Conditions: Leukemia Lymphoma HIV
Keywords: HIV ALL AML MDS Non-Hodgkin Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
The rationale for this trial is to demonstrate the feasibility and safety of allogeneic HCT for patients with chemotherapy-sensitive hematological malignancies and coincident HIV-infection. In particular, the trial will focus on the 100-day non-relapse mortality as an indicator of the safety of transplant in this patient population. Correlative assays will focus upon the incidence of infectious complications in this patient population, the evolution of HIV infection and immunological reconstitution. Where feasible (and when this can be accomplished without compromise of either the donor quality or the timeliness of transplantation), an attempt will be made to identify donors who are homozygotes for the delta32 mutation for CCR5.

Detailed description:
The study is designed to evaluate the feasibility and safety of reduced-intensity and fully-ablative allogeneic hematopoietic cell transplantation (HCT) for patients with hematological malignancies or myelodysplastic syndromes (MDS) who have HIV infection. The goal of the study is to assess the 100 day Non-relapse Mortality as well as immunological reconstitution in this patient population. Where feasible, an attempt will be made to identify human leukocyte antigen (HLA)-compatible hematopoietic stem cell donors who are homozygotes for the delta32 mutation of the chemokine receptor 5 (CCR5delta32). Patients will undergo a treatment plan review prior to registration on the trial. All patients will undergo allogeneic HCT from a matched sibling or unrelated donor.

Arms:
arm 1: One regimen from either reduced-intensity conditioning (RIC) (Fludarabine and Busulfan; or Fludarabine and Melphalan) or myeloablative conditioning (MAC) (Busulfan and Fludarabine; or Cyclophosphamide and Total Body Irradiation) will be administered prior to allogeneic hematopoietic cell transplantation (HCT).

Interventions: intervention 1: Fludarabine and Busulfan intervention 2: Fludarabine and Melphalan intervention 3: Busulfan and Fludarabine intervention 4: Cyclophosphamide and Total Body Irradiation
Intervention descriptions: intervention 1: RIC Regimen (Flu/Bu): Fludarabine total dose: 120-180 mg/m\^2, Busulfan: ≤ 8 mg/kg PO or 6.4 mg/kg IV). Recommended regimen:

* Days -6 to -2: Flu (30 mg/m\^2/day, total dose of 150 mg/m\^2)
* Days -5 to -4: Busulfan (4mg/kg/day PO or 3.2 mg/kg IV, 130 mg/m\^2/day, total dose of 8 mg/kg PO or 6.4 mg/kg IV, or 260 mg/m\^2 IV, respectively)

Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.

Busulfan will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125 percent of IBW, in which case the drug will be dosed according to the adjusted IBW. intervention 2: RIC Regimen (Flu/Mel): Fludarabine total dose: 120-180 mg/m\^2, Melphalan total dose: less than or equal to 150 mg/m\^2. Recommended regimen:

* Days -5 to -2: Flu (30mg/m\^2/day, total dose of 120 mg/m\^2)
* Day -1: Mel (140mg/m\^2)

Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage. intervention 3: MAC Regimen (Bu/Flu): Fludarabine total dose: 120-180mg/m\^2 Busulfan total dose less than or equal to 16mg/kg PO or 12.8 mg/kg IV. Recommended regimen:

* Days -5 to -2: Busulfan (4 mg/kg/day PO with Bu Css 900 plus/equal to 100 ng/mL (or per institutional standard), 3.2 mg/kg/day IV or 130 mg/m\^2/day IV; total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m\^2, respectively)
* Days -5 to -2: Flu (30 mg/m\^2/day, total dose of 120 mg/m\^2)

Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) should have a 20 percent dose reduction in Fludarabine dosage.

Busulfan will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs more than 125 percent of IBW, in which case the drug will be dosed according to the adjusted IBW. intervention 4: MAC Regimen (Cy/TBI): Cyclophosphamide total dose: 120 mg/kg, Fractionated TBI total dose: 1200-1420 cGy Recommended regimen:

* Days -7 to -4: TBI (total dose of 1200-1420 cGy)
* Days -3 to -2: Cy (60 mg/kg/day, total dose of 120 mg/kg)

Cyclophosphamide will be dosed according to the recipient's ideal body weight (IBW), unless the patient weighs less than IBW, in which case the drug will be dosed according to the actual body weight.

Protocol document:
Prot_ICF_000.pdf: 
 
 
 
 


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Core Study Participants: 
Affiliate Study Participants: 
 
City of Hope National Medical Center 
H. Lee Moffitt Cancer Center 
Johns Hopkins Medical Institutions 
Memorial Sloan-Kettering Cancer Center 
Ohio State Consortium 
University of California San Francisco 
University of Florida 
University of Texas MD Anderson Cancer Center 
 
Texas Transplant Institute 
Weill Cornell Medical College 
University of Maryland Medical Systems 
Mayo Clinic - Phoenix 
Hackensack University Medical Center 
AMC Study Participants 
University of California Los Angeles 
University of Utah 
 
 
 


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PROTOCOL SYNOPSIS - BMT CTN PROTOCOL #0903  
 
Allogeneic Hematopoietic Cell Transplant for Hematological Cancers  
and Myelodysplastic Syndromes in HIV-Infected Individuals 
 
Study Chairpersons:  
Joseph Alvarnas, M.D. and Richard Ambinder, M.D.  
 
Primary Objective: 
The primary objective is to assess the feasibility and safety of 
allogeneic hematopoietic cell transplantation (HCT) in HIV-
infected patients.  The primary endpoint is 100-Day Non-Relapse 
Mortality (NRM). 
 
Secondary Objectives: 
Patients will be assessed for the following endpoints:  
1. 
Disease status at Day 100 post-HCT 
2. 
Time to hematopoietic recovery  
3. 
Chimerism at 4 weeks, 100 days, and 6 months 
4. 
Hematologic function at 100 days and 6 months 
5. 
Infections 
6. 
Six-month overall survival 
7. 
Acute graft-vs-host disease 
8. 
Chronic graft-vs-host disease 
9. 
Immunologic reconstitution at 8 weeks, 6, 12 and 24 
months  
10. 
To 
determine 
whether 
a 
strategy 
for 
optimized 
antiretroviral therapy can be maintained throughout the 
peritransplant period. 
11. 
Impact of HCT on the HIV reservoir at Day 100, 6, 12 and 
24 months post-HCT for all patients and for those who 
have been maintained on optimized antiretroviral therapy 
throughout. 
 
 
 
Study Design: 
This study is designed as a Phase II multi-center trial. 
 
Accrual Objective: 
The trial will accrue 15 patients. 
 
Accrual Period:  
The estimated accrual period is 2 years. 
 
Eligibility Criteria: 
Patients ≥ 15 years old, HIV-infected and diagnosed with acute 
myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) in 
first or second complete remission (CR); Int-2 or high-risk 
myelodysplastic syndrome (MDS) with < 10% marrow blasts and 
no circulating myeloblasts after their most recent therapy; or 
Hodgkin or non-Hodgkin lymphoma beyond first CR with at least 


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a partial response to last treatment.  Patients must have either an 
8/8 matched related donor at HLA-A, -B, -C, (serologic typing or 
higher resolution) and –DRB1 (at high resolution using DNA 
based typing), or at least a 7/8 matched unrelated donor at HLA-A, 
-B, -C and DRB1 (at high resolution using DNA based typing).  A 
7/8 matched related donor match is permitted only if an 8/8 
unrelated donor cannot be identified.  A secondary matching 
criterion is the presence of homozygosity for the CCR5delta32 
mutation.  Allogeneic transplantation using cord blood, T-cell 
depletion or prior allogeneic HCT are not allowed for this study.  
 
 
Patients must have adequate organ function defined as 1) left 
ventricular ejection fraction at rest ≥40%; 2) DLCO, FEV1, FVC ≥ 
45% predicted; 3) total bilirubin ≤ 2.0 mg/dL, and ALT and AST ≤ 
5 x upper limit of normal (ULN); 4) creatinine clearance > 
40mL/min 
(measured 
or 
calculated). 
 
Karnofsky/Lansky 
performance status ≥ 70%. 
 
Treatment Description: 
Patients with HIV infection and hematological malignancies or 
myelodysplastic syndromes (MDS) will be treated with either 
reduced-intensity or fully ablative allogeneic hematopoietic cell 
transplantation (HCT).  Where feasible, an attempt will be made to 
identify hematopoietic cell donors who are homozygotes for the 
CCR5delta32 
mutation. 
 
Patients 
will 
receive 
standard 
immunosuppressive therapy post-transplant that will be tapered as 
per the institutional standard of care.  Graft-versus-host disease 
will be treated per the institutional standard of care. 
 
Study Duration: 
Patients will be followed for two years following allogeneic HCT. 
 
 


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TABLE OF CONTENTS 
 
1. 
BACKGROUND AND RATIONALE ......................................................................... 1-1 
1.1. 
Background .................................................................................................................... 1-1 
1.2. 
Autologous Hematopoietic Cell Transplantation for Patients with HIV Infection . 1-2 
1.3. 
Allogeneic HCT for Patients with HIV Infection ........................................................ 1-2 
2. 
STUDY DESIGN ............................................................................................................ 2-1 
2.1. 
Study Overview .............................................................................................................. 2-1 
2.2. 
Study Objectives and Rationale .................................................................................... 2-1 
2.2.1. 
Primary Objective ....................................................................................................... 2-1 
2.2.2. 
Secondary Objectives .................................................................................................. 2-1 
2.3. 
Patient Eligibility ........................................................................................................... 2-2 
2.3.1. 
Patient Inclusion Criteria............................................................................................. 2-2 
2.3.2. 
Patient Exclusion Criteria ........................................................................................... 2-3 
2.4. 
Donor Selection Criteria................................................................................................ 2-4 
2.4.1. 
Donor Exclusion Criteria ............................................................................................ 2-4 
2.5. 
Study Treatments ........................................................................................................... 2-5 
2.5.1. 
Reduced Intensity Conditioning Regimens ................................................................. 2-5 
2.5.2. 
Myeloablative Conditioning Regimens ...................................................................... 2-6 
2.5.3. 
GVHD Prophylaxis Regimen ...................................................................................... 2-8 
2.5.4. 
Antiretroviral Therapy Overview .............................................................................. 2-13 
2.5.5. 
Initiation of Antifungal Prophylaxis in Ritonavir-Based Antiretroviral Therapy ..... 2-18 
2.6. 
Supportive Care ........................................................................................................... 2-20 
2.6.1. 
Post-HCT .................................................................................................................. 2-20 
2.7. 
Participant Risks .......................................................................................................... 2-20 
2.8. 
Therapy Toxicities ....................................................................................................... 2-21 
2.8.1. 
Busulfan .................................................................................................................... 2-21 
2.8.2. 
Melphalan .................................................................................................................. 2-21 
2.8.3. 
Fludarabine ................................................................................................................ 2-22 
2.8.4. 
Cyclophosphamide .................................................................................................... 2-22 
2.8.5. 
Total Body Irradiation ............................................................................................... 2-22 
2.8.6. 
Tacrolimus................................................................................................................. 2-23 
2.8.7. 
Sirolimus ................................................................................................................... 2-23 
2.8.8. 
Methotrexate ............................................................................................................. 2-23 
2.8.9. 
Mycophenolate Mofetil (MMF) ................................................................................ 2-23 
3. 
STUDY ENDPOINTS .................................................................................................... 3-1 
3.1. 
Primary Endpoints......................................................................................................... 3-1 
3.2. 
Secondary Endpoints ..................................................................................................... 3-1 
3.2.1. 
100-day Disease Status Following Transplant ............................................................ 3-1 
3.2.2. 
Time to Hematopoietic Recovery ............................................................................... 3-1 
3.2.3. 
Chimerism ................................................................................................................... 3-1 
3.2.4. 
Hematologic Function ................................................................................................. 3-1 


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3.2.5. 
Occurrence of Infections ............................................................................................. 3-1 
3.2.6. 
Six Month Overall Survival ........................................................................................ 3-1 
3.2.7. 
Acute Graft-versus-Host Disease (GVHD) ................................................................. 3-2 
3.2.8. 
Chronic Graft-versus-Host Disease (GVHD) ............................................................. 3-2 
3.2.9. 
Immunologic Reconstitution ....................................................................................... 3-2 
3.2.10. 
Impact of Therapy on the HIV Reservoir ................................................................... 3-2 
3.3. 
Disease Status Assessment ............................................................................................. 3-2 
3.3.1. 
Lymphoma .................................................................................................................. 3-2 
3.3.2. 
Acute Leukemia and Myelodysplastic Syndromes ..................................................... 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 ........................................................................................................... 4-2 
4.2.1. 
Follow-up Schedule .................................................................................................... 4-2 
4.2.2. 
Adverse Event Reporting ............................................................................................ 4-3 
4.2.3. 
Patient Evaluations prior to the HCT conditioning therapy ........................................ 4-3 
4.2.4. 
Patient 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 and Stopping Guidelines .................................................... 5-1 
5.3. 
Demographic and Baseline Characteristics ................................................................. 5-3 
5.4. 
Analysis Plan .................................................................................................................. 5-4 
5.4.1. 
Analysis of the Primary Endpoint ............................................................................... 5-4 
5.4.2. 
Analysis of Secondary Endpoints ............................................................................... 5-4 
 
 
LIST OF APPENDICES 
 
APPENDIX A: 
HUMAN SUBJECTS 
APPENDIX B: 
INFORMED CONSENT 
APPENDIX C: 
LABORATORY PROCEDURES 
APPENDIX D: 
TREATMENT REVIEW COMMITTEE 
APPENDIX E: 
SUGGESTED PROPHYLAXIS 
APPENDIX F: 
PHARMACOKINETIC DRUG-DRUG INTERACTIONS WITH 
ANTIRETROVIRAL MEDICATIONS 
APPENDIX G: 
KARNOFSKY AND LANSKY PERFORMANCE STATUS SCALES 
APPENDIX H: 
SEQUENTIAL PROBABILITY RATIO TEST USING FUTILITY 
BOUNDARY 


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APPENDIX I: 
IDENTIFICATION OF CCR5DELTA32 MUTATION 
HOMOZYGOUS DONORS 
APPENDIX J: 
REFERENCES 


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1-1 
CHAPTER 1 
 
 
1. 
BACKGROUND AND RATIONALE 
 
1.1. 
Background 
 
Survival in patients with Human Immunodeficiency Virus (HIV) has improved dramatically with 
the advent of Highly-Active Antiretroviral Therapy (HAART).  Despite improvements in HIV-
infection-related survival, the risk of malignancies remains significant in patients with HIV 
infection.  While Non-Hodgkin lymphoma (NHL) is an AIDS-defining diagnosis, a comparison 
of a large cohort of HIV-infected patients to the Surveillance, Epidemiology and End Results 
(SEER) data demonstrates a significantly higher incidence of several cancers that are treated 
with allogeneic HCT, including Hodgkin lymphoma and leukemias in patients with HIV 
infection (Patel).   
 
Prior to the advent of HAART, the treatment of patients with malignancy in the setting of HIV 
infection was hamstrung by limited chemotherapy tolerance and complications due to 
opportunistic infection.  Since the widespread availability of HAART, there have been 
significant improvements in the capacity to treat this patient population in a fashion comparable 
to that of patients without HIV infection.  This has, in turn, lead to marked improvements in the 
outcomes of patients with malignancies in the setting of HIV infection.  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.  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. HAART 
allows a significant portion of patients to often reduce their viral load to undetectable levels and 
therefore tolerate far more aggressive therapeutic interventions than would have been possible 
previously. 
 
Although HIV disease progression can be reversed with combination antiretroviral (ARV) 
therapy, antiretrovirals don’t cure HIV-infected individuals. This is because HIV establishes 
latent infection in long-lived resting memory CD4+ T cells.  This cellular reservoir of latent virus 
is the major barrier to HIV cure. Antiretrovirals only have activity against actively replicating 
virus and therefore “intensified” combinations of 4 and 5 drugs do not affect latent infection. 
 
Antiretrovirals are effective at preventing establishment of chronic HIV infection. For example, 
administration of antiretrovirals are very effective in blocking maternal to child transmission and 
in blocking health care worker infection following needlestick exposure.  
 


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1.2. 
Autologous Hematopoietic Cell Transplantation for Patients with HIV Infection 
 
Based upon the opportunity afforded by this degree of viral suppression, high-dose therapy with 
autologous hematopoietic cell transplantation (HCT) has been extended to patients with AIDS-
related NHL and Hodgkin lymphoma with results that appear to be comparable to those achieved 
in patients without HIV infection.  Treatment-related complications appear to be comparable to 
those seen in the non-HIV-infected patient population.  Across multiple trials, the probability of 
survival after high-dose conditioning followed by autologous HCT for patients with AIDS-
related NHL ranges between 39% to 85% as seen in Table 1.2. 
 
TABLE 1.2: CUMULATIVE OUTCOMES AFTER AUTOLOGOUS HEMATOPOIETIC 
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 
Gabarre 
? 
14 
? 
1 
71 
Serrano 
0 
11 
0% 
32 
73 
EBMT 
NA 
68 
7.5% 
32 
61 
* Abstracts of references are provided in Appendix I 
 
1.3. 
Allogeneic HCT for Patients with HIV Infection 
 
The experience with allogeneic HCT transplantation for patients with HIV infection has been 
quite limited.  Prior to the advent of HAART therapy, the key limiting factors in the use of 
allogeneic HCT in this patient population was control of the HIV infection and management of 
opportunistic infections.  In a paper published in 1987, 3 patients who were diagnosed with HIV 
infection following transplantation were managed through the use of donor lymphocyte infusions 
and cytokine therapy (Vilmer).  Two of the patients had undergone prior HCT for aplastic 
anemia and the third had been treated for acute leukemia.  All of the patients demonstrated 
evidence of marrow failure.  Patients were treated with 6 donor lymphocyte infusions, a 3-month 
course of alpha interferon and subsequently received gamma interferon.  While all 3 patients had 
improvements in their blood counts following treatment, all had detectable HIV infection and 
suppressed CD4 levels. 
 
In a case report published by the Johns Hopkins group, a 41-year-old man with AIDS-related 
lymphoma was treated with fully ablative allogeneic HCT using total body irradiation combined 
with cyclophosphamide (Holland).  The patient received 2 weeks of pre-treatment with 
zidovudine prior to transplant and received the drug post-transplant.  He achieved engraftment on 
Day + 17 but unfortunately died of complications related to progressive disease on Day + 47.  
Polymerase chain reaction (PCR) studies of peripheral blood were negative for HIV at Day + 32 


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and analysis of multiple autopsy tissues did not demonstrate detectable virus at the time of the 
patient’s death. 
 
Additional case reports from the pre-HAART era demonstrated the feasibility of performing 
allogeneic transplantation for patients with HIV infection who were treated with multiple anti-
retroviral agents prior to and following allogeneic HCT, but in 2 of 3 cases, the patients remained 
PCR-positive for evidence of residual HIV infection (Torlontano, Giri).  The 1 patient who did 
not demonstrate evidence of post-transplant HIV infection had poor count recovery following 
transplant and died of ARDS (Contu). 
 
The availability of HAART therapy seems to have had an impact upon the feasibility of HCT in 
this patient population.  In a review of the CIBMTR registry data, 23 patients with HIV infection 
were identified as having undergone allogeneic transplant (Gupta).  Nine of the 23 (39%) 
underwent allogeneic HCT HIV after 1996, in the HAART era.  At a median follow-up of 59 
months, six of the 23 patients were alive.  Four of the nine post-1996 patients were alive whereas 
only 2 of 14 pre-1996 patients were alive.  The data suggest that allogeneic HCT is feasible for 
selected HIV-positive patients. 
 
Despite the capacity of HAART therapy to suppress HIV viral loads to low or undetectable 
levels, the experience with allogeneic HCT remains quite limited.  In a 2002 case report, a 33-
year-old woman with acute myelogenous leukemia (AML) in first complete remission, HIV and 
hepatitis C infection underwent fully ablative CD34-selected allogeneic graft from a sibling 
donor (Sora).  She was treated with HAART prior to transplant and achieved an undetectable 
viral load.  The transplant course was complicated by grade II graft-versus-host disease (GVHD) 
that responded to treatment.  At the time of the report, the patient remained in a complete 
remission with an undetectable HIV viral load at 39 months post-HCT. 
 
One of the challenges in managing patients with HAART through the transplant course may be 
the risk of HIV-reactivation/graft infection during periods of antiretroviral therapy interruption.  
In a 2001 report of 2 patients treated with reduced-intensity allogeneic transplant, 1 of the 
patients developed a febrile illness consistent with acute HIV reactivation (Kang).  The viral load 
rose to 1,000,000 copies/mL during this time.  This patient eventually died of relapsed Hodgkin 
lymphoma 12 months post-HCT.  The other patient who underwent transplant for AML received 
a gene-modified graft that was engineered to inhibit wild type Rev. This patient demonstrated an 
undetectable HIV viral load post-transplant and remains free of disease.  In another case report 
from 2007, a 34-year-old man with HIV infection and severe aplastic anemia (SAA) underwent 
allogeneic HCT (Wolf).  During interruption of HAART therapy, the patient demonstrated a 
rapid rise in his HIV viral load.  Despite this, the patient engrafted at Day + 18.  He achieved 
viral suppression following retreatment with his antiretroviral regimen. 
 
Conversely there are some data that show that the donor graft may be capable of mounting and 
anti-HIV response mediated by CD8+ cells (Woolfrey).  Two patients with AML underwent 
allogeneic HCT (1 matched sibling, 1 unrelated donor) following a non-myeloablative regimen 
(fludarabine 90 mg/m2 and TBI 2 Gray) and were monitored with HIV RNA levels, proviral 
DNA levels and peripheral blood mononuclear cell quantitative HIV cultures post-transplant.  
Antiretroviral therapy was chosen to avoid significant drug interactions and hepatotoxicity 


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potentially related to nevirapine.  GVHD prophylaxis consisted of cyclosporine and 
mycophenolate.   HAART was administered throughout the transplant course.  One patient 
suffered a relapse of his disease at Day + 44.  Immunosuppression was withdrawn.  This patient 
died as a result of complications related to GVHD and obliterative bronchiolitis.  Both donors 
had wild type CCR5 coreceptor.  Both patients had undetectable viral loads from prior to 
transplant through Day + 180.  HIV proviral DNA was detected in 1 patient at Days + 56 and 
+180.  Through an analysis of donor T-cell responses to multiple HIV epitopes, cells recovered 
from patient 2 demonstrated anti-HIV-specific T-cell responses to 8 of the 26 selected epitopes. 
 
The experience with reduced-intensity allogeneic HCT for patients with HIV has expanded with 
the recent publication of the Ohio State University experience (Hamadani).  Three patients with 
HIV underwent allogeneic HCT following conditioning with fludarabine and busulfan with or 
without antithymocyte globulin (1 patient without).  GVHD prophylaxis consisted of tacrolimus 
and mini-dose methotrexate.  The patients underwent transplant for AML in 2nd complete 
remission, Burkitt lymphoma and plasmablastic lymphoma, respectively.  Patients continued 
HAART throughout the transplant course without interruption.  One patient developed acute 
GVHD.  At the time of the study publication, all patients were alive, free of disease and off of 
immunosuppressive therapy (range 368-802 days).  One patient had a detectable viral load 
beyond 1 year following HCT. 
 
The “Holy Grail” for allogeneic transplantation for patients with HIV-infection would be a cure 
of the underlying disorder for which transplant was performed and the concomitant eradication 
of the HIV infection.  The recent case report of a patient who underwent allogeneic HCT for 
AML and received a graft from a donor with the CCR5delta32/delta32 mutation may herald this 
possibility (Hütter).  One of the key mechanisms for HIV-1 entry into CD4 lymphocytes is 
chemokine receptor 5 (CCR5).  The delta32 mutation represents a 32 base pair deletion in the 
allele that may confer significant resistance to HIV infection in homozygotes for the mutation.  
In this case report, a 40-year-old man with AML and concomitant HIV infection underwent 
allogeneic transplant from an unrelated donor.  At the time of diagnosis with acute leukemia, the 
viral load was undetectable and the CD4 count was 415/mcl.  The patient achieved a complete 
response following standard therapy, but relapsed 7 months following treatment.  At the time of 
relapse, the patient underwent an unrelated donor transplant using a donor who was a 
homozygote for the delta32 allele.  The patient received a CD34-selected graft.  GVHD 
prophylaxis consisted of cyclosporine A and rabbit antithymocyte globulin.  The patient 
engrafted on Day + 13.  He experienced grade I GVHD of the skin that responded to therapy.  
The patient relapsed at Day +391 and was treated with a second transplant from the same donor 
following preparation with 2 Gray TBI.  The patient’s HIV viral load remains undetectable at 20 
months following transplant despite discontinuation of HAART.   
 
While a graft from a donor with the CCR5delta32/delta32 mutation may result in cure, evidence 
has been emerging that transplant using such donors may not be necessary for cure.  
Maintenance of antiretroviral therapy throughout the transplant period may prevent infection of 
donor cells and thus prevent the establishment of a retroviral reservoir in donor cells. 
Achievement of full chimerism with replacement of host-derived CD4 T cells with donor cells 
may abolish the host reservoir. The failure to detect residual infectious virus in the Berlin patient 
suggests that no cellular reservoir of infectious virus survived transplantation (including donor 


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lymphocyte infusion). Recent data from Boston suggests that two patients who underwent 
allotransplantation from donors who were not selected to be resistant to HIV, also cleared the 
long term reservoir and have had antiretroviral therapy stopped. As of this writing (October 
2013), they appear to be retrovirus-free off therapy. Thus in the context of the present study we 
may be able to learn whether antiretrovirals can prevent the infection of HIV-susceptible donor 
cells and if infection is prevented, whether the patient will be cured of HIV as host infected cells 
are replaced by donor cells. 
 
Subcutaneous enfuvirtide. The HIV-1 fusion inhibitor enfuvirtide (T20, Fuzeon), will be 
administered during high-risk periods for nausea and vomiting, specifically during the 
administration of high dose ARV during alloHSCT when oral medications cannot be tolerated as 
for example during high dose cyclophosphamide or during  periods of severe mucositis. 
Enfuvirtide or T20, is the only available non-oral antiretroviral approved for treatment of HIV-1 
infection, besides the intravenous form of zidovudine (AZT) which is contraindicated during 
alloHSCT due to bone marrow suppression. In most cases, enfuvirtide monotherapy is not 
sufficiently potent to suppress active viral replication in most patients; however we believe that 
the temporary use of enfuvirtide monotherapy in patients undergoing alloHSCT population is 
justified for several reasons. First, it has been demonstrated ARV simplification to less potent 
regimens, such as protease inhibitor monotherapy, is effective; this suggests that less 
antiretroviral activity is required to maintain viral suppression compared to the amount of 
antiretroviral activity required to induce viral suppression. Second, patients undergoing 
alloHSCT are likely to be profoundly lymphopenic due to conditioning chemotherapy; viral 
dynamic theory states that the amount of viral replication is directly related to the number of 
lymphocytes. Therefore in cytopenic patients with already suppressed plasma HIV-1 RNA 
levels, there should be less viral replication to inhibit. During any periods of enfuvirtide 
monotherapy, weekly viral loads will be measured using real-time PCR with a sensitivity of 20 
copies HIV-1 RNA per milliliter of plasma. If there is virologic failure/breakthrough, defined as 
2 consecutive measures of > 200 copies HIV-1 RNA/mL, enfuvirtide will be discontinued. The 
patient would then be off all antiretroviral medications and this would be considered a failure to 
maintain ARV. Enfuvirtide monotherapy does present the risk of development of enfuvirtide 
resistance. In clinical trials of enfuvirtide monotherapy, it took 14 days for resistance to develop. 
In this clinical trial, we anticipate the use of enfuvirtide monotherapy on the order of days. If 
virologic failure is observed with this strategy, resistance testing for enfuvirtide will be 
performed. If resistance does develop it is highly unlikely to compromise future management of 
the patient’s HIV infection as enfuvirtide is rarely used in clinical practice due to the availability 
of many other oral antiretrovirals and no cross-resistance exists between enfuvirtide and other 
antiretroviral agents. 


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CHAPTER 2 
 
 
2. 
STUDY DESIGN  
 
2.1. 
Study Overview 
 
The study is designed to evaluate the feasibility and safety of reduced-intensity and fully-ablative 
allogeneic hematopoietic cell transplantation (HCT) for patients with hematological 
malignancies or myelodysplastic syndromes (MDS) who have HIV infection.  The goal of the 
study is to assess the 100 day Non-relapse Mortality as well as immunological reconstitution in 
this patient population.  Where feasible, an attempt will be made to identify HLA-compatible 
hematopoietic stem cell donors who are homozygotes for the delta32 mutation of the chemokine 
receptor 5 (CCR5delta32).  Patients will undergo a treatment plan review prior to registration on 
the trial. All patients will undergo allogeneic HCT from a matched sibling or unrelated donor. In 
addition, the subcutaneous antiretroviral, enfuvirtide, will be added during any periods when oral 
medications are unlikely to be tolerated due to nausea (e.g. during administration of high dose 
cyclophosphamide) or cannot be tolerated for other reasons (e.g. mucositis). 
 
2.2. 
Study Objectives and Rationale 
 
The rationale for this trial is to demonstrate the feasibility and safety of allogeneic HCT for 
patients with chemotherapy-sensitive hematological malignancies and coincident HIV-infection.  
In particular the trial will focus upon the 100-day non-relapse mortality as an indicator of the 
safety of transplant in this patient population.  Correlative assays will focus upon the incidence 
of infectious complications in this patient population, the evolution of HIV infection and 
immunological reconstitution.  Where feasible (and when this can be accomplished without 
compromise of either the donor quality or the timeliness of transplantation), an attempt will be 
made to identify donors who are homozygotes for the delta32 mutation for CCR5. 
 
In light of emerging evidence that it may be possible to prevent infection of transplanted cells 
with HIV, we are also seeking to optimize the antiretroviral strategy so as to minimize or 
eliminate interruptions and to capture detailed compliance information. If it emerges that some 
patients are cured of retroviral infection while others are not, it will be important to determine 
whether the failures were associated with treatment interruptions in antiretroviral therapy or 
other explanations. 
 
2.2.1. Primary Objective 
 
The primary objective of this multicenter study is to assess the feasibility and safety of 
allogeneic hematopoietic cell transplantation (HCT) in HIV-infected patients.  The primary 
endpoint is 100-Day Non-Relapse Mortality (NRM). 
 
2.2.2. Secondary Objectives 
• Disease status at Day 100 post-HCT 


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• Time to hematopoietic recovery  
• Chimerism at 4 weeks, 100 days and 6 months post-HCT 
• Hematologic function at 100 days and 6 months post-HCT 
• Infections 
• Six-month overall survival 
• Acute graft-vs.-host disease 
• Chronic graft-vs.-host disease 
• Immunologic reconstitution at 8 weeks and 6, 12, and 24 months post-HCT 
• To determine whether a strategy for optimized antiretroviral therapy can be maintained 
throughout the peritransplant period. 
• Impact of HCT on the HIV reservoir at Day 100, 6, 12 and 24 months post-HCT for all 
patients and for those who have been maintained on optimized antiretroviral therapy 
throughout. 
 
2.3. 
Patient Eligibility 
 
Patients must meet specified eligibility criteria for entry into the study.   
 
2.3.1. Patient Inclusion Criteria 
 
Patients fulfilling the following criteria will be eligible for entry into this study: 
1. HIV-1 infection, as documented by a rapid HIV test or any FDA-Approved HIV-1 
Enzyme or Chemiluminescence Immunoassay (E/CIA) test kit and confirmed by Western 
Blot at any time prior to study entry.  HIV antigen, plasma HIV-1 RNA, or a secondary 
antibody test by a method other than rapid HIV and E/CIA is acceptable as an alternative 
test.  Alternatively, if a rapid HIV test or any FDA-Approved HIV-1 Enzyme or 
Chemiluminescence Immunoassay (E/CIA) test is not available, two HIV-1 RNA values 
≥ 2000 copies/mL at least 24 hours apart performed by any laboratory that has CLIA 
certification, or its equivalent, may be used to document infection. 
2. Patients must be willing to comply with effective Antiretroviral Therapy. 
3. Patients must be ≥ 15 years of age. 
4. Hematological malignancy associated with a poor prognosis with medical therapy alone. 
Diagnoses to be included: 
a) Patients with the diagnosis of Acute Myeloid or Lymphocytic Leukemia (AML or 
ALL) in first or second complete remission.  
b) Patients with advanced myelodysplastic syndromes (MDS), including those with 
International Prognostic Scoring System (IPSS) Int-2 and high-risk disease with 
less than 10% marrow blasts and no circulating myeloblasts after most recent 
therapy.  Patients with acute leukemia that develops from a pre-existing MDS 
must meet the inclusion criteria for patients with AML detailed above. 
c) Hodgkin Lymphoma beyond first remission achieving at least a partial response 
to most recent therapy with no evidence of progression prior to transplant. 


