Clinical trial NCT00923364
Conditions: MDS Immunodeficiency GATA2
Keywords: GATA2 Transplant Immunodeficiency Myelodysplasia MonoMAC
Sponsor: National Cancer Institute (NCI)
Start date: 2009-05-07; Completion date: 2017-02-26
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Stem cells are immature blood cells that grow in the bone marrow and produce all of the cells needed for normal blood and immunity. Stem cells can be taken from one person (donor) and given to another person (recipient) through allogeneic stem cell transplantation. Donor stem cells can then replace the recipients stem cells in the bone marrow, restoring normal blood production and immunity. Most allogeneic transplants now use stem cells collected from the donors blood in a process called peripheral blood stem cell transplantation.
* Monocytopenia and mycobacterial infection (MonoMAC) is an immunodeficiency disease that is characterized by a lack of monocytes, a type of white blood cell, and an increased risk of developing mycobacteria infections that may cause tuberculosis.
* Allogeneic stem cell transplantation has been used successfully to treat many kinds of immune diseases and cancers that develop in blood or immune system cells. Researchers have been studying a particular kind of stem cell transplantation that uses lower than usual doses of chemotherapy and particular combinations of drugs to improve the results of the procedure for patients with blood-related cancers and pre-cancerous conditions.

Objectives:

* To determine the safety and efficacy of reduced-intensity hematopoietic stem cell transplants (a particular stem cell transplantation procedure) for treating MonoMAC.

Eligibility:

* Patients 18-60 years of age who have MonoMAC and who have been matched with a suitable stem cell donor.

Design:

* Donors and recipients will undergo separate procedures as part of this protocol.
* Donors:
* National Institutes of Health researchers will take the donor s medical history, perform a physical exam, take blood samples, and explain the procedure. Tests will be performed to check the donors heart, lung, kidney, and liver function.
* Donors will receive injections of a drug called filgrastim (G-CSF), which causes stem cells to travel from bone marrow into blood. The G-CSF shots will be given for 5 to 7 days before the collection procedure.
* Donors will undergo apheresis to collect white blood cells and stem cells directly from the blood, which can be done as an outpatient procedure. Researchers may consider the alternative of directly collecting bone marrow from the donor, which will require an overnight hospital stay.
* Recipients:
* Recipients will receive 3 days of pre-transplant chemotherapy and radiation therapy to prepare for the transplant. For 4 days before the transplant, recipients will receive the chemotherapy drug fludarabine, followed by a single dose of radiation therapy, and will also receive the drugs tacrolimus and sirolimus to prevent the donor cells from attacking the recipient s normal tissues.
* Recipients will then receive the transplant of donor stem cells and will continue to receive tacrolimus and sirolimus for 3 months after the transplant to prevent the donor cells from attacking the recipient s normal tissues. Recipients will be discharged from the hospital once their condition is stable.
* Recipients will visit the NCI clinic regularly for the first 5 months after the transplant, and then less often for at least 5 years. Recipients may receive additional donor immune cells (donor lymphocyte infusion) after the transplant if the study doctors believe they are needed.

Detailed description:
BACKGROUND:

Mutations in GATA binding protein 2 (GATA2) lead to an immunodeficiency disease that transforms into myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). This syndrome, previously known as MonoMAC, has 4 clinical features: 1) infections with Mycobacterium Avium Complex (MAC) and other opportunistic infections as a teenager or young adult, 2) a peripheral blood leukocyte flow cytometry profile with T-lymphocytes, but a severe deficiency of monocytes, B-lymphocytes, and Natural Killer (NK) cells, 3) the propensity to progress to MDS/AML, and 4) mutations in the gene GATA2. In this pilot study we propose to evaluate the efficacy and safety of a reduced intensity allogeneic hematopoietic stem cell transplantation (HSCT) regimen for patients with mutations in GATA2. We are particularly interested in determining whether allogeneic HSCT using this regimen reconstitutes normal hematopoiesis in patients with mutations in GATA2.

OBJECTIVES:

Primary Objective:

* To determine efficacy, namely whether reduced-intensity allogeneic HSCT results in engraftment and restores normal hematopoiesis by day +100 in patients with mutations in GATA2.
* To determine the safety of this HSCT regimen in patients with mutations in GATA2, including transplant related toxicity, the incidence of acute and chronic graft-versus host disease, immune reconstitution, overall survival, and disease-free survival

ELIGIBILITY:

Eligibility includes patients 12-60 years old with mutations in GATA2 who have a life expectancy of \> 3 months but \< 24 months, and who have a 10/10 matched related donor, a 10/10 or 9/10 matched unrelated donor (HLA -A, -B, -C, DRB1, DQB1 by high resolution typing identified through the National Marrow Donor Program), a 4/6 (or greater human leukocyte antigens (HLA -A), -B, DRB1) matched unrelated umbilical cord donor, or a haploidentical donor. Patients with GATA2 mutations who are 12-17 years of age are required to have MDS with chromosomal abnormalities to be eligible for this protocol.

DESIGN:

* Patients with mutations in GATA2 with a 10/10 matched related or 10/10 matched unrelated donor, will receive a reduced-intensity pre-transplant conditioning regimen consisting of fludarabine 30 mg/m(2)/day on days -4, -3, and -2, 200 centigray (cGy) total body irradiation (TBI) on day -1, and HSCT on day 0. Patients with mutations in GATA2 and a 9/10 matched unrelated donor will receive a reduced-intensity pre-transplant conditioning regimen consisting of fludarabine 30 mg/m(2)/day on days -4, -3, and -2, 300cGy total body irradiation (TBI) on day -1, and HSCT on day 0. Patients with mutations in GATA2 with umbilical cord blood units will receive a reduced-intensity conditioning regimen with cyclophosphamide 50 mg/kg on day -6, fludarabine 40 mg/m(2) on days -6 to -2, equine anti-thymocyte globulin (ATG) 30 mg/kg intravenous (IV) on days -6, -5 and -4, 200 cGy TBI on day -1, and HSCT on day 0. Patients with a haploidentical donor will receive a reduced intensity-conditioning regimen with cyclophosphamide 14.5 mg/kg on days -6 and -5, fludarabine 30 mg/m(2) on 4days -6 to -2, and 200 cGy TBI on day -1. Donor bone marrow cells will be infused on day 0.
* Post-transplant immunosuppression for graft-versus-host-disease prophylaxis will consist of sirolimus (Rapamycin) and tacrolimus until day +180, provided that there is no evidence of graft-versus-host disease. Post-transplant immunosuppression for graft versus-host-disease prophylaxis for recipients of haploidentical donors will consist of cyclophosphamide 50 mg/kg on days +3 and +4, along with sirolimus from day +5 to day 180, and tacrolimus from day +5 to day 180, providing that there is no graft-versus-host disease (GVHD).

Arms: arm 1: Hematopoietic Stem Cell Transplant for MonoMAC: 10/10 Human Leukocyte Antigen (HLA) Matched Related Donor (MRD) or Unrelated Donor (URD) Transplant. 9/10 HLA Matched Related Donor or Unrelated Donor Transplant. Haploidentical Related Donor Transplant. Umbilical Cord Blood Transplant.
Interventions: intervention 1: Cyclophosphamide (CTX, Cytoxan) intervention 2: Fludarabine(Fludara,Berlex Laboratories) intervention 3: Total Body Irradiation (TBI) intervention 4: Allogeneic Hematopoietic Stem Cell (HSC) intervention 5: Equine Anti-Thymocyte Globulin
Intervention descriptions: intervention 1: 14.5 mg/kg intravenous (IV) (in the vein) infusion over 30 minutes once daily on days -6 and -5 (weight based dosing) or 50 mg/kg IV infusion over 2 hours on day -6 (weight based dosing) or 50/kg IV once daily x 2 doses on days +3 and +4 intervention 2: 40 mg/m2 IV (in the vein) over 30 minutes (in the vein) once daily on Days -6, -5, -4, and -3 or 30 mg/m(2) IV over 30 minutes (in the vein) once daily on Days -6, -5, -4, -3, and -2 intervention 3: 200 centigray (cGy) on Day -1 or 300 cGy on Day -1 (for 9/10 URD and Haplo patients) intervention 4: stem cell transplant intervention 5: 30mg/kg IV (in the vein) once daily x 3 days on Days -6, -5, -4 (3 doses total)

Protocol documents:
ICF_002.pdf: 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               • Adult Patient or • Parent, for Minor Patient 
 
 
INSTITUTE: 
National Cancer Institute 
 
 
STUDY NUMBER: 
09-C-0096 
PRINCIPAL INVESTIGATOR:  Dennis Hickstein, M.D. 
 
 
STUDY TITLE: 
Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem Cell Transplant 
for Patients with GATA2 Mutations 
 
 
Continuing Review Approval by the IRB on 06/30/15 
Amendment Approved by the IRB on 06/10/16 (T) 
 
 
Date Posted to Web: 06/11/16  
Donor 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (7-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (2) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
 
Now we will describe this research study.   Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional. 
 
Why is this study being done? 
 
The purpose of this study is to test if stem cells from related or unrelated donors will be able to 
survive (engraft) after allogeneic stem cell transplantation (alloSCT) in patients with mutations 
the gene GATA2.  
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  2  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
Why are you being asked to take part in this study? 
 
Because your relative has this disease (GATA2 deficiency), we are inviting him/her to 
participate in this research study, called: “Pilot and Feasibility Study of Reduced-Intensity 
Hematopoietic Stem Cell Transplant for Patients with GATA2 Mutations.”  This research study 
is for patients with this newly described disease that have a potential HLA-matched related 
donor, or unrelated donor identified through one of the bone marrow donor registries such as the 
National Marrow Donor Program.  To be eligible to participate on this study you must match on 
at 5 out of 10 or 10 out of 10 Human Leukocyte Antigen (HLA) markers with your relative. 
HLA are proteins (or markers), found on most cells in your body.  Your immune system uses 
these markers to recognize which cells belong in your body and which do not.  To be a donor on 
this study, you must be 15-60 years of age. 
 
How many people will take part in this study? 
 
Up to 15 patients and their donors will participate in this study. 
 
Description of Research Study 
 
Your Evaluation for Donation of Cells 
 
On your first visit to the NIH Clinical Center, you will see a physician and other members of the 
transplant team.  The doctor will take your medical history, perform a physical exam, and 
explain the procedure.  Approximately 4 to 10 teaspoons of your blood will be drawn to see if 
you and your relative are a good match.  You and your relative must be a match on ten of ten 
genetic (hereditary) HLA tests.   
 
To donate cells, you must be in good health.  In particular, your blood will be analyzed to 
determine that you have no evidence in your blood for mutations in GATA2 for which your 
relative is receiving the transplant.  This testing will be done in the laboratory of Dr. Steven 
Holland at the NIH, and you will be informed of the results and counseled as to the significance 
of the testing by Dr. Holland and his associates.  Your lungs and your heart will also be tested.  If 
you have symptoms of heart disease, you cannot be a donor.  If you have had any heart 
operations such as a bypass graft or angioplasty, a cardiologist must evaluate you and state that 
you are not putting yourself at risk by donating cells.  If you have had cancer you may not be 
eligible to donate your stem cells. You must not have any infection in order to be a donor.  If you 
have history of rheumatic diseases or immune thyroid disorders, or a history of blood clots in the 
legs or lungs, you are ineligible to serve as a donor.  Donors receiving experimental therapy or 
investigational agents are not eligible to serve as donors. If you have psychiatric disorder that 
prevents you from providing appropriate informed consent, this may prevent you from being a 
donor.  
 
We will also test your kidneys and liver.  As mentioned above, your blood will also be tested for 
Hepatitis B and C, T. Cruzi (Chagas agent), a virus called cytomegalovirus (CMV), adenovirus, 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  3  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
Epstein-Barr virus, herpes simplex virus, toxoplasmosis, and syphillis. As part of this study, we 
will test you for infection with the human immunodeficiency virus (HIV), the virus that causes 
AIDS.  If you are infected with HIV you will not be able to participate in this study.  We will tell 
you what the results mean, how to find care, how to avoid infecting others, how we report HIV 
infection, and the importance of informing your partners at possible risk because of your HIV 
infection.  Approximately 6-10 teaspoons of blood will be collected to perform these tests. If you 
have a positive Hepatitis B or C test the study doctor will determine if you are allowed to be a 
donor.   
 
If you are female able to have children, you will have a urine pregnancy test.  Because of health 
risks to the fetus or newborns, pregnant women cannot be donors.  A donor who is breastfeeding 
must be willing and able to interrupt breastfeeding or substitute formula feeding for her infant 
during the period of G-SCF stimulation and for two days following the final dose of G-CSF if 
you are donating peripheral blood stem cells.  
 
We will also look at your arms to make sure that the veins are suitable for the apheresis 
procedure (the procedure that collects your stem cells).  If it is decided that your veins cannot be 
used for apheresis, it will be necessary to insert the I.V. into a large vein in your groin or neck.  
If you are donating bone marrow, you will be evaluated by the anesthesia service to determine 
your eligibility. 
 
How Stem Cells Are Collected:  
 
Your relative can receive the bone marrow of others to help them fight their cancer.  That is why 
we are inviting you to donate cells from your bone marrow (called stem cells).  If accepted by 
your relative’s body, your stem cells will help their body begin to grow normal bone marrow 
cells. 
 
If you are donating peripheral blood stem cells, before you donate your stem cells, you will have 
had several injections (shots) of a drug called filgrastim or G-CSF for short.  G-CSF is a protein 
normally produced by your body in small amounts.  The U.S. Food and Drug Administration and 
the National Marrow Donor Program have both approved G-CSF for use in stem cell collection.  
It causes your stem cells to travel from your bone marrow into your blood.  Once the stem cells 
are in your blood, they can be taken from your veins using a process called apheresis.   An I.V. 
(intravenous catheter) is placed into a vein in each of your arms.  This will mean two 
needlesticks.  Your blood will circulate through a machine that will collect and save your white 
blood cells and stem cells.  The rest of your blood will go back into your body.  The I.V. will be 
removed after the cells are collected.  The whole procedure usually takes 4 to 6 hours.  Apheresis 
avoids the need for an operation that would take the stem cells from your hipbone.  It will be 
performed by trained personnel from the NIH Department of Transfusion Medicine. 
 
If you are donating bone marrow cells, you will receive a general or a spinal anesthesia, and the 
bone marrow cells will be harvested from the back of your hips while you are under anesthesia.   
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  4  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
The Donation: 
 
Once it is decided that you can be a peripheral blood stem cell donor, you will then be started on 
G-CSF shots.  You will receive them in the arm or thigh.  We will teach you or a family member 
how to give you these shots at home.  They will be given for a period of 5, 6, or 7 days.  Usually, 
you will be ready for the apheresis procedure for stem cell collection on day 5.  We usually 
collect enough stem cells at this time to be able to perform a transplant to your relative.  
Sometimes, it is necessary to continue the G-CSF shots and repeat the apheresis on the next day 
(day 6).  In the unusual case that we still do not have enough cells to perform the transplant, we 
will ask that you rest for two weeks before repeating the G-CSF shots and apheresis.  Within one 
week after the apheresis procedure(s), you will be checked for any side effects at the Outpatient 
NCI Clinic.  If your stem cells are accepted (not rejected) by your relative’s body but their 
disease is still not under control, you may be asked also to donate immune cells.   
 
Birth control: 
 
Men and women who are sexually active on this study must agree to use an effective form of 
contraception (examples include: intrauterine device (IUD), hormonal (birth control pills, 
injections, or implants), tubal ligation/hysterectomy, partner’s vasectomy, barrier methods 
(condom, diaphragm, or cervical cap), or abstinence while participating in this study. 
 
