Clinical trial NCT01141712
Conditions: Lymphoma HIV
Keywords: HIV B-cell Lymphoma Burkitt's Lymphoma Follicular Lymphoma Hodgkin's Lymphoma
Sponsor: Medical College of Wisconsin
Start date: 2010-04-01; Completion date: 2016-06-01
Enrollment: 43 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is a Phase II, multicenter trial assessing overall survival after autologous hematopoietic stem cell transplantation using a BEAM transplant regimen (carmustine, etoposide, cytarabine, melphalan) in lymphoma patients with HIV.

Detailed description:
BACKGROUND:

Non-Hodgkin lymphoma (NHL) is an AIDS-defining diagnosis for patients infected with the Human Immunodeficiency Virus (HIV). While the incidence of NHL has decreased amongst HIV-infected patients since the advent of highly-active anti-retroviral therapy (HAART), lymphoma remains a significant cause of death for this patient population. The prognosis for patients with AIDS-related lymphoma is dramatically different in the era of HAART therapy. In a comparison of treatment outcomes for patients treated before and after the advent of HAART, there is a statistically significant improvement in the overall survival of patients treated with HAART. Unfortunately, despite considerable advances in the treatment of AIDS-related NHL, induction-failure and disease relapse remain key challenges. The prognosis for patients with refractory and relapsed NHL is poor with overall survival rates of less than 20 percent for patients treated with non-transplant salvage therapies. Based upon a randomized trial and numerous phase II trials, high-dose therapy with autologous hematopoietic cell transplantation (HCT) has been established as the standard of care for patients with chemotherapy-sensitive relapsed non-Hodgkin lymphoma.

DESIGN NARRATIVE:

All patients must have chemosensitive disease as demonstrated by response to induction or salvage chemotherapy. Patients must also have less than or equal to 10percent bone marrow involvement after their most recent salvage therapy. Patients cannot have had prior autologous or allogeneic HCT. Patients must initiate conditioning therapy within 3 months of mobilization or bone marrow harvest.

Mobilization therapy may be employed per institutional guidelines. Patients must have an adequate autograft to be eligible for the protocol. Patients may not have HIV refractory to pharmacologic therapy. Patients must not have opportunistic infection that is not responding to therapy. Patients will receive Carmustine (BCNU) 300 mg/m\^2 Day -6, Etoposide 100 mg/m\^2 twice a day (BID) on Days -5 to -2, Cytarabine 100 mg/m2 BID on Days -5 to -2, and Melphalan 140 mg/m2 Day -1 followed by autologous HCT.

Patients will be followed for 2 years post-transplant. Survival data, time to progression data, progression-free survival data, time to progression after Complete Remission (CR) data, lymphoma disease-free survival data, time to hematopoietic recovery data, hematologic function data, toxicity data, incidence of infections, treatment-related mortality data, immunologic reconstitution data, data assessing the impact of therapy on the HIV reservoir and microbial gut translocation will be recorded and reported periodically to the BMT CTN Data and Coordinating Center (DCC).

Arms: arm 1: Patients will receive BCNU 300 mg/m\^2 Day -6, Etoposide 100 mg/m\^2 BID Days -5 to -2, Cytarabine 100 mg/m\^2 BID Days -5 to -2, and Melphalan 140 mg/m\^2 Day -1 followed by autologous HCT.
Interventions: intervention 1: Autologous transplant intervention 2: BCNU intervention 3: Etoposide intervention 4: Cytarabine intervention 5: Melphalan
Intervention descriptions: intervention 1: Participants will receive the BEAM conditioning regimen followed by autologous HCT. intervention 2: Participants will receive BCNU 300 mg/m\^2 Day -6 intervention 3: Participants will receive Etoposide 100 mg/m\^2 BID Days -5 to -2 intervention 4: Participants will receive Cytarabine 100 mg/m\^2 BID Days -5 to -2 intervention 5: Participants will receive Melphalan 140 mg/m\^2 Day -1

Protocol documents:
Prot_SAP_ICF_000.pdf: 
BMT CTN 0803  
High Dose Chemotherapy with Autologous Stem 
Cell Rescue for Aggressive B Cell Lymphoma and 
Hodgkin Lymphoma in HIV-infected Patients 
NCT01141712 


 
 
 
High Dose Chemotherapy with Autologous Stem Cell Rescue 
for Aggressive B Cell Lymphoma and Hodgkin Lymphoma 
in HIV-infected Patients  
 
BMT CTN PROTOCOL 0803 (AMC-071) 
VERSION 2.0 
 
Study Chairpersons 
Joseph Alvarnas, M.D.1 
Richard Ambinder, M.D.2 
 
 
Protocol Team 
 
Gorgun Akpek, M.D., M.H.S.3 
Robert Baiocchi, M.D., PhD.4 
Shelly Carter, Sc.D.5 
Steve Devine, M.D.4 
Charles Flexner, M.D.2 
Steve Forman, M.D.1 
Mary Horowitz, M.D, M.S.6 
Heather Jacene, M.D.2 
Rick Jones, M.D.2 
Lawrence Kaplan, M.D.7 
Amrita Krishnan, M.D.1 
Jennifer Le-Rademacher, Ph.D.6 
Alexandra Levine, M.D.1 
Richard Little, M.D.8 
Brent Logan, Ph.D.6 
Richard Maziarz, M.D. 9 
Willis Navarro, M.D. 10 
Uday Popat, M.D.11 
Jason Thompson5 
Aruna Subramanian, M.D.2 
John Zaia, M.D.1
 
Sponsored by the National Institutes of Health 
National Heart, Lung, and Blood Institute 
National Cancer Institute 
 
1City of Hope National Medical Center 
2Johns Hopkins Medical Institutions 
3University of Maryland Medical Center 
4The Ohio State University Medical Center 
5The EMMES Corporation  
 
       6Medical College of Wisconsin 
7University of California, San Francisco 
8National Cancer Institute 
9Oregon Health and Science University 
10National Donor Marrow Program 
11The University of Texas M.D. Anderson Cancer Center 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
i 
 
Core Study Participants: 
Affiliate Study Participants: 
 
City of Hope National Medical Center 
Johns Hopkins Medical Institutions 
University Hospitals of Cleveland, CWRU 
University of California, San Diego 
University of Minnesota 
University of Texas, MD Anderson Cancer 
Center 
 
Ohio State University Medical Center 
Virginia Mason Medical Center 
 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
ii 
PROTOCOL SYNOPSIS - BMT CTN PROTOCOL #0803  
 
High Dose Chemotherapy with Autologous Stem Cell Rescue for Aggressive B Cell 
Lymphoma and Hodgkin Lymphoma in HIV-infected Patients  
 
 
Study Chairpersons:  
Joe Alvarnas, M.D. and Richard Ambinder, M.D.  
 
Primary Objective: 
The primary objective of this multi-center study is to assess the 
overall survival after autologous hematopoietic stem cell 
transplantation (HCT) for chemotherapy-sensitive aggressive B 
cell lymphoma or Hodgkin’s lymphoma in patients with HIV using 
BEAM for pre-transplant conditioning.  
 
Secondary Objectives: 
Patients will be assessed for the following endpoints:  
1. Time to progression 
2. Progression-free survival 
3. CR and CR+PR proportion at Day 100 
4. Time to progression after CR 
5. Lymphoma disease-free survival 
6. Time to hematopoietic recovery 
7. Hematologic function at Day 100 
8. Toxicities 
9. Incidence of infections 
10. Treatment-related mortality 
11. Immunologic reconstitution 
12. Assessment of the impact of therapy on the HIV reservoir 
13. Assessment of microbial gut translocation 
14. Assessment of DNA in blood (clonal Ig DNA in plasma, EBV 
DNA in plasma and PBMC) as tumor markers will be 
assessed. 
 
Study Design: 
This study is designed as a Phase II multi-center trial. 
 
Accrual Objective: 
The trial will accrue 40 patients.  
 
Accrual Period: 
The estimated accrual period is two years. 
 
Eligibility Criteria: 
Eligible patients are a minimum of 15 years of age with Karnofsky 
performance status ≥ 70% that have persistent or recurrent diffuse 
large B-cell, immunoblastic, plasmablastic, Burkitt’s or Burkitt-
like, or classical Hodgkin lymphoma.  Patients must have received 
1-3 prior treatment regimens, including an induction chemotherapy 
and < 2 salvage regimens.  Monoclonal antibody therapy and local 
radiation will not be counted as prior therapies.  Patients must have 
chemosensitive disease as demonstrated by response to induction 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
iii 
or salvage chemotherapy.  Patients must also have ≤ 10% bone 
marrow involvement after their most recent salvage therapy.  
Patients cannot have had prior autologous or allogeneic HCT.  
Patients must initiate conditioning therapy within 3 months of 
mobilization or bone marrow harvest.  Mobilization therapy may 
be employed per institutional guidelines.  Patients must have an 
adequate autograft to be eligible for the protocol.  Patients may not 
have HIV refractory to pharmacologic therapy.  Patients must not 
have opportunistic infection that is not responding to therapy. 
 
Treatment Description: 
Patients will receive BCNU 300 mg/m2 Day -6, Etoposide 100 
mg/m2 BID Days -5 to -2, Cytarabine 100 mg/m2 BID Days -5 to  
-2, and Melphalan 140 mg/m2 Day -1 followed by autologous 
HCT.   
 
Study Duration: 
Patients will be followed on study for two years post-HCT.  


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
iv 
TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
NHL and Hodgkin Lymphoma in Patients with HIV Infection ................................ 1-1 
1.2. 
Autologous Hematopoietic Cell Transplantation for Patients with HIV Infection . 1-2 
1.3. 
HIV Infection and Risk of Opportunistic Infection following Autologous HCT ..... 1-4 
1.4. 
New Frontiers ................................................................................................................. 1-4 
1.4.1. 
HIV Single Copy PCR ................................................................................................ 1-4 
1.4.2. 
Immune Reconstitution ............................................................................................... 1-5 
1.4.3. 
DNA in Blood ............................................................................................................. 1-5 
1.4.4. 
Microbial Translocation .............................................................................................. 1-5 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview .............................................................................................................. 2-1 
2.2. 
Study Objectives............................................................................................................. 2-1 
2.2.1. 
Primary Objective ....................................................................................................... 2-1 
2.2.2. 
Secondary Objectives .................................................................................................. 2-1 
2.3. 
Patient Eligibility ........................................................................................................... 2-1 
2.3.1 
Patient Inclusion Criteria............................................................................................. 2-2 
2.3.2 
Patient Exclusion Criteria ........................................................................................... 2-3 
2.4. 
Study Treatments ........................................................................................................... 2-4 
2.5. 
Supportive Care ............................................................................................................. 2-4 
2.5.1. 
Post-HCT .................................................................................................................... 2-4 
2.5.1.1. 
Prophylaxis against infections..................................................................................... 2-4 
2.5.1.2. 
Cryopreservation ......................................................................................................... 2-5 
2.5.1.3. 
Post-HCT Growth Factors .......................................................................................... 2-5 
2.5.1.4. 
Post-HCT Lymphoma Therapy ................................................................................... 2-5 
2.5.1.5. 
Anti-Retroviral Therapy .............................................................................................. 2-5 
2.6. 
Participant Risks ............................................................................................................ 2-6 
2.7. 
Therapy Toxicities ......................................................................................................... 2-6 
2.7.1. 
Carmustine (BCNU) ................................................................................................... 2-6 
2.7.2. 
VP-16 (Etoposide) ....................................................................................................... 2-6 
2.7.3. 
Cytarabine (Ara-C)...................................................................................................... 2-7 
2.7.4. 
Melphalan .................................................................................................................... 2-7 
3. 
STUDY ENDPOINTS .................................................................................................... 3-1 
3.1. 
Definition of Disease Status ........................................................................................... 3-1 
3.2. 
Primary Endpoints......................................................................................................... 3-5 
3.3. 
Secondary Endpoints ..................................................................................................... 3-5 
3.3.1. 
Time to Progression .................................................................................................... 3-5 
3.3.2. 
Progression-free Survival ............................................................................................ 3-5 
3.3.3. 
CR and CR+PR Proportion at Day 100 ...................................................................... 3-5 
3.3.4. 
Time to Progression after CR (Response Duration) ................................................... 3-5 
3.3.5. 
Lymphoma Disease-Free Survival .............................................................................. 3-5 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
v 
3.3.6. 
Time to Hematopoietic Recovery ............................................................................... 3-6 
3.3.7. 
Hematologic Function at Day 100 .............................................................................. 3-6 
3.3.8. 
Toxicities ..................................................................................................................... 3-6 
3.3.9. 
Incidence of Infections ................................................................................................ 3-6 
3.3.10. 
Treatment-Related Mortality ....................................................................................... 3-6 
3.3.11. 
Immunologic Reconstitution ....................................................................................... 3-6 
3.3.12. 
HIV Single-Copy PCR ................................................................................................ 3-6 
3.3.13. 
Microbial Translocation Markers ................................................................................ 3-7 
3.3.14. 
Ig and EBV DNA in Blood ......................................................................................... 3-7 
4. 
PATIENT ENROLLMENT AND EVALUATION .................................................... 4-1 
4.1. 
Enrollment Procedures .................................................................................................. 4-1 
4.1.1. 
Screening and Eligibility Procedures .......................................................................... 4-1 
4.2. 
Study Monitoring ........................................................................................................... 4-1 
4.2.1. 
Follow-up Schedule .................................................................................................... 4-1 
4.2.2 
Adverse Event Reporting ............................................................................................ 4-3 
4.2.1.1. 
Evaluations prior to the HCT conditioning therapy .................................................... 4-3 
4.2.1.2. 
Post-HCT evaluations ................................................................................................. 4-5 
5. 
STATISTICAL CONSIDERATIONS ......................................................................... 5-1 
5.1. 
Study Overview .............................................................................................................. 5-1 
5.1.1. 
Accrual ........................................................................................................................ 5-1 
5.1.2. 
Primary Endpoint ........................................................................................................ 5-1 
5.2. 
Sample Size Calculations ............................................................................................... 5-1 
5.3. 
Interim Analysis and Stopping Guidelines .................................................................. 5-2 
5.4. 
Demographic and Baseline Characteristics ................................................................. 5-4 
5.5. 
Analysis Plan .................................................................................................................. 5-4 
5.5.1. 
Analysis of the Primary Endpoint ............................................................................... 5-4 
5.5.2. 
Analysis of Secondary Endpoints ............................................................................... 5-4 
 
 
 
 
LIST OF APPENDICES 
 
APPENDIX A 
 
HUMAN SUBJECTS 
APPENDIX B 
 
CONSENT FORMS 
APPENDIX C 
 
LABORATORY PROCEDURES 
APPENDIX D 
 
SUGGESTED PROPHYLAXIS 
APPENDIX E 
 
REFERENCES 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
1-1 
CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. 
NHL and Hodgkin Lymphoma in Patients with HIV Infection 
 
Non-Hodgkin lymphoma (NHL) is an AIDS-defining diagnosis for patients infected with the 
Human Immunodeficiency Virus (HIV).  While the incidence of NHL has decreased amongst 
HIV-infected patients since the advent of highly-active anti-retroviral therapy (HAART), 
lymphoma remains a significant cause of death for this patient population.1, 2, 3  The majority of 
patients with AIDS-related lymphoma have B-cell malignancies that include common entities 
such as diffuse large B-cell lymphoma, Burkitt lymphoma and Burkitt-like lymphoma as well as 
less common clinical entities such as primary effusion lymphoma, plasmablastic lymphoma and 
primary central nervous system lymphoma.4 
 
The prognosis for patients with AIDS-related lymphoma is dramatically different in the era of 
HAART therapy.  In a comparison of treatment outcomes for patients treated before and after the 
advent of HAART, there is a statistically significant improvement in the overall survival of 
patients treated with HAART (p = 0.002).  While the International Prognostic Index (IPI) 
remains a useful tool for estimating the prognosis of patients with AIDS-related NHL, the CD4 
count of less than 100 per microliter has independent prognostic value for this group of patients.1  
The impact of HAART therapy upon the immunological and functional status of patients with 
HIV infection has permitted the extension of aggressive therapeutic regimens to this patient 
population.  Amongst HAART-treated patients with diffuse large B-cell lymphoma, the outcome 
for treatment using CHOP or rituximab-CHOP appears to be similar to that for patients without 
HIV infection.5, 3, 6  Similarly, HIV patients with Burkitt or Burkitt-like lymphomas may be 
treated with intensive immunochemotherapeutic regimens similar to those utilized for patients 
without HIV infection.7, 8, 9  While toxicities are somewhat greater for those patients with AIDS, 
treatment outcomes appear to approach those achieved in patients without HIV-infection.8   
 
Unfortunately, despite considerable advances in the treatment of AIDS-related NHL, induction-
failure and disease relapse remain key challenges.  In a retrospective evaluation of 111 patients 
with AIDS-related NHL treated following the availability of HAART, patients were evaluated 
based upon IPI score and CD4 count at the time of diagnosis.  For patients in the two highest risk 
quartiles at the time of diagnosis, the 1-year survival rates were only 20% and 15% respectively.1  
In another trial comparing outcomes for patients prior to and subsequent to the availability of 
HAART, the median survival for patients with diffuse large B-cell lymphoma and Burkitt 
lymphoma treated in the post-HAART era was only 38.1 months and 5.1 months, respectively.3   
 
While Hodgkin lymphoma is not an AIDS-defining diagnosis, the incidence of this disease is 
increased amongst patients with HIV infection.2, 3  Hodgkin lymphoma is the third most common 
non-AIDS-defining malignancy amongst patients with HIV infection.10  Hodgkin lymphoma 
occurs more frequently in HIV infected patients than the general population with a standardized 
risk ratio of 14.7 (95% CI, 11.6-18.2).  The survival for this group of patients has improved in 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
1-2 
the HAART era, but a review of 47 patients diagnosed between 1997 and 2001, the estimated 2-
year overall survival was only 62%.11 
 
1.2. 
Autologous Hematopoietic Cell Transplantation for Patients with HIV Infection 
 
The prognosis for patients with refractory and relapsed NHL is poor with overall survival rates 
of less than 20% for patients treated with non-transplant salvage therapies.  Based upon a 
randomized trial and numerous phase II trials, high-dose therapy with autologous hematopoietic 
cell transplantation (HCT) has been established as the standard of care for patients with 
chemotherapy-sensitive relapsed non-Hodgkin lymphoma.12, 13, 14 
 
The use of autologous HCT for a patient with AIDS-related lymphoma was initially published as 
a case report in 1996.15  This initial transplant experience was marked by what appeared to be an 
increased risk of opportunistic infection.  Since the available of HAART, however, the transplant 
experience has evolved considerably and several groups have now demonstrated the feasibility of 
performing high-dose therapy with autologous HCT in patients with HIV-related Hodgkin and 
non-Hodgkin lymphoma. 
 