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d) Non-Hodgkin Lymphoma beyond first remission achieving at least a partial 
response to most recent therapy with no evidence of progression prior to 
transplant.  
5. Donor/Recipient HLA Matching: 
a) Related donor: must be an 8/8 match at HLA-A, -B, -C, (serologic typing or 
higher resolution) and –DRB1 (at high resolution using DNA based typing).  A 
7/8 related donor match is permitted only if an 8/8 unrelated donor cannot be 
identified. 
b) Unrelated donor: must be a 7/8 or 8/8 match at HLA-A, -B, -C, and -DRB1 (at 
high resolution using DNA based typing). 
6. Patients with adequate organ function as measured by:  
a) Cardiac: Left ventricular ejection fraction at rest ≥ 40% demonstrated by MUGA 
or echocardiogram.  Patients with known heart disease must have a functional 
status no worse than American Heart Association Class I defined as patients with 
cardiac disease but without resulting limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal 
pain.   
b) Hepatic:  
i. Total Bilirubin < 2.0 mg/dL (except for isolated hyperbilirubinemia 
attributed to Gilbert syndrome or antiretroviral therapy as specified in 
Appendix E) and ALT and AST < 5x the upper limit of normal. 
ii. Concomitant Hepatitis: Patients with chronic hepatitis B or C may be 
enrolled on the trial providing the above bilirubin and transaminase criteria 
are met. In addition, there must be no clinical or pathologic evidence of 
irreversible chronic liver disease, and there must be no active viral 
replication as evidenced by an undetectable hepatitis viral load by a PCR-
based assay. 
c) Renal: Creatinine clearance (calculated creatinine clearance is permitted) > 
40 mL/min. 
d) Pulmonary: DLCO, FEV1, FVC ≥ 45% of predicted (corrected for hemoglobin). 
7. Signed Informed Consent 
 
2.3.2. Patient Exclusion Criteria 
 
Patients with the following will be ineligible for registration onto this study: 
1. Karnofsky/Lansky performance score < 70%. 
2. Active CNS malignancy; however, patients with a history of positive CSF cytology that 
has become negative with intrathecal chemotherapy are eligible. 
3. Uncontrolled bacterial, viral or fungal infection (currently taking medication and with 
progression or no clinical improvement).  


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4. Active CMV retinitis or other CMV-related organ dysfunction. 
5. AIDS related syndromes or symptoms that pose a perceived excessive risk for 
transplantation-related morbidity as determined by the principal investigator.  
6. Untreatable HIV infection due to multidrug antiretroviral resistance.  Patients with a 
detectable viral load > 750 copies/ml should be evaluated with an HIV drug resistance 
test (HIV-1 genotype).  The results should be included as part of the Antiretroviral 
Review (described in Appendix D).  This Review Committee will make the final 
determination as to whether HIV viremia could potentially be suppressed with alternate 
antiretroviral therapy. . 
7. Pregnant (positive β-HCG) or breastfeeding.   
8. Fertile men or women unwilling to use contraceptive techniques from the time of 
initiation of mobilization until six-months post-transplant. 
9. Prior allogeneic HCT. 
10. Patients with psychosocial conditions that would prevent study compliance and follow-
up, as determined by the principal investigator.  
11. T-cell depletion (including ATG or alemtuzumab) is not allowed. 
12. Use of cord blood as the source of hematopoietic cells is not allowed. 
 
2.4. 
Donor Selection Criteria 
 
Patients are eligible for transplantation using either compatible related donors or an appropriately 
compatible unrelated donor as identified through the National Marrow Donor Program (NMDP) 
that meets institutional criteria.  Allogeneic transplantation using cord blood unit(s) as a 
hematopoietic stem cell source is prohibited under this protocol. 
 
Donor Inclusion Criteria 
1. Unrelated donors will be identified through the National Marrow Donor Program 
(NMDP). 
2. No contraindications to donation of hematopoietic stem cells. 
3. CCR5delta32 mutation: An additional matching criterion for this study will be the 
presence of homozygosity for the CCR5delta32 mutation.  When feasible based on donor 
likelihood of CCR5delta32 homozygosity and timeliness, potential donors will be 
assessed for CCR5delta32 homozygosity.  Among equivalently desirable donors as 
determined by transplant center donor selection criteria, a donor who is found to be a 
homozygote for CCR5delta32 will be favored as long as such a selection does not 
compromise the optimal timing of HCT.  HLA matching as a selection criterion will 
always take precedence over CCR5delta32 homozygosity (see Appendix E for details). 
 
2.4.1. Donor Exclusion Criteria 
1. Monozygotic twin donors. 


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2. Females who are pregnant (positive serum β HCG) or breastfeeding. 
3. HIV seropositive. 
 
2.5. 
Study Treatments  
 
In general reduced-intensity conditioning (RIC) is reserved for patients with co-morbidities or 
older patients in whom regimen-related mortality weighs against myeloablative conditioning 
(MAC).  However, the selection of a RIC or MAC regimen in any particular patient is left to the 
discretion of investigators at the participating center in accordance with institutional standards. 
 
Table 2.5A outlines the diseases, conditioning regimens and GVHD prophylaxis regimens 
allowed for this study. 
 
 
TABLE 2.5A- DIAGNOSES, PREPARATIVE REGIMENS,  
AND GVHD PROPHYLAXIS REGIMENS 
 
Diagnosis 
RIC 
MAC 
GVHD 
AML in morphologic CR1/2 
MDS: IPSS int-2/high with 
<10% marrow blasts  
HL beyond CR1 in PR/CR 
ALL in morphologic CR1/2 
NHL beyond CR1 in PR/CR 
Flu/Bu  
 
Tac/MTX or 
Tac/Sirolimus or  
Post-Tx Cy with 
Tac/MMF 
 
Bu/Flu 
Tac/MTX or Post-
Tx CY with 
Tac/MMF 
(Tac/MMF not 
required with post-
tx CY for 8/8 
matches) 
Flu/Mel 
Cy/TBI 
Tac/MTX or 
Tac/Sirolimus 
 
2.5.1. Reduced Intensity Conditioning Regimens  
 
Reduced intensity conditioning regimens permitted in this protocol are detailed below.   
 
2.5.1.1. Fludarabine and busulfan (Flu/Bu) 
 
Fludarabine will be given in a total dose of 120-180 mg/m2 and busulfan will be given in a total 
dose of ≤ 8 mg/kg PO or 6.4 mg/kg IV with the recommended Flu/Bu regimen as follows: 
• Days -6 to -2: Flu (30 mg/m2/day, total dose of 150 mg/m2) 
• Days -5 to -4: Busulfan (4mg/kg/day PO or 3.2 mg/kg/day IV, 130 mg/m2/day IV, total 
dose of 8 mg/kg PO or 6.4 mg/kg IV, or 260 mg/m2 IV, respectively) 
 


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The sequence of fludarabine and busulfan administration in RIC regimens will be done 
according to institutional standards.  Intravenous busulfan may be administered in divided doses 
or once daily. Oral busulfan must be administered in divided doses. Busulfan dose adjustments 
for obesity are listed in Section 2.5.2.4.  Fludarabine dose adjustments for renal impairment are 
listed in Section 2.5.2.3. 
 
See Section 2.5.4 and Table 2.5.4 for critical information about antiretroviral management in the 
setting of a busulfan-containing reduced intensity conditioning regimen when the antiretroviral 
regimen includes ritonavir. 
 
2.5.1.2. Fludarabine and melphalan (Flu/Mel) 
 
Fludarabine will be given in a total dose of 120-180 mg/m2 and melphalan in a total dose of 
≤ 150 mg/m2 with the recommended Flu/Mel regimen as follows: 
• Days -5 to -2: Flu (30mg/m2/day, total dose of 120 mg/m2) 
• Day -1: Mel (140mg/m2) 
 
The sequence of fludarabine and melphalan administration in RIC regimens will be done 
according to institutional standards as long as the prescribed doses are the same as the regimen 
above.  Dividing the dose of melphalan over two days is permitted.  Fludarabine dose 
adjustments for renal impairment are listed in Section 2.5.2.3. 
 
2.5.2. Myeloablative Conditioning Regimens 
 
Myeloablative regimens permitted in this protocol are detailed below.  See Section 2.5.4 and 
Table 2.5.4 for critical information about antiretroviral management in the setting of a 
myeloablative regimen when the antiretroviral regimen includes ritonavir. 
 
2.5.2.1. Busulfan and fludarabine (Bu/Flu)  
 
Fludarabine will be given in a total dose of 120-180mg/m2 and busulfan will be given in a total 
dose of ≤16mg/kg PO or 12.8 mg/kg IV with the Bu/Flu regimen as follows: 
• Days -5 to -2: Busulfan (4 mg/kg/day PO with Bu Css 900±100 ng/mL (or per 
institutional standard), 3.2 mg/kg/day IV or 130 mg/m2/day IV; total dose of 16 mg/kg, 
12.8 mg/kg or 520 mg/m2, respectively) 
• Days -5 to -2: Flu (30 mg/m2/day, total dose of 120 mg/m2)   
• The sequence of busulfan and fludarabine administration in MAC regimens will be done 
according to institutional standards.  Busulfan may be administered intravenously in 
divided doses or once daily.  Appropriate busulfan dosing adjustments per institutional 
standard should be made when levels are available to achieve the target Css.  Busulfan 
dose adjustments for obesity are listed in Section 2.5.2.4.  Fludarabine dose adjustments 
for renal impairment are listed in Section 2.5.2.3. 
 


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2.5.2.2.Cyclophosphamide and total body irradiation (Cy/TBI)  
 
Cyclophosphamide will be given in a total dose of 120 mg/kg and fractionated total body 
irradiation will be given in a total dose of 1200-1420 cGy with the recommended Cy/TBI 
regimen as follows: 
• Days -7 to -4: TBI (total dose of 1200-1420 cGy) 
• Days -3 to -2: Cy (60 mg/kg/day, total dose of 120 mg/kg)   
• The sequence of cyclophosphamide, TBI and TBI administration practices in MAC 
regimens will be done accordingly to institutional standards.  Cyclophosphamide dose 
adjustments for obesity are listed in Section 2.5.2.4. 
 
(See Appendix F for detailed information on pharmacokinetic interactions.) 
 
MESNA will be given to reduce the risk of cyclophosphamide-associated hemorrhagic cystitis.  
MESNA will be dosed based on cyclophosphamide dose and may be administered per 
institutional guidelines. 
 
2.5.2.3.Conditioning agent dose adjustments for renal impairment 
 
Fludarabine: Patients with a creatinine clearance of 40-70 ml/min (measured or calculated) 
should have a 20% dose reduction. 
 
2.5.2.4.Conditioning agent dose adjustments for obesity 
 
Busulfan: Busulfan will be dosed according to the recipient’s ideal body weight (IBW), unless 
the patient weighs more than 125% of IBW, in which case the drug will be dosed according to 
the adjusted IBW (AIBW; see below for formulas). 
 
Fludarabine: Fludarabine will not be dose adjusted for obesity. 
 
Cyclophosphamide: Cyclophosphamide will be dosed according to the recipient’s ideal body 
weight (IBW), unless the patient weighs less than IBW, in which case the drug will be dosed 
according to the actual body weight. 
 
Ideal Body Weight (IBW) Formulas: 
 
Males IBW = 50 kg + 2.3 kg/inch over 5 feet 
 
Females IBW = 45.5 kg + 2.3 kg/inch over 5 feet 
 
Adjusted Ideal Body Weight (AIBW) Formula: 
 
AIBW = IBW + [(0.25) x (ABW - IBW)] 
 


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2.5.3. GVHD Prophylaxis Regimen 
 
Transplant centers must use the GVHD prophylaxis regimens that are listed below in Table 2.5B.  
Guidelines for continuing ARV therapy with various prophylaxis regimens are detailed below in 
Table 2.5C. 
 
Table 2.5B GVHD PROPHYLAXIS REGIMENS 
 
Conditioning Regimen / Match 
GVHD Prophylaxis  
Fludarabine/Busulfan (Flu/Bu) – RIC /  
7/8 or 8/8 Match 
 
Tacrolimus 
• 
Blood trough levels 5-15 ng/mL 
• 
Tacrolimus initiation tapering and 
discontinuation is per institutional guidelines 
Methotrexate  
• 
15 mg/m2 Day 1 
• 
5-10 mg/m2 Days 3, 6 and 11 
Tacrolimus 
• 
Blood trough levels 5-10 ng/mL 
• 
Tacrolimus initiation tapering and 
discontinuation is per institutional guidelines 
Sirolimus 
• 
12 mg loading dose on Day -3 
• 
4 mg daily starting on Day -2 adjusted to 
maintain a trough level between 3-12 ng/ml 
• 
Sirolimus tapering and discontinuation is per 
institutional guidelines 
Post-transplant Cyclophosphamide 
• 
50 mg/kg Days 3 and 4 (with MESNA) 
Tacrolimus 
• 
Beginning on Day 5, administer tacrolimus to 
achieve trough levels 5-15 ng/mL for 6 months 
• 
1 mg Day 5 and dose adjusted weekly after Day 
7 and continued for 6 months post-
transplantation 
• 
Tacrolimus tapering and discontinuation is per 
institutional guidelines 
MMF 
• 
15 mg/kg  po TID (max dose 1 gm po TID) Day 
5 to Day 35 
Busulfan/Fludarabine (Bu/Flu) – MAC / 
7/8 or 8/8 Match 
 
Tacrolimus 
• 
Blood trough levels 5-15 ng/mL 
• 
Tacrolimus initiation tapering and 
discontinuation is per institutional guidelines 
Methotrexate  
• 
15 mg/m2 Day 1 
• 
5-10 mg/m2 Days 3, 6 and 11 


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Conditioning Regimen / Match 
GVHD Prophylaxis  
Busulfan/Fludarabine (Bu/Flu) – MAC 
8/8 Match 
 
Post-transplant Cyclophosphamide (8/8 match) 
• 
50 mg/kg Days 3 and 4 (with MESNA) 
• 
Note that tacrolimus/MMF is not required in this 
setting 
Busulfan/Fludarabine (Bu/Flu) – MAC 
7/8 Match 
 
Post-transplant Cyclophosphamide 
• 
50 mg/kg Days 3 and 4 (with MESNA) 
Tacrolimus 
• 
Beginning on Day 5, administer tacrolimus to 
achieve trough levels 5-15 ng/mL for 6 months 
• 
1 mg Day 5 and dose adjusted weekly after Day 
7 and continued for 6 months post-
transplantation 
• 
Tacrolimus tapering, and discontinuation is per 
institutional guidelines 
MMF 
15 mg/kg  po TID (max dose 1 gm po TID) Day 5 to 
Day 35 
Fludarabine/Melphalan (Flu/Mel) - RIC 
Cyclophosphamide/Total Body Irradiation 
(Cy/TBI) – MAC/ 
7/8 or 8/8 Match 
Tacrolimus 
• 
Blood trough levels 5-15 ng/mL 
• 
Tacrolimus initiation  tapering and 
discontinuation is per institutional guidelines 
Methotrexate  
• 
15 mg/m2 Day 1 
• 
5-10 mg/m2 Days 3, 6 and 11 
Tacrolimus 
• 
Blood trough levels 5-10 ng/mL 
• 
Tacrolimus initiation tapering and 
discontinuation is per institutional guidelines 
Sirolimus 
• 
12 mg loading dose on Day -3 
• 
4 mg daily starting on Day -2 adjusted to 
maintain a trough level between 3-12 ng/ml 
• 
Sirolimus tapering and discontinuation is per 
institutional guidelines 
 


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TABLE 2.5C CONTINUATION OF ANTIRETROVIRAL THERAPY BASED ON GVHD 
 PROPHYLAXIS REGIMEN1 
 
 
Raltegravir or 
Dolutegravir 
Based Regimen 
NNRTI2  
Based Regimen 
Boosted PI3, 4  
Based Regimen 
Other 
GVHD Prophylaxis 
Agent 
Tacrolimus 
Continue 
antiretroviral 
therapy as 
tolerated 
Continue 
antiretroviral 
therapy.  
Tacrolimus dose 
adjustments will 
be required 
(Appendix F) 
Continue 
antiretroviral 
therapy.  
Tacrolimus dose 
adjustments will 
be required 
(Appendix F) 
Consultation 
recommended, 
reviewed on a case 
by case basis 
Sirolimus 
Continue 
antiretroviral 
therapy as 
tolerated 
Continue 
antiretroviral 
therapy.  
Sirolimus dose 
adjustments will 
be required 
(Appendix F) 
Continue 
antiretroviral 
therapy.  Sirolimus 
dose adjustments 
will be required 
(Appendix F) 
Consultation 
recommended, 
reviewed on a case 
by case basis 
Cyclophosphamide 
(Cy) 
Continue 
antiretroviral 
therapy as 
tolerated 
Continue 
antiretroviral 
therapy as 
tolerated with 
caution and 
frequent 
monitoring 
(Appendix F) 
Hold antiretroviral 
therapy during Cy 
prophylaxis.  
Restart 
antiretrovirals at 
Day +5 as 
tolerated.4 
Consultation 
recommended, 
reviewed on a case 
by case basis5 
1Patients should be switched to raltegravir or dolutegravir-based regimens whenever possible. 
2NNRTI (Non-nucleoside Reverse Transcriptase Inhibitors). 
3PI (Protease Inhibitors). 
4Ritonavir – containing antiretroviral therapy. 
5Restart antiretroviral therapy after cyclophosphamide prophylaxis (Day +5) as soon as patient can tolerate oral medications. 
 
 
(See Appendix F for detailed information on each interaction.) 
 
Recommendations on GVHD prophylaxis are included in Sections 2.5.3.1 to 2.5.3.4. 
 
2.5.3.1. Tacrolimus 
 
Tacrolimus doses are adjusted to target whole blood levels between 5 and 15 ng/mL, except 
when the patient is receiving both tacrolimus and sirolimus, in which case it is recommended that 
serum trough levels of tacrolimus do not exceed 10 ng/mL.  When a patient is switched from 
intravenous to oral tacrolimus, the dose is increased by 3-4 fold to adjust for the lower 
bioavailability of oral compared to intravenous tacrolimus. 
 


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Drugs that may affect tacrolimus levels are: 
1. Caspofungin, phenobarbital, phenytoin, rifampin, carbamazepine, rifabutin, St. John’s 
Wort (lowers levels); 
2. Glucocorticoids, fluconazole, voriconazole, posaconazole, ketoconazole, itraconazole, 
grapefruit juice, amprenavir, bromocriptine, chloramphenicol, cimetidine, cisapride, 
clarithromycin, clotrimazole, danazol, diltiazem, erythromycin, ethinyl estradiol, 
metoclopramide, 
metronidazole, 
mibefradil, 
nefazodone, 
nelfinavir, 
nifedipine, 
omeprazole, 
quinupristin/dalfopristin, 
ritonavir, 
saquinavir, 
theophylline, 
troleandomycin, verapamil (increases levels). 
 
Per the tacrolimus package insert, when initiating therapy with posaconazole or voriconazole in 
patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to 
one-third of the original dose and followed with frequent monitoring of the tacrolimus blood 
levels.  Increased tacrolimus levels have been associated with nephrotoxicity.  When 
posaconazole or voriconazole are discontinued, tacrolimus levels should be carefully monitored 
and the dose increased as necessary (see Appendix F).  Cyclosporine may be substituted for 
tacrolimus if the patient is intolerant of tacrolimus. 
 
2.5.3.2. Methotrexate 
 
The regimen of methotrexate for GVHD prophylaxis will employ intravenous doses of 15 mg per 
m2 on Day 1 post-transplant, and 10 or 5 mg/m2 on Days 3, 6, and 11 post-transplant according 
to institutional standards.  Third space syndromes with large accumulation of ascites or pleural 
effusions are a contraindication to the use of methotrexate.  Dose reductions per institutional 
guidelines should be made for renal, hepatic and mucosal toxicity.  Determinations of blood 
levels are indicated 24-72 hours after administration in patients with impaired renal function.  
Leucovorin rescue should be considered in patients with decreased clearance, severe toxicity or 
fluid accumulation/effusions. 
 
Drugs that may increase methotrexate levels are: 
1. Non-steroidal anti inflammatory drugs 
2. Penicillins 
3. Diuretics 
 
2.5.3.3. Sirolimus  
 
Sirolimus is recommended to be given to adult patients in a loading dose of 12 mg on Day –3 
followed by a daily oral dose of 4 mg per day.  Doses may be repeated if the subject vomits 
within 15 minutes of an oral dose.   
 
Levels of sirolimus need to be monitored frequently during initiation of treatment until target 
level is reached.  Monitoring should be done weekly or monthly once the level reaches steady 


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state.  Frequent monitoring is required if a new medication is initiated or if the patient develops 
renal insufficiency.  The target serum level for sirolimus is 3-12 ng/mL. 
 
Dose adjustments are based on clinical judgment of the treating physician after considering 
clinical toxicity, serum levels, GVHD, concomitant drug use and the rate of rise or decline of the 
serum level.  For levels < 3 ng/mL, it is suggested, but not required, that the dose of sirolimus be 
increased by approximately 25% increments no more frequently than every 2 days, rounded to 
the nearest full milligram until the target range is achieved.  Conversely, for levels > 12 ng/mL, it 
is suggested, but not required, that the dose be decreased by approximately 25% no more 
frequently than every 2 days until the target level is achieved.  Alternatively, sirolimus can be 
held entirely as long as serum levels are monitored and the drug is restarted when the level 
returns to the therapeutic range and the treating physician feels it is appropriate to restart the 
agent. 
 
Drugs that may increase sirolimus blood concentrations include:  
• 
Calcium channel blockers: diltiazem, nicardipine, verapamil.  
• 
Calcineurin inhibitors: cyclosporine. 
• 
Antifungal agents: ketoconazole, clotrimazole, fluconazole, itraconazole, voriconazole, 
posaconazole.  
• 
Macrolide antibiotics: clarithromycin, erythromycin, troleandomycin.  
• 
Gastrointestinal prokinetic agents: cisapride, metoclopramide.  
• 
Other drugs: rifampin, bromocriptine, cimetidine, danazol, HIV-protease inhibitors (e.g., 
ritonavir, indinavir).  
 
Drugs that may decrease sirolimus concentrations include: 
• 
Anticonvulsants: carbamazepine, phenobarbital, phenytoin. 
• 
Antibiotics: rifabutin, rifapentine.  
• 
Herbal preparations: St. John's Wort (Hypericum perforatum) could result in reduced 
sirolimus concentrations.  
 
Due to extreme interactions with sirolimus, voriconazole is contraindicated during sirolimus 
therapy.  In the event of suspected or documented fungal infection, alternative antifungal therapy 
should be used wherever possible (see Appendix F for further details).  The uses of sirolimus and 
myeloablative doses of busulfan are associated with hepatic veno-occlusive disease (sinusoidal 
obstructive syndrome) and thus should be avoided.   
 
2.5.3.4.Post-transplantation Cyclophosphamide with MESNA 
 
Post-transplantation 
cyclophosphamide 
with 
MESNA 
may 
only 
be 
used 
with 
fludarabine/busulfan for non-myeloablative and busulfan/fludarabine for myeloablative 
conditioning regimens. 
 


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MESNA will be given to reduce the risk of cyclophosphamide-associated hemorrhagic cystitis.  
MESNA will be dosed based on cyclophosphamide dose and may be administered per 
institutional guidelines. 
 
It is crucial that no immunosuppressive agents are given until 24 hours after the 
completion of the post-transplant Cy.  This includes corticosteroids for any reason. 
 
Tacrolimus and MMF should not be used with post-transplant cyclophosphamide if the patient 
received a myeloablative conditioning regimen and the donor/recipient match is 8/8. 
 
Additional immunosuppression for patients receiving post-transplant cyclophosphamide: 
• Full myeloablative regimen and donor/recipient match is 8/8: no additional prophylaxis is 
given 
• Full myeloablative regimen with a 7/8 match and for Flu/Bu non-myeloablative regimen: 
− On Day 5, patients will begin prophylaxis with Tacrolimus and Mycophenolic Acid 
Mofetil (MMF).  Tacrolimus will be given at a dose of 1 mg IV daily then will be 
changed to a PO dosing schedule once a therapeutic level is achieved or as per 
institutional standards.   
− MMF will be given at a dose of 15 mg/kg PO TID (based upon actual body weight) 
with the maximum total daily dose not to exceed 3 grams (1 g PO TID). 
− MMF prophylaxis will be discontinued after the last dose on Day 35 and Tacrolimus 
prophylaxis will be discontinued per institutional standards typically around Day 180. 
 
2.5.4. Antiretroviral Therapy Overview  
 
Based on preliminary results from the Dana-Farber group showing that continuous antiretroviral 
(ARV) treatment may help prevent HIV infection in transplanted cells (ref), ARV treatment 
should be continued throughout the transplant process whenever possible. Antiretroviral (ARV) 
therapy is optimally effective when administered in combination and with consistency. However, 
almost all ARV medications are orally administered. It should be noted that the integrase strand 
transfer inhibitors (INSTIs, raltegravir and dolutegravir) are associated with low levels of GI 
toxicity and may be better tolerated in patients experiencing nausea than ritonavir-boosted 
protease inhibitor based-regimens. Elvitegravir, also an INSTI, is co-formulated (Stribild) with 
tenofovir, emtricitabine, and cobicistat. Co-administration of Stribild is contraindicated with 
drugs that are highly depending on CYP3A for clearance due to the cobicistat component. It 
should be used with caution in this study. 
 
Use of Enfuvirtide as a Bridging Agent When Oral ARVs Cannot Be Tolerated 
When oral medications cannot be tolerated due to nausea and vomiting, mucositis, or other 
reasons, the patient should receive the subcutaneously administered antiretroviral enfuvirtide at 
standard doses in order to maintain HIV suppression. Enfuvirtide monotherapy may lead to HIV 
resistance if used as monotherapy for prolonged periods of time, but in the short-term, the risk of 
acquired resistance is modest. In addition to subcutaneous administration, the benefits of 


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enfuvirtide include that it has few drug interactions and that it is in a unique drug class without 
cross-resistance with other ARVs should resistance to enfuvirtide develop. Intravenous 
zidovudine is not allowed because of the possible marrow suppressive effects which could 
impact engraftment.  
 
ARVs and High Dose Chemotherapy 
The ARV guidelines (Appendices D and E) are designed to minimize the possibility of drug 
interactions with high dose chemotherapy.  
 
Patients on Myeloablative Conditioning Regimens Receiving Ritonavir-Containing ARV 
Therapy:  Ritonavir-containing ARV therapy will restart not sooner than 12 hours after the last 
chemotherapy infusion, including post-transplant cyclophosphamide, as tolerated. Enfuvirtide 
monotherapy at standard doses should be administered as a bridging ARV therapy irrespective of 
the conditioning regimen when oral ARV cannot be tolerated until multi-agent ARV therapy can 
be resumed.  
 
Patients on Reduced Intensity Conditioning Regimens:  Patients will continue on oral ARV 
therapy. Enfuvirtide monotherapy should be administered as above if for any reason, the patient 
is unable to tolerate oral ARV therapy. 
 
Table 2.5.4 outlines continuation guidelines for ARV regimens based on the conditioning 
regimen used. 
 
 


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TABLE 2.5.4: CONTINUATION OF ANTIRETROVIRAL THERAPY (ARV)  
BASED ON THE CONDITIONING REGIMEN 
 
 
Raltegravir or 
Dolutegravir 
Based Regimen 
NNRTI Based 
Regimen 
Boosted PI Based 
Regimen** 
Other 
Reduced Intensity 
Conditioning 
Fludarabine  
Busulfan  
Continue 
throughout 
conditioning as 
tolerated 
Continue 
throughout 
conditioning as 
tolerated† 
Discontinue ARV 
96 hours prior to 
conditioning and 
resume after 
conditioning as 
tolerated 
Consultation 
recommended, 
reviewed on a case 
by case basis 
Fludarabine Melphalan  
Continue 
throughout 
conditioning as 
tolerated 
Continue 
throughout 
conditioning as 
tolerated 
Continue 
throughout 
conditioning as 
tolerated 
Consultation 
recommended, 
reviewed on a case 
by case basis 
Myeloablative Conditioning 
Fludarabine Busulfan* 
Continue 
throughout 
conditioning as 
tolerated 
Continue 
throughout 
conditioning as 
tolerated† 
Discontinue ARV 
96 hours prior to 
conditioning and 
resume after 
conditioning  as 
tolerated 
Consultation 
recommended, 
reviewed on a case 
by case basis 
Cyclophosphamide Total 
Body Irradiation (1200 – 
1420 cGy) 
Continue 
throughout 
conditioning as 
tolerated 
Continue 
throughout 
conditioning as 
tolerated† 
Discontinue ARV 
96 hours prior to 
conditioning and 
resume after 
conditioning  as 
tolerated 
Consultation 
recommended, 
reviewed on a case 
by case basis 
*PO doses adjusted to maintain BU Css at 900 ± 100 ng/mL or per institutional standard  
** Patients receiving cyclophosphamide for GVHD prophylaxis should not resume boosted PI based regimens until Day +5 as 
tolerated 
†Busulfan levels may be decreased when co-administered with NNRTIs 
 
See Appendix F [Table F-1] for detailed information on each interaction. 
 
Ritonavir-Based ARV Therapy and Immunosuppressive Medications  
Serious and prolonged toxicity is possible for patients concurrently receiving ritonavir-based 
(boosted-PI) therapy and the immunosuppressive agents tacrolimus or sirolimus.  The 
introduction of immunosuppressive therapy must be systematic, carefully monitored and 
consistent throughout the peri-transplantation period.  At the inception of immunosuppression, 
patients may or may not be receiving antiretroviral therapy based on the conditioning regimen 
selected.  Patients receiving ritonavir throughout conditioning are to be managed differently than 
those who are not.  This is due to the potent inhibition of CYP3A4 and P-glycoprotein by 
ritonavir, resulting in the delayed metabolism and consequently higher serum levels of 
tacrolimus, and sirolimus. 
 
Daily monitoring of serum trough levels of cyclosporine, tacrolimus and sirolimus is the most 
accurate way to provide effective immunosuppression while minimizing toxicity.  In the setting 


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of less frequent monitoring, dose adjustments can be predicted based on the metabolic pathways 
for each agent; however, the drug-drug interactions with ritonavir have not been studied 
extensively and must be supported by routine therapeutic drug monitoring as soon as possible.  
Only the doses of tacrolimus and sirolimus should be adjusted; antiretroviral therapy must be 
continued at the dose prescribed. 
 
For all patients, the following is recommended: 
1) Intravenous tacrolimus is preferred to avoid gastrointestinal cytochrome P450 co-enzyme 
inhibition during the peri-transplantation period, however oral therapy with tacrolimus, or 
sirolimus is permitted 
2) Serum trough levels should be obtained no later than Day 5 of concurrent 
immunosuppressive and antiretroviral therapy 
3) If clinical signs or symptoms of severe toxicity (neurotoxicity) are present OR if serum 
trough levels of tacrolimus/sirolimus exceed the upper limits of acceptable (tacrolimus 
>25 ng/mL, sirolimus >25 ng/mL), then BOTH antiretroviral therapy and 
tacrolimus/sirolimus should be held, a level repeated in 24 hours and therapy resumed 
once the level is within the target range 
4) No dose adjustments are required for mycophenolate mofetil or methotrexate 
5) Dosing recommendations based on serum levels are provided below and in Appendix F 
6) Recommended standard dosing (or per institutional standard): 
a. Tacrolimus 
i. 
IV: 0.03 mg/kg every 24 hours (based on Ideal Body Weight) 
ii. 
PO: 0.12 mg/kg/day divided into 2 doses 
b. Sirolimus 
i. 
PO: 12 mg once, then 4 mg daily as a single dose 


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Dosing recommendations are provided for each of the following: 
 
1) Patients continuing ritonavir-based therapy throughout conditioning 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Day 1 represents the first day of concurrent therapy with cyclosporine, tacrolimus, or sirolimus and ritonavir-based antiretroviral 
therapy. 
 