Collection of Stem Cells by Bone Marrow Harvest 
 
If you are a haploidentical donor, you will donate bone marrow.  If you are a 10 out of 10 
matched related donor, you will donate peripheral blood stem cells.  In the unusual event that 
you are unable to donate peripheral blood stem cells, bone marrow will be used as the source of 
stem cells.  Such cases where peripheral blood stem cell cannot be obtained may involve donors 
who are medically not eligible to receive G-CSF, donors for whom the G-CSF results in a sub-
optimal collection of stem cells, or donors who prefer the marrow procedure relative to the 
apheresis procedure.  The stem cells will be collected from the bone marrow in the operating 
room using anesthesia.  Bone marrow will be obtained from the hipbones in the same way that a 
standard bone marrow test is performed.  Needles will be inserted into the hip bones and liquid 
bone marrow will be drawn into syringes.  The amount that will be collected will be based on the 
size of the transplant recipient and the white blood cell count performed on the bone marrow 
during collection. Approximately 1-2 teaspoons of marrow is required for every pound of 
recipient body weight.  As much as 3 pints may be needed.  The anesthesia options (general 
anesthesia versus spinal anesthesia), risks, and procedures will be discussed with you prior to the 
bone marrow collection and you will sign a separate informed consent form at that time.  You 
may be admitted to the hospital the night before the bone marrow harvest depending on the 
scheduled time of the collection.  You will remain in the hospital for 1 night after the harvest. 
Alternative Approaches or Treatments 
 
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options: 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  5  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
• As discussed above, there is an alternative approach to apheresis where you would have 
an operation on your hipbone to collect bone marrow cells, but most donors prefer 
collection of stem cells by apheresis.  Also, stem cell collection by apheresis avoids the 
risks of general anesthesia (“putting you under”) that is required with an operation. 
Usually, enough of your stem cells can be collected by apheresis. However, for 
haploidentical donors, bone marrow is the preferred source of stem cells.  
 
Risks or Discomforts of Participation 
 
The risks and discomforts of participating as a donor include the shots of G-CSF, blood drawing, 
and the apheresis procedure. 
 
G-CSF can cause the following side effects (these side effects stop once G-CSF has been 
stopped):  
Likely: 
Less likely: 
Rare: 
• bone pain,  
• muscle aches, and  
• headache  
 
• Some people who 
receive G-CSF shots 
and apheresis have a 
low number of blood 
platelets for a short 
period of time.  
Platelets help your 
blood to clot.  
However, low platelet 
count from G-CSF has 
not caused an 
increased amount of 
bleeding.  To be safe, 
your platelet count 
will be checked during 
and after the apheresis 
procedure.   
• Other common lab 
abnormalities have 
been seen but are 
reversible once G-CSF 
is stopped.   
 
• allergic reactions,  
• chest pain, and a 
lowering of the blood 
pressure.     
• There is a very rare 
side effect (1 in 
486,000 people) of 
one’s spleen rupturing 
due to G-CSF. 
Side effects of blood being drawn include pain and bruising in the area where the needle was put 
in, lightheadedness, or rarely, fainting.  When too much blood is taken, one’s red blood cell 
count may drop causing anemia.  However, the amount of blood that you will donate in this 
study (a total of 20 teaspoons) should not cause anemia.  To be safe, we will check your red 
blood cell level.  If we find that you have anemia, we will give you treatment for this condition 
(in the form of iron tablets). 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  6  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Side effects of the apheresis procedure may include low blood pressure.  If this happens, we will 
adjust the apheresis machine to correct this problem.  Other side effects include tingling in the 
mouth, fingers and toes, and mild muscle cramps.  These discomforts can be stopped by 
adjusting or stopping the procedure. 
 
Side effects of a temporary I.V. in the groin or neck vein (if required) include bleeding, bruising, 
blood clot, or pain where the I.V. was placed.  The I.V. will be put in only by physicians with 
experience in this procedure.  They will discuss the risks with you before the procedure. 
 
For donors who elect to donate stem cells by bone marrow harvest, other specific risks should be 
considered.  These risks are the same for donors of any age. The main risk of marrow harvest 
relates to the need for anesthesia, which will involve either general anesthesia or spinal 
anesthesia.  The specific risks of these procedures will be discussed in a separate consent 
procedure performed by the anesthesiology department.  Bone marrow donation is very safe.  
The procedure commonly causes temporary pain and bruising over the sites where the marrow 
was collected. This usually can be managed with pain medicine (e.g., Tylenol) alone.  
Occasionally, stronger pain medicines like codeine are required. Rarely, infection or bleeding at 
the needle sites may occur.  Anemia due to removal of large amounts of bone marrow may 
require treatment with iron or a blood transfusion. Serious side effects of bone marrow harvest 
are extremely rare and include fat embolism (like blood clots in the lungs) and risks of 
anesthesia.   
 
Potential Benefits of Participation 
 
By being a donor, you will provide a source of stem cells and immune cells for your relative.  
Hopefully, your donation of cells will help his or her cancer treatment.  Your participation may 
also help advance our understanding of stem cell transplants and improve the way that we treat 
cancer.  Knowledge gained from this study may help others in the future who have cancer. 
 
Research Subject’s Rights 
 
Participation in this research study is voluntary.  You may stop your participation in the study at 
any time.  There are no penalties for withdrawing from the study.  The study doctor may remove 
you from this study if he/she feels it is in your best interest. 
 
You will be given a copy of the consent for your records.  We encourage you to ask our staff any 
questions that you have. 
You will be told about new findings that pertain to this research study.  If we are required to stop 
this study because of serious side effects, we will continue to provide care for you according to 
the study protocol. 
 
What are the costs of taking part in this study? 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  7  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
There will be no cost to you to donate your stem cells and immune cells for your relative.  You 
will not be paid for your donation; however, you may be eligible for partial travel and housing 
reimbursement while participating in this study. 
 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive your history and physical exam at no charge to you.  This may 
include laboratory testing, x-rays or scans done at the Clinical Center, National 
Institutes of Health (NIH). Medicines that are not part of the study treatment will not 
be provided or paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH. 
Stopping Participation 
Your doctor may decide to stop your participation for the following reasons: 
• if he/she believes that it is in your best interest 
• if you have side effects from the donation that your doctor thinks are too severe 
• if new information shows that another treatment would be better for your relative. 
 
In this case, you will be informed of the reason your participation is being stopped. 
 
You can stop taking part in the study at any time.  However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor first. 
 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide    You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
Your records will be reviewed by representatives of the National Cancer Institute. 
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
09-C-0096                                       CONTINUATION:  page  8  of  9  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (7-09) 
 
P.A.: 09-25-0099 
 
 
 
File in Section 4:  Protocol Consent 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or 
at scientific meetings, the people who take part are not named and identified.  In most cases, the 
NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or other authorized hospital accreditation 
organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term 
medical care for any injury resulting from your participation in research here.  In general, no 
long-term medical care or financial compensation for research-related injuries will be provided 
by the National Institutes of Health, the Clinical Center, or the Federal Government.  However, 
you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
 
4. Problems or Questions. If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Dennis D. Hickstein, M.D. Telephone:  301-594-1718; Blackberry: 301-795-8778 
or Dr. Mark Parta240-409-4120. 
 
You may also call the Clinical Center Patient Representative at 301-496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
 
 
 
 
 
 
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
09-C-0096                                       CONTINUATION:  page  9  of  9  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (7-09) 
 
P.A.: 09-25-0099 
 
 
 
File in Section 4:  Protocol Consent 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
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Date 
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Print Name 
 
 
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C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
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Date 
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THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 30, 2015 THROUGH JUNE 29, 2016.  
 
 
 
 
 
 
 
 
 
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Prot_SAP_000.pdf: 
Version Date: May 18, 2016
Amendment Letter: T
PROTOCOL NUMBER: 09-C-0096
PROTOCOL TITLE: Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem 
Cell Transplant for Patients with GATA2 Mutations
Abbreviated Title: HSCT for GATA2 Mutation
Principal Investigator:
Dennis D. Hickstein M.D. 1 
Telephone:  301-594-1718
Email:  hicksted@mail.nih.gov
Lead Associate Investigator:
Mark Parta, M.D.9
Telephone: 301-451-4955
Email: mark.parta@nih.gov
Medical Advisory Investigator:
Juan Gea-Banacloche, M.D.1
Telephone: 301-675-9512
Email: banacloj@mail.nih.gov
Associate Investigators:
Terry Fry, M.D.7
Steve Holland, M.D.2
Ronald Gress, M.D. 1
#Brenna Hansen, R.N. 10
Steven Pavletic, M.D. 1
#Constance Yuan, MD, PhD9
Daniel Fowler, M.D.1
James Kochenderfer, M.D.1
#Charles Bolan, M.D. 6
#Jennifer Wilder, R.N.8
#Daniele Avila, C.R.N.P. 1
#Seth Steinberg, Ph.D. 4
#Fran Hakim, Ph.D.1
#Cynthia Delbrook, R.N.10
#Bazetta Blacklock-Schuver, R.N.10
#Thomas Hughes, Pharm.D.3
#Maryalice Stetler-Stevenson, MD, PhD9
#Hanh Khuu, M.D. 5
#David Stroncek, M.D. 5
#Jennifer Mann, C.R.N.P.1
#Sharon Adams, M.T. 5
#Stephanie Cotton, R.N. 10
#Kristen Cole, R.N. 10
1 Experimental Transplantation and Immunology Branch, CCR, NCI, NIH
2 Clinical Infectious Diseases, NIAID, NIH
3 Pharmacy Department, Clinical Center, NIH
4 Biostatistics and Data Management Section, National Cancer Institute
5 Department of Transfusion Medicine, Clinical Center, NIH
6 Hematology Branch, NHLBI, NIH 
7 Pediatric Oncology Branch, CCR, NCI, NIH
8 Leidos Biomedical Research, Inc. (NCI ETIB Contractor)
9 Laboratory of Pathology, CCR, NCI, NIH
10 Office of Clinical Director, CCR, NCI, NIH
Referral contact: Dennis D. Hickstein M.D
#Denotes individuals who will not make any clinical protocol decisions
Study coordinator: Kristen Cole, R.N


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
Email: colekr@mail.nih.gov
Telephone: 301-827-0374


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
Précis
Background
x
Mutations in GATA2 lead to an immunodeficiency disease that transforms into 
myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML).  This 
syndrome, previously known as MonoMAC, has 4 clinical features: 1) infections with 
Mycobacterium Avium Complex (MAC) and other opportunistic infections as a teenager 
or young adult, 2) a peripheral blood leukocyte flow cytometry profile with T-
lymphocytes, but a severe deficiency of monocytes, B-lymphocytes, and Natural Killer 
(NK) cells, 3) the propensity to progress to MDS/AML, and 4) mutations in the gene 
GATA2.  In this pilot study we propose to evaluate the efficacy and safety of a reduced-
intensity allogeneic hematopoietic stem cell transplantation (HSCT) regimen for patients 
with mutations in GATA2.  We are particularly interested in determining whether 
allogeneic HSCT using this regimen reconstitutes normal hematopoiesis in patients with 
mutations in GATA2. 
Objectives
x
Primary Objective:
1) To determine efficacy, namely whether reduced-intensity allogeneic HSCT results in 
engraftment and restores normal hematopoiesis by day +100 in patients with 
mutations in GATA2. 
2) To determine the safety of this HSCT regimen in patients with mutations in GATA2, 
including transplant related toxicity, the incidence of acute and chronic graft-versus-
host disease, immune reconstitution, overall survival, and disease-free survival 
Eligibility
Eligibility includes patients 12-60 years old with mutations in GATA2 who have a life-
expectancy of > 3 months but < 24 months, and who have a 10/10 matched related donor, 
a 10/10 or 9/10 matched unrelated donor (HLA -A, -B, -C, DRB1, DQB1 by high 
resolution typing identified through the National Marrow Donor Program),  a 4/6 (or 
greater HLA -A, -B, DRB1) matched unrelated umbilical cord donor, or a haploidentical 
donor.  Patients with GATA2 mutations who are 12-17 years of age are required to have 
MDS with chromosomal abnormalities to be eligible for this protocol.
Design
x
Patients with mutations in GATA2 with a 10/10 matched related or 10/10 matched 
unrelated donor, will receive a reduced-intensity pre-transplant conditioning regimen 
consisting of fludarabine 30 mg/m2/day on days -4, -3, and -2, 200 cGy total body 
irradiation (TBI) on day -1, and HSCT on day 0.  Patients with mutations in GATA2 and 
a 9/10 matched unrelated donor will receive a reduced-intensity pre-transplant 
conditioning regimen consisting of fludarabine 30 mg/m2/day on days -4, -3, and -2, 300 
cGy total body irradiation (TBI) on day -1, and HSCT on day 0.  Patients with mutations 
in GATA2 with umbilical cord blood units will receive a reduced-intensity conditioning 
regimen with cyclophosphamide 50 mg/kg on day -6, fludarabine 40 mg/m2 on days -6 to 
-2, equine ATG 30 mg/kg IV on days -6, -5 and -4, 200 cGy TBI on day -1, and HSCT on 
day 0. Patients with a haploidentical donor will receive a reduced intensity-conditioning 
regimen with cyclophosphamide 14.5 mg/kg on days -6 and -5, fludarabine 30 mg/m2 on 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
days -6 to -2, and 200 cGy TBI on day -1.  Donor bone marrow cells will be infused on 
day 0.
x
Post-transplant immunosuppression for graft-versus-host-disease prophylaxis will consist 
of sirolimus (Rapamycin) and tacrolimus until day +180, provided that there is no 
evidence of graft-versus-host disease.  Post-transplant immunosuppression for graft-
versus-host-disease prophylaxis for recipients of haploidentical donors will consist of 
cyclophosphamide 50 mg/kg on days +3 and +4, along with sirolimus from day +5 to day 
180, and tacrolimus from day +5 to day 180, providing that there is no GVHD. 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
TABLE OF CONTENTS
Table of Contents............................................................................................................................ 5 
1 
INTRODUCTION .................................................................................................................. 8 
1.1 
Primary Study Objectives................................................................................................. 8 
1.2 
Background and Rationale ............................................................................................... 8 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT....................................................... 26 
2.1 
Inclusion Criteria - Recipient......................................................................................... 26 
2.2 
Exclusion Criteria- Recipient......................................................................................... 27 
2.3 
Inclusion Criteria- Matched Related Donor................................................................... 27 
2.4 
Inclusion Criteria- Matched Unrelated Donor ............................................................... 28 
2.5 
Inclusion Criteria- Haploidentical Related Donor ......................................................... 28 
2.6 
Exclusion Criteria- Matched Related Donor.................................................................. 28 
2.7 
Exclusion Criteria- Matched Unrelated Donor .............................................................. 29 
2.8 
Exclusion Criteria- Haploidentical donor ...................................................................... 29 
2.9 
Inclusion Criteria- Umbilical Cord Blood Unit-HLA Typing and Dose ....................... 30 
2.10 
Review of UCB Unit HLA Typing and Selection of the UCB Unit .......................... 30 
2.11 
Recipient Research Eligibility Evaluation.................................................................. 31 
2.12 
Matched Related Donor and Haploidentical Donor Research Eligibility Evaluation 31 
2.13 
Unlicensed Cord Blood Units..................................................................................... 32 
2.14 
Patient Registration..................................................................................................... 32 
3 
STUDY IMPLEMENTATION ............................................................................................ 34 
3.1 
Study Design .................................................................................................................. 34 
3.2 
Drug Administration ...................................................................................................... 37 
3.3 
Treatment Modifications................................................................................................ 42 
3.4 
Pharmacokinetic Studies (Not Applicable).................................................................... 44 
3.5 
Protocol Evaluation........................................................................................................ 44 
3.6 
Concurrent Therapies ..................................................................................................... 46 
3.7 
Surgical Guidelines (Not Applicable)............................................................................ 46 
3.8 
Radiation Guidelines...................................................................................................... 46 
3.9 
Off Treatment Criteria- Not Applicable......................................................................... 47 
3.10 
Off Study Criteria....................................................................................................... 47 
3.11 
Post Study Evaluation (Follow-Up) ........................................................................... 47 
3.12 
Immunologic Studies.................................................................................................. 48 
3.13 
Restrictions for Blood Drawn for Research Samples:................................................ 48 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
4 
SUPPORTIVE CARE........................................................................................................... 49 
4.1 
Infection Prophylaxis ..................................................................................................... 49 
4.2 
Management of Engraftment Syndrome ........................................................................ 49 
4.3 
Treatment of Graft-Versus-Host Disease....................................................................... 49 
4.4 
Menses Suppression and Contraception......................................................................... 49 
4.5 
Blood Product Support................................................................................................... 50 
4.6 
Nutritional Support......................................................................................................... 50 
4.7 
Anti-emetic Usage.......................................................................................................... 50 
4.8 
Intravenous Immune Globulin (IVIG) ........................................................................... 50 
4.9 
Hepatic Function Support............................................................................................... 50 
4.10 
Central Nervous System Prophylaxis......................................................................... 51 
5 
DATA COLLECTION AND EVALUATION..................................................................... 52 
5.1 
Data Collection............................................................................................................... 52 
5.2 
Response criteria ............................................................................................................ 53 
5.3 
Toxicity Criteria:............................................................................................................ 54 
5.4 
Statistical Considerations............................................................................................... 54 
5.5 
Data and Safety Monitoring Plan................................................................................... 55 
6 
HUMAN SUBJECTS PROTECTIONS ............................................................................... 56 
6.1 
Rationale for Subject Selection...................................................................................... 56 
6.2 
Evaluation of Benefits and Risks/Discomforts- Patients ............................................... 56 
6.3 
Risks in Relation to Benefit ........................................................................................... 58 
6.4 
Consent and Assent Processes and Documents.............................................................. 59 
7 
DATA REPORTING............................................................................................................ 60 
7.1 
Definitions...................................................................................................................... 60 
7.2 
NCI-IRB Reporting........................................................................................................ 62 
8 
PHARMACEUTICAL INFORMATION............................................................................. 64 
8.1 
Fludarabine (Fludara, Berlex Laboratories)................................................................... 64 
8.2 
Sirolimus (Rapamune®) ................................................................................................ 64 
8.3 
Tacrolimus (FK506, Prograf)......................................................................................... 65 
8.4 
Filgrastim (G-CSF; Neupogen ®).................................................................................. 65 
8.5 
Diphenhydramine........................................................................................................... 66 
8.6 
Acetaminophen............................................................................................................... 67 
8.7 
Acyclovir........................................................................................................................ 67 
8.8 
Trimethoprim/Sulfamethoxazole (TMP/SMX, Cotrimoxazole, Bactrim, Septra)......... 67 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
8.9 
Ursodeoxycholic Acid (Ursodiol, Actigall®) ................................................................. 68 
8.10 
Ceftazidime  (Fortaz ®).............................................................................................. 68 
8.11 
Levofloxacin  (Levaquin ®)....................................................................................... 69 
8.12 
Cyclophosphamide  (CTX, Cytoxan)......................................................................... 69 
8.13 
Equine Anti-thymocyte globulin (Atgam).................................................................. 70 
9 
APPENDICES ...................................................................................................................... 71 
9.1 
Appendix A:   Preparative Regimen .............................................................................. 71 
9.2 
Appendix B:   Protocol Evaluation Checklist ................................................................ 73 
9.3 
Appendix C:  Immunizations Post-Transplant............................................................... 76 
9.4 
Appendix D:  Grading and Management of Acute Graft-Versus-Host Disease ............ 77 
9.5 
Appendix E:  Management of Engraftment Syndrome.................................................. 79 
9.6 
Appendix F- NMDP Criteria for Matched Unrelated Donor........................................ 81 
9.7 Appendix G: Experimental Transplantation and Immunology Branch Preclinical Service 
Policy for Sample Handling...................................................................................................... 83 
10 REFERENCES ..................................................................................................................... 87 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
1
INTRODUCTION
1.1
PRIMARY STUDY OBJECTIVES
1) In a pilot fashion, to determine efficacy, namely whether reduced-intensity allogeneic 
hematopoietic stem cell transplant (HSCT) results in engraftment and restores normal 
hematopoiesis by day +100 in patients with mutations in GATA2.
2) To determine the safety of reduced-intensity allogeneic HSCT regimen in patients with 
mutations in GATA2 including transplant related toxicity, the incidence of acute and chronic 
graft-versus-host disease, immune reconstitution, overall survival, and disease-free survival.
1.2
BACKGROUND AND RATIONALE 
1.2.1
Introduction
Since its first description 50 years ago, the number of hematopoietic stem cell transplants 
(HSCT) has increased steadily; 50,000 patients worldwide received a HSCT in 2006 (Thomas et 
al. 1957; Appelbaum 2007).  Although allogeneic HSCT can cure hematological malignancies, 
bone marrow failure syndromes, and genetic hematological and immunodeficiency diseases, the 
success of therapy depends upon the prompt identification of a suitable donor.  Because matched 
related donors were required in the initial HSCT, this limited the number of HSCT performed; 
only 30 percent of otherwise eligible patients with leukemia in the United States have a related 
histocompatible donor.  A major factor in the increase in HSCT over the preceding 20 years has 
resulted from the use of alternative donors.  
1.2.2
Reduced-Intensity Conditioning Regimens for Matched Related Donors
Allogeneic hematopoietic stem cell transplantation with a myeloablative-conditioning regimen 
represents a potentially curative therapy for hematological malignancies, however this treatment 
approach has not been pursued in many instances due to the high regimen-related toxicity with 
age greater than 60 years, or with concomitant co-morbidities.  The unacceptable risk of death 
from conventional myeloablative transplantation has also precluded this curative therapy for 
patients with other non-malignant hematological diseases.  However, it has recently been shown 
that these high intensity regimens may not be required for engraftment.  As a result of these 
findings, many centers are now exploring reduced-intensity conditioning regimens in order to 
reduce the toxicity associated with HSCT in both malignant and non-malignant hematological 
diseases.  The evolution in thinking regarding myeloablative versus reduced-intensity 
conditioning regimens is described in the ensuing paragraphs.
The use of conditioning regimens containing high doses of alkylating agents, often in 
combination with total body irradiation, are considered “myeloablative;” these regimens were 
perceived to be essential both for eradication of malignant disease and for suppression of the 
host-versus-graft response to the donor stem cells (i.e. rejection) (Copelan 2006). Myeloablative 
conditioning regimens caused severe damage to normal organs within the body resulting in a 
high incidence of morbidity and mortality (Bearman et al. 1988). This limited the application of 
allogeneic HSCT to younger patients (< 60 years of age) who could tolerate these toxicities.  
Subsequent studies and observations challenged the assumption that myeloablative conditioning 
was necessary to eliminate malignancy and permit the engraftment of the donor hematopoietic 
and immune systems. 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
The high frequency of relapse observed in the setting of T-cell-depleted allogeneic HSCT 
suggested that a significant proportion of the curative potential of allogeneic HSCT resulted from 
a T-cell-mediated graft-versus-tumor (GVT) effect (Champlin 1990).  It was also recognized that 
conventional myeloablative regimens do not completely eliminate the host response to the 
allograft, even in recipients of HLA-matched allografts.  For example, one study indicated that 
30 to 40% of patients will reject a T-cell-depleted, HLA-matched allogeneic stem cell graft after 
myeloablative conditioning (Martin et al. 1988).  In addition, there are certain clinical situations 
where the malignancy is very susceptible to the allogeneic GVT effect (e.g. AML in complete 
remission, chronic leukemia or low-grade lymphoma.  In these clinical situations, the use of a 
myeloablative-conditioning regimen may be adding toxicity without eradicating the tumor. 
These limitations of myeloablative conditioning regimens, combined with the high levels of 
morbidity and mortality associated with myeloablation, result in a compromised therapeutic 
index for this form of allogeneic HSCT.  Reducing treatment-related toxicity would improve the 
therapeutic index of allogeneic HSCT, permitting the broader application and potential benefit of 
this treatment to more patients.  This principle led to the development of less intensive 
“nonmyeloablative” and “reduced-intensity” conditioning regimens for allogeneic HSCT, which 
were designed with the purpose of allowing engraftment of donor cells to exploit the potential 
allogeneic GVT effect (Giralt et al. 1997; Slavin et al. 1998; Childs et al. 1999; Spitzer et al. 
2000; Khouri et al. 2001).
The early reports of studies employing nonmyeloablative and reduced-intensity conditioning 
regimens prior to allogeneic HSCT demonstrated that early engraftment occurred in the majority 
of patients, and early transplant-related toxicities (first 100 days after transplantation) were 
reduced.  This indicated that reduced-intensity regimens could be used for older patients and 
patients with co-morbidities.  However, it was also observed that both nonmyeloablative and 
reduced-intensity conditioning were associated with high incidences of incomplete donor 
chimerism, higher incidences of graft rejection/failure, and increased relapse rates, as compared 
to results with myeloablative conditioning regimens (Khouri et al. 1998; Aoudjhane et al. 2005).
Mixed chimerism and graft rejection were also associated with HLA-disparity and the use of 
unrelated donors, and correlated inversely with the amount of therapy prior to transplant 
(McSweeney et al. 2001; Maris et al. 2003; Carvallo et al. 2004).  It was also observed that a 
GVT effect was not observed until full donor chimerism was achieved (Truitt and Atasoylu 
1991; Mackinnon et al. 1994; Childs et al. 2000; Orsini et al. 2000; Petrus et al. 2000).
To decrease toxicity, and to develop immunosuppressive as opposed to myeloablative regimens, 
many centers explored combinations of regimens including the use of low dose radiation.  Low 
dose radiation alone has been shown to have anti-leukemia properties.  A dose of 200 cGy total 
body irradiation (TBI) was adequate for inducing remission, albeit short lived, in refractory 
patients ineligible for other standard treatments (Shulman et al. 1998).  Doses of 100 to 500 cGy 
have been shown to have very little toxicity in both murine and rhesus transplant models (Huhn 
et al. 1999; Kang et al. 2001).  Even patients with Fanconi anemia, who would be considered 
high risk for radiation induced toxicity, tolerate moderate dose (500 cGy) radiation based 
regimens (Dufour et al. 2001).  While regarded as a method designed for the creation of “space” 
within the marrow in bone marrow transplantation (BMT) regimens, radiation has long been the 
basis of the establishment of immunosuppressive protocols for both BMT and solid organ 
transplantation in animal models (Myburgh et al. 1980; Myburgh et al. 1984).  There is extensive 
clinical experience demonstrating stable mixed chimerism with the use of 200 cGy total body 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
irradiation and fludarabine, followed by GVHD prophylaxis with Cyclosporine (CSP) and 
mycophenolic acid (MMF) (Hegenbart et al. 2006).
This protocol aims to take advantage of the immunodeficiency state in patients with mutations in 
GATA2 to achieve a high level of donor chimerism following HSCT using a reduced intensity 
conditioning regimen with low-dose TBI and fludarabine.  Because opportunistic infections are 
present in many of these patients, along with MDS, both high levels of chimerism and low 
regimen related toxicity are important considerations in designing a transplant regimen for this 
cohort.
1.2.3
Reduced-Intensity Conditioning Regimens for Matched Unrelated Donors
Allogeneic HSCT is potentially curative for many hematological malignancies, however, as 
previously noted, stem cell donor availability limits the broader application of this treatment.  
Only 25% to 30% of patients have a sibling donor who is fully matched at the class I and II 
major histocompatibility complex (MHC) loci that encode for the human leukocyte antigens 
(HLA-A, -B, -C, DRB1, and DQB1) (Appelbaum 2007).  This limitation prompted the 
exploration of alternative stem cell sources for allogeneic HSCT including the use HLA-matched 
unrelated donors (Kernan et al. 1993).  Enrollment of volunteer donors in national and 
international registries, such as National Marrow Donor Program (NMDP) in the United States, 
has facilitated the identification of unrelated stem cell donors for patients without HLA-matched 
sibling donors.  However, transplants from unrelated donors are complicated by higher rates of 
graft rejection, acute and chronic GVHD, and treatment-related mortality.  These complications 
are partially balanced by lower relapse rates attributed to increased histocompatibility 
differences.  These complications have limited matched unrelated donor myeloablative HSCT to 
patients less than 55 years of age and without any significant co-morbidity.  Within these 
limitations, matched unrelated donor transplant has become widely utilized to treat 
hematological malignancies. 
In light of the high treatment-related morbidity and mortality associated with myeloablative 
allogeneic HSCT from unrelated donors, clinical studies utilizing nonmyeloablative and reduced-
intensity conditioning regimens were initiated after encouraging results with these regimens for 
HLA-matched siblings had been reported.  However, because of greater genetic disparity 
between the donors and recipients, it was hypothesized that nonmyeloablative conditioning 
regimens for unrelated donor transplantation might require more intense immunosuppression 
than a transplant from an HLA-matched sibling.  Since 2001, there have been a number of 
relatively large single-institution and multi-institutional studies on nonmyeloablative and 
reduced-intensity allogeneic HSCT utilizing unrelated donors (Tables 1A and 1B) (Giralt et al. 
2001; Chakraverty et al. 2002; Kroger et al. 2002; Maris et al. 2003; Niederwieser et al. 2003; 
Wong et al. 2003).  Of note, the median ages of recipients has ranged from 44 to 59 years with 
patients as old as 72 years successfully undergoing this procedure. 
The incidence of graft rejection in these HSCT ranged from 0 to 21%.  The primary adverse 
factors related to graft rejection were: use of nonmyeloablative conditioning regimens, HLA-
mismatching, transplant with bone marrow rather than mobilized peripheral blood, and a 
minimal amount of prior therapy prior to transplant.  Using a variety of GVHD prophylaxis 
regimens, the reported incidences of Grade II-IV and Grade III-IV acute GVHD have been 21-
63% and 6-39%, respectively.  Early (< 100 days post-transplant) treatment-related mortality 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
rates have varied from 10 to 48%; one-year treatment-related mortality rates have varied from 17 
to 55%.  One-year overall survival rates have been reported to be 32 to 75% (Tables 1A and 1B).
The majority of the reduced-intensity regimens are based on chemotherapy, however a 
considerable experience, primarily from the Fred Hutchinson Cancer Research Center, has 
accumulated using 200 cGy low-dose TBI in the conditioning regimen along with fludarabine 
(Maris et al. 2003; Niederwieser et al. 2003).  This work was first described in the 1990’s in the 
canine model and demonstrated that 200 cGy TBI pre-transplant combined with post-transplant 
immunosuppression with Cyclosporine (CSP) and Mycophenolate (MMF) resulted in stable 
engraftment of dog leukocyte antigen (DLA)-matched littermate recipients (Storb et al. 1999).
When these results were translated to humans it was shown that the addition of fludarabine 
significantly increased the rate of engraftment of donor hematopoietic stem cells (Mielcarek et 
al. 2007).  Using this regimen the Seattle group recently reported comparable engraftment 
between matched unrelated and matched related recipient.
This protocol uses a reduced-intensity regimen to treat patients with mutations in GATA2 who 
have a 10/10 matched related donor, a 10/10 matched unrelated donor, or a 9/10 matched 
unrelated donor.  This regimen carries one of the lowest incidences of transplant related 
mortalities (Maris et al. 2003).  This factor is important since patients with mutations in GATA2 
are frequently debilitated from infections with opportunistic organisms such as mycobacterium 
avium complex (MAC).   
Table 1A - Patient and Treatment Characteristics of Reported Trials of Non-myeloablative 
and Reduced-intensity Allogeneic HSCT Utilizing HLA-matched Unrelated Donors
Author/Institute
Journal/Date
Patient #
Median 
Age
HLA 
Loci
Degree 
match
Level of HLA 
Match
Conditioning Regimen
GVHD
Prophylaxis
Stem Cell 
Source
CD34
Dose 
(106/kg)
CD3 Dose 
( 108/kg)
Class I
Class II
Giralt et al. MDACC 
Blood 2001
N = 86 
(URD = 
40)
52 years 
(22-70)
6
6/6
Serology Molecular Flu (25 mg/m2/d) x 5d
Mel 90–140 mg/m2
Clad (12 mg/m2/d) x 5d
Mel 90–140 mg/m2
FK506 x 6 months
MTX (5 mg/m2)
+1,+3,+6,+11
NA
NA
NA
Chakraverty et al. 
UK multi-institute 
Blood 2002
N = 47
44 years 
(18–62)
10
9-10/10 
(s)
8-10/10 
(m)
serologic 
– A,B
mole – C
Molecular Flu (30 mg/m2/d) x 5d
Mel 140 mg/m2
CAMPATH (20 mg/kg) 
-8,-7,-6,-5,-4,-3
CsA x 3 months
[CAMPATH]
BM = 46
PB = 1
NA
NA
Kroger et al. German 
multi-institute 
Blood 2002
N = 21 
(all 
multiple 
myeloma)
50 years
(32-61)
8
HLA-A,B, 
DRB1,DQB1
7-8/8
Serology
c
Molecular Flu (30 mg/m2/d) x 5d
Mel 100 mg/m2
ATG (10 mg/kg) -3,-2,-1
CsA x 3 months
MTX (10 mg/m2)
+1,+3,+6
BM = 6
PB = 15
3.9
(0.4 -
12.5)
NA
Niederwieser et al. 
FHCRC Consortium 
Blood 2003
N = 52
48 years
(6–65)
8 (10)
HLA-A,B,C, 
DRB1, 
(DQB1)
7-8/8 (s)
6-8/8 (m)
Serologi
c
Molecular Flu (30 mg/m2/d) x 3d
TBI 200 cGy
CsA x 2-3  
months, taper until 
+180)
MMF x 40d,taper
BM = 13
PB = 39
6.0 (1.5 –
21.6)
(BM = 
2.7)
3.4 (0.8 –
10.0)
(BM = 0.3)
Maris et al. FHCRC 
Consortium 
Blood 2003
N = 85
53 years
(5–69)
10
HLA-A,B,C, 
DRB1,DQB1
10/10
serologic
(81% 
molecula
r at 
Class I)
Molecular Flu (30 mg/m2/d) x 3d
TBI 200 cGy
CsA x 3 months, 
taper until +180
MMF x 40d,taper
BM = 18
PB = 71
6.99 (1.26 
-16.4)
2.61 
(0.8 -37.7)
Wong et al. MDACC 
Blood 2003
N = 29
59 years 
(55-69)
6
6/6
5/6 (n = 2)
Serologi
c
Molecular Flu (25 mg/m2/d) x 5d
Mel 90–140 mg/m2
+/- ATG (n = 17)
FK506 x 6 - 8 
months
MTX (5 mg/m2)
+1,+3,+6,+11
BM = 28
PB = 1
4.46 (0.37 
– 8.6)
NA


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Table 1B - Clinical Outcomes of Reported Trials of Non-myeloablative and Reduced-
intensity Allogeneic HSCT Utilizing HLA-matched Unrelated Donors
Author/Institute
Journal/Date
Graft 
Rejection 
and Failure
Acute GVHD
Chronic 
GVHD
TRM
OAS
II-IV
III-IV
Day 100
1 year
2 year
1 year
2 year
Giralt et al. 
MDACC Blood 
2001
5% (n =2)
62%
(11 deaths)
39%
68%
37.4%
NA
45% (all 
patients) 
32%
(URD)
28% (all 
patients)
Chakraverty et al. 
UK multi-institute 
Blood 2002
3% (n= 2)
21.3%
6.4%
8% (all 
limited)
15%
20%
(~25%)
75%
NA
Kroger et al. 
German multi-
institute Blood 
2002
0
38%
19%
37%
Limited = 
25%
Extensive = 
12%
10%
26%
NA
74%
74%
Niederwieser et al.
FHCRC 
Consortium Blood 
2003
12%
(low CD3; 
low CD34)
63%
21%
60%
Limited = 
30%
Extensive = 
30%
11%
29%
40%
44%
35%
(19 mo)
Maris et al. 
FHCRC 
Consortium Blood 
2003
21% (PB vs. 
BM: 15% vs. 
44%)
52%
10%
45% (85)
Extensive = 
37%
11%
17%
NA
52%
(~42%)
Wong  MDACC 
Blood 2003
14% (n= 4) 
41%
20%
62.5%
48%
55%
NA
44%
(~44%)
1.2.4
Effect of HLA on Transplant Outcomes:
Since its inception, the NMDP has required evaluation of donor-recipient histocompatibility 
matching (HLA-A, -B, and -DR) prior to unrelated donor HSCT (Bray et al. 2008). The 
minimum acceptable match was originally defined by serologic testing at these 3 loci (6 possible 
antigens) and required at least 5 matches, that is, a “5 of 6 match”. This requirement has changed 
little over the years. Currently, to request a donor for transplantation, the minimal acceptable 
level of matching remains a 5 of 6 match for HLA-A, -B, and -DRB1. Although only evaluated 
at antigen level of resolution (“low resolution”) for donor release, each of these 3 loci must now 
be typed at high-resolution by DNA-based methods. High-resolution typing is defined as the 
identification of alleles based on differences in the antigen recognition site (ARS) domains 
(Exons 2 and 3 of Class I and exon 2 of Class II genes). In 2005, a requirement for HLA-C
typing was added. The most recent studies have clearly shown that transplant outcomes can be 
improved by matching strategies that increase the overall degree of HLA compatibility above the 
minimum accepted level by matching also for HLA-C, -DP, -DQ, and haplotypes (Petersdorf 
2006).
As data on high resolution typing accumulated, the NMDP performed an analysis on the effects 
of HLA matching (low or high resolution or both) on engraftment, graft-versus-host disease 
(GVHD), and mortality in 1874 donor-recipient pairs that were retrospectively typed using high 
resolution techniques for HLA-A, -B, -C, -DRB1, -DQ, and -DP (Flomenberg et al. 2004).
There was no effect of any mismatch on engraftment, and only a mismatch at HLA-A affected 
whether the patients experienced Grade II-IV acute GVHD or chronic GVHD. Single 
mismatches at HLA-A, -B, -C, and -DRB1 each had similar adverse effects on mortality (relative 
risk 1.23 - 1.33), as compared to individuals matched at all four loci.  The 5-year overall survival 
rates for a match at all four loci (“8 of 8” as compared to a single mismatch (“7 of 8”) was 39% 


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and 31%, respectively.  In this analysis, mismatches at HLA-DQ or -DP did not appear to exert 
any significant effect on survival (5-year overall survival = 39%) or any other outcome.  The 
observed adverse effects on outcome were more evident in transplants with low-resolution versus 
only high-resolution mismatches.  When high-resolution mismatches at HLA-A, -B, -C, and -
DRB1 were considered together, adverse effects on survival and GVHD were observed.  The 
authors concluded that matching for HLA-C should be incorporated into algorithms for unrelated 
donor selection, along with HLA-A, -B, and -DRB1 (i.e. “8 of 8”).
In a subsequent analysis, the NMDP looked at data from 3857 transplantations.  Patient-donor 
pairs were fully typed for HLA-A, -B, -C, -DRB1, -DQB1, -DQA1, -DPB1, and -DPA1 alleles 
(Lee et al. 2007).  High-resolution DNA matching for HLA-A, -B, -C, and -DRB1 (8 of 8 match) 
was the minimum level of matching associated with the highest survival.  A single mismatch 
detected by low- or high-resolution DNA testing at HLA-A, -B, -C or -DRB1 (7/8 match) was 
associated with higher mortality (relative risk = 1.25; 95% CI, 1.13-1.38; P < 0.001) and 1-year 
survival of 43% compared with 52% for 8 of 8 matched pairs.  Single mismatches at HLA-B or 
HLA-C appeared to be better tolerated than mismatches at HLA-A or HLA-DRB1.  Mismatching 
at 2 or more loci compounded the risk.  Mismatching at HLA-DP or -DQ loci and donor factors 
other than HLA type were not associated with survival.  In multivariate modeling, patient age, 
race, disease stage, and cytomegalovirus status were as predictive of survival as donor HLA 
matching. The authors concluded that high-resolution DNA matching for HLA-A, -B, -C, and -
DRB1 alleles is associated with higher rates of survival.
Based on these results, the NMDP has established guidelines relative to donor selection based on 
HLA-typing (Bray et al. 2008).  The optimal donor should be matched at HLA-A, -B, -C, and -
DRB1 by high-resolution typing.  When there are multiple donors with this degree of matching, 
further matching at HLA-DQ may be utilized; however, the clinical utility does not reach 
statistical significance.  If a mismatch is unavoidable, a single mismatch at HLA-A, -B, -C, and -
DRB1 should be sought.  In the NMDP data, mismatches at HLA-B and -C may be less 
detrimental than those at HLA-A and -DRB1.
1.2.5
Reduced Intensity Umbilical Cord Blood Transplantation
Umbilical cord blood (UCB) represents an alternative to bone marrow as a source of HSC for 
transplantation in individuals who lack an HLA-matched donor, and has been used as a source of 
donor hematopoietic stem cells HSC to treat a variety of malignant and non-malignant 
hematological disorders (Kurtzberg et al. 1996; Wagner et al. 2002).  The advantages of UCB 
include the ease of procurement, lack of donor attrition, absence of maternal risk, reduced risk of 
GVHD, and less stringent criteria for HLA matching (Wagner and Kurtzberg 1997).  The major 
limitations in UCB are the relatively decreased cell dose leading to delayed engraftment, 
extended post-transplant neutropenia and thrombocytopenia, and an increased incidence of 
infection and bleeding.  The developments since the first HSCT using UCB in 1989 are 
described in the ensuing paragraphs. 
Unrelated Donor UCB HSCT in Pediatrics 
The initial descriptions of significant cohorts of patients treated using UCB transplant involved 
the use of single UCB units in children and myeloablative conditioning regimens (Kurtzberg et 


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al. 1996; Gluckman et al. 1997).  Both studies confirmed the potential of UCB transplant to 
induce remission in patients with refractory hematological malignancies.  The two studies also 
reported a lower than predicted frequency of GVHD. 
These early studies with UCB HSCT from sibling donors led to the banking of unrelated donor 
UCB.  Using banked UCB (from the New York Blood Center) in 167 children with 
hematological malignancies, congenital / acquired bone marrow failure syndromes, and genetic 
diseases, 93% of the patients engrafted.  Engraftment was subsequently found to correlate with 
the number of CD34+ cells transplanted, rather than the degree of HLA matching.  Retrospective 
analysis indicated that a dose of CD34+ cells <2-3 x 105 CD34+ cells/kg resulted in diminished 
and delayed engraftment of platelets and neutrophils.  Multivariate analysis revealed that any 
dose >3 x 105 CD34+ cells/kg results in fairly consistent engraftment. 
Unrelated Donor UCB HSCT in Adults
Three studies specifically addressed the use of UCB grafts in adults (Gluckman 2000; Laughlin 
et al. 2001; Sanz et al. 2001).  These studies consisted of adult patients with hematological 
diseases who underwent myeloablative conditioning followed by HLA-matched or mismatched 
UCB infusion.  The probability of myeloid engraftment and the probability of developing acute 
GVHD grades II-IV ranged from 81% to 100% and 38% to 60%, respectively.  The event free 
survival (EFS) (with at least 1 year of follow up) ranged from 21% to 53%.  These data indicated 
that UCB SCT led to lower than expected rates of acute GVHD, especially in the setting of 
mismatched HLA grafts, and encouraged further study using UCB.   
Two recent reports specifically compared the outcomes of adult patients with acute leukemia or 
myelodysplastic syndrome (MDS) transplanted with either HLA-mismatched UCB or HLA-
matched and mismatched BM grafts (Laughlin et al. 2004; Rocha et al. 2004).  Time to 
neutrophil and platelet engraftment and recovery were significantly longer after UCB SCT than 
BMT.  Acute GVHD was more likely after mismatched marrow transplant, however chronic 
GVHD was more likely after UCB transplant.  Treatment-related mortality (TRM), treatment 
failure (i.e. relapse or death), and overall mortality were lowest in patients receiving HLA-
matched BM grafts.  There was no difference in the rate of recurrence of leukemia among the 
groups.  The adjusted probability of three-year survival was 26% for patients receiving UCB 
grafts; this was similar to patients receiving HLA-mismatched BM. 
The conclusion from these studies was that UCB represented a curative alternative donor source 
for patients with hematological malignancies who lacked a bone marrow donor.  When compared 
with URD BMT, there is a delay in neutrophil and platelet engraftment, a higher risk of graft 
failure, and an increase in TRM during the first 100 days.  This is balanced in part by a decrease 
in acute GVHD seen in recipients of UCB. 
Reduced Intensity Unrelated Donor UCB HSCT
The use of UCB SCT in the adult population has been tempered by the increased risk of graft 
failure and decreased survival associated with the small cell dose in physically larger patients.  
Investigators at Case Western Reserve University found that a higher nucleated cell dose and 
higher CD34+ cell dose correlated with more rapid neutrophil recovery and improved survival, 
respectively in adult patients undergoing UCB HSCT (Laughlin et al. 2001).  The importance of 
cell dose was further supported by data which showed that UCB recipients infused with < 1.8 x 


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107 NC/kg or < 1.7 x 105 CD34+ cells/kg body weight had significantly decreased engraftment 
and survival (Wagner et al. 2002).
Anti-thymocyte globulin (ATG) has been used as part of the preparative regimen prior to the 
infusion of donor cells to decrease the incidence of graft rejection and to decrease the incidence
of GVHD by eliminating donor T-cells in the graft.  Animal experiments originally 
demonstrated the synergistic immunosuppressive effects between ATG and alkylating agents. 
The combination of ATG and cyclophosphamide was subsequently used widely in HSCT.
In a non-malignant disease setting, substitution of cyclophosphamide by fludarabine and rabbit 
ATG in a busulfan based regimen of matched related donor transplant in 5 children and adults 
with beta-thalassemia, all patients engrafted with 2 of the 5 maintaining 100% donor chimerism 
(Sauer et al. 2005).
Additional support for the use of ATG in UCB appeared in late 2007 with the description of 110 
adult patients who received UCB following a nonmyeloablative-conditioning regimen (Brunstein 
et al. 2007).  This large study of 110 patients utilized a conditioning regimen consisting of 
Fludarabine 200 mg/m2, Cytoxan 50 mg/kg, and 200 cGy TBI, and Equine ATG (ATGAM) 15 
mg/kg IV every 12 hours on day -6, -5, and -4.  The investigators aimed to transplant at least 3 x 
107 total nucleated cells (TNC)/kg in each patient, and if the cord blood unit contained less than 
that amount, two UCB units were infused.  This resulted in 85% of patients receiving two UCB 
units.  With the double UCB units neutrophils recovered to 500/μl at a median of 12 days and 
platelets required a mean of 49 days to achieve a level of 20,000/μl.  Grade 3 and 4 GVHD 
occurred in 22% and 23% of patients, respectively.  Interestingly, by 21 days post-transplant one 
of the units prevailed in over 80% of the patients. Survival was 45% at 3 years with an event free 
survival of 38%. 
Advantages of UCB
The reasons for the expanded use of UCB as a donor source are many.  The first advantage lies 
in the immediate availability of cells.  The median time from request to acquisition of the UCB is 
13.5 days (Barker et al. 2002).  Since there is no risk to the donor, there is no donor 
unavailability, such as that which occurs with unrelated donors in which an estimated 25 percent 
of donors who are identified are subsequently unable to donate HSC (Wagner et al. 2002).
Second, acceptable cord-blood units can be identified for most patients because less stringent 
HLA-compatibility with the recipient is required (Rocha et al. 2000).  Third, the incidence and 
severity of GVHD are not excessive with UCB, even with cord-blood units mismatched for more 
than one HLA antigen (Brunstein et al. 2007).   Moreover, the graft-versus-leukemia effects are 
maintained with UCB grafts (Laughlin et al. 2004).
UCB banks have been developed worldwide and standardized banking procedures have been 
implemented (Rubinstein et al. 1998).  The low rate of viral infection at birth and the collection 
of cord blood from ethnic groups not well represented in bone marrow donor registries are 
additional advantages of UCB.  There are an estimated 170,000 units in 37 cord blood registries 
in 21 countries (Bone Marrow Donors Worldwide Homepage  (www.bmdw.org).
The main obstacle for use of cord blood transplant in adults has been the low number of stem 
cells in cord blood units leading to delayed engraftment and graft failure.  The number of HSC 
in a unit of cord blood is approximately one tenth the number of HSC in a marrow harvest 
(Laughlin et al. 2001).  The low number of HSC in UCB results in more gradual reconstitution 
of hematopoiesis following UCB grafts compared to bone marrow or peripheral blood stem cell 


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grafts, and this contributes to the increased rates of post-transplant infection and early death 
(Rocha et al. 2000).  This limitation in UCB SCT has been decreasing with the increasing use of 
double cord units. 
We propose to consider the use UCB as the source of donor HSC for patients with mutations in 
GATA2 who lack a 10/10 matched related or unrelated donor.  The ability to acquire UCB 
within two weeks of the request represents a potential advantage for patients with mutations in 
GATA2 who may have a narrow window of opportunity for transplant between severe 
infections.  
1.2.6
HLA-Haploidentical Hematopoietic Stem Cell Transplantation Using Nonmyeloablative 
Conditioning and High-Dose, Post-Transplantation Cyclophosphamide
During the previous decade there has been an increasing body of evidence that high-dose 
cyclophosphamide given post-transplant prevents both graft rejection and graft-versus-host 
disease.  Cyclophosphamide has a long history as an immunosuppressive agent that is selectively 
toxic to lymphocytes that are proliferating in response to recent antigen stimulation. 
Cyclophosphamide can be safely administered in high doses after allogeneic HSCT with a 
favorable safety profile, especially a lack of toxicity to hematopoietic stem cells. In animal 
models both graft rejection and GVHD were inhibited by administration of high-dose 
cyclophosphamide after allogeneic bone marrow transplantation.  When given in high doses after 
allogeneic HSCT cyclophosphamide targets proliferating, alloreactive T-cells and prevents 
GVHD (Luznik et al. 2002).
In 2002 O'Donnell and colleagues at Johns Hopkins described results using a nonmyeloablative 
bone marrow transplant from partially HLA-mismatched related donors using post-transplant 
cyclophosphamide (O'Donnell et al. 2002).  Donors were partially HLA-matched (up to 3 HLA 
antigens) from first-degree relatives.  They demonstrated comparable levels of engraftment and 
GVHD to that seen with matched unrelated donor transplants.  The regimen is shown (Figure 1).
Figure 1. Nonmyeloablative haploidentical BMT conditioning and post grafting 
immunosuppressive regimen.
Non-malignant diseases were also amenable to the nonmyeloablative regimen described.  In 
2008 Brodsky described HSCT for thrombotic paroxysmal nocturnal hemoglobinuria using the 
regimen described (228, Brodsky, BMT).  Two of three patients were disease free with full donor 


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chimerism and on no immunosuppressive therapy and nonmyeloablative HLA-haploidentical 
HSCT using post-transplant cyclophosphamide. 
The largest series of HLA-haploidentical nonmyeloablative HSCT was reported from Johns 
Hopkins and the Fred Hutchinson Cancer research Center by Luznik in 2008 (Luznik et al. 
2008).  A total of 67 patients were transplanted using the regimen shown in Figure 1 only with 
either one day of cyclophosphamide post-transplant on day +3 or two days of cyclophosphamide 
on days + 3 and +4.  There were 9 graft failures (13%).  There was no difference in GVHD with 
one or two days of cyclophosphamide post-transplant.  The overall survival at one year was 46% 
with an event-free survival of 34% in a high risk population of patients with leukemia. 
When this data was summarized recently, there was a total of 210 recipients of mini-Haplo 
HSCT at Johns Hopkins with 87% sustained donor engraftment(Munchel et al.).  The cumulative 
incidence of grades II-IV acute GVHD and chronic GVHD were 27% and 13%, respectively.  
The 5-year cumulative incidence of non-relapse mortality was 18%; relapse was 55%, actuarial 
overall survival 35%, event-free survival 27%.  Thus, mini-Haplo HSCT with post-transplant 
cyclophosphamide was associated with favorable toxicity and overall survival for patients 
without matched related or unrelated donors. 
1.2.7
Hematopoietic Stem Cell Transplant for Primary Immunodeficiency Disease 
Most primary immunodeficiency diseases (PID) consist of intrinsic genetic defects of 
hematopoietic lineage-derived cells.  Therefore, replacement of genetically impaired cells by 
normal HSC represents a logical therapeutic approach. It has now been demonstrated that HSCT 
can reverse the phenotype in a variety of PID.  The initial reports of successful HSCT in PID 
included severe combined immunodeficiency disease (SCID) and Wiskott-Alrich Syndrome 
(WASP) (Bach et al. 1968; Gatti et al. 1968).  By 2003, over 1200 patients with PID had 
undergone allogeneic HSCT (Buckley 2003).  In all, 26 different inherited immune deficiencies 
had been corrected by HSCT, including a number of SCID variants, WASP, and various 
phagocytic disorders such as chronic granulomatous disease (CGD), and leukocyte adhesion 
deficiency (LAD) (Le Deist et al. 1989; Buckley 2003).
In the largest cohort of patients with SCID receiving HSCT, Buckley reported on 89 infants 
transplanted at Duke between 1992 and 1998 (Buckley et al. 1999).  The majority of patients 
with SCID were boys with X-OLQNHGFRPPRQ-chain SCID.  However, six had Janus kinase 3 
(Jak3) mutations, 13 had adenosine deaminase deficiency (ADA)-SCID, three had IL-7R alpha-
chain defects, and 21 infants had unclassified autosomal recessive SCID.  A total of 77 infants 
received T-cell depleted, HLA haploidentical parental marrow and 12 received HLA-identical 
marrow from a related donor.  Just over 80 percent of the patients were alive 3 months to 16.5 
years post-transplant, including all 12 patients who received HLA-identical related donor 
marrow.  None of these patients received chemotherapy pre-transplant or GVHD prophylaxis.  
T-cell function became normal within two weeks of transplant in the patients who received 
unfractionated HLA-identical marrow.  B-cell function was reconstituted in less than 50 per cent 
of the long-term survivors necessitating life-long immunoglobulin replacement in those patients 
without B-cell reconstitution.  Although GVHD developed in 28 of the 77 infants who received 
T-cell depleted haploidentical marrow, in most cases the GVHD was mild and did not require 
treatment. 


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Although most of the initial studies in PID used related donors, matched unrelated donor HSCT 
has been successfully employed in a number of patients with PID (Ash et al. 1990; Filipovich et 
al. 1992; Kernan et al. 1993).  Kernan reported a 50 percent success rate using matched URD 
HSCT to treat PID (Kernan et al. 1993).
In primary immune deficiency diseases (PID) donor engraftment may be achieved following 
allogeneic HSCT with no or reduced-intensity conditioning due to the inability of the host 
immune system to mediate graft rejection (Buckley et al. 1999; Rao et al. 2005).  Thus, PID 
constitutes an experiment of nature in which a nonmyeloablative-conditioning regimen may 
result in sufficient levels of donor engraftment to mediate a graft-versus-leukemia effect without 
the toxicity of a myeloablative-conditioning regimen. Reduced intensity conditioning regimens 
are particularly well suited for allogeneic stem cell transplantation in patients with non-malignant 
stem cell disorders where tumor kill is not required and co-morbid conditions are frequent.  Also, 
since a reduced-intensity conditioning regimen allows autologous recovery if the graft should 
fail, a second transplant remains a possibility. 
The optimal nonmyeloablative-conditioning regimen for HSCT in PID has yet to be defined.  
However, a number of non-malignant diseases have been successfully treated using reduced-
intensity conditioning regimens in stem cell transplantation, often leading to a state of mixed 
chimerism.  Immunodeficiency diseases treated with non-myeloablative transplantation include 
hyper-IgM syndrome (Kato et al. 1999), adenosine deaminase deficiency (Honig et al. 2007),
chronic granulomatous disease (Horwitz et al. 2001), Wiskott-Aldrich syndrome (Kapoor et al. 
1981; Longhurst et al. 2002), and leukocyte adhesion deficiency–I (LAD-I) (Engel et al. 2006).
In a study of 14 patients with PID receiving either no conditioning or conditioning with 200 cGy 
TBI +/- fludarbine prior to matched related or unrelated donor HSCT, event-free survival was 62 
per cent (Burroughs et al. 2007).  This was a heterogeneous group with six patients receiving 
matched related donor HSCT, and 8 receiving matched unrelated donor HSCT.  Correction of the 
immune dysfunction was achieved in 8 of 10 patients with stable donor engraftment.  There was 
a transplant-related mortality of 23 percent.
The use of unrelated donors for HSCT in PID has been successful in a several other studies.  In 
the most extensive use of reduced-intensity conditioning in patients with PID receiving unrelated 
donor HSCT, Veys and colleagues demonstrated a 94 percent survival in 33 patients treated with 
a reduced-intensity regimen consisting of Melphalan 140 mg/m2, fludarabine 150 mg/m2, and 
alemtuzumab (Campath 1H 1 mg/kg) (Veys et al. 2005).  All HSCT were T-cell replete.  They 
observed rapid engraftment in 32 of the 33 patients with neutrophil recovery at 13 days and 
platelet recovery at 16 days.  Of note, at one-year post-transplant only 55 percent of the patients 
had 100 percent donor chimerism.  Possibly as a result of the low level of complete donor 
chimerism, only 9 percent of the patients in the RIC group had acute GVHD more than grade II.  
There was also a very high rate of viral reactivation associated with the use of Campath.
The lower regimen-related toxicity with low-dose TBI plus fludarabine 30 mg/m2/day for 3 days 
supports the use of this regimen in patients with mutations in GATA2 who have co-morbidities 
related to their underlying immunodeficiency.  The use of Campath, although an effective 
immunoablative agent, poses an unacceptable risk in patients who are already at high risk for 
opportunistic infections.


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Version Date: 05/18/2016
1.2.8
GATA2 Mutation Syndrome
Nearly three years ago Dr. Steve Holland of the NIAID Clinical Infectious Diseases Branch at
the NIH identified a unique immunodeficiency disease syndrome, subsequently named 
MonoMAC, in which patients have a severe deficiency of monocytes (Mono) in the peripheral 
blood, and the propensity to develop Mycobacterium Avium Complex (MAC) infections (Vinh 
et al. 2010).  These patients have now been shown  to harbor mutations in GATA2 (Hsu et al.).
The important differences between patients with mutations in GATA2 and previously described 
primary immunodeficiency diseases are that patients with mutations in GATA2 have: 1) onset of 
disease beyond infancy, frequently in late adolescence or early adulthood, 2) a clinical history of 
life-threatening opportunistic infections, primarily MAC, 3) a peripheral blood leukocyte subset 
profile with the presence of T-lymphocytes, but a severe deficiency of B-lymphocytes, NK cells, 
and monocytes, 4) a genetic component suggestive of a dominant pattern of inheritance, and 5) 
frequent progression to MDS.  This contrasts with the vast majority of genetic PID which 
manifest in infancy, rarely have both disseminated MAC and disseminated fungal infections, 
lack T-lymphocytes, and do not progress to MDS/AML.  
Previously described PID are characterized by loss of the T-lymphocyte compartment.  The first 
category, recognized over 50 years ago, consists of T-, B+, and Natural Killer (NK)- (severe 
combined immunodeficiency disease (SCID).  The largest group of these patients is X-SCID due 
to mutations in the common gamma chain of the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and 
IL-21.  Autosomal recessive forms of T-,B+, NK- SCID are due to mutations in the Jak3 kinase.  
The second group of PID consists of T-, B-, NK+ SCID.  These patients have defects in the 
variable, diversity, joining (VDJ) recombination machinery.  Examples of this form of PID 
include Rag (Recombination activating gene) defects, Omenn syndrome, and Artemis deficiency. 
Both these forms of PID manifest at birth with severe infections; these infections commonly lead 
to death by 6 months of age. 
Patients with mutations in GATA2 present in their late teens or early twenties, and ultimately 
succumb to either disseminated infection or MDS/AML over 2-10 years.  It appears that the loss 
of monocytes and NK cells accounts for the propensity to develop opportunistic infections with 
MAC and fungal organisms, including histoplasmosis and aspergillus.  The onset of MDS is 
variable, but usually develops within several years of the onset of the disease.  Current 
management of the GATA2 mutation syndrome is palliative and revolves around treatment with 
antibiotics, anti-viral, anti-tuberculous, and anti-fungal agents.  However, relapses with 
additional opportunistic infections invariably occur leading to progressive disability.  The lung is 
the organ system most frequently affected.  Total lung pulmonary alveolar lavage has been used 
to transiently improve pulmonary function.  HSCT has been used successfully to treat both 
genetic immunodeficiency diseases and MDS/AML, the two characteristics of the patients with 
mutations in GATA2, and therefore represents a potential therapy to reverse the inevitably fatal 
course in these patients.
A brief case history of a patient with a GATA2 mutation illustrates the natural history of the 
disease.
JD: 33 yr old man presented in November of 2006 with disseminated histoplasmosis.  He had a 
history of pneumonias every few months for the preceding year, and a history of severe warts. 
During his 16-month hospitalization he suffered multiple pulmonary infections including 
pulmonary histoplasmosis, Neosartorya utagawa, and disseminated Mycobacterium avium.  He 


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was subsequently found to have severely reduced B-lymphocytes, natural killer (NK) cells, and 
monocytes with CD4 496, CD8 150, NK cells 0, B-cells 0, monocytes 0. In February of 2007 he 
developed myelodysplasia with 5-10 % blasts and monosomy 7 in 4-5% of metaphase spreads. 
By August 1997 95% of metaphase spreads displayed monosomy 7.  While hospitalized he 
developed cerebral aspergillus and died in March of 2008.  His family history was significant for 
an older sister who developed an immunodeficiency at age 14 and died from disseminated zoster 
at age 17 awaiting HSCT for MDS.  The patient JD was 13 yr old at the time of his sister’s death.
Thus, patients with mutations in GATA2 succumb to either from opportunistic infection or bone 
marrow failure from MDS/AML.  Six of the 20 patients with mutations in GATA2 have died 
either from infection or progression to MDS and/or leukemia.  Patient JD described above died at 
the Clinical Center in March of 2008 awaiting unrelated donor transplant for MDS.  Several of 
the current patients with mutations in GATA2 have had first-degree relatives die from infections 
or MDS/AML.  The biological question for patients with mutations in GATA2 is whether the 
individual leukocyte compartments that are lost in this syndrome (B-lymphocytes, NK cells, and 
monocytes) will be constituted with HSCT. , 
Both autosomal dominant and sporadic cases of GATA2 mutation occurs in this syndrome.  To 
date, we have identified 12 distinct mutations in GATA2 affecting 20 patients and relatives with 
this syndrome, including recurrent missense mutations affecting the zinc finger-2 domain 
(R398W and T354M) (Hsu et al.).  Four discrete insertion/deletion mutations leading to frame 
shifts and premature termination implicate haploinsufficiency as a possible mechanism of action.  
These mutations were identified in several families, indicating germ line transmission in those 
kindred's.  Thus, GATA2 joins RUNX1 and CEBPA not only as familial leukemia genes, but also 
as a cause of a complex congenital immunodeficiency that evolves over decades and combines 
predisposition to infection and myeloid malignancy. 
Table 2. GATA2 Mutations Identified in MonoMAC Patients
Kindred*
Patient*
DNA change#
Codon#
Null&
1
1.II.1
c.1192 C>T
R398W
1
1.II.5
c.1192 C>T
R398W
2
2.II.3
c.1192 C>T
R398W
3
3.I.1
c.1192 C>T
R398W
5
5.II.1
c.1061 C>T
T354M
8
8.I.1
c.243_244delAinsGC
G81fs
+
9
9.III.1
c.1192 C>T
R398W
10
10.1.1
c.1113 C>G
N371K
12
12.I.1
c.1083_1094del 12bp
R361delRNAN
13
13.II.1
c.1-200_871+527del 2033bp
M1del290
+
13
13.I.2
c.1-200_871+527del 2033bp
M1del290
+
15
15.II.1
c.1186 C>T
R396W
17
c.1061 C>T
T354M
18
c.1187 G>A
R396Q
19
c.1061 C>T
T354M
20
c.778_779ins 10bp
D259fs
+
21
c.1192 C>T
R398W
22
c. 951_952ins 11bp
N317fs
+


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
23
c. 751 C>T
P254L
24
c. 1018-1 G>A
D340-381
* - Numbering refers to patient and kindred numbers from Vinh et al. BLOOD 2010.
# - Numbering relative to adenine in the ATG start codon of GATA2 (GenBank 
NM_001145661.1) and the first methionine (GenBank NP_116027. & - Predicted to result in loss
of mRNA or protein from mutant allele. 
Figure 2. Genomic organization of GATA2 showing two 5’ untranslated and five coding exons. 
Dark boxes indicate coding regions.  Insertion/deletion mutations predicted to result in null 
alleles are shown above.  B. Protein domains of GATA2, showing N and C-terminal zinc fingers 
(ZF-1, ZF-2) and nuclear localization signal (N). C. Missense and in-frame deletion mutations 
identified within ZF-2. Superscript numerals indicate number of independent mutations.
1.2.9
HSCT for Myelodysplasia
MDS are a heterogeneous group of clonal hematopoietic disorders characterized by impaired 
peripheral blood cell production (cytopenias) and most commonly a hypercellular, dysplastic-
appearing bone marrow (Nimer 2008).  The incidence of MDS increases with increasing age; the 
median age at diagnosis is in the seventh decade (Greenberg et al. 1997).  Survival after 
diagnosis varies from a few months to several years.  
MDS were originally called pre-leukemia, but the term MDS replaced pre-leukemia in the 
1970’s due to the clinical observation that that many individuals with MDS succumbed to the 
effects of the cytopenias without transforming to acute myelogenous leukemia (AML) (Nimer 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
2008).  Approximately 50 percent of patients with MDS will develop leukemia.  Progressive 
single or multilineage cytopenias account for the majority of the remaining deaths.
There are a number of different prognostic systems developed to predict outcomes for patients 
with MDS with the most widely utilized system being the International Prognostic Scoring 
System (IPSS) (Greenberg et al. 1997).  The IPSS uses cytogenetics, bone marrow myeloblast 
percentage, and peripheral cytopenias to predict leukemia transformation and survival.  Patients 
are grouped into one of four prognostic categories: low-risk, intermediate 1 risk, intermediate 2 
risk, and high risk.
In MDS cytogenetic risk groups defined by the IPSS are: good -normal isolated –Y, del (5q), and 
deletion 20q; poor- complex >3 abnormalities, and/or any chromosome 7 anomalies; 
intermediate- all other abnormalities (Greenberg et al. 1997). In terms of frequency, deletions of 
all or part of chromosome 7 represent the second most common cytogenetic abnormality in 
MDS, next to deletions of 5q.  In a recent comprehensive analysis correlating the cytogenetics 
with the clinical outcome in MDS, monosomy 7 as an isolated abnormality led to a median 
survival of 14 months (Haase et al. 2007).
Monosomy 7 is a characteristic cytogenetic abnormality in acquired aplastic anemia and 
congenital neutropenia (Maciejewski et al. 2002).  Cells lacking chromosome 7 frequently 
express a short isoform of the G-CSF receptor, and this short isoform preferentially signals 
proliferation over differentiation leading to clonal expansion in the setting of neutropenia or 
cytokine administration (Maciejewski et al. 2002).
Good prognostic factors for HSCT include: age, low IPSS score, short duration of disease (< 3-6
months), blast percentage < 5%, and complete remission before transplant.  The long-term 
disease-free survival with HSCT for MDS from either a matched related or unrelated donor in 
patients less than 50 years old ranges from 36% for matched related donors to 25% for matched 
unrelated donors (de Witte et al. 2001).
In patients with mutations in GATA2 allogeneic HSCT represents a potential curative therapy 
for MDS.  Of particular relevance to patients with mutations in GATA2with progression to 
MDS, many centers are now using a reduced-intensity approach because of age and frequent co-
morbidities in patients with MDS.  In a Spanish study 20 MDS patients received conditioning 
with busulfan 10 mg/kg and fludarabine 150 mg/m2 and peripheral blood stem cells from HLM-
matched related donors (Martino et al. 2002).  The transplant related mortality at one year was 
5%.
In one of the largest studies using reduced-intensity conditioning followed by allogeneic HSCT 
to treat 148 patients with MDS and MPS, patients received a conditioning regimen consisting of 
low-dose TBI (200 cGy) alone or with fludarabine 30 mg/m2/day for 3 days, and post-grafting 
immunosuppression with CSP and MMF (Laport et al. 2008).  Approximately one-half of the 
patients received matched related donor HSCT, and the other half received matched unrelated 
donor HSCT.  The three-year relapse-free survival and overall survival were 27% for all patients.  
Recipients of matched unrelated donor grafts did not have higher non-relapse mortality, and 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
relapse did not constitute the leading cause of death.  These results provide support for the use of
this regimen in patients with mutations in GATA2 who also have co-morbidities. 
1.2.10 Sirolimus and Tacrolimus for GVHD Prophylaxis after HSCT
The optimal series of drugs for GVHD prophylaxis following allogeneic HSCT would include 
medications that are well tolerated with minimal side effects/toxicities, prevent GVHD, and 
enable engraftment without an excess rate of disease relapse.  Commonly used drugs for the 
prevention of GVHD after HSCT include: cyclosporine (CSP), methotrexate (MTX), and 
corticosteroids. 
For patients undergoing transplantation with either HLA matched or 
mismatched unrelated donors who are receiving regimens of the above medications the incidence 
of acute GVHD has been reported being 40-70% (Beatty et al. 1985; Anasetti et al. 1990; Hansen 
et al. 1998).  In addition to incompletely suppressing GVHD, these medications are also 
associated with a wide variety of undesirable side effects.  Due to these problems, there is a 
continued interest in the development of more efficacious regimens.
In recent studies the immunosuppressive agent sirolimus (Rapamycin) has been shown to prevent 
GVHD (Antin et al. 2003).  Sirolimus inhibits T-cell and dendritic cell function through 
inhibition of mTOR, which in contrast to the mRNA inhibition associated with calcineurin 
blockade, operates via a post-transcriptional mechanism to reduce cell signaling and modulates 
protein translation and phosphorylation (Hackstein et al. 2003).  It appears that sirolimus 
prevents the translation of mRNAs encoding cell cycle regulators and inhibits the ability of 
lymphocytes to proliferate in response to IL2 (Chakraverty et al. 2002).  Sirolimus also has 
profound effects on dendritic cell function and survival, and this may contribute to prevention of 
GVHD (Chakraverty et al. 2002). Initial results indicate that sirolimus may be an effective agent 
for prevention of graft rejection and GVHD when used in conjunction with a second agent. 
Recently, sirolimus has been used as a third agent for GVHD prophylaxis after genetically 
disparate transplantation (Antin et al. 2003).  Clinical studies have not evaluated single-agent 
sirolimus for GVHD prophylaxis, and in fact, murine data indicate that single-agent sirolimus 
potently abrogates CD8+ T cell mediated GVHD, but not CD4+ T cell mediated GVHD (Blazar, 
1998).  As such, sirolimus may represent a replacement of calcineurin inhibitor mediated GVHD 
prophylaxis.  In a study of matched sibling allotransplant in sickle cell anemia, sirolimus 
prevented both graft rejection and GVHD (Hsieh et al. 2009). Sirolimus was also reported to be 
well tolerated at a dosing schedule designed to maintain a level of 10, with hypertriglyceridemia 
representing the primary specific drug toxicity.
The use of tacrolimus for the suppression of GVHD has been supported by research in canine 
and murine models and pilot studies in humans (Markus et al. 1991; Storb et al. 1993; Nash et al. 
1995; Fay et al. 1996).  Several phase III studies have prospectively compared tacrolimus to CSP 
with or without MTX in adolescent or adult patients undergoing related or unrelated SCT (Nash 
et al. 2000; Hiraoka et al. 2001). The incidences of grade II-IV acute GVHD were significantly 
decreased when patients were treated with tacrolimus.  The incidence of acute GVHD for 
patients receiving tacrolimus versus CSP ranged from 17.5% to 56% and 44.4% to 74%, 
respectively.  However, there was no statistically significant difference in the rate of chronic 
GVHD between the groups.  Data from the first two trials revealed that the relapse rate and OS 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
were also similar between those receiving tacrolimus and CSA.  Both trials found that tacrolimus 
was well tolerated, but was associated with increased (but transient) nephrotoxicity that resolved 
over time.  Although the third trial supported the previous two with regards to the decreased 
incidence of acute GVHD and relapse rate, the 2-year OS was worse in the arm receiving 
tacrolimus than cyclosporine, 50.4% and 40.5%, respectively.  When the DFS among patients 
with no advanced disease was compared, the outcomes were similar.  
Although sirolimus and tacrolimus both bind to FKBP12, the two drugs are not competitive and 
appear to be synergistic (Stepkowski et al. 1997).  To take advantage of this synergistic effect, 
the combination of the two drugs was evaluated in a trial using myeloablative HSCT with 
matched related or unrelated donors at the Dana Farber Cancer Institute (Antin et al. 2003).  In 
that study the incidence of grade II-IV GVHD was markedly reduced compared to historical 
controls.  
1.2.11 Interim Summary of HSCT for Patients with Mutations in GATA2
Ten patients have been enrolled on this study to date: three patients received a matched related 
donor hematopoietic stem cell transplant (HSCT), three patients received matched unrelated 
donor HSCT, and four patients have received umbilical cord transplant.  The results to date with 
HSCT for MonoMAC are summarized below.
Patient # 1: 33 yo man with R81fs mutation in GATA2 on 5 liters of oxygen from extensive 
pulmonary alveolar proteinosis received his peripheral blood stem cell (PBSC) transplant on 
5/12/2009.  He tolerated his conditioning regimen (Fludarabine and 200cGY TBI) well.  He 
engrafted within two weeks of transplant and was discharged from the hospital within one 
month of transplant. He is now 24 months from transplant with a normal hematocrit, white 
blood cell count, and platelet count. He now has normal levels of monocytes, NK cells, and B-
cells. His donor lymphoid chimerism is 100% and his donor myeloid chimerism is 100%.  He 
had a re-admission 6 months post-transplant for chronic GVHD, which occurred when the 
immunosuppression was tapered. The acute GVHD resolved on corticosteroids, however he 
now has chronic GVHD.  
He is now almost three years post-transplant, and off all 
immunosuppressive agents.
Patient #2: 33 yo man with R398W mutation in GATA2 and myelodysplasia (MDS) received 
his PBSC from an unrelated donor on 8/12/2009.  He tolerated his conditioning regimen 
(Fludarabine and 200cGY TBI) well with the exception of an episode of emesis.  He engrafted 
within 14 days of HSCT and was discharged. He has had a completely unremarkable course 
since transplant.  He is now nearly two and one-half years after transplant with a normal 
hematocrit, white blood cell count, and platelet count. He now has normal levels of monocytes, 
NK cells, and B-cells.   His most recent donor lymphoid chimerism was 91% and his donor 
myeloid chimerism is 100% at 12 months post-transplant. The patient had no acute GVHD and 
no signs of chronic GVHD at this time.  He is off all medications.  
Patient #3: 41 yo woman with T354M mutation in GATA2 and MDS with monosomy 6. 
Following conditioning with Cytoxan 50 mg/kg, Fludarabine 150 mg/m2, and 200 cGy TBI, she 
underwent a single umbilical cord hematopoietic stem cell transplant on December 29, 2009. The 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
cord blood unit was a 4/6 match. Chimerism on the bone marrow was 100% at day 28, 60, 100, 6 
months, 12 months and two years. Her course was complicated by slow engraftment requiring 
100 days.  She now is 24 months post-transplant, living at home, and requiring no transfusions. 
Both lymphoid and myeloid chimerism was 100% 18 months post-transplant. The recipient did 
not develop acute GVHD and has no signs of chronic GVHD.  
Patient #4:
23 yo woman with R396Q mutation in GATA2 and MDS with trisomy 8. 
Following conditioning with Fludarabine 90 mg/m2, and 200 cGy TBI, she underwent a 
matched unrelated donor transplant on 8/5/2010. She is now one and one-half years post-
transplant and was recently admitted for GVHD requiring immunosuppression.
Patient #5: 15 yo adolescent with D259fs mutation in GATA2 and MDS with monosomy 7. 
He received a double umbilical cord blood transplant in September of 2010.  His course was 
complicated by autoimmune hemolytic anemia and thrombocytopenia and nephrotic syndrome. 
He is now one and one-half years post-transplant and has returned to school.  He is on no 
immunosuppressant.
Patient #6: 26 yo man with R361delRNAN in GATA2 along with fibrotic liver injury, and 
MDS with monosomy 7 who died of sepsis 5 days after double cord blood transplant. 
Patient #7: 41 yo woman with mutation in GATA2 and MDS who received conditioning with 
Fludarabine 90 mg/m2, and 200 cGy TBI followed by a matched related donor transplant on 
12/14/2010. She has had an uncomplicated course, however at one-year post-transplant she as 
found to have recurrence of her cytogenetic abnormality.
Patient #8: 26 yo woman with a 318fs mutation in GATA2 and MDS with primary graft failure 
after double umbilical cord blood transplant. She received a haplo/cord transplant on April 28, 
2011 and engraftment primarily with haploidentical cells. She died 8 months post-second 
transplant from septic shock from Klebsiella pneumonia.
Patient #9:
32 yo Hispanic man with a T354M mutation in GATA2 and MDS received a 
matched related donor HSCT.  He engrafted on day 14 and has now returned home.  He is now 
more than 100 days post-HSCT.
Patient #10:
39 yo woman with an N371K mutation in GATA2 and MDS who received a 
matched unrelated donor transplant over 100 days ago. She had engraftment within 14 days and 
has had no re-admissions. She has returned home.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT
2.1
INCLUSION CRITERIA - RECIPIENT
a) Patient age of 12-60 years.
b) Mutation in the GATA2 gene performed by the CLIA certified laboratory 
c) Clinical history of at least two episodes of life-threatening infection d Available 10/10 HLA-
matched related donor, 10/10 or 9/10 matched unrelated donor, 4/6 (or greater) matched 
umbilical cord blood (UCB) unit(s) with a total dose of greater than or equal to 3.5 x107
TNC/kg, or a haploidentical donor.
e) Patients may have evidence of MDS with one or more peripheral blood cytopenias and greater 
than 5% blasts but less than 10% blasts in the bone marrow in the absence of G-CSF.
Patients previously treated for acute myelogenous leukemia are eligible if they have less than
or equal to 5% blasts in the bone marrow in the absence of G-CSF. Subjects 12-17 years of 
age are required to have MDS with chromosomal abnormalities in addition to mutation in the 
GATA2 gene for enrollment on this protocol.  
f) Left ventricular ejection fraction > 50%, preferably by 2-D echo, or by MUGA, or shortening 
fraction > 28% by ECHO, obtained within 28 days of enrollment  
g) Pulmonary Function Tests:  Adult patients:  Corrected DLCO diffusion capacity and FEV1 > 
10% of expected value obtained within 28 days of enrollment.  Pediatric patients:  DLCO 
corrected for hemoglobin and alveolar volume > 20% of predicted.  
h) Creatinine: Adult patients: < 2.0 mg/dl and creatinine clearance > 30 ml/min; Pediatric 
patients:  age-adjusted normal serum creatinine (see Table below) OR a creatinine clearance 
> 60 mL/min/1.73m2.
ge (years)
aximum Serum Creatinine (mg/dl)
8
< age < 10
0
< age < 15
2
5
5
d) Serum tRWDOELOLUXELQPJGOVHUXP$/7DQG$67WLPHVXSSHUOLPLWRIQRUPDO
e) Adequate central venous access potential.
f) Written informed consent/assent obtained from patient/parent or legal guardian.
g) Life expectancy of at least 3 months but less than 24 months.
h) Disease status: Patients are to be referred in remission for evaluation. Should a patient have 
progressive disease or a donor not be available after enrollment, the patient will be referred 
back to their primary hematologist-oncologist for treatment. If this course of action is not in 
the best interest of the patient according to the clinical judgment of the PI/LAI, then the 
patient may receive standard treatment for the malignant disease under the current study. If 
under either of these settings, it becomes apparent that the patient will not be able to proceed 
to transplant, then he/she must come off study. Recipient-Subjects receiving a standard 
therapy will be told about the therapy, associated risks, benefits alternatives of the proposed 
therapy, and availability of receiving the same treatment elsewhere, outside of a research 
protocol. 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
2.2
EXCLUSION CRITERIA- RECIPIENT 
a) HIV infection. 
b) Chronic active hepatitis B. Patient may be hepatitis B core antibody positive.  For patients 
with a concomitant positive hepatitis B surface antigen, patients will require a hepatology 
consultation.  The risk-benefit profile of transplant and hepatitis B will be discussed with the 
patient, and eligibility determined by the PI and the protocol chairperson
c) History of psychiatric disorder which may compromise compliance with transplant protocol, 
or which does not allow for appropriate informed consent. 
d) Active infection that is not responding to antimicrobial therapy.
e) Active CNS involvement by malignancy (patients with known positive CSF cytology or 
parenchymal lesions visible by CT or MRI). 
f)
Pregnant or lactating. 
g) Sexually active individuals capable of becoming pregnant who are unable or unwilling to use 
effective form(s) of contraception during time enrolled on study and for 1 year post-
transplant.  Effective forms of contraception include one or more of the following: 
intrauterine device (IUD), hormonal (birth control pills, injections, or implants), tubal 
ligation/hysterectomy, partner’s vasectomy, barrier methods, (condom, diaphragm, or 
cervical cap), or abstinence.  The effects on breast-milk are also unknown and may be 
harmful to the infant; therefore, women should not breast feed during the interval from study 
entry to one year post-transplant.  Males on the protocol must use an effective form of 
contraception at study entry, and for one year post-transplant.  The effects of transplant, the 
radiation, and the medications used after transplant may be harmful to a fetus.
h) Presence of active malignancy in another organ system other than the hematopoietic. 
No available 10/10 HLA-matched related donor,9/10 or 10/10 matched unrelated donor,  4/6 
(or greater) matched UCB unit(s) with a total dose of greater than or equal to 3.5 x107
TNC/kg, or haploidentical donor.
i)
Lack of mutation in GATA2 as demonstrated by the CLIA certified laboratory
2.3
INCLUSION CRITERIA- MATCHED RELATED DONOR 
a) Related donor matched at HLA-A, B, C, DR, and DQ loci by high resolution typing (9/10 or 
10/10 antigen/allele match) are acceptable donors (Maris et al. 2003).
b) Matched related donors for pediatric recipients must be 18 years of age or older.  If more 
than one matched related donor is available, we will select the oldest donor to further 
decrease the risk of potential disease transmission.
c) Ability to give informed consent
d) Age 18-60 years
e) No history of life-threatening opportunistic infection 
f)
Adequate venous access for peripheral apheresis, or consent to use a temporary central 
venous catheter for apheresis.
g) Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C antibody 
negative.  This is to prevent the possible transmission of these infections to the recipient.
h) A donor who is lactating must be willing and able to interrupt breast-feeding or substitute 
formula feeding for her infant during the period of filgrastim administration and for two days 
following the final dose. Filgrastim may be secreted in human milk, although its 
bioavailability from this source is not known. Limited clinical data suggest that short-term 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
administration of filgrastim or sargramostim to neonates is not associated with adverse 
outcomes (Bernstein et al. 2002).
2.4
INCLUSION CRITERIA- MATCHED UNRELATED DONOR
a) Unrelated donor matched at 10/10 or 9/10 HLA-A, B, C, DRB1, and DQB1 loci by high 
resolution typing (Maris et al. 2003).
b) Matched unrelated donors for pediatric recipients must be 18 years of age or older.
c) The evaluation of donors shall be in accordance with existing NMDP Standard Policies and 
Procedures. General donor inclusion criteria specified in the NMDP Standards (19th Edition, 
Appendix F). 
2.5
INCLUSION CRITERIA- HAPLOIDENTICAL RELATED DONOR
a) A haploidentical donor that shares one haplotype in common with the recipient such that 
HLA compatibility will be a minimum of 5 out of 10 HLA loci matched. The HLA loci to be 
tested will be HLA A, B, Cw, DRB1, and DQB1. A minimum number of mismatches is 
desirable; however if several options are available the selection of a donor will be based on 
the loci where the mismatch occurs and the relative importance of its potential 
immunological function. Donor-recipient pairs will initially be typed molecularly to provide 
a low resolution typing (antigen-level) to aid in the selection of the potential donor. Upon 
review of the familial inheritance pattern, a qualified HLA staff member will review 
haplotype inheritance.
High resolution (allele-level) typing will be performed.
Final 
selection of a donor will be in consultation with NCI physicians and qualified HLA 
personnel. Haploidentical related donors for pediatric recipients must be 15 years of age or 
older.  If more than one haploidentical related donor is available, we will evaluate each donor 
individually according to overall health, ABO matching, CMV, etc. to select the donor
b) Age 15-60 years
c) No history of life-threatening opportunistic infection 
d) Adequate venous access for peripheral apheresis, or consent to use a temporary central
venous catheter for apheresis.
e) Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C antibody 
negative.  This is to prevent the possible transmission of these infections to the recipient.
f)
Haploidentical donors will undergo marrow harvest with general anesthesia.  Subjects will 
undergo anesthesia consultation, and meet criteria for eligibility/enrollment. CD34+ fraction 
will be determined.  
g) Subjects will also undergo the Donor Health History Screen to determine donor eligibility 
using standard DTM criteria in the Dowling Apheresis Clinic by skilled staff in the Blood 
Services Section for adult patients and age-appropriate questioning when indicated for 
pediatric subjects.  
h) Subjects will undergo follow-up history and physical examination within 1 week of donation. 
2.6
EXCLUSION CRITERIA- MATCHED RELATED DONOR
a) Age less than 18 years.
b) HIV infection
c) Chronic active hepatitis B.  Donor may be hepatitis core antibody positive. 
d) History of psychiatric disorder which in the opinion of the PI may compromise compliance 
with transplant protocol, or which does not allow for appropriate informed


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
e) History of hypertension that is not controlled by medication, stroke, or severe heart disease.  
Individuals with symptomatic angina will be considered to have severe heart disease and will 
not be eligible to be a donor.
f)
Other medical contraindications to stem cell donation (i.e. severe atherosclerosis, 
autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular accident) 
(Anderlini et al. 1997).
g) History of prior malignancy. However, cancer survivors who have undergone potentially 
curative therapy may be considered for stem cell donation on a case-by-case basis. The 
risk/benefit of the transplant and the possibility of transmitting viable tumor cells at the time 
of transplantation will be discussed with the patient.
h) Donors must not be pregnant.  Pregnancy is an absolute contraindication under this protocol. 
The effects of cytokine administration on a fetus are unknown. Donors of childbearing 
potential must use an effective method of contraception. Effective forms of contraception 
include one or more of the following: intrauterine device (IUD), hormonal (birth control 
pills, injections, or implants), tubal ligation/hysterectomy, partner’s vasectomy, barrier 
methods, (condom, diaphragm, or cervical cap), or abstinence.  
i)
Thrombocytopenia (platelets less than 150,000 per Pl) at baseline evaluation.
j)
Donors receiving experimental therapy or investigational agents.
k) Sensitivity to filgrastim or to E. coli-derived recombinant protein products.
l)
History of autoimmune disorders, with the exception of thyroid disorders  
m) History of documented deep vein thrombosis or pulmonary embolism
n) Mutation in GATA2
2.7
EXCLUSION CRITERIA- MATCHED UNRELATED DONOR 
Failure to qualify as an NMDP donor as described in Appendix F.
2.8
EXCLUSION CRITERIA- HAPLOIDENTICAL DONOR
a) Age less than 15 years.
b) HIV infection
c) Chronic active hepatitis B.  Donor may be hepatitis core antibody positive. 
d) History of psychiatric disorder which in the opinion of the PI may compromise compliance 
with transplant protocol, or which does not allow for appropriate informed
e) History of hypertension that is not controlled by medication, stroke, or severe heart disease.  
Individuals with symptomatic angina will be considered to have severe heart disease and will 
not be eligible to be a donor.
f)
Other medical contraindications to stem cell donation (i.e. severe atherosclerosis, 
autoimmune disease, iritis or episcleritis, deep venous thrombosis, cerebrovascular accident) 
(Anderlini et al. 1997).
g) History of prior malignancy. However, cancer survivors who have undergone potentially 
curative therapy may be considered for stem cell donation on a case-by-case basis. The 
risk/benefit of the transplant and the possibility of transmitting viable tumor cells at the time 
of transplantation will be discussed with the patient.
h) Donors must not be pregnant.  Pregnancy is an absolute contraindication under this protocol. 
The effects of cytokine administration on a fetus are unknown. Donors of childbearing 
potential must use an effective method of contraception. Effective forms of contraception 
include one or more of the following: intrauterine device (IUD), hormonal (birth control 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
pills, injections, or implants), tubal ligation/hysterectomy, partner’s vasectomy, barrier 
methods, (condom, diaphragm, or cervical cap), or abstinence.  
i)
Thrombocytopenia (platelets less than 150,000 per Pl) at baseline evaluation.
j)
Donors receiving experimental therapy or investigational agents.
k) Sensitivity to filgrastim or to E. coli-derived recombinant protein products.
l)
History of autoimmune disorders, with the exception of thyroid disorders  
m) History of documented deep vein thrombosis or pulmonary embolism
n) Mutation in GATA2
2.9
INCLUSION CRITERIA- UMBILICAL CORD BLOOD UNIT-HLA TYPING AND DOSE
a) At least an HLA UCB 4/6 match (Class I-A, B by low resolution, and Class II-DR by high 
resolution) to recipient.  The following algorithm will be applied to determine if patient will 
receive single or double umbilical cord graft: 
b) For Single UCB SCT:
x
If 6/6 match the unit must have > 3 x 107 nucleated cells /kg of recipient body weight.
x
If 5/6 match the unit must have > 4 x 107 nucleated cells /kg of recipient body weight.
x
If 4/6 match the unit must have > 5 x 107 nucleated cells/kg of recipient body weight. 
Recipient body weight will be determined as per standard guidelines.
c) If no single UCB with the above characteristics is available, a double UCB will be 
considered.  Units will be selected with the following criteria:
x
Both units will be at least 4/6 match (Class I-A, B by low resolution, Class II-DR by high 
resolution) to recipient, and should be at least a 4/6 match (Class I-A, B by low 
resolution, Class II-DR by high resolution) to each other.
x
At least one UCB will have a minimum cell dose of 2.0 X 107 TNC/kg of recipient body 
weight.  
x
The minimum combined dose of both units must be at least 3.5 x 107 TNC/kg of recipient 
body weight.
x
The smaller of the two units (UCB2) will have a minimum of 1.5 X 107 TNC/kg of 
recipient body weight. 
x
The TNC of non-RBC reduced units will be dose corrected by -25% to allow for cell loss 
while washing the unit. 
2.10 REVIEW OF UCB UNIT HLA TYPING AND SELECTION OF THE UCB UNIT
a) Single UCB SCT: First preference will be given to cell dose, as long as the UCB units are 4/6 
matches or greater.  Second preference will be given to HLA matching (e.g. if two units have 
the same cell dose, the unit with a better HLA match will be selected).  Priority will be given 
to Class II matched units.  
b) Double UCB SCT: First preference will be given to cell dose, as long as the UCB units are 
4/6 matches or greater.  Second preference will be given to HLA matching (DR matching 
will be preferred over Class I matching) (e.g. if two units have the same cell dose, the unit 
with a better HLA match will be selected).  In double UCB SCT, the units should be at least 
a 4/6 HLA match or greater to the recipient, and at least a 4/6 HLA match to each other. The 
matching between the UCB units and recipient, and UCB units to each other can be at 
different loci.  Dr. Hickstein or his delegate will review all HLA typing on the patient and 
potential cord units.  High-resolution HLA typing will be reviewed, and, if necessary, an 
aliquot of the cord unit will be retyped as per standard practice.  After review of the typing, 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
the cord unit(s) will be requested and will be at the DTM Laboratory prior to the start of the 
conditioning therapy. 
2.11 RECIPIENT RESEARCH ELIGIBILITY EVALUATION 
The following clinical, laboratory, and radiological assessment must be performed in the patient 
(recipient) within 28 days before the recipient signs the consent form (unless otherwise 
specified)
a) Complete medical history and physical examination.
b) Antibody screen for hepatitis A, B, and C; HIV, T.Cruzi (Chagas agent), HTLV-I/II, CMV, 
adenovirus, EBV, HSV, Toxoplasmosis, and syphilis.
c) PPD test (in recipients considered to be in a high-risk group).
d) The following should be obtained at initial screening and also within 48 hours before starting 
induction chemotherapy:
x
CBC with differential, PT, and PTT, and ABO typing
x
Acute care panel, hepatic panel, mineral panel, and lipid profile
x
Urine EHCG in women of childbearing potential
e) Urinalysis and 24 hour urine collection (for determination of creatinine clearance).
f)
CT scans of head, sinus, chest, abdomen, and pelvis.
g) Cardiac 2-D Echo or MUGA exam.
h) Pulmonary Function Test, including DLCO measurement.
i)
Bone marrow aspiration and biopsy; flow cytometry, cytogenetics, and molecular studies 
(within 60 days of signing consent, unless clinically indicated).
j)
All biopsy specimens will be reviewed by the Laboratory of Pathology/CCR/NCI, for 
confirmation of the histological diagnosis prior to enrollment on study.
k) Lymphocyte phenotyping panel (T, B, NK). 
l)
Serum troponin. 
m) Lipid profile with triglycerides.
n) MRI scan of the head if there is clinical suspicion of CNS disease.
o) Radiation Oncology Consult (within 28 days of initiating conditioning chemotherapy).
2.11.1 Recipient (perform within 90 days before initiation of conditioning chemotherapy)
a) Nutritional assessment (initial consult).
b) Social work consultation. 
c) Electrocardiogram.
2.11.2 Recipient (perform within 6 months before initiation of conditioning chemotherapy)
a) Dental consultation to assess need for teeth cleaning or removal.
2.11.3 Recipient pre-transplant evaluation (perform any time before initiation of induction 
chemotherapy)
a) Typing for HLA-A, -B, -C, and DR.
PCR test of DNA mini-satellite regions for future determination of chimerism.
2.12 MATCHED RELATED DONOR AND HAPLOIDENTICAL DONOR RESEARCH ELIGIBILITY 
EVALUATION
2.12.1 Donor Research Evaluation
(perform any time before initiation of induction 
chemotherapy)
a) Typing for HLA A, B, C, DR, DQ.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
b) PCR test of DNA mini-satellite regions for future determination of chimerism.
2.12.2 Donor Research Evaluation (perform within 90 days of signing consent)
a) Complete medical history and physical examination.
b) Antibody screen for hepatitis A, B, and C; HIV, HTLV-I/II, CMV, adenovirus, EBV, HSV, 
Toxoplasmosis, T. cruzi (Chagas agent), and syphilis.
c) CBC with differential, PT, and PTT, and ABO, Rh typing.
d) Acute care panel, hepatic panel, and mineral panel.
e) Urinalysis. 
f)
Urine E-HCG in women of childbearing potential.
g) Chest radiograph.
h) Electrocardiogram.
i)
Screening for Hb S. 
j)
Lymphocyte phenotyping panel (T, B, NK). 
2.13 UNLICENSED CORD BLOOD UNITS
There is a new federal requirement for licensing UCB units. In October, 2009, the FDA 
released licensure guidance for UCB which outlines how a cord blood bank can apply for 
licensure of UCB units. If the unit meets the criteria for licensure, then that unit can be 
distributed as a licensed product. However, starting October 20, 2011, units that do not meet 
the requirements are considered "unlicensed" and can only be distributed for transplant under an 
IND.
For those patients whose best cord blood option is an unlicensed unit, the unit will be obtained 
under an IND which allows access to unlicensed cord blood units. For ease of access, the 
NMDP has developed a protocol through which most unlicensed CBUs may be obtained. The 
corresponding NCI protocol number is 12-C-0027. Patients will be consented and signed on to 
this protocol, unless their CB is obtained from a non-participating cord blood bank. Unlicensed 
CBs from non-participating cord blood banks will be obtained through a single patient IND if 
deemed appropriate by the PI, or through the bank’s own IND protocol, which will be 
submitted to the NCI IRB for review.
2.14 PATIENT REGISTRATION
a) Protocol “entry date” is considered to be the day that the informed consent form has been 
signed by the recipient and donor (matched related donor, when applicable) OR confirmation 
from the NMDP that the requested donor is available (unrelated donor), meets the inclusion 
criteria, and has signed the intent to donate form.  The treatment start date is considered to be 
the day the recipient begins his/her conditioning regimen.
b) Authorized staff must register an eligible candidate with Central Registration Office (CRO) 
no later than 24 hours after the patient (recipient) has signed an informed consent form.  The 
patient may not sign consent before the matched unrelated donor has been identified and 
cleared by NMDP and the patient has been determined to be eligible, OR the patient may not 
sign consent before the matched related donor has been identified and has signed consent 
(when applicable).  The patient will not be registered before she/he has signed consent and 
confirmation from the NMDP that the donor has signed consent.  The patient and matched 
related donor (when applicable) must be registered prior to beginning this study.  A 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
registration 
Eligibility 
Checklist 
is 
available 
from 
the 
web 
site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) for NCI patients and must be 
completed and faxed to 301-480-0757.  After confirmation of eligibility at Central 
Registration Office, CRO staff will call pharmacy to advise them of the acceptance of the 
patient on the protocol.  For questions regarding registration authorized staff should call 301-
402-1732 between the hours of 8:30 a.m. and 5:00 p.m., Monday through Friday.  Voicemail 
is available during non-business hours.
2.14.1 Off-Study Procedure: 
Authorized staff must notify Central Registration Office (CRO) when a patient is taken off-
study. An off-study form from the web site main page must be completed and faxed to 301-480-
0757. The website is: http://home.ccr.cancer.gov/intra/eligibility/welcome.htm)


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
3
STUDY IMPLEMENTATION 
3.1
STUDY DESIGN
10/10 HLA 
Matched 
Related 
Donor 
Mutation in GATA2 +/- MDS, General 
Eligibility Except Donor Type Confirmation
No
10/10 HLA 
Matched 
Unrelated 
Donor
9/10 HLA Matched 
Unrelated Donor, or
Haploidentical Donor, or 
6/6, 5/6 or 4/6  Matched 
Umbilical Cord Blood 
No
Yes,
Eligible
Preparative Regimen for 10/10 MRD and 10/10 URD
1) Fludarabine 30 mg/m2 per day, IV, Days -4, -3, -2
2) Total Body Irradiation (TBI) 200 cGy, Day -1
Preparative Regimen for 9/10 URD
1) Fludarabine 30 mg/m2 per day, IV, Days -4, -3, -2
2) Total Body Irradiation (TBI) 300 cGy, Day -1
Preparative Regimen for Haploidentical Donor
1) Fludarabine 30 mg/m2 per day, IV, Days -6, -5, -4, -3, -2
2) Total Body Irradiation (TBI) 300 cGy, Day -1
3) Cyclophosphamide 14.5 mg/kg IV, Days -6, -5
Preparative Regimen for UCB
1) Fludarabine 40 mg/m2 per day, IV, Days -6, -5, -4, -3, -2
2) Cyclophosphamide 50 mg/kg on Day -6
3) Total Body Irradiation (TBI) 200 cGy, Day -1
4) Equine ATG 30mg/kg IV on Days -6, -5, -4 (3 doses total)
Allogeneic HSC Transplantation
1) Mobilized PBSC (Day 0); > 5 x 106 CD34+ /kg if Matched Related or Unrelated Donor 
> 3.5 v 105 TNC/kg if UCB, and > or equal to 350 x106 TNC/kg.2). Sirolimus from  Day -2
tapering at Day +180
3) Tacrolimus 0.02 mg/kg continuous IV infusion from Day -3 tapering at Day +180.
4) For Haploidentical Donors Cyclophophamide 50 mg/kg IV on days +3 and +4, and 
Sirolimus and Tacrolimus from day +5 tapering at day +180. 
Figure 3. Protocol schematic.  
No
Ineligible
Yes,
Eligible
Yes,
Eligible


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
3.1.1
Donor Stem Cell Mobilization and Collection 
a) Matched related and unrelated donors will receive filgrastim as an outpatient for stem cell 
mobilization at a dose of 10 Pg/kg/day by subcutaneous injection.  Doses can be rounded to 
vial sizes (300 mcg and 480 mcg) according to NMDP standards.  The dose should not 
exceed 1200 Pg/day, and the volume per injection site shall not exceed 2.0 ml.  Filgrastim 
will be administered upon awakening in the morning.  The fifth dose should be given at least 
one hour prior to apheresis. 
b) Apheresis will typically start on the fifth day of filgrastim administration and 15-25 liters will 
be processed daily based on: (1) donor pre-apheresis circulating CD34 cell count in related 
donors undergoing apheresis in DTM, or (2) recipient weight for unrelated NMDP donors. 
(Table 3).  The target cell dose will be > 5 x 106 CD34+ cells/kg-recipient weight. 
c) Whole blood apheresis will be performed via a 2-armed approach or a temporary central 
venous catheter in the femoral position using the Baxter CS3000Plus, Cobe Spectra, or an 
equivalent instrument (typically 4 to 6 hour procedure). 
d) The apheresis procedure will use ACD-A anti-coagulant or heparin at the discretion of the 
DTM physician.
Table 3 - Blood Volume Processed in Relation to Recipient Weight
Recipient 
Weight 
(kg)
Volume Processed 
(L)
Procedure
< 35
12
Single 12 liter apheresis.
36 – 45
15
Single 15 liter apheresis.
46 – 55
18
Single 18 liter apheresis or two 12 L 
aphereses.
56 – 65
22
Single 22 liter apheresis or two 12 liter 
aphereses.
> 65
24
Single 24 liter apheresis or two 12 liter 
aphereses.
e) For related donors, PBSC will be processed, cryopreserved, and stored in liquid nitrogen 
until the day of transplant upon delivery to the NIH Department of Transfusion Medicine 
(DTM).  Donor cells from unrelated donors will be used without cryopreservation under 
routine circumstances. 
f)
The concentration of CD34+ cells in the apheresis product will be determined by flow 
cytometry, and the number of CD34+ cells in each cryopreserved bag calculated. 
g) Matched related donors will be evaluated clinically following apheresis, and they will be 
seen in the day hospital for follow-up one day following the apheresis.  The nurse 
practitioner or physician assistant covering the Day Hospital will conduct this evaluation.
3.1.2
Cord Blood Collection:
The cords will be obtained from qualified cord blood banks through the NMDP. The cords
will be scheduled for shipping in order to arrive 1 week prior to the patient beginning the 
transplant conditioning regimen. They will remain frozen until ready for use. If the cord has 
an attached segment, the segment will be sent to the HLA lab where DNA will be extracted 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
from the segment for HLA confirmatory typing. The DNA will be shared with the 
Chimerism Lab who will use it to develop the STR profile for later use. If there is more than 
one segment, the second segment will be used to check viability of the cord. This will be 
done using 7-AAD which is a flow cytometric marker which separates viable from apoptosed 
cells. Note: The viability of the segment does not necessarily correlate with the viability of 
the cord unit. The number and type of available cord blood specimens vary by bank, 
collection date and typing history. Viable cell aliquots and spot cards may also be used for 
HLA testing and STR analysis. 
Once they are thawed, the cords will be diluted 1:1 with a dextran/HSA mix and transferred 
to a larger bag. From that bag, CBC, nucleated cell count, colony forming units, flow 
cytometry, and sterility will be sent. This volume should total about 1.5 mL. After the CBC is 
done, the concentration of cells will be known and the number of cells can be calculated. If 
the unit did not have a detached segment, HLA testing and the STR profile will be done from 
this sample. The viability will be repeated on the diluted cord unit.  
3.1.3
Haploidentical Donor Bone Marrow Harvest
a)  Haploidentical donors will undergo marrow harvest with general anesthesia.  Subjects will 
undergo anesthesia consultation, and meet criteria for eligibility/enrollment. CD34+ fraction 
will be determined.  Subjects will also undergo the Donor Health History Screen to 
determine donor eligibility using standard DTM criteria in the Dowling Apheresis Clinic by 
skilled staff in the Blood Services Section for adult patients and age-appropriate questioning 
when indicated for pediatric subjects.  Subjects will undergo follow-up history and physical
examination within 1 week of donation.  The target dose is > or equal to 3.5 x 108 total 
nucleated cells per kilogram.  Of this product, 5 million total donor nucleated cells will be 
reserved for biologic studies and go to the clinical core of ETIB (Bldg 10, Room 12C-216,
301 402 3627. Cell selection will not be performed on the HSC grafts.     
3.1.4 Transplant Procedure (Day 0)
a) On day 0, the patient will receive fresh or cryopreserved peripheral blood stem cells from an 
HLA-matched related or unrelated donor, umbilical cord blood units, or fresh or 
cryopreserved haploidentical donor bone marrow. The cryopreserved PBSC product will be 
thawed and immediately administered intUDYHQRXVO\7KHWDUJHWGRVHRIWKH3%6&LV[
106 CD34+ cells per kg.  If the collection exceeds 5 x 106 CD34+ cells per kg, the PI will 
decide if greater than 5 x 106 CD34+ cells per kg will be infused.  The target dose for 
haploidentical bone marrow is > 3.5 x 108 nucleated cells/kg recipient body weight. 
b) Approximately 5 x 106 donor total nucleated PBSC will be reserved for Dr. Fran Hakim 
(Bldg. 10, Room 12C-216, Tel 301-402-3627). 
3.1.5 Determination of Engraftment 
a) Neutrophil Recovery: Designated by the first of 3 consecutive days with an ANC above 
500/mm3.
b) Platelet Recovery: Designated by the first of 7 days where the platelet count remains above 
20,000/mm3 without transfusion support.
c) Sustained Donor Engraftment: Neutrophil recovery associated with complete donor 
chimerism at day 100.  Any patient who dies before day 28 will not be evaluated for 
engraftment.
d) Primary Graft Failure: Failure to achieve sustained donor engraftment


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
e) Secondary Graft Failure:  Documented sustained donor engraftment as defined above 
followed by:  1) severe neutropenia (ANC < 500/mm3) and bone marrow biopsy revealing a 
cellularity of less than 25% or 2) absence of donor cells in the marrow 
or 
blood 
as 
demonstrated by a chimerism assay without subsequent improvement occurring either 
spontaneously or after growth factor treatment.  Improvement is defined as ANC > 500/mm3
consistently.  Severe neutropenia with marrow cellularity > 25% is not secondary graft 
failure.
f)
Aplasia: Less than 5% marrow cellularity as measured on bone marrow biopsy. 
3.1.6 Complication of Mixed Chimerism or Persistent/Progressive Disease
a) Donor Lymphocyte Infusion: Patients with persistent or progressive MDS post-HSCT, or 
mixed chimerism that does not improve after tapering or discontinuing immune suppression 
may be eligible to receive donor lymphocytes (donor lymphocyte infusion, or “DLI”) or G-
CSF mobilized DLI if they can be obtained from the donor.  Additional lymphocytes will be 
collected by apheresis from the patient’s stem cell donor, either in steady state (i.e. no donor 
therapy) or after filgrastim.  DLI or mobilized DLI may be administered alone or after 
chemotherapy.
b) DLI may be sequentially administered for mixed chimerism or progression of the MDS at 
doses 1 -10 x 106 CD3+ T cells per kg. Recipients with mixed chimerism or progression of 
MDS will receive DLI consisting of unmanipulated donor T cells.  
c) Alternatively, in cases where additional donor stem cells are desired, the donor product may 
be administered without lymphocyte purification.  
d) Recipients with mixed chimerism at day +30 will undergo repeat chimerism assessment at 
day +60 and every 30 days thereafter as deemed necessary.  If there is persistent mixed 
donor-recipient chimerism (< 95% donor chimerism on whole blood, lymphoid, or myeloid 
subsets), recipients without Grade 2 or higher GVHD, patients will be eligible to receive 
DLI.  DLI may be repeated every 4 weeks with dose escalation as indicated above, until 
donor chimerism > 95% is achieved or until GVHD develops. 
e) Recipients with progression of MDS and without Grade 2 or higher GVHD will be eligible to 
receive DLI every 4 weeks with dose escalation as indicated above, until donor chimerism > 
95% is achieved or until GVHD develops. 
f)
In addition to DLI, patients with persistent or progressive disease may be offered therapy on 
other NCI protocols. Alternatively, persistent or progressive disease may be treated with any 
approved therapy thought to be in the best interest of the patient including chemotherapy, 
radiation therapy, or monoclonal antibody therapy.
3.2
DRUG ADMINISTRATION
3.2.1
Transplant Conditioning Regimen for 10/10 Matched Related Donor or a 10/10 Matched 
Unrelated Donor Transplant
a) Central line access will be required prior to the start of the preparative regimen, and a triple 
lumen Hickman catheter is recommended, however clinical determination for the most 
appropriate line type and placement will be made on a case-by-case basis.
b) Conditioning Regimen with 200 cGy TBI and Fludarabine for 10/10 matched related and 
10/10 matched unrelated donor transplant.  If anesthesia is required in pediatric patients, an 
additional consent will be obtained for TBI anesthesia.
Agent
Dose
Days
Fludarabine
30 mg/m2 per day
Transplant Days –4, -3, -2


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
IV infusion over 30 
min, daily for 3 days
Total body Irradiation
200 cGy
Transplant Day -1
c) The dose of Fludarabine will be dose adjusted for renal dysfunction. For Creatinine 
Clearance of 30-70 mL/min/1.73m2, there will be a 20% dose reduction. If the Creatinine 
Clearance is less than 30mL/min/1.73m2, Fludarabine will not be administered.  
3.2.2
Transplant Conditioning Regimen for 9/10 Matched Unrelated Donor Transplant
a) Central line access will be required prior to the start of the preparative regimen, and a triple 
lumen Hickman catheter is recommended, however clinical determination for the most 
appropriate line type and placement will be made on a case-by-case basis.
b) Conditioning Regimen with 300 cGy TBI and Fludarabine for 9/10 matched matched 
unrelated donor transplant.  If anesthesia is required in pediatric patients, an additional 
consent will be obtained for TBI anesthesia.
c) The dose of Fludarabine will be dose adjusted for renal dysfunction. