite resolution of non-
GvHD cause: 
Stage as GI GvHD  
Improving diarrhea after the diagnosis 
of skin or liver GvHD (irrespective of 
treatment) OR persistent diarrhea 
without resolution of underlying non-
GvHD cause: 
Do not stage as GI GvHD  
 
 
Differentiating Acute GvHD, Chronic GvHD, and Overlap Syndrome  
 
There is often confusion differentiating acute from chronic GvHD, especially in the setting of reduced 
intensity transplants, DLI and new prophylactic treatments. The NIH Working Group recently published 
new classifications for GvHD: 
 
 

 
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Table 4 Acute GvHD, Chronic GvHD, and Overlap Syndrome 
 
Category  
Time of Symptoms 
after HCT or DLI  
Presence 
of 
Acute 
GvHD features  
Presence of Chronic 
GvHD features  
Acute GvHD  
 
 
 
Classic acute GvHD  
≤100 d  
Yes  
No  
Persistent, 
recurrent, 
or 
late-onset acute GvHD  
>100 d  
Yes  
No  
Chronic GvHD  
 
 
 
Classic chronic GvHD 
No time limit  
No  
Yes  
Overlap syndrome  
No time limit  
Yes  
Yes  
 
• 
Scoring of acute GvHD may need to occur past day 100. In particular, patients should continue to 
be scored for acute GvHD when classic acute GvHD symptoms (maculopapular rash, nausea, 
vomiting, anorexia, profuse diarrhea - particularly if bloody and ileus) persist past day 100 or if 
identical symptoms previously scored as acute GvHD resolve and then recur within 30 days during 
immunosuppression taper but past day 100. 
• 
Those patients being scored as having acute GvHD should NOT have diagnostic or distinctive signs 
of chronic GvHD. 
• 
Patients with both acute and chronic symptoms should be diagnosed as having Overlap 
Syndrome and scored according to their chronic GvHD score.  
 
 
Further Explanation of Criteria presented in Tables 2 and 3. 
 
1.0 Assessment of Skin GvHD  
1.1 Presence or Absence of Skin GvHD: Skin GvHD will be considered present if a rash characteristic 
of acute GvHD develops after allogeneic marrow transplantation involving more than 25% of the 
body surface not clearly attributable to causes such as drug administration or infection. The extent 
of the body surface area involved can be estimated by the “Rule of Nines”. In estimating the extent 
of skin GvHD, the area involved is calculated for individual anatomic areas, such as the arm or leg, 
and then the total is derived from a simple summation. Areas that are non-blanching should not be 
considered involved regardless of the overlying color of the rash (red, brown, etc.). Limited 
distribution erythema (with the exception of palms and soles) in the absence of associated rash 
elsewhere on the body will not be considered GvHD.  
 
2.0 Assessment of Liver GvHD  
2.1 Assessing for the Presence or Absence of Liver GvHD 
A. Hyperbilirubinemia (total bilirubin > 2.0 mg/dL) in the absence of other signs of acute GvHD 
in the skin or GI tract: 
i) Day 0-35: If hyperbilirubinemia alone is present with no other signs of acute GvHD in 
other organ systems, acute GvHD will not be diagnosed based solely on laboratory 
abnormalities. Acute GvHD will be diagnosed if findings on histopathology studies of liver 
from a biopsy or autopsy are confirmatory. 
ii) Day 35-100: If hyperbilirubinemia (must be conjugated bilirubin) is not improving or is 
exacerbated (especially if serum alkaline phosphatase is increased), in the absence of 
acute GvHD in other organ systems, no other etiologies are identified, and does not 
improve with discontinuation of hepatotoxic drugs, acute GvHD will be diagnosed. 
However, it is distinctly unusual to develop ascites or a coagulopathy in the early stages 