2) Patients discontinuing ritonavir-based therapy prior to conditioning 
a. Antiretroviral therapy should be discontinued 4-7 days prior to any 
myeloablative conditioning regimen and busulfan-containing reduced-
intensity conditioning 
b. Antiretroviral therapy should be restarted no sooner than Day -1 as tolerated 
c. For patients receiving post-transplant cyclophosphamide for GVHD 
prophylaxis, antiretroviral therapy will be restarted on Day +5 as tolerated 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Day 1 represents the first day of concurrent therapy with tacrolimus, or sirolimus and ritonavir-based antiretroviral therapy.  For 
patients restarting antiretroviral therapy, this should be Day -1, unless they are unable to tolerate oral medications or receive 
cyclophosphamide for GVHD prophylaxis. 
 
Antiretroviral Therapy Continued 
 Tacrolimus/Sirolimus 
Day 1* 
Day 2 
Day 5 
Day 4 
Day 3 
Administer 50% 
of standard dose 
Dose according 
to level or give 
10% of standard 
dose if a level is 
not available 
Dose according 
to level or give 
10% of standard 
dose if a level is 
not available 
Dose according 
to level or give 
10% of standard 
dose if a level is 
not available 
Dose ONLY 
according to level 
Tacrolimus/Sirolimus 
Antiretroviral Therapy Restarted (Day -1 as tolerated)   
Day 1* 
Day 2 
Day 5 
Day 4 
Day 3 
Administer 50% 
of standard dose 
Dose according 
to level or give 
25% of standard 
dose if a level is 
not available 
Dose according 
to level or give 
17% of standard 
dose if a level is 
not available 
Dose according 
to level or give 
10% of standard 
dose if a level is 
not available 
Dose ONLY 
according to level 


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3) Dosing based on a serum trough level of tacrolimus, or sirolimus while receiving 
ritonavir-based therapy 
Immunosuppressive 
Agent 
Target Trough 
Recommendation1 
Tacrolimus 
5 – 15 ng/mL 
< 5 ng/mL: Administer 1 mg (PO) or 0.25 mg (IV)2 
 
>5 - 15 ng/mL: Administer 0.5 mg (PO) or 0.125 mg (IV) 2 
 
>15 - 25 ng/mL: HOLD tacrolimus & repeat level in 24h 
 
> 25 ng/mL: HOLD both tacrolimus and ARV 
 
Sirolimus 
3 – 12 ng/mL 
< 3 ng/mL: Administer 0.4 mg (PO) 2  
 
>3 - 12 ng/mL: Administer 0.3 mg (PO) 2 
 
>12-25ng/mL: HOLD sirolimus & repeat level in 24h 
 
>25ng/mL: HOLD both sirolimus and ARV 
 
ARV= Antiretroviral Therapy 
1See Appendix F (Table F-3) for detailed information 
2Administer a one-time dose in response to the observed level 
 
2.5.5. Initiation of Antifungal Prophylaxis in Ritonavir-Based Antiretroviral Therapy  
 
Detailed information is available in Appendix F Table F-6 for patients receiving ritonavir-based 
antiretroviral therapy. 
 
Initiating antifungal prophylaxis in patients concomitantly receiving ritonavir may result in 
serious toxicity.  Moreover, many antifungal agents affect the metabolism of the 
immunosuppressive agents, tacrolimus, sirolimus and cyclophosphamide, also resulting in the 
increased risk of serious adverse events.  Careful selection of the most appropriate antifungal 
agent and routine therapeutic drug monitoring are strategies to minimize the risk of severe 
toxicity.   
 
Fluconazole is effective against yeasts other than Candida krusei and some C. glabrata, but is 
not effective against moulds.  For patients at high risk for mould infections (such as those with 
cell-mediated immunodeficiency from GVHD) or those with a prior history of invasive 
aspergillosis, prophylaxis with an anti-mould agent is recommended.  Given the three-way 
interaction between selected immunosuppressive drugs, HIV medications (especially protease 
inhibitors) and triazole agents (especially voriconazole, itraconazole, and to a lesser extent 
posaconazole), the echinocandins (anidulafungin, caspofungin, micafungin) and amphotericin B 
(either the aerosolized or intravenous formulations) are preferred for prophylaxis.  The 
echinocandins are effective against Aspergillus mould only, whereas amphotericin B has a 
broader spectrum of mould activity.  Aerosolized liposomal amphotericin B has been shown to 
be effective in reducing invasive pulmonary aspergillosis in leukemic and HCT patients.  


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2.5.5.1.Voriconazole 
 
Voriconazole is metabolized by, and inhibits the activities of, human cytochrome P450 enzymes 
CYP2C19, CYP3A4 and CYP2C9.  The affinity of voriconazole is the highest for CYP2C19, 
followed by CYP2C9 and CYP3A4; however there is a large degree of inter-individual 
variability in voriconazole pharmacokinetics.  The interactions between voriconazole and the 
antiretroviral agents, specifically ritonavir, are complex.  Concurrent use of high-dose ritonavir 
(400-600 mg twice daily) is contraindicated due to significant reduction in plasma concentration 
of voriconazole.  Low-dose ritonavir (100mg twice daily) has been shown to decrease the 
voriconazole AUC by 39% in healthy subjects after 9 days; however, upon initiation of 
voriconazole, the AUC may be increased by 4.5 fold.  This is due to a time- and dose-dependent 
interaction where ritonavir initially inhibits voriconazole metabolism, followed by delayed 
induction. 
 
Moreover, voriconazole may further inhibit the metabolism of immunosuppressive agents, such 
as tacrolimus, sirolimus and cyclophosphamide.  The following is recommended for initiating 
voriconazole prophylaxis in patients receiving protease inhibitor-based antiretroviral therapy: 
1) No high-dose ritonavir (contra-indicated due to significant reduction of plasma 
voriconazole concentrations) 
 
2) Avoid loading doses (due to significant voriconazole effect on calcineurin inhibitors and 
sirolimus levels); initiate prophylaxis with voriconazole 4 mg/kg IV or 200mg PO every 
12 hours  
 
3) Therapeutic drug monitoring of voriconazole is required within 7 days of concomitant 
therapy (due to significant effect of protease inhibitors on voriconazole) 
 
a. Serum trough levels ≥ 1 mcg/ml are desired for optimal efficacy 
b. Serum trough levels > 6 mcg/ml are associated with greater toxicity 
 
4) Close monitoring (daily if possible) of serum levels for cyclosporine, tacrolimus or 
sirolimus is strongly recommended (due to significant effect of voriconazole on these 
agents) 
a. In the absence of an appropriate level, administer 10% of the standard dose of 
cyclosporine, tacrolimus or sirolimus (see Section 2.5.4) 
 
5) Monitor closely for signs or symptoms of voriconazole toxicity (hepatotoxicity, CNS 
toxicity) 
 
2.5.5.2.Posaconazole 
 
Posaconazole also inhibits the activity of human cytochrome P450 enzymes especially the 
isoform CYP3A4, which can increase the plasma concentration and exposure of drugs 
metabolized by this enzyme.  However, posaconazole does not inhibit the CYP450 isoforms 
CYP1A2, 2C8/9, 2D6, or 2E1, and thus potentially has a lower drug interaction potential than 
voriconazole.  Unlike voriconazole, posaconazole metabolism is mediated primarily by uridine 
diphosphate glucuronosyltransferase.  In general, the metabolic pathways of posaconazole and 


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ritonavir suggest that posaconazole may increase the plasma concentrations of ritonavir, and 
ritonavir may decrease the plasma concentration of posaconazole.  Posaconazole may further 
inhibit the metabolism of immunosuppressive agents, such as tacrolimus, sirolimus and 
cyclophosphamide.  The following is recommended for initiating posaconazole prophylaxis in 
patients receiving protease inhibitor-based antiretroviral therapy: 
1) No high-dose ritonavir (contra-indicated due to significant reduction of plasma 
posaconazole concentrations) 
2) Therapeutic drug monitoring of posaconazole is required within 7 days of concomitant 
therapy (due to significant effect of protease inhibitors on posaconazole). Therapeutic 
levels of posaconazole have not been established, but low levels have been encountered 
in the setting of impaired absorption with poor food intake, acute GVHD, or diarrhea.  
3) Close monitoring (daily if possible) of serum levels for cyclosporine, tacrolimus or 
sirolimus is strongly recommended (due to significant effect of posaconazole on these 
agents) 
a. In the absence of an appropriate level, administer 10% of the standard dose of 
tacrolimus or sirolimus (see Section 2.5.4) 
 
2.6. 
Supportive Care 
 
2.6.1. Post-HCT 
 
All supportive care will be given in keeping with BMT CTN MOP and local institutional 
guidelines. 
 
2.6.1.1. 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 E.  
 
2.6.1.2. Cryopreservation 
 
Donor’s stem cells may be cryopreserved prior to transplantation at the discretion of treating 
institution and in keeping with NMDP policy if an unrelated donor.  
 
2.6.1.3. Post-HCT growth factors 
 
Use of Post-HCT growth factors will be according to institutional standards. 
 
2.7. 
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, 


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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 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. 
 
2.8. 
Therapy Toxicities  
 
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0.  All of the following listed agents are commercially available.  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. 
 
2.8.1. Busulfan 
 
Busulfan is a bi-functional alkylating agent.  Toxicities include the following: Severe bone 
marrow hypoplasia, which would be fatal without administration of bone marrow, stem cells; 
nausea and vomiting, which can be decreased by the use of sedation and anti-emetics; stomatitis 
and diarrhea, which can be treated symptomatically with fluid replacement and atropine or 
diphenoxylate HCl; pulmonary fibrosis characterized by delayed onset of cough, shortness of 
breath and low-grade fever; hepatic damage, which can occur in combination with 
cyclophosphamide or as a single agent and can result in significant hepatic toxicity, which can be 
fatal; temporary hyperpigmentation of the skin and nail bed changes; and grand mal seizures, 
which can be prevented by the prophylactic administration of phenytoin. 
 
2.8.2. 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.   
 


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2.8.3. Fludarabine 
 
a. Neurotoxicity: Agitation or confusion, blurred vision, loss of hearing, peripheral 
neuropathy or weakness have been reported.  Severe neurologic effects, including 
blindness, coma, and death are seen in 36% of patients treated with doses approximately 
four times greater than recommended; severe CNS toxicity is rarely seen with doses in 
the recommended range for non-transplant therapy of hematologic malignancies.  Effect 
of chronic use on the CNS is unknown, although patients have received recommended 
doses for up to 15 courses.  The dose used in this study is approximately 1.5 times the 
usual one-course dose given in non-transplant settings.  Doses and schedules such as 
those used in this study have been used in adult and pediatric patients and increased 
neurotoxicity has not been observed.  
b. Anemia: Life-threatening and sometimes fatal autoimmune hemolytic anemia has been 
reported after one or more cycles of therapy in patients with or without a previous history 
of autoimmune hemolytic anemia or a positive Coombs’ test and who may or may not be 
in remission; no mechanisms for development of this complication have been identified.  
Corticosteroids may or may not be effective in controlling these episodes.  The majority 
of patients re-challenged developed a recurrence of the hemolytic process.  
c. Cardiovascular: Deep venous thrombosis, phlebitis, transient ischemic attack, and 
aneurysm (1%) are reported.    
d. Fever: 60% of patients develop fever. 
e. Skin Rash: 15% of patients develop a skin rash, which may be pruritic.  
f. Digestive: Gastrointestinal side effects include: nausea/vomiting (36%), diarrhea (15%), 
stomatitis (9%), anorexia (7%), GI bleeding and esophagitis (3%), mucositis (2%), liver 
failure, abnormal liver function test, constipation, dysphagia (1%) and mouth sores.  
g. Some other effects are: Chills (11%), peripheral edema (8%), myalgia (4%), osteoporosis 
(2%), pancytopenia, arthralgia (1%), dysuria (4%), urinary tract infection and hematuria 
(2%); renal failure, abnormal renal function test, and proteinuria (1%); and, very rarely, 
hemorrhagic cystitis and pulmonary toxicity.  
 
2.8.4. Cyclophosphamide  
 
Cyclophosphamide side effects include: nausea/vomiting, cardiomyopathy, skin rash, mucositis, 
stomatitis, sterility, diarrhea, hemorrhagic cystitis, fluid weight gain/edema, alopecia and 
hemolytic anemia. 
 
2.8.5. Total Body Irradiation  
 
TBI can cause: nausea and vomiting, diarrhea, parotitis (rapid onset within 24-48 hours, usually 
self-limited), generalized mild erythema, hyperpigmentation, fever, mucositis, and alopecia. 
 


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Late effects include: possible growth retardation, vertebral deformities, cataracts, probable 
increased risk of secondary malignant neoplasms, sterility, nephropathy, interstitial pneumonitis 
and veno-occlusive disease. 
 
2.8.6. Tacrolimus 
 
Side effects include: reversible renal insufficiency, hypertension, hypomagnesemia, 
hypokalemia, and neurologic toxicity.  A syndrome of thrombotic microangiopathy, comprised 
of microangiopathic hemolytic anemia, thrombocytopenia and renal dysfunction has been 
described in association with sirolimus and tacrolimus use.  In common with all other 
immunosuppressants, it may increase the risk of opportunistic infections and post-transplant 
lymphoproliferative disorders. 
 
2.8.7. Sirolimus 
 
Despite the similarity between sirolimus and tacrolimus, sirolimus is not associated with 
neurotoxicity or nephrotoxicity because of its inability to inhibit calcineurin.  Phase III clinical 
trials have indicated that the primary toxicities are hypertriglyceridemia, hypercholesterolemia, 
mild thrombocytopenia, anemia, leukopenia, hypokalemia, elevated LDH, arthralgia, epistaxis, 
edema, and infections.  Clinically significant elevations in hepatic transaminases without 
sequelae were noted in the prior Phase II study with this drug.   
 
2.8.8. Methotrexate 
 
The most frequently reported adverse reactions associated with methotrexate use as GVHD 
prophylaxis include ulcerative stomatitis, leucopenia and suppressed hematopoiesis, nausea, and 
abdominal distress.  Other frequently reported adverse effects are malaise, undue fatigue, chills 
and fever, dizziness and decreased resistance to infection.  Methotrexate may be associated with 
increased rates of pulmonary complications after transplantation.  The risk of infections is due to 
the suppression of hematopoiesis after transplantation. 
 
2.8.9. Mycophenolate Mofetil (MMF) 
 
The most frequent reported adverse reactions associated with MMF include infection, upset 
stomach and nausea.  Less common reported adverse effects are low blood counts, vomiting and 
diarrhea.  Some rare but serious reported adverse reactions include serious injury to the gut 
including bloody stools and vomit, secondary cancers such as lymphoproliferative disease or 
lymphoma, serious infections of the brain, risks to a baby in pregnancy and progressive 
multifocal leukoencephalopathy (PML). 
 
 


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3-1 
CHAPTER 3 
 
 
3. 
STUDY ENDPOINTS 
 
3.1. 
Primary Endpoints 
 
Patients will be assessed for 100-Day Non-Relapse Mortality. The events for non-relapse 
mortality are death due to any cause other than relapse of the underlying malignancy. 
 
3.2. 
Secondary Endpoints  
 
3.2.1. 100-day Disease Status Following Transplant 
 
Patients will be assessed for disease status at Day 100 post-HCT: complete remission, partial 
remission (HL, NHL), stable disease (HL, NHL), relapse. 
 
3.2.2. Time to Hematopoietic Recovery  
 
Time to neutrophil recovery will be the first of three consecutive days of > 500 neutrophils/μL 
following the expected nadir.  Patients who never nadir will be censored for time to neutrophil 
recovery.  Time to platelet engraftment will be the date platelet count is > 20,000/μL for the first 
of three consecutive labs with no platelet transfusions 7 days prior.  
 
3.2.3. Chimerism  
 
Blood samples will be evaluated for T cell and myeloid chimerism at 4 weeks, Day 100, and 6 
months post-transplant. 
 
3.2.4. Hematologic Function  
 
Hematologic function will be defined by ANC >1500, Hemoglobin >10g/dL without transfusion 
support, and platelets >100,000 and measured at Day 100 and6 months.  Use of growth factors 
will be noted. 
 
3.2.5. Occurrence of Infections  
 
Microbiologically documented infections will be reported by site of disease, date of onset, 
severity, and resolution, if any.   
 
3.2.6. Six Month Overall Survival 
 
Overall survival is defined as time from transplant to death or last follow-up. 
 


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3.2.7. Acute Graft-versus-Host Disease (GVHD) 
 
Acute GVHD will be graded according to the BMT CTN MOP.  The time to onset of acute 
grades II-IV GVHD and grades III-IV GVHD will be recorded, as well as the maximum grade 
experienced. 
 
3.2.8. Chronic Graft-versus-Host Disease (GVHD) 
 
Chronic GVHD will be scored according to the BMT CTN MOP.  The time to onset of limited 
and extensive chronic GVHD will be recorded.   
 
3.2.9. Immunologic Reconstitution  
 
This will be measured in all patients at 8 weeks, 6, 12 and 24 months.  Tests to be performed on 
peripheral blood at those time points include CD2, CD3, CD4, CD8, CD19, CD3+/CD25+, 
CD45 RA/RO, CD56+/CD3-, and quantitative immunoglobulins (IgM, IgG and IgA).  
 
3.2.10. Impact of Therapy on the HIV Reservoir  
 
HIV-1 RNA in plasma will be measured by standard real-time RT-PCR (detection limit 40 
copies/ml) and by the investigational single copy assay (SCA, detection limit 0.38 copy/ml).  
HIV-1 DNA in peripheral blood mononuclear cells (PBMCs) and other cells will be quantified 
using the same primers and probes used for SCA but without a reverse transcription step.  HIV-1 
DNA levels will be normalized by cell number and amplifiable cellular DNA (GAPDH).  Assays 
will be performed in triplicate on each sample.  HIV-1 RNA levels will be measured in plasma 
prior to the initiation of ablative chemotherapy, and at Day 100, 6, 12 and 24 months post-
transplant.  The latent HIV reservoir measurement assay at approximately 13 months will only 
occur in those patients who have no measurable viral load by single copy HIV assay at 12 
months (Appendix C).    
 
Definition of maintenance of ARV: All attempts should be made to maintain the oral ARV 
regimen through the first year after transplantation. Subcutaneous enfuvirtide should be added 
during administration of high-dose cyclophosphamide (due to the risk of nausea and vomiting) 
and other similarly nauseating regimens and during any other periods when oral ARV is not 
tolerated (e.g. mucositis). If participants are unable to take oral ARV but are maintained on 
subcutaneous enfuvirtide alone, this will be considered maintenance of ARV. Failure to maintain 
ARV will be defined as ≥ 24 hours after the next scheduled dose is expected to be received 
without any ARV therapy. 
 
3.3. 
Disease Status Assessment 
 
3.3.1. Lymphoma 
 
Patients at each data collection period are classified into one of the disease statuses specified 
below (CR, PR, SD, PD).  After HCT and until relapse/progression, all disease status 
classifications are relative to the patient’s pre-HCT disease status.  Tests used for evaluation of 


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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.” 
 
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 
clonal lymphocytes by flow cytometry will be considered a CR until data become 
available demonstrating a clear difference in patient outcome. 
 


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TABLE 3.1:  RESPONSE DEFINITIONS – NON-HODGKINS’S LYMPHOMA* 
 
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 
 
 
 
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. 
* Cheson B, Pfistner B, Juweid M, et al. Revised Response Criteria for Malignant Lymphoma. J Clin Oncol 25: 579-586, 1997. 
**   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. 
 


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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. 
 


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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 FDG-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 cm in 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 


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only using CT scans.  However, residual masses should not be assigned CRu status, but 
should be considered partial responses. 
 
3.3.2. Acute Leukemia and Myelodysplastic Syndromes 
 
Assessment after transplantation response will be assessment as follows: 
 
Complete Remission: 
• 
Bone marrow myeloblasts < 5% by morphologic assessment; 
• 
No circulating blasts; 
• 
Neutrophil count  ≥ 1,000/µL; 
• 
Absence of previous cytogenetic or molecular abnormality identified prior to 
transplantation in the bone marrow aspirate.  
 
Disease Relapse for Patients with AML: 
• 
Increase in bone marrow blast to ≥ 5% by morphologic assessment not attributed to other 
causes (e.g., bone marrow regeneration); or if < 5%, reappearance of blasts with the same 
leukemia phenotype as present at diagnosis.  
• 
Reappearance of blasts with aberrant phenotype by flow cytometry. 
• 
Reappearance of leukemic blasts in the peripheral blood. 
• 
Reappearance of previous cytogenetic or molecular marker of disease present prior to 
transplantation.  
• 
The development of extramedullary leukemia or leukemic cells in the cerebral spinal 
fluid. 
 
Disease Relapse for Patients with MDS: 
• 
Satisfying above criteria for evolution into acute leukemia; or, 
• 
Reappearance of pre-transplant morphologic abnormalities, detected in two 
consecutive bone marrow specimens taken at least one month apart; or,  
• 
Reappearance of pre-transplant cytogenetic abnormality in at least one metaphase 
on each of two separate consecutive examinations at least one month apart, 
regardless of the number of metaphases analyzed. 
 
 


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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. An authorized user at the transplant center completes the Segment 0 Screening Form 
(patient demographic data and the date that informed consent was signed).  A study 
number will be generated for the patient with the submission of the Segment 0 Screening 
Form. 
• 
Potential Unrelated Donor Transplant:  Patients requiring an unrelated donor should 
be enrolled in the Segment 0 at least 3 months prior to the proposed start of 
conditioning.  In some cases, patients will not be able to be enrolled at least 3 months 
prior to the proposed start of conditioning.  If this is the case, the patient should be 
enrolled as early as possible but no less than 2 weeks prior to the proposed start of 
conditioning.   
• 
Potential Related Donor Transplant: Patients with an available related donor should 
be enrolled in Segment 0 approximately 8 to 10 weeks (but no less than 2 weeks) 
prior to the proposed start of conditioning.  
Note:  There are two reasons for completing the screening enrollment phase early.  First, 
blood specimens are collected at baseline to address important research questions in this 
study.  Secondly, for patients requiring an unrelated donor, sufficient time is needed for 
the unrelated donor search. 
2. The transplant coordinator at the transplant center should proceed with their institution’s 
standard procedure to identify a sibling donor, if applicable.  If an unrelated donor search 
is to be pursued, then the coordinator should inform the transplant center’s assigned 
NMDP coordinator through the standard procedure for any unrelated donor. 
3. Due to the complex nature of the patient population and the potential for numerous drug-
drug interactions between the antiretroviral regimen and the allogeneic HCT treatment 
regimen, each patient’s treatment regimen must be reviewed with the Treatment Review 
Committee.  Appendix D details the process for getting Treatment Review Committee 
approval.  This review should typically occur at least 4 weeks prior to the planned 
transplant date in order to allow sufficient time for any necessary adjustments to the 
patient’s medication regimen.  In some patients’ circumstances, a 4-week lead time may 
not be possible; this alone will not make the patient ineligible for the study. 
4. Prior to initiation of conditioning therapy (typically 1-2 weeks), an authorized user at the 
transplant center completes Segment A of the Enrollment Form in AdvantageEDC.  


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Segment A includes questions that verify eligibility and captures the proposed start date 
of conditioning. 
 
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 is 24months. 
 
TABLE 4.2.1: FOLLOW-UP SCHEDULE  
 
Study Visit 
Target Day 
(+ 2 Days to Day 100 Post-HCT) 
(+ 28 Days After Day 100 Post-HCT) 
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 
13 month 
395 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 and Coordinating Center’s (DCC) master database or until an exception is granted 


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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 on the Death Form.  If the cause of death is 
unknown at that time, the cause of death field may be left blank.  However, once the cause of 
death is determined, the form must be updated in AdvantageEDC.  In addition, all deaths must be 
reported via the Unexpected Grade 3-5 Adverse Event Forms in AdvantageEDC for this study. 
 
CIBMTR Data Reporting: Centers participating in BMT CTN trials must register pre- and 
post-transplant outcomes on all consecutive hematopoietic stem 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 #0903 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.   
 
Weekly GVHD Monitoring:  GVHD should be monitored in accordance with BMT CTN 
guidelines as specified in the Manual of Procedures.  Patients should be assessed weekly until 
Day 56 post-transplant for GVHD.  After Day 56, patients will be assessed at each follow-up 
visit (Day 100, and 6, 12, and 24 months) for the presence of GVHD.  For scheduling, a target 
day range has been provided in Table 4.2.1. 
 
4.2.2. Adverse Event Reporting 
 
Unexpected, grade 3-5 adverse events (AE) and all deaths 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 4.0 at regular intervals as defined on 
the Form Submission Schedule. 
 
Tables 4.2.2.A and 4.2.2.B summarize patient clinical assessments over the course of the study. 
 
4.2.3. Patient Evaluations prior to the HCT conditioning therapy 
 
The following observations need to be performed within 3 months of initiation of conditioning: 
1. CMV IgG, hepatitis panel (HAV Ab, HBsAb, HBsAg, HBcAb, HCVAb), HSV 1 and 2 
IgG, RPR or VDRL, toxoplasma IgG, VZV IgG, and HTLV1 antibody. 
2. EKG 
3. Creatinine clearance (calculated creatinine clearance is permitted). 


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4. CMV PCR or antigenemia assay. 
5. DLCO, FEV1 and FVC. 
6. HIV-1 RNA level (HIV viral load by standard assay). 
7. CD4 count. 
8. If hepatitis B core and/or hepatitis C antibodies are positive, hepatitis B DNA PCR and/or 
hepatitis C RNA PCR must be checked. 
9. Cardiac ejection fraction by MUGA or echocardiography. 
10. Signed informed consent form. 
 
The following observations need to be performed within 8 weeks prior to initiation of 
conditioning: 
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 patients with 
either non-Hodgkin's lymphoma or acute lymphocytic leukemia is required. 
b. Duration of HIV/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 infection 
prophylaxis.  
2. β-HCG serum pregnancy test for females of childbearing potential. 
3. Blood samples for evaluation of immune reconstitution by flow cytometry (CD2, CD3, 
CD4, CD8, CD19, CD3+/CD25+, CD45RA/RO, and CD56+/CD3-) and quantitative 
immunoglobulins (IgM, IgG, and IgA). 
4. Blood collected for latent virus recovery assay; will be collected for only those patients 
that have documented undetectable plasma HIV-1 by standard assay at the time of 
enrollment (see Appendix C). 
 
The following tests and observations will be performed within 4 weeks prior to initiation of 
conditioning: 
1. For lymphoma patients: CT scans of neck, chest, abdomen and pelvis.  Neck CT only 
required if previous site of disease. PET scan should be performed. 
2. Bone marrow aspiration and biopsy, including cytogenetics 
 
The following tests and observations will be performed within 1-3 weeks prior to initiation of 
conditioning: 
1. Blood for HIV single copy measurements (see Appendix C). 


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2. Optional future research sample collection for consenting patients (see Appendix C). 
 
The following tests and observations will be performed within 1 week prior to initiation of 
conditioning: 
1. Karnofsky/Lansky performance status. 
2. CBC with differential, platelet count, creatinine, bilirubin, LDH, alkaline phosphatase. 
3. ALT, AST, sodium, magnesium, potassium, chloride, and CO2. 
4. Blood for Microbial Translocation Markers collected within 1 week prior to the initiation 
of conditioning and on Day -3 of conditioning (see Appendix C). 
5. Blood for HIV single copy measurement (see Appendix C). 
 
4.2.4. Patient Post-HCT Evaluations 
1. Physical examination and weight weekly until 4 weeks then at 8 weeks, 100 days, 6, 12 
and 24 months post-HCT. 
2. 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, 12 and 24 months post-HCT. 
3. Toxicity assessments at 4 weeks, 8 weeks, Day 100, 6, 12, and 24 months post-HCT. 
4. Evaluation of immune reconstitution by flow cytometry (CD2, CD3, CD4, CD8, CD19, 
CD3+/CD25+, CD45 RA/RO, and CD56+/CD3-) and quantitative immunoglobulins 
(IgM, IgG and IgA) at 8 weeks, 6, 12, and 24 months post-HCT.   
5. CMV PCR or antigenemia assay measured weekly Day 0 through 8 weeks; follow-up at 
Day 100.  
6. HIV-1 RNA level at 100 days, 12 and 24 months (viral load) by standard assay.   
7. Blood for HIV single copy measurement at Day 100, and 6, 12, and 24 months post-HCT 
(see Appendix C). 
8. Blood collected for latent virus recovery assay to be scheduled for only those patients 
where HIV-1 RNA by standard assay and the single copy research assay are negative at 
12 months post-transplant to be done at approximately 13 months post-HCT (see 
Appendix C). 
9. Blood collected for Microbial Translocation Monitoring at Days 7, 14 and 100 (see 
Appendix C). 
10. Blood collected for Immune Reconstitution Studies (Research) at 8 weeks and 6 and 12 
months (see Appendix C). 
11. Acute Graft versus Host Disease assessments weekly Day 0 through 8 weeks; follow-up 
at Day 100.  
12. Chronic Graft versus Host Disease assessments at 100 days, 6, 12, and 24 months. 


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13. Chimerism (T cell and myeloid) will be assessed at 4 weeks, 100 days and 6 months. 
14. Weekly phone calls from the CIBMTR Survey Research Group inquiring about any 
missed doses of ARV or immunosuppressive medications after initial hospital discharge 
from allogeneic marrow transplant until completion of the study, disease relapse, or until 
discontinuation of ARV. 
15. Disease restaging: 
a) Lymphoma 
• CT scan at 100 days, 6 and 12 months post-transplant 
• 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 
• Bone marrow biopsy/aspirate for patients with previously documented marrow 
involvement at Day 100 and 12 months post-transplant 
b) Acute Leukemia or Myelodysplastic Syndromes 
• Bone marrow biopsy/aspirate for pathology and cytogenetics at 100 days and 12 
months post-transplant. 
 


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TABLE 4.2.2A: PRE-HCT EVALUATIONS 
 
Required Studies/Testing 
Prior to Conditioning 
−3 
months 
−8 
weeks 
−4  
weeks 
−1-3 
weeks 
−1  
week 
Day −3 of 
Condition-
ing 
CMV IgG, Hepatitis Panel (HAV Ab, HBsAg, HBcAb, HBsAb, HCV Ab), HSV 
1/2 IgG, Toxoplasma IgG, VZV IgG, Syphilis (RPR or VDRL), HTLV1 antibody 
X 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
DLCO, FEV1, FVC 
X 
 
 
 
 
 
Creatinine Clearance 
X 1 
 
 
 
 
 
CMV PCR or Antigenemia Assay  
X 
 
 
 
 
 
HIV-1 RNA Viral Load, CD4 Count 
X 
 
 
 
 
 
HepB DNA PCR and HepC RNA PCR if HepB and/or HepC Ab are positive, 
respectively 
X 
 
 
 
 
 
Ejection Fraction (MUGA or ECHO) 
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 
 
 
 
 
For lymphoma patients: CT scans of neck, chest, abdomen and pelvis.  Neck CT 
only required if previous site of disease. PET scan should be performed 
 
 
X2 
 
 
 
Lumbar puncture(s) for determination of presence of CNS disease for patients 
with either non-Hodgkin's lymphoma or acute lymphocytic leukemia 
 
X2 
 
 
 
 
Bone Marrow Aspiration and Biopsy, including cytogenetics 
 
 
X 
 
 
 
β –HCG Serum Pregnancy Test for Females of Childbearing Potential 
 
X 
 
 
 
 
Informed Consent  
X 
 
 
 
 
 
Immune Reconstitution Assays (Transplant Center) 
 
X3 
 
 
 
 
Karnofsky/Lansky Performance Score 
 
 
 
 
X 
 
CBC with Differential, Platelet Count, Creatinine, Bilirubin, Alkaline 
Phosphatase, AST, ALT, LDH, Sodium, Magnesium, Potassium, Chloride and 
CO2 
 
 
 
 
X 
 
Blood for Microbial Translocation Monitoring (See Appendix C) 
 
 
 
 
X 
X 
Blood for HIV Single Copy PCR Assessment (See Appendix C) 
 
 
 
X 
X 
 


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Required Studies/Testing 
Prior to Conditioning 
−3 
months 
−8 
weeks 
−4  
weeks 
−1-3 
weeks 
−1  
week 
Day −3 of 
Condition-
ing 
Blood for Latent HIV Reservoir Measurements (See Appendix C) 
 
X4 
 
 
 
 
Optional Future Research Blood Sample 
 
 
 
X 
 
 
 
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 and Acute Lymphoblastic Leukemia 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) for lymphoma patients. 
d. Medication list to include all antiviral, antibiotics and opportunistic prophylaxis.  
3 To include: CD2, CD3, CD4, CD8, CD19, CD3+/CD25+, CD45RA/RO, and CD56+/CD3- and quantitative immunoglobulins (IgM, IgG, and IgA). 
4 Collection of blood for Latent HIV Reservoir testing.  Once the patient is consented and enrolled on the trial, a peripheral blood sample will be collected at approximately 8 
weeks prior to initiation of conditioning for only those patients that have documented undetectable plasma HIV-1 by standard assay upon enrollment (see Appendix C).  
 