In a trial published by City of Hope, patients with induction-failure NHL, chemotherapy-
sensitive disease and IPI high-risk disease for eligible for treatment.  Twenty patients were 
enrolled in the trial, including 4 with IPI high-risk disease and 2 patients with Hodgkin 
lymphoma.  All of the patients successfully achieved adequate autologous stem cell collections.  
Patients were treated either with high-dose chemotherapy (17 patients - carmustine, etoposide, 
cyclophosphamide) or intensive chemo-radiotherapy (3 patients - fractionated total body 
irradiate, etoposide, cyclophosphamide).  One patient died of regimen-related toxicity and 2 
patients suffered early relapses of their disease.  At a median follow-up of 31.8 months, 17 of 20 
patients were alive and free of evidence of disease.  Treatment-related complications were 
comparable to those seen in the non-HIV-infected patient population.16 
 
In a trial published by the AIDS Malignancy Consortium, 27 patients with either AIDS-related 
NHL or Hodgkin lymphoma in the setting of HIV infection were enrolled.17  Twenty patients, 
including 15 with NHL and 5 patients with Hodgkin lymphoma, subsequently underwent 
autologous HCT using a preparative regimen that consisted of dose-reduced busulfan and 
cyclophosphamide.  One patient died of regimen-related toxicity.  At a median follow-up time of 
23 weeks, 10 patients were alive and free of disease. 
 
Re, et al described a group of patients with HAART-responsive HIV infection and either 
relapsed or refractory NHL (8) or Hodgkin lymphoma (8) who enrolled on trial.  Twelve patients 
collected an adequate stem cell dose.  One patient suffered disease progression prior to 
transplant.  Ten patients underwent autologous HCT following preparation with the BEAM 
(carmustine, etoposide, cytarabine, melphalan) regimen.18  Patients continued HAART 
throughout the entire treatment regimen.  All patients achieved engraftment post-transplant and 
there were no regimen-related deaths.  The 2-year estimated overall survival at a follow-up of 18 
months was 39.3% +/- 18.9%. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
1-3 
Several other groups have demonstrated the feasibility of performing autologous HCT in this 
patient population.  Gabarre, et al. reported the results of autologous HCT for 14 HIV-infected 
patients with relapsed or refractory NHL (8) or Hodgkin lymphoma (6).15  At the time of 
transplant, 11 patients had either achieved a complete or partial remission and 3 demonstrated 
evidence of progressive disease.  At 1 month post-transplant, 10 patients were in complete 
remission.  At the time of the study publication, 5 patients remained alive, including 4 in 
complete remission.  Serrano, et al. reported on 14 patients who underwent autologous HCT for 
AIDS-related lymphoma.19  All patients collected adequate numbers of stem cells.  Eleven 
patients underwent transplant and there was no transplant-related mortality.  At a median follow-
up of 32 months, 8 patients remained alive in complete remission. 
 
More recently, the EBMT Lymphoma Working Party published treatment outcomes for 68 
patients with HIV-related lymphoma (including 18 patients with Hodgkin lymphoma) that 
underwent autologous HCT.20  Patients were treated at 20 different institutions.  Sixty-five 
patients were treated with the BEAM regimen and the remainder was treated with radiation 
therapy-based regimens.  At a median follow-up of 32 months, the 3-year estimated progression-
free and overall survivals for the group were 56% and 61%, respectively.  Overall cumulative 
incidence of non-relapse mortality was 4.4% and 7.5%, at three and 12 months respectively. 
Relapse or progression was identified in 20 patients after a median time of 4.1 months from 
autologous HCT with the predicted cumulative incidence of relapse of 30% at 24 months. 
Multivariate analyses of these outcomes suggested that a) age > 50 years at autologous HCT was 
the only independent adverse prognostic factor for non-relapse mortality, b) histology, use of 
more than two chemotherapy regimens prior to autologous HCT and not being in remission at 
the time of autologous HCT were associated with increased risk of relapse, and c) not achieving 
complete remission in having chemotherapy resistant disease at autologous HCT were associated 
with worse progression free survival and overall survival.  A subsequent EBMT study reported 
the results of a matched case control study of outcomes of Hodgkin's disease and non-Hodgkin's 
lymphoma patients undergoing autologous HCT stratified by HIV+ status.21  The results of this 
comparative study revealed that HIV+ patients undergoing autologous HCT for lymphoma had 
similar relapse rates, progression free survival and overall survival.  There was a slight increase 
in non-relapse mortality at one year in HIV+ lymphoma patients versus those who were HIV- 
(8% vs. 2%), but this difference did not reach statistical significance. 
 
In sum, the probability of survival after high-dose conditioning followed by autologous stem cell 
transplantation ranges between 39% to 85% as seen in Table 1.2. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
1-4 
TABLE 1.2 CUMULATIVE OUTCOME AFTER AUTOLOGOUS STEM CELL 
TRANSPLANTATION IN PATIENTS WITH HIV-ASSOCIATED NHL AND HL 
 
Reference 
Failed to 
Mobilize (n) 
Patients 
Transplanted (n)  
TRM 
Median follow-
up (months) 
Patients 
Surviving (%) 
Krishnan 
0 
20 
5% 
32 
85 
Spitzer 
2 
20 
5% 
5.8 
50+?? 
Re 
4 
10 
0% 
18 
39 
Gabare 
? 
14 
? 
1 
71 
Serrano 
0 
11 
0% 
32 
73 
EBMT 
NA 
68 
7.5% 
32 
61 
 
 
1.3. 
HIV Infection and Risk of Opportunistic Infection following Autologous HCT 
 
Prior to the advent of HAART, opportunistic infection was a key limitation to the use of 
autologous HCT for patients with HIV-related lymphoma.  In the evolving transplant experience 
in the era of HAART, opportunistic infection has not proven to be a significant limitation to the 
use of high-dose therapy.  In the City of Hope group, Gabarre et al and AIDS Malignancy 
Consortium trial, CMV reactivation was noted in 3, 2 and 4 patients, respectively.16, 17, 22 
 
A key finding in the transplant experience to date has been that with availability of HAART, 
uncontrolled HIV infection has not been a significant transplant-related complication.  Even 
amongst those groups in which HAART therapy was withheld on a planned basis during the 
peri-transplant period, most patients were able to achieve suppression of HIV to undetectable 
levels by the end of the first post-transplant year.16  Similarly Gabarre, et al noted marked viral 
suppression in evaluable patients by 2 years post transplant.  
 
CD4 reconstitution following transplant appears comparable between groups.  The City of Hope 
group, the AIDS Malignancy Consortium trial and Gabarre, et al all have noted a decrement in 
the CD4 count that occurs through the 3rd transplant month, followed by a progressive rise in the 
median CD4 counts through the first and second post-transplant years. 
 
1.4. 
New Frontiers 
 
As the safety of HIV auto transplants have gained acceptance,  new questions have emerged with 
regard to aspects of HIV biology, HIV lymphoma tumor markers, and the relationship between 
gut and liver dysfunction that can be uniquely addressed in the context of a trial involving high 
dose myeloablative chemotherapy. 
 
1.4.1. HIV Single Copy PCR 
 
In patients with undetectable viral load as measured in conventional assays, there may be 
persistent viremia that can be measured at single copy/ml by specialized PCR analysis.  This 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
1-5 
viremia may reflect virus being released by the decay of latently infected cells or possibly 
ongoing viral replication.   
1.4.2. Immune Reconstitution 
 
The dynamics that occur with adaptive, innate, and humoral immune networks during and after 
stem cell engraftment in patients with AIDS-related Lymphoma (ARL) remain poorly 
characterized.  These studies will address immune reconstitution that occurs during and after 
engraftment of autologous stem cells in patients with HIV.  Examining the nature of adaptive 
immune reconstitution will involve use of a multi panel flow cytometric assay to track changes 
in naïve, memory, activated and regulatory T cell subsets.  Parallel studies will evaluate adaptive 
responsiveness to viral recall antigens (CMV, EBV and HIV pooled peptides).  Innate immune 
reconstitution studies will examine natural killer (NK) cell subsets with a multi panel flow 
cytometric assay as well as address NK cell cytokine and FcRIIIa responsiveness (with IFN 
and granzyme B or CD107a as biologic readout).  All of these studies have been successfully 
performed on peripheral blood mononuclear cell subsets that have been acquired from fresh or 
frozen samples in HIV- patients following allogeneic and autologous stem cell transplantation.   
 
1.4.3. DNA in Blood 
 
Tumor DNA detected in plasma is emerging as a potentially useful tumor marker.  Two 
candidate tumor markers in patients with HIV lymphomas have emerged.  These are: i) clonal Ig 
DNA as recognized by Ig rearrangements or characteristic somatic hypermutation; and, ii) EBV 
DNA.  In a small series, clonal Ig DNA is characteristic of a particular patient’s B cell tumor and 
is detected in approximately half of AIDS diffuse large B cell lymphoma prior to treatment.  In 
that series, patients in whom clonal Ig DNA persists in plasma inevitably relapse.  EBV DNA 
detected in plasma is useful as a tumor marker in nasopharyngeal carcinoma where evidence 
suggests that viral genomes are released from apoptotic tumor cells rather than being present as 
virions.  In AIDS, high copy numbers of EBV genomes is present in many HIV patients and in 
studies from the Multi-Center AIDS Cohort Study, have demonstrated very modest value to EBV 
determinations.  Recent evidence suggests that tumor cell derived viral DNA may be 
distinguished from virion DNA because virion DNA is not CpG methylated.  Thus meCpG EBV 
DNA may specifically mark tumor DNA. 
 
1.4.4. Microbial Translocation 
 
Hepatic injury is one of the potentially fatal complications of high-dose and stem cell therapies.  
Liver disease has emerged as a leading cause of death among patients with immunodeficiency.22  
Liver disease in association with hepatitis B or C infection progresses more rapidly in HIV 
patients than others.23  One of the hypothesized mechanisms has to do with HIV-related 
depletion of mucosal CD4 T cells with disruption of gut epithelial integrity and increased 
mucosal translocation (MT) of bacteria and bacterial products including LPS.  Hepatic tissues are 
directly affected by MT.  Emerging evidence also suggests that alcohol related liver injury is also 
linked to MT.  Some evidence also suggests that graft-versus-host related liver disease and celiac 
liver disease are also mediated in part by microbial translocation.  The proposed study would 
provide information about MT in association with high dose therapy in HIV patients and allow a 
preliminary analysis of an association with liver function abnormalities. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
1-6 
 
Recent observations that persons with chronic HIV-1 infection and AIDS demonstrate increased 
MT from the gut compared to uninfected persons may be related to the massive depletion of 
intestinal CD4+ lymphocytes within weeks of HIV-1 acquisition (1).  MT in HIV-HCV co-
infection was strongly associated with more rapid progression of liver cirrhosis.  A key finding 
was that serum endotoxin (LPS) level, a marker of microbial translocation, was higher in patients 
with more advanced fibrosis (2).  Autologous transplant patients are at risk for hepatic veno-
occlusive disease (VOD).  A high level of circulating MT markers (such as LPS) at the time of 
transplant could be a risk factor for liver damage especially in HIV patients.  Moreover, 
monitoring serum levels temporally to explore associations with liver associated morbidity 
including VOD, may provide insights into defining risk factors for VOD.   


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
2-1 
CHAPTER 2 
 
 
2. 
STUDY DESIGN  
 
2.1. 
Study Overview  
 
All patients will undergo an autologous HCT.  Collection of an adequate graft is a prerequisite of 
study entry but must be not more than three months prior to start of conditioning.  Pre-transplant 
conditioning will consist of BCNU 300 mg/m2 on Day -6.  Ara-C 100 mg/m2 BID and VP-16 
100 mg/m2 BID will be administered on Days -5, -4, -3 and -2.  Melphalan 140 mg/m2 will be 
administered on Day -1 and HCT on Day 0.  Patients will be followed for at least two years after 
enrollment. 
 
2.2. 
Study Objectives  
 
2.2.1. Primary Objective 
 
The primary objective of this multi-center study is to assess the overall survival after autologous 
hematopoietic stem cell transplantation (HCT) for chemotherapy-sensitive aggressive B cell 
lymphoma or Hodgkin’s lymphoma in patients with HIV using BEAM for pre-transplant 
conditioning.    
 
2.2.2. Secondary Objectives 
 
The secondary objectives are:  
1. Time to progression 
2. Progression-free survival 
3. CR and CR+PR proportion at Day 100 
4. Time to progression after CR 
5. Lymphoma disease-free survival 
6. Time to hematopoietic recovery 
7. Hematologic function at Day 100 
8. Toxicities 
9. Incidence of infections 
10. Treatment-related mortality 
11. Immunologic reconstitution 
12. Assessment of the impact of therapy on the HIV reservoir 
13. Assessment of microbial gut translocation 
14. Assessment of DNA in blood (clonal Ig DNA in plasma, EBV DNA in plasma and 
PBMC) as tumor markers will be assessed. 
 
2.3. 
Patient Eligibility 
 
Patients must meet specified eligibility criteria for entry into the study.   
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
2-2 
2.3.1 Patient Inclusion Criteria 
 
Patients fulfilling the following criteria will be eligible for entry into this study: 
1. Diagnosis of persistent or recurrent WHO classification diffuse large B-cell lymphoma, 
composite lymphoma with > 50% diffuse large B-cell lymphoma, mediastinal B-cell 
lymphoma, immunoblastic, plasmablastic, Burkitt’s or Burkitt-like or classical Hodgkin’s 
lymphoma.  Patients transformed from follicular lymphoma are eligible for the study, 
pending fulfillment of other criteria. 
2. 15 years old or older 
3. Three or fewer prior regimens of chemotherapy over the entire course of their disease 
treatment (including one induction chemotherapy and no more than 2 salvage 
chemotherapies).  Monoclonal antibody therapy and involved field radiation therapy will 
not be counted as prior therapies.   
4. All patients must have chemosensitive disease as demonstrated by at least a partial 
response (as defined by the criteria in Chapter 3) to induction or salvage therapy. 
5. ≤ 10% bone marrow involvement. 
6. Patients with adequate organ function as measured by: 
a) Cardiac:  American Heart Association Class I: Patients with cardiac disease but 
without resulting limitation of physical activity.  Ordinary physical activity does 
not cause undue fatigue, palpitation, dyspnea, or anginal pain.  Additionally, all 
patients 
must 
have 
a 
left 
ventricular 
ejection 
fraction 
at 
rest  
≥ 40% demonstrated by MUGA or echocardiogram. 
b) Hepatic:   
i. Bilirubin < 2.0 mg/dL (except for isolated hyperbilirubinemia attributed to 
Gilbert syndrome or antiretroviral therapy as specified in Appendix D) and 
ALT and AST < 3x the upper limit of normal.    
ii. Concomitant Hepatitis: Patients with chronic hepatitis B or C may be 
enrolled on the trial providing the above criteria are met. In addition, no 
active viral replication - undetectable (viral load <500 copies/ml) hepatitis 
B DNA level by PCR and no clinical or pathologic evidence of irreversible 
chronic liver disease.  See Appendix D for additional information and 
management guidelines. 
c) Renal: Creatinine clearance (calculated creatinine clearance is permitted) > 40 
mL/min. 
d) Pulmonary:  DLCO, FEV1, FVC ≥  45% of predicted (corrected for hemoglobin). 
7. Autologous peripheral stem cell graft with a minimum of  1.5 x 106 CD 34+ cells/kg 
(target  2.0 x 106 CD 34+ cells/kg) or if PBSC mobilization fails, cells can be obtained 
by bone marrow harvest per institutional practices (in cases where bone marrow 
will be used for transplantation, the required CD34+ dose does not apply and 
institutional requirements for total nucleated cell dose should apply). 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
2-3 
8. Initiate conditioning therapy within 3 months of mobilization or bone marrow harvest. 
9.  Signed informed consent. 
10. Patients on antiretroviral therapies (ARVs) can either have: 
a. Undetectable HIV viral load (VL < 50 copies). 
b. If VL detectable at < 2000 copies/mL must have review of previous antiretroviral 
regimens or previous genotypic or phenotypic testing which indicate the ability to 
fully suppress virus by addition of sensitive drugs.  This review will be carried out 
by the ID specialist caring for the patient.  
c. If VL detectable at >2000 copies/mL, a current HIV genotype and/or phenotype 
must be obtained.  If a HAART regimen to which the patient’s virus is sensitive 
can be determined based on genotype and previous antiretroviral experience, then 
the patient will be considered eligible in this regard. This review will be carried 
out by the ID specialist caring for the patient.  
 
