Haploidentical Transplant for Patients With Chronic Granulomatous Disease (CGD) Using Post-Transplant Cyclophosphamide
Phase: PHASE1
Conditions: Chronic Granulomatous Disease
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 CGD Haplo Transplant with Cyclophosphamide  
 
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1  
 
 
 
Haploidentical Transplant for Patients with Chronic Granulomatous Disease 
(CGD) using Post-Transplant Cyclophosphamide 
 
NIAID Protocol Number: 15-I-0007 
 
Sponsored by:  
National Institute of Allergy and Infectious Diseases (NIAID) 
 
 
Principal Investigator: Elizabeth Kang 
 
Version Number: 6.0 
 
4 April 2018 
 
 
 
 
 
 

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STUDY STAFF ROSTER 
 
Medical Advisory Investigator:  
Elizabeth Kang 
 
 
NIAID/LHD  
301-402-7567 
 
Research Contact/Study Coordinator(s): 
Corin Kelly, RN, BSN 
 
NIAID/LHD  
301-451-7906 
Nana Kwatemaa, RN, MSN 
NIAID/LHD  
301-451-7820 
Associate Investigator(s): 
Suk See De Ravin, MD, PhD 
NIAID/LHD  
301-496-6772 
Harry Malech, MD  
 
NIAID/LHD  
301-480-6916 
Mark Parta, MD 
 
 
Contractor 
 
301-451-4955 
Corin Kelly, RN, BSN 
 
NIAID/LHD  
301-451-7906 
Nana Kwatemaa, RN, MSN 
NIAID/LHD  
301-451-7820 
 
Collaborator 
Citrin, Deborah 
 
 
NCI/ROB 
 
301-496-5457 
 
 
 

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TABLE OF CONTENTS 
STUDY STAFF ROSTER ............................................................................................................. 2 
LIST OF ABBREVIATIONS ......................................................................................................... 6 
PROTOCOL SUMMARY ............................................................................................................ 7 
PRÉCIS .................................................................................................................................... 8 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .................................................... 9 
1.1 
Background Information ......................................................................................................... 9 
Description of the Study Agent/Intervention(s) .................................................................................. 9 
1.2 
Scientific and Clinical Justification ........................................................................................ 11 
STUDY OBJECTIVES ............................................................................................................... 14 
1.3 
Primary Objective ................................................................................................................. 14 
1.4 
Secondary Objectives ........................................................................................................... 14 
STUDY DESIGN ...................................................................................................................... 14 
1.5 
Description of the Study Design ............................................................................................ 14 
1.6 
Study Endpoints ................................................................................................................... 15 
Primary Endpoint .............................................................................................................................. 15 
Secondary Endpoints ......................................................................................................................... 15 
1.7 
STUDY POPULATION ............................................................................................................. 15 
1.8 
Subject Inclusion Criteria ...................................................................................................... 15 
1.9 
Participant Exclusion Criteria ................................................................................................ 16 
STUDY SCHEDULE ................................................................................................................. 16 
1.10 
Screening ........................................................................................................................... 16 
All Recipients – Initial Screening and Baseline Evaluations ............................................................... 16 
1.11 
Baseline ............................................................................................................................. 17 
Recipients Baseline Clinical Safety Evaluations & Procedures .......................................................... 17 
Recipients Baseline Research Evaluation .......................................................................................... 18 
1.12 
Study Phase ....................................................................................................................... 18 
Collection of Donor Cellular Products ............................................................................................... 18 
Recipient Intervention ...................................................................................................................... 18 
Treatment Plan .................................................................................................................................. 18 
1.13 
Post-Transplant Follow-up (Week 2 to Discharge) .............................................................. 20 
Hospital Discharge Criteria (anticipated anywhere from Day 21 on) ................................................ 20 
Discharge to Day 100 (Out-Patient) .................................................................................................. 21 
Beyond Day 100 ................................................................................................................................ 21 
1.14 
Final Study Visit .................................................................................................................. 21 
1.15 
Early Termination Visit ....................................................................................................... 22 
1.16 
Re-contact of Participants after Trial Termination .............................................................. 22 
CLINICAL MANAGEMENT OF RECIPIENT POST-TRANSPLANT ................................................. 22 
1.17 
Clinical Management .......................................................................................................... 22 
1.18 
Laboratory Evaluations ....................................................................................................... 22 
Analysis of the Research Samples ..................................................................................................... 22 
1.19 
Chimerism Studies .............................................................................................................. 22 
1.20 
Bone Marrow Samples ....................................................................................................... 23 

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POTENTIAL RISKS AND BENEFITS .......................................................................................... 23 
1.21 
Potential Risks to the Recipient .......................................................................................... 23 
Related to the Transplant ................................................................................................................. 23 
Related to GvHD prophylaxis ............................................................................................................ 23 
Related to the Chemotherapies ........................................................................................................ 23 
Related to line placement and venipuncture .................................................................................... 24 
1.22 
Potential Benefits to the Recipient ..................................................................................... 24 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA ................................... 24 
REMUNERATION PLAN FOR PARTICIPANTS ........................................................................... 25 
ASSESSMENT OF SAFETY ....................................................................................................... 25 
1.23 
Toxicity Scale ...................................................................................................................... 25 
1.24 
Specification of Safety Parameters ..................................................................................... 25 
1.25 
Recording/Documentation ................................................................................................. 25 
1.26 
Recipients’ Adverse Events ................................................................................................. 25 
Adverse Events during the Screening Period .................................................................................... 25 
Adverse Events for Enrolled Recipients ............................................................................................ 26 
1.27 
Definitions ......................................................................................................................... 27 
1.28 
Reporting Procedures ......................................................................................................... 29 
Expedited Reporting to the NIAID IRB ............................................................................................... 29 
Waiver of Reporting Anticipated Protocol Deviations, Expected non-UP AEs and Deaths ............... 29 
Annual Reporting to the NIAID IRB ................................................................................................... 29 
Reporting Serious Adverse Events to the Principal Investigator ....................................................... 29 
1.29 
Type and Duration of the Follow-up of Participant after Adverse Events ............................ 29 
1.30 
Safety Monitoring Plan ....................................................................................................... 30 
Expedited Reporting to the NIAID DSMB .......................................................................................... 30 
1.31 
Stopping/Pausing Rules for the Protocol ............................................................................ 30 
1.32 
Halting Rules for the Protocol ............................................................................................. 31 
1.33 
Study Discontinuation ........................................................................................................ 31 
1.34 
Premature Withdrawal of a Participant .............................................................................. 31 
Recipient Voluntary Withdrawal ....................................................................................................... 31 
Involuntary Withdrawal of a Recipient ............................................................................................. 31 
• 
If the Recipient develops a medical condition or circumstance where, in the opinion of the 
investigator, it is in the subject’s best interest to discontinue participation in the study. .................. 31 
1.35 
Involuntary Participant Withdrawal ................................................................................... 31 
Clinical Monitoring Structure ................................................................................................ 32 
1.36 
Site Monitoring Plan ........................................................................................................... 32 
STATISTICAL CONSIDERATIONS ............................................................................................. 33 
1.37 
Informed Consent Process .................................................................................................. 33 
Non-English–Speaking Participants ................................................................................................... 34 
1.38 
Confidentiality ................................................................................................................... 34 
DATA HANDLING AND RECORD KEEPING .............................................................................. 35 
1.39 
Data Capture and Management ......................................................................................... 35 
1.40 
Record Retention ............................................................................................................... 35 
Appendix A: Scientific References ......................................................................................... 36 

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Appendix B: Selection criteria for donor when more than one available ............................... 39 
Appendix C: C1_C5 Recipient SOE Spreadsheet (attached) .................................................... 43 
Appendix D:  Total Body Irradiation Guidelines ..................................................................... 43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
 
Adverse Event/Adverse Experience 
ß-hCG 
beta-human chorionic gonadotropin  
CBC  
Complete blood count  
CFR  
Code of Federal Regulations 
CGD  
Chronic Granulomatous Disease 
CMV  
Cytomegalovirus 
CRF  
Case Report Form 
DHR  
Dihydrorhodamine 123 assay  
DSMB  
Data and Safety Monitoring Board 
EBV  
Epstein Barr Virus  
ECOG 
Eastern Cooperative Oncology Group 
ESR  
Erythrocyte sedimentation rate  
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GTT  
Green Top Tube 
GvHD  
graft versus host disease 
HLA   
human leukocyte antigen  
HSC  
Hematopoietic stem cells 
IB 
 
Investigator’s Brochure 
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
LHD  
Laboratory of Host Defenses 
MUD  
Matched unrelated donor  
MUGA 
multi-acquisition gated  
NIAID  
National Institute of Allergy and Infectious Diseases  
NIH 
 
National Institutes of Health 
OHRP  
Office for Human Research Protections 
PBSC  
Peripheral Blood Stem Cell 
PI 
 
Principal Investigator 
PID 
 
Primary Immune Deficiency 
PTLD  
post-transplant lymphoproliferative disease  
RCHSPB 
Regulatory Compliance and Human Subjects Protection Branch 
RCHSPP 
Regulatory Compliance and Human Subjects Protection Program 
RTT  
Red Top tube 
SAE  
Serious Adverse Event/Serious Adverse Experience 
SCID  
severe combined immunodeficiency  
SMC  
Safety Monitoring Committee 
TB 
 
Tuberculosis 
TBI 
 
Total Body Irradiation 
TREC  
T-cell Receptor Excision Circles  
TTVs  
Transfusion-transmitted viruses  
UP 
 
Unanticipated Problem 
UPnonAE 
Unanticipated Problem that is not an Adverse Event 

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PROTOCOL SUMMARY 
Full Title: 
Haploidentical Transplant for Patients with Chronic Granulomatous 
Disease (CGD) using Post-Transplant Cyclophosphamide 
 
Short Title:  
 
Haplo Transplant with Cyclophosphamide for CGD  
 
Clinical Phase: 
 
0 (Pilot study) 
 
IND Sponsor: 
 
Elizabeth Kang, MD 
 
Conducted by: 
 
Laboratory of Host Defenses 
 
Principal Investigator: 
Elizabeth Kang, MD 
 
Sample Size: 
N=10  CGD recipients  
 
Accrual Ceiling: 
 
20 
 
Study Population:  
Patients with CGD and no human leukocyte antigen (HLA)  
 
 
 
 
fully matched donor 
 
Study Design: 
To perform a haploidentical transplant for patients with CGD 
who have an ongoing infection refractory to standard 
medical intervention. 
 
Study Duration: 
 
Start Date:   1 October 2014  
 
 
 
 
End Date:  1 January 2024 
Study Agent/  
Intervention Description: Post-transplant cyclophosphamide 
 
Primary Objective: 
To determine the efficacy of this allogeneic transplant approach in 
reconstituting normal hematopoiesis and reversing the clinical phenotype 
of CGD   
 
Secondary Objectives: 
To determine the safety of this allogeneic HSCT approach in patients 
with CGD including transplant related toxicity, the incidence of acute and 
chronic graft-versus-host disease, immune reconstitution, overall and 
disease-free survival 

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PRÉCIS 
Allogeneic transplant using HLA matched donors, both related and unrelated, has 
proven curative for patients with various immunodeficiencies, including those with 
ongoing infections.  However donor availability remains a limiting factor in the 
application of this treatment modality.  The use of haploidentical related donors has in 
the past been fraught with a greater rate of complications related to both higher rates of 
GvHD and delayed immunorecovery.  Newer transplant regimens appear to have 
diminished these risks and improved outcomes.  We propose using a reduced intensity 
conditioning regimen followed by post-transplant cyclophosphamide for patients with 
CGD who do not have an HLA matched donor but whose circumstances necessitate the 
use of a potentially curative, albeit high-risk treatment modality. 
 