 
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of acute GvHD of the liver alone. In the absence of histopathology studies of liver from 
a biopsy or autopsy specimen, ascites or a coagulopathy secondary to liver dysfunction 
will be considered to indicate the presence of another disease process (e.g. veno-occlusive 
disease). 
Recommended 
non-invasive 
studies 
to 
define 
an 
etiology 
for 
hyperbilirubinemia are: 
a. Imaging of liver (CT or ultrasound) 
b. Hepatitis screen (only if ALT is elevated) 
c. PT 
d. Blood cultures 
e. Review of medication list for potentially hepatotoxic drugs 
f. 
Review of risk factors for viral liver infection (HSV, CMV, VZV, adenovirus, 
EBV, HBV, and HCV) 
g. Hemolysis screen 
B. Pre-existing hyperbilirubinemia clearly attributed to an etiology other than acute GvHD in the 
presence of signs of acute GvHD in other organ systems. 
i) If pre-existing non-GvHD liver disease (documented clinically, by lab assessment, or by 
imaging studies) is stable or improving at the onset of signs of acute GvHD in other organs, 
then acute GvHD of the liver will not be considered to be present unless proven by liver 
biopsy or autopsy. 
ii) If hyperbilirubinemia worsens several days before or at the time of onset of signs of acute 
GvHD in other organ systems, GvHD will be considered to be present unless histopathology 
studies of liver are available and negative on a biopsy during that time interval or autopsy 
results exclude GvHD. 
iii) If hyperbilirubinemia persists and is not improving after resolution of a pre-existing non-GvHD 
liver disease process (e.g. localized infection of liver, systemic sepsis, biliary tract obstruction) 
when signs of acute GvHD are present in other organ systems or no other intervening cause 
has been diagnosed, then acute GvHD will be considered to be present in the absence of a new, 
clearly identifiable cause of non-GvHD liver disease or unless a liver biopsy or autopsy 
specimen is negative.  
C. Prior acute GvHD in liver with new onset of a disease process that exacerbates pre-existing or 
recently resolved hyperbilirubinemia: 
i) If an etiology other than acute GvHD is clearly identified as causing or exacerbating 
hyperbilirubinemia and acute liver GvHD has been diagnosed and has been stable, improving, 
or resolved, then the liver will not be restaged for acute GvHD until the resolution or stabilizing 
of the concurrent disease process (i.e., the liver stage prior to the onset of the new disease 
process will be carried forward until the new disease process resolves). Example: Acute GvHD 
of the liver and gut is diagnosed on day 20. Treatment of acute GvHD results in falling bilirubin 
levels to liver stage 1. Sepsis or TTP develops with transient worsening of the 
hyperbilirubinemia. The liver stage is not increased, despite a higher bilirubin level, because 
the cause of worsening hyperbilirubinemia is attributed to sepsis or TTP. 
ii) If an etiology other than acute GvHD is clearly identified as causing or exacerbating 
hyperbilirubinemia in the presence of already worsening acute liver GvHD or GvHD of the 
skin or GI tract is simultaneously worsening, then the liver GvHD will be staged according to 
the actual bilirubin level, even though another cause of hyperbilirubinemia is present. 
 
3.0 Assessment of GvHD of the Gastrointestinal Tract 
3.1 Assessing for the Presence or Absence of GvHD of the Gastrointestinal Tract 
A. Diarrhea (≥ 500 mL/day in adults or > 10 mL/kg in pediatric patients) in the absence of other 
signs of acute GvHD in other organ systems 
i) Day 0-engraftment: If diarrhea alone is present without other signs of acute GvHD in other 
organ systems, acute GvHD will not be considered present. Diarrhea will be attributed to 