2.3.2 Patient Exclusion Criteria 
 
Patients with the following will be ineligible for registration onto this study: 
1. Karnofsky performance score < 70%. 
2. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with 
progression or no clinical improvement).  
3. Prior malignancy in the 5 years prior to enrollment except resected basal cell carcinoma, 
treated cervical carcinoma in situ or Kaposi’s sarcoma.  
a. Symptomatic Kaposi’s sarcoma currently requiring therapy is excluded (patients 
receiving topical therapy for minimal disease are not included in this definition). 
b. Prior treatment with topical agents, local radiation, or up to 6 cycles of cytotoxic 
chemotherapy at least six months prior is permitted.   
c. Other cancers treated with curative intent < 5 years previously will not be allowed 
unless approved by the Medical Monitor or Protocol Chair.  
d. Cancer treated with curative intent > 5 years previously will be allowed.  
4. Pregnant (positive β-HCG) or breastfeeding.   
5. Fertile men or women unwilling to use contraceptive techniques from the time of 
initiation of mobilization until six-months post-transplant. 
6. Prior autologous or allogeneic HCT. 
7. Patients with evidence of MDS/AML or abnormal cytogenetic analysis indicative of 
MDS on the pre-transplant bone marrow examination.  Pathology report documentation 
need not be submitted. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
2-4 
2.4. 
Study Treatments  
 
The immediate pre-HCT evaluation will be carried out according to the operating procedures of 
the participating institutions and should be in keeping with the data reporting requirements of 
this study.  Similarly, special orders and procedures will be those defined by the BMT CTN 
Manual of Procedures (MOP).  All patients enrolled on this protocol will be hospitalized in 
accordance with the procedures for recipients of HCT as defined by the treating institutions.  See 
the conditioning regimen in Table 2.4 below. 
 
TABLE 2.4: BEAM + HCT REGIMEN 
 
Day 
-6 
-5 
-4 
-3 
-2 
-1 
0 
BCNU 
300 
mg/m2 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Ara-C  
100 mg/m2 
BID 
 
VP-16  
100 mg/m2 
BID 
Melphalan 
140 mg/m2 
HCT 
1. BCNU:  300 mg/m2 on Day –6, to be administered per institutional guidelines. 
2. Cytarabine (Ara-C):  100 mg/m2 BID on Days –5 through –2, for a total of 8 doses, to 
be administered per institutional guidelines. 
3. VP-16: 100 mg/m2 BID on Days –5 through –2, for a total of 8 doses, to be administered 
per institutional guidelines. 
4. Melphalan: 140 mg/m2 on Day -1, to be administered per institutional guidelines. 
5. Conditioning Regimen Administration Schedule: The conditioning regimen 
administration schedule may be modified ± 1 day according to institutional practice.  Day 
0 will be the day of HCT. 
 
2.5. 
Supportive Care 
 
2.5.1. Post-HCT 
 
All supportive care will be given in keeping with BMT CTN MOP and local institutional 
guidelines. 
 
2.5.1.1.Prophylaxis against infections  
 
All patients will receive prophylaxis against bacterial, fungal and viral infections during the post-
HCT period according to the BMT CTN MOP.  Additional guidelines for HIV patients in this 
study are summarized in Appendix D.  
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
2-5 
2.5.1.2.Cryopreservation 
 
Hematopoietic progenitor cells will be cryopreserved according to the institutional standards. 
 
2.5.1.3.Post-HCT Growth Factors 
 
All patients will receive G-CSF 5-10 mcg/kg beginning no later than Day +7 post-transplant 
until an ANC > 500/mm3 is obtained for 3 consecutive days.  If patients fall below this level 
once the G-CSF has been stopped, it can be restarted.   
 
2.5.1.4.Post-HCT Lymphoma Therapy 
 
Consolidative localized radiation therapy (maximum 3 sites) is allowed to areas of previous bulk 
disease (> 5 cm).  Localized radiation should be completed by Day 100 post-transplant.  No other 
anti-lymphoma therapy is allowed in the post-transplant setting or the patient will be considered 
to have progressed.   
 
2.5.1.5.Anti-Retroviral Therapy 
 
Anti-retroviral (ARV) therapy is only effective when administered in combination and with 
consistency.  Single agent therapy or repeated interruptions in therapy lead to resistance.  The 
ARV guidelines below are designed to minimize the possibility of drug interactions with high 
dose chemotherapy and to administer ARV only when it is anticipated that the ARV regimen can 
be consistently complied with (i.e. preparative regimen toxicities such as nausea and mucositis 
will not interfere with dosing schedules). 
 
ARV naïve patients, patients who are on ARV, and patients who are ARV experienced are 
eligible for the protocol.  
 
Two ARVs require special mention: efavirenz and AZT. 
 
Efavirenz has a long half life and resistance develops especially rapidly when it is administered 
in the absence of other ARVs.  When an efavirenz containing regimen is stopped, levels of other 
ARVs will fall much more rapidly than those of efavirenz resulting in the functional equivalent 
of single agent therapy and risking resistance.  In order to avoid this risk, another ARV should be 
substituted for efavirenz for at least 2 weeks before ARV therapy is stopped. 
 
AZT is myelosuppressive and should not be used in the ARV regimen administered after HCT. 
 
Patients on established antiretroviral regimens: 
1) If patient not on efavirenz (sustiva)-containing regimen, continue the ARVs until 
conditioning chemotherapy is started and then discontinue all ARVs at once. 
2) If patient is on efavirenz (sustiva)-containing regimen, change efavirenz to an alternative 
medicine (such as a protease inhibitor) for at least 2 weeks prior to starting conditioning 
and then discontinue all ARVs at the time of starting conditioning regimen.  


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
2-6 
3) Resume an ARV regimen at least 7 days after the preparative regimen and after mucositis 
has resolved and the patient is consistently able to tolerate oral medications. The ARV 
regimen should not include AZT. 
If patient is ARV naïve:  
1) Check genotype if never done previously (or obtain results of previous genotype) 
Start ARV regimen that does not contain AZT based on genotype results anytime after 
Day 7 post transplant once mucositis is resolved and patient is able to tolerate oral 
medications.  
 
2.6. 
Participant Risks 
 
HCT recipients incur risks from high-dose conditioning and post-HCT therapy, which must be 
weighed against the risk of the disease for which the HCT is prescribed.  Major risks following 
transplantation include: 1) Infection which can be bacterial, viral, parasitic, or fungal.  Often, 
these infections are life-threatening, particularly when caused by viral or fungal agents, and are 
associated with high mortality in the transplant population.  The published experience shows 
increased risk of CMV viremia, but no increase in mortality related to that virus; 2) Damage of 
all or any of the major organs may occur as a result of reactions to drugs (e.g., chemotherapy, 
antibiotics, anti-fungal medications), and as a result of destructive processes (e.g., infection), and 
may have a fatal outcome; brain damage can result in severe loss of cognitive or neurologic 
function; 3) Relapse or progression of lymphoma may occur, especially in patients with 
advanced disease status at time of treatment; 4) Unknown toxicities may occur in any individual 
patient due to multiple events and cumulative effects which may involve any and all organs, 
including the brain; and, 5) Death. 
 
2.7. 
Therapy Toxicities 
 
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0.  All of the following listed agents are commercially available.  Please 
refer to www.fda.gov for full adverse event information regarding the agents listed below.  All of 
the following agents should be administered per institutional standards, and stored per package 
insert instructions. 
 
2.7.1. Carmustine (BCNU) 
 
Carmustine is an alkylating agent.  Common side effects include myelosuppression, nausea, 
vomiting, headache, and jaw pain.  Less common side effects include transient hypotension, 
dizziness, hyperpigmentation of the skin, hepatoxicity and a delayed inflammatory lung response 
(pneumonitis).   
 
2.7.2. VP-16 (Etoposide) 
 
VP-16 is a semi-synthetic podophyllotoxin derivative.  Side effects that are likely to occur 
include nausea, vomiting and diarrhea, myelosuppression, mucositis, alopecia, and fatigue.  Less 
likely side effects include a skin rash, peripheral neuropathy, and hepatotoxicity.  Hypotension 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
2-7 
may occur if the drug is infused quickly.  A rare but serious side effect is a small risk of 
developing a second cancer. 
 
2.7.3. Cytarabine (Ara-C) 
 
Cytarabine, commonly known as Ara-C, is a synthetic nucleoside.  Likely side effects include 
myelosuppression, nausea, vomiting and diarrhea, oral and anal inflammation or ulceration, 
hepatic dysfunction, fever, rash, and thrombophlebitis.  Less likely side effects include 
conjunctivitis (when Ara-C is given at high doses, and preventable by the prophylactic use of 
corticosteroid eye drops), abdominal pain, alopecia, pruritis, headache, and the occurrence of a 
cytarabine syndrome characterized by fever, myalgias, arthralgias, chest pain, maculopapular 
rash, conjunctivitis and malaise - this syndrome occurs 6-12 hours following drug administration.  
Corticosteroids are beneficial in treating this syndrome.  A rare but serious side effect is 
cerebral/cerebellar dysfunction (more common at very high doses and in older patients).   
 
2.7.4. Melphalan 
 
Melphalan, an alkylating agent, is a phenylalanine derivative of nitrogen mustard.  At high doses, 
the likely toxicities include myelosuppression, gastrointestinal toxicity and alopecia.  The 
duration of profound myelosuppression decreases with the use of stem cell transplantation and 
colony stimulating factors.  Gastrointestinal toxicity, which includes potentially severe 
stomatitis, esophagitis and diarrhea, may require intravenous narcotics for mucositis related pain, 
intravenous hydration and alimentation, and antibiotics.  Less likely is hepatotoxicity.  Rare but 
serious toxicities reported include pulmonary fibrosis and interstitial pneumonitis, veno-
occlusive disease of the liver, skin hypersensitivity, vasculitis, hemolytic anemia, allergic 
reactions, and a small risk of developing second cancers.   
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
3-1 
CHAPTER 3 
 
 
3. 
STUDY ENDPOINTS 
 
3.1. 
 Definition of Disease Status 
 
Patients at each data collection period are classified into one of the following states. After HCT 
and until relapse/progression, all disease classifications are relative to the patient’s pre-HCT 
disease status.   Tests used for evaluation of disease status would be physical examination, 
laboratory testing, bone marrow biopsy and aspirate, PET scans, and CT scans of neck, chest, 
abdomen and pelvis as indicated.   
 
Segments of this section are excerpts from the Bruce Cheson, et al, article “Revised Response 
Criteria for Malignant Lymphoma.”24 
TABLE 3.1:  RESPONSE DEFINITIONS 
 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
 
(a) FDG-avid or PET positive 
prior to therapy; mass of any 
size permitted if PET negative 
(b) Variably FDG-avid or PET 
negative; regression to normal 
size on CT 
Not palpable, 
nodules 
disappeared 
 
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable 
disease and no 
new sites 
 
≥ 50% decrease in SPD of up to 
6 largest dominant masses; no 
increase in size of other nodes 
(a) FDG-avid or PET positive 
prior to therapy; one or more 
PET positive at previously 
involved site 
(b) Variably FDG-avid or PET 
negative; regression on 
CT 
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule 
in greatest 
transverse 
diameter); no 
increase in size 
of liver or 
spleen 
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified 
 
SD 
Failure to 
attain CR/PR 
or PD 
 
(a) FDG-avid or PET positive 
prior to therapy; PET positive at 
prior sites of disease and no 
new sites on CT or PET 
(b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
3-2 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
Relapsed 
disease or 
PD 
Any new 
lesion or 
increase by 
≥ 50% of 
previously 
involved sites 
from nadir 
 
Appearance of a new lesion(s)  
> 1.5 cm in any axis, ≥ 50% 
increase in SPD of more than 
one node, or ≥ 50% increase in 
longest diameter of a previously 
identified node > 1 cm in short 
axis 
 
Lesions PET positive if FDG-
avid lymphoma or PET 
positive prior to therapy 
> 50% increase 
from nadir in 
the SPD of any 
previous 
lesions 
 
New or recurrent 
involvement 
 
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed 
tomography; PR, partial remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease. 
 
**   In relation to Response Definitions, be aware of HIV adenopathy, this can be avid in patients with equivocal scans. 
*** Additional follow-up PET needed if 90-day results are equivocal. 
 
Complete Remission (CR): 
The designation of CR requires the following (Table 3.1): 
• Complete disappearance of all detectable clinical evidence of disease and disease-related 
symptoms if present before therapy. 
• Typically FDG-avid lymphoma: in patients with no pretreatment PET scan or when the 
PET scan was positive before therapy, a post-treatment residual mass of any size is 
permitted as long as it is PET negative. 
• Variably FDG-avid lymphomas/FDG avidity unknown: in patients without a pretreatment 
PET scan, or if a pretreatment PET scan was negative, all lymph nodes and nodal masses 
must have regressed on CT to normal size (≤ 1.5 cm in their greatest transverse diameter 
for nodes > 1.5 cm before therapy).  Previously involved nodes that were 1.1 to 1.5 cm in 
their long axis and more than 1.0 cm in their short axis before treatment must have 
decreased to ≤ 1.0cm in their short axis after treatment. 
• The spleen and/or liver, if considered to be enlarged before therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical exam and should be 
considered normal size by imaging studies, and nodules related to lymphoma should 
disappear.  However, determination of splenic involvement is not always reliable because 
a spleen considered normal in size may still contain lymphoma, whereas an enlarged 
spleen may reflect variations in anatomy, blood volume, the use of hematopoietic growth 
factors, or causes other than lymphoma. 
• If bone marrow was involved by lymphoma before treatment, the infiltrate must have 
cleared on repeat bone marrow biopsy.  The biopsy sample on which this determination is 
made must be adequate (with a goal of > 20 mm unilateral core).  If the sample is 
indeterminate by morphology, it should be negative by immunohistochemistry.  A sample 
that is negative by immunohistochemistry but that demonstrates a small population of 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
3-3 
clonal lymphocytes by flow cytometry will be considered a CR until data become 
available demonstrating a clear difference in patient outcome. 
 
Complete Remission Undetermined (CRu):  
• The use of the above definition for CR and that below for PR eliminates the category of 
CRu. 
 
Partial Remission (PR): 
The designation of PR requires all of the following: 
• At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the 
largest dominant nodes or nodal masses.  These nodes or masses should be selected 
according to all of the following: they should be clearly measurable in at least 2 
perpendicular dimensions; if possible they should be from disparate regions of the body; 
and they should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved. 
• No increase should be observed in the size of other nodes, liver or spleen. 
• Splenic and hepatic nodules must regress by  50% in their SPD or, for single nodules in 
the greatest transverse diameter. 
• With the exception of splenic and hepatic nodules, involvement of other organs is usually 
assessable and no measurable disease should be present. 
• Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment.  However, if positive, the cell type should be specified (eg, 
large-cell lymphoma or small neoplastic B cells).  Patients who achieve a CR by the 
above criteria, but who have persistent morphologic bone marrow involvement will be 
considered partial responders.  When the bone marrow was involved before therapy and a 
clinical CR was achieved, but with no bone marrow assessment after treatment, patients 
should be considered partial responders. 
• No new sites of disease should be observed. 
• Typically FDG-avid lymphoma: for patients with no pretreatment PET scan or if the PET 
scan was positive before therapy, the post-treatment PET should be positive in at least 
one previously involved site. 
• Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, CT criteria should be 
used.  In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only 
indicated with one, or at most two, residual masses that have regressed by more than 50% 
on CT; those with more than two residual lesions are unlikely to be PET negative and 
should be considered partial responders. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
3-4 
Stable Disease (SD): 
Stable disease (SD) is defined as the following: 
• A patient is considered to have SD when he or she fails to attain the criteria needed for a 
CR or PR, but does not fulfill those for progressive disease (see Relapsed Disease [after 
CR]/Progressive Disease [after PR, SD]). 
• Typically FGD-avid lymphomas: the PET should be positive at prior sites of disease with 
no new areas of involvement on the post-treatment CT or PET. 
• Variably FDG-avid lymphomas/FDG-avidity unknown: for patients without a 
pretreatment PET scan or if the pretreatment PET was negative, there must be no change 
in the size of the previous lesions on the post-treatment CT scan. 
 
Relapsed Disease (RD, after CR)/ Progressive Disease (PD after PR, SD): 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of 
the short axis.  If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered 
abnormal if its short axis is more than 1.0. Lymph nodes ≤ 1.0 x ≤ 1.0cm will not be considered 
as abnormal for relapse or progressive disease. 
• Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size.  Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities.  In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histologic 
confirmation. 
• At least a 50% increase from nadir in the SPD of any previously involved nodes or in a 
single involved node, or the size of other lesions (e.g, splenic or hepatic nodules).  To be 
considered progressive disease, a lymph node with a diameter of the short axis of less 
than 1.0 cm must increase by  50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in 
the long axis. 
• At least a 50% increase in the longest diameter of any single previously identified node 
more than 1 cmin its short axis 
• Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected with 
current PET systems (< 1.5 cm in its long axis by CT).  Measurable extranodal disease 
should be assessed in a manner similar to that for nodal disease.  For these 
recommendations, the spleen is considered nodal disease.  Disease that is only assessable 
(e.g. pleural effusions, bone lesions) will be recorded as present or absent only, unless, 
while an abnormality is still noted by imaging studies or physical examination, it is found 
to be histologically negative.  In clinical trials where PET is unavailable to the vast 
majority of participants, or where PET is not deemed necessary or appropriate for use 
(e.g. a trial in patients with MALT lymphoma), response should be assessed as above, but 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
3-5 
only using CT scans.  However, residual masses should not be assigned CRu status, but 
should be considered partial responses. 
 
3.2. 
Primary Endpoints 
 
The primary endpoint is one-year overall survival.  
 
3.3. 
Secondary Endpoints  
 
3.3.1. Time to Progression 
 
The event is relapse/progression or receiving anti-lymphoma therapy, other than post-transplant 
consolidative localized radiation (maximum 3 sites) to sites of prior bulk disease pre-transplant 
(> 3cm).  The time to this event is measured from transplant.  Deaths without relapse/progression 
are considered as a competing risk.  Surviving patients with no history of relapse/progression are 
censored at time of last follow-up. 
 
3.3.2. Progression-free Survival 
 
Patients are considered a failure for this endpoint if they die or if they relapse/progress or receive 
anti-lymphoma therapy, other than post-transplant consolidative localized radiation (maximum 3 
sites) to sites of prior bulk disease pre-transplant (> 3cm).  The time to this event is the time from 
transplant until death, relapse/progression, receipt of anti-lymphoma therapy, or last follow up, 
whichever comes first. 
 
3.3.3. CR and CR+PR Proportion at Day 100  
 
CR (or PR) will be assessed at Day 100.   
 