 


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TABLE 4.2.2B:  POST-HCT EVALUATIONS 
 
 
Weeks  
Post-HCT 
Months  
Post-HCT 
Study Assessments/ 
Testing 
1 
2 
3 
4 
5 
6 
8 
Day 
100 
6 
12 
13 
24 
CBC1, Physical Exam, and Weight1 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
Immune Reconstitution Assays2 (Transplant Center) 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
HIV-1 RNA Viral Load3 
 
 
 
 
 
 
 
X 
 
X 
 
X 
PET or PET-CT (lymphoma patients) 
 
 
 
 
 
 
 
X4 
X 
 
 
 
CT Scan (lymphoma patients) 
 
 
 
 
 
 
 
X 
X 
X 
 
 
Bone marrow biopsy/aspirate for pathology (acute leukemia, 
MDS patients and lymphoma patients with previously 
documented marrow involvement; include cytogenetics for 
acute leukemia and MDS patients) 
 
 
 
 
 
 
 
X 
 
X 
 
 
Toxicity Assessment 
 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
Chimerism (T cell and myeloid) 
 
 
 
X 
 
 
 
X 
X 
 
 
 
CMV PCR or antigenemia 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Acute GVHD Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Chronic GVHD Assessment 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
CIBMTR Survey Research Group Phone Call 
Weekly after initial hospital discharge from HCT until completion of the study, 
disease relapse, or until discontinuation of ARV 
Blood for Microbial Translocation Monitoring (See Appendix 
C) 
X 
X 
 
 
 
 
 
X 
 
 
 
 
Blood for HIV Single Copy PCR Assessment (See Appendix 
C) 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
Blood for Latent HIV Reservoir Measurements6 (See 
Appendix C) 
 
 
 
 
 
 
 
 
 
 
X 
 


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Weeks  
Post-HCT 
Months  
Post-HCT 
Study Assessments/ 
Testing 
1 
2 
3 
4 
5 
6 
8 
Day 
100 
6 
12 
13 
24 
Blood for Immune Reconstitution Assays (Research) 
 
 
 
 
 
 
X 
 
X 
X 
 
 
Notes for Table 4.2.2B: 
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, 12 and 24 months post-HCT. 
2 Immune reconstitution assays by flow cytometry (CD2, CD3, CD4, CD8, CD19, CD3+/CD25+, CD45 RA/RO, and CD56+/CD3) and quantitative immunoglobulins (IgM, 
IgG and IgA). 
3 HIV-1 viral RNA plasma level (viral load) at 100 days, 12 and 24 months by standard assay.   
4PET or PET-CT performed if the Day 100 Scan results are equivocal at 6 months. 
5 For lymphoma patients, CT scans of neck, chest, abdomen and pelvis.  Neck CT only required if previous site of disease. 
6 Collection of blood sample to be scheduled for only those patients where HIV-1 RNA by standard assay is undetectable at 12 months post-transplant (see Appendix C). 
 


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CHAPTER 5 
 
 
5. 
STATISTICAL CONSIDERATIONS 
 
5.1. 
Study Overview 
 
This study is designed as a Phase II multi-center trial to assess the feasibility and safety of 
allogeneic hematopoietic cell transplantation (HCT) in HIV-infected patients.  The target 
enrollment is 15 patients.   
 
5.1.1. Accrual 
 
Accrual will be across multiple sites and remain open until 15 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 100-day Non-Relapse Mortality (NRM).   
 
5.2. 
Sample Size Calculations and Stopping Guidelines 
 
The sample size is 15 patients for this trial.  Allogeneic transplant for patients with HIV is 
considered unacceptable if 100-day non-relapse mortality probability is 45% or higher.  The 
objective of the study is to show that 100-day NRM is lower than 45%.  In patients without HIV, 
non relapse mortality probability 100 days after allogeneic transplant is expected to be lower 
than 15%.  Therefore, we framed this objective as a hypothesis test of the null hypothesis 
H0:p>=0.45, where p is the 100 day NRM probability, and this study is adequately powered 
against the alternative hypothesis H1:p=0.15.  The stopping rule and study design described in 
detail below has a 8% chance of concluding that allogeneic transplant for patients with HIV has 
less than 45% NRM when in fact the 100 day NRM rate is 45% (type I error), and an 83% 
chance of concluding that the NRM rate is lower than 45% when the 100 day NRM rate is 15% 
(power). 
 
To guard against excessive mortality, non-relapse mortality will be monitored up to 100 days 
post transplant 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. 
 
A truncated Sequential Probability Ratio Test (SPRT) based on a binomial test of proportions for 
non-relapse mortality will be used as described below.  This sequential testing procedure 
conserves type I error across all of the monitoring looks for NRM.  The SPRT can be represented 
graphically.  At each interim analysis, the number of patients enrolled is plotted against the total 


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number of patients who have experienced NRM.  The continuation region of the SPRT is defined 
by two parallel lines.  For a hypothesis test H0:  = 0 versus H1:  = 1 where 0 > 1, if the 
graph falls above the upper boundary, accept H0 and if the graph falls below the lower boundary 
reject H0 and conclude H1.  Only the upper boundary will be used to protect against excessive 
NRM which would make it unlikely that we could conclude that the NRM is less than 45% by 
the end of the study.   
 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting 
H0 when  = 0 and of accepting H0 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 testing H0: p = 45% versus H1: p = 15% NRM, with nominal type I and II 
errors of 7% and 30%, respectively.   
• The slope of the parallel lines for monitoring NRM is 0.283 and the intercepts are –1.53 
and 0.74. 
• Note that the stopping rule shown in Table 5.1 was constructed using the futility 
boundary of this SPRT test.  The futility boundary was used to ensure that the DSMB 
will be notified if it is no longer likely that we will be able to demonstrate that 100-day 
NRM is lower than 45%, thus protecting against excessive NRM.   
 
The futility stopping boundary is shown in Figure 5.1 for the SPRT test. 
 
FIGURE 5.1 SPRT STOPPING BOUNDARY FOR 100-DAY NRM 
 
 
 


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The futility stopping rules are summarized in Table 5.1 for the SPRT test. 
 
TABLE 5.1 STOPPING GUIDELINES FOR 100-DAY NRM  
AMONG PATIENTS ENROLLED 
Number of patients enrolled 
(n) 
SPRT stopping boundary 
(x) 
2-4 
2 
5-7 
3 
8-11 
4 
12-15 
5 
* Stopping guideline is triggered if ≥ x patients out of n patients enrolled experience NRM. 
 
The actual operating characteristics of the truncated test (shown in Table 5.2) were determined in 
a simulation study.  The simulation assumed uniform accrual of 15 patients over a two-year time 
period.   
 
TABLE 5.2 OPERATING CHARACTERISTICS OF SEQUENTIAL TESTING 
PROCEDURE FOR 100-DAY NRM FROM A SIMULATION STUDY  
WITH 10,000 REPLICATIONS 
 
Non-relapse Mortality 
True 100-day rate 
45% 
35% 
25% 
15% 
Probability stop and accept the null hypothesis 
.92 
.75 
.47 
.17 
Probability continue to full recruitment and reject 
the null hypothesis 
0.08 
0.25 
0.53 
0.83 
Mean month stopped 
11.8 
15.6 
20.2 
24.5 
Mean # endpoints 
2.7 
2.9 
2.8 
2.0 
Mean patients with 100 days follow up 
6.0 
8.2 
10.8 
13.4 
 
The SPRT stops and accepts the null hypothesis 92% of the time when the true 100-day NRM is 
45% and 17% of the time when the true 100-day NRM is 15%.  This corresponds to a type I 
error of 8% and type II error of 17%.  When the true 100-day NRM rate is 45%, on average the 
DSMB will be consulted 11.8 months after opening, when 2.7 events have been observed in 6 
patients.   
 
5.3. 
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, donor 
type, donor gender, donor-recipient CMV, HLA matching, graft type, HIV load, CD4 counts, 
and number of prior chemotherapy regimens as treatment of primary malignancy and number of 
prior HIV regimens. 
 


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5.4. 
Analysis Plan 
 
5.4.1. Analysis of the Primary Endpoint 
 
The primary analysis will consist of estimating the 100-day NRM probability along with a 95% 
confidence interval using the cumulative incidence function.   
 
In a secondary analysis, a Cochran-Mantel-Haenszel test will be used to compare 100-day NRM 
probabilities between patients enrolled in this study to matched non-HIV-infected patients from 
the CIBMTR database.  Closely matched controls will be identified at ratio 1:4 using the 
following criteria: age, gender, year of transplant, performance status, interval from diagnosis to 
transplant, diagnosis, disease status, preparative regimen/intensity, GVHD prophylaxis regimen, 
cytogenetics if available for acute leukemias. 
 
5.4.2. Analysis of Secondary Endpoints 
 
Disease Status 
The proportion of patients in complete remission, partial remission, stable disease, and relapse at 
100 days post-transplant will be described. 
 
Time to Hematopoietic Recovery  
Time to neutrophil recovery and platelet engraftment will be described separately in the 
myeloablative and reduced intensity groups, using cumulative incidence function with death 
prior to engraftment as the competing risk. 
 
Chimerism 
Donor T-cell and myeloid chimerism at4 weeks, 100 days, and 6 months will be described 
separately in the myeloablative and reduced intensity groups, according to proportions with 
mixed (5-95% donor cells), full (>95%), or graft rejection (<5%). 
 
Hematologic Function 
The proportions of patients with hematologic function at 100 days and 6 months will be 
described in patients surviving to these time points.   
 
Occurrence 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 two years post-transplant or relapse.  The incidence of 
viral, fungal and bacterial infections will be tabulated for each patient according to Chapter 5 of 
the BMT CTN Technical Manual of Procedures.  
 


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Overall Survival 
The 6-month overall survival probability with 95% confidence interval will be estimated using 
the Kaplan-Meier product limit estimator.  In an additional analysis, a Cochran-Mantel-Haenszel 
test will be used to compare 6-month overall survival probabilities between patients in the study 
to matched controls selected for the secondary analysis of 100-day NRM of Section 5.5.1. 
 
Acute Graft versus Host Disease:  
Cumulative incidence of grade II-IV and III-IV acute GVHD will be estimated at 100 days, 
treating death as a competing risk. 
 
Chronic Graft versus Host Disease:  
Cumulative incidence of chronic GVHD will be estimated at 100 days, 6 and 24 months, treating 
death as a competing risk. 
 
Immunologic Reconstitution  
Immune reconstitution assays on peripheral blood which include CD2, CD3, CD4, CD8, CD19, 
CD3+/CD25+, CD45 RA/RO, CD56+/CD3-, and quantitative immunoglobulins (IgM, IgG and 
IgA) will be measured in all patients prior to the conditioning, at 8 weeks, and 6 and 12 months 
post-transplant.  These will be summarized at each time point using descriptive statistics. 
 
Maintenance of Antiretroviral Therapy 
Maintenance of antiretroviral therapy will be monitored in all patients until time or death or two 
years post HCT whichever occurs first.  Number and proportion of patients maintaining ARV 
will be summarized at 6, 12, and 24 months post-transplant. 
 
Impact of Therapy on HIV-1 Reservoir  
HIV RNA levels will be measured prior to initiation of ablative chemotherapy, and at Day 100, 
12 months, 13 months (for some patients) and 24 months post-transplant.  Standard assay will 
measure HIV RNA levels (viral load) and for patients with no detectable viral RNA using the 
standard assay, a single copy assay will be performed to assess persistent viremia.  The 
proportion of patients with undetectable viral loads at Day 100, and 12 and 24 months will be 
examined and an exact binomial confidence interval will be calculated.  Additionally, change in 
viral loads status between consecutive time points will be described by the proportion of patients 
whose viral loads changed from detectable to undetectable between assessment times. 
 


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A-1 
APPENDIX A 
 
HUMAN SUBJECTS 
 


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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.  Potential risks associated HCT 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 masking of individual names and assignment of a patient 
identifier code.  The identifier code representing the patient’s identity will be kept separately 
from the research file at the center.  The ID code will be transmitted to the BMT CTN Data and 
Coordinating Center upon enrollment. 
 
 
3. 
Participation of Women and Minorities and Other Populations 
 
Women, 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 the incidence of AML, 
ALL, MDS, and Hodgkin and Non-Hodgkin Lymphoma.  Centers will be notified if their rates 
differ significantly from those expected and asked to develop appropriate recruitment strategies. 
 


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APPENDIX B 
 
INFORMED CONSENT AND ASSENT 


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Informed Consent to Participate in Research 
 
 
 
 
 
 
 
 
 
Your Name:  
________________________________ 
 
Study Title:  
Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and 
Myelodysplastic Syndromes in HIV-Infected Individuals 
 
Protocol: 
 
BMT CTN #0903 (AMC 080) 
 
Principal 
Co-Investigator:  
Joseph Alvarnas, M.D. 
City of Hope, Department of Hematology/HCT  
MOB 3001  
1500 E Duarte Road, Duarte, CA 91010  
email: jalvarnas@coh.org 
phone: 626-359-8111 x 60329 
fax: 626-301-8973 
 
Principal 
Co-Investigator:  
Richard Ambinder, MD, PhD 
Johns Hopkins Medical Institutions 
389 Cancer Research Building 1, Rm 389, 1650 Orleans,  
Baltimore, MD 21287 
email: rambind1@jhmi.edu 
phone: 410-955-8839 
fax: 410 -550-960 
 
Transplant Center 
Investigator:  
________________________ 
(Insert contact information for PI at your site) 
 
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).  


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1. Introduction 
We invite you to join this clinical trial, also known as a research study.  We are doing this study 
because we want to find out how well allogeneic marrow transplant (a marrow transplant using 
cells from someone other than the patient) treats specific blood cancers in people with HIV 
(human immunodeficiency virus).  
 
This study will take at least two (2) years and will include 15 participants.  
 
This Consent Form will tell you about the purpose of the study, its possible risks and benefits, 
other options available to you, and your rights as a participant in the study.  
Everyone who takes part in research at [insert facility name] should know that: 
▪ Being in any research study is voluntary. 
▪ You may or may not benefit from being in the study.  Knowledge we gain from this study 
may benefit others. 
▪ If you join the study, you can quit the study at any time.  
▪ If you decide to quit the study, it will not affect your care at [insert name of facility or 
institution]. 
▪ Please ask the study staff questions about anything that you do not understand, or if you 
would like to have more information. 
▪ You can ask questions now or any time during the study. 
▪ Please take the time you need to talk about the study with your doctor, study staff, and 
your family and friends. It is your decision to be in the study. If you decide to join, please 
sign and date the end of the Consent Form. 
 
You and your doctor will discuss other treatment choices if you do not want to participate in this 
study. 
 
2. Background 
The National Institutes of Health (NIH), through the Blood and Marrow Transplant Clinical 
Trials Network (BMT CTN), are providing staff support and money for this research study.  
 
This study will look at the risks and benefits of allogeneic transplant for people with specific 
kinds of blood cancers and HIV infection.   
 


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Blood Cancer and Transplant 
For people with a blood cancer, the main treatment choices include chemotherapy, radiation 
therapy, immunotherapy, and a transplant using cells that can make blood.  The blood-making 
cells are most often collected from bone marrow and the bloodstream.  These cells are called 
hematopoietic cells and transplant using these kinds of cells is called hematopoietic cell 
transplant, or HCT.  These treatments may be used alone or used in combination.  For some 
people with a blood cancer, a HCT transplant may offer the best chance to be free of signs of 
disease for a long time (long-term remission).  
This clinical trial will study how well allogeneic transplant works as a treatment for people who 
have a blood cancer and HIV.  An allogeneic transplant uses blood-making cells from a family 
member or an unrelated donor to remove and replace the abnormal blood cells in the patient.  
An allogeneic transplant is a common treatment for patients with a blood cancer that has either 
returned (relapsed) or does not respond well to other treatments (refractory), or is known to be 
likely to return (high risk).  The blood cancers we will include in this study are: acute myeloid or 
lymphocytic leukemia (AML or ALL), myelodysplastic syndrome (MDS), Hodgkin lymphoma 
and non-Hodgkin lymphoma.  
Conditioning Regimen 
We will use a combination of chemotherapy and in some cases radiation as a treatment to destroy 
cancer cells and help donor cells start to grow in your bone marrow.  Depending on the 
combination used, each treatment (or “conditioning regimen”) can have a different intensity or 
strength.  
▪ High intensity treatment uses a combination of chemotherapy that uses strong or higher 
amounts of drugs and sometimes radiation.  This is also called “myeloablative 
conditioning”. 
▪ Reduced intensity treatment uses a combination of chemotherapy, using less strong or 
lower amounts of drugs and sometimes radiation.  This is also called “reduced intensity 
conditioning”. 
 
Both kinds of treatments are used by blood and marrow transplant doctors around the world and 
are not experimental.  You and your doctor will decide which conditioning regimen intensity is 
the best choice for you.  This study will help us to better understand how to use these treatments 
in people with HIV who have an allogeneic transplant to treat their blood cancer.  
If you volunteer to join this study, the treating physician at the center will assign you to have 
either a high intensity or a reduced intensity treatment before you receive the blood stem cells or 
bone marrow from your donor.  
 


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3. Purpose 
The main purpose of this study is to learn how well allogeneic transplant treats blood cancers in 
people with HIV. We invite you to participate in this study because you have HIV and a blood 
cancer. 
 
4. Right to Ask Questions  
You have the right to ask questions about the study at any time.  If you have questions about 
your rights as a participant or you want to leave the study, please contact:  
[insert contact info] 
 
5. Procedures  
Before you join the study, we will evaluate your general health, medical history, and your current 
medications. 
Study Participation 
Your study participation will last for 2 years after your transplant.  
Follow-up tests for your transplant (described below) will last as long as you need care.  
We would like to keep track of your medical condition for the rest of your life.  We would 
contact you and the doctor who gives your regular medical care by phone or mail once a year.  
Following up with you every year helps us learn about the long-term effects of the study and 
transplant.  Many transplant centers include this type of long-term follow-up as part of their 
regular medical care.  
Before You Start Your Treatment 
You will need to have health evaluations before you start treatment, while you receive your 
treatment, and for several years after you finish your treatment.  These tests are standard care for 
patients with blood cancer and would happen even if you were not part of this study.  It will be up 
to your study doctor to decide what tests you need and when. 
If you decide to join, we will ask you to sign this Consent Form, and you will get a copy of the 
signed form to keep. 
You will have several tests to find out if you can be in the study. The tests include: 
▪ Medical history 
▪ Physical examination, including height and weight 
▪ Blood and urine tests 
▪ Heart function tests, including a MUGA or an electrocardiogram (ECG) 


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▪ Lung (pulmonary) function tests  
▪ Tests to evaluate your blood cancer including a bone marrow biopsy/aspirate  
▪ If you have lymphoma, you will also have PET (positron-emission tomography) and/or 
CT (computed tomography) scans  
▪ 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  
▪ Study Evaluations 
We will evaluate your health at specific points during your participation.  These tests and 
how often they are scheduled are standard care for patients receiving an allogeneic 
transplant and would be done even if you were not part of this study. 
▪ Research Study Evaluations 
Researchers are trying to learn more about HIV and the effect of HCT on HIV.  Much of 
this research is done using blood samples.  As a result, blood samples will be collected 
from you during the study to help researchers learn more about the effect of HCT on your 
HIV.  
− In patients that do not have any detectable HIV using standard tests, 30 mL (about 
6 teaspoons) of blood will be drawn at two times before your HCT and at 100 
days, 6 months, 12 months and 24 months after your HCT. Another 180 mL 
(about 36 teaspoons) of blood will also be drawn before your HCT and 13 months 
after your HCT if necessary. This blood will be used to look closer at any HIV 
that may still be present in your body. 
− In all patients, 10 mL (about 2 teaspoons) of blood will be drawn at two times 
before your HCT and at 1 week, 2 weeks and 100 days after your HCT. Another 
37 mL (about 7 teaspoons) will be drawn at 8 weeks, 6 months and 12 months 
after your HCT. This blood will be used to look at how your immune system is 
responding to the treatment. 
▪ Antiretroviral Therapy 
Your antiretroviral therapy (your HIV therapy) will be reviewed.  An outside review 
committee will look at your therapy and discuss with your doctor the best way to adjust 
your therapy throughout your HCT.  Your doctor may or may not adjust your therapy 
depending on what is best for you.  
 
Taking your anti-HIV and transplant-related medicines is very important and the study 
team would like to understand how you are doing taking your medications regularly and 
on schedule. In order to track that, a study representative will contact you weekly, for up 
to two years, to check in with you and ask if you were able to take your anti-HIV 
medicines and certain medicines used for your transplant. If you have been unable to take 
your medicines for any reason, it is very important to let your transplant team know right 


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away. For safety, a study representative may also contact your study team to let them 
know if you are having trouble taking your anti-HIV or certain transplant medicines.  
 
In order for study staff to contact you if you have moved or changed your contact 
information, it might be necessary to use an internet-based search service to find you.  By 
choosing to participate in the BMT CTN 0903 study, you are giving the NMDP, 
CIBMTR, and/or your transplant center authorization and instruction to use such a 
service to search public and non-public information solely for the purpose of attempting 
to locate you. If you change you move or change your contact information, you should let 
the study staff know. 
▪ Conditioning Regimen (Chemotherapy) 
The conditioning regimen is a combination of chemotherapy and/or radiation given to 
patients before the donor cells are infused.  This treatment allows donor cells to start 
growing (or “engraft”) in your bone marrow.  The conditioning regimen also helps to 
destroy remaining cancer cells that might not be found in tests.  
Several chemotherapy drugs can be used as part of the conditioning treatment.  The 
choice and amount of drugs or radiation determines the treatment intensity (strength).  
Common drug combinations used in allogeneic transplant include:  
1) Busulfan and fludarabine 
2) Fludarabine and melphalan 
3) Radiation and cyclophosphamide (Cytoxan) 
Allogeneic transplantation kills cancer through the conditioning regimen and through the 
immune cells from the donor that might recognize cancer cells and destroy them.  
Conditioning regimens with high intensity are also known as myeloablative conditioning 
regimens.  High intensity treatments work very well to destroy remaining cancer cells 
because they use very high amounts chemotherapy or radiation.  High intensity 
treatments can also have more side effects during and after transplant. 
Using a lower or “reduced” intensity treatment before transplant can have fewer serious 
problems from the chemotherapy drugs.  While the cancer killing effects may also be 
lower, studies show that immune cells given during the transplant can help destroy 
remaining cancer cells.  Allogeneic transplants with reduced intensity conditioning (RIC) 
regimens are often used for people who cannot have high doses of chemotherapy drugs or 
radiation because of their age or other medical problems.  
Your doctor will decide which type of conditioning treatment is the best choice for you, 
depending on the kind of blood cancer you have and your overall health.  The table below 
lists the 4 conditioning regimens that will be used in this study. 
 
 


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TABLE B-1: CONDITIONING REGIMENS 
Reduced Intensity Treatments 
 
High Intensity Treatments 
A 
Fludarabine + Busulfan (Flu/Bu) 
 
C 
Busulfan  + Fludarabine (Bu/Flu) 
B 
Fludarabine + Melphalan (Flu/Mel) 
 
D 
Cyclophosphamide + Total Body 
Irradiation (Cy/TBI) 
 
▪ Reinfusion of Stem Cells (Transplant) 
We will use your intravenous catheter or central line to give you the blood or bone 
marrow stem cells that were collected before your transplant.  The cells will travel to 
your bone marrow where they will start to make healthy, new blood cells after several 
weeks.  
 
6. Alternative Treatments 
Participation in this study is optional.  If you choose not to participate you may still receive an 
allogeneic transplant for treatment of your disease.  It is possible that the treatment and the 
evaluations you would receive could be very similar to what would be if you were enrolled in 
this clinical trial.  
Your study doctor will talk with you about your options.  If you decide not to participate in this 
research study, your medical care will not be affected in any way. 
Your other choices may include: 
▪ Treatment with other drugs, radiation, or a combination of drugs and radiation without a 
transplant.  
▪ An allogeneic hematopoietic cell transplant that is not part of the study, or another type of 
transplant. 
▪ Participation in another clinical trial (if available, check with your doctor). 
▪ No treatment for your blood cancer at this time. 
 
Every treatment option has benefits and risks.  Talk with your doctor about your treatment 
choices before you decide if you will take part in this study. 
 
7. Risks and Discomforts 
You will have side effects while on the study.  Side effects can range from mild to very serious.  
The risks and discomforts in participating in this study will be similar to what you may have with 
a blood or bone marrow cell transplant if you do not participate in this trial.  There are 
differences in side effects from medications based on the strength of your conditioning regimen.  
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intensity regimens.  Other complications from transplants, such as graft-versus-host disease 
(GVHD) and infections happen equally in patients who have either type of regimen.  
Your health care team will give you medicines to help lower side effects such as feeling sick to 
your stomach (nausea).  In some cases, side effects can be long lasting or may never go away.  
A. Side Effects of Allogeneic Transplant  
Short term (days to weeks): During the transplant, you will have a higher risk of infection 
and bleeding from low blood counts.  There is also the risk that your blood counts will 
not recover even though we gave you donated blood stem cells.  This risk is rare, but it 
can happen.  After your transplant, you have a higher risk of infections.  This is because 
the new immune system needs time to learn again how to best fight some infections and 
because you will need to take medicines that lower immunity to reduce the risk of graft-
versus-host disease (GVHD).  See below for more information about GVHD. 
Long term (years): If you have an allogeneic transplant, you will have a higher risk of 
developing cancers that are caused by the chemotherapy given as part of the transplant or 
to treat the blood cancer before your transplant.  These secondary cancers can be of any 
type, including blood cancers such as leukemia.  Your HIV infection also gives you a 
higher risk for some cancers, so the true risk for allogeneic transplant for HIV-associated 
cancers is not yet known. 
B. Risks Related to Medications or Radiation Used in Conditioning Regimens  
All chemotherapy and radiation treatments used as conditioning regimens in this study 
are commonly used in allogeneic hematopoietic cell transplantation.  The side effects 
may vary, based on the dose that is given.  This applies to busulfan, which is used in 
different amounts for myeloablative and reduced intensity regimens.  
 
TABLE B-2 – ADVERSE EVENTS 
 
Likely Side Effects 
(May happen in 20% of 
patients or more) 
Less Likely 
(May happen in less than 
20% of patients) 
Rare 
(May happen in less 
than 2% of patients) 
Busulfan (Bu) 
Abdominal discomfort 
Constipation 
Diarrhea 
Dizziness 
Fluid retention 
Headache 
Heartburn 
Insomnia 
Lack of appetite 
Mouth sores  
Nausea and vomiting 
Running nose 
Skin rashes 
Irregular or no 
Cough 
Hepatic Veno-occlusive 
disease 
High blood pressure 
High magnesium and 
phosphorus levels in the 
blood 
High sugar levels in the 
blood 
Infertility 
Low blood pressure 
Seizures 
Cataracts 
Lung fibrosis 
 


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Likely Side Effects 
(May happen in 20% of 
patients or more) 
Less Likely 
(May happen in less than 
20% of patients) 
Rare 
(May happen in less 
than 2% of patients) 
menstrual cycles 
Tachycardia 
Cyclophosphamide 
(Cy) 
Damage to male (testes) 
and female (ovaries) 
sex glands 
Diarrhea 
Fluid retention 
Hair loss 
Infertility 
Irregular or no 
menstrual cycles 
Loss of appetite  
Nausea, Vomiting 
Suppression of the 
immune system 
Bleeding in the bladder 
Inflammation of the heart 
muscle (heart failure) 
Shortness of breath 
 
Allergic reaction 
Lung fibrosis 
Serious skin rashes 


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Likely Side Effects 
(May happen in 20% of 
patients or more) 
Less Likely 
(May happen in less than 
20% of patients) 
Rare 
(May happen in less 
than 2% of patients) 
Fludarabine (Flu) 
Diarrhea 
Mouth sores  
Nausea and vomiting 
Suppression of the 
immune system 
 
Fever 
Numbness in the 
extremities 
Sleepiness 
Visual changes 
Weakness 
 
Coma 
Cough 
Inflammation of the 
lung 
Interstitial Pneumonia 
Skin rash 
Melphalan (Mel) 
Constipation 
Diarrhea 
Hair loss 
Mucositis 
Nausea and vomiting 
Heart rhythm 
abnormalities 
Hepatitis 
Kidney failure 
Allergic reaction 
Interstitial Pneumonia 
Seizure 
Lung fibrosis 
Total Body 
Irradiation (TBI) 
Fatigue 
Hair loss 
Infertility 
Loss of appetite 
Mouth sores 
Nausea and vomiting 
Cataracts 
Inflammation of the 
parotid glands 
Skin pigmentation 
(reversible) 
Stunted Growth  
Lung fibrosis 
Second cancers 
 
 
C. Risks Related to the Medication Used to Help Prevent Graft-versus-Host Disease 
(GVHD) 
Graft-versus-Host Disease (GVHD) is a medical condition that can become very serious 
and may cause death.  GVHD is a common development after allogeneic stem cell 
transplant.  It happens when the donor cells attack and damage your organ tissues after 
transplant.  GVHD can cause:  
▪ Skin problems including rashes, sores or blisters 
▪ 
Feeling sick to your stomach (nausea)  
▪ 
Throwing up (vomiting)  
▪ 
Abdominal pain 
▪ 
Diarrhea  
▪ Liver damage or jaundice (yellowing of the skin or eyes)   
▪ There are other side effects that may be seen 
▪ GVHD may be bad enough to cause death 
 
The most common forms of GVHD are relatively mild.  Other forms of GVHD can be 
chronic and last well past your transplant date.  GVHD can be very hard to predict.  You 
will be monitored closely for this condition. 
 


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We will give you medications to try and prevent GVHD.  These medications are usually 
started around the time you receive the donor cells and can continue many months after 
the transplant.  These medications do not completely prevent GVHD and more 
medications might be needed if you do develop GVHD.  
 
Your doctor will decide which GVHD prevention treatment you will receive.  This choice 
is not part of this research study and your doctor will decide on the medications based on 
what is routinely used in this institution as part of allogeneic transplants.  Below is a list 
of commonly used medications to prevent GVHD.  Your doctor may choose to use other 
medications than what is listed here. 
 
▪ Tacrolimus:  This medication is used to try to prevent GVHD.  The immediate side 
effects you may experience include nausea (feeling sick to your stomach) or 
vomiting (throwing up) when the medications are given orally.  Other side effects 
you may experience include high blood pressure (hypertension), shaking of the 
hands (tremor), increased hair growth and possibly an effect on mental function.   
 
If you have these effects, they generally go away if your doctor lowers the amount 
of medication you take.  A few patients have had a seizure while on this medication.   
 
Your liver or kidneys might not work as well as they did before.  If this happens, 
your doctor may lower the amount of drug you take or stop giving the drug 
completely.  The effect on kidneys seems to increase when other medications, 
which might cause kidney problems, are given at the same time, especially 
antibiotics.  Occasionally, the kidney damage caused may require the use of an 
artificial kidney machine (hemodialysis).  
Some patients given tacrolimus develop diabetes and must take insulin while taking 
tacrolimus. 
Rarely, patients receiving tacrolimus may develop low platelets and kidney 
problems that require stopping the tacrolimus, which can increase the risk of 
GVHD.  This condition, called TTP/HUS Syndrome, can also be life-threatening. 
It is very important that you do not eat grapefruit or drink grapefruit juice.  
Grapefruit has an ingredient called bergamottin, which can affect some of the 
treatment drugs, including tacrolimus, used in this study.  Common soft drinks 
that have bergamottin are Fresca, Squirt and Sunny Delight. 
▪ Sirolimus:  This medication is used to try to prevent GVHD.  The immediate side 
effects you may experience include fast heart rate, pain during breathing, shortness 
of breath, chest pain, nausea or vomiting.  Other side effects you may experience 
include pale skin, easy bruising, fever, chills, body aches, night sweats, swelling in 
your face, stomach, hands or feet, pain or burning when you urinate, headache or 
skin rash.  If you experience these effects, they generally go away when the dose of 
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Sirolimus may increase your risk of developing lymphoma or other forms of cancer.  
Talk with your doctor about your specific cancer risk. 
Rarely, patients receiving sirolimus may develop low platelets and kidney problems 
that require stopping the sirolimus, which can increase the risk of GVHD.  This 
condition, called TTP/HUS Syndrome, can also be life-threatening. 
It is very important that you do not eat grapefruit or drink grapefruit juice.  
Grapefruit has an ingredient called bergamottin, which can affect some of the 
treatment drugs, including tacrolimus, used in this study.  Common soft drinks 
that have bergamottin are Fresca, Squirt and Sunny Delight. 
▪ 
Mycophenolate Mofetil: MMF is a potent immunosuppressive drug that blocks the 
growth of the immune cells that can cause GVHD.  Side-effects you might 
experience include nausea and vomiting, diarrhea, infection, low blood counts, 
serious injury to your gut (digestive tract) including bloody stools and vomit, 
secondary cancers, such as lymphoproliferative disease or lymphoma, serious 
infections of the brain, risk to an unborn child, or Progressive Multifocal 
Leukoencephalopathy (PML). 
▪ Cyclophosphamide: This is a chemotherapy drug that works by slowing or 
stopping cell growth.  Side-effects you might experience include nausea and 
vomiting, bone marrow suppression, stomach ache, diarrhea, darkening of the skin 
or nails, hair loss (alopecia) or thinning of hair, changes in color and texture of the 
hair, and feeling tired.  Blood in your urine (hemorrhagic cystitis) is a common 
complication.  Although it is used to treat cancer, it may increase your risk of 
developing another kind of cancer, sometimes months to years after treatment. 
 