 
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acute GvHD if histopathology studies of gastrointestinal tract from a biopsy or autopsy are 
diagnostic. 
ii) Engraftment-Day 100: If diarrhea persists and is not improving, is exacerbated, or develops 
de novo in the absence of acute GvHD in other organ systems, histopathology studies of 
gut biopsies or from autopsy specimens are not available, and no other etiologies are clearly 
identified, acute GvHD will be considered to be the cause. A stool specimen should be 
examined to rule out infectious causes (e.g. rotavirus, adenovirus, and C. difficile toxin). It 
is recommended, if at all possible, that biopsies be obtained for diagnostic purposes. 
B. Pre-existing diarrhea clearly attributed to an etiology other than acute GvHD in the presence 
of signs of acute GvHD in other organ systems: 
i) If pre-existing diarrhea caused by a process other than GvHD has been documented 
clinically or by lab assessment and is stable or improving at the onset of signs of acute 
GvHD in the skin or liver, then acute GvHD of the intestine will not be considered to be 
present in the absence of biopsy confirmation or autopsy report. 
ii) If diarrhea or gastrointestinal symptoms are already present, but worsen significantly at 
the time of onset of signs of acute GvHD in the skin or liver, GvHD will be considered 
present, unless biopsy or autopsy are negative. 
iii) If diarrhea persists after resolution of a pre-existing disease process with signs of acute 
GvHD present in other organ systems, GvHD will be considered present, unless biopsy 
or autopsy are negative. 
C. Prior or present acute GvHD in other organ systems with new onset of diarrhea: 
If diarrhea is clearly attributable to an etiology other than acute GvHD (e.g., infection) and 
a history of acute GvHD exists or acute GvHD is present in other organ systems and is 
stable, then the gastrointestinal tract will not be evaluable for acute GvHD until the 
resolution or stabilizing of the other disease process (e.g., infection) in the absence of 
biopsy or autopsy confirmation. 
D. Persistent anorexia, nausea or vomiting in the absence of signs of acute GvHD in other 
organ systems:  
Persistent anorexia, nausea or vomiting in the absence of other known causes of these 
symptoms will be considered stage 1 acute GvHD if confirmed by endoscopic biopsy. 
If a biopsy is not possible (e.g. secondary to thrombocytopenia) but clinical findings are 
compatible with acute GvHD, then the patient will be treated and recorded as having acute 
GvHD. 
 
3.2 Staging of the Gastrointestinal Tract for the Severity of Acute GvHD 
The severity of gastrointestinal tract GvHD will be staged according to modified Glucksberg criteria. 
To minimize errors caused by large day-to-day variation, diarrhea volume is measured as an average 
over 3 days and reported as the volume in milliliters per day. When urinary mixing is noted the stool 
volume will be considered half of the total volume unless nursing staff is able to give a better estimate 
from direct observation. Abdominal cramps are considered significant for staging if the severity 
results in a clinical intervention (e.g. analgesia, fasting, etc.). Blood in the stools is considered 
significant if the blood is visible or hematochezia/ melena is present and not clearly attributed to a 
cause other than GvHD (e.g. epistaxis/ hemorrhoids). 
 
 

 
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APPENDIX VI: POSSIBLE DRUG INTERACTIONS 
 
Some drugs, food, and supplements may interact with rituximab (or biosimilar). Examples include: 
 
Drugs that may interact with rituximab (or biosimilar)* 
• Arthritis medications 
• 
Leflunomide, tofacitinib 
• Heart or high blood pressure medications 
• 
Amlodipine, atenolol, captopril, carvedilol, clonidine, enalapril, lisinopril, metoprolol, 
nicardipine, propranolol, sotalol 
• Other medications 
• 
Abatacept, abciximab, baricitinib, belimumab, certolizumab pegol, clozapine, 
deferiprone, natalizumab 
 
Food and supplements that may interact with rituximab (or biosimilar)** 
• Echinacea 
 
*Sometimes these drugs are used with rituximab (or biosimilar)on purpose.  Discuss all drugs with 
your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, 
or dried herbs. All forms should be avoided.  
 
The list above does not include everything that may interact with your chemotherapy. Talk to 
your doctor before starting any new medications, over-the-counter medicines, or herbal 
supplements and before making a significant change in your diet. 
 
 
 
 

 
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APPENDIX VII: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ANHL1522 
(for children from 7 through 12 years of age) 
 
A study of a drug (Rituximab) and cells (LMP-TC) to treat PTLD 
  
1. We have been talking with you about your tumor. The kind of tumor you have is called PTLD. PTLD 
happens when a type of white blood cell that fights infection does not grow normally. After doing 
tests, we have found that you have this type of tumor. 
 
2. We are asking you to take part in a research study because you have PTLD. A research study is when 
doctors work together to try out new ways to help people who are sick. The goal of this study is to 
learn more about how to treat PTLD and reduce the bad effects of drugs used to treat PTLD.  
 
3. If you are newly diagnosed with PTLD or if the PTLD has relapsed (come back) you will receive a 
drug called rituximab. Then some children will get a therapy called LMP-specific T cells (LMP-TC). 
LMP-TC is made from another person’s cells in order to help the immune system fight the PTLD. The 
treatment you get will depend on how well the rituximab works, and if enough LMP-TC doses are 
ready. Your doctor will tell you whether you will receive LMP-TC therapy.  
 