3.3.4. Time to Progression after CR (Response Duration) 
 
This will be assessed in patients with CR.  The time to this event is measured from 
documentation of complete response for patients entering the trial in PR and from enrollment for 
patients entering the trial in CR.  Patients are considered failure for this end point if they relapse 
after complete remission.  Surviving patients with no history of relapse/progression are censored 
at time of last follow-up. 
 
3.3.5. Lymphoma Disease-Free Survival 
 
This will be assessed in patients with CR.  The time to this event is measured from 
documentation of complete response for patients enrolling in PR and from enrollment for 
patients entering the trial in CR.  Patients are considered failure for this end point if they die or if 
they relapse after complete remission.  Patients with no history of relapse or death after complete 
remission are censored at time of last follow up. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
3-6 
3.3.6. Time to Hematopoietic Recovery 
 
Time to neutrophil recovery will be the first of two consecutive days of > 500 neutrophils/μL 
following the expected nadir.  Time to platelet engraftment will be the date platelet count is  
> 20,000/μL for the first of two consecutive labs with no platelet transfusions 7 days prior. 
 
3.3.7. Hematologic Function at Day 100 
 
Hematologic function will be defined by ANC>1500, Hemoglobin>10g/dL without transfusion 
support, and platelets>100,000and measured at Day 100 and 1 year.  Use of growth factors will 
be noted. 
 
3.3.8. Toxicities 
 
Toxicities will be defined by using the version 3.0 CTCAE criteria.  Only grade 3 and higher 
toxicities will be collected. 
 
3.3.9. Incidence of Infections  
 
Microbiologically documented infections will be reported by site of disease, date of onset, 
severity, and resolution, if any.  This data will be captured via an event-driven case report form 
and will be collected from Day 0 until one year post-transplant.   
 
3.3.10. Treatment-Related Mortality 
 
Treatment-Related Mortality (TRM) is defined as death occurring in a patient from causes other 
than relapse or progression and will be measured at 100 days.  
 
3.3.11. Immunologic Reconstitution  
 
Immune reconstitution assays on peripheral blood will include (i) immunophenotypic analysis of 
both T and natural killer subsets; (ii) functional evaluation of adaptive and innate immune 
responsiveness; and (iii) quantitative immunoglobulin measurement (IgM, IgG and IgA). Studies 
will be performed at Days 60, 180, and 365 post-transplant. Quantitative immunoglobulin 
measurements (IgM, IgG and IgA) will also be performed prior to initiation of conditioning. 
These will be summarized at each time point using descriptive statistics. 
 
3.3.12. HIV Single-Copy PCR 
 
HIV RNA within 90 days prior to start of conditioning, at Day 100, 180, and 1 year post 
transplant will be measured.  For those patients with no detectable viral RNA in their baseline 
sample using the standard clinical test performed at the clinical site, additional blood samples 
will be collected at two time points prior to the initiation of ablative chemotherapy (at 2 time 
points) and at Days 180, 365 and 730 post-transplant. Plasma aliquots from these time points will 
be sent for further analysis at a project laboratory for possible low-level HIV-1 viremia by a 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
3-7 
sensitive single-copy PCR assay (capable of detecting HIV-1 RNA levels down to 1 copy per 
milliliter of plasma). 
 
3.3.13. Microbial Translocation Markers 
 
Blood specimens for microbial translocation will be collected within 1 week prior to the 
initiation of conditioning, on Day -3 of conditioning and Days 7, 14 and 100 after stem cell 
infusion. 
 
3.3.14. Ig and EBV DNA in Blood 
 
Blood specimens will be collected within 1 week prior to the initiation of conditioning, on Day -
3 of conditioning and at 100 days, 6 months and 1 year.  The presence of clonal Ig DNA in 
plasma will be assessed, as will EBV copy number in plasma and in PBMC at each of these time 
points. 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
4-1 
CHAPTER 4 
 
 
4. 
PATIENT ENROLLMENT AND EVALUATION 
 
4.1. 
 Enrollment Procedures 
 
4.1.1. Screening and Eligibility Procedures 
 
Patients will be registered using the BMT CTN Electronic Data Capture System 
(AdvantageEDCSM).  The following procedures should be followed: 
1. Within 3 weeks to 1 week prior to initiation of conditioning therapy, an authorized user at 
the transplant center completes initial screening by entering patient demographics and 
Segment A of the Enrollment Form in AdvantageEDC.  The eligibility screening includes 
questions that will verify eligibility, capture the proposed start date of conditioning, and a 
question confirming that the patient signed the informed consent form. The patient must 
also be registered with the CIBMTR and have a valid CRID number. 
2. If the patient is eligible, a study number is generated. 
 
4.2. 
 Study Monitoring 
 
4.2.1. Follow-up Schedule 
 
The follow-up schedule for scheduled study visits is outlined in Table 4.2.1.  A detailed 
description of each of the forms and the procedures required for forms completion and 
submission can be found in the Data Management Handbook and User’s Guide.  The Data 
Management Handbook, including the Forms Submission Schedule, is available on the 
homepage of the Internet data entry system. 
 
Follow-up Visits: Follow-up visits will begin as soon as patients are enrolled onto the study.  
The follow-up period for Segment A is 2 years. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
4-2 
TABLE 4.2.1:  FOLLOW-UP SCHEDULE  
 
Study Visit 
Target Day 
(+ 2 Days Prior to Day 100 Post-ASCT) 
(+ 28 Days After Day 100 Post-ASCT) 
1 week 
7 days 
2 week 
14 days 
3 week 
21 days 
4 week 
28 days 
5 week 
35 days 
6 week 
42 days 
8 week 
56 days 
100 day 
100 days 
6 month 
180 days 
12 month 
365 days 
24 month 
730 days 
 
 
Criteria for Forms Submission: Criteria for timeliness of submission for all study forms are 
detailed in the Data Management Handbook and User’s Guide.  Forms that are not entered into 
AdvantageEDC within the specified time will be considered delinquent.  A missing form will 
continue to be requested either until the form is entered into the AdvantageEDC and integrated 
into the Data Coordinating Center’s (DCC) master database or until an exception is granted and 
entered into the Missing Form Exception File, as detailed in the Data Management Handbook. 
 
Reporting Patient Deaths: Recipient Death Information must be entered into AdvantageEDC 
within 24 hours of knowledge of the patient’s death.  If the cause of death is unknown at that 
time, it need not be recorded at that time.  However, once the cause of death is determined, the 
form must be updated in AdvantageEDC. 
 
CIBMTR Data Reporting: Centers participating in BMT CTN trials must register pre and post-
transplant outcomes on all consecutive hematopoietic stem cell transplants done at their 
institution during their time of participation to the Center for International Blood and Marrow 
Transplant Research (CIBMTR).  Registration is done using procedures and forms of the Stem 
Cell Transplant Outcomes Database (SCTOD).  (Note: Federal legislation requires submission of 
these forms for all US allotransplant recipients.)  Enrollment of BMT CTN #0803 must be 
indicated on the SCTOD pre-transplant registration form.  Additionally, CIBMTR pre- and post- 
transplant Report Forms must also be submitted for all patients enrolled on this trial.  CIBMTR 
forms will be submitted directly to the CIBMTR at the times specified on the Form Submission 
Schedule.   


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
4-3 
 
4.2.2 Adverse Event Reporting 
 
Unexpected, grade 3-5 adverse events (AE) will be reported through an expedited AE reporting 
system via AdvantageEDC.  Unexpected, grade 4-5 AEs must be reported within 24 hours of 
knowledge of the event.  Unexpected, grade 3 AEs must be reported within three business days 
of knowledge of the event.  Expected AEs will be reported using NCI’s Common Terminology 
Criteria for Adverse Events (CTCAE) Version 3.0 at regular intervals as defined on the Form 
Submission Schedule. 
 
Tables 4.2.1.2A and 4.2.1.2B summarize patient clinical assessments over the course of the 
study. 
 
4.2.1.1.Evaluations prior to the HCT conditioning therapy 
 
The following observation need to be performed within 3 months of enrollment: 
1. CMV IgG, hepatitis panel (HAV Ab, HBsAb, HBsAg, HBcAb, HCVAb), HSV 1 and 2 
IgG, RPRor VDRL, toxoplasma IgG, VZV IgG, and HTLV1 antibody. 
2. EKG 
3. PET or PET-CT scan.  
4. Creatinine clearance (calculated creatinine clearance is permitted). 
5. CMV PCR or antigenemia assay. 
6. DLCO, FEV1 and FVC. 
7. Bone marrow biopsy for pathology 
8. HIV RNA, CD4 Count. 
9. If the core Ab are positive, HepB DNA PCR and HepC DNA PCR 
10. Ejection fraction 
 
The following observations need to be performed within 8 weeks prior to enrollment: 
1. History, physical examination, height and weight, body surface area, neurologic 
examination, measurement of all palpable peripheral lymph nodes and measurement of 
other sites of disease present on physical. 
a. Lumbar puncture(s) for determination of presence of CNS disease for non-Hodgkin's 
lymphoma patients only. 
b. Duration of AIDS diagnosis, history of prior opportunistic illnesses. 
c. Presence or absence of “B”-symptoms (unexplained fevers, night sweats, involuntary 
weight loss greater than 10% normal body weight). 
d. Medication list to include all antiviral, antibiotics and opportunistic prophylaxis.  


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
4-4 
2. β-HCG serum pregnancy test for females of childbearing potential. 
 
The following observation will be performed 4 weeks prior to enrollment: 
1. Karnofsky performance status 
2. CBC 
with 
differential, 
platelet 
count, 
creatinine, 
bilirubin, 
LDH, 
alkaline 
phosphataseALT, AST, sodium, magnesium, potassium, chloride, and CO2. 
3. CT: CT scans of neck, chest, abdomen and pelvis.  Neck CT only required if previous site 
of disease. 
 
The following observations will be performed after patient enrollment and within 1 week 
prior to initiation of conditioning therapy: 
1. Karnofsky performance status 
2. CBC with differential, platelet count, creatinine, bilirubin, LDH, alkaline phosphatase, 
ALT, AST, sodium, magnesium, potassium, chloride, and CO2. 
 
The following samples should be collected after enrollment but prior to initiation of 
conditioning: 
1. Blood samples for evaluation of quantitative immunoglobulins (IgM, IgG, and IgA). 
Note: Quantitative immunoglobulins will be performed at the clinical center. 
2. Collection of additional peripheral blood samples for HIV single copy assessment in only 
those patients with undetectable baseline HIV viral levels by conventional assay (See 
Appendix C) 
3. Microbial translocation monitoring peripheral blood sample collected within 1 week prior 
to initation of conditioning. (See Appendix C). 
4. Future research sample collection for consenting patients (See Appendix C). 
5. DNA monitoring in blood (EBV and Ig DNA) collected within one week prior to 
initiation of conditioning. (See Appendix C). 
 
The following samples should be collected on Day -3 of conditioning: 
1. Microbial translocation monitoring sample (See Appendix C). 
2. DNA monitoring in blood (EBV and Ig DNA) samples (See Appendix C). 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
4-5 
4.2.1.2. Post-HCT evaluations 
1. CBC at least twice a week from Day 0 until ANC > 500/mm3 for 2 days after nadir 
reached.  Thereafter CBC twice per week until Day 28 (or 4 weeks), then at 8 weeks,  
Day 100, 6 months, one year and two years post-HCT. 
2. Toxicity assessments at 4 weeks, 8 weeks, Day 100, 6 months, one year and two years 
post-HCT. 
3. Mucositis assessment twice a week until Day 21 using the modified oral mucositis 
assessment scale (OMAS). 
4. Disease restaging: 
a. CT scan at 100 days, 6 months and one year post-transplant 
b. PET or PET CT at 100 days post-transplant, with a 6 month PET or PET-CT 
performed if the Day 100 scan results are equivocal 
5. Evaluation 
of 
immune 
reconstitution 
by 
flow 
cytometry 
and 
quantitative 
immunoglobulins (IgM, IgG and IgA) at Day 60, 180 and one year post-HCT. Note: 
Flow cytometry will be performed at project laboratory (See Appendix C) and 
quantitative immunoglobulins will be performed at the clinical center. 
6. CMV PCR or antigenemia assay measured weekly Day 0 through 8 weeks; follow-up at 
Day 100.  
7. Diagnostic lymphoma pathology specimens (paraffin blocks or 10 unstained slides) sent 
to the AIDS Cancer and Specimen Resource/AIDS Malignancy Consortium Pathology 
Laboratory central laboratory within 4 weeks post transplant (See Appendix C).   
8. HIV viral copy number, performed at the clinical centers at 100 days, 6 months, 1 year, 2 
years by standard clinical assay.    
9. For those patients with no detectable viral RNA in their baseline sample using the 
standard clinical test performed at the clinical site, additional post-transplant blood 
samples will be collected at Day 180, 365 and 730 (See Appendix C).   
10. Blood DNA (EBV and Ig DNA) assessments at 100 days, 6 months, and 1 year.   
11. Microbial Translocation Monitoring at Days 7, 14 and 100. 


BMT CLINICAL TRIALS NETWORK 
 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
4-6 
TABLE 4.2.1.2A: PRE-ASCT EVALUATIONS 
 
 
Prior to initiation of BEAM 
 
Required Studies/Testing 
3 months 
8 weeks 
4 weeks 
1-3 weeks  
1 week  
Day -3 of 
Conditionin
g 
CMV IgG, Hepatitis Panel (HAV Ab, HBsAg, HbcAb, HbsAb, HCV Ab), HSV ½ IgG, toxoplasma IgG, 
VZV IgG, Syphilis (RPR or VDRL) , HIV and HTLV antibody 
X 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
PET or PET-CT 
X 
 
 
 
 
 
DLCO, FEV1, FVC 
X 
 
 
 
 
 
Creatinine Clearance 
X 1 
 
 
 
 
 
CMV PCR or antigenemia assay  
X 
 
 
 
 
 
Bone marrow biopsy for pathology 
X 
 
 
 
 
 
HIV RNA, CD4 Count 
X 
 
 
 
 
 
HepB DNA PCR and HepC DNA PCR are required only if the core Ab are positive 
X 
 
 
 
 
 
Ejection Fraction 
X 
 
 
 
 
 
History, Physical Examination, Height and Weight, body surface area, neurologic examination, careful 
measurement of all palpable peripheral lymph nodes and measurement of other sites of disease present on 
physical.  
 
X2 
 
 
 
 
β –HCG Serum Pregnancy Test for Females of Childbearing Potential 
 
X 
 
 
 
 
Quantitative Immunoglobulins 
(IgM, IgG, and IgA) 
 
 
 
X 
 
 
CT 
 
 
X3 
 
 
 
Karnofsky Performance Score 
 
 
X 
 
X 
 
CBC with differential, Platelet Count, Creatinine, Bilirubin, Alkaline Phosphatase, AST, ALT, LDH, 
Sodium, Magnesium, Potassium, Chloride and CO2 
 
 
X 
 
X 
 
Central Pathology Review 
X4 
 
 
 
 
 
Plasma DNA Tumor Monitoring (Ig and EBV) 
 
 
 
 
X 
X 
Microbial Translocation Monitoring 
 
 
 
 
X 
X 
HIV Single Copy PCR Assessment 
 
 
 
X5 
X5 
 
Optional Future Research Blood Sample 
 
 
 
X 
 
 
Notes for Table 4.2.1.2A are on the next page. 
 


BMT CLINICAL TRIALS NETWORK 
 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
4-7 
Notes for Table 4.2.1.2A  
1 Calculated creatinine clearance is permitted. 
2 To include: 
a.  Lumbar puncture(s) for determination of presence of CNS disease for non-Hodgkin's lymphoma patients only. 
b.  Duration of AIDS diagnosis, history of prior opportunistic illnesses. 
c.  Presence or absence of “B”-symptoms (unexplained fevers, night sweats, involuntary weight loss greater than 10% normal body weight). 
d.  Medication list to include all antiviral, antibiotics and opportunistic prophylaxis.  
3 CT scans of neck, chest, abdomen and pelvis.  Neck CT only required if previous site of disease. 
4 Tissue block is preferred but 10 unstained slides may be used as an alternative. Pre-enrollment samples collected during the enrollment evaluation process should be saved, but 
will only be shipped to Central Pathology Laboratory for review on those patients enrolled onto the study (See Appendix C). 
5 Collection of additional blood for HIV single copy PCR assessments will be required for only those patients with undetectable baseline HIV viral levels by conventional assay 
(See Appendix C). 
 
 


BMT CLINICAL TRIALS NETWORK 
 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
4-8 
 
TABLE 4.2.1.2B:  POST-HCT EVALUATIONS 
 
 
Weeks  
Post-HCT 
Months  
Post-HCT 
Study Assessments/ 
Testing 
1 
2 
3 
4 
5 
6 
7 
8 
Day 
100 
6 
12 
24 
CBC1 
X1 
 
 
 
X 
X 
X 
X 
X 
Toxicity Assessment 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
Mucositis Assessment2 
X 
X 
X 
 
 
 
 
 
 
 
 
 
CT  
 
 
 
 
 
 
 
 
X 
X 
X 
 
PET or PET-CT 
 
 
 
 
 
 
 
 
X 
X3 
 
 
Immune Reconstitution Assays4 
 
 
 
 
 
 
 
X 
 
X 
X 
 
CMV PCR or Antigenemia5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diagnostic Lymphoma Pathology6 
 
 
 
X 
 
 
 
 
 
 
 
 
HIV Titer by Standard Assay  
 
 
 
 
 
 
 
 
X 
X 
X 
X 
HIV Single Copy PCR Assessment7 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Microbial Translocation Monitoring 
X 
X 
 
 
 
 
 
 
X 
 
 
 
Plasma DNA Tumor Monitoring (Ig and EBV) 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Notes for Table 4.2.1.2B on the next page 


BMT CLINICAL TRIALS NETWORK 
 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
4-9 
Notes for Table 4.2.1.2B 
1 To be performed at least twice weekly from Day 0 until ANC > 500/mm3 for 2 days after nadir reached.  Thereafter, twice weekly until Day 28 (or 4 weeks), then at 8 
weeks, Day 100, 6 months, one year and two years post-ASCT. 
2 To be performed twice weekly until Day 21 using the modified oral mucositis assessment scale (OMAS) 
3 6 month scan performed if the Day 100 scan results are equivocal 
4 Immune reconstitution assays by flow cytometry and quantitative immunoglobulins (IgM, IgG and IgA). Flow cytometry will be performed at project laboratory (See 
Appendix C) and quantitative immunoglobulins will be performed at clinical center 
5 CMV PCR or antigenemia assay measured weekly Day 0 through 8 weeks; follow-up at Day 100.  
6 Diagnostic lymphoma pathology specimens (paraffin blocks or 10 unstained samples) collected pre-enrollment should be sent to the AIDS Cancer and Specimen 
Resource/AIDS Malignancy Consortium Pathology Central Laboratory within 4 weeks of transplant. 
7 Collection of additional blood for HIV single copy PCR assessments will be required for only those patients with undetectable baseline HIV viral levels by conventional 
assay (See Appendix C). 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
5-1 
CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. 
 Study Overview 
 
This study is designed as a Phase II multi-center trial to assess the overall survival after 
autologous hematopoietic stem cell transplantation (HCT) for chemotherapy-sensitive aggressive 
B cell lymphoma or Hodgkin’s lymphoma in patients with HIV using BEAM for pre-transplant 
conditioning.  The target enrollment is 40 patients.   
 