▪ Methotrexate:  This is also a medication used to try to prevent GVHD.  
Methotrexate causes damage to cells, and therefore can affect many different tissues 
of your body.  It may cause or can worsen the mouth sores or inflammation of the 
mouth which you may have already developed from the procedures and medications 
used to prepare you for the transplant.  Methotrexate may slow down the recovery 
of blood cells after transplantation.  Methotrexate can cause kidney damage.  If your 
kidneys are already damaged for other reasons, it can worsen kidney function. If 
kidney damage does occur, the methotrexate dose may be reduced or the medication 
may not be given at all. 
▪ Tacrolimus and Methotrexate:  These medications interfere with the body’s 
defense system (the immune system).  This may cause you to have more infections 
(especially viral infections and pneumonia) for several months after transplant. 
 


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D. Risks Related to the Transplant Procedure 
The following risks are part of the transplant process and not connected to any one 
medication or the transplanted donor cells. 
− Bleeding: Platelets help your blood to clot.  Your platelets will be low until the new 
bone marrow grows and, as a result, bleeding may occur.  This can be minor 
bleeding, such as nosebleeds or bruising, but more serious, life-threatening bleeding 
in the lungs and brain can occur if the platelet count remains low.  Usually, there is 
success in preventing major bleeding problems with transfusions of platelets.  
However, some patients may not respond well to transfused platelets and may be at 
serious risk for bleeding.  
− Veno-Occlusive Disease (VOD): This can occur as a result of high dose 
chemotherapy, radiation therapy and/or medications used to prevent GVHD.  VOD 
causes severe damage to the liver.  Symptoms include jaundice (yellowing of the skin 
and eyes), weight gain, and extra fluid build-up in the abdominal cavity and other 
parts of the body.  It can often be managed successfully, and completely resolve.  
However, complications can arise that may be fatal. 
− Mouth Sores and Diarrhea: The large doses of chemotherapy and radiation cause 
irritation in the lining of the mouth and intestines.  This can result in painful mouth 
sores and diarrhea.  If you have severe mouth sores you will be given medicine to 
help control the pain.  If your mouth sores are severe you may not be able to eat 
normally until the sores are healed.  Mouth sores get better when the white blood 
count starts to rise, and engraftment occurs. 
− Capillary Leak Syndrome: This may occur as a result of chemotherapy and 
radiation therapy.  The blood vessels may become ‘leaky’ and fluid enters the 
abdominal cavity, lungs, and other tissues.  You may gain water weight and not go to 
the bathroom as often as you normally do.  Capillary leak syndrome can be difficult 
to manage if extra fluid enters the lungs and causes difficulty breathing, and can be 
life-threatening.  You may die if there is continued fluid collection in the lungs.  
− Unexpected Organ Damage and Other Side Effects: It is possible you may 
experience unexpected, life-threatening heart, lung, kidney, or liver damage as a 
result of the transplant.  Occasionally, the high doses of chemotherapy and radiation 
cause severe lung damage that cannot always be treated.  If this happens, you may 
need to use oxygen or even a respirator.  The lung damage may get worse and be life-
threatening.  Rarely, multi-organ failure (such as lung and kidney failure) may occur, 
which is often fatal. 
− Late Effects: You may experience side effects that occur several months to many 
years after your transplant.  You may experience poor function of the thyroid gland, 
requiring you to take thyroid medication.  As a result of radiation, cataracts may 
occur earlier in life compared to a person who had not had a transplant.  If you 
develop cataracts (cloudiness in the eyes) they may require treatment.  It is rare, but 
your kidneys could be affected, causing anemia (low red blood cell count) or high 
blood pressure.  There is also a risk you may develop a second cancer as a result of 


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the chemotherapy, radiation and/or underlying disease.  If secondary cancers occur 
they generally do not occur until 10 to 15 years after the transplant.  The long-term 
effects upon heart, lung, and brain are unknown. 
− Fluid Build-up: You will receive intravenous fluids during the transplant process and 
your body may have trouble eliminating this fluid.  
 
E Additional Side Effects for People with HIV 
Most of the risks in this Consent Form can happen to all patients undergoing transplant, 
but some, such as risk of infection or organ damage, may be different in patients with 
HIV.  There is a risk that a temporary stop to antiretroviral treatment could lead to HIV 
resistance to the medications you are taking.   
Your HIV viral load will be monitored by your doctor and if HIV resistance were to 
develop, alternate antiretroviral therapy may be needed.   
Many of the medications used for HIV will react with important medications to reduce 
the complications of the transplant (HCT).  These reactions may require frequent blood 
checks to make sure the amount of medications in the blood are correct.  It is possible 
those medications interactions will result in complications. 
      F    Enfuvirtide 
Enfuvirtide may be given to you by your doctor if you are unable to take your pills for 
your HIV therapy if your doctor feels it is best for you. The following risks are associated 
with enfuvirtide: 
• Injection site reactions: Almost all people have skin reactions at the site where 
enfuvirtide is injected. Reactions may include:  itching, swelling, redness, pain or 
tenderness, hardened skin, bumps. Most reactions are mild. Occasionally they may be 
severe or rarely associated with infections or collection of thick liquid (abscess) at the 
injection site.  Individuals receiving bone marrow transplant may have more serious 
reactions to enfuvirtide because of low blood platelets.    
• Lung infection (pneumonia). You should contact your healthcare provider right away if 
you have a cough, fever, or trouble breathing.   
• Serious allergic reactions. Symptoms may include: trouble breathing, fever, nausea, 
vomiting, chills, shakes, skin rash, blood in your urine, swelling in your feet, dizziness, 
severe muscle weakness starting in your feet and quickly moving to your upper body 
(Guillain-Barre syndrome). Contact your healthcare provider right away if you get any of 
these allergic reaction symptoms and do not take any more enfuvirtide. Enfuvirtide 
should not be restarted if your doctor thinks that you had an allergic reaction that was 
related to enfuvirtide. 
• Numbness and tingling of the hands and feet 
• Difficulty sleeping 
• Depression, or anxiety  
• Decreased appetite 


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• Sinus infections and other infections in other places, including the skin (herpes), and the 
blood  (sepsis)  
• Swollen glands (lymphadenopathy)  
• Muscle pain  
• Constipation     
 
G Infections 
You will need to take several antibiotics to prevent infection.  You will also be watched 
carefully for any infections while you are being treated for HIV related Leukemia or 
Lymphoma.  Tell your doctors right away if you get a fever, chills, cough or any other 
symptoms that might be a sign of an infection.  Infections may be bad enough to cause 
death. 
H Reproductive Risks 
Risk to the unborn: The treatments in this study have NOT been proven to be safe at any 
stage of pregnancy.  Therefore, if you are pregnant or nursing, you are not eligible for 
this study.  Women who have the potential of becoming pregnant must use some form of 
effective birth control while receiving chemotherapy and GVHD prophylaxis.  Effective 
birth control is defined as the following: 
1) Refraining from all acts of vaginal intercourse (ABSTINENCE) 
2) Consistent use of birth control pills 
3) Injected birth control methods (Depro-Provera, Norplant) 
4) Tubal sterilization or male partner who has undergone a vasectomy 
5) Placement of an IUD (intrauterine device) 
6) Use, with every act of intercourse, of a diaphragm with contraceptive jelly and/or 
condoms with contraceptive foam. 
 
Sterility and future childbearing potential for men and women: Chemotherapy and/or 
irradiation may affect your ability to have children.  Male patients may become sterile 
(unable to produce sperm) and should discuss with their doctor regarding sperm banking 
prior to transplantation.   Female patients who have attained puberty may find that their 
menstrual cycle becomes irregular or stops permanently.  However, this DOES NOT 
MEAN THAT YOU CANNOT BECOME PREGNANT, and you must use some 
effective method of birth control during transplant and afterwards until you are off 
GVHD prophylaxis.  Damage to reproductive tissue may result in infertility (inability to 
have children).  It is not known if the damage could result in birth defects. 
You should discuss risks and options in detail with your doctor before entering this study. 


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I 
Unforeseen Risks 
New risks might appear at any time during the study that are different from the risks 
listed in this Consent Form.  We will promptly tell you of any new information that may 
affect your decision to participate. 
J 
Other Treatments or Medications 
Some medicines react with each other, and it is important that you tell the study doctor or 
staff about any other drugs, treatments, or medicines you are taking.  This includes non-
prescription medications, vitamins and herbal treatments.  
It is also important that you tell the study staff about any changes to these medications 
during your participation in the study. 
For more information about risks and side effects, ask your study doctor. 
 
8. Possible Benefits 
Taking part in this study may or may not make your health better.  The information from this 
study will help doctors learn more about transplant as a treatment for people with a blood cancer 
and HIV.  This information could help future people with HIV who may need a transplant. 
 
9. New Information Available During the Study 
During this research study, the study doctors may learn about new information about the study drug 
or the risks and benefits of the study.  If this happens, they will tell you about the new information.  
The new information may mean that you can no longer participate in the study, or that you may not 
want to continue in the study.  
If this happens, the study doctor will stop your participation in the study and will offer you all 
available care to suit your needs and medical conditions. 
 
10. Privacy, Confidentiality and Use of Information  
Your confidentiality is one of our main concerns.  We will do our best to make sure that the 
personal information in your medical record is kept private.  However, we cannot guarantee total 
privacy.  
We may give out your personal information 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.  
Information about your transplant from your original medical records may be seen or sent to 
national and international transplant registries, including:  
▪ The Center for International Blood and Marrow Transplant Research (CIBMTR) 


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▪ The National Marrow Donor Program (NMDP) 
▪ The Food and Drug Administration (FDA) 
▪ The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood 
Institute (NHLBI) and the National Cancer Institute (NCI) 
▪ Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network 
(BMT CTN)  
▪ Other authorized study organizations.   
 
We will not identify you by name in any publications or reports that come from these organizations 
or groups. 
Information that does not include personally identifiable information about this clinical trial has 
been or will be submitted, at the appropriate and required time, to the government-operated 
clinical trial registry data bank, which contains registration, results, and other information about 
registered clinical trials.   
This data bank can be accessed by you and the general public at www.ClinicalTrials.gov.  
Federal law requires clinical trial information for certain clinical trials to be submitted to the data 
bank. 
 
11. Ending Your Participation 
Being in this study is voluntary.  You can choose to not be in this study, or leave this study at 
any time.  If you choose not to take part or leave this study, your regular medical care will not be 
affected in any way.  This includes standard care for your blood cancer and HIV.  Tell your 
doctor if you are thinking about stopping or decide to stop.  He or she will tell you how to stop 
safely. 
 
The study doctor or the study sponsor may stop the study at any time, and we may ask you to 
leave the study.  We may ask you to leave the study if you do not follow directions or if you 
suffer from side effects of the treatment.  If we ask you to leave the study, the reasons will be 
discussed with you.  Possible reasons to end your participation in this study include: 
▪ You do not meet the study requirements.  
▪ You need a medical treatment not allowed in this study. 
▪ The study doctor decides that it would be harmful to you to stay in the study. 
▪ You are having serious side effects. 
▪ You become pregnant. 
▪ You cannot keep appointments or take study drugs as directed. 
▪ The study is stopped for any reason. 


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If you decide to leave this study after taking the study treatment, or are asked to leave by your 
doctor for medical reason, you will need to come back to the doctor’s office for tests for your 
safety.  Even if you leave the study, the information collected from your participation will be 
included in the study evaluation, unless you specifically ask that it not be included. 
 
 
12. Physical Injury as a Result of Participation  
It is important that you tell your doctor, __________________ [investigator's name(s)] or study 
staff 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.  
In case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form. 
 
13. Compensation or Payment 
You will not be paid for your participation in the research study.  You will not get compensation or 
reimbursement for any extra expenses (travel, meals, etc.) you may have through your participation 
on this trial. 
 
14. Costs and Reimbursements 
Most of the visits for this research study are standard medical care for patients undergoing 
allogeneic transplants and will be billed to your insurance company.  You and/or your health 
plan/insurance company will need to pay for some or all of the costs of standard treatment in this 
study.   
You or your insurance will not be charged for optional blood samples for research on 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. 
 
15. Ethical Review 
The ethical aspects of this research study have been reviewed and approved by [name of IRB]. 


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16. Further Information 
If you need more information about this study, or if you have problems while you are participating 
in this study, you can contact the study doctor or his/her staff.  They can be reached at the telephone 
numbers listed here: 
[Insert name and contact details] 
 
17. Independent Contact 
If you wish to speak to someone not directly involved in the study, or if you have any complaints 
about any aspect of the project, the way it is being conducted or any questions about your rights as a 
research participant, then you may contact:  
[Insert appropriate contact details] 
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).  
 
18. CCR5 Donor Screening 
Human Immunodeficiency Virus (HIV) uses a protein called CCR5 as a way to get inside of 
cells.  A few people are naturally able to block HIV infection because their body does not make 
the CCR5 protein.  As a result, HIV does not have a way to enter their cells and cause an 
infection.  
 
Proteins are in every cell in our body and help keep the blood, skin and other parts of our bodies 
healthy.  Every protein is made by a specific kind of gene.  Every person has 2 copies of the gene 
that makes the CCR5 protein.  One copy is from their mother and the other copy is from their 
father.  Some people have changes to their genes that make the CCR5 protein.  Another word for 
changes to a gene is mutation.  Changes to the CCR5 gene means the body can’t make the CCR5 
protein.  People who have 2 copies of the CCR5 gene mutation are called 
CCR5delta32homozygotes and they are naturally able to block HIV infection. 
 
Very few people in the world have mutations to both copies of their CCR5 gene.  If you are 
Caucasian with a family background from northern Europe, the chance is about 1 out of 100 
people in finding a matched donor with 2 copies of the CCR5 gene mutation.  If you do not have 
a northern European background, the chance is very, very small that you would find a donor who 
has 2 copies of the CCR5 gene mutation.  
 


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In one case, a person with 2 copies of the CCR5 gene mutation donated their blood-making cells 
for a transplant in a patient who had HIV and a blood cancer.  Now the patient does not have any 
signs of HIV and does not need drugs to treat his HIV.  We do not know if this will happen 
again, even if a donor has the CCR5 gene mutation 
 
Besides the possible benefit of blocking HIV infection, some risks may come with a donor who 
has the CCR5 mutations.  Research has shown that people with 2 copies of the CCR5 gene 
mutation may not fight off infections from West Nile virus (WNV) very well.  WNV spreads 
through mosquito bites.  Serious cases of WNV can cause a brain infection. 
 
In addition to doing the standard tests to make sure a donor is a good match for you, we will also 
test possible donors to see if they have the CCR5 gene mutations.  This testing will not slow 
down our search for your donor.  We will let you know if we find a donor and if that donor has 
the CCR5 mutations.  At that point, you and your doctor will need to decide if you want to use a 
donor with or without the CCR5 mutations.  
 
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Blood Samples for Research (optional) 
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 17 mL) blood sample for future research.  If 
you agree, this sample will be obtained pre-transplant.  It 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 
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. 
 


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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.  
 
A new federal law (2009), called the Genetic Information Nondiscrimination Act (GINA), 
generally makes it illegal for health insurance companies, group health plans, and employers of 
15 or more persons to discriminate against you based on your genetic information.  Health 
insurance companies and group health plans may not request your genetic information that we 
get from this research.  This means that they must not use your genetic information when making 
decisions regarding insurability.  Be aware that this new federal law will not protect you against 
genetic discrimination by companies that sell life insurance, disability insurance, or long-term 
care insurance. 
 
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.  
 


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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 and 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 a blood sample may be collected and that my blood and related 
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.  
❑ I do agree to give a blood sample for research. 
❑ I do not agree to give a blood sample for research. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date 
 
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Health Insurance Portability and Accountability Act 1 (HIPAA1) Authorization to use and 
disclose individual health information for research purposes 
 
A. Purpose:   
As a research participant, I authorize the Principal Investigators and the researcher’s staff to 
use and disclose my individual health information for the purpose of conducting the research 
study:  
Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and Myelodysplastic 
Syndromes in HIV-Infected Individuals 
 
B. Individual Health Information to be Used or Disclosed:  
My individual health information that may be used or disclosed to do this research includes:  
▪ Demographic information (for example: date of birth, sex, weight).  
▪ Medical history (for example: diagnosis, complications with prior treatment). 
▪ Findings from physical exams. 
▪ Laboratory test results obtained at the time of work up and after transplant (for example: 
blood tests, biopsy results).  
 
C. Parties Who May Disclose My Individual Health Information:  
The researcher and the researcher’s staff may collect 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: 
 
Principal Investigator and the researcher’s staff 
Dr. Joseph Alvarnas, Co-Principal Investigator  
Dr. Richard Ambinder, Co-Principal Investigator  
 
Study Sponsors  
▪ National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute 
(NCI), both of the National Institutes of Health (NIH),  
▪ Blood and Marrow Transplant Clinical Trials Network (BMT CTN), Data and 
Coordinating Center 
 
1 HIPAA is the Health Insurance Portability and Accountability Act of 1996, a federal law related to privacy of health 
information 


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▪ 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. 
 
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 treatment related to research that is 
provided through the study.   
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 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. 
 
 
 


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I have read and understood this Consent Form.  The nature and purpose of the research study has 
been explained to me. 
▪ I have had the chance to ask questions, and understand the answers I have been given.  I 
understand that I may ask questions at any time during the study. 
▪ I freely agree to be a participant in the study. 
▪ I understand that I may not directly benefit from taking part in the study. 
▪ I understand that, while information gained during the study may be published, I will not 
be identified and my personal results will stay confidential. 
▪ I have had the chance to discuss my participation in this research study with a family 
member or friend. 
▪ I understand that I can leave this study at any time, and doing so will not affect my 
current care or prevent me from receiving future treatment. 
▪ I understand that I will be given a copy of this signed consent form. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant Name 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
Date 
 
 
I certify that I have provided a verbal explanation of the details of the research study, including 
the procedures and risks.  I believe the participant has understood the information provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Counseling Physician 
 
 
 
Date 
 
 
 
 
 
 
 
 
                                                                
Signature of Counseling Physician 
 
    
 
Date 


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Pediatric Assent to Participate in Research 
 
Study Title: 
Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and 
Myelodysplastic Syndromes in HIV-Infected Individuals 
 
Protocol: 
BMT CTN 0903 (AMC 080) 
 
A. Why am I here? 
We are inviting you to join our study because you have HIV (human immunodeficiency 
virus) and you need a transplant to treat your blood cancer. 
 
B. Why are you doing this study? 
We are doing this study because we want to learn how well hematopoietic cell transplant 
treats blood cancers in people like you who have HIV.  The kind of transplant we would do 
for you would use blood or bone marrow from another person who matches you.  This is 
called an allogeneic transplant. 
 
This form gives you information to help you decide if you want to be in this study.  You 
should read this form and ask any questions you have before agreeing to be in the study.  It is 
up to you to decide if you want to be in the study.   
 
C. What will happen to me? 
Before enrolling on study: 
Your doctor will check to see if you have a type matched donor for your transplant.  You will 
have several tests to see if it is okay for you to be on this study.  
 
Before the transplant: 
You will have several tests done to check your organ function.  These tests will check your 
heart, lungs, and brain.  Most of these tests are X-rays or scans, questions, or blood tests.  
The doctors will look at the results of all these tests to make sure that it is okay for you to 
have a transplant.   
 
You will also need to have several tests for research.  We will ask if we can take some blood 
from you up to 4 times (10-47 mL or about 2-13 teaspoons) with a very small needle.  Eight 
weeks before your transplant, we will also ask to take more blood from you (about 36 
teaspoons) only if the HIV in your body does not show up in a standard test.  
 
Preparation for the transplant: 
Before the transplant, you will need to receive medicines so that your body can accept the 
new bone marrow cells.  This is called a ‘conditioning regimen.’   
 


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You will receive chemotherapy medicine before your transplant.  Chemotherapy is a 
combination of strong drugs that work to destroy your cancer cells and get your body ready 
for transplant.  
 
Post-transplant follow-up and care:  
After the transplant you will continue to get medicines to help the donor cells grow.  These 
drugs will also help lower the chance of getting graft-versus-host disease (GVHD).  GVHD 
is a complication that happens when the donor’s cells attack your body.  You will receive one 
or more medicines to prevent GVHD.  You will continue to receive these drugs for at least 
six months after the transplant.  
 
You will be in the hospital for about four weeks after your transplant.  You will be allowed to 
go home from the hospital when your doctor feels it is safe.  After you go home you will 
need to return to visit your doctors so they can check your recovery.  Your doctors will need 
to check your blood and bone marrow after the transplant to make sure the new blood cells 
are growing in your body.  Your doctors will also do blood tests and other tests to make sure 
your organs are working well. The study team will also check in with you weekly to see if 
you missed any HIV medicines or certain medicines used as part of the transplant. 
 
This study will last for 2 years and we will watch you carefully for side effects, fevers, 
infections and other problems.  
 
You will also need to have several tests for research.  We will take some blood from you up 
to 7 times (about 2-14 teaspoons each time) with a very small needle.  Also, 13 months after 
your transplant, we will ask to take more blood from you (about 36 teaspoons) only if the 
HIV in your body still does not show up in a standard test.  
 
Optional Test for Future Research 
Between 1 and 3 weeks prior to your transplant, we will ask your permission to take some 
more blood (about 6 teaspoons of blood) from you to use for future research.  
 
You don't have to be in this research.  If you don't want to give blood samples for future 
research you can still be in the other parts of the study.  Your care will not be changed if 
you decide not to give these blood samples for research purposes.  Please mark your choice 
below (check only one box): 
 
❑ I do agree to give a blood sample for research.  
❑ I do not agree to give a blood sample for research. 
 
 
 


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D. Will it hurt? 
When you have your blood 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. 
 
E. What are the risks of being in this study?  
 
The drugs may cause a skin rash, hair loss, nausea and vomiting, diarrhea and infections.  
Your blood counts will fall and you may get fevers, infections or start bleeding.  You may 
also get mouth sores.  These are temporary and you will feel better as your new bone marrow 
grows.   
 
Since you will not be able to fight infections while your new bone marrow is growing back, 
you may need to get antibiotics.  You may also need to get blood transfusions since your new 
bone marrow will not be making new blood cells right away.   
 
Even with medicines to prevent it, you may get GVHD.  This can cause skin rash, vomiting, 
diarrhea, stomach pain, lung and liver problems, swelling of the hands and feet, dry eyes, 
stiff joints, and tiredness.  These problems are usually mild but can become very serious and 
prolonged.  Medicines are given to prevent GVHD during and after transplant.  If GVHD 
occurs even after taking these medicines, other medicines will need to be started and hospital 
stays may be necessary.  The medicines used to treat GVHD also have side effects.  They can 
cause tiredness, depression, sleep problems and mood swings.  They can also make you get 
severe infections very easily.  Your doctors will do their best to make you feel better and 
keep you safe.  Often this may require many hospital stays.  However, it is important to 
understand that there is a small risk (about a 1 in 10 chance) that you may die as a result of 
one or more of the complications of unrelated donor transplantation.   
 
F. Will the study help me? 
You may or may not benefit from taking part in this study. 
 
G. What if I have questions? 
You can ask us 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. 
 
H. Do I have to be in this study? 
It is up to you if you want to participate in this research study.  If you don’t want to be in the 
study, you can tell us and your parent or guardian.  Your doctor will not be upset or angry if 
you don’t want to join.  You can say yes now and change your mind at any time.  If you 


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leave the study you can still get medical care from your doctor and transplant center.  You 
will be told about new information or changes in the study that may affect your health or 
your willingness to continue in the study. 
 
I. Can the doctor who is the Principal Investigator withdraw me from this study?   
You can be taken off the study (with or without your consent) for any of the following 
reasons: 
• You need a medical treatment not allowed in this study 
• The investigator decides that continuing in the study would be harmful to you 
• You become pregnant and the study participation could be harmful to the fetus 
• The study is cancelled by the Food and Drug Administration (FDA) or the National 
Institutes of Health (NIH) 
 
J. Will my medical information be kept private?   
 
We will do our best to make sure that the personal information in your medical record 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.  
 
You will receive a copy of this form.  If you need more information about this study, ask the 
study doctor. 
 
************************************************* 
Minor’s Assent 
 
I have read the information in this consent form and have had the study explained to me.  My 
questions have been answered to my satisfaction.  I agree to participate in the study. 
 
 
______________________________________________ 
_____________ 
Signature of Minor 
 
 
 
 
 
Date 
 
 
___________________________________________ 
_____________ 
Print Name of Minor Age of Minor 
 
 
Certification of Counseling Healthcare Professional 
I certify that the nature and purpose, the potential benefits, and possible risks associated with 
participation in this study have been explained to the above individual and that any questions 
about this information have been answered. 
 


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______________________________________________ 
_____________ 
Counseling Healthcare Professional  
 
 
Date 
 
 


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APPENDIX C 
 
LABORATORY PROCEDURES 


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APPENDIX C 
 
LABORATORY PROCEDURES 
 
 
1. MICROBIAL TRANSLOCATION MARKERS: 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 that 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 allogeneic stem cell transplant.  Microbial translocation marker 
levels will then be correlated with clinical outcome (hyperbilirubinemia, development of 
VOD, death) as patients are followed longitudinally. 


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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 the conditioning regimen. 
 
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). 
 


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2. HIV SINGLE COPY PCR ASSESSMENT AND LATENT HIV RESERVOIR 
MEASUREMENTS: CHARACTERIZATION OF HIV INFECTION IN AIDS 
RELATED MALIGNANCIES 
 
Background and Rationale 
The effect of marrow ablative and reduced intensity chemotherapy on the HIV reservoir is 
not known, but the model of AIDS-related malignancies 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 treatment of hematological 
malignancies and Myelodysplastic syndromes, 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 AIDS-related malignancies using dose-intense or cytotoxic 
reduced-intensity 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 such conditioning therapies with allogeneic 
hematopoietic stem cell transplant—although the approach has been used multi-institutional 
studies of antiretroviral therapies. 
 
HIV Cellular Reservoir Analysis & Single-Copy HIV Assays  
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.  Pre-transplant 
conditioning therapies 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. 
 
Sample Requirements   
 
Latent HIV Cellular Reservoir Analysis 
 
Pre-transplant  
Once the patient is consented and enrolled on the trial, a peripheral blood sample will be 
collected at approximately 8 weeks prior to initiation of ablative therapy for only those 
patients that have documented undetectable plasma HIV-1 by standard assay.  A 180 mL 
peripheral blood sample will be collected and placed in to eighteen (18) 10 mL EDTA 
containing, lavender-top Vacutainer tubes. 
 


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Post-transplant 
A peripheral blood collection will be scheduled sometime after 12 months post-transplant, 
typically at 13 months post-HCT, for only those patients that are found to have undetectable 
plasma HIV-1 RNA by the standard assay performed at the clinical site on the 12 months 
sample.  A 180 mL peripheral blood sample will be collected and placed in to eighteen (18) 
10 mL EDTA containing, lavender-top Vacutainer tubes. 
Sample 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. 
 
Single-Copy HIV Assays (Plasma & PBMC) 
Pre-transplant  
A 30 mL peripheral blood sample will be collected in EDTA containing Vacutainer tubes 1-3 
weeks and 1 week prior to initiation of ablative therapy. 
Post-transplant 
A 30 mL peripheral blood sample will be collected in EDTA containing Vacutainer tubes on 
Day 100, and at 6, 12, and 24 months post-transplant. 
 
Sample Processing and Shipment 
Transplant centers will ship whole blood tubes by priority overnight FedEx on the day of 
collection to the BMT CTN 0903-specific Central Processing Laboratory for sample plasma 
and PBMC aliquot processing and temporary sample storage.  Available sample aliquots will 
be periodically shipped to the designated project laboratory for testing. 
 
 
3. IMMUNE RECONSTITUTION ASSAYS (RESEARCH): IMMUNOPHENOTYPIC 
AND FUNCTIONAL CHARACTERIZATION OF IMMUNE RECONSITUTION  
 
Background and Rationale: 
Little is known about immune reconstitution following allogeneic hematopoietic 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 hematopoietic 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.  
 


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Hypothesis: 
We hypothesize that quantitative and qualitative differences in adaptive and innate immune 
reconstitution will correlate with clinical outcome in HIV+ patients who undergo allogeneic 
hematopoietic 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 multi 
time point study has been performed to evaluate reconstitution of adaptive immunity in HIV+ 
patients treated with peripheral blood hematopoietic 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 
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 


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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).  
 
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 


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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.  
 
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 
responsiveness 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, such as: chronic viral 
infection/reactivation (EBV, CMV, HIV).  
 
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 tube 8 weeks, and 6 and 12 months post-transplant. 
 
Sample 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.   
 


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4. 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 17 mL peripheral blood sample will be collected in two 8.5 mL-fill Vacutainer blood tubes 
(yellow) containing ACD solution A 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 Aids Cancer Research Specimen Repository (ACSR) Repository for sample 
aliquot processing and sample storage. 
 
 


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TABLE C-1: 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 prior to 
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 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 0903 Laboratory Sample Guide. 
Characterization 
of HIV Infection 
and Latent HIV 
Reservoirs 
HIV  
Single-Copy PCR 
(Plasma & PBMC)  
30 mL peripheral 
blood sample 
collected in three 
10 mL EDTA 
containing, 
lavender-top 
Vacutainer tubes. 
Gently mix blood with EDTA by inverting 
the tubes 8-10 times. Store at room 
temperature while preparing to ship to 
central sample processing laboratory. 
Pre-transplant 
Within 1-3 weeks prior to 
initiation of conditioning  
Within 1 week prior to 
initiation of conditioning   
Post-transplant 
Day 100, and 6, 12 and 
24 months 
Peripheral blood tubes will be shipped at ambient 
temperature on the day of collection, to the BMT 
CTN 0903-specific Central Processing Laboratory 
by priority overnight FED EX delivery for plasma 
and PBMC processing, temporary storage and 
batched distribution directly to the project 
laboratory for testing. 


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RESEARCH 
TOPIC 
RESEARCH 
SAMPLE 
TYPE OF  
SAMPLE 
SAMPLE COLLECTION, 
PROCESSING AND STORAGE 
REQUIREMENTS 
SAMPLE 
COLLECTION TIME 
POINTS 
SHIPPING SPECIFICATIONS 
Characterization 
of HIV Infection 
and Latent HIV 
Reservoirs 
Latent HIV Reservoir 
Measurements 
180 mL peripheral 
blood sample 
collected in  
18-10 mL EDTA 
containing, 
lavender-top 
Vacutainer tubes. 
Gently mix blood with the EDTA 
anticoagulant by inverting the tube 8-10 
times. Store at room temperature while 
preparing to ship to project laboratory. 
Pre-transplant 
Once the patient is 
consented and enrolled on 
the trial, sample will be 
collected at 
approximately 8 weeks 
prior to initiation of 
ablative therapy for only 
those patients that have 
documented undetectable 
plasma HIV-1 by 
standard assay. 
Post-transplant 
Will be scheduled 
sometime at 13 months 
post-transplant, for only 
those patients that are 
found to have 
undetectable plasma HIV-
1 RNA by the standard 
assay performed at the 
clinical site on the 12 
month sample. 
Peripheral blood tubes will be shipped at ambient 
temperature on the day of collection, to the 
Project Laboratory 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 0903 Laboratory Sample Guide. 
Immune 
Reconstitution 
Studies 
T/NK 
Immunophenotyping, 
Innate Immune 
Function, Adaptive 
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 
Vacutainer tube 
(lavender) 
containing EDTA. 
Gently mix blood with the ACD 
anticoagulant by inverting the tube 8-10 
times. Store at room temperature while 
preparing to ship to project laboratory  
Post-transplant 
8 weeks, and 6 and 12 
months post-transplant 
Peripheral blood tubes will be shipped at ambient 
temperature on the day of collection, to the 
Project Laboratory 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 0903 Laboratory Sample Guide. 


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RESEARCH 
TOPIC 
RESEARCH 
SAMPLE 
TYPE OF  
SAMPLE 
SAMPLE COLLECTION, 
PROCESSING AND STORAGE 
REQUIREMENTS 
SAMPLE 
COLLECTION TIME 
POINTS 
SHIPPING SPECIFICATIONS 
(Optional) 
Investigational 
Future Research 
Sample 
Undefined Future 
Research 
17 mL peripheral 
blood sample 
collected in  
2-8.5 mL ACD 
containing, yellow-
top Vacutainer 
tubes. 
Gently mix blood with ACD by inverting 
the tube 8-10 times. Store at room 
temperature while preparing to ship to the 
ACSR Sample Repository. 
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 0903 Laboratory 
Sample Guide. 


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APPENDIX D 
 
TREATMENT REVIEW COMMITTEE 


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APPENDIX D 
 
TREATMENT REVIEW COMMITTEE 
 
 
The treating institution will review patients with the Treatment Review Committee prior to the 
initiation of transplant therapy by a five member review panel composed of experts in HIV drug 
resistance, 
HIV 
care, 
pharmacology, 
transplant 
infectious 
diseases 
and 
oncology.  
Recommendations for transplant are based on data contained in the patient registration and pre-
transplant forms, as well as in supporting documentation, which includes the following: 
− Current Diagnosis 
− Past Medical History 
− Prior ARV History 
− Documented ARV Drug Toxicities 
− Drug Allergies 
− History of HLA B57 Antigen Testing, if available 
− Current Creatinine and Liver Function Tests 
− Past and Recent HIV Drug Resistance Test Results, if applicable 
− Current ARV Drug Regimen 
− Current Concomitant Medications 
 
The Committee will review available past and current HIV-1 genotype results for patients with 
detectable viremia so as to exclude patients with multi-drug resistant HIV-1 who are unlikely to 
achieve viral suppression on alternate antiretroviral therapy.  The Committee will also advise 
with regard to various drug interactions anticipated during the course of transplantation.  The 
Treatment Review Committee will include well-qualified investigators from the University of 
Pittsburgh and Johns Hopkins University and other institutions as appropriate.  Review materials 
will be sent to the panel four weeks prior to initiation of transplant therapy to allow sufficient 
time for implementation of recommendations for the antiretroviral regimen. 
 


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APPENDIX E 
 
SUGGESTED PROPHYLAXIS


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E-2 
APPENDIX E 
 
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. Pneumocystis 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; and, 5) Aerosolized or IV 
pentamidine monthly, or per institutional standard. 
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.  
Since all medications for toxoplasmosis prophylaxis are oral, and some patients may be 
unable to take po medications in the peri-transplant period, PCR for toxoplasmosis should 
be checked at least weekly whenever prophylaxis must be held in toxoplasma IgG 
positive patients for more than a week and the CD4 count is less than 100. 
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.  (See Appendix F for detailed interactions with antiretroviral medications.) 
5. HSV/VZV:  One of the following regimens should be used for 12 months after HCT, or 
per institutional standard, unless the patient remains on immunosuppressive 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. Hepatitis: 
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. Lamivudine 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.  


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c. Patients should be maintained on anti-Hepatitis B treatment throughout 
chemotherapy, 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. 
e. Liver biopsy must be performed 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.  
 


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F-1 
APPENDIX F 
 
PHARMACOKINETIC DRUG-DRUG INTERACTIONS WITH 
ANTIRETROVIRAL MEDICATIONS 
 


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APPENDIX F 
 
PHARMACOKINETIC DRUG-DRUG INTERACTIONS WITH ANTIRETROVIRAL 
MEDICATIONS 
 
 
Preferred Antiretroviral Regimens for Patients Undergoing Allogeneic Hematopoietic Cell 
Transplant 
 
Tier 1: Raltegravir (INSTI) based therapy (no interruption of therapy is required) 
 
Tier 2: NNRTI based therapy (interruption of therapy may be required, see Table F-1) 
 
Tier 3: Boosted-PI based therapy (interruption of therapy may be required, see Table F-
1) 
 
Summary of Antiretroviral Agents and Drug-Drug Interactions 
 
1. Protease Inhibitors [PI] (amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, 
lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir) 
a. Dosing 
i. All protease inhibitors (except nelfinavir) are typically given in 
combination with ritonavir to reach optimal pharmacokinetic targets 
b. Toxicity 
i. All protease inhibitors can cause gastrointestinal intolerance, 
hyperglycemia, lipohypertrophy, osteonecrosis, hepatotoxicity and 
hyperlipidemia. 
c. Metabolism 
i. Protease inhibitors are metabolized hepatically via cytochrome P450 co-
enzymes, especially CYP3A4 
d. Drug Interactions 
i. When given in combination with ritonavir, all protease inhibitors are 
potent CYP3A4 inhibitors 
ii. Ritonavir 
1. Substrate for CYP1A2 (minor), 2B6 (minor), 2D6 (major), 3A4 
(major) 
2. Inhibits CYP 2C8 (strong), 2C9 (weak), 2C19 (weak), 2D6 
(strong), 2E1 (weak), 3A4 (strong) 
3. Induces CYP1A2 (weak), 2C8 (weak), 2C9 (weak), 3A4 (weak) 
 
2. Non-Nucleoside Reverse Transcriptase Inhibitors [NNRTI] (delavirdine, efavirenz, 
nevirapine, etravirine) 
a. Dosing 
i. Efavirenz is the preferred agent in this class, nevirapine should be used 
with caution due to toxicity 


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b. Toxicity 
i. Class adverse effects include, rash, hepatotoxicity and gastrointestinal 
intolerance 
c. Metabolism 
i. NNRTIs are metabolized hepatically via cytochrome P450 co-enzymes 
d. Drug Interactions 
i. All NNRTIs induce CYP3A4 (etravirine > efavirenz > nevirapine) 
ii. Efavirenz 
1. Substrate for CYP3A4 (major), 2B6 (major) 
2. Inhibits CYP2C9 (moderate), 2C19 (moderate), 3A4 (moderate) 
3. Induces CYP2B6 (weak), 3A4 (strong) 
 
3. Nucleoside Reverse Transcriptase Inhibitors [NRTI] (abacavir, didanosine, emtricitabine, 
lamivudine, stavudine, tenofovir, zidovudine) 
a. Dosing 
i. Zidovudine (AZT) should not be used in patients receiving  hematopoietic 
cell transplantation 
b. Toxicity 
i. Adverse effects of the class include lactic acidosis, peripheral neuropathy 
and hepatic steatosis 
c. Metabolism 
i. Not extensively metabolized, eliminated renally (except abacavir) 
d. Drug Interactions 
i. None of the NRTIs are metabolized via CYP450 co-enzymes 
ii. Avoid additive toxicities 
 
4. Other Agents 
a. Raltegravir (INSTI): Preferred agent due to excellent tolerability and lack of drug-
drug interactions 
b. Maraviroc: Substrate of CYP3A4, but does not induce or inhibit the metabolism 
of other agents 
c. Enfuvirtide: No clinically relevant drug interactions, reserved for salvage therapy 
only 
 
 


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TABLE F-1: SUMMARY OF ANTIRETROVIRAL DRUG-DRUG INTERACTIONS BASED  
ON CONDITIONING REGIMEN TO BE USED 
 
Conditioning 
Regimen 
Metabolism 
(Primary Site) 
Interaction Potential* 
(Predicted Effect) 
Recommendation/Evidence 
Flu/Bu  
• 
Fludarabine 
• 
Busulfan 
Fludarabine (Liver):  
• Rapid 
dephosphorylation to 2-
fluoro-ara-A, then 
phosphorylated to 2-
fluoro-ara-ATP 
intracellularly 
 
Busulfan (Liver): 
• Metabolized hepatically; 
substrate of CYP3A4 
High 
 
Concomitant administration of ritonavir-
boosted PIs may increase the levels of 
busulfan. 
 
NNRTIs may decrease levels of busulfan. 
 
 
 
Strength of evidence: LOW 
Raltegravir-Based: May continue HAART as tolerated 
 
NNRTI-Based: May continue HAART as tolerated 
 
PI-Based: Regimens including ritonavir should be 
discontinued a minimum of 48 hours prior to the 
administration of myeloablative regimens containing busulfan 
 
Antiretroviral therapy should not be resumed until, at least, 48 
hours after the last dose of busulfan and once the patient is 
able to consistently tolerate oral medications 
 
RIC with Flu/Bu has been given to one patient who was 
concomitantly receiving unboosted atazanavir and two 
patients receiving efavirenz (1) 
 
Flu/TBI was given successfully with concomitant efavirenz-
based HAART in two patients (2) 
Flu/Mel  
• 
Fludarabine 
• 
Melphalan 
Fludarabine (Liver):  
• Rapid 
dephosphorylation to 2-
fluoro-ara-A, then 
phosphorylated to 2-
fluoro-ara-ATP 
intracellularly 
 
Melphalan (Blood): 
• Chemical hydrolysis in 
the plasma to inactive 
metabolites 
 
Low 
 
The effects of ritonavir-boosted PIs on 
levels of fludarabine are unknown. 
 
Efavirenz has been given in combination 
with fludarabine. 
 
 
Strength of evidence: MODERATE 
 
Raltegravir-Based: May continue HAART as tolerated 
 
NNRTI-Based: May continue HAART as tolerated 
 
PI-Based: The potential for interactions with ritonavir-
boosted PIs or NNRTIs is low.  Antiretroviral therapy should 
only be continued if the benefits clearly outweigh the risks. 
 
Flu/Mel has been given successfully as a reduced-intensity 
conditioning regimen in a patient on lopinavir/ritonavir, 
tenofovir, and lamivudine (3) 
 
Flu/TBI was given successfully with concomitant efavirenz-
based HAART in two patients (2) 
 


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Conditioning 
Regimen 
Metabolism 
(Primary Site) 
Interaction Potential* 
(Predicted Effect) 
Recommendation/Evidence 
Cy/TBI 
• 
Cyclophospha
mide 
• 
Total Body 
Irradiation 
 
Cyclophosphamide 
(Liver):  
• Prodrug is converted by 
hepatic microsomal 
enzymes to the active 
form. The activation 
pathway involves 
CYP2B6, CYP2C9 and 
CYP3A4 isoenzymes. 
• Substrate for CYP2A6 
(minor), 2B6 (major), 
2C8/9 (minor), 2C19 
(minor), 3A4 (major) 
• Inhibits CYP3A4 
(weak) 
• Induces CYP2B6 
(weak), 2C8/9 (weak) 
• Active metabolites 
include acrolein 
High 
 
Concomitant administration of ritonavir 
may increase the levels of busulfan. 
 
 
Complex interactions exist between 
ritonavir and cyclophosphamide or 
acrolein. Cyclophosphamide levels may be 
increased when combined with protease 
inhibitors, but the active metabolites may 
be decreased. 
 
NNRTIs may increase levels of acrolein 
through CYP induction.  Other CYP 
inducers like phenytoin have been shown 
to increase the AUC of active metabolites 
by 50%. 
 
 
Strength of evidence: LOW 
Raltegravir-Based: May continue HAART as tolerated 
 
NNRTI-Based: Regimens including NNRTIs should be used 
with caution and frequent monitoring due to the increase in 
toxic metabolites caused by CYP450 induction 
 
PI-Based: Regimens including ritonavir should be 
discontinued a minimum of 48 hours prior to the 
administration of myeloablative regimens containing 
cyclophosphamide. 
 
Antiretroviral therapy should not be resumed until, at least, 72 
hours after the last dose of cyclophosphamide and once the 
patient is able to consistently tolerate oral medications. 
 
 
*Combinations have not been studied and the interaction potential has been predicted based on the metabolic pathways of each agent. 
RIC = Reduced intensity conditioning


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-6 
TABLE F-2: EXPERIENCE WITH DRUG-DRUG INTERACTIONS IN PATIENTS RECEIVING  
AUTOLOGOUS STEM-CELL TRANSPLANTATION 
 
Study 
Conditioning Regimen 
Antiretroviral 
Regimen 
Interactions/Toxicity 
Krishnan (6) 
 
ASCT, n=20 
BCNU, VP-16, Cy (n=17) 
 
or 
 
TBI, VP-16, Cy (n=3) 
*PI-based (n=15) 
 
NNRTI-based (n=5) 
• Only 9/20 patients tolerated ARV throughout transplantation 
• 19/20 had abnormal LFTs 
• ARV resumed by 2 months after ASCT in most 
• 10/17 survivors required a change in ARV due to virologic failure 
• One patient died of regimen-related toxicity at Day +22 
Spitzer (7) 
 
ASCT, n=20 
Dose-reduced Bu, Cy 
Bu: 14 mg/kg (PO) or 11.2 
mg/kg (IV) 
Cy: 120 mg/kg 
*PI-based (n=20) 
(Ritonavir and AZT 
not included) 
• One patient died of regimen-related toxicity at Day +33 (VOD) 
• No grade III or IV nausea or vomiting 
• Number of patients who discontinued ARV is unknown 
Re (8) 
 
ASCT, n=10 
BEAM 
*NA 
• 7/10 patients had gastrointestinal toxicity and 2/10 had hepatic toxicity 
• 3/10 patients stopped ARV after BEAM due to toxicity 
Balsalobre (9) 
 
ASCT, n=68 
BEAM and variants (n=65) 
 
TBI based regimens (n=3) 
NA 
• HAART continued in 95% of patients, but withdrawn in 22.5% 
• Of the patients who discontinued HAART, mucositis was the most common 
reason 
 
Serrano (10) 
 
ASCT, n=11 
BEAM (n=10) 
 
or 
 
BEAC (n=1) 
*NNRTI-based 
(n=8) 
 
PI-based 
(n=2) 
 
• No patients died from treatment related complications 
• No apparent interference between HAART and conditioning regimens was 
observed 
• No patients were concomitantly receiving AZT 
 
*HAART continued through conditioning. 
ASCT = Autologous Stem-Cell Transplantation; AZT = Zidovudine 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-7 
 
References 
 
1. 
Hamadani M, Devine SM. Reduced-Intensity Conditioning Allogeneic Stem Cell 
Transplantation In HIV Patients With Hematologic Malignancies: Yes, We Can. Blood. 
2009;114(12):2564-6. 
2. 
Woolfrey AE, Malhotra U, Harrington RD, Mcnevin J, Manley TJ, Riddell SR, et al. 
Generation Of HIV-1-Specific CD8+ Cell Responses Following Allogeneic Hematopoietic 
Cell Transplantation. Blood. 2008;112(8):3484-7. PMCID: 2569185. 
3. 
Bryant A, Milliken S. Successful Reduced-Intensity Conditioning Allogeneic HSCT For 
HIV-Related Primary Effusion Lymphoma. Biol Blood Marrow Transplant. 
2008;14(5):601-2. 
4. 
Gupta V, Tomblyn M, Pedersen TL, Atkins HL, Battiwalla M, Gress RE, et al. Allogeneic 
Hematopoietic Cell Transplantation in Human Immunodeficiency Virus-Positive Patients 
With Hematologic Disorders: A Report From The Center For International Blood and 
Marrow Transplant Research. Biol Blood Marrow Transplant. 2009;15(7):864-71. 
5. 
Polizzotto MN, Skinner M, Cole-Sinclair MF, Opat SS, Spencer A, Avery S. Allo-SCT F 
for Hematological Malignancies in the Setting of HIV. Bone Marrow Transplant. 2009. 
6. 
Krishnan A, Molina A, Zaia J, Smith D, Vasquez D, Kogut N, et al. Durable Remissions 
with Autologous Stem Cell Transplantation for High-Risk HIV-Associated Lymphomas. 
Blood. 2005;105(2):874-8. 
7. 
Spitzer TR, Ambinder RF, Lee JY, Kaplan LD, Wachsman W, Straus DJ, 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(1):59-66. 
8. 
Re A, Cattaneo C, Michieli M, Casari S, Spina M, Rupolo 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;21(23):4423-7. 
9. 
Balsalobre P, Diez-Martin JL, Re A, Michieli M, Ribera JM, Canals C, et al. Autologous 
Stem-Cell Transplantation in Patients With HIV-Related Lymphoma. J Clin Oncol. 
2009;27(13):2192-8. 
10. Serrano D, Carrion R, Balsalobre P, Miralles P, Berenguer J, Buno I, et al. HIV-Associated 
Lymphoma Successfully Treated with Peripheral Blood Stem Cell Transplantation. Exp 
Hematol. 2005;33(4):487-94. 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-8 
TABLE F-3: PHARMACOKINETIC INTERACTIONS FOR GVHD PROPHYLAXIS AND ANTIRETROVIRALS 
 
I. Tacrolimus 
a. Standard Dose 
i. 
IV: 0.03 mg/kg every 24 hours as a continuous IV infusion to begin 3 days prior to transplant (based on IBW) 
ii. 
PO: 0.12 mg/kg/day divided into 2 doses (Convert to oral administration when patient is able to tolerate) 
b. Target Trough Level 
i. 
5 – 15 ng/mL 
Concomitant Medication 
Effect on Tacrolimus 
Mechanism 
Recommendation 
Protease Inhibitors (boosted) 
• 
Atazanavir/ritonavir (ATZ/r) 
• 
Fosamprenavir/ritonavir (fAPV/r) 
• 
Indinavir/ritonavir (IND/r) 
• 
Lopinavir/ritonavir (LPV/r) 
• 
Saquinavir/ritonavir (SQV/r) 
• 
Tipranavir/ritonavir (TPV/r) 
↑↑↑ Tacrolimus Levels 1-9 
 
May result in severe and 
prolonged tacrolimus toxicity. 
 
 
Potent inhibition of 
CYP3A4 and P-
glycoprotein 
Hold tacrolimus upon initiation of ARV and monitor trough 
levels daily 
Based on level: 
• < 5 ng/mL: Administer 1 mg (PO) or 0.25 mg (IV)* 
• 5-15 ng/mL: Administer 0.5 mg (PO) or 0.125 mg (IV)* 
• >15 ng/mL: HOLD tacrolimus until next level 
Once dosing is stable, tacrolimus levels may be monitored 
according to local guidelines.  Most patients are maintained on 
0.5 – 1 mg/week. 
Protease Inhibitors (unboosted) 
• 
Atazanavir (ATZ) 
• 
Nelfinavir (NFV) 
↑↑ Tacrolimus Levels 2, 6-7, 10-
11 
 
May result in severe and 
prolonged tacrolimus toxicity. 
 
Strong inhibition of 
CYP3A4 
Hold tacrolimus upon initiation of ARV and monitor trough 
levels daily 
Based on level: 
• < 5 ng/mL: Administer 1 mg (PO) or 0.25 mg (IV)* 
• 5-15 ng/mL: Administer 0.5 mg (PO) or 0.125 mg (IV)* 
• >15 ng/mL: HOLD tacrolimus until next level 
Once dosing is stable, tacrolimus levels may be monitored 
according to local guidelines.   
NNRTIs 
• 
Efavirenz (EFV) 
• 
Nevirapine (NVP) 
↓ Tacrolimus Levels 6 
 
 
 
 
Strong induction of 
CYP3A4 
Continue tacrolimus at the same dose and monitor trough levels 
daily. 
Based on level: 
• < 5 ng/mL: Increase tacrolimus daily dose by 25% 
• 5-15 ng/mL: No adjustment  
• >15 ng/mL: Decrease tacrolimus daily dose by 25% 
Full induction effects may take up to two weeks.  Daily 
tacrolimus doses are substantially increased for most patients 
with co-administration of NNRTIs.  Efavirenz is a more potent 
inducer of CYP3A4 than is nevirapine. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-9 
Concomitant Medication 
Effect on Tacrolimus 
Mechanism 
Recommendation 
NNRTIs 
• 
Etravirine (ETV) 
↓↓ Tacrolimus Levels 
(Thoeretical) 
Potent induction of 
CYP3A4 
Concomitant use of etravirine and tacrolimus should be 
discouraged. 
NRTIs 
• 
Abacavir (ABC) 
• 
Didanosine (ddI) 
• 
Emtricitabine (FTC) 
• 
Lamivudine (3TC) 
• 
Stavudine (d4T) 
• 
Tenofovir (TDF) 
• 
Zidovudine (AZT, ZDV) 
None 12 
N/A 
No adjustments necessary. 
 
Monitor tacrolimus trough levels 2-3 times/week. 
 
Frequent monitoring of renal function is required for those 
patients on tenofovir due to the increased risk of nephrotoxicity. 
 
For patients with renal impairment, adjust NRTI doses according 
to local guidelines. 
Integrase Inhibitor 
• 
Raltegravir (RLV) 
None 
N/A 
No adjustments necessary.   
Monitor tacrolimus trough levels 2-3 times/week. 
 
Raltegravir based regimens may be preferred over PI- or NNRTI- 
based regimens as it is primarily metabolized via glucuronidation 
and not by CYP3A4. 
Fusion Inhibitor 
• 
Enfuvirtide (ENF, T20) 
None 
N/A 
No adjustments necessary.   
Monitor tacrolimus trough levels 2-3 times/week. 
CCR5 Antagonist 
• 
Maraviroc (MVC) 
None 
N/A 
No adjustments necessary.   
Monitor tacrolimus trough levels 2-3 times/week. 
*To be administered in a one-time dose in response to the observed level. 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-10 
II. Sirolimus 
a. Standard Dose 
i. 
PO: 12 mg once on Day -3, then 4 mg daily as a single dose (administer on an empty stomach) 
b. Target Trough Level 
i. 
3 – 12 ng/mL 
Concomitant Medication 
Effect on Sirolimus 
Mechanism 
Recommendation 
Protease Inhibitors (boosted) 
• 
Atazanavir/ritonavir (ATZ/r) 
• 
Fosamprenavir/ritonavir (fAPV/r) 
• 
Indinavir/ritonavir (IND/r) 
• 
Lopinavir/ritonavir (LPV/r) 
• 
Saquinavir/ritonavir (SQV/r) 
• 
Tipranavir/ritonavir (TPV/r) 
↑↑↑ Sirolimus Levels 3, 8 
 
May result in severe and 
prolonged sirolimus toxicity. 
 
 
Potent inhibition of 
CYP3A4 and P-
glycoprotein 
Hold sirolimus upon initiation of ARV and monitor trough levels 
daily 
Based on level: 
• < 3 ng/mL: Administer 0.4 mg (PO)  
• 3 - 12 ng/mL: Administer 0.3 mg (PO) 
• >12 ng/mL: HOLD sirolimus until next level 
Once dosing is stable, sirolimus levels may be monitored 
according to local guidelines. 
Protease Inhibitors (unboosted) 
• 
Atazanavir (ATZ) 
• 
Nelfinavir (NFV) 
↑↑ Sirolimus Levels 13 
 
May result in severe and 
prolonged sirolimus toxicity. 
 
Strong inhibition of 
CYP3A4 
Hold sirolimus upon initiation of ARV and monitor trough levels 
daily 
 
Based on level: 
• < 3 ng/mL: Administer 0.4 mg (PO)  
• 3 - 12 ng/mL: Administer 0.3 mg (PO) 
• >12 ng/mL: HOLD sirolimus until next level 
 
Once dosing is stable, sirolimus levels may be monitored 
according to local guidelines. 
NNRTIs 
• 
Efavirenz (EFV) 
• 
Nevirapine (NVP) 
↓ Sirolimus Levels 
 
 
 
 
Strong induction of 
CYP3A4 
Continue sirolimus at the same dose and monitor trough levels 
daily. 
 
Based on level: 
• < 3 ng/mL: Increase sirolimus daily dose by 25% 
• 3 - 12 ng/mL: No adjustment  
• >12 ng/mL: Decrease sirolimus daily dose by 25% 
 
Full induction effects may take up to two weeks.  Daily sirolimus 
doses are substantially increased for most patients with co-
administration of NNRTIs.  Efavirenz is a more potent inducer of 
CYP3A4 than is nevirapine. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-11 
Concomitant Medication 
Effect on Sirolimus 
Mechanism 
Recommendation 
NNRTIs 
• 
Etravirine (ETV) 
↓↓ Sirolimus Levels 
(Thoeretical) 
Potent induction of 
CYP3A4 
Concomitant use of etravirine and sirolimus should be 
discouraged. 
NRTIs 
• 
Abacavir (ABC) 
• 
Didanosine (ddI) 
• 
Emtricitabine (FTC) 
• 
Lamivudine (3TC) 
• 
Stavudine (d4T) 
• 
Tenofovir (TDF) 
• 
Zidovudine (AZT, ZDV) 
None 
N/A 
No adjustments necessary. 
 
Monitor sirolimus trough levels 2-3 times/week. 
 
Frequent monitoring of renal function is required for those 
patients on tenofovir due to the increased risk of nephrotoxicity. 
 
For patients with renal impairment, adjust NRTI doses according 
to local guidelines. 
Integrase Inhibitor 
• 
Raltegravir (RLV) 
None 
N/A 
No adjustments necessary.   
Monitor sirolimus trough levels 2-3 times/week. 
 
Raltegravir based regimens may be preferred over PI- or NNRTI- 
based regimens as it is primarily metabolized via glucuronidation 
and not by CYP3A4. 
Fusion Inhibitor 
• 
Enfuviritide (ENF, T20) 
None 
N/A 
No adjustments necessary.   
Monitor sirolimus trough levels 2-3 times/week. 
CCR5 Antagonist 
• 
Maraviroc (MVC) 
None 
N/A 
No adjustments necessary.   
Monitor sirolimus trough levels 2-3 times/week. 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-12 
III. Cyclophosphamide 
a. Standard dose24 
i. 
50 mg/kg IV over 1-2 hours is given on Day 3 post-transplant (between 60 and 72 hours after marrow infusion) and again on day 
4 post-transplant (approximately 24 hours after first dose) (based on IBW) 
Concomitant Medication 
Effect on 
Cyclophosphamide (Cy) 
Mechanism 
Recommendation 
Protease Inhibitors (boosted) 
• 
Atazanavir/ritonavir (ATZ/r) 
• 
Fosamprenavir/ritonavir (fAPV/r) 
• 
Indinavir/ritonavir (IND/r) 
• 
Lopinavir/ritonavir (LPV/r) 
• 
Saquinavir/ritonavir (SQV/r) 
• 
Tipranavir/ritonavir (TPV/r) 
The conversion of Cy (a prodrug) 
to its active metabolites will be 
delayed, resulting in increased 
levels of Cy in the serum. 
Inhibition of CYP3A4 
Conversion of Cy to its active metabolites will be delayed, 
resulting in reduced efficacy of Cy.  Certain metabolites may be 
increased or decreased.   
 
Hold ritonavir-boosted regimens during GVHD prophylaxis. 
Protease Inhibitors (unboosted) 
• 
Atazanavir (ATZ) 
• 
Nelfinavir (NFV) 
The conversion of Cy (a prodrug) 
to its active metabolites will be 
delayed, resulting in increased 
levels of Cy in the serum. 
 
Inhibition of CYP3A4 
Conversion of Cy to its active metabolites will be delayed, 
resulting in reduced efficacy of Cy.  Certain metabolites may be 
increased or decreased.   
 
The concomitant use of unboosted PIs should be used with 
caution as Cy efficacy may be decreased.  Consultation with 
pharmacokinetic team is required. 
NNRTIs 
• 
Efavirenz (EFV) 
• 
Nevirapine (NVP) 
Rapid conversion of Cy to its 
active metabolites results in 
decreased Cy concentrations and 
increase levels of active 
metabolites 
 
Induction of CYP3A4 
and CYP2B6 
Dose reductions of Cy may be recommended to prevent toxicity.  
This has been shown to be effective with other CYP inducers, 
such as phenytoin.25 
 
Monitor patients closely for toxicity from active metabolites of 
cyclophosphamide. 
NNRTIs 
• 
Etravirine (ETV) 
Rapid conversion of Cy to its 
active metabolites results in 
decreased Cy concentrations and 
increase levels of active 
metabolites 
Potent induction of 
CYP3A4 and CYP2B6 
Avoid concomitant use due to the unpredictable interaction 
potential. 
NRTIs 
• 
Abacavir (ABC) 
• 
Didanosine (ddI) 
 
None 
N/A 
No adjustment necessary 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-13 
Concomitant Medication 
Effect on 
Cyclophosphamide (Cy) 
Mechanism 
Recommendation 
NRTIs 
• 
Stavudine (d4T) 
• 
Zidovudine (AZT, ZDV) 
None 
N/A 
No adjustment necessary 
NRTIs 
• 
Lamivudine (3TC) 
• 
Emtricitabine (FTC) 
• 
Tenofovir (TDF) 
None 
N/A 
No adjustments necessary 
 
 
 
 
Integrase Inhibitor 
• 
Raltegravir (RLV) 
None 
N/A 
No adjustments necessary.   
 
Fusion Inhibitor 
• 
Enfuviritide (ENF, T20) 
None 
N/A 
No adjustments necessary.   
 
CCR5 Antagonist 
• 
Maraviroc (MVC) 
None 
N/A 
No adjustments necessary.   
 
 
References 
1. 
Jain AB, Venkataramanan R, Eghtesad B, et al. Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration 
in liver transplantation patients. Liver Transpl 2003;9:954-60. 
2. 
Neff GW, Bonham A, Tzakis AG, et al. Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver 
disease. Liver Transpl 2003;9:239-47. 
3. 
Barau C, Blouin P, Creput C, Taburet AM, Durrbach A, Furlan V. Effect of coadministered HIV-protease inhibitors on tacrolimus and 
sirolimus blood concentrations in a kidney transplant recipient. Fundam Clin Pharmacol 2009;23:423-5. 
4. 
Mertz D, Battegay M, Marzolini C, Mayr M. Drug-drug interaction in a kidney transplant recipient receiving HIV salvage therapy and 
tacrolimus. Am J Kidney Dis 2009;54:e1-4. 
5. 
Schonder KS, Shullo MA, Okusanya O. Tacrolimus and lopinavir/ritonavir interaction in liver transplantation. Ann Pharmacother 
2003;37:1793-6. 
6. 
Jain AK, Venkataramanan R, Shapiro R, et al. The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant 
patients. Liver Transpl 2002;8:841-5. 
7. 
Teicher E, Vincent I, Bonhomme-Faivre L, et al. Effect of highly active antiretroviral therapy on tacrolimus pharmacokinetics in hepatitis C 
virus and HIV co-infected liver transplant recipients in the ANRS HC-08 study. Clin Pharmacokinet 2007;46:941-52. 
8. 
Frassetto LA, Browne M, Cheng A, et al. Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney 
transplant recipients. Am J Transplant 2007;7:2816-20. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-14 
9. 
Guaraldi G, Cocchi S, Codeluppi M, et al. Role of therapeutic drug monitoring in a patient with human immunodeficiency virus infection and 
end-stage liver disease undergoing orthotopic liver transplantation. Transplant Proc 2005;37:2609-10. 
10. 
Schvarcz R, Rudbeck G, Soderdahl G, Stahle L. Interaction between nelfinavir and tacrolimus after orthoptic liver transplantation in a patient 
coinfected with HIV and hepatitis C virus (HCV). Transplantation 2000;69:2194-5. 
11. 
Sheikh AM, Wolf DC, Lebovics E, Goldberg R, Horowitz HW. Concomitant human immunodeficiency virus protease inhibitor therapy 
markedly reduces tacrolimus metabolism and increases blood levels. Transplantation 1999;68:307-9. 
12. 
Chittick GE, Zong J, Begley JA, Alianti JR, Sorbel JJ, Blum MR. Pharmacokinetics of emtricitabine/tenofovir disoproxil fumarate and 
tacrolimus at steady state when administered alone or in combination. Int J Clin Pharmacol Ther 2008;46:627-36. 
13. 
Jain AK, Venkataramanan R, Fridell JA, et al. Nelfinavir, a protease inhibitor, increases sirolimus levels in a liver transplantation patient: a 
case report. Liver Transpl 2002;8:838-40. 
14. 
Vogel M, Voigt E, Michaelis HC, et al. Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor 
lopinavir/ritonavir in liver-transplanted HIV-infected patients. Liver Transpl 2004;10:939-44. 
15. 
Brinkman K, Huysmans F, Burger DM. Pharmacokinetic interaction between saquinavir and cyclosporine. Ann Intern Med 1998;129:914-5. 
16. 
Frassetto L, Baluom M, Jacobsen W, et al. Cyclosporine pharmacokinetics and dosing modifications in human immunodeficiency virus-
infected liver and kidney transplant recipients. Transplantation 2005;80:13-7. 
17. 
Frassetto L, Thai T, Aggarwal AM, et al. Pharmacokinetic interactions between cyclosporine and protease inhibitors in HIV+ subjects. Drug 
Metab Pharmacokinet 2003;18:114-20. 
18. 
Guaraldi G, Cocchi S, Codeluppi M, et al. Pharmacokinetic interaction between Amprenavir/Ritonavir and FosAmprenavir on cyclosporine in 
two patients with human immunodeficiency virus infection undergoing orthotopic liver transplantation. Transplant Proc 2006;38:1138-40. 
19. 
Tseng A, Nguyen ME, Cardella C, Humar A, Conly J. Probable interaction between efavirenz and cyclosporine. AIDS 2002;16:505-6. 
20. 
Wenning LA, Friedman EJ, Kost JT, et al. Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrob Agents 
Chemother 2008;52:3253-8. 
21. 
Di Biagio A, Rosso R, Siccardi M, D'Avolio A, Bonora S, Viscoli C. Lack of interaction between raltegravir and cyclosporin in an HIV-
infected liver transplant recipient. J Antimicrob Chemother 2009;64:874-5. 
22. 
Margolis DM, Kewn S, Coull JJ, et al. The addition of mycophenolate mofetil to antiretroviral therapy including abacavir is associated with 
depletion of intracellular deoxyguanosine triphosphate and a decrease in plasma HIV-1 RNA. J Acquir Immune Defic Syndr 2002;31:45-9. 
23. 
Heredia A, Margolis D, Oldach D, Hazen R, Le N, Redfield R. Abacavir in combination with the inosine monophosphate dehydrogenase 
(IMPDH)-inhibitor mycophenolic acid is active against multidrug-resistant HIV-1. J Acquir Immune Defic Syndr 1999;22:406-7. 
24. 
Luznik L, Bolanos-Meade J, Zahurak M, et al. High-dose cyclophosphamide as single agent, short-course prophylaxis of graft-versus-host 
disease. Blood 2010. 
25. 
de Jonge ME, Huitema AD, van Dam SM, Beijnen JH, Rodenhuis S. Significant induction of cyclophosphamide and thiotepa metabolism by 
phenytoin. Cancer Chemother Pharmacol 2005;55:507-10. 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-15 
TABLE F-4: CONTINUATION OF ANTIRETROVIRAL THERAPY BASED ON ANTIFUNGAL PROPHYLAXIS REGIMEN 
 
*Monitor azole drug levels routinely. 
 
 
Raltegravir Based 
Regimen 
NNRTI Based Regimen 
Boosted PI Based Regimen 
Other 
Antifungal Agent 
Voriconazole 
No adjustments 
↑ voriconazole dose to 400mg 
BID* 
↓ efavirenz dose to 300mg 
daily. 
Consider alternative 
antifungal agent; monitor 
voriconazole levels and 
increase dose based on level* 
Consultation recommended, 
reviewed on a case by case 
basis 
Posaconazole 
No adjustments 
Consider alternative 
antifungal agent; monitor 
posaconazole levels and 
increase dose as needed* 
Consider alternative 
antifungal agent; monitor 
closely for PI toxicity* 
Consultation recommended, 
reviewed on a case by case 
basis 
Fluconazole 
No adjustments 
No adjustments. Monitor 
closely for hepatotoxicity. 
Do not use doses >200mg/day 
Consultation recommended, 
reviewed on a case by case 
basis 
Echinocandins  
(Anidulafungin, Micafungin, Caspofungin) 
No adjustments 
No adjustments 
No adjustments 
Consultation recommended, 
reviewed on a case by case 
basis 
Amphotericin B and derivatives 
No adjustments 
No adjustments 
No adjustments 
Consultation recommended, 
reviewed on a case by case 
basis† 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-16 
TABLE F-5: DOSE ADJUSTMENTS FOR CONCOMITANT USE OF ANTIFUNGAL AGENTS AND IMMUNOSUPPRESSION 
 
*Monitor immunosuppression levels routinely. 
 
 
 
Tacrolimus (FK) 
Cyclosporine (CY) 
Sirolimus 
Mycophenolate 
Cyclophosphamide28 
Antifungal Agent 
Voriconazole 
↓ FK dose by 67%* 
↓ CY dose by 50%* 
Avoid concomitant use (see 
below) 
↓ Sirolimus dose by 90%* 
No adjustments 
Avoid concomitant use (see 
below) 
Posaconazole 
↓ FK dose by 67%* 
↓ CY dose by 25%* 
Avoid concomitant use (see 
below) 
↓ Sirolimus dose by 67% 
No adjustments 
Avoid concomitant use (see 
below) 
Fluconazole 
No adjustments* 
No adjustments* 
No adjustments 
No adjustments            (see 
below) 
Echinocandins  
(Anidulafungin, Micafungin, Caspofungin) 
No adjustments 
No adjustments 
No adjustments 
No adjustments 
Amphotericin B and derivatives 
No adjustments 
No adjustments 
No adjustments 
No adjustments 


BMT CLINICAL TRIALS NETWORK 
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Version 3.0 dated February 18, 2014 
 
 
F-17 
TABLE F-6: PHARMACOKINETIC INTERACTIONS BETWEEN ANTIFUNGAL, ANTIRETROVIRAL AND IMMUNOSUPPRESSIVE 
AGENTS 
I. 
Voriconazole 
a. Standard Dose 
i. IV: 6 mg/kg every 12 hours for 2 doses, then 4 mg/kg every 12 hours 
ii. PO: 4 mg/kg every 12 hours for 2 doses, then 200 mg twice daily 
b. Target Trough Level 
i. 0.5 – 5 µg/mL 
Concomitant Medication 
Voriconazole Effect [24,25] 
Mechanism 
Recommendation 
Calcineurin Inhibitors 
• 
Tacrolimus 
• 
Cyclosporine 
↑↑ Calcineurin Levels 
Moderate inhibition of 
CYP3A4 
Upon initiation of voriconazole: 
• 
Decrease tacrolimus daily dose by 67% 
• 
Decrease cyclosporine daily dose by 50% 
Monitor daily trough levels of the calcineurin inhibitors and 
adjust doses as needed. 
mTOR Inhibitors 
• 
Sirolimus 
↑↑↑ Sirolimus Levels 
 
 
Moderate inhibition of 
CYP3A4 
Voriconazole should not be used unless deemed absolutely 
clinically necessary. If voriconazole must be added to control 
fungal infection, then following the 90% reduction in sirolimus 
dosing serum levels should be measured 24-48 hours later and 
then every 3-4 days until levels are stable and in the desired 
range.  If voriconazole is given intravenously, or if voriconazole 
and sirolimus are not given together, these guidelines may not 
apply because the effect on bioavailability of sirolimus will be 
weaker. 
Antimetabolites 
• 
Mycophenolate mofetil 
None 
 
N/A 
No adjustments necessary. 
Alkylating Agents 
• 
Cyclophosphamide 
↑↑ Cyclophosphamide and 4-
hydroxycyclophosphamide 
Moderate inhibition of 
CYP3A4 and 2C19 
Concomitant use is discouraged due to the accumulation of the 
toxic metabolite 4-hydroxycyclophosphamide28 
Protease Inhibitors 
• 
Ritonavir (400mg BID) 
↓↓↓ Voriconazole 
(Decreased by 66 – 80%) 
Strong induction of 
CYP2C9 and 2C19 
Contraindicated. 
Protease Inhibitors (boosted) 
• 
Fosamprenavir/ritonavir (fAPV/r) 
• 
Indinavir/ritonavir (IND/r) 
• 
Lopinavir/ritonavir (LPV/r) 
• 
Saquinavir/ritonavir (SQV/r) 
• 
Tipranavir/ritonavir (TPV/r) 
↓↓ Voriconazole 
(Decreased by 24 – 40%) 
Strong induction of 
CYP2C9 and CYP2C19 
Avoid concomitant use whenever possible. 
 
Monitor voriconazole trough levels bi-weekly and adjust as 
needed. 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
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F-18 
Concomitant Medication 
Voriconazole Effect [24,25] 
Mechanism 
Recommendation 
Protease Inhibitors (unboosted) 
• 
Amprenavir (AMP) 
• 
Atazanavir (ATZ) 
• 
Indivavir (IDV) 
• 
Nelfinavir (NFV) 
• 
Saquinavir (SQV) 
↑ Protease Inhibitor Level 
Weak inhibition of 
CYP3A4 
Frequent monitoring of adverse effects. 
NNRTIs 
• 
Efavirenz (EFV) 
↓ Voriconazole  
(Decrease AUC by 77%) 
↑ Efavirenz 
(Increase AUC by 44%) 
Two way interaction 
via CYP3A4 
Increase voriconazole dose to 400 mg twice daily and decrease 
efavirenz dose to 300mg daily. 
 
Monitor voriconazole trough levels bi-weekly and adjust as 
needed. 
NNRTIs 
• 
Etravirine (ETV) 
↑ Voriconazole (possible) 
↑ Etravirine (possible) 
Two way interaction 
via CYP3A4 
Frequent monitoring of adverse effects. 
 
Monitor voriconazole trough levels bi-weekly and adjust as 
needed. 
NNRTIs 
• 
Nevirapine (NVP) 
↓ Voriconazole (possible) 
↑ Nevirapine (possible) 
Two way interaction 
via CYP3A4 
Frequent monitoring of adverse effects. 
 
Monitor voriconazole trough levels bi-weekly and adjust as 
needed. 
NRTIs 
• 
Abacavir (ABC) 
• 
Didanosine (ddI) 
• 
Emtricitabine (FTC) 
• 
Lamivudine (3TC) 
• 
Stavudine (d4T) 
• 
Tenofovir (TDF) 
• 
Zidovudine (AZT, ZDV) 
None 
N/A 
No adjustments necessary. 
Integrase Inhibitor 
• 
Raltegravir (RLV) 
None 
N/A 
No adjustments necessary.   
 
Raltegravir based regimens may be preferred over PI- or NNRTI- 
based regimens as it is primarily metabolized via glucuronidation 
and not by CYP3A4. 
Fusion Inhibitor 
• 
Enfuviritide (ENF, T20) 
None 
N/A 
No adjustments necessary.   
 
CCR5 Antagonist 
• 
Maraviroc (MVC) 
↑ Maraviroc Levels 
N/A 
Decreased maraviroc dose to 150 mg twice daily 
 
 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-19 
II. 
Posaconazole 
a. Standard Dose 
i. PO: 200 mg three times a day (5 mL of oral suspension given with a high-fat meal) 
b. Target Trough Level 
i. ≥ 0.5 µg/mL 
Concomitant Medication 
Posaconazole Effect [24,26] 
Mechanism 
Recommendation 
Calcineurin Inhibitors 
• 
Tacrolimus 
• 
Cyclosporine 
↑↑ Calcineurin Levels 
Moderate inhibition of 
CYP3A4 
Upon initiation of posaconazole: 
• 
Decrease tacrolimus daily dose by 67% 
• 
Decrease cyclosporine daily dose by 25% 
 
Monitor daily trough levels of the calcineurin inhibitors and 
adjust doses as needed. 
mTOR Inhibitors 
• 
Sirolimus 
↑↑↑ Sirolimus Levels 
(Increase by 788%) 
 
 
Moderate inhibition of 
CYP3A4 
Contraindicated, use alternative antifungal therapy whenever 
possible. 
Antimetabolites 
• 
Mycophenolate mofetil 
None 
 
N/A 
No adjustments necessary. 
Alkylating Agents 
• 
Cyclophosphamide 
↑↑ Cyclophosphamide and 4-
hydroxycyclophosphamide 
Moderate inhibition of 
CYP3A4 
Concomitant use is discouraged due to the accumulation of the 
toxic metabolite 4-hydroxycyclophosphamide28 
Protease Inhibitors (boosted) 
• 
Fosamprenavir/ritonavir (fAPV/r) 
• 
Indinavir/ritonavir (IND/r) 
• 
Lopinavir/ritonavir (LPV/r) 
• 
Saquinavir/ritonavir (SQV/r) 
• 
Tipranavir/ritonavir (TPV/r) 
↑ Protease Inhibitor Level 
Weak inhibition of 
CYP3A4 
Frequent monitoring of adverse effects.  Consider alternative 
antifungal therapy. 
 
Monitor posaconazole trough levels bi-weekly and adjust as 
needed.  Dose of posaconazole may be decreased with high level. 
 
 
Protease Inhibitors (unboosted) 
• 
Amprenavir (AMP) 
• 
Atazanavir (ATZ) 
• 
Indivavir (IDV) 
• 
Nelfinavir (NFV) 
• 
Saquinavir (SQV) 
↑ Protease Inhibitor Level 
Weak inhibition of 
CYP3A4 
Frequent monitoring of adverse effects. 
 
Atazanavir AUC increased by 268%. 
NNRTIs 
• 
Efavirenz (EFV) 
↓ Posaconazole  
(Decrease AUC by 50%) 
 
Strong induction of  
CYP3A4 and UDP-G 
induction 
Consider alternative antifungal therapy. 
Monitor posaconazole trough levels bi-weekly and adjust as 
needed.  Dose may be increased with low level. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-20 
Concomitant Medication 
Posaconazole Effect [24,26] 
Mechanism 
Recommendation 
NNRTIs 
• 
Etravirine (ETV) 
↑ Etravirine (possible) 
Weak inhibition of 
CYP3A4 
No adjustments necessary. 
NNRTIs 
• 
Nevirapine (NVP) 
↓ Posaconazole (possible) 
↑ Nevirapine (possible) 
Two way interaction 
via CYP3A4 
Frequent monitoring of adverse effects. 
 
Monitor Posaconazole trough levels bi-weekly and adjust as 
needed. 
NRTIs 
• 
Abacavir (ABC) 
• 
Didanosine (ddI) 
• 
Emtricitabine (FTC) 
• 
Lamivudine (3TC) 
• 
Stavudine (d4T) 
• 
Tenofovir (TDF) 
• 
Zidovudine (AZT, ZDV) 
None 
N/A 
No adjustments necessary. 
Integrase Inhibitor 
• 
Raltegravir (RLV) 
None 
N/A 
No adjustments necessary.   
 
Raltegravir based regimens may be preferred over PI- or NNRTI- 
based regimens as it is primarily metabolized via glucuronidation 
and not by CYP3A4. 
Fusion Inhibitor 
• 
Enfuvirtide (ENF, T20) 
None 
N/A 
No adjustments necessary.   
 
CCR5 Antagonist 
• 
Maraviroc (MVC) 
None 
N/A 
No adjustments necessary.   
 
 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-21 
III. 
Fluconazole 
a. Standard Dose 
i. IV: 200 – 400 mg daily (Convert to oral administration when patient is able to tolerate) 
ii. PO: 200 – 400 mg daily 
Concomitant Medication 
Fluconazole Effect [24,27] 
Mechanism 
Recommendation 
Calcineurin Inhibitors 
• 
Tacrolimus 
• 
Cyclosporine 
↑ Calcineurin Levels 
Weak inhibition of 
CYP3A4 
Monitor daily trough levels of the calcineurin inhibitors and 
adjust doses as needed. 
mTOR Inhibitors 
• 
Sirolimus 
↑ Sirolimus Levels 
 
 
Weak inhibition of 
CYP3A4 
Monitor daily trough levels of the calcineurin inhibitors and 
adjust doses as needed. 
Antimetabolites 
• 
Mycophenolate mofetil 
None 
 
N/A 
No adjustments necessary. 
Alkylating Agents 
• 
Cyclophosphamide 
Minimal effect on 
cyclophosphamide  
Minimal inhibition of 
2C9 
No adjustments necessary.28  
Protease Inhibitors (boosted) 
• 
Fosamprenavir/ritonavir (fAPV/r) 
• 
Indinavir/ritonavir (IND/r) 
• 
Lopinavir/ritonavir (LPV/r) 
• 
Saquinavir/ritonavir (SQV/r) 
• 
Tipranavir/ritonavir (TPV/r) 
None 
↑ Tipranavir Levels 
 
 
 
 
Weak inhibition of 
CYP3A4 
No adjustments necessary. 
 
Fluconazole doses > 200 mg are not recommended with co-
administration of TPV/r. 
Protease Inhibitors (unboosted) 
• 
Amprenavir (AMP) 
• 
Atazanavir (ATZ) 
• 
Indivavir (IDV) 
• 
Nelfinavir (NFV) 
• 
Saquinavir (SQV) 
None 
 
 
 
 
N/A 
No adjustments necessary. 
NNRTIs 
• 
Efavirenz (EFV) 
None 
 
 
N/A 
No adjustments necessary. 
NNRTIs 
• 
Etravirine (ETV) 
↑ Etravirine (possible) 
N/A 
No adjustments necessary. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-22 
Concomitant Medication 
Fluconazole Effect [24,27] 
Mechanism 
Recommendation 
NNRTIs 
• 
Nevirapine (NVP) 
↑ Nevirapine 
(Increase AUC by 110%) 
Weak inhibition of 
CYP3A4 
Frequent monitoring of liver function tests as combination results 
in an increased risk of hepatotoxicity. 
 
NRTIs 
• 
Abacavir (ABC) 
• 
Didanosine (ddI) 
• 
Emtricitabine (FTC) 
• 
Lamivudine (3TC) 
• 
Stavudine (d4T) 
• 
Tenofovir (TDF) 
• 
Zidovudine (AZT, ZDV) 
None 
N/A 
No adjustments necessary. 
Integrase Inhibitor 
• 
Raltegravir (RLV) 
None 
N/A 
No adjustments necessary.   
 
Raltegravir based regimens may be preferred over PI- or NNRTI- 
based regimens as it is primarily metabolized via glucuronidation 
and not by CYP3A4. 
Fusion Inhibitor 
• 
Enfuvirtide (ENF, T20) 
None 
N/A 
No adjustments necessary.   
 
CCR5 Antagonist 
• 
Maraviroc (MVC) 
None 
N/A 
No adjustments necessary.   
 
 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
F-23 
IV. 
Echinocandin Agents (Anidulafungin, Micafungin, Caspofungin) 
a. Drug Interactions 
i. Not metabolized through CYP co-enzymes.  The potential for drug-drug interactions is low. 
 
V. 
Amphotericin B and derivatives 
a. Drug Interactions 
i. Not metabolized through CYP co-enzymes.  The potential for drug-drug interactions is low. 
 
References 
1. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and 
adolescents. Department of Health and Human Services. December 1, 2009; 1-161. Available at 
http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.  Accessed (2 February 2010) [p. 130-140] 
2. Vfend [package insert].  New York, NY: Pfizer Inc.; 2008. 
3. Noxafil [package insert]. Kenilworth, NJ: Schering-Plough; 2008. 
4. Diflucan [package insert]. New York, NY: Pfizer Inc.; 2008. 
5. Marr KA, Leisenring W, Crippa F, et al. Cyclophosphamide metabolism is affected by azole antifungals.  Blood 2004;103:1557-1559.


BMT CLINICAL TRIALS NETWORK 
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Version 3.0 dated February 18, 2014 
 
 
G-1 
APPENDIX G 
 
KARNOFSKY AND LANSKY  
PERFORMANCE STATUS SCALES 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
G-2 
APPENDIX G 
 
KARNOFSKY AND LANSKY PERFORMANCE STATUS SCALES 
 
 
 
KARNOFSKY SCALE ≥ 16 YEARS 
 
Percentage 
 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled, hospitalization indicated.  Death not imminent 
20 
Very sick, hospitalization necessary, active supportive treatment necessary 
10 
Moribund, fatal processes, progressing rapidly 
0 
Dead 
 
 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
G-3 
 
LANSKY SCALE < 16 YEARS 
 
Percentage 
 
100 
Fully Active 
90 
Minor restriction in physically strenuous play 
80 
Restricted in strenuous play, tires more easily, otherwise active 
70 
Both greater restrictions of, and less time spent in, active play 
60 
Ambulatory up to 50% of time, limited active play with assistance/supervision 
50 
Considerable assistance required for any active play; fully able to engage in quiet 
play 
40 
Able to initiate quiet activities 
30 
Needs considerable assistance for quiet activity 
20 
Limited to very passive activity initiated by others (e.g., TV) 
10 
Completely disabled, not even passive play 
0 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
REFERENCE   
 
Karnofsky DA: Meaningful clinical classification of therapeutic responses to anti-cancer drugs.  
Editorial: Clin Pharmacol Ther 2:709-712, 1961. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
H-1 
APPENDIX H 
 
SEQUENTIAL PROBABILITY RATIO TEST USING FUTILITY 
BOUNDARY 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
H-2 
APPENDIX H 
 
SEQUENTIAL PROBABILITY RATIO TEST USING FUTILITY BOUNDARY 
 
 
I. Background – The Sequential Probability Ratio Test 
 
Let 
( ; )
f x be the density function for random variable X.  According to the Neyman-Pearson 
theory, the most powerful test of 
o
H

=
:
0
 versus
1
1 :

=
H
 decides in favor of 
1
H  if
n
L
c

and in favor of 
0
H if

c
Ln 
, respectively, where 


1
0
( ;
)/
( ;
)
n
n
i
i
i
L
f x
f x


=
is the likelihood 
ratio, and 

c is determined to have the size.  When the sample size is not fixed in advance, 
further improvement is possible by using Wald’s Sequential Probability Ratio Test (SPRT).  The 
SPRT continues to sample as long as 
A
L
B
n 

 for some constant 
A
B

1
, stops sampling 
and decides in favor of 
1
H as soon as 
A
Ln 
, and stops sampling and decides in favor of 
0
H as 
soon as 
B
Ln 
. 
 
The usual measures of performance of such a procedure are the error probabilities α and of 
rejecting 
0
H when
0

=
, and of accepting 
0
H when
1

=
, respectively, and the expected 
sample size
)
(
)
|
(
N
E
N
E
j
j 

.  Wald and Wolfowitz showed that among all tests, sequential or 
not, for which 


)
reject 
(
Pr
0
0
H
 and
1
0
 Pr (reject 
)
H


, and for which 
)
(N
E j
 are finite, j=0, 
1, the SPRT with error probabilities α and minimizes 
)
(
0 N
E
 and
)
(
1 N
E
.  If, in addition, 
,...
2
,1 x
x
 are independent and identically distributed (i.i.d.) with density function
)
,
(

x
f
, with 
monotone likelihood ratio in
)
(x

, then any SPRT for testing 
0
against 
1
 has non-decreasing 
power function. 
 
For the SPRT with error probabilities α and , the SPRT boundaries are given approximately by 

/)
1( −
=
A
 and 
)
1
/(


−
=
B
.  The operating characteristics of the SPRT are given by 
)
/(
)1
(
)
,
,
,
,
(
)
(
)
(
)
(
1
0








h
h
h
B
A
A
O
−
−
=
 where 
)
(
h
is the non-trivial solution to the equation

=1
)
;
(
))
,
(
/)
;
(
(
)
(
2
1
dx
x
f
x
f
x
f
h




.   
 
The formula 
(
)
(
; )
1
( ) log
( )log
/
( ; )
E N
O
A
O
B
E z




=
−
+




provides the average sample number 
for an arbitrary.  The sample size distribution is very highly skewed,
2
)]
(
[
)
(
N
E
N
Var

.  Thus 
we will consider a truncated test with maximum sample size of 
0
N  and simulate to obtain the 
operating characteristics of the test. 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
H-3 
II. Sequential Probability Ratio Test for Binomial Random Variable Using Futility 
Boundary 
The goal of the study is to assess feasibility and safety of allogeneic HCT in HIV-infected 
patients using 100-day NRM as the primary endpoint.  To establish safety we want to show that 
100-day NRM is lower than 45% with a targeted NRM probability of 15%.  This is equivalent to 
testing H0: p ≥ 0.45 vs. Ha: p ≤ 0.15.  To guard against excessive non-relapse mortality, we wish 
to construct stopping guidelines using the futility boundary of an SPRT test of H0: p = 0.45 vs. 
Ha: p = 0.15 with nominal Type I error α = .07 and Type II error β = .30.  The stopping boundary 
is reached when NRM is high and it is no longer likely that we would be able to reject the null 
hypothesis at the end of the study.  Otherwise, the trial will continue on.   
 
Let 𝑌1, 𝑌2, ⋯, 𝑌𝑛 be the indicator of non-relapse mortality status at day 100 for patient i where 
𝑌𝑖, 𝑖= 1, ⋯, 𝑛, are i.i.d. Bernoulli random variables with probability p.  Let 𝑋= ∑
𝑌𝑖
𝑛
𝑖=1
 be the 
total number of non-relapse deaths observed by day 100, then X is a binomial random variable 
with probability mass function 𝑓(𝑥; 𝑝) = (𝑛
𝑥) 𝑝𝑥(1 −𝑝)(𝑛−𝑥).  The SPRT is derived based on a 
simple null and alternative hypothesis H0: p = p0 = 0.45 vs. Ha: p = p1 = 0.15 with α = .07 and β = 
.30.  Since the log-likelihood ratio for the binomial,  
𝑙𝑜𝑔[𝑓(𝑥; 𝑝1)/𝑓(𝑥; 𝑝0)] = 𝑥𝑙𝑜𝑔[𝑝1/𝑝0] + (𝑛−𝑥)𝑙𝑜𝑔[(1 −𝑝1)/(1 −𝑝0)] 
is a monotone function of x, the test has non-decreasing power function.  Therefore, the SPRT is 
a one-sided level 0.07 test for a composite null hypothesis H0: p ≥ 0.45 versus a composite 
alternative hypothesis Ha: p ≤ 0.15 with power 1 - β = .70. 
 
In this study, stopping only occurs when non-relapse mortality is too high that it is unlikely that 
the null hypothesis would be rejected at full recruitment.  The SPRT pauses when the likelihood-
ratio statistics, 
𝐿𝑛= 𝑓(𝑥; 𝑝1)
𝑓(𝑥; 𝑝0) = 𝑝1
𝑥(1 −𝑝1)(𝑛−𝑥)
𝑝0𝑥(1 −𝑝0)(𝑛−𝑥) < 𝐵 
or equivalently,  
log (𝐿𝑛) = 𝑥∗𝑙𝑜𝑔(𝑝1
𝑝0
) + (𝑛−𝑥) ∗𝑙𝑜𝑔(1 −𝑝1
1 −𝑝0
) < 𝑙𝑜𝑔𝐵 
𝑥∗(𝑙𝑜𝑔(
𝑝1
𝑝0) −𝑙𝑜𝑔(
1−𝑝1
1−𝑝0)) < 𝑙𝑜𝑔𝐵−𝑛∗𝑙𝑜𝑔(
1−𝑝1
1−𝑝0). 
When 𝑝1 < 𝑝0, 𝑙𝑜𝑔(𝑝1/𝑝0) −𝑙𝑜𝑔((1 −𝑝1)/(1 −𝑝0)) < 0.  The stopping region is defined by 
𝑥>
𝑙𝑜𝑔𝐵
𝑙𝑜𝑔(𝑝1
𝑝0)−𝑙𝑜𝑔(1−𝑝1
1−𝑝0) −𝑛∗
𝑙𝑜𝑔(1−𝑝1
1−𝑝0)
𝑙𝑜𝑔(𝑝1
𝑝0)−𝑙𝑜𝑔(1−𝑝1
1−𝑝0) = .738 + .283𝑛. 
 
The SPRT can be represented graphically by plotting the number of non-relapse deaths by day 
100 (x) versus the number of patients enrolled in the study (n).  The stopping boundary is 
represented by the line with the slope equals to .283 and an intercept of .738.  The stopping 
region is the area above the stopping boundary and the continuation region is the area below the 
boundary.  See figure H.1. 
 


BMT CLINICAL TRIALS NETWORK 
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Version 3.0 dated February 18, 2014 
 
 
H-4 
FIGURE H.1 SPRT STOPPING GUIDELINES USING FUTILITY BOUNDARY 
 
 
 
The futility stopping guidelines derived from the SPRT are summarized in Table H.1.   
 
TABLE H.1: FUTILITY STOPPING GUIDELINES FOR 100-DAY NRM 
 
Number of patients enrolled 
(n) 
SPRT stopping boundary 
(x) 
2-4 
2 
5-7 
3 
8-11 
4 
12-15 
5 
 
The operating characteristics of the truncated SPRT with maximum sample size of 15 resulting 
from a simulation study with 10,000 replications are shown in Table H.2.  The truncated SPRT 
test has Type I error of 8% and power of 83%. 
 
TABLE H.2: OPERATING CHARACTERISTICS FOR FUTILITY STOPPING 
GUIDELINES FOR 100-DAY NRM 
 
Non-relapse Mortality 
True 100-day rate 
45% 
35% 
25% 
15% 
Probability stop and accept the null hypothesis 
.92 
.75 
.47 
.17 
Mean month stopped 
11.8 
15.6 
20.2 
24.5 
Mean # endpoints 
2.7 
2.9 
2.8 
2.0 
Mean patients with 100 days follow up 
6.0 
8.2 
10.8 
13.4 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
I-1 
APPENDIX I 
 
IDENTIFICATION OF CCR5DELTA32  
MUTATION HOMOZYGOUS DONORS 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
I-1 
APPENDIX I 
 
NMDP PROCEDURE FOR IDENTIFICATION OF CCR5DELTA32 MUTATION 
HOMOZYGOUS DONORS RELATED TO BMT CTN PROTOCOL 0903 
 
 
Background 
 
A recent case report by Hütter et al. (NEJM, 2009) documented the outcome of an allogeneic 
hematopoietic cell transplant (HCT) performed for the treatment of acute myeloid leukemia 
(AML) in which the well-matched donor was selected for homozygosity for the CCR5delta32 
mutation.  The recipient had been known to be HIV-infected prior to developing AML and the 
German transplant team hypothesized that hematopoietic cells from such a donor could confer 
natural resistance to HIV infection in the transplanted hematopoietic and immune cells.  A single 
HLA-matched donor homozygous for the CCR5delta32 mutation was identified among 
approximately 80 well-matched donors and an allogeneic HCT for the treatment of the patient’s 
AML was performed using that donor.  Following the transplant, the recipient’s antiretroviral 
medications were discontinued and viral titers were monitored.  No subsequent recrudescence of 
HIV replication was detected.  The recipient relapsed with AML approximately one year later 
but a second HCT using the same donor was successfully performed with continued primary 
disease remission and HIV control with undetectable HIV viral loads two years following the 
second transplant (Hütter, personal communication). 
 
The of BMT CTN 0903 Protocol Team would like to replicate these findings in the context of 
allogeneic HCT as proposed under Protocol 0903.  The enrollment for the study is 15 patients.  It 
is known that the incidence of CCR5delta32 homozygosity is essentially limited to European 
populations, with highest incidence in Northern Europeans (Galvani and Novembre, 2005); from 
these data, it is apparent that non-European populations manifest homozygosity too rarely to 
warrant evaluation.  Additionally, it is also known that donor ethnicity strongly correlates with 
recipient ethnicity.  As a consequence, it is expected that only subject enrolled on 0903 who is of 
European descent will have a reasonable likelihood of a suitably HLA-matched donor who also 
has CCR5delta32 homozygosity.  It is estimated that of the 15 patients to be enrolled on study, 
approximately 2/3 or 10 patients will be of European descent.  Of those 10 patients, 
approximately 7 will not have a sibling match.  The search for an HLA well-matched donor with 
homozygosity will therefore be limited to this population.  In order to understand how many 
patients would be expected to have sufficient donors to have a chance of having a CCR5delta32 
homozygous donor, 30 consecutive Caucasian patients searching for a suitably matched donor 
were assessed for availability of potential 5/6 or 6/6 donors at HLA-A, -B, and –DRB1 using 
HapLogic 2. In that study, 3 of 30 patients had more than 200 potentially matched donors. 
Another 6 of 30 had at least 20 but less than 100 donors.  Thus, of the 15 patients to be studied 
on 0903, approximately 1 patient is likely to have a suitably matched CCR5delta32 homozygous 
donor.  Two other patients have a smaller chance of identifying such a donor, so it is estimated 
that 1-2 patients will be able to undergo HCT with such a donor.  
 
It should be noted that the 0903 Protocol Team feels that a patient with multiple unrelated donors 
should be given the option to receive product from a well-matched unrelated donor even if a 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
I-2 
sibling donor is available as long as logistical and financial barriers for such an HCT can be 
managed. 
 
Guiding Principles for Donor Selection on BMT CTN 0903  
1) The first priority for donor selection should be HLA matching such that an 8/8 non-
homozygous donor, including a sibling, for example, would be selected over a 7/8 
CCR5delta32 homozygous donor. 
2) If a sibling donor and a well-matched CCR5delta32 homozygous donor are both 
available, then the transplant team and patient should decide together which donor is to 
be selected. 
 
For Whom Will an Assessment of Donor CCR5delta32 Homozygosity Be Done? 
1) An attempt to identify a suitably HLA-matched donor with CCR5delta32 homozygosity 
for a patient screened and enrolled on 0903 will take place when the following minimum 
conditions are met: 
a. There is a donor with at least a 50% chance of having a 5/6 match using 
HapLogic 2 or a 7/8 match (HLA-A, -B, -C, -DR) based on HapLogic 3 
prediction when available 
2) The assumption is that, in parallel with the search for a CCR5delta32 homozygous donor, 
the standard process for identifying a donor will be followed with typical NMDP and 
transplant center procedures (i.e. donors will be selected by HLA and non-HLA factors, 
other than CCR5delta32 mutation status). 
3) The identification of a suitable unrelated donor must not be delayed by the process to 
identify a donor who is CCR5delta32 homozygous. 
 
Overview of the Process for Identification of a CCR5delta32 Homozygous Donor 
1) When a preliminary search for a patient on 0903 meets the criteria above, potential 
donors as defined by the HapLogic search and the matching criteria above will be 
contacted by the NMDP Member Services Donor Contact Team to confirm continued 
interest and availability to serve as a donor.  The Member Services Donor Contact Team 
will also inform the potential donor that there is a research protocol associated with 
donation and that the research component will be explained by the CIBMTR Survey 
Research Group in a separate conversation. 
2) For donors who are available and willing to donate, then the donor information will be 
passed to the CIBMTR Survey Research Group to inform the donor about BMT CTN 
0903 and the goal of obtaining a CCR5 delta 32 homozygous donor.  The donor will be 
asked to participate in CCR5delta32 screening and those who provide verbal agreement 
will be sent a buccal swab kit by mail with a consent form to sign and return and an 
instruction sheet with the swabs.  The potential donor will return the buccal swab to the 
NMDP Sample Repository for logging and then batching to the CCR5 research testing 
laboratory.  Donors will be informed that CCR5 testing is unlikely to reveal 
homozygosity and unless they are contacted specifically about homozygosity, then the 
result did not reveal homozygosity.  If the donor is homozygous, s/he will be counseled 
about the significance of this finding, irrespective of whether that donor is ultimately 
chosen as the donor for an 0903 subject. 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
I-3 
3) The testing laboratory will provide results to the Protocol Officer or his/her NMDP 
designee and the Protocol Officer or his/her NMDP designee will notify stakeholders as 
appropriate in the event a CCR5delta32 homozygous donor is identified (as well as all 
CCR5 homozygous donors as described above).  Confirmatory CCR5 testing will be 
performed in CLIA-certified lab at the time of donor work-up. 
4) The Protocol Officer and/or his/her NMDP designee will assist the NMDP teams with the 
process.  
 
 
References 
 
Hütter G, Nowak D, Mossner M, Ganepola S, Müßig A, Allers K, Schneider T, Hofmann J, 
Kücherer K, Blau O, Blau IW, Hofmann WK, Thiel E. Long-Term Control of HIV by CCR5 
Delta32/Delta32 Stem-Cell Transplantation. New Engl J Med. 2009; 360:692-8. 
 
Galvani A, Novembre J. The evolutionary history of the CCR5-D32 HIV-resistance mutation. 
Microbes Infect. 2005; 7: 302–309. 
 
 
CCR5delta32 TESTING LABORATORY INFORMATION: 
 
CLIA-Certified Laboratory 
Susan H. Hsu, PhD 
Director, Histocompatibility / Molecular Genetics 
American Red Cross Blood Services 
Penn-Jersey Region 
700 Spring Garden St 
Histocompatibility/Molecular Genetics Dept 
Philadelphia, PA 19123-3594 
Phone : (215) 451-4273 
Fax : (215) 451-2535 
E-mail : shsu@usa.redcross.org 
 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
J-1 
APPENDIX J 
 
REFERENCES 


BMT CLINICAL TRIALS NETWORK 
HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
J-2 
APPENDIX J 
 
REFERENCES 
 
 
Balsalobre, P., J. L. Diez-Martin, et al. (2009). "Autologous stem-cell transplantation in patients 
with HIV-related lymphoma." J Clin Oncol 27(13): 2192-8. 
 
Contu, L., G. La Nasa, et al. (1993). "Allogeneic bone marrow transplantation combined with 
multiple anti-HIV-1 treatment in a case of AIDS." Bone Marrow Transplant 12(6): 669-71. 
 
Gabarre, J., V. Leblond, et al. (1996). "Autologous bone marrow transplantation in relapsed 
HIV-related non-Hodgkin's lymphoma." Bone Marrow Transplant 18(6): 1195-7. 
 
Giri, N., M. R. Vowels, et al. (1992). "Failure of allogeneic bone marrow transplantation to 
benefit HIV infection." J Paediatr Child Health 28(4): 331-3. 
 
Gupta, V., M. Tomblyn, et al. (2009). "Allogeneic hematopoietic cell transplantation in human 
immunodeficiency virus-positive patients with hematologic disorders: a report from the center 
for international blood and marrow transplant research." Biol Blood Marrow Transplant 15(7): 
864-71. 
 
Hamadani, M. and S. M. Devine (2009). "Reduced-intensity conditioning allogeneic stem cell 
transplantation in HIV patients with hematologic malignancies: yes, we can." Blood 114(12): 
2564-6. 
 
Holland, H. K., R. Saral, et al. (1989). "Allogeneic bone marrow transplantation, zidovudine, and 
human immunodeficiency virus type 1 (HIV-1) infection. Studies in a patient with non-Hodgkin 
lymphoma." Ann Intern Med 111(12): 973-81. 
 
Hutter, G., D. Nowak, et al. (2009). "Long-term control of HIV by CCR5 Delta32/Delta32 stem-
cell transplantation." N Engl J Med 360(7): 692-8. 
 
Kang, E. M., M. de Witte, et al. (2002). "Nonmyeloablative conditioning followed by 
transplantation of genetically modified HLA-matched peripheral blood progenitor cells for 
hematologic malignancies in patients with acquired immunodeficiency syndrome." Blood 99(2): 
698-701. 
 
Krishnan, A., A. Molina, et al. (2005). "Durable remissions with autologous stem cell 
transplantation for high-risk HIV-associated lymphomas." Blood 105(2): 874-8. 
 
Re, A., C. Cattaneo, et al. (2003). "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 21(23): 4423-7. 
 


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HCT for HIV+ Patients – Protocol 0903 
 
 
Version 3.0 dated February 18, 2014 
 
 
J-3 
Rossi, G., A. Donisi, et al. (1999). "The International Prognostic Index can be used as a guide to 
treatment decisions regarding patients with human immunodeficiency virus-related systemic 
non-Hodgkin lymphoma." Cancer 86(11): 2391-7. 
 
Seaberg, E. C., D. Wiley, et al. "Cancer incidence in the multicenter aids cohort study before and 
during the HAART era: 1984 to 2007." Cancer. 
 
Serrano, D., R. Carrion, et al. (2005). "HIV-associated lymphoma successfully treated with 
peripheral blood stem cell transplantation." Exp Hematol 33(4): 487-94. 
 
Sora, F., A. Antinori, et al. (2002). "Highly active antiretroviral therapy and allogeneic CD34(+) 
peripheral blood progenitor cells transplantation in an HIV/HCV coinfected patient with acute 
myeloid leukemia." Exp Hematol 30(3): 279-84. 
 
Spitzer, T. R., R. F. Ambinder, et al. (2008). "Dose-reduced busulfan, cyclophosphamide, and 
autologous stem cell transplantation for human immunodeficiency virus-associated lymphoma: 
AIDS Malignancy Consortium study 020." Biol Blood Marrow Transplant 14(1): 59-66. 
 
Torlontano, G., P. Di Bartolomeo, et al. (1992). "AIDS-related complex treated by antiviral 
drugs and allogeneic bone marrow transplantation following conditioning protocol with 
busulphan, cyclophosphamide and cyclosporin." Haematologica 77(3): 287-90. 
 
Vilmer, E., A. Rhodes-Feuillette, et al. (1987). "Clinical and immunological restoration in 
patients with AIDS after marrow transplantation, using lymphocyte transfusions from the 
marrow donor." Transplantation 44(1): 25-9. 
 
Wolf, T., V. Rickerts, et al. (2007). "First case of successful allogeneic stem cell transplantation 
in an HIV-patient who acquired severe aplastic anemia." Haematologica 92(4): e56-8. 
 
Woolfrey, A. E., U. Malhotra, et al. (2008). "Generation of HIV-1-specific CD8+ cell responses 
following allogeneic hematopoietic cell transplantation." Blood 112(8): 3484-7. 
 
 

SAP_001.pdf: 
1 
 
BMT CTN #0903 Statistical Analysis Plan (SAP) 
Drafted by: Maggie Wu on 7/14/16 
 Reviewed by DCC STAT Committee on: 7/15/16 
Reviewed by the Protocol team on: 9/27/16 
Approved on: 12/31/2016 
Updated (based on IQAT recommendations) on: 3/23/2018, version 1.0 
 
 
Protocol:  
BMTCTN #0903 Allo TX for HIV Participants v3.0 
 
Protocol Synopsis:  
The BMT CTN protocol #0903 titled “Allogeneic Hematopoietic Cell Transplant for 
Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals” is a Phase 
II, multicenter trial.  The primary objective is to assess the feasibility and safety of allogeneic 
hematopoietic cell transplantation (HCT) in HIV-infected participants.  The primary endpoint is 
100-Day Non-Relapse Mortality (NRM).  Secondary endpoints include disease status at Day 
100 post-HCT, time to hematopoietic recovery, hematologic function, chimerism, infections, 
overall survival, acute graft vs. host disease and chronic graft vs. host disease, immune 
reconstitution, and impact of HCT on the HIV reservoir.  The target sample size was 15 
participants and participants are being followed for 2 years post-HCT. 
Study Status and Publication Plan: 
The study opened to accrual in May 2012 and the last participant was enrolled in June 2016 
with a total of 20 participants enrolled to the study.  Seventeen participants proceeded to 
transplant as of July 14, 2016 and the last participant was pending transplantation due to donor 
issues.  It is expected that all transplanted participants would have completed 100-day follow up 
by Dec 2016. And it is expected that all participants would complete 2-year follow up per 
protocol by August 2018.  The Endpoint Review Committee (ERC) was formed in July 2016 and 
the ERC is planning to initiate the data review since September 2016 based on the ERC Charter 
developed by DCC statistician and approved by the protocol team.  It is expected that ERC 
process including data QC for the primary endpoint will be completed by November 2016.  Data 
lock is planned as soon as the ERC data compilation will be done to generate the preliminary 
analysis report.  The analysis report will be provided to the team within 2 weeks of the data lock.  
The writing team will prepare a Tandem abstract (submission deadline in December 2016) and 
also work on the manuscript for publication. 
Due to the ERC progress, primary endpoint review was completed in December 2016 and 
already passed the Tandem deadline, the team decided to target a ASCO abstract with deadline 
in Feb 2017. The Abstract was presented at the ASCO as oral presentation. 
 


2 
 
Primary Endpoint and Analysis: 
The primary objective is to assess the feasibility and safety of allogeneic hematopoietic cell 
transplantation (HCT) in HIV-infected participants.  The primary endpoint is 100-Day Non-
Relapse Mortality (NRM) post transplant. The events for non-relapse mortality are death due to 
any cause other than relapse of the underlying malignancy.  The primary analysis will consist of 
estimating the 100-day NRM probability along with a 95% confidence interval using the 
cumulative incidence function. 
There are no interim analyses for this study.  A stopping guideline using the futility boundary 
of a truncated Sequential Probability Ratio Test (SPRT) based on a binomial test of proportions 
for non-relapse mortality was implemented during the trial duration to guard against excessive 
mortality.  
 
Sample Size Calculations and Stopping Guidelines 
 
The sample size is 15 patients for this trial.  Allogeneic transplant for patients with HIV is 
considered unacceptable if 100-day non-relapse mortality probability is 45% or higher.  The 
objective of the study is to show that 100-day NRM is lower than 45%.  In patients without HIV, 
non relapse mortality probability 100 days after allogeneic transplant is expected to be lower 
than 15%.  Therefore, we framed this objective as a hypothesis test of the null hypothesis 
H0:p>=0.45, where p is the 100 day NRM probability, and this study is adequately powered 
against the alternative hypothesis H1:p=0.15.  The stopping rule and study design described in 
detail below has a 8% chance of concluding that allogeneic transplant for patients with HIV has 
less than 45% NRM when in fact the 100 day NRM rate is 45% (type I error), and an 83% 
chance of concluding that the NRM rate is lower than 45% when the 100 day NRM rate is 15% 
(power). 
To guard against excessive mortality, non-relapse mortality will be monitored up to 100 days 
post transplant 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. 
A truncated Sequential Probability Ratio Test (SPRT) based on a binomial test of proportions for 
non-relapse mortality will be used as described below.  This sequential testing procedure 
conserves type I error across all of the monitoring looks for NRM.  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 NRM.  The continuation region of the 
SPRT is defined by two parallel lines.  For a hypothesis test H0:  = 0 versus H1:  = 1 where 0 > 
1, if the graph falls above the upper boundary, accept H0 and if the graph falls below the lower 
boundary reject H0 and conclude H1.  Only the upper boundary will be used to protect against 
excessive NRM which would make it unlikely that we could conclude that the NRM is less than 
45% by the end of the study.   


3 
 
The usual measures of performance of an SPRT are the error probabilities  and  of rejecting 
H0 when  = 0 and of accepting H0 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 testing H0: p = 45% versus H1: p = 15% NRM, with nominal type I and II errors 
of 7% and 30%, respectively.   
• 
The slope of the parallel lines for monitoring NRM is 0.283 and the intercepts are –1.53 
and 0.74. 
• 
Note that the stopping rule shown in Table 5.1 was constructed using the futility 
boundary of this SPRT test.  The futility boundary was used to ensure that the DSMB will 
be notified if it is no longer likely that we will be able to demonstrate that 100-day NRM is 
lower than 45%, thus protecting against excessive NRM.   
 
The futility stopping boundary is shown in below Figure 5.1 for the SPRT test. 
FIGURE 5.1 SPRT STOPPING BOUNDARY FOR 100-DAY NRM 
 
The futility stopping rules are summarized in Below Table 5.1 for the SPRT test. 
TABLE 5.1 STOPPING GUIDELINES FOR 100-DAY NRM AMONG PATIENTS ENROLLED 
Number of patients 
enrolled (n) 
SPRT stopping 
boundary (x) 
2-4 
2 


4 
 
5-7 
3 
8-11 
4 
12-15 
5 
* Stopping guideline is triggered if ≥ x patients out of n patients enrolled experience NRM. 
 
Participants to Include: 
The study enrolled a total of 20 participants.  Only transplanted participants will be included to 
evaluate the post-transplant outcomes, which will be specified below for each.  The participant’s 
eligibility criteria will also be reviewed/adjudicated by the ERC.  
 
Additional data source and data analysis: 
 
Some data will be retrieved from CIBTMR data system including the platelet engraftment 
information and others as needed. 
 
In a secondary analysis, a Cochran-Mantel-Haenszel test will be used to compare 100-day 
NRM probabilities between participants enrolled in this study to matched non-HIV-infected 
participants from the CIBMTR database.  Closely matched controls will be identified at ratio 1:4 
using the following criteria: age, gender, year of transplant, performance status, interval from 
diagnosis to transplant, diagnosis, disease status, preparative regimen/intensity, GVHD 
prophylaxis regimen, cytogenetics if available for acute leukemia. 
Due to the CIBMTR decision, data was not extracted from CIBMTR database and the team 
decided to proceed the publication plan without addition the additional data analysis. 
Software: 
All analyses will be conducted using SAS 9.4 or higher software, or R version 3.1.0 or higher. 
Major procedures will include proc lifetest, proc means, proc freq in SAS and CUMINC in R. 
 
Table of Contents 
 
Data Summary 
Exhibit 0903-1: Demographics and Baseline Characteristics.   


5 
 
Demographics and baseline characteristics will be described by median and range for 
continuous variables and by frequencies and percents for categorical variables.  Characteristics 
to be examined inlcude: age, gender, race, ethnicity, performance status, disease stage, 
genotype, donor type, donor gender, donor-recipient CMV, HLA matching, graft type, 
conditioning regimen, HIV load, CD4 counts, number of prior chemotherapy regimens as 
treatment of primary malignancy and number of prior HIV regimens, bilirubin, creatinine 
clearance, ALT, AST. Data will be tabulated in a table as below: 
 
Table 1: Demographics and Baseline Characteristics 
 
 
 


6 
 
 
Total Enrolled 
 
Total Transplanted 
 
Gender 
 
Male 
 
Female 
 
Ethnicity 
 
Hispanic or Latino 
 
Not Hispanic or Latino 
 
Unknown / not answered 
 
Race 
 
American Indian/Alaskan Native 
 
Black or African American 
 
White 
 
Multi-race 
 
Other (not specified) 
 
Unknown / not answered 
 
Age (yrs) 
 
Mean (Std. Dev.) 
 
Median (Range) 
 
Karnofsky Performance Score 
 
100 
 
90 
 
80 
 
70 
 
 
 
 


7 
 
 
 
Participant Diagnosis 
 
Acute Myeloid Leukemia (AML) 
 
Acute Lymphocytic Leukemia (ALL) 
 
Myelodysplastic Syndromes (MDS) 
 
Hodgkin's Lymphoma 
 
Non-Hodgkin's Lymphoma 
 
Leukemia Stage 
 
First Complete Remission 
 
Second Complete Remission 
 
Lymphoma Stage 
 
Complete Remission 
 
Partial Remission 
 
HIV Load 
 
Undetectable 
 
Detectable 
 
Mean (copies/mL) 
 
Median (Range) 
 
Pre-transplant CMV Status 
 
Positive 
 
Negative 
 
Number of Induction Chemotherapy 
 
1 
 
2 
 
3 
 
4 
 
 
 
 
 


8 
 
 
HLA Match Score 
 
7/8 
 
8/8 
 
Number of Salvage Chemotherapy 
 
0 
 
1 
 
3 
 
5 
 
Conditioning Regimen 
 
Myeloablative 
 
Reduced Intensity 
 
Bilirubin (mg/dL) 
 
Mean (Std. Dev.) 
 
Median (Range) 
 
Creatinine Clearance (mL/min) 
 
Mean (Std. Dev.) 
 
Median (Range) 
 
ALT (units/L) 
 
Mean (Std. Dev.) 
 
Median (Range) 
 
AST (units/L) 
 
Mean (Std. Dev.) 
 
Median (Range) 
 
Baseline CD4 Count (cells/µL) 
 
Mean (Std. Dev.) 
 
Median (Range) 
 
 
 
 
 
 
 


9 
 
Exhibit 0903-2: Non-Relapse Mortality  
The primary endpoint is 100-Day Non-Relapse Mortality (NRM) post transplant. The 100-day 
NRM along with a 95% confidence interval using the cumulative incidence function will be 
provided.  A cumulative incidence curve will be generated. 
Figure 1: Non-Relapse Mortality 
 
Note: Outcomes post the Day 100 of transplant as described below will be provided when data 
becomes available, which is NOT the same time as the evaluation of the primary endpoint – 
Day 100 NRM. 
 
Exhibit 0903-3: Overall Survival  
The overall survival probability at 6 month, 1-year and 2-years with 95% confidence interval will 
be estimated using the Kaplan-Meier product limit estimator.  A survival curve will be generated. 
In an additional analysis, a Cochran-Mantel-Haenszel test will be used to compare 6-month 
overall survival probabilities between participants in the study to matched controls selected for 
the secondary analysis of 100-day NRM as described for the primary endpoint. 
Figure 2: Overall Survival 
 
Exhibit 0903-4: Relapse/Progression  
The event is relapse/progression.  Death without relapse/progression is considered a competing 
risk.  Participants 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.  Relapse rate at 
6 months, 1 year and 2 years will be computed with a 95% confidence interval. A cumulative 
incidence curve will be generated.  
Figure 3: Relapse/Progression 
 
Exhibit 0903-5: Primary Cause of Death 
Table listing the primary causes of death (COD) and time of death post transplant.  The ERC 
adjudicated COD will be used instead of the center-reported COD. Results will be shown in 
Table 2. 
  


10 
 
Table 2: Cause Of Death 
 
Participant # 
Primary COD 
Time of Death 
 
 
 
 
 
 
  
Total Deaths (N) 
 
Exhibit 0903-6: Cumulative Incidence of Neutrophil Recovery 
Time to neutrophil recovery will be the first of two consecutive days of > 500 neutrophils/μL 
following the expected nadir.  It will be estimated using cumulative incidence function with death 
prior to engraftment as the competing risk. Time to neutrophil recovery will also be described 
separately in the myeloablative and reduced intensity groups.  Estimates at Day 28 along with 
95% confidence interval will be provided. 
Figure 4 (A) Neutrophil Recovery for all transplanted participants  
Figure 4 (B) Neutrophil Recovery by Conditioning Regimen  
No need to create curves for by conditioning regimen due to the small sample size, just 
describe 
 
Exhibit 0903-7: Cumulative Incidence of Platelet Recovery 
Time to platelet recovery to > 20,000/μL will be the date platelet count is > 20,000/μL for the first 
of two consecutive labs with no platelet transfusions 7 days prior.  Time to platelet recovery to > 
50,000/μL will be the date platelet count is > 50,000/μL for the first of two consecutive labs with 
no platelet transfusions 7 days prior.  Both will be estimated using cumulative incidence function 
with death prior to engraftment as the competing risk. Time platelet recovery will also be 
described separately in the myeloablative and reduced intensity groups.  Estimates at Day 100 
along with 95% confidence interval will be provided. 
Figure 5 (A) Platelet Recovery to > 20,000/μL for all transplanted participants  


11 
 
Figure 5 (B) Platelet Recovery to > 20,000/μL by Conditioning Regimen  
Figure 5 (C) Platelet Recovery to > 50,000/μL for all transplanted participants  
Figure 5 (D) Platelet Recovery to > 50,000/μL by Conditioning Regimen  
 Due to the small patient number, agreed to remove platelet recovery by conditioning regimen 
and only do the overall.  
Exhibit 0903-8: Hematologic function 
Hematologic function was defined by ANC >1500, Hemoglobin >10g/dL without transfusion 
support, and platelets >100,000.  Table 3 (A) will display the summary statistics for neutrophil 
counts, platelet counts and hemoglobin at Day 100 and 6 months.  
The proportions of participants with hematologic function at Day 100 and 6 months will be 
described with confidence intervals in participants surviving to these time points in table (B).   
Exploratory analysis to examine the relationship between hematologic function and cell dose 
may be conducted in an additional analysis.  
Table 3 (A): Summary Statistics for ANC, platelets and hemoglobin 
Table 3 (B): Summary of Hematologic Function 
Hematologic Function  at Day 100 
 
Yes 
 
No 
 
Have not reached Day 100 post transplant 
 
Hematologic Function at Day 180 
 
Yes 
 
No 
 
Died within 180 days post transplant 
 
Have not reached Day 180 post transplant 
 
Total Evaluable  
 
Total Transplanted 
 
 
Exhibit 0903-9: Disease response  


12 
 
The proportion of participants in complete remission (CR), partial remission (PR), stable 
disease, and relapse at 100 days post-transplant will be described.  ERC adjudicated disease 
status will be used for the analysis. 
Table 4: Disease Response at Baseline and Day 100 
 
Exhibit 0903-10: Chimerism  
Donor T-cell and myeloid chimerism at 4 weeks, 100 days, and 6 months will be described 
separately in the myeloablative and reduced intensity groups, according to proportions with 
mixed (5-95% donor cells), full (>95%), or graft rejection (<5%).  Donor chimerism will be based 
on T-cell assays; If T-cell assay not done, marrow samples will be used.  If marrow assay not 
done, blood samples will be used. Results will be summarized by conditioning group as in Table 
4. 
Table 4: Chimerism 
Chimerism for Myeloablative Group Participants (n=) 
Assessment 
Time point post 
transplant 
Full chimerism 
N (%) 
Mixed chimerism    
N (%) 
Graft rejection 
N (%) 
Total # participants 
surviving/followed to the 
time point N (%) 
@4 weeks 
 
 
 
 
@Day 100 
 
 
 
 
@6 months  
 
 
 
 
Chimerism for Reduced Intensity Group Participants (n=) 
Assessment 
Time point post 
transplant 
Full chimerism 
N (%) 
Mixed chimerism    
N (%) 
Graft rejection 
N (%) 
Total # participants 
surviving/followed to the 
time point N (%) 
@4 weeks 
 
 
 
 
@Day 100 
 
 
 
 
@6 months  
 
 
 
 
 
Exhibit 0903-11: Unexpected Grades 3-5 Adverse Events  


13 
 
Table listing the unexpected grades 3-5 adverse events (AEs) including onset date, severity, 
relationship to protocol and medical monitor assessment. 
 
Table 5: Unexpected Grades 3-5 Adverse Events 
Patient 
ID 
Center 
AE Onset 
Date 
Days 
Since 
Transplant 
Adverse Event 
Description 
[Medical Monitor 
Description] 
Event 
Severity 
Relationship 
to Protocol 
Effect on 
Therapy/ 
Intervention 
DCC 
Expected? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exhibit 0903-12: Grades 3-5 Core and Protocol-Specific Toxicities  
Use bar graphs to show the toxicity frequency within 2 years post transplant for each 
assessment period and overall from transplant through 2 years. Toxicities as expected AEs 
were assessed at Day 28, Day 56, Day 100, Day 180, Day 365 and Day 730 using NCI CTCAE 
version 4.0.  A summary table will be generated to show frequency with maximum toxicity of 
participants experiencing grade 3-5 toxicities and unexpected adverse events classified by 
system organ class. Results for this endpoint will be summarized in the below tables, besides 
the bar graphs. 
 
Table 6: Grades 3-5 Adverse Events (Unexpected AEs and expected Toxicities) 
Within 2 Years of Transplant 
 
Maximum Grades 3-5 AEs by System Organ Class 
Total  
System Organ Class 
Grade 
Blood and lymphatic system disorders 
3 
4 
5 
Grades 3-5 
Cardiac disorders 
3 
4 
5 
Grades 3-5 
Eye disorders 
3 
4 
5 
Grades 3-5 
Gastrointestinal disorders 
3 
4 
5 
Grades 3-5 


14 
 
Maximum Grades 3-5 AEs by System Organ Class 
Total  
…… 
3 
4 
5 
Grades 3-5 
…… 
3 
4 
5 
Grades 3-5 
…… 
3 
4 
5 
Grades 3-5 
Any organs 
3 
4 
5 
Grades 3-5 
 
Figure 6: Toxicity Frequency Within 2 Years of Transplant  
 
Exhibit 0903-13:  Acute GVHD 
Table to summarize the maximum acute GVHD post transplant.  Plots of cumulative incidence 
of acute GVHD grade II-IV (Panel A) and acute GVHD grade III-IV (Panel B) from the time of 
transplant.  Provide estimates of cumulative incidence of acute GVHD grade II-IV or III-IV at day 
100 (as well as Day 180) post transplant, with 95% confidence intervals.  Death prior to 
occurrence of acute GVHD will be considered as a competing risk.   
Results for this endpoint will be summarized in the below table, besides the cumulative 
incidence curves. 
 
Table 7: Acute GVHD 
 
Maximum Acute GVHD Grade 
 
Total 
N 
(%) 
Grade 0, No aGVHD 
Grade I 
Grade II 
Grade III 
Grade IV 
 
 
Total Transplanted 


15 
 
Maximum Acute GVHD Grade 
 
Total 
N 
(%) 
Day 100 Incidence Rate (95% CI) of Grade II-IV acute GVHD 
Day 100 Incidence Rate (95% CI) of Grade II-IV acute GVHD 
 
Figure 7: Acute GVHD 
 
Exhibit 0903-14:  Chronic GVHD 
Table to summarize the maximum grade and overall maximum severity of chronic GVHD.  
Cumulative incidence of chronic GVHD post transplant will be plotted.  Provide incidence rate of 
chronic GVHD at 1-year and 2 years post transplant with 95% confidence intervals.  Death prior 
to occurrence of chronic GVHD will be considered as a competing risk.  
Results for this endpoint will be summarized in the below table, besides the cumulative 
incidence curve. 
 
Table 8: Chronic GVHD 
 
                                          
 N (%)     
1 year Incidence Rate (95% CI)  
 
2 year Incidence Rate (95% CI) 
Maximum Grade of chronic GVHD 
         Limited 
         Extensive 
 
Maximum Severity of chronic GVHD 
         Mild 
         Moderate 
         Severe 
 
 
Figure 8: Chronic GVHD 
 
Exhibit 0903-15: Infections 
Table to summarize the site-reported infections. Number of infections per participant and 
maximum severity of infections per participant will be tabulated.  Total number of infections by 
type of organism will also be tabulated.  Results for this endpoint will be summarized in the 
below table. 


16 
 
 
Table 9: Infections 
 
 
Total 
N    (%) 
# Patients Transplanted 
 
# Patients with Infections 
 
# Patients with Infection Reports 
 
           =1 
 
           =2 
 
           =3 
 
           =4 
 
           =5 
 
           >=6 
 
Total Infection Events 
 
Maximum Severity by Patient 
 
           None 
 
           Moderate 
 
           Severe 
 
           Life Threatening/Fatal 
 
Infection by Type (# of patients) 
 
           Bacterial 
 
           Viral 
 
           Fungal 
 
           Protozoal 
 
           Other 
 
 
Exhibit 0903-16: Immune Reconstitution 
Immune reconstitution assays on peripheral blood which include CD2, CD3, CD4, CD8, CD19, 
CD3+/CD25+, CD45 RA/RO, CD56+/CD3- and quantitative immunoglobulins (IgM, IgG and IgA) 
are measured in all patients prior to the conditioning, at 8 weeks, and 6 and 12 months (and 
possibly 2 years) post-transplant.  These will be summarized at each time point using 
descriptive statistics. 
Table of descriptive statistics as well as box plots across time point will be provided. 
Table 10: Immune Reconsitution 
 
N 
Mean 
Std Dev 
Median 
Min 
Max 
CD2 (cells/µL) 
Baseline 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 


17 
 
 
N 
Mean 
Std Dev 
Median 
Min 
Max 
6 Months 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD3 (cells/µL) 
Baseline 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 (cells/µL) 
Baseline 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD8 (cells/µL) 
Baseline 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD19 (cells/µL) 
Baseline 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 


18 
 
 
 
N 
Mean 
Std Dev 
Median 
Min 
Max 
CD3+/CD25+ (cells/µL) Baseline 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD45 RA/RO (cells/µL) Baseline 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD56+/CD3- (cells/µL) 
Baseline 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgA (mg/dL) 
 
Day 56 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgM (mg/dL) 
Day 56 
 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgG (mg/dL) 
Day 56 
 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
 
1 Year 
 
 
 
 
 
 
 
2 Years 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 9: Immune Reconstitution 
 
 


19 
 
Exhibit 0903-17: Accrual Over Time By Center 
Table showing accrual numbers for each participating center, actual accrual versus projected 
accrual number.   
Table 11: Accrual 
 
Exhibit 0903-18: Significant Protocol Deviations 
Table listing the cumulative significant protocol violations/deviations occurred during the study, 
including transplant center, patient ID, description of the protocol deviations. 
Table 12: Protocol Deviations 
 
Protocol also defined the following two secondary endpoints.  Data are needed from 
outside resource in order to proceed with the intended analysis.  The protocol team 
decision is:  The protocol team will closely follow up with NMDP repository for the lab 
results. If these can be made available prior to the submission of the primary 
manuscript, it will be included in the primary manuscript, otherwise it will be included in 
a follow up analysis to update the manuscript submission or in a secondary manuscript.  
Maintenance of Antiretroviral Therapy 
Maintenance of antiretroviral therapy will be monitored in all patients until time or death or two years 
post HCT whichever occurs first.  Number and proportion of patients maintaining ARV will be 
summarized at 6, 12, and 24 months post-transplant. 
Impact of Therapy on HIV-1 Reservoir  
HIV RNA levels will be measured prior to initiation of ablative chemotherapy, and at Day 100, 12 
months, 13 months (for some patients) and 24 months post-transplant.  Standard assay will measure 
HIV RNA levels (viral load) and for patients with no detectable viral RNA using the standard assay, a 
single copy assay will be performed to assess persistent viremia.  The proportion of patients with 
undetectable viral loads at Day 100, and 12 and 24 months will be examined and an exact binomial 
confidence interval will be calculated.  Additionally, change in viral loads status between consecutive 
time points will be described by the proportion of patients whose viral loads changed from detectable to 
undetectable between assessment times.