4. If you have PTLD that hasn’t responded to treatment with rituximab prior to taking part of this study, 
you will get the therapy called LMP-TC.  
 
5. You will have regular tests during your treatment. These tests help doctors to decide the best 
treatment for you and to see how you are doing with treatment. We will take samples of blood for the 
study. These samples would be taken when other standard blood tests are being done, so there would 
be no extra blood draws.  
 
6. Sometimes good things can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is getting rid of the PTLD 
for as long as possible, and with fewer bad effects but we don’t know for sure if there is any benefit of 
being part of this study. 
 
7. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” The risks to you from this study are that you will have more bad effects with the 
rituximab or LMP-TC than you would with the usual medicines. We do not know this for sure which 
is why we are doing this study. Other things may happen to you that we don’t yet know about. 
 
8. Your family can choose to be part of this study or not. Your family can also decide to stop being in 
this study at any time once you start. There may be other treatments for your illness that your doctor 
can tell you about. Make sure to ask your doctors any questions that you have and talk with your 
family as they are making this decision. 
 
9. We are asking your permission to collect additional blood. We want to see if there are ways to tell 
how the PTLD will respond to treatment. These samples would be taken when other standard blood 
tests are being performed, so there would be no extra blood draws. You can still take part in this study 
even if you don't allow us to collect the extra blood samples for research. 
 
 

 
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INFORMATION SHEET REGARDING RESEARCH STUDY ANHL1522 
(for teens from 13 through 17 years of age) 
 
A Study of Rituximab and LMP-specific T cells (LMP-TC) to Treat 
Post-Transplant Lymphoproliferative Disease (PTLD). 
 
1. We have been talking with you about your Post-Transplant Lymphoproliferative Disease (PTLD). PTLD 
is a type of tumor of the immune system. PTLD happens when a type of white blood cell that fights 
infection does not grow normally. Sometimes this abnormal growth is caused by a virus called Epstein-
Barr virus (EBV). After doing tests, we have found that you have this type of tumor. 
 
2. We are asking you to take part in a research study because you have PTLD. A research study is when 
doctors work together to try out new ways to help people who are sick. The goal of this study is to learn 
more about how to better treat PTLD and to reduce the bad effects of the drugs used to treat PTLD.  
 
3. If you are newly diagnosed with PTLD or if the PTLD has relapsed (come back after treatment) you will 
first be treated with a drug called rituximab. Then some children will get an immune cell therapy called 
LMP-specific T cells (LMP-TC). The LMP-TC doses are made from another person’s cells in order to 
help the immune system fight the PTLD by targeting the EBV infected tumor cells. The treatment you get 
will depend on how well the rituximab works and whether enough LMP-TC doses are matched and 
available. Your doctor will tell you whether you will receive LMP-TC therapy.  
 
4. If you have PTLD that hasn’t responded to treatment with rituximab prior to taking part of this study, you 
will get the therapy called LMP-TC.   
 
5. You will have regular tests during your treatment. These tests help doctors in deciding the best treatment 
for your PTLD and to see how you are doing with treatment. We will take samples of blood to study the 
response to treatment. These samples would be taken when other standard blood tests are being performed, 
so there would be no extra blood draws.  
 
6. Sometimes good effects can happen to people when they are in a research study. These good things are 
called “benefits.” We hope that a benefit to you of being part of this study is getting rid of the PTLD for as 
long as possible, and with fewer side effects from the treatment. But we don’t know for sure if there is any 
benefit of being part of this study. 
 
7. Sometimes effects that are not helpful and might be harmful or negative can happen to people when they 
are in a research study. These negative effects are called “risks.” The risks to you from this study are that 
you will have more bad side effects with the study medicines than you would with the medicines that are 
usually given for PTLD. We do not know this for sure which is why we are doing this study. Other things 
may happen to you that we don’t yet know about. 
 
8. Your family can choose for you to be a part of this study or not. Your family can also decide for you to 
stop being in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have and talk with your 
family as they are making this decision.  
 
9. We are asking your permission to collect additional blood. We want to see if there are ways to tell how the 
PTLD will respond to treatment. These samples would be taken when other standard blood tests are being 
performed, so there would be no extra blood draws. You can still be treated on this study even if you don't 
allow us to collect the extra blood samples for research. 
 

 
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