5.1.1. Accrual 
 
Accrual will be across multiple sites and remain open until 40 patients are transplanted.  It is 
estimated that two years of accrual will be necessary to enroll the targeted sample size. 
 
5.1.2. Primary Endpoint 
 
The primary endpoint for the study is overall survival.  Time-to-event is measured from 
transplantation to the minimum of the date of death or last follow-up.  If any patients are lost to 
follow-up, they will be censored at the time of the last observation.  The study will remain open 
until the last patient enrolled has been followed for two years. 
 
5.2. 
Sample Size Calculations 
 
The sample size is 40 patients for this trial.  Ninety-five percent confidence intervals were 
calculated for varying probabilities based on the sample size.  Table 5.2 provides confidence 
intervals for a variety of true underlying proportions.  Of particular interest is where the OS 
probability is 50%, which is the targeted one-year survival probability.  For this setting, the 
confidence interval length is 32.4%.  The percentage above and below 50% are meant to 
represent other plausible survival rates. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
5-2 
TABLE 5.2 POSSIBLE 95% CONFIDENCE INTERVAL FOR VARIOUS 
UNDERLYING OVERALL SURVIVAL RATES WITH N=40 
 
Overall Survival 
Rate (%) 
Possible 95% Confidence 
Intervals (%) 
Length of 95% 
Confidence Interval 
80 
64.4 
91.0 
26.6 
75 
58.8 
87.3 
28.5 
70 
53.5 
83.4 
29.9 
65 
48.3 
79.4 
31.1 
60 
43.3 
75.1 
31.8 
55 
38.5 
70.7 
32.2 
50 
33.8 
66.2 
32.4 
45 
29.3 
61.5 
32.2 
40 
24.9 
56.7 
31.8 
35 
20.6 
51.7 
31.1 
30 
16.6 
46.5 
29.9 
 
The OS probability estimate will be based on the Kaplan-Meier product limit estimator.  In the 
absence of censoring, the Kaplan-Meier estimate reduces to the binomial proportion.  
 
5.3. 
Interim Analysis and Stopping Guidelines 
 
There will be no interim analyses for efficacy.  Monitoring of a key safety endpoint (treatment-
related mortality (TRM)) will be conducted at Day 30 and if rates significantly exceed pre-set 
thresholds, the NHLBI will be notified in order that the DSMB can be advised.  Policies and 
composition of the DSMB are described in the BMT CTN's Manual of Procedures.  The stopping 
guidelines serve as a trigger for consultation with DSMB for additional review, and are not 
formal “stopping rules” that would mandate automatic closure of study enrollment. 
 
The rate of TRM will be monitored up to 30 days post-transplant.  A truncated Sequential 
Probability Ratio Test (SPRT) based on a binomial test of proportions for treatment-related 
mortality will be used as described below.  This sequential testing procedure conserves type I 
error across all of the monitoring looks for TRM.  The SPRT can be represented graphically.  At 
each interim analysis, the number of patients enrolled is plotted against the total number of 
patients who have experienced TRM.  The continuation region of the SPRT is defined by two 
parallel lines.  Only the upper boundary will be used for monitoring to protect against excessive 
TRM.  If the graph falls above the upper boundary, the SPRT rejects the null hypothesis, and 
concludes that there are more TRM than predicted by the number of patients on study.  
Otherwise, the SPRT continues until enrollment reaches the target goal. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
5-3 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting 
H0 when  = 0 and of accepting H1 when  = 1, respectively, and the expected sample size 
E(N|i).  Note that since the test uses only the upper boundary, and is truncated by a finite 
sample size, the size of the test will be slightly lower than the nominal level.  The test to be used 
in this protocol was developed from the following SPRT:   
 
• An SPRT contrasting 5% versus 15% TRM, with nominal type I and II errors of 9% and 
20%, respectively.   
• The slope of the parallel lines for monitoring TRM is 0.092 and the intercepts are –1.252 
and 1.806. 
The stopping rule is summarized in Table 5.3A.   
 
TABLE 5.3A STOPPING GUIDELINES FOR 30-DAY TRM  
AMONG PATIENTS ENROLLED 
Number of patients enrolled 
Stopping boundary 
3-12 
3 
13-23 
4 
24-34 
5 
35-40 
6 
* Stopping guideline is triggered if >= x patients out of n patients 
enrolled experience TRM. 
 
The actual operating characteristics of the truncated test, shown in Table 5.3B, were determined 
in a simulation study.  The simulation assumed uniform accrual of 40 patients over a two-year 
time period.   
 
TABLE 5.3B OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FOR 30-DAY TRM FROM A SIMULATION STUDY  
WITH 10,000 REPLICATIONS 
 
Treatment-related Mortality 
True 30-day rate 
5% 
10% 
15% 
20% 
Probability reject the null hypothesis 
0.047 
0.332 
0.683 
0.885 
Mean month stopped 
24.4 
21.0 
16.0 
12.0 
Mean # endpoints 
1.9 
3.4 
3.8 
3.7 
Mean patients with 30 days follow-up 
39.0 
33.4 
25.4 
18.9 
 
Treatment-related mortality is monitored in all patients.  The SPRT rejects the null hypothesis in 
favor of the alternative 5% of the time when the true 30-day TRM is 5%, and 88% of the time 
when the true 30-day TRM is 20%.  This corresponds to a type I error rate of =0.05 and a type 
II error rate of =0.12.  When the true 30-day TRM rate is 20%, on average, the DSMB will be 
consulted 12 months after opening, when 3.7 events have been observed in 18.9 patients.  Note 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
5-4 
that the SPRT procedure is adequately powered to distinguish between a TRM rate of 5% and 
20%. 
 
5.4. 
Demographic and Baseline Characteristics 
 
Demographics and baseline characteristics will be summarized for all patients.  Characteristics to 
be examined are: age, gender, race/ethnicity, performance status, disease stage, genotype, HIV 
load, CD4 counts, and number of prior chemotherapy regimens as treatment of primary 
malignancy and number of prior HIV regimens. 
 
5.5. 
Analysis Plan 
 
5.5.1. Analysis of the Primary Endpoint 
 
The primary analysis will consist of estimating the 1 year OS probability from the time of 
transplantation based on the Kaplan-Meier product limit estimator.  The 1 year OS and 
confidence interval will be calculated. 
 
5.5.2. Analysis of Secondary Endpoints 
 
Time to Progression 
The event is relapse/progression.  Death without relapse/progression is considered a competing 
risk.  Patients alive with no history of relapse/progression are censored at the time of the last 
observation.  Time-to-relapse or progression will be measured from transplant.  A cumulative 
incidence curve will be computed along with a 95% confidence interval. 
 
Progression-Free Survival (PFS)  
The event is relapse/progression or death.  The time to this event is the time from enrollment 
until death, relapse/progression, receipt of anti-lymphoma therapy, or last follow up, whichever 
comes first.  Progression-free survival (PFS) will be estimated using the Kaplan Meier product 
limit estimator.  The PFS probability and confidence interval will be calculated at one and two 
years post-transplant. 
 
CR and CR+PR Proportion at Day 100 
The frequencies and proportions of patients who have a CR (or PR) will be described with 
confidence intervals at Day 100. 
 
Time to Progression after CR 
The event is relapse/progression after complete response.  Death after CR without 
relapse/progression is considered a competing risk.  Patients who achieved CR and alive with no 
history of relapse/progression are censored at the time of the last observation.  Time-to-relapse or 
progression will be measured from documentation of complete response for patients entering the 
trial in PR and from enrollment for patients entering the trial in CR.  A cumulative incidence 
curve will be computed. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
5-5 
 
Lymphoma Disease-Free Survival 
The event is death or relapse after complete response.  The time to this event is the time to 
relapse, death or last follow-up, whichever comes first, measured from documentation of 
complete response for patients entering the trial in PR and from enrollment for patients entering 
the trial in CR.  Lymphoma Disease-Free survival will be estimated using the Kaplan Meier 
product limit estimator.  
 
Time to Hematopoietic Recovery   
Time to neutrophil recovery and platelet engraftment will be estimated using cumulative 
incidence function with death prior to engraftment as the competing risk. 
 
Hematologic Function 
The proportions of patients with hematologic function at Day 100 and 1 year will be described 
with confidence intervals in patients surviving to these time points.   
 
Toxicities 
Toxicities that occur over the course of time will be tabulated using the version 3.0 CTC AE 
criteria.  The proportion of patients developing toxicity will be described by type of toxicity, 
grade, and time period. 
 
Incidence of Infections 
Microbiologically documented infections will be reported by site of disease, date of onset, 
severity, and resolution, if any, up to two years post-transplant.   
 
Treatment-related Mortality  
Treatment-related mortality (TRM) is defined as death occurring in a patient from causes other 
than relapse or progression.  A cumulative incidence curve will be computed along with a 95% 
confidence interval at 100 days post-transplant. 
 
Immunologic Reconstitution  
Immune reconstitution assays on peripheral blood, which include (i) immunophenotypic analysis 
of both T and natural killer subsets; (ii) functional evaluation of adaptive and innate immune 
responsiveness; and (iii) quantitative immunoglobulin measurement (IgM, IgG and IgA). Studies 
will be performed at Days 60, 180, and 1 year post-transplant.  These will be summarized at each 
time point using descriptive statistics.   
 
HIV Reservoir  
HIV RNA assay prior to transplant and at Day 100, 180 and 1 year post transplant (for HIV load) 
will be performed. For patients with no detectable viral RNA using the standard clinical test, a 
single copy assay will be used to measure the viral reservoir.  We will summarize this 
assessment of the viral copy number using descriptive statistics at each time point, and we will 
investigate changes in the viral copy number from pre-transplant to post-transplant time points 
using Friedman’s nonparametric test.   


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
5-6 
 
Microbial Translocation 
Association between outcome (hyperbilirubinemia, VOD, and death) at Day 30 and Day 100 
post transplant and level of microbial translocation markers will be determined by nonparametric 
Mann-Whitney tests comparing the distribution of prior microbial translocation markers between 
patients with vs. without each outcome.   
 
Blood DNA 
Plasma DNA (clonal Ig, EBV) and PBMC EBV DNA  measured within 1 week of initiation of 
conditioning, on Day -3 of conditioning, at Day +100, 6 months and 1 year post-transplant will 
be summarized using descriptive statistics.   
 
The probability of patients relapsing or progressing by one or two years post-transplant will be 
estimated using the cumulative incidence function separately for patients with vs. without the 
presence of plasma DNA at each measured time points (both pre- and post-transplant).  For 
plasma DNA measured post-transplant, the analysis will be restricted to patients who are alive 
and have not yet relapsed/progressed by the time of plasma DNA measurement.  The association 
between the presence of plasma DNA at each time point and subsequent progression/relapse at 
one or two years will be determined by the Chi-square test. 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
A-1 
 
APPENDIX A 
 
HUMAN SUBJECTS 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
A-2 
APPENDIX A 
 
HUMAN SUBJECTS 
 
 
1. 
Subject Consent 
 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for the treatment of the underlying disease.  The Principal Investigator or 
another designated physician will conduct the conference.  All potential risks associated with 
BEAM and HSCT or should be discussed as objectively as possible.   
 
The consent document should be reviewed with the patient and family prior to proceeding to 
ablative therapy. 
 
Informed consent from the patient will be obtained using a form approved by the Institutional 
Review Board of the institution enrolling the patient.  
 
 
2. 
Confidentiality 
 
Confidentiality will be maintained by individual names being masked and assigned a patient 
identifier code.  The code relaying the patient’s identity with the ID code will be kept separately 
at the center.  The ID code will be transmitted to the BMT CTN Data Coordinating Center upon 
enrollment. 
 
 
3. 
Participation of Women and Minorities and Other Populations 
 
Women and ethnic minorities and other populations will be included in this study.  Accrual of 
women and minorities at each center will be monitored to determine whether their rates of 
enrollment are reflective of the distribution of potentially eligible women and minorities 
expected from data reported to the CIBMTR and from published data on incidence of DLCL in 
these groups.  Centers will be notified if their rates differ significantly from those expected and 
asked to develop appropriate recruitment strategies. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-1 
 
APPENDIX B 
 
CONSENT FORMS 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-2 
 
Informed Consent to Participate in Research 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator Contact Information 
(Insert contact information for PI at your site) 
 
 
Study Sponsor: The National Institutes of Health (NIH) is sponsoring this study by providing 
financial support through the Blood and Marrow Transplant Clinical Trials Network (BMT 
CTN).   
 
Introduction 
This is a clinical trial, which is a research study to answer specific medical questions.  The 
information from this study will help future patients.  The Study doctor (the person in charge of 
the research) will explain the clinical trial to you.  Clinical trials include only people who choose 
to join the study.  
 
Please take your time to decide if you want to join this study.  Some people find it helpful to talk 
about the study with their family and friends before they make a decision.  It may also be useful 
to talk with your doctor and other people on your health care team about the study.  If you have 
questions or want to know more about the study, you can ask them for more information. 
 
You are being asked to take part in this study because you have an HIV related chemotherapy-
sensitive aggressive B cell lymphoma or Hodgkin’s lymphoma which has either not fully 
responded to the initial treatment or has returned.  An autologous peripheral blood stem cell 
transplant is when your own stem cells are collected from your blood, frozen, and then given 
back to you after you receive chemotherapy, also referred to as conditioning therapy.   
 
 
Why is this study being done?  
This approach is fairly standard for patients with lymphoma. However, in patients with HIV, 
there are some special issues. This study is being carried out to better define the risks and 
benefits of this approach to therapy in HIV patients.   Results of this trial will help guide 
treatment decisions for future HIV patients. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-3 
 
How many people will take part in the study? 
Forty patients will take part in this study.   
 
 
What will happen if I take part in this research study? 
Before you begin the study -- You will need to have the following exams, tests or procedures to 
find out if you can be in the study.  These exams, tests or procedures are part of regular cancer care 
and may be done even if you do not join the study.  If you have had some of them recently, they 
may not need to be repeated.  This will be up to your study doctor.  The tests include: 
• Medical history 
• Physical examination, including height and weight 
• Blood and urine tests 
• EKG 
• Heart function tests 
• Pulmonary (lung) function tests  
• Tests to evaluate your lymphoma including PET/CT scans and a bone marrow biopsy 
• A blood pregnancy test if you are a woman able to have children; if you are pregnant, you 
will not be able to take part in this study. 
 
During the study (you can refer to the Study Chart later in this consent as you read this) – 
 
Antiretorviral Therapy 
Antiretroviral therapy will be stopped before transplant chemotherapy begins and will not be 
reinitiated until the WBC has recovered.  This is done for two reasons.  It is common for the 
chemotherapy to cause nausea and vomiting that would interrupt antiretroviral therapy.  We 
believe repeated interruptions are more dangerous than a planned stop and then restart after 
nausea has resolved.  In addition, some antiretroviral therapies may have effects on the bone 
marrow during its recovery (zidovudine) or may interact with chemotherapy drugs so as to lead 
to increased or unpredictable toxicities.  Patients who were on zidovudine prior to transplant will 
be started on an alternative antiretroviral in place of zidovudine. 
 
Conditioning Regimen 
The conditioning regimen is used to kill the lymphoma cells in your body.  BEAM is the pre-
transplant conditioning regimen you will receive.  You will receive BEAM chemotherapy 
starting 6 days before your transplant.  BEAM is a very common combination of chemotherapy 
drugs that has been widely used in transplants for Lymphomas.   
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-4 
Reinfusion of Stem Cells (Transplantation) 
After the conditioning regimen, the stem cells that were previously collected and frozen will be 
thawed and reinfused into you through your catheter.  You will then receive the autologous cells 
that were collected and frozen during mobilization (this day that you receive your cells is 
referred to as Day 0).  The cells will travel to your bone marrow where they’ll begin making 
healthy, new blood cells.  This step is necessary because the high dosages of chemotherapy given 
to you during the conditioning regimen will not only destroy lymphoma cells, but healthy cells in 
your bone marrow as well.  Until the new stem cells begin producing healthy blood cells, you 
will be at an increased risk of excessive bleeding or developing an infection. 
 
Description of Study Drugs 
 
BEAM-  BEAM is a mixture of several chemotherapy drugs that interfere with the growth of 
cancer cells and are widely used to treat NHL:   
BCNU (also called carmustine) 
Etoposide (also called VP-16)  
Ara-C (also called cytarabine) 
Melphalan 
 
When you are finished taking these drugs and have received your transplant, you will be watched 
closely.  For this study, you will have the following tests at least twice per week for the first 4 
weeks and then again at 8 weeks, 100 days, six months, one year and two years after 
transplantation: 
• Medical history 
• Physical examination 
• Blood and urine tests  
 
In addition to these tests, you will have blood drawn to test how well your immune system is 
working before you begin treatment and at 60 days, six months and one year after your 
transplant.   
 