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 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
1.1 
Background Information 
Description of the Study Agent/Intervention(s) 
This is an open-label pilot study using haploidentical transplantation (Hematopoietic 
transplantation using a related donor that matches at least ½ by Human leukocyte 
antigen (HLA) typing) to treat patients with CGD.  The conditioning regimen will consist 
of standard FDA approved drugs, but the unmanipulated graft will be followed by 
cyclophosphamide to prevent graft versus host disease.  
 
Chronic Granulomatous Disease (CGD) 
CGD is one of a group of inherited disorders affecting neutrophil function.  Due to 
mutations in one of the genes encoding the phagocyte NADPH oxidase, patients with 
CGD are susceptible to recurrent bacterial and fungal infections.  Besides life 
threatening infections, these patients develop granulomas that can result in 
genitourinary or gastrointestinal tract obstruction.  Iatrogenic or infection related end 
organ damage has also been seen in long-term survivors of CGD.  Despite 
improvements in infection prevention and control, 2% of patients with CGD die each 
year, and few patients survive to age 50.(3)   
 
Treatment of CGD - Prophylactic Antibiotics and Interferon gamma 
All CGD patients receive prophylactic antibiotic coverage with agents such as 
trimethoprim/sulfamethoxazole.  Prophylactic Interferon gamma therapy has been 
shown to decrease the incidence of infection but it is not well tolerated, and long-term 
compliance is rare.  When infections do arise, emphasis is placed on identifying the 
pathogen and treating with the appropriate antibiotic for a prolonged period of time.  
When granuloma formation complicates an infection, a course of steroids is often 
effective.(1) 
 
Gene Therapy for CGD 
The genes responsible for the 4 most common forms of CGD have been cloned.  A fifth 
type of CGD with a mutation in the P40 gene has also been described but only 2 
patients have been documented with this form of CGD. A number of small animal 
studies including xenogeneic models have shown proof of principal using vectors 
corrective for both the p47 mutation and the gp91 mutation.(2-4) Results of a Phase I 
clinical trial of gene therapy for patients with the p47-deficient form of CGD have also 
been reported as well as a more recent study treating patients with the gp91 mutations. 
(5) The authors demonstrated that autologous hematopoietic progenitors can be 
transduced with a retroviral vector containing the missing gene.  These progenitor cells 
were then safely infused back into the patient, and small numbers of gene-corrected 
neutrophils were detectable in the peripheral blood for up to 6 months.  However, 
without a selective advantage conferred upon the transduced cells, there was 
insufficient engraftment and/or proliferation to sustain a long-term cure. In 2006, a 
German-Swiss collaborative study resulted in two patients achieving clinical benefit after 
receiving genetically transduced cells with the use of busulfan preconditioning.  Both 

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patients maintained a level of 20% of corrected cells in the peripheral blood (6); 
however the first patient succumbed to a CGD related infection felt to be secondary to 
poor expression of the gp91 protein on a per cell level and both patients developed a 
myelodysplasia as well as evidence of silencing of the vector-derived gene.   At the NIH, 
we initiated a clinical protocol treating 3 patients with X-linked CGD using a retroviral 
vector.  One patient expired of his infection after apparently rejecting the genetically 
modified cells.  The other two remain marked albeit at low levels including one patient 
who is 7 years post gene therapy who still has 0.5% marking.  This is the highest level 
of long term marking in any patient to date. We are now in the process of establishing a 
new clinical gene therapy trial for patients with X-linked CGD using a lentiviral vector.  
The protocol is designed for patients who have an underlying infection without an 
available HLA matched donor, related or unrelated, but is still awaiting FDA approval.  
 
Allogeneic (Allo) Transplantation  
Allogeneic transplantation (transplant of hematopoietic derived stem cells from a related 
or unrelated donor) has been used successfully to cure patients with CGD.  The best 
donors are those who match as closely as possible by HLA typing (Human leukocyte 
antigen).  These are a set of proteins or markers that determine immune reactions 
within the body. The vast majority of successful transplants have also used 
myeloablative conditioning regimens (regimens that essentially wipe out the marrow 
necessitating replacement with new cells). The toxicity and associated morbidity and 
mortality of these regimens, however, have limited the widespread use of allo 
transplants as a therapeutic option for many patients and their referring physicians.  
More recent efforts using  reduced intensity and nonmyeloablative regimens have 
reduced mortality and morbidity, but these regimens have simultaneously incurred an 
increased rate of graft rejection.  In addition, despite an overall reduction in toxicity, 
patients still experienced significant GvHD as in the study performed here, where 2 of 
15 patients died within one year of transplantation.(7) A third patient died suddenly from 
sepsis 2 years post-transplant, although there was no obvious evidence of GvHD and 
the patient had had a successful engraftment.  However of the remaining patients, 
including those who did not engraft, all are alive.   A number of these survivors have 
successfully undergone second transplants with good results. Thus, alternative 
regimens are needed to improve initial engraftment and further reduce GvHD incidence. 
 
Matched Unrelated Donor Transplantation 
Matched unrelated donor transplantation has also been shown to be curative of CGD.  
Gungor et al recently published results in 54 patients (35 using unrelated donors, 19 
with related donors) transplanted in 16  different centres using targeted dose busulfan 
(AUC target 45-64mg*h/L or 10976-15854 min*uMol/L.)(8)   
Under NIH Protocol 07-I-0075, using a nonmyeloablative conditioning regimen, we have 
transplanted 34 patients to date (thus the largest single centre for CGD transplant to 
date) using unrelated donors with no patient developing greater than grade 2 acute graft 
versus host disease with the initial transplant. Included in this group were 28 patients 
considered high risk due either to the presence of ongoing infection and/or active 
inflammation from autoimmune disease.   (In patients receiving a stem cell boost for 
graft loss, we have seen Grade 3 GvHD).  We have also had only one patient develop 

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chronic graft versus host disease, which responded well to treatment. This data is 
similar to the results obtained by Gungor et al.(8) which had an overall 96% survival in a 
less high risk population compared to the NIH group. Thus for patients without an HLA 
matched sibling donor, using an unrelated HLA matched donor is a reasonable option 
and preferable to a haploidentical transplant.  However, the ability to find a donor is 
always a limiting option for this form of therapy and more difficult for patients of less 
common or mixed ethnicity.  Although we have had good success in finding donors for 
38 patients, we have had 5 patients with no available HLA matched donor in our 
searching. 
 
Haploidentical Transplantation 
Although, there is almost universal availability of a haploidentical related donor for any 
given patient, other than for patients with severe combined immunodeficiency (SCID), 
haploidentical transplantation has been used only when there is no available HLA 
matched donor.  In most cases, haploidentical transplants have been associated with 
higher rates of graft rejection, as well as graft versus host disease and slow immune 
reconstitution.   Novel techniques are now expanding the application of haploidentical 
transplantation and have been used to transplant a number of patients with 
immunodeficiencies who do not have an available HLA matched donor. Further, using 
older techniques, the rates of success between mismatched unrelated donor and 
haploidentical related donor transplant has been similar. Thus, with improvements in 
haploidentical transplantation, the readily available haploidentical related donor may be 
preferable to a mismatched related donor.  
1.2 
Scientific and Clinical Justification 
We are proposing this protocol to treat patients with allogeneic transplantation, as it is 
the only known curative treatment for CGD, using related donors that match at least ½ 
by HLA typing (haploidentical).  Although we have a matched related and unrelated 
donor protocol available, many patients will not have an available HLA matched donor.  
In order to provide this curative option, we need to use a haploidentical graft in order to 
treat patients whose clinical condition justifies higher risk but potentially curative 
treatment.  
 
This protocol aims to decrease the risk of transplant related mortality associated with 
haploidentical transplantation, while offering the potential for cure of CGD. 
 
As described previously, matched related donor transplantation is curative for patients 
with CGD as well as for other Primary Immune Deficiencies (PIDs), and for those 
patients who lack an HLA-matched sibling donor.  Matched unrelated donor (MUD) 
transplantation has also been used. In a retrospective study that reviewed patients with 
various types of SCID, the survival of patients was 80% at 168 months post 
transplantation. Most deaths were related to either GvHD or infection, and 3 of 41 
patients experienced graft failures. There was a 73% incidence of GvHD, but only 22% 
of patients had Grade 3 or higher. As this study was retrospective, the conditioning 
regimens and GvHD prophylaxis differed amongst the centers and patients, so the 
effects of conditioning cannot be determined from this study.(9)  

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Matched unrelated donor and umbilical cord transplantations have also been used in 
patients with immunodeficiencies, although the number of patients is limited, particularly 
in CGD.   
 
Umbilical cord blood is an attractive option as there is data to suggest that there is less 
risk of GvHD induction, given the immunologic immaturity of these cells.  It is also 
possible to transplant across more HLA mismatches with less risk of GvHD or rejection.  
However, the disadvantages to using cord blood have been related to the smaller 
number of grafted cells and the resultant delayed immune recovery post-transplant.  In 
a 1997 analysis, better survival was associated with: age less than 6 years, weight less 
than 20 kg, an infusion of greater than 37 million nucleated cells per kg, and a CMV 
(cytomegalovirus) negative donor.(10) Hence, cord blood transplant has been 
traditionally limited to recipients of young age and low body mass.  In an effort to 
increase the cell dose, the University of Minnesota in particular has been using more 
than one cord blood product per patient, with very promising results.  In these patients 
with high-risk hematologic malignancies, the disease free survival was 57% at 1 year, 
and 72% overall survival for patients transplanted while in remission.(11)  
 
Cord blood from an HLA matched sibling was used in 1 patient with CGD after a 
busulfan based conditioning regimen.  One year post-transplant, the patient appeared to 
have a Dihydrorhodamine 123 assay (DHR) of 92% and normal T and B cell numbers.   
 
In addition, transplantation centers have been developing reduced intensity (or 
nonmyeloablative conditioning regimens) for use in MUD and umbilical cord blood 
transplantation, and have applied these methods to both adults and children.  With a 
median nucleated cell dose of 3.7 x 107/kg recipient body weight, the overall 
engraftment was between 76% and 95% depending on the conditioning regimen used in 
a single center trial.  The incidence of GvHD was 9% and survival was 39% in this high-
risk group of patients.(12) However, in our experience at the NIH, 2 patients with CGD 
rejected cord blood grafts.  Further, data from Duke suggests that a myeloablative 
regimen is necessary for engraftment with a cord blood transplant(13),  thus making this 
less desirable for patients with a progressive infection. Further, hematopoietic recovery 
is also significantly slower when using cord blood products, which is also problematic in 
the face of an ongoing infection in the recipient.  
 
Only 25% of patients have a matched sibling, and in the setting of a congenital disorder, 
this is reduced to 10-15%, and only one-half of individuals have a matched unrelated 
donor. Alternative options include mismatched unrelated donors, and haplotype ( a type 
of mismatched) related donors. The particular advantage of a haplotype family member 
include: donor availability for almost all patients, ability to select the best donor family 
member, and the absence of delay in obtaining the graft source.(14) Historically, the 
major drawback of haploidentical related donor transplant has been the very strong 
graft-versus-host and host-versus-graft allo-responses due to the high frequency of T 
cells that recognize major class I or class II disparities between donor and recipient (15) 

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but when T cell depletion was used to modify the donor graft, there was a high rate of 
rejection of the donor grafts.(16) 
 
In recent years there has been a renewed interest in both T cell depleted and T-cell 
replete full haplotype mismatched allogeneic transplant.(17, 18) With T-cell depleted 
haploidentical transplant, the major problem remains rejection and delayed immune 
reconstitution. Infection is a major problem in immunodeficiency diseases where 
patients may enter transplant with serious opportunistic infections. Moreover, T-cell 
depletion has not been shown to improve outcomes after HLA-mismatched allogeneic 
transplant.  
 
An effort to improve outcomes with  haploidentical transplant has been pioneered by a 
group at Johns Hopkins Hospital, whereby they administer cyclophosphamide (Cytoxan) 
a few days after the graft has been given.  The rationale is that the T cells that become 
activated post infusion are responsible for the generation of graft versus host disease.  
These cells are then susceptible to the cyclophosphamide, which is a highly 
immunosuppressive drug that targets cycling cells as opposed to quiescent non-reactive 
T cells.  This allows the use of a T-replete graft, thus reducing the recovery time for 
immune recovery, while still decreasing the risk of GvHD. (19) Other centers have 
started to use this same technique, including investigators in the NCI, where they are 
treating patients with DOCK8 and GATA2 deficiency who do not have an HLA matched 
donor, related or otherwise and investigators in NHLBI treating patients with Sickle Cell 
Disease.  Results have been promising, but data is also preliminary with some graft 
versus host disease, but successful engraftment in all patients to date.  As noted 
previously, patients that appear to have higher resistance to engraftment, such as those 
with sickle cell anemia, have not had as much success at least with lower doses of 
cyclophosphamide. Now with higher doses of cyclophosphamide, they have had better 
engraftment and have not seen any GvHD to date. (Personal communication John 
Tisdale).  Further, there is a report of a haploidentical transplant using post transplant 
cyclophosphamide being done using the Hopkins protocol for two patients with CGD at 
Children’s Hospital of Pennsylvania, but these patients did not engraft (personal 
communication, Kathleen Sullivan, ASBMT oral presentation).   
 
We therefore propose using post-transplant cyclophosphamide similar to the Hopkins 
regimen and also similar to that being used by Dennis Hickstein (principal investigator 
using haploidentical transplant to treat patients with the disorders of DOCK8 and 
GATA2 deficiency) and John Tisdale/Courtney Fitzhugh using haploidentical transplant 
for the treatment of patients with Sickle Cell Anemia.  Due to the engraftment difficulties 
in CGD patients as described, above we are increasing slightly the target AUC of the 
busulfan compared to the DOCK8 protocol.  We are also planning to use mobilized 
peripheral blood stem cells (as being used in the Sickle Cell Haploidentical protocol) to 
increase the cell dose and improve the likelihood of engraftment.  These two changes 
should improve the engraftment rates as compared to the results from the patients 
transplanted at Children’s Hospital of Philadelphia.    
 

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In the majority of these studies, there has been little to no post-transplant GvHD 
prophylaxis used, but we will include low dose sirolimus as it is a tolerizing agent (as 
opposed to calcineurin inhibitors such as tacrolimus or cyclosporine). It is generally well 
tolerated and may allow us to further decrease the degree of conditioning required for 
engraftment.  This is similar to the NHLBI Sickle Cell protocol which is also using single 
agent sirolimus.  
 
Finally, the dose of busulfan being used is not fully myeloablative.(20, 21) However our 
target (4000-6000 uM/min) is higher than that used by Beri et al. (22) (3600-4800 
uM/min) as patients with CGD have a higher resistance to engraftment.   Therefore this 
dose is higher than that being used in the standard regimen, but still low enough that we 
should see autologous recovery in the setting of graft failure. (23) (It is also in fact lower 
than the targeted dose used in the European nonmyeloablative regimen for 
transplantation of CGD patients-see above.) Thus this is considered a reduced intensity 
regimen.(24) 
 
Given this higher dose, when feasible, we will obtain an autologous back up product 
from the recipient, which would provide a source of rescue cells should autologous 
recovery not occur; however this is not mandatory as the expectation, consistent with 
our experience from the matched unrelated donor transplant data whereby patients 
receiving busulfan in the ranges of 4000-8000uM/min combined with TBI have had 
autologous recovery, is to have bone marrow recovery in the setting of graft failure. 
STUDY OBJECTIVES 
1.3 
Primary Objective 
To determine the efficacy of this allogeneic transplant approach in reconstituting normal 
hematopoiesis and reversing the clinical phenotype of CGD   
1.4 
Secondary Objectives  
To determine the safety of this allogeneic HSCT approach in patients with CGD 
including transplant related toxicity, the incidence of acute and chronic graft-versus-host 
disease, immune reconstitution, overall and disease-free survival. 
STUDY DESIGN 
1.5 
Description of the Study Design 
This is an open-label study designed to treat patients with CGD using a reduced 
intensity conditioning regimen and post-transplant cyclophosphamide. 
 
 
 
 
 
 
 

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1.6 
Study Endpoints 
Primary Endpoint 
Engraftment of a haploidentical graft without incurring graft versus host disease as 
determined by Day 30 
Secondary Endpoints  
1) Stable Chimerism as indicated by 30-50% myeloid engraftment and 50% 
lymphoid engraftment  as assessed by 1 year post transplant 
2) Immune reconstitution levels with DHR as a marker of normal neutrophil function 
by 1 year post transplant. 
1.7 
STUDY POPULATION 
We will recruit up to 10 patients with CGD who do not have an HLA matched donor but 
whose circumstances necessitate the use of a potentially curative, albeit high-risk 
treatment modality.  The needed progenitor cells will be provided from a biologically 
related donor of the affected recipient. 
  
We plan to evaluate both parents and any eligible siblings as potential donors utilizing 
NIAID LHD screening protocol 05-I-0213 and will use the attached algorithm to 
determine the best donor when feasible (see Appendix B). Once the determination has 
been made,the donor will be collected on our NIAID approved apheresis protocol 94-I-
0073. 
 
See section 10.10 Stopping/Pausing Rules for Protocol.   
1.8 
Subject Inclusion Criteria 
• 
Must have sufficient complications  from underlying disease to warrant undergoing 
transplantation  
• 
Ages 2 years – 65 years 
No appropriate HLA matched donor (available donor has greater than 1 
mismatch or the single mismatch is not at DQ for unrelated donors (including 
cord blood products), or no available 6 out of 6 HLA matched related donor), or 
patients who may have an unrelated donor, but whose clinical status is such that 
the time required to obtain an unrelated donor would be life threatening. 
 
• 
HLA haploidentical family donor graft available.   
• 
Ability to comprehend and willingness to sign the informed consent or have a 
parent/guardian consent if the donor is a minor; assent being obtained from minors 
as appropriate 
• 
Must be HIV negative 

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• 
Must not be pregnant (confirmed by a negative serum beta-human chorionic 
gonadotropin (ß-hCG) for women of child-bearing potential) or breastfeeding 
• 
Must be able to stay within one hour’s travel of the NIH for the first 3 months after 
transplantation and have a family member or other designated companion to stay 
with during the post-transplant period. 
• 
Must provide a durable power of attorney for health care decisions to an 
appropriate adult relative or guardian in accordance to NIH Form-200 “NIH Durable 
Power of Attorney for Health Care Decision Making.” 
• 
Where appropriate, subjects must agree to use contraception for 3 months post-
transplant 
1.9 
Participant Exclusion Criteria  
• Major anticipated illness or organ failure incompatible with survival from Allo-
transplant 
• Inadequate collection from prospective donors. 
STUDY SCHEDULE 
1.10 Screening  
 All Recipients – Initial Screening and Baseline Evaluations 
The following will be done to aid in determining study eligibility (results may be obtained 
on another NIH approved protocol or from an outside source) 
 
• 
Informed consent signed 
• 
Low resolution molecular HLA typing of patient recipient and as many family 
members as possible to confirm complete matching of the donor 
• 
Confirmation low resolution molecular HLA typing of selected donor. 
• 
HLA antibody screen 
• 
KIR typing (At the discretion of the PI) 
• 
ABO typing  
• 
CMV antibody testing  (If test has been completed at some point in the past and 
the results are positive, the test does not need to be repeated.  Otherwise, tests 
results must be obtained within 1 month of transplant.)  
• 
Epstein Barr Virus (EBV) antibody testing (If test has been completed at some 
point in the past and the results are positive, the test does not need to be repeated.  
Otherwise, tests results must be obtained within 1 month of transplant.) 
• 
Chem 20 panel (or the equivalent as per NIH ordering system) 
• 
Transfusion-transmitted viruses (TTVs) as per Department of Transfusion Medicine 
(DTM) SOPs. 

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• 
Infectious Disease Screening (If test have been completed previously within 3 
months of transplant, do not need to be repeated.) 
o May include HSV 1 and 2, Toxoplasmosis, syphilis, TB-anergy panel  
o TB testing will be completed.  In countries where the BCG vaccination is 
administered, Quantiferon testing may be done in place of PPD testing.  
• 
Disease Specific testing 
• 
Serum ß-HCG for women of child-bearing potential 
• 
Cardiac function: EKG, and multi-acquisition gated (MUGA) scan or 
Echocardiogram 
• 
Durable power of attorney form completed 
• 
Complete medical history and physical examination, including weight. 
 
Please note: Blood draw amounts will conform with MAS M(95-9) policy.  
1.11 Baseline  
Recipients Baseline Clinical Safety Evaluations & Procedures 
These baseline studies will be performed as medically necessary to ensure no occult 
infection or other medical condition, which could necessitate delay of the transplant 
procedure.   
• Coagulation screen 
• Complete blood count (CBC) with differential 
• Erythrocyte sedimentation rate (ESR) 
• C-reactive protein 
• WBC short tandem repeat chimerism profile (blood or buccal swab) 
• Complete lipid profile with triglycerides 
• Bone marrow aspirate 
• Collection of 24-hour urine for assessment of creatinine clearance 
• Pulmonary Function Test (at the discretion of the PI.) 
• Imaging appropriate to assess the status of the patient which may include:  CT scan 
of chest, abdomen, pelvis and sinuses 
• Nutritional assessment 
• Dental exam and clinical review 
• Social worker interview 
• Ophthalmology consultation 

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• Pediatric Consult for patient under 18 years 
• Autologous Recipient Collection (back up collection-when feasible): Patient will be 
consented on to NIH Protocol 94-I-0073 
Recipients Baseline Research Evaluation 
These will be used to evaluate research study endpoints 
• T cell Receptor Vß spectra type 
• Lymphocyte phenotype 
• T-cell Receptor Excision Circles (TREC) 
• Research Blood (1 sodium heparin green top tube (GTT), 1 Red top tube (RTT)) 
• Quantitative Immunoglobulins 
1.12 Study Phase 
Collection of Donor Cellular Products 
Potential donors will be screened under protocol 05-I-0213. An appropriate donor will be 
selected by the PI using Appendix B of this protocol as guidance.  All donors will 
undergo mobilization and collection of cellular products under protocol 94-I-
0073.  Products will be processed as per cell processing PSI for protocol 15-I-0007. 
Recipient Intervention 
Treatment Plan 
The Recipient will be admitted to an inpatient unit for a minimum of 13 days prior to PBSC 
infusion.  The total anticipated number of inpatient days is 40. (See Appendix D2-D5: 
Schedule of Events) 
 
Busulfan test dose (within 1 month starting conditioning.) 
Single Busulfan test dose: 0.8 mg/kg IV infusion over 1-2 hours given anytime within 1 
month prior to starting conditioning. 
 
Drug (busulfan) levels will be obtained for the single Busulfan test dose at the end of 
infusion, and approximately 135, 150, 180, 240, 300, 360, and 480 minutes after 
starting the infusion of the drug. 
 
Day  -6 (6 days prior to cell infusion) 
Fludarabine 30 mg/m2 over 30 minutes 
Cyclophosphamide 14.5 mg/kg IV over one hour 
Blood tests+/- 3 days:  ESR, CRP  
 
 

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Day  -5  (5 days prior to cell infusion) 
Fludarabine 30 mg/m2 over 30 minutes 
Cyclophosphamide 14.5 mg/kg IV over one hour 
 
 
 
 
  
Day  -4, -3, -2 (2-4 days prior to cell infusion) 
Fludarabine 30 mg/m2 over 30 minutes 
Busulfan 3.2 mg/kg IV once daily over 2-3 hours (adjusted based on test dose to target AUC 
of 4000-6000 uM/min) 
 
Drug (busulfan) levels will be obtained on Day -4 prior to the infusion, at the end of 
infusion, and approximately 135, 150, 180, 240, 300, 360, and 480 minutes after 
starting the infusion of the drug.  (Day -3 and Day -2 do not require Busulfan drug 
levels.)  
 
Day  -1 
Total Body Irradiation (TBI) 200cGy (see Appedix E) 
 
 
 
 
 
Day 0 (Day of Cell Infusion) 
Infuse donor graft.  
Blood tests:  ESR, CRP  
Research blood:   Red top serum tube (10 ml for adults, 5 ml for pediatric patients). * 
 
Day +1 
Blood tests + 3 days:  ESR, CRP 
Research blood:   Red top serum tube (10 ml for adults, 5 ml for pediatric patients). * 
 
 
 
Day +2 
Intravenous hydration will be started 12 hours prior to cyclophosphamide and will 
continue for approximately 24 hours after cyclophosphamide infusion.    
 
Day +3 and +4  
Cyclophosphamide 50 mg/kg/d IV infused over 90 minutes. 
Mesna, 50 mg/kg/day, given over 24 hours.  
 
Lasix to be administered as clinically indicated. 
 
Refer to the “BMT consortium Supportive Care Guidelines: Hemorrhagic Cystitis 
Prevention with High-Dose Cyclophosphamide” at  
http://intranet.cc.nih.gov/bmt/education/supportive-care.shtml.  (Adjustments may be 
made to these guidelines based on the clinical status of the patient.) 
 
Day +5 
For pediatric patients:  Begin sirolimus 1 mg/m2 PO q4h for 3 doses, then 1 mg/m2 once a day 
(QD).  
For adult patients, begin sirolimus 5 mg PO q4h for 3 doses, then 5 mg once a 
day (QD). 
 

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Doses may be adjusted to maintain trough levels between 8-14 ng/mL. Recipients will take 
sirolimus from Day +5 to at least Day 100 (minimum). 
 
*These will be drawn at the discretion of the PI.  
 
  
1.13 Post-Transplant Follow-up (Week 2 to Discharge) 
Hospital Discharge Criteria (anticipated anywhere from Day 21 on) 
Recipient will be discharged when the following criteria are fulfilled:   
• 
Recipient afebrile, positive weight balance, no parenteral feeding 
required. 
• 
Neutrophil count greater than 500 on 3 consecutive days. 
• 
Platelet transfusion requirement absent or manageable as an outpatient. 
• 
Recipient or family able to care for central venous catheter. 
The following research labs may be obtained while the Recipient is an inpatient until 
discharged: 
 
Table 1: Research Labs for the Recipient 
LABS 
Week 2 
Week 3 
Week 4 
Week 5 
 
ESR 
 
1 X week 
1 X week 
1 X 
week 
 
1 X week 
CRP 
1 X week 
1 X week 
1 X 
week 
1 X week 
Chimerism 
 
 
+ Day 14  
(+/- 4 days) 
 
+ Day 30 
(+/- 4 days) 
Sirolimus 
Levels 
 
1 X week 
1 X week 
1 X 
week 
1 X week 
Lymph Pheno 
(BMT) 
 
+ Day 14 
(+/- 4days or 
when absolute 
lymphocyte 
count is >0.2 
K/uL 
 
+ Day 30 
(+/- 4 days) 
(or when 
absolute 
lymphocyte 
count is >0.2 
K/uL 
DHR 
 
Day 14 
(+/- 4 days) 
 
Day 30 
(+/- 4 days) 

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Research Labs 
Red Top Tube; Na 
Heparin GTT 
 
Day 14 
(+/- 4 days) 
 
Day 30 
(+/- 4 days) 
• Clinical Safety labs will be obtained.  These may include: CBC with 
differential, DHR in appropriate recipient, Chem 20 panel, CMV/EBV-
PCR, Lipid panel and Sirolimus levels to guide dosing. 
 Discharge to Day 100 (Out-Patient) 
• Clinical Safety labs will be obtained at least weekly or in some cases monthly.  
These may include: CBC with differential, DHR in appropriate recipients, Chem 
20 panel, CMV/EBV-PCR, lipid panel, pregnancy test, and Sirolimus levels to 
guide dosing. 
 
• Research Labs will be obtained as follows: 
• Weekly: ESR, CRP, Serum Quantitative Immunoglobulin levels  
• Day +60 (+/-10 days) and Day +100 (+/- 10 days). Chimerism, DHR,  1-10 
ml sodium heparin GTT, 1-10 ml red top serum (pediatric patients may 
have 5 ml.), Lymphocyte phenotype  
• (D+100 only) will be drawn.  A bone marrow aspirate may be obtained on 
day 100 only.   
Beyond Day 100 
At 6, 12, 18, 24, 36, 48, and 60 months (+/- 30 days):  
• Clinical Safety Labs (as specified above) 
• Chest CT  
• Research Labs - ESR, CRP, Serum Quantitative Immunoglobulin levels, Chimerism, 
DHR, 1-10 ml sodium heparin GTT, 1-10 ml red top serum (pediatric 
patients may have 5 ml.), Lymphocyte phenotype  
• CMV/EBV (6 months only) 
• Vß spectra type or flow at 2 years only 
• TREC analysis 
• Bone marrow aspirate at 1 year 
• Pulmonary function test at 12 and 24 months minimum 
• Post immune responses per PI discretion 
1.14 Final Study Visit 
Recipients:  Participants will have their final study visit 5 years post-transplant.  Visit 
evaluations are specified above in section 5.4. 
 

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1.15 Early Termination Visit 
Please see below section 10.12 Premature withdrawal of a Participant 
1.16 Re-contact of Participants after Trial Termination 
Participants will be followed on NIAID IRB protocol 05-I-0213 “Screening and Baseline 
Assessment of Patients with Abnormalities of Immune Function” starting 5 years after 
transplantation on this study and will continue to be followed annually as long as the 
patient is willing to return to NIH. 
CLINICAL MANAGEMENT OF RECIPIENT POST-TRANSPLANT 
1.17 Clinical Management  
We will manage the transplant recipient appropriately according to standard of care and 
“Supportive Care Guidelines of the NIH”* in the event of the medical complications such 
as those listed below, which are known to occur in this patient population post-
transplant, as well as anything not listed but related to the transplant  
• Infection 
• Fever (including neutropenic fever) 
• GvHD (acute and chronic) 
• Decrease in patient daily caloric intake 
• CMV Reactivation 
• Epstein Barr Virus (EBV) associated post-transplant lymphoproliferative disease 
(PTLD) 
• Relapse of Original Disease 
*(See also Supportive Care Guidelines, available at 
http://intranettst2.cc.nih.gov/bmt/clinicalcare) 
1.18 Laboratory Evaluations 
Please see section 5.4.2 for specific laboratory evaluations and the distinction between 
the research driven evaluations and those done for the clinical/medical management 
(clinical safety labs) of the participant. 
Analysis of the Research Samples 
Specimens collected strictly for research purposes will not be read by a pathologist.  
Samples will be ordered and tracked through the CRIS Research Screens.  Should a 
CRIS screen not be available, the NIH Form 2803-1 will be completed and will 
accompany the specimen and be filed in the medical record. 
1.19 Chimerism Studies 
We will use PCR analysis of microsatellites to identify the contribution of the donor 
Hematopoietic stem cells (HSCs) to post-transplant hematopoiesis and to detect donor 
lymphocytes in the circulation (i.e., donor-recipient chimerism). 

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1.20 Bone Marrow Samples 
A volume (up to 25 mL) of bone marrow aspirate will be collected for research studies.  
These will be used to help elucidate the contribution of the progenitor cells to the 
circulating component. 
POTENTIAL RISKS AND BENEFITS 
1.21 Potential Risks to the Recipient 
Related to the Transplant 
The mortality from conventional BMT may be as high as 40%.  Although our data as 
well as that of others suggest a significant reduction in transplant-related mortality with 
nonmyeloablative “mini” PBSC transplantation, the procedure nevertheless carries 
significant risk.  It is therefore only appropriate to carry out this experimental procedure 
in the context of debilitating or life-threatening conditions and with full informed consent 
from the patient, donor, and immediate family.  The specific hazards of this study using 
a subablative preparative regimen and high HSC-content graft are graft rejection, graft 
versus host disease, and disease relapse.  The major discomforts are those of nausea, 
anorexia, diarrhea, fever and malaise, and intolerance of the isolation period.  
Related to GvHD prophylaxis 
Sirolimus: The anticipated toxicities of sirolimus in this trial are those related to its 
immunosuppressive properties. Please refer to the package insert attached (Attachment 
A). 
Related to the Chemotherapies 
Related to Busulfan 
Busulfan on this study is being used as part of the conditioning regimen for its 
myelosuppressive properties. Commonly listed adverse events include nausea and 
vomiting, hair loss, and seizure.  The risk of seizure will be minimized by the 
administration of a prophylactic anticonvulsant medication started prior to busulfan 
administration. Please refer to the package insert attached (Attachment B). 
Related to Fludarabine 
Fludarabine is being used as part of the immunosuppression required to obtain 
engraftment of a haploidentical transplant.  Please refer to the pack insert attached. 
(Attachment C). 
 
Related to Cyclophosphamide 
Cyclophosphamide is intrinsic to the study design as it specifically targets activated T 
cells, eliminating the cells presumed responsible for GvHD.  It is associated with 
immunosuppression and gonadal dysfunction as well as hemorrhagic cystitis.  Mesna 
and hydration are the best prevention for this complication and will be used in the 
protocol.  Refer to Package insert attached (Attachment D). 

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Related to line placement and venipuncture 
Patients may experience pain, bleeding or bruising, and rarely an infection at the 
needle insertion site from venipuncture.  Lightheadedness or more rarely fainting can 
also occur with repeated blood draws.  
Risks from the catheter itself include pain, bleeding, infection, inflammation of the skin 
and vein or swelling at the site. A clot may form in the vein and may require the use of 
anticoagulants.  Finally, placement of the line can also cause injury to a nearby artery 
or nerve. 
1.22 Potential Benefits to the Recipient 
Clinically the approach is ethically acceptable because we are targeting patients with 
significant disease burden who are incurable with conventional treatments other than 
allogeneic BMT.  Allogeneic transplantation has also been shown to be effective for the 
treatment of autoimmune complications associated with CGD.  For patients with 
ongoing or refractory disease, HSC transplantation is currently the only curative 
treatment available.  The protocol aims to decrease the risk of transplant related 
mortality while offering the potential for cure of the disease. 
The research, therefore, involves more than a minor increase over minimal risk to 
subjects with the prospect of direct benefit (45 CFR 46.102)  
 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
• Intended Use: Samples and data collected under this protocol may be used to study 
graft versus host disease as well as rejection/engraftment related to transplant. 
Genetic testing will be performed for HLA typing as well as confirmation of 
underlying disease where appropriate.  
• Storage:  Access to stored samples will be limited using either a locked room or a 
locked freezer.  Samples and data will be stored using codes assigned by the 
investigators.  Data will be kept in password-protected computers.  Only 
investigators will have access to the samples and data.  
• Tracking: Samples and data acquired will be tracked using BSI. 
• Disposition at the Completion of the Protocol:  
o In the future, other investigators (both at NIH and outside) may wish to study 
these samples and/or data.  In that case, IRB approval must be sought prior to 
any sharing of samples and/or data.  Any clinical information shared about the 
sample would similarly require prior IRB approval.  
o At the completion of the protocol (termination), samples and data will either be 
destroyed, or transferred to NIAID IRB protocol 05-I-0213 “Screening and 
Baseline Assessment of Patients with Abnormalities of Immune Function.” 
• Reporting the Loss or Destruction of Samples/Specimens/Data to the IRB: 
• Any loss or unanticipated destruction of samples or data (for example, due to freezer 
malfunction) that meets the definition of Protocol Deviation and/or compromises the 
scientific integrity of the data collected for the study, will be reported to the NIAID 
IRB.  

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• Additionally, participants may decide at any point not to have their samples stored.  
In this case, the principal investigator will destroy all known remaining samples and 
report what was done to both the participant and to the IRB.  This decision will not 
affect participation in this protocol or any other protocols at NIH.  
 
REMUNERATION PLAN FOR PARTICIPANTS 
No remuneration will be provided.  All medical treatments associated or necessitated by 
the protocol will be provided without charge to the recipient, including medications taken 
as an outpatient. 
 
ASSESSMENT OF SAFETY 
1.23 Toxicity Scale 
The scoring for adverse event from any of the research procedures we will refer to the 
NCI Common Terminology Criteria for Adverse Events, where the normal value will be 
determined by the participants baseline and grading will then be adjusted based on the 
number of deviations from baseline in relation to the deviations from normal values as 
indicated on the NCI Common Terminology Criteria for Adverse Events.   (CTC version 
4.0, http://ctep.cancer.gov/forms/CTCAEv3.pdf)  
1.24 Specification of Safety Parameters 
Policy Link: https://federation.nih.gov/ohsr/nih/pnp.php  
1.25 Recording/Documentation 
At each contact with the participant, information regarding adverse events will be 
elicited by appropriate questioning and examinations. All events, both 
expected/unexpected and related/unrelated will be recorded on a source document. 
Source documents will include: progress notes, laboratory reports, consult notes, phone 
call summaries, survey tools and data collection tools. Source documents will be 
reviewed in a timely manner by the research team. All reportable adverse events that 
are identified will be recorded in the source documents.   The start date, the stop date, 
the severity of each reportable event, and the PI’s judgment of the AEs relationship and 
expectedness to the study agent/intervention will also be recorded in the source 
documents.   
1.26 Recipients’ Adverse Events 
Adverse events used to evaluate the safety of this protocol regimen will be collected to 
include any unexpected events, which either occur during the study, having been 
absent at baseline or if present at baseline, appear to worsen and are determined to be 
possibly, probably or definitely related to this investigational treatment.   
Adverse Events during the Screening Period 
As part of the screening portion of this study, we will conduct diagnostic tests that may 
lead to the discovery of conditions that may necessitate the stopping of enrollment into 

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the trial.  If any of the following events occur or are discovered that have no relation to 
the screening interventions, we will document but will not be reporting to the IRB unless 
they meet the criteria of an SAE: 
• Eastern Cooperative Oncology Group (ECOG) or equivalent performance status of 3 
or more. (See Supportive Care guidelines, available at 
http://intranet.cc.nih.gov/bmt/clinicalcare) 
• Transaminases > 5x upper limit of normal based on the recipient’s clinical situation 
and at the discretion of the investigator. 
• Psychiatric disorder or mental deficiency severe enough as to make compliance with 
the BMT treatment unlikely, and/or making informed consent impossible. 
• Major anticipated illness or organ failure incompatible with survival from AlloPBSC 
transplant. 
• Recipient becomes pregnant  
• HIV positive 
• Uncontrolled seizure disorder 
Adverse Events for Enrolled Recipients 
The following expected occurrences will be documented but will not be reported to the 
IRB unless they meet the criteria of an SAE. 
• Transient cardiac arrhythmias 
• Transient cardiac insufficiency 
• Pulmonary insufficiency 
• Neutropenia and its complications 
• Thrombocytopenia and its complications 
• Anemia and its complications 
• Transfusion reactions 
• Treatable infections from bacteria, viruses, protozoa, and fungi 
• Late effects of transplant regimens including: cataracts, infertility, growth impairment, 
hypothyroidism, and dental caries. 
• Headache, insomnia, psychosis, mood changes, disorientation, seizures from 
metabolic imbalance. 
• Nausea, vomiting, diarrhea, mucositis, weight loss, dry mouth, hiccoughs, 
constipation. 
• Well characterized drug reactions – allergic manifestation, red man syndrome 
• Well characterized drug adverse effects from drugs routinely used in transplant 
recipients (e.g., preparative regimen, immunosuppressive drugs, and antimicrobials). 
• Common adverse effects of antiemetics, analgesics, anti-inflammatory agents, and 
known complications of steroid therapy. 
• Complications from intravenous catheters, thrombotic occlusion, infection, local 
reactions, cardiac arrhythmia.  
 
 
 

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The following expected occurrences will not be reported to the IRB at each occurrence 
unless they meet the criteria of an SAE. They will be reported in summary form at the 
time of continuing review and at termination of the clinical study. 
• Acute GvHD 
• Chronic GvHD 
• Graft failure ⁄graft rejection 
• Veno-occlusive disease 
• Hemorrhagic cystitis 
• Regimen-related toxicity 
• CMV disease 
• EBV Lymphoproliferative Disease 
1.27 Definitions  
Adverse Event: Any untoward medical occurrence in a research participant, including 
any abnormal sign, symptom, or disease, temporally associated with the participation in 
research, whether or not considered related to the participation in the research.   
 
Serious adverse event: Any adverse event that 
• results in death; 
• is life-threatening (places the subject at immediate risk of death from the event as 
it occurred).  For the purpose of this study, this type of event is 
defined as any adverse event that places the subject at immediate risk of death 
from Haploidentical transplantation.  The event that requires life-sustaining 
intervention (ventilator support, vasopressors, and/or dialysis) as it occurred. A 
life-threatening event does not include an event that, had it occurred in a more 
severe form, might have caused death, but as it actually occurred, did not create 
an immediate risk of death (i.e seizures, respiratory distress).; 
• results in inpatient hospitalization or prolongation of existing hospitalization. For 
the purpose of the study is for overnight admissions only. Emergency room and 
day or night visits are not considered hospitalizations. Any elective hospitalization 
for a preexisting condition that has not worsened does not constitute a serious 
adverse event. In addition, hospitalization for ease of administration of standard 
treatments (i.e. medical treatments to manage complications of transplant) will 
also not be considered a serious adverse event.; 
• results in a persistent or significant disability/incapacity 
• results in a congenital anomaly/birth defect; or 
• based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. (Examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse) 
 
 
 

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Protocol Deviation: Any change, divergence, or departure from the IRB approved study 
procedures in a research protocol. Protocol deviations are designated as serious or 
non-serious and further characterized as 
 
1. Those that occur because a member of the research team deviates from the 
protocol. 
2. Those that are identified before they occur, but cannot be prevented. 
3. Those that are discovered after they occur 
 
Serious Protocol Deviation: A deviation that meets the definition of a Serious Adverse 
Event or compromises the safety, welfare or rights of research participants or others. 
 
Non-compliance: The failure to comply with applicable NIH HRPP policies, IRB 
requirements, or regulatory requirements for the protection of human subjects. Non-
compliance is further characterized as 
1. Serious: Non-compliance that 
a. Increases risks, or causes harm, to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the NIH-HRPP 
d. Invalidates the study data 
2. Continuing: Non-compliance that is recurring 
3. Minor: Non-compliance that, is neither serious nor continuing. 
Unanticipated Problem (UP): Any incident, experience, or outcome that meets all three 
of the following criteria would be considered a serious UP:  
 
1. unexpected in terms of nature, severity, or frequency in relation to 
a. the research risks that are described in the IRB-approved research protocol 
and informed consent document,  Investigator’s Brochure or other study 
documents; and 
b. the characteristics of the patient population being studied 
2. related or possibly related to participation in the research 
3. suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
Unanticipated problem that is not an Adverse Event (UPnonAE): An unanticipated 
problem that does not fit the definition of an adverse event, but which may, in the 
opinion of the investigator, involve risk to the participant, affect others in the research 
study, or significantly impact the integrity of research data.  These events may involve a 
greater risk of social or economic harm to study participants or others rather than 
physical/psychological harm. Such events would be considered a non-serious UP. 
Examples of a UPnonAE include a breach of confidentiality, accidental destruction of 
study records, or unaccounted-for study drug. 
 
 

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1.28 Reporting Procedures  
Expedited Reporting to the NIAID IRB 
 
Serious and non-serious Unanticipated Problems, deaths, serious deviations, and 
serious or continuing non-compliance will be reported within 7 calendar days of 
investigator awareness. Serious Adverse Events that are possibly, probably, or 
definitely related to the research will be reported to the NIAID IRB within 7 calendar 
days of investigator’s awareness, regardless of expectedness. 
Waiver of Reporting Anticipated Protocol Deviations, Expected non-UP AEs and Deaths 
Anticipated deviations in the conduct of the protocol will not be reported to the IRB. 
Expected adverse events will not be reported to the IRB.  If the rate of these events 
exceeds the rate expected by the study team, the events will be classified and reported 
as though they are unanticipated problems. Death unrelated to research (i.e., due to the 
underlying disease) will only be reported at the time of continuing review. 
Annual Reporting to the NIAID IRB 
 
The following items will be reported to the NIAID IRB in summary at the time of 
Continuing Review: 
 
- 
Serious and non-serious unanticipated problems  
- 
Expected serious adverse events that are possibly, probably, or definitely 
related to the research 
- 
Serious adverse events that are not related to the research 
- 
All adverse events, except expected AEs and deaths granted a waiver of 
reporting.  
- 
Serious and Non-Serious Protocol deviations  
- 
Serious, continuing, and minor non-compliance 
- 
Any trends or events which in the opinion of the investigator should be 
reported 
Reporting Serious Adverse Events to the Principal Investigator 
All SAEs will be reported to: 
 
 
Elizabeth Kang, M.D. 
 
 
Building 10-CRC, 6W- Room 63752 
 
 
Phone: 301-402-7567 
 
 
Email: Ekang@niaid.nih.gov  
1.29 Type and Duration of the Follow-up of Participant after Adverse Events 
Any adverse event experienced by the patient resulting from the haploidentical 
transplant will be followed by the protocol investigator until such time it is 
resolved or is sufficiently stable to allow the patient to be treated by his local 
physicians. 
 
 

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1.30 Safety Monitoring Plan 
NIAID Intramural Data and Safety Monitoring Board (DSMB): While the NIAID 
Intramural Data and Safety Monitoring Board (DSMB) is required to monitor studies that 
use gene therapy methodology or involve multi-center studies presenting more than 
minimal risk to subjects or that generate randomized blinded data, there is provision that 
allows DSMB to monitor studies that pose more than minimal risk to its subjects.  
 
This study involves pediatric patients as young as 2 years who will undergo a 
haploidentical bone marrow transplantation, which carries a risk of mortality. While this 
study aims to decrease the risk of transplant related mortality with the use of 
cyclophosphamide post cell infusion day, this regimen is a novel approach to patients 
with this disease process. Because this study poses more than a minimal risk to 
subjects, it falls under the NIAID DSMB policy on studies that may require DSMB 
monitoring. 
 
The NIAID DSMB will review the data and analysis plans of all intramural NIAID clinical 
studies that require DSMB oversight. The DSMB consists of experts in transplant 
related infectious diseases, biostatistics, and clinical trials. After the initial review, which 
occurs prior to opening the study to enrollment, the DSMB will review cumulative study 
data to evaluate safety, study conduct, and scientific validity and integrity of the trial on 
a semi-annual basis. All serious adverse events (SAEs) will be included in these interim 
reviews. All cumulative safety data reports from the trial will be submitted to the Board 
within 14 business days prior to the review. The DSMB will also assess the performance 
of overall study operations and any other relevant issues, as necessary. The DSMB 
members must be satisfied that the timeliness, completeness, and accuracy of the data 
submitted to them for review is sufficient for evaluation of the safety and welfare of 
study participants. 
 Expedited Reporting to the NIAID DSMB 
 
Serious and non-serious Unanticipated Problems, deaths, serious deviations, and 
serious or continuing non-compliance will be reported within 7 calendar days of 
investigator awareness via the DSMB Executive Secretary. Serious Adverse Events that 
are possibly, probably, or definitely related to the research will be reported to the NIAID 
DSMB within 7 calendar days of investigator’s awareness, regardless of expectedness. 
The DSMB may recommend early termination of the study for considerations of safety 
and efficacy. 
1.31 Stopping/Pausing Rules for the Protocol  
The study will be paused after the third CGD patient has completed the 100 day post-
transplant assessment.  The outcome data and status of the three individuals will be 
reported to the NIAID DSMB  and the NIAID IRB, unless a more timely report is more 
warranted.   
The study will also be paused if there are 2 patients experiencing either a protocol 
related death, graft failure,  or grade 3 or 4 GvHD, and will be resumed only after 
agreement with the IRB. 

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1.32 Halting Rules for the Protocol  
The NIAID- IRB, or other government agencies, as part of their duties to ensure that 
research participants are protected; may discontinue the study at any time. Subsequent 
review of serious, unexpected and related adverse events by the Medical Monitor, Data 
and Safety Monitoring Board (DSMB), ethics review committee or IRB, and other 
regulatory authorities may also result in suspension of further trial 
interventions/administration of study agent. The FDA and other regulatory authorities, 
retain the authority to suspend additional enrollment and Study Agent(s)/Intervention(s) 
administration for the entire study as applicable. 
1.33  Study Discontinuation 
Graft Rejection 
This transplant study uses a reduced intensity preparative regimen.  Therefore, 
autologous recovery is anticipated in the recipients should they fail to engraft.    
1.34 Premature Withdrawal of a Participant 
Recipient Voluntary Withdrawal 
The Recipient will be allowed to withdraw at any time, even after receiving the 
conditioning regimen (as autologous recovery is expected) or after receiving the 
allograft, although withdrawal at this stage would be highly discouraged.  Once the 
conditioning regimen is complete and/or allograft infused, if the Recipient wishes to 
withdraw, he or she will have to remain within the care of the study physicians until 
either autologous or graft-mediated recovery is attained. 
 
Post – Infusion Obligations 
The Recipient will be required to report to the clinic for follow-up assessments as 
specified in the study guidelines and Section 5.4 
Involuntary Withdrawal of a Recipient  
• The Recipient may be withdrawn from the study if an inadequate number of cells is 
collected from the Donor and if cell collection is inadequate in a second donor or if a 
second donor is not available.  
• If the Recipient develops a medical condition or circumstance where, in the opinion 
of the investigator, it is in the subject’s best interest to discontinue participation in the 
study.  
1.35 Involuntary Participant Withdrawal 
Participants who fail to demonstrate donor cell engraftment will be taken off 
this study but we will continue to monitor for 6 months post transplant for 
possible infectious complications related to the conditioning 
regimen.  Participants may be offered other therapies as appropriate.  If 
they do not proceed with other treatments, the participants will be referred 

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back to their primary physician after the 6 month monitoring period for 
ongoing care. .   
Participants with disease relapse will be taken off of the study protocol..  The 
participant will then be presented with the opportunity to enroll onto 
the  NIAID IRB Protocol 05-I-0213: Screening and Baseline Assessment 
of Participants with Abnormalities of Immune Function.  This will be 
offered if the participant is not already enrolled in other alternative 
treatments or referred back to his/her referring physician, depending on 
what is considered to be in the best interest of the participant.  
Participants will be removed from the protocol in any situation where  the 
investigator, the sponsor or any regulatory agency terminates the entire 
study for any reason. 
If a subject becomes pregnant, she will be taken off of the study protocol and 
referred back to their primary physician for further therapy but will have 
contact follow-up by the study staff to document the outcome of the 
pregnancy. 
If a participant develops a medical condition or circumstance where, in the 
opinion of the investigator, it is in the subject’s best interest to discontinue 
participation in the study, they will be withdrawn off the study. 
Clinical Monitoring Structure 
1.36 Site Monitoring Plan  
This study monitoring will be conducted according to the “NIAID Intramural Clinical 
Monitoring Guidelines”.   
 
Monitors under contract to the NIAID/RCHSPB will visit the clinical research site to 
monitor several aspects of the study in accordance with the appropriate regulations and 
the approved protocol.  Only pediatric subjects will be monitored and the objectives of a 
monitoring visit will be: 1) to verify the existence of signed informed consent documents 
and documentation of the IC process for each monitored pediatric subject; 2) to verify 
AEs and SAEs, including the prompt reporting of all SAEs; 3) to compare applicable 
electronic research data abstracts with individual participants’ records and source 
documents (participants’ charts, laboratory analyses and test results, physicians’ 
progress notes, nurses’ notes, and any other relevant original subject information); and 
4) to help ensure investigators’ are in compliance with the protocol.  
 
The investigator (and/or designee) will make study documents (e.g., consent forms, 
electronic research data abstracts and pertinent NIH Clinical Center or outside medical 
records readily available for inspection by the local IRB the site monitors, and the NIAID 
staff for confirmation of the study data.  
 
A specific protocol monitoring plan will be discussed with the Principal Investigator and 
study staff prior to enrollment. The plan will outline the frequency of monitoring visits 

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based on such factors as study enrollment, data collection status and regulatory 
obligations.  
STATISTICAL CONSIDERATIONS 
This is an open-label pilot study. The primary goal is to evaluate the ability to achieve 
engraftment with minimal graft versus host disease by using a reduced intensity 
conditioning regimen followed by post-transplant cyclophosphamide for haploidentical 
transplant CGD patients. We will transplant 3 patients as an initial pilot and then 
consider expansion after discussion with the IRB for amending the protocol.   
This trial will be paused if at any time 2 or more grade III or IV GvHD events are 
observed.  
 
For different values of grade III-IV GvHD probability, the following table is given the 
probability of stopping this trial earlier. 
 
  
Table 2: Probability of Stopping the Trial Earlier 
Grade II-IV 
GvHD 
probability 
0.05 
0.1 
0.15 
0.2 
Stop earlier 
0.09 
0.26 
0.46 
0.62 
  
  
If 10, 9 or 8 engraftments are observed out of 10 transplant patients, then the 95% 
confidence intervals for the engraftment rate are, respectively, (0.73, 1), (0.56, 1) and 
(0.44, 0.96). 
  
If no grade III-IV GvHD is observed after 10 recipients, the 90%, 95% and 99% 
confidence intervals for the grade III-IV GvHD probability are, respectively, (0, 0.21), (0, 
0.26) and (0, 0.37). 
  
The statistical analysis and stopping rules applies for 10 patients enrolled.   
 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
1.37 Informed Consent Process 
Informed consent is a process where information is presented to enable persons to 
voluntarily decide whether or not to participate in a research trial. It is an on-going 
conversation between the human research participant and the researchers which 
begins before consent is given and continues until the end of the participant's 
involvement in the research. Discussions about the research will provide essential 
information about the study and include: purpose, duration, experimental procedures, 
alternatives, risks and benefits.  Participants will be given the opportunity to ask 
questions and have them answered.  

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The participant will sign the informed consent document prior to undergoing any 
research procedures. The participant may withdraw consent at any time throughout the 
course of the trial.  A copy of the informed consent document will be given to the 
participant for their records. The researcher will document the signing of the consent 
form in the participant’s research record. The rights and welfare of the participant will be 
protected by emphasizing to him or her that the quality of his or her medical care will not 
be adversely affected if he or she declines to participate in this study.  
The Principal and/or Authorized Delegate will counsel the participant and his or her 
parents to obtain the consent during a face-to-face interview when consenting a minor 
participant.   
 
During this study, all new information relating to risks and/or adverse events will be 
provided orally and/or in writing to all the study participants.  Documentation will be 
provided to the IRB and if necessary, the informed consent document will be amended 
to reflect relevant information. 
Non-English–Speaking Participants 
If a non-English speaking participant is unexpectedly eligible for enrollment, the 
participant will be provided with the CC Short Written Consent Form for Non-English 
Speaking Research Participants in the participant’s native language and a verbal 
explanation of the purpose, procedures and risks of the study as described in MAS 
Policy M77-2, NIH HRPP SOP 12 and 45 CFR 46.117(b)(2). The IRB-approved English 
consent form will serve as basis for the verbal explanation of the study. The investigator 
will obtain an interpreter unless the investigator is fluent in the prospective participant’s 
language. Preferably, the interpreter will be someone who is independent of the 
participant (i.e., not a family member). Interpreters provided by the CC will be used 
whenever possible. The interpreters will translate the IRB-approved English consent 
form verbatim and facilitate discussion between the participant and investigator. 
The IRB-approved English consent form will be signed by the investigator obtaining 
consent and a witness to the oral presentation. The CC Short Written Consent Form will 
be signed by the participant and a witness who observed the presentation of 
information. The interpreter may sign the consent document as the witness and, in this 
case, will note “Interpreter” under the signature line. A copy of both signed forms will be 
provided to the participant to take home. 
The investigator obtaining consent will document the consent process in the 
participant’s research record, including the name of the interpreter. Further, all 
instances of use of the CC Short Written Consent Form will be reported to the IRB at 
the time of annual review. If the CC Short Written Consent Form is used three times or 
more for the same language, this will be reported to the IRB immediately. 
1.38 Confidentiality 
All records will be kept confidential to the extent provided by federal, state and local law. 
The study monitors and other authorized representatives of the Sponsor may inspect all 
documents and records required to be maintained by the Investigator, including but not 
limited to, research records.  Records will be kept locked and all computer entry and 

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networking programs will be done with coded numbers only.  Clinical information will not 
be released without written permission of the subject, except as necessary for 
monitoring by IRB, the FDA, the NIAID, and the OHRP. 
DATA HANDLING AND RECORD KEEPING 
1.39 Data Capture and Management  
Study data will be maintained in an electronic records system and collected directly from 
participants during study visits and telephone calls, or will be abstracted from 
participants’ clinical center or other research related records. Source documents include 
all recordings of observations or notations of clinical activities and all reports and 
records necessary to confirm the data abstracted for this study. Data entry onto the 
electronic records system will be performed by authorized individuals. The Investigator 
is responsible for assuring that the data collected are complete, accurate, and recorded 
in a timely manner. 
 
1.40 Record Retention  
The investigator is responsible for retaining all essential documents listed in the ICH 
Good Clinical Practice Guideline.  Study records will be maintained by the PI for a 
minimum of 3 years and in compliance with institutional, IRB, state, and federal medical 
records retention requirements, whichever is longest. All stored records will be kept 
confidential to the extent required by federal, state, and local law. 
 
Should the investigator wish to assign the study records to another party and/or move 
them to another location, the investigator will provide written notification of such intent to 
RCHSPB/NIAID with the name of the person who will accept responsibility for the 
transferred records and/or their new location. Destruction or relocation of research 
records will not proceed without written permission from NIAID/RCHSPB. 

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Appendix A: Scientific References 
 
1. 
Johnston RB, Jr. Clinical aspects of chronic granulomatous disease. Curr Opin 
Hematol. 2001;8(1):17-22. Epub 2001/01/04. PubMed PMID: 11138621. 
2. 
Roesler J, Brenner S, Bukovsky AA, Whiting-Theobald N, Dull T, Kelly M, Civin 
CI, Malech HL. Third-generation, self-inactivating gp91(phox) lentivector corrects the 
oxidase defect in NOD/SCID mouse-repopulating peripheral blood-mobilized CD34+ 
cells from patients with X-linked chronic granulomatous disease. Blood. 
2002;100(13):4381-90. PubMed PMID: 12393624. 
3. 
Mardiney M, 3rd, Jackson SH, Spratt SK, Li F, Holland SM, Malech HL. 
Enhanced host defense after gene transfer in the murine p47phox- deficient model of 
chronic granulomatous disease. Blood. 1997;89(7):2268-75. PubMed PMID: 
0009116268. 
4. 
Dinauer MC, Li LL, Bjorgvinsdottir H, Ding C, Pech N. Long-term correction of 
phagocyte NADPH oxidase activity by retroviral-mediated gene transfer in murine X-
linked chronic granulomatous disease. Blood. 1999;94(3):914-22. PubMed PMID: 
10419882. 
5. 
Malech HL, Maples PB, Whiting-Theobald N, Linton GF, Sekhsaria S, Vowells 
SJ, Li F, Miller JA, DeCarlo E, Holland SM, Leitman SF, Carter CS, Butz RE, Read EJ, 
Fleisher TA, Schneiderman RD, Van Epps DE, Spratt SK, Maack CA, Rokovich JA, 
Cohen LK, Gallin JI. Prolonged production of NADPH oxidase-corrected granulocytes 
after gene therapy of chronic granulomatous disease. Proc Natl Acad Sci U S A. 
1997;94(22):12133-8. Epub 1997/10/29. PubMed PMID: 9342375; PubMed Central 
PMCID: PMC23727. 
6. 
Ott MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, 
Kuhlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball 
C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Luthi U, Hassan M, Thrasher AJ, 
Hoelzer D, von Kalle C, Seger R, Grez M. Correction of X-linked chronic granulomatous 
disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 
or SETBP1. Nature medicine. 2006;12(4):401-9. Epub 2006/04/04. doi: nm1393 [pii] 
10.1038/nm1393. PubMed PMID: 16582916. 
7. 
Horwitz ME, Barrett AJ, Brown MR, Carter CS, Childs R, Gallin JI, Holland SM, 
Linton GF, Miller JA, Leitman SF, Read EJ, Malech HL. Treatment of chronic 
granulomatous disease with nonmyeloablative conditioning and a T-cell-depleted 
hematopoietic allograft. N Engl J Med. 2001;344(12):881-8. Epub 2001/03/22. doi: 
10.1056/NEJM200103223441203. PubMed PMID: 11259721. 
8. 
Gungor T, Teira P, Slatter M, Stussi G, Stepensky P, Moshous D, Vermont C, 
Ahmad I, Shaw PJ, Telles da Cunha JM, Schlegel PG, Hough R, Fasth A, Kentouche K, 
Gruhn B, Fernandes JF, Lachance S, Bredius R, Resnick IB, Belohradsky BH, Gennery 
A, Fischer A, Gaspar HB, Schanz U, Seger R, Rentsch K, Veys P, Haddad E, Albert 
MH, Hassan M, Inborn Errors Working Party of the European Society for B, Marrow T. 
Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell 
transplantation in patients with chronic granulomatous disease: a prospective 
multicentre study. Lancet. 2014;383(9915):436-48. doi: 10.1016/S0140-6736(13)62069-
3. PubMed PMID: 24161820. 

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9. 
Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, Notarangelo 
LD, Roifman CM. Bone marrow transplantation for severe combined immune deficiency. 
JAMA : the journal of the American Medical Association. 2006;295(5):508-18. doi: 
10.1001/jama.295.5.508. PubMed PMID: 16449616. 
10. 
Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R, 
Ortega J, Souillet G, Ferreira E, Laporte JP, Fernandez M, Chastang C. Outcome of 
cord-blood transplantation from related and unrelated donors. Eurocord Transplant 
Group and the European Blood and Marrow Transplantation Group. N Engl J Med. 
1997;337(6):373-81. doi: 10.1056/NEJM199708073370602. PubMed PMID: 9241126. 
11. 
Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. Rapid and 
complete donor chimerism in adult recipients of unrelated donor umbilical cord blood 
transplantation after reduced-intensity conditioning. Blood. 2003;102(5):1915-9. doi: 
10.1182/blood-2002-11-3337. PubMed PMID: 12738676. 
12. 
Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, McGlave PB, Miller JS, Verfaillie 
CM, Wagner JE. Transplantation of 2 partially HLA-matched umbilical cord blood units 
to enhance engraftment in adults with hematologic malignancy. Blood. 
2005;105(3):1343-7. Epub 2004/10/07. doi: 2004-07-2717 [pii] 
10.1182/blood-2004-07-2717. PubMed PMID: 15466923. 
13. 
Parikh SH, Szabolcs P, Prasad VK, Lakshminarayanan S, Martin PL, Driscoll TA, 
Kurtzberg J. Correction of chronic granulomatous disease after second unrelated-donor 
umbilical cord blood transplantation. Pediatric blood & cancer. 2007;49(7):982-4. Epub 
2007/10/18. doi: 10.1002/pbc.21365. PubMed PMID: 17941061. 
14. 
Reisner Y, Hagin D, Martelli MF. Haploidentical hematopoietic transplantation: 
current status and future perspectives. Blood. 2011;118(23):6006-17. doi: 
10.1182/blood-2011-07-338822. PubMed PMID: 21921045. 
15. 
Beatty PG, Clift RA, Mickelson EM, Nisperos BB, Flournoy N, Martin PJ, Sanders 
JE, Stewart P, Buckner CD, Storb R, et al. Marrow transplantation from related donors 
other than HLA-identical siblings. N Engl J Med. 1985;313(13):765-71. doi: 
10.1056/NEJM198509263131301. PubMed PMID: 3897863. 
16. 
Kernan NA, Bordignon C, Keever CA, Cunningham I, Castro-Malaspina H, 
Collins NH, Small TN, Brochstein J, Emanuel D, Laver J, et al. Graft failures after T cell 
depleted marrow transplants for leukemia: clinical and in vitro characteristics. 
Transplantation proceedings. 1987;19(6 Suppl 7):29-32. PubMed PMID: 2962353. 
17. 
Lapidot T, Terenzi A, Singer TS, Salomon O, Reisner Y. Enhancement by 
dimethyl myleran of donor type chimerism in murine recipients of bone marrow 
allografts. Blood. 1989;73(7):2025-32. PubMed PMID: 2653469. 
18. 
Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley 
TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolanos-Meade J, 
Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier 
BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for 
hematologic malignancies using nonmyeloablative conditioning and high-dose, 
posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641-
50. doi: 10.1016/j.bbmt.2008.03.005. PubMed PMID: 18489989; PubMed Central 
PMCID: PMC2633246. 
19. 
Munchel A, Kesserwan C, Symons HJ, Luznik L, Kasamon YL, Jones RJ, Fuchs 
EJ. Nonmyeloablative, HLA-haploidentical bone marrow transplantation with high dose, 

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post-transplantation cyclophosphamide. Pediatric reports. 2011;3 Suppl 2:e15. doi: 
10.4081/pr.2011.s2.e15. PubMed PMID: 22053277; PubMed Central PMCID: 
PMC3206539. 
20. 
Geddes M, Kangarloo SB, Naveed F, Quinlan D, Chaudhry MA, Stewart D, 
Savoie ML, Bahlis NJ, Brown C, Storek J, Andersson BS, Russell JA. High busulfan 
exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine 
allogeneic transplant regimen. Biol Blood Marrow Transplant. 2008;14(2):220-8. doi: 
10.1016/j.bbmt.2007.10.028. PubMed PMID: 18215782. 
21. 
Russell JA, Kangarloo SB, Williamson T, Chaudhry MA, Savoie ML, Turner AR, 
Larratt L, Storek J, Bahlis NJ, Shafey M, Brown CB, Yang M, Geddes M, Zacarias N, 
Yue P, Duggan P, Stewart DA, Daly A. Establishing a target exposure for once-daily 
intravenous busulfan given with fludarabine and thymoglobulin before allogeneic 
transplantation. Biol Blood Marrow Transplant. 2013;19(9):1381-6. doi: 
10.1016/j.bbmt.2013.07.002. PubMed PMID: 23871781. 
22. 
Beri R, Chunduri S, Sweiss K, Peace DJ, Mactal-Haaf C, Dobogai LC, Shord S, 
Quigley JG, Chen YH, Mahmud N, Rondelli D. Reliability of a pretransplant i.v. BU test 
dose performed 2 weeks before myeloablative FluBu conditioning regimen. Bone 
Marrow Transplant. 2010;45(2):249-53. doi: 10.1038/bmt.2009.133. PubMed PMID: 
19543331. 
23. 
Bolinger AM, Zangwill AB, Slattery JT, Glidden D, DeSantes K, Heyn L, Risler LJ, 
Bostrom B, Cowan MJ. An evaluation of engraftment, toxicity and busulfan 
concentration in children receiving bone marrow transplantation for leukemia or genetic 
disease. Bone Marrow Transplant. 2000;25(9):925-30. doi: 10.1038/sj.bmt.1702371. 
PubMed PMID: 10800058. 
24. 
Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, Apperley J, Slavin S, 
Pasquini M, Sandmaier BM, Barrett J, Blaise D, Lowski R, Horowitz M. Defining the 
intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 
2009;15(12):1628-33. doi: 10.1016/j.bbmt.2009.07.004. PubMed PMID: 19896087; 
PubMed Central PMCID: PMC2861656. 
 

APPENDICES 
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Appendix B: Selection criteria for donor when more than one available  
 
Historically, HLA typing has been the most important predictor of outcome after BMT. 
Recent data suggest reconsideration of donor prioritization. Clearly, HLA identical 
siblings will be given priority over any other potential donor. Data from J0457 (still 
unpublished) showed that that a 1 antigen mismatch in the GVH direction should be 
avoided if possible. Our current studies give us the guidelines: 
 
Donor selection criteria, in decreasing order of priority: 
 
1. Patient should lack antibodies against donor HLA molecules.  Specifically, 
complement dependent cytotoxicity and flow cytometric crossmatch assays must be 
negative, and the mean fluorescence intensity (MFI) of any anti-donor HLA antibody 
by solid phase immunoassay should be <3000.  Consult with Immunogenetics for 
the clinical significance of any anti-donor antibody.  Desensitization to remove anti-
donor antibody should only be performed for patients who have no other donor 
options 
 
2. ABO compatibility (in order of priority). 
 
a. Compatible or minor ABO incompatibility 
b. Major ABO incompatibility 
 
3. CMV status 
 
The CMV status of the pair donor-recipient is frequently employed to select a potential 
donor. This is a controversial issue and the data available is somewhat limited (1). The 
following guidelines are recommended: 
 
a. For a CMV seronegative recipient, use a CMV seronegative donor 
b. For a CMV seropositive recipient, use a CMV seropositive donor 
 
In CMV- patients with CMV+ stem-cell donors, primary CMV infection/reactivation 
develops in about 30% (2). Data from the European Registry shows the following(3): 
Seropositive patients receiving grafts from CMV+ HLA-identical sibling donors had the 
same survival as patients grafted from CMV- donors. However, MUD recipients 
receiving grafts from CMV+ donors had an improved 5-year survival, an improved 
event-free survival, and a reduced transplant-related mortality. There was no influence 
on the relapse incidence. The effects of donor CMV status remained in multivariate 
analyses. The effect of donor status was different among different disease categories. 
In patients with chronic myelogenous leukemia, T-cell depletion abrogated the beneficial 
effect of donor status, suggesting that the effect is mediated through transfer of donor 
immunity. These data suggest that donor CMV status influences outcome of unrelated 
SCT. 
 

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4. Other donor characteristics 
 
Donor parity and sex mismatch, have also been associated with an increased risk of a 
GVHD and decreased survival in some but not all studies(4-8). Donor age and weight 
should be also taken into consideration. 
 
Suggestions (in no order of priority): 
a. Younger (18 years of age or older) and lighter donors should be preferred. 
b. If all else is equal, male donors may be preferred over nulliparous female 
donors who may be preferred over multiparous female donors. 
 
5. Considerations regarding transfusion requirements for ABO mismatched 
donor/recipient transplants.  
 
ABO 
Incompatibilit
y 
Blood 
Component
s 
Up to Start 
of 
Preparativ
e Regimen 
Start 
of  Preparativ
e Regimen 
Stem 
Cell 
Infusio
n 
Original 
Antibody 
Undetectabl
e 
Original 
RBCs 
Undetectabl
e 
Major 
Recip 
Donor 
  
  
  
  
  
  
O 
A 
RBC 
O 
O 
O 
A 
Not 
Applicable 
Plts/Plasma 
O 
A (AB) 
A (AB) 
A 
O 
B 
RBC 
O 
O 
O 
B 
Not 
Applicable 
Plts/Plasma 
O 
B (AB) 
B (AB) 
B 
A 
AB 
RBC 
A 
A 
A 
AB 
Not 
Applicable 
Plts/Plasma 
A 
AB (A, B) 
AB (A, 
B) 
AB 
B 
AB 
RBC 
B 
B 
B 
AB 
Not 
Applicable 
Plts/Plasma 
B 
AB (B, A) 
AB (A,B) 
AB 
O 
AB 
RBC 
O 
O 
O 
AB 
Not 
Applicable 
Plts/Plasma 
O 
AB (A, B) 
AB (A, 
B) 
AB 
Minor 
Recip 
Donor 
  
  
  
  
  
  
A 
O 
RBC'S 
A 
O 
O 
Not  
Applicable 
O 
Plts/Plasma 
A 
A (AB) 
A (AB) 
O 
B 
O 
RBC'S 
B 
O 
O 
Not  
O 

APPENDICES 
CGD Haplo Transplant with Cyclophosphamide  
 
4 April 2018 
Kang 
Version 6 
Page 41 of 43 
Plts/Plasma 
B 
B (AB) 
B (AB) 
Applicable 
O 
AB 
O 
RBC'S 
AB 
O 
O 
Not 
Applicable 
O 
Plts/Plasma 
AB 
AB (A, B) 
AB(A, B) 
O 
AB 
A 
RBC'S 
AB 
A 
A 
Not  
Applicable 
A 
Plts/Plasma 
AB 
AB (A, B) 
AB(A, B) 
A 
AB 
B 
RBC'S 
AB 
B 
B 
Not  
Applicable 
B 
Plts/Plasma 
AB 
AB (B, A) 
AB(B, A) 
B 
Major & Minor 
  
  
  
  
  
  
Recip 
Donor 
A 
B 
RBC'S 
A 
O 
O 
B 
B 
Plts/Plasma 
A 
AB (A, B) 
AB(A, B) 
AB(A, B) 
B 
B 
A 
RBC'S 
B 
O 
O 
A 
A 
Plts/Plasma 
B 
AB (B, A) 
AB(B, A) 
AB(B, A) 
A 
Rh 
Incompatibilit
y 
Blood 
Component
s 
Up to Start 
of 
Preparativ
e Regimen 
Start 
of  Preparativ
e Regimen 
Stem 
Cell 
Infusio
n 
D Antigen 
Undetectabl
e 
D Antigen 
Detected 
 
Recip 
Donor 
  
  
  
  
  
  
Rh 
pos 
Rh 
neg 
RBC 
Pos 
Neg 
Neg 
Neg 
Neg 
Plts/Plasma 
Pos or Neg 
Pos or Neg 
Pos or 
Neg 
Pos or Neg 
Pos or Neg 
Rh 
neg 
Rh 
pos 
RBC 
Neg 
Neg 
Neg 
Neg 
Pos 
Plts/Plasma 
Pos or Neg 
Pos or Neg 
Pos or 
Neg 
Pos or Neg 
Pos or Neg 
( ) indicates 2nd, then 3rd choices for platelets  
 
 
 
 
 
 Donor Selection Reference List 

APPENDICES 
CGD Haplo Transplant with Cyclophosphamide  
 
4 April 2018 
Kang 
Version 6 
Page 42 of 43 
 
 (1)  Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and 
recipient before hematopoietic stem cell transplantation in the era of antiviral 
prophylaxis and preemptive therapy. Blood 2004; 103(6):2003-2008. 
 (2)  Ljungman P. Risk assessment in haematopoietic stem cell transplantation: viral 
status. Best Pract Res Clin Haematol 2007; 20(2):209-217. 
 (3)  Ljungman P, Brand R, Einsele H, Frassoni F, Niederwieser D, Cordonnier C. 
Donor CMV serologic status and outcome of CMV-seropositive recipients after 
unrelated donor stem cell transplantation: an EBMT megafile analysis. Blood 2003; 
102(13):4255-4260. 
 (4)  Flowers ME, Pepe MS, Longton G et al. Previous donor pregnancy as a risk factor 
for acute graft-versus-host disease in patients with aplastic anaemia treated by 
allogeneic marrow transplantation. Br J Haematol 1990; 74(4):492-496. 
 (5)  Weisdorf D, Hakke R, Blazar B et al. Risk factors for acute graft-versus-host 
disease in histocompatible donor bone marrow transplantation. Transplantation 
1991; 51(6):1197-1203. 
 (6)  Bross DS, Tutschka PJ, Farmer ER et al. Predictive factors for acute graft-versus-
host disease in patients transplanted with HLA-identical bone marrow. Blood 1984; 
63(6):1265-1270. 
 (7)  Nash RA, Pepe MS, Storb R et al. Acute graft-versus-host disease: analysis of risk 
factors after allogeneic marrow transplantation and prophylaxis with cyclosporine 
and methotrexate. Blood 1992; 80(7):1838-1845. 
 (8)  Larsson K, Aschan J, Remberger M, Ringdén O, Winiarski J, Ljungman P. 
Reduced risk for extensive chronic graft-versus-host disease in patients receiving 
transplants with human leukocyte antigen-identical sibling donors given 
polymerase chain reaction-based preemptive therapy against cytomegalovirus. 
Transplantation 2004; 77(4):526-531. 
 
 
 

APPENDICES 
CGD Haplo Transplant with Cyclophosphamide  
 
4 April 2018 
Kang 
Version 6 
Page 43 of 43 
Appendix C: C1_C5 Recipient SOE Spreadsheet (attached) 
 
Appendix D:  Total Body Irradiation Guidelines 
Energy 
All recipients should be treated with a linear accelerator using energies higher than 
4MV. 
 
Timing 
It is anticipated that TBI will be delivered on days -1  
 
Technique 
TBI will be delivered with lateral fields using extended SAD values of 600cm.   Tissue 
compensators (head and neck, e.g.) will be used as appropriate for all 
recipients.  Gonadal shielding will be used in male patients if possible.  At times, 
additional modifications may be used to provide optimal dose distribution, such as beam 
spoilers. 
 
Dose/Fractionation 
Treatment will be delivered in a single fraction.  Dose will be prescribed to mid plane.  
 
Dose Modifications 
Occasionally, the total dose/technique of TBI may require modifications due to patient 
factors (unexpected or serious (grade 4-5) adverse events, serious medical illnesses 
not conducive to stable patient transfer, patient refusal, etc) or treatment factors (linear 
accelerator machine offline, etc.) Modifications to the radiation treatment will be at the 
discretion of the treating radiation oncologist and will be discussed and with the PI.