Tests and exams to look at the status of your lymphoma will be done 100 days, 6 months, 1 year 
and 2 years after your transplant.  These will include PET and CT scans.  
 
All of these exams, tests or procedures are part of regular medical care after a transplant and may 
be done even if you do not join the study.  The schedule for testing is only for tests required for the 
study.  Some of these tests will be done more frequently than described here if your doctor thinks it 
is necessary for your medical care.   
 
 
How long will I be on this study? 
After your transplant, the study doctor will ask you to visit the office for follow-up exams for 
two years to receive the study tests and procedures described above.  
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-5 
Follow up for your transplant will last as long as you require care.  However, we would like to 
keep track of your medical condition for the rest of your life by contacting you and the doctor 
providing your regular medical care by phone or mail once a year.  Keeping in touch with you 
and checking on your condition every year helps us look at the long-term effects of the study and 
transplantation in general.  Many transplant centers include this type of long-term follow-up as 
part of their regular medical care.  It is not necessary for you to agree to follow-up for longer 
than 5 years to participate in this study. 
 
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell your doctor if you are thinking about stopping or 
decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell your doctor if you are thinking about stopping so any risks from the 
medications can be evaluated.  Another reason to tell your doctor that you are thinking about 
stopping is to discuss what follow-up care and testing could be most helpful for you. 
 
 
Can the Study Doctor withdraw me from the study? 
You can be taken off the study (with or without your consent) for any of the following reasons: 
• You do not qualify to be in the study because you do not meet the study requirements.  
Ask your doctor if you would like more information about this. 
• You need a medical treatment not allowed in this study. 
• The study doctor decides that continuing in the study would be harmful to you. 
• The study treatments have a bad effect on you. 
• You become pregnant. 
• You are unable to keep appointments or take study drugs as directed. 
• Other study-specific reasons; for example, if the dose of study drug you are taking is 
found to be unsafe. 
• The study is cancelled by the Food and Drug Administration (FDA) or the National 
Institutes of Health (NIH). 
 
 
What side effects or risks can I expect from being in the study? 
You will have side effects while on the study.  Side effects may be mild or very serious.  Your 
health care team will give you medicines to help lessen side effects such as nausea.  In some 
cases, side effects can be serious, long lasting, or may never go away.  There is also a risk of 
death.  Most of these risks are common to all patients undergoing autologous transplant but 
some, such as risk of infection or organ damage may be different in patients with HIV. 
 
You should talk to your study doctor about any side effects that you have while taking part in the 
study.  
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-6 
Potential Side Effects 
 
BEAM 
Likely 
Less Likely 
Rare but Serious 
• Low blood counts 
• Nausea/vomiting 
• Mouth sores 
• Sores in esophagus 
• Abdominal 
pain/diarrhea 
• Difficulty eating 
• Hair loss 
• Fatigue 
• Liver problems 
• Lung problems 
• Low blood pressure 
• High levels of uric acid 
• Skin rash 
• Chills 
• Liver failure 
• Severe lung problems 
• Severe allergic 
reactions 
• Second cancers, 
including 
Myelodysplastic 
Syndromes (MDS) and 
leukemia 
• Life-threatening 
infection 
• Disease of the 
peripheral nervous 
system 
• Sterility 
 
 
Reproductive Risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  Women should not breastfeed a baby 
while on this study.  It is important you understand that you need to use birth control while on 
this study.  Check with your study doctor about what kind of birth control methods to use and 
how long to use them.  Some methods might not be approved for use in this study.  Some of the 
drugs used in the study may make you unable to have children in the future. 
 
This study is designed to help persons who are suffering from lymphoma.  However, this 
treatment may not cure your lymphoma. We do not expect that this treatment will have any long 
term effect on the course of your HIV infection. 
 
For more information about risks and side effects, ask your study doctor. 
 
 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better.  We do know that the 
information from this study will help doctors learn more about transplantation for lymphoma in 
HIV patients.  This information could help future HIV patients with lymphoma. 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-7 
What other choices do I have if I do not take part in the study? 
Your other choices may include: 
• Treatment with other drugs or a combination of drugs without a transplant.  
• An autologous stem cell transplant that is not part of the study or another type of 
transplant. 
•  No therapy directed against your lymphoma at this time. 
 
Talk to your doctor about your treatment choices before you decide if you will take part in this 
study. 
 
 
What are the costs of taking part in this study? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
 
All costs of your care including the chemotherapy drugs and costs associated with administration 
of them will need to be paid by you and/or your health plan/insurance company.  All of the 
medical tests, evaluations and procedures in this study are considered part of standard medical 
care. 
 
The companies that make the drugs used in this study did not plan or design this clinical trial.  
They will also not have a part in analyzing the results of this study. 
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage.  You 
can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy. 
 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your doctor, __________________ [investigator's name(s)], if you 
feel that you have been injured because of taking part in this study.  You can tell the doctor in 
person or call him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment.  


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-8 
 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or not to take part in 
the study.  If you decide to take part in this study, you may leave the study at any time.  No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits.  Leaving the study will not affect your medical care.  You can still get your 
medical care from our institution.  
 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.  
 
 
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
 
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
• 
The National Marrow Donor Program and the Center for International Blood and Marrow 
Transplant Research, organizations involved in research on blood and marrow 
transplantation and in the coordination of this study 
• 
The EMMES Corporation, a research organization that is helping to coordinate this study 
• 
Members of the Blood and Marrow Transplant Clinical Trials Network, which is 
conducting this study 
• 
The National Heart, Lung, and Blood Institute (NHLBI), the National Cancer Institute 
(NCI) and other government agencies, like the Food and Drug Administration (FDA), 
involved in keeping research safe for people  
 
 
HIPAA1 authorization to use and disclose individual health information for research 
purposes 
 
a. Purpose:  As a research participant, I authorize the Principal Investigator and the 
researcher’s staff to use and disclose my individual health information for the purpose of 
conducting the research study entitled High Dose Chemotherapy with Autologous Stem 
 
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-9 
Cell Rescue for Aggressive B Cell Lymphoma and Hodgkin Lymphoma in HIV-infected 
Patients. 
 
b. Individual Health Information to be Used or Disclosed: My individual health information 
that may be used or disclosed to conduct this research includes: demographic information 
(e.g., age, date of birth, sex, weight), medical history (e.g., diagnosis, complications with 
prior treatment), physical examination findings, and laboratory test results obtained at the 
time of work up and after transplantation (e.g., blood tests, biopsy results).  
 
c. Parties Who May Disclose My Individual Health Information: The researcher and the 
researcher’s staff may obtain my individual health information from: 
(list hospitals, clinics or providers from which health care information can be requested) 
 
 
 
 
d. Parties Who May Receive or Use My Individual Health Information: The individual 
health information disclosed by parties listed in item c and information disclosed by me 
during the course of the research may be received and used by the following parties: 
• Members of the BMT CTN Data and Coordinating Center and 0803 Protocol 
Team 
• National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer 
Institute (NCI), both of the National Institutes of Health (NIH), study sponsors  
• U.S. government agencies that are responsible for overseeing research such as the 
Food and Drug Administration (FDA) and the Office of Human Research 
Protections (OHRP) 
• U.S. government agencies that are responsible for overseeing public health 
concerns such as the Centers for Disease Control (CDC) and federal, state and 
local health departments 
• Other: 
 
 
 
 
e. Right to Refuse to Sign this Authorization: I do not have to sign this Authorization.  If I 
decide not to sign the Authorization, I will not be allowed to participate in this study or 
receive any research-related treatment that is provided through the study.  However, my 
decision not to sign this authorization will not affect any other treatment, payment, or 
enrollment in health plans or eligibility for benefits.   
f. Right to Revoke:  I can change my mind and withdraw this authorization at any time by 
sending a written notice to the Principal Investigator to inform the researcher of my 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-10 
decision.  If I withdraw this authorization, the researcher may only use and disclose the 
protected health information already collected for this research study.  No further health 
information about me will be collected by or disclosed to the researcher for this study. 
g. Potential for Re-disclosure: My individual health information disclosed under this 
authorization may be subject to re-disclosure outside the research study and no longer 
protected.  Examples include potential disclosures for law enforcement purposes, 
mandated reporting or abuse or neglect, judicial proceedings, health oversight activities 
and public health measures. 
h. This authorization does not have an expiration date. 
 
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study. 
Contact your study doctor __________________ [name(s)] at ______________ [telephone 
number]. 
 
For questions about your rights while taking part in this study, call the __________[name of 
center] Institutional Review Board (a group of people who review the research to protect your 
rights) at __________________ (telephone number).  
 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor. 
 
************************************************ 
About Using Blood for Research 
Please note: This section of the informed consent form is about future research studies that 
will be done using blood samples from people who are taking part in the main study described 
above.  You may give small blood samples for these future research studies if you want to.  
You can still be a part of the main study even if you say 'no' to giving blood samples for future 
research studies.  You can say "yes" or "no" to giving blood samples for future research 
studies.  Please mark your choice at the end of this section. 
 
We would like to have one small (4 teaspoons or 20 mL) blood sample for future research.  If 
you agree, this sample will be obtained pre-transplant.  They will be kept and may be used in 
research to learn more about HIV, cancer and other diseases.  Usually the blood can be drawn 
from your central venous catheter at the time of the other blood collections.  If this is not 
possible, it will be taken from a vein.  When the sample is given to investigators for research, no 
information about your name, address, phone number or other information that will let the 
researcher know who you are will be provided. 
 
The samples collected for research purposes will be sent to the AIDS and Cancer Specimen 
Resource Repository.  The samples will be labeled with unique codes that do not contain 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-11 
information that could identify you.  A link to this code does exist.  The link is stored at the Data 
and Coordinating Center for the Blood and Marrow Transplant Clinical Trials Network (BMT 
CTN).  The staff at the repository where your sample is being stored does not have a link to this 
code.  Your research samples will continue to be stored at the ACSR Repository until they are 
used up for approved research. 
 
DNA from your stored blood and tissue samples and your health information might be used 
in genome-wide association (GWA) studies for a future project either done or supported by 
the National Institutes of Health (NIH).   
Genome-wide association studies are a way for scientists to identify genes involved in human 
disease. This method searches the genome for small genetic changes that are more common 
in people with a particular disease than in people without the disease. Each study can look at 
hundreds of thousands of genetic changes at the same time. Researchers use data from this 
type of study to find genes that may add to a person’s risk of developing a certain disease. 
If your coded genetic and clinical information is used in such a study, the researcher is 
required to add the DNA test results and non-identifying information into a public research 
database.  This public database is called the NIH Genotype and Phenotype Database and it is 
managed by the National Center for Biotechnology Information (NCBI). The NCBI will 
never have any information that would identify you, or link you to your information or 
research samples.  
 
The research that may be done with your blood is not designed specifically to help you.  It might 
help people who have HIV, cancer and other diseases in the future.  
 
Reports about research done with your blood will not be given to you or your doctor.  These 
reports will not be put in your health record.  The research will not have an effect on your care.  
 
Things to Think About: The choice to let us have blood samples for future research is up to 
you.  No matter what you decide to do, it will not affect your care.  
 
If you decide now that your blood can be kept for research, you can change your mind at any 
time.  Just contact your study doctor and let him or her know that you do not want us to use your 
blood sample.  Then any blood that remains will no longer be used for research.  
 
In the future, people who do research on these blood samples may need to know more about your 
health.  While the study doctor or others involved in running this study may give the researchers 
reports about your health, it will not give them your name, address, phone number, or any other 
information that will let the researchers know who you are.  
 
Sometimes blood is used for genetic research (about diseases that are passed on in families).  
Even if your blood is used for this kind of research, the results will not be put in your health 
records.  
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-12 
Your blood will be used only for research and will not be sold.  The research done with your 
blood may help to develop new products in the future.  
 
Benefits: The benefits of research using blood include learning more about what causes HIV, 
cancer and other diseases, how to prevent them, and how to treat them.  
 
Risks: The greatest risk to you is the release of information from your health records.  We will 
do our best to make sure that your personal information will be kept private.  The chance that 
this information will be given to someone else is very small.  
 
Making Your Choice: Please read each sentence below and think about your choice.  After 
reading each sentence, please indicate your choice below.  If you have any questions, please talk 
to your doctor or nurse, or call our research review board at ___________________.  
 
No matter what you decide to do, it will not affect your care. 
 
Statement of consent 
The purpose of storing blood samples, the procedures involved, and the risks and benefits 
have been explained to me. I have asked all the questions I have at this time and I have 
been told whom to contact if I have more questions. I have been told that I will be given a 
signed copy of this consent form to keep. 
I understand that I do not have to allow the use of my blood for research. If I decide to not 
let you store research samples now or in the future, it will not affect my medical care in any 
way. 
I voluntarily agree that my blood and information can be stored indefinitely by the BMT 
CTN and/or AIDS and Cancer Specimen Resource Repository for research to learn about, 
prevent, or treat health problems. I also understand that my DNA and health information 
may or may not be used in genome-wide association studies. 
 
 
❑ Yes, I agree to have a blood sample drawn for future research. 
 
❑ No, I do not agree to have a blood sample drawn for future research. 
 
 _____________________________________   _____________________________  
Signature 
Date 
************************************************ 
 
SIGNATURE 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this study. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-13 
Participant ________________________________ 
 
Date _____________________________________ 
 
Witness __________________________________ 
 
Date_____________________________________ 
 
As a representative of this study, I have explained the purpose, the procedures, the benefits, and 
the risks that are involved in this research study: 
 
 
 
 
 
 
 
 
 
 
Signature of person conducting informed consent   
 
Date_____________________________________ 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-14 
ASSENT FORM 
 
High Dose Chemotherapy with Autologous Stem Cell Rescue for Aggressive B Cell 
Lymphoma and Hodgkin Lymphoma in HIV-infected Patients 
 
 
A. Why am I here? 
We are inviting you to join our study because your first treatment for your lymphoma did not 
work or your lymphoma has come back, and because you have HIV. 
 
 
B. Why are you doing this study? 
We want to know how well autologous transplant treats lymphoma in people with HIV. 
 
 
C. What will happen to me? 
If you say you want to be in the study, we will ask you for several things: 
▪ Permission to let us read your medical records and x-rays.  
▪ Participate in getting tests done to find out more about your health. 
▪ Check-ups with the study doctors for at least two years. 
▪ Some blood from you (about 12 teaspoons).  A very small needle will be used to get 
blood.  
 
For this study, you will have an autologous transplant.  
 
What is an autologous transplant? 
An autologous transplant uses stem cells collected from your blood stream or bone marrow to 
rebuild your immune system.  There are three main steps to this type of transplant.  First, we 
will give you a series of four drugs (chemotherapy) to destroy your unhealthy cells 
(lymphoma) in your blood steam and bone marrow.  Second, we will collect the rest of your 
cells from your blood stream or bone marrow, treat them and store them.  Third, we will give 
you back your treated cells that, after a brief delay, will make new, healthy cells. 
 
During and after your transplant, we will watch you carefully for fevers, any sign of infection 
or other problems.  You may have to stay in the hospital.  You may require daily visits to a 
clinic during your transplant.  Once your transplant is complete, you will need to come back 
for regular visits and testing for at least 2 years for this study.  Your doctor may want to see 
you for longer than 2 years. 
 
 
D. Will it hurt? 
You will get sick from the chemotherapy.  Side effects of these drugs include nausea and 
vomiting, mouth sores, stomach pain, skin rash, and lowering of your blood counts.  We will 
give you drugs to treat most of these side effects.  One side effect, which we cannot prevent, 
will be hair loss.  This will occur about 2-3 weeks after you receive the medicines.  This is 
only temporary. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-15 
 
When you have your blood and cells taken with a needle, it may feel like a pinch.  It will hurt 
for a minute and sometimes the place where the needle went might be red and sore.  You 
might get a little bruise where the blood was taken but it goes away in a few days.  
 
A stem cell transplant requires us to give you many drugs through your vein, and to sample 
your blood many times.  To make this easier for you, we will place a tube in your neck or 
chest.  We will give drugs before the tube is placed in to make you sleepy, so you won't feel 
it going in.  Once this tube is place, you will not need any more needle sticks.  When the 
transplant is done and you are feeling well, the tube will be removed. 
 
 
E. Will the study help me? 
We don’t know if the study will help you or not.  Your lymphoma may stay the same, it may 
get better, or it may get worse.  It is not known if the study will help your HIV. 
 
 
F. What if I have questions? 
You can ask any questions that you have about the study.  If you forget to ask a question and 
think of it later, you can call me [insert office number].  You can also ask your question the 
next time you see me. 
 
You can call the study office at any time to ask questions about the study. 
 
 
G. Do I have to be in this study? 
▪ If you don’t want to be in the study, you need to tell us and your parent or guardian. 
Your doctor will not be angry or upset if you don’t want to join.   
▪ Whether you are in the study or not, you will still need to have treatment for your 
lymphoma. 
▪ You can say yes now and change your mind at any time.   
▪ Please talk this over with your parent or guardian, and other family members, before 
you decide if you want to be in the study.  We will also ask your parents to give their 
permission for you to join this study.  


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
B-16 
 
Writing your name on this page means that you agree to be in the study, and know what will 
happen to you.  If you decide to quit the study, all you have to do is tell the person in charge. 
 
You and your parent or guardian will get a copy of this form after you sign it. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Child 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Researcher  
 
 
 
 
Date 
 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-1 
APPENDIX C 
 
LABORATORY PROCEDURES 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-2 
APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
1. CHARACTERIZATION OF THE RATES, SPECTRUM, RISK FACTORS, AND 
OUTCOMES OF INFECTIONS 
 
HCT-related risk factors for infection (time to engraftment, degree of mucositis, duration of 
neutropenia) and HIV-related (CD4, VL, HAART resistance) risk factors will be 
investigated.  Specimens will be collected to allow the analysis of the relationship of 
microbial translocation markers to febrile neutropenia and infectious outcomes. 
 
Background 
Recent observations that persons with chronic HIV-1 infection and AIDS demonstrate 
increased microbial translocation (MT) from the gut compared to uninfected persons may be 
related to the massive depletion of intestinal CD4+ lymphocytes within weeks of HIV-1 
acquisition (1).  Our group also recently demonstrated that microbial translocation in HIV-
HCV co-infection was strongly associated with more rapid progression of liver cirrhosis.  A 
key finding was that serum endotoxin (LPS) level, a marker of microbial translocation, was 
higher in patients with more advanced fibrosis (2).  The detection of microbial translocation 
in peripheral blood likely underestimates the higher quantities of microbial products that 
enter the portal venous circulation with resulting sequelae in the liver.   
 
Previous studies have shown that HIV+ recipients of autologous stem cell transplant are at 
risk for early hepatic veno-occlusive disease (VOD) (3).  VOD is a condition which is 
characterized by endothelial cell injury in the hepatic sinusoids leading to sinusoidal 
thrombosis and occlusion.  LPS is known to have a procoagulant effect by inducing gene 
expression of several inflammatory mediators including the procoagulant protein, tissue 
factor (4).  Therefore, a high level of circulating MT markers (such as LPS) at the time of 
transplant could be a risk factor for development of early hepatic VOD.  Moreover, 
monitoring serum levels temporally to explore associations with liver associated morbidity 
including VOD, may provide insights into defining risk factors for VOD.  The long term goal 
of this approach is to provide a rational basis for targeted antimicrobial therapy to reduce 
microbial translocation in patients at higher risk of developing VOD.   
 
Hypothesis 
We hypothesize that increased microbial translocation in HIV infected recipients of induction 
chemotherapy may increase the risk for development of veno occlusive disease after 
autologous or allogeneic stem cell transplant.   
 
Study Objectives 
We propose testing archived sera for microbial translocation markers from HIV-infected 
persons who have received autologous stem cell transplant.  Microbial translocation marker 
levels will then be correlated with clinical outcome (hyperbilirubinemia, development of 
VOD, death) as patients are followed longitudinally. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-3 
 
Study Design 
Clinical data that will be obtained at baseline will include age, gender, race, HCV RNA 
levels, HIV RNA levels, CD4+ lymphocyte count, AST, ALT, total bilirubin, antibiotic 
usage within the prior 6 weeks, antiretroviral therapy, MELD score, and a history of liver-
related complications.   
 
Microbial Translocation Measurements 
Markers of microbial translocation that will be tested include plasma LPS, LPS-binding 
protein (LBP), soluble CD14 (sCD14), and the polyclonal IgM antibody directed toward the 
LPS core polysaccharide (EndoCAb IgM).  LPS testing will be done using the Limulus 
Amebocyte Lysate (LAL) assay (Lonza), while LBP (Cell Sciences), sCD14 (R&D 
Systems), and EndoCAb IgM (Hycult Biotechnology) assays are all standard plate-based 
ELISA tests.  Microbial translocation markers will be log-transformed to normalize the data, 
as has been done previously.  Values of the LAL assay < 10 pg/mL are considered below the 
linear range of the assay and will be considered 5 pg/mL (mean of 0 and 10 pg/mL) for 
standard calculations. 
 
Statistical Components 
Association between outcome (hyperbilirubinemia, VOD, and death) at Days 7, 14 and 100 
post transplant and level of microbial translocation markers will be determined by 
nonparametric Mann-Whitney tests comparing the distribution of prior microbial 
translocation markers between patients with vs. without each outcome.   
 
Samples Required 
Pre-transplant  
A 10 mL peripheral blood sample will be collected in an EDTA containing Vacutainer tube 1 
week prior to conditioning as well as on day 3 of ablative chemotherapy.      
Post-transplant 
A 10 mL peripheral blood sample will be collected in an EDTA containing Vacutainer tube 
will be collected at Days 7, 14, and 100 post transplant. 
 
Samples Shipment 
Transplant centers will ship whole blood tube by priority overnight FedEx on the day of 
collection to the project laboratory for processing and microbial translocation marker testing. 
 
References 
 1.  J. M. Brenchley et al., Nature Medicine 12, 1365-1371 (2006). 
 2.  A. Balagopal et al., Gastroenterology 135, 226-233 (2008). 
 3.  T Spitzer et al., Biol of Blood and Marrow Transpl. 14, 59-66 (2008). 
 4.  Luyendik et al., J Immunol. 180, 4218-4226 (2008). 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-4 
 
2. CHARACTERIZATION OF HIV INFECTION IN AIDS RELATED LYMPHOMA 
 
Background and Rationale 
The effect of marrow ablative chemotherapy on the HIV reservoir is not known, but the 
model of ARL treatment does provide an opportunity to define changes which are associated 
with HCT.  In the current study, we propose to characterize the HIV infection during and 
after such lymphoma treatment, by measurement of HIV load including the use of an assay 
which measures HIV at less than 1 copy per milliliter. In patients with no detectable viral 
load by standard clinical assays, this assay regularly detects low copy number viral RNA. 
This RNA is believed to be released from latency compartments established in hematopoietic 
cells.  
 
Hypothesis 
We hypothesize that treatment of ARL using dose-intense cytotoxic therapy in patients will 
result in a substantial reduction in the size of the HIV reservoirs and thus in this very low 
level viremia. This study will represent the first application of this single copy PCR 
technique to high dose therapy with autologous hematopoietic stem cell transplant—although 
the approach has been used multi-institutional studies of anti-retroviral therapies. 
 
HIV Single-Copy HIV Viral Titer Measurements  
In patients with undetectable viral load as measured in conventional assays, there is persistent 
viremia that can be measured at single copy/ml by specialized PCR analysis. This viremia 
may reflect virus being released by the decay of latently infected cells or possibly ongoing 
viral replication. Therapies that impact on the latently infected reservoir might be expected to 
change the viremia if it mainly reflected the decay of latently infected cells. Myeloablative 
chemotherapy may kill cells that constitute the latency reservoir and thus might thus be 
expected to impact on the reservoir and the very low level viremia that can be assessed by 
this assay. 
 
 
Samples Required   
 
Pre-transplant  
A 20 mL peripheral blood sample will be collected in EDTA containing Vacutainer tubes 1-3 
weeks and 1 week prior to initiation of ablative therapy. 
Samples collected only on patients with negative pre-transplant baseline HIV titer by 
standard assay. 
 
Post-transplant 
A 20 mL peripheral blood sample will be collected in EDTA containing Vacutainer tubes on 
Days 180, 365, 730 post-transplant. 
Samples collected only on patients with negative pre-transplant baseline HIV titer by 
standard assay. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-5 
 
Sample Processing and Shipment 
Transplant centers will process plasma sample, snap freeze, and ship frozen twice a year by 
priority overnight FedEx on the day of collection to the project laboratory for testing. See 
BMT CTN 0803 Laboratory Sample Guide for detailed procedure for specimen processing. 
 
 
3. CHARACTERIZATION OF THE UTILITY OF PLASMA DNA MARKERS FOR 
AIDS LYMPHOMA 
 
Background 
As the safety of HIV auto transplants have gained acceptance,  new questions have emerged 
with regard to aspects of HIV biology, HIV lymphoma tumor markers, and the relationship 
between gut and liver dysfunction that can be uniquely addressed in the context of a trial 
involving high dose myeloablative chemotherapy. 
 
Plasma DNA 
Tumor DNA detected in plasma is emerging as a potentially useful tumor marker. Two 
candidate tumor markers in patients with HIV lymphomas have emerged. These are i) clonal 
Ig DNA as recognized by Ig rearrangements or characteristic somatic hypermutation and ii) 
EBV DNA. In a small series, clonal Ig DNA is characteristic of a particular patient’s B cell 
tumor and is detected in approximately half of AIDS diffuse large B cell lymphoma prior to 
treatment. In that series, patients in whom clonal Ig DNA persists in plasma inevitably 
relapse. EBV DNA detected in plasma is useful as a tumor marker in nasopharyngeal 
carcinoma where evidence suggests that viral genomes are released from apoptotic tumor 
cells rather than being present as virions.  In AIDS, high copy numbers of EBV genomes is 
present in many HIV patients and in studies from the Multi-Center AIDS Cohort Study, have 
demonstrated very modest value to EBV determinations. Recent evidence suggest that tumor 
cell derived viral DNA may be distinguished from virion DNA because virion DNA is not 
CpG methylated. Thus meCpG EBV DNA may specifically mark tumor DNA. 
 
Plasma DNA (clonal Ig, methyl EBV) measured prior to conditioning, prior to stem cell 
infusion, and at Day +100, 6 months and 1 year post-transplant will be summarized using 
descriptive statistics.   
 
The probability of patients relapsing or progressing by one or two years post transplant will 
be estimated using the cumulative incidence function separately for patients with vs. without 
the presence of plasma DNA at each measured time points (both pre and post transplant).  
For plasma DNA measured post transplant, the analysis will be restricted to patients who are 
alive and have not yet relapsed/progressed by the time of plasma DNA measurement.   The 
association between the presence of plasma DNA at each time point and subsequent 
progression/relapse at one or two years will be determined by the Chi-square test.   
 
Samples Required 
Pre-transplant  


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-6 
A 10 mL peripheral blood sample will be collected in an EDTA containing Vacutainer tube 
within 1 week prior to initiation of ablative therapy. 
A 10 mL peripheral blood sample will be collected in an EDTA containing Vacutainer tube 
on Day -3 of conditioning.. 
 
Post-transplant 
A 10 mL peripheral blood sample will be collected in an EDTA containing Vacutainer tube 
will be collected at Days 100, 180, and 365 post-transplant. 
 
Samples Shipment 
Transplant centers will ship whole blood tubes by priority overnight FedEx on the day of 
collection to the project laboratory for processing and testing. 
 
 
 
4. IMMUNOPHENOTYPIC 
AND 
FUNCTIONAL 
CHARACTERIZATION 
OF 
IMMUNE RECONSITUTION  
 
Background and Rationale: 
Little is known about immune reconstitution following autologous stem cell transplantation to 
treat patients with hematologic malignancies in patients with HIV infection.  Multiple variables 
including adaptive immune dysfunction and chronic viral infections raise the possibility that 
HIV+ patients will encounter more infectious complications compared to HIV- individuals 
following stem cell transplantation.  It will therefore, be critical to perform correlative laboratory 
investigations examining adaptive and innate immune surveillance in this very unique setting. 
The use of multiparametric flow cytometry to identify specific adaptive and innate immune cell 
subsets, and use of available pathogen-specific epitopes should allow us to characterize the 
dynamics of immune reconstitution and identify first responses against HIV and other common 
pathogens post-ASCT.  
 
Hypothesis: 
We hypothesize that quantitative and qualitative differences in adaptive and innate immune 
reconstitution will correlate with clinical outcome in HIV+ patients who undergo autologous 
stem cell transplantation.  Improved understanding of immune reconstitution in this very unique 
setting will lead to advances in the management of HIV+ patients with cancer and lead to novel 
approaches to improve long term survival of these patients.   
 
Study Design: 
Immunophenotypic Evaluation of T and NK Cell Subsets: To date no comprehensive muti 
time point study has been performed to evaluate reconstitution of adaptive immunity in HIV+ 
patients treated with peripheral blood stem cell transplantation.  Examining the nature of 
adaptive and innate immune reconstitution will involve use of a multi panel flow cytometric 
assay to track changes in naïve, memory, activated and regulatory T cell subsets. Specifically, 
these studies will involve a detailed in vivo analysis of early, mid, early-late and late activation 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-7 
of B and T lymphocytes and characterization of T cell subsets including naïve, memory, Th1, 
Th2 and T regulatory cells.  In addition we will evaluate maturation status of NK cells and their 
activation status.  Multiparametric flow analysis will be performed on fresh peripheral blood 
samples collected at 60, 180 and 365  days post stem cell infusion.  
 
 
Samples of ACD (yellow top) and EDTA (lavender top) anticoagulant containing blood will be 
received at the project laboratory within 24h following collection and processed immediately 
upon receipt in the clinical flow cytometry laboratory.  Prior to staining, all samples will be 
analyzed for viability using 7AAD method. Only samples with mononuclear cell viability > 90% 
will be considered acceptable for further analysis. Viability of >95% is achieved in ACD tubes 
stored at room temperature for up to 48 hours.  All samples will be stained using a PrepPlus2 
automated staining system (Beckman Coulter) utilizing a five color whole blood staining 
technique with panels of directly conjugated monoclonal antibodies (see tables 1 and 2) used in 
quantities that have been predetermined and standardized in our flow cytometric laboratory.  
Following 30 minutes of incubation at room temperature in the dark, red cells will be lysed using 
a Q-prep instrument and Coulter Lyse reagent according to manufacturer’s recommendations.  
Samples will be analyzed on FC500 flow cytometer equipped with CXP software version 2.1 (all 
equipment and reagents by Beckman Coulter).  Multiparametric analysis will be performed with 
a gating strategy based on CD45 staining and light side scatter characteristics that allow adequate 
separation of lymphocyte, monocyte and myeloid cell populations. Detailed immunophenotypic 
characterization of the lymphocyte gate will be performed using Prism plot algorithm (Beckman 
Coulter). The results will be reported as percent of lymphocyte gate and as percent of total 
leukocytes analyzed. The results will also be reported as an absolute number of specific cell 
subset types per microliter of whole blood. Absolute cell number will be calculated based on 
duel platform method using percent of lymphocytes expressing specific immunophenotypic 
profile (derived from prism plot) and absolute number of lymphocytes derived  from analysis of 
each whole blood sample using  ActDIFF hematology analyzer (Beckman Coulter).  


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-8 
 
Functional Evaluation of Adaptive Immune Reconstitution: We will serially evaluate 
adaptive cellular immunity by tracking responsiveness to viral recall antigens.  We will follow 
responsiveness to HIV as well as common viral pathogens like CMV and EBV. Studies will use 
pools of overlapping 15-18mer peptides from full length viral proteins (JPT Technologies) 
encoded by CMV (pp65), EBV (BZLF1) and HIV (gag).  Aliquots of frozen PBMCs will be 
thawed and enumerated.  1x106 PBMCs will be cultured in the presence of individual viral 
pooled peptide preparations (or actin control pooled peptides, 1ug/ml final concentration) in the 
presence or absence of agonistic anti CD28 monoclonal antibody to control for costimulatory 
signals and provide an optimal condition for evaluation of responsiveness.  Following overnight 
incubation (in presence of brefeldin A golgi plug reagent), a multi color flow cytometric 
evaluation will identify CD3/CD8 subsets that costain with IFN or CD107a (degranulation 
marker). Separate controls with 7AAD will evaluate PBMC viability.  1 x 105 CD3+ events will 
be collected using a FC500 flow cytometer and percentage of CD3/CD8+ T cells staining 
positive for IFN and or CD107a will be determined.  Outcome of these bioassays will be 
correlated with immunophenotypic and clinical patient data.   
 
Functional Evaluation of Innate Immune Reconstitution: Innate immune reconstitution 
studies will examine natural killer (NK) cell responsiveness to cytokines and to FcRIIIa 
signaling. NK cell responsiveness assays will be performed on purified NK cells that will be 
isolated via rosette-sep immuno selection kits.  To test cytokine responsiveness, 1x105 NK cells 
will be incubated overnight in standard culture medium (supplemented with human AB serum) 
in interleukin 2 (IL-2 10nM) +/- IL-12 (10ng/ml).  To evaluate FcRIIIa responsiveness, 2 
methods will be employed: (i) Immobilized IgG in presence or absence of IL12; and (ii) anti 
FcRIIIa monoclonal antibody treatment +/- IL12.  For FcgRIIIa signaling studies, 96-well flat-
bottom plates will be coated with 100 g/mL huIgG in cold PBS overnight at 4°C, washed with 
cold PBS, and then plated with immune cells (2 x 105 cells/well) +/- 10 ng/mL IL-12 (or saline 
control).  At 24 and 48 hours cell-free culture supernatants will be harvested and analyzed for 
levels of IFN- by enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, 
MN).  NK cells will be checked for viability following the overnight pretreatment period and 
again at the conclusion of the experiment. The readout for the assay will be IFN- measured by 
ELISA or intracellular IFN and CD107a expression determined by flow cytometry (as in 
adaptive immune reconstitution studies) at 24 and 48 hrs. FcRIIIa responsiveness can also be 
tested via use of anti FcRIIIa mAb (clone 3G8) to cross link receptors +/- IL12 and IFN and 
CD107a detected via flow cytometry.  Positive controls will include PBMCs collected from 
immune-competent individuals, purified NK cells from immune-competent individuals incubated 
with IL2 + IL12, IL-15 + IL-18 and IL-15 + IL-21. We will correlate the outcome of these 
biologic studies with immunophenotypic studies examining NK cell subsets and clinical patient 
data.  
 
Quantitative Immunoglobulin Measurement:   
Measurement of IgA, IgG, IgM will be performed at individual institutions and data collected 
periodically.  Time points for collection include prior to initiation of conditioning, days 60, , 180  
and 1 year post transplantation.  
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-9 
Correlative Evaluation of Immune Reconstitution Studies:  
Immunophenotypic and functional immune reconstitution studies will produce quantitative and 
qualitative data that can be compared to multiple clinical and laboratory outcomes in this unique 
setting.  Specifically:  
1) Clinical outcome: Recovery of specific T and NK cell subsets and functional immune 
responseiveness in the above assays can be compared to (a) documented infections post 
transplant (bacterial, fungal, viral) CR; (b) lymphoma disease free survival; (c) overall 
survival.  
2) Laboratory comparisons: immunophenotypic and functional immune reconstitution can 
be 
compared 
to 
the 
following 
laboratory 
correlates: 
(a) 
chronic 
viral 
infection/reactivation (EBV, CMV, HIV); (b) virion EBV genome copy number 
(Methylated CpG containing episomes).  
 
Statistical Components: 
Immune reconstitution results will be summarized at each post transplant time point using 
descriptive statistics. Individual T, B and NK cell subsets identified by flow cytometry will be 
reported as percent of total mononuclear cells and as absolute cell numbers per microliter of 
peripheral blood.  Statistical evaluation of functional studies evaluating adaptive and innate 
immune reconstitution will be reported as percentage of mononuclear cell subsets staining 
positive for IFN or granzyme B relative to control conditions. Two sided T tests will be 
employed for evaluation of statistical significance with p<0.05 considered significant.  
 
Samples Required: 
A total of 37 mL peripheral blood will be collected and placed into (1) four 8.5 mL-fill, ACD 
Vacutainer tubes (yellow top) tubes containing ACD anticoagulant solution, and (2) one 3 mL 
EDTA containing (lavender) Vacutainer tubeSample shipment Transplant centers will ship 
whole blood tubes by priority overnight FedEx on the day of collection to the project laboratory 
for immediate processing for flow cytometry and for procurement of viable cells for functional 
immunology assays.   
 
Project Laboratory Sample Processing & Testing: Upon arrival, mononuclear cell count in 
whole blood will be determined and, depending on absolute mononuclear cell count, 1 – 2 tubes 
will be immediately processed for flow cytometry immunophenotyping panels. PBMC will be 
cryopreserved for innate and adaptive functional studies that will be performed in batch at a later 
date.   
 
 
5. LYMPHOMA PATHOLOGY REVIEW 
 
HIV patients show a spectrum of lymphoid hyperplasia that includes some tumor types that are 
rare in other settings such as plasmablastic lymphoma, primary effusion lymphoma and 
immunoblastic lymphoma. The AIDS Malignancy Consortium has found that approximately 
15% of diagnoses submitted to central review have been substantially changed at review.  A 
tissue block or 10 unstained slides should be sent within 60 days of enrollment to the project 
laboratory. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-10 
 
6. OPTIONAL RESEARCH SAMPLE FOR UNDEFINED FUTURE RESEARCH 
 
Patients consenting to provide research samples to be submitted to The AIDS and Cancer 
Specimen Resource Repository for future undefined testing will have an additional baseline 
peripheral blood sample collected. 
 
Samples Required 
A 20 mL peripheral blood sample will be collected in two 10 mL-fill Vacutainer blood tubes 
(lavender) containing EDTA anticoagulant. Samples will be collected 1-3 weeks prior to 
initiation of ablative therapy.   
 
Sample Shipment 
Transplant centers will ship whole blood tubes by priority overnight FedEx on the day of 
collection to the ACSR Repository central processing laboratory for sample aliquot processing 
and sample storage. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-11 
Collection and Shipping Procedures and Sample Collection Schedule for 
Patient Blood Samples for Protocol-Defined Research Testing 
 
RESEARCH 
TOPIC 
RESEARCH 
SAMPLE 
TYPE OF  
SAMPLE 
SAMPLE COLLECTION, 
PROCESSING AND STORAGE 
REQUIREMENTS 
SAMPLE 
COLLECTION TIME 
POINTS 
SHIPPING SPECIFICATIONS 
Optimizing 
Diagnostics and 
Preventative Care 
for Infections 
Microbial Translocation 
Markers  
10 mL peripheral 
blood sample 
collected in an 
EDTA containing, 
lavender-top 
Vacutainer tube. 
Gently mix blood with EDTA by inverting 
the tube 8-10 times. Store at room 
temperature while preparing to ship to 
project laboratory. 
Pre-transplant 
Within 1 week of 
conditioning and day -3 
of conditioning 
Post-transplant Days 7, 
14 and 100 
Peripheral blood tubes will be shipped at ambient 
temperature on the day of collection, to the Project 
Laboratory (TBD) by priority overnight FED EX 
delivery for processing and research testing. 
Guidelines for specimen handling and shipment to 
the Project Laboratory is detailed in the BMT CTN 
0803 Laboratory Sample Guide. 
Characterization 
of HIV Infection in 
AIDS-Related 
Lymphoma 
HIV Load 
Single-Copy PCR 
 
(Collected only on 
patients with negative 
pre-transplant baseline 
HIV titer by standard 
assay) 
20 mL peripheral 
blood sample 
collected in two 
10mL EDTA 
containing, 
lavender-top 
Vacutainer tubes. 
Gently mix blood with EDTA by inverting 
the tube 8-10 times. Centrifuge the EDTA 
containing whole blood tubes at 1000-
1300 x g (~2100 rpm) for 10 minutes 
within 30 minutes of collection.  
Carefully remove the separated plasma 
(approximately 4-6 mL plasma from each 
tube, depending on patient hematocrit), 
and aliquot equally all plasma into three 
(3) sterile, screw-cap, polypropylene, 5 
mL cryovials. Plasma in cryovials will 
need to be promptly snap frozen and 
stored at ≤ -70°C in a scientific grade 
freezer until shipped to the protocol-
specified testing laboratory. 
Pre-transplant 
Within 1-3 weeks prior to 
initiation of ablative 
therapy  
Within 1 week prior to 
initiation of ablative 
therapy  
Post-transplant 
Days 180, 365 and 730 
Plasma aliquots for patients with undetectable 
baseline HIV viral titers will be shipped frozen 
twice a year to the Project Laboratory (TBD) by 
priority overnight FED EX delivery for research 
testing. Guidelines for specimen handling and 
shipment to the Project Laboratory is detailed in the 
BMT CTN 0803 Laboratory Sample Guide. 
Plasma DNA 
Tumor Monitoring 
Tumor Viral DNA 
Assays, Clonal B-cell 
DNA 
 
10 mL peripheral 
blood sample 
collected in an 
EDTA containing, 
lavender-top 
Vacutainer tube. 
Gently mix blood with EDTA by inverting 
the tube 8-10 times. Store at room 
temperature while preparing to ship to 
project laboratory. 
Pre-transplant 
Within 1 week prior to 
initiation of ablative 
therapy, and Day -3 of 
conditioning. 
Post-transplant 
Days 100, 180, 365 
Peripheral blood tubes will be shipped at ambient 
temperature on the day of collection, to the Project 
Laboratory (TBD) by priority overnight FED EX 
delivery for processing and research testing. 
Guidelines for specimen handling and shipment to 
the Project Laboratory is detailed in the BMT CTN 
0803 Laboratory Sample Guide. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
C-12 
RESEARCH 
TOPIC 
RESEARCH 
SAMPLE 
TYPE OF  
SAMPLE 
SAMPLE COLLECTION, 
PROCESSING AND STORAGE 
REQUIREMENTS 
SAMPLE 
COLLECTION TIME 
POINTS 
SHIPPING SPECIFICATIONS 
Immune 
Reconstitution 
Studies 
T/NK 
Immunophenotyping, 
Innate Immune 
Function, Adaptive 
Immune Function, 
Humoral Immune 
Function 
37 mL peripheral 
blood sample will 
be collected in four 
8.5 mL-fill ACD 
solution (yellow 
top) containing 
Vacutainer tubes 
and one 3 mL 
Vacuatiner tube 
(lavender) 
containing 
EDTA... 
Gently mix blood the blood tubes with the 
anticoagulant  by inverting the tube 8-10 
times. Store at room temperature while 
preparing to ship to project laboratory  
Post-transplant 
Days 60, 180 and 365 
post transplant 
Peripheral blood tubes will be shipped at ambient 
temperature on the day of collection, to the Project 
Laboratory (TBD) by priority overnight FED EX 
delivery for processing and research testing. 
Guidelines for specimen handling and shipment to 
the Project Laboratory is detailed in the BMT CTN 
0803 Laboratory Sample Guide. 
Lymphoma 
Pathology 
Consultation 
Review of Diagnostic 
Lymphoma Pathology 
A tissue block 
preferred; 10 
unstained slides as 
an alternative 
Store at room temperature while preparing 
to ship to project laboratory. 
Sample should be 
collected pre-enrolment 
during the evaluation 
period and saved.  
Specimens on enrolled 
patients will be submitted 
to project lab within 4 
weeks of transplant. 
Tissue samples will be shipped at ambient 
temperature to the Project Laboratory (TBD) by 
priority overnight FED EX delivery for processing 
and pathology consultation. Guidelines for specimen
handling and shipment to the Project Laboratory is 
detailed in the BMT CTN 0803 Laboratory Sample 
Guide. 
Optional 
Investigational 
Future Research 
Sample 
Undefined Future 
Research 
20 mL peripheral 
blood sample 
collected in 2-
10mL  EDTA 
containing, 
lavender-top 
Vacutainer tubes 
Gently mix blood with EDTA by inverting 
the tube 8-10 times. Store at room 
temperature while preparing to ship to 
project laboratory. 
Pre-transplant 
1-3 weeks prior to 
ablative therapy  
Peripheral blood tubes will be shipped at ambient 
temperature on the day of collection, to the Aids 
Cancer Research Specimen Repository by priority 
overnight FED EX delivery for processing and 
research testing. Guidelines for specimen handling 
and shipment to the Project Laboratory is detailed in
the BMT CTN 0803 Laboratory Sample Guide. 
  


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
D-1 
APPENDIX D 
 
HIV MANAGEMENT 
 
ANTIRETROVIRALS AND BILIRUBIN 
  
The following antiretroviral medications lead to elevated bilirubin 
in the absence of other evidence of liver dysfunction. 
 
 
SUGGESTED PROPHYLAXIS


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
D-2 
APPENDIX D 
 
SUGGESTED PROPHYLAXIS 
 
 
Infectious prophylaxis for HIV patients undergoing HCT will include prophylaxis for: 
1. Bacteria:  In keeping with the BMT CTN MOP and local institutional standards. 
2. Pneumocystits Jiroveci Pneumonia:  Prophylaxis will be administered until CD4 counts 
are >200 and for a minimum of 6 months. Several effective regimens are available. 
Patient tolerance (nausea, allergic reaction, G6PD or other considerations) may 
contraindicate a particular regimen. Choices in order of preference are 1) TMP/SMX 1 
DS daily 2) TMP/SMX 1 SS daily 3) Dapsone 100 mg daily (may be decreased to 50 mg 
daily if given in combination with pyrimethamine as described below for toxoplasmosis 
prophylaxis, 4)Atovaquone 1500 mg daily, 5) Aerosolized pentamidine monthly. 
3. Toxoplasmosis:  Patients on TMP/SMX do not require additional prophylaxis. If 
toxoplasma IgG is positive and TMP/SMX cannot be used patients should be prophylaxed 
for at least 3 months after HCT and until CD4>100.  This prophylaxis may be either: 1) 
dapsone 50 mg po daily and pyrimethamine 50 mg/week and leucovorin 25 mg/week or 
2) atovaquone 1500 mg daily plus pyrimethamine 25 mg/day plus leucovorin 10 mg/day 
4. Fungi:  Anti-fungal prophylaxis will be per local institutional practice. It is noted that in 
histoplasma endemic areas (Midwest and Puerto Rico) antifungal prophylaxis is standard 
for CD4 <150 and would be appropriate for at least 3 months after HCT and until 
CD4>150. 
5. HSV/VZV:  One of the following regimens should be used for 1 year after HCT unless 
Acyclovir 400 - 800 mg bid, valaciclovir 500 mg bid, or famciclovir 500 mg po bid.  
6. M. Avium Complex (MAC):  If CD4 less than 50,  Azithromycin suggested at 1200 mg q 
week or 600 mg twice weekly . 
7. Heptatitis: 
a. Patients with positive hepatitis B surface antigen should be evaluated for viral 
DNA replication (viral load) by a quantitative PCR method before enrolling the 
patient on the study.  
b. Lamuvudine or newer generation of anti-hepatitis B agents, like Tenofovir, should 
be started in those with detectable Hepatitis B viral load according to institutional 
preferences. The goal of the treatment should be achieving undetectable (<500 
copies/ml) viral load status before stem cell mobilization chemotherapy.  
c. Patients should be maintained on anti-Hepatitis B treatment throughout the 
transplant and at least 12 months after the transplant. 
d. Patients with hepatitis-C infection may be enrolled on the trial providing the above 
Hepatic criteria are met. Anti-hepatitis C treatment with ribavirin and interferon 
alpha is recommended but not required to be eligible for the study. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
D-3 
e. Liver biopsy must be preformed in patients with Hepatitis-B or C infections if the 
severity assessment of liver disease based on Child-Turcotte-Pugh (CTP) 
classification indicates all of the following  criteria; Serum bilirubin >2, serum 
albumin <3.5, and INR > 1.7 
f. Patients with no pathologic evidence of irreversible chronic liver disease such as 
bridging necrosis and/or significant fibrosis can be eligible for the study.  
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
E-1 
APPENDIX E 
 
REFERENCES 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
E-2 
APPENDIX E 
 
REFERENCES 
 
 
1 Bower M, Gazzard B, Mandalia S, et al.  A prognostic index for system AIDS-related non-
Hodgkin lymphoma treated in the era of highly active antiretroviral therapy.  Ann Intern Med.  
2005;143:265. 
 
2 Engels EA, Biggar RJ, Hall HI, et al.  Cancer risk in people infected with the human 
immunodeficiency virus in the United States.  Int J Cancer.  2008;123:187. 
 
3 Lim ST, Karim R, Nathwani B, et al.  AIDS-related Burkitt’s lymphoma versus diffuse large-
cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras:  
significant differences in survival with standard chemotherapy.  J Clin Oncol.  2005;23:4430. 
 
4 Ribera JM, Navarro JT.  Human immunodeficiency virus related non-Hodgkin’s lymphoma.  
Haematologica.  2008;93:1129. 
 
5 Boue F, Gabarre J, Gisselbrecht C, et al.  Phase II trial of CHOP plus rituximab in patients with 
HIV-associated non-Hodgkin’s lymphoma.  J Clin Oncol.  2008;24:4123. 
 
6 Navarro JT, Lloveras N, Ribera JM, et al.  The prognosis of HIV-infected patients with diffuse 
large B-cell lymphoma treated with chemotherapy and highly active antiretroviral therapy is 
similar to that of HIV-negative patients receiving chemotherapy.  Haematologica. 
2005;90(5):704. 
 
7 Galicier L, Fieschi C, Borie R, et al.  Intensive chemotherapy regimen (LMB86) for St Jude 
stage IV AIDS-related Burkitt lymphoma/leukemia:  a prospective study.  Blood 
2007;110:2846. 
 
8 Oriol A, Ribera JM, Berqua J, et al.  High-dose chemotherapy and immunotherapy in adult 
Burkitt lymphoma:  comparison of results in human immunodeficiency  virus-infected and 
non-infected patients.  Cancer.  2008;113:117. 
 
9 Wang ES, Straus DJ, Teruya-Feldstein J, et al.  Intensive chemoterhapy with 
cyclophosphamide, doxorubicine, high-dose methotrexate/ifosfamide, etoposide and high-
dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt 
lymphoma.  Cancer 2003;98:1196. 
 
10 Patel P, Hanson DL, Sullivan PS, et al.  Incidence and types of cancer among HIV-infected 
persons compared with the general population in the United States 1992-2003.  Ann Intern 
Med.  2008;148:728.  
 
11 Gerard L, Galicier L, Boulanger E, et al.  Improved survival in HIV-related Hodgkin’s 
lymphoma since the introduction of highly active antiretroviral therapy.  AIDS.  2003;17:81. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0803 
 
 
Version 2.0 dated April 30, 2010 
 
 
E-3 
 
12 Kessinger A, Nademanee A, Forman SJ, Armitage JO.  Autologous bone marrow 
transplantation for Hodgkin’s and non-Hodgkin’s lymphoma.  Hematol Oncol Clin North Am.  
1990;4:577. 
 
13 Philip T, Guglielmi C, Hagenbeek A, Somers R, van der Lelie H, Bron D, Sonnefeld P, 
Gisselbrecht C, Cahn J-Y, Harousseau J-L, Coiffier B, Biron P, Mandelli F, Chauvin F: 
Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses 
of chemotherapy sensitive non Hodgkin's lymphoma. N Engl J Med 1995;333:1540. 
 
14 Vose JM, Anderson JR, Kessinger A, Bierman Ph, Coccia P, Reed EC, Gordon B, Armitage 
JO: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for 
aggressive non-Hodgkin's lymphoma. J Clin Oncol 1993;11:1846. 
 
15 Gabarre J, LeBlond V, Sutton L, et al.  Autologous bone marrow transplant in relapsed HIV-
related non-Hodgkin’s lymphoma.  Bone Marrow Transplant.  1996;18:1195. 
 
16 Krishnan A, Molina A,, Zaia, J, et al.  Durable remission with autologous stem cell 
transplantation for high-risk HIV-associated lymphomas.  Blood. 2005;105:874. 
 
17 Spitzer TR, Ambinder RF, Lee JY, et al.  Dose-reduced busulfan, cyclophosphamide and 
autologous stem cell transplantation for human immunodeficiency virus-associated 
lymphoma:  AIDS Malignancy Consortium study 020.  Biol Blood Marrow Transplant.  
2008;14:59. 
 
18 Re A, Cattaneo C, Michieli M, et al.  High-dose therapy and autologous peripheral blood stem-
cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving 
highly active antiretroviral therapy.  J Clin Oncol.  2003;23:4423. 
 
19 Serrano D, Carrion R, Balsolobre P, et al.  HIV-associated lymphoma successfully treated with 
peripheral blood stem cell transplantation.  Exp Hematol.  2005;33:487. 
 
20 Balsalobre P, Diez-Martin JL, Re A et al.  Autologous stem-cell transplantation in patients 
with HIV-related lymphoma.  J Clin Oncol. 2009: 27:2192. 
 
21 Diez-Martin JL, Balsalobre P, Re A, et al. Comparable survival between HIV+ and HIV- non-
Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell 
transplantation.  Blood 2009: 113:6011. 
 
22 Weber R, Sabin C, Friis-Moller N , et al.  Liver-Related Deaths in Persons Infected With the 
Human Immunodeficiency Virus. Arch Int Med 2006; 166:1632-1641. 
 
23 Balagopal, A, Philip F, Astemborski J, et al, Human Immunodeficiency Virus-Related 
Microbial Translocation and Progression of Hepatitis C.  Gastroenterology 2008; 135:1, 226-
233. 
 
24 Cheson B, Pfistner B, Juweid M, et al. Revised Response Criteria for Malignant Lymphoma. J 
Clin Oncol 25: 579-586, 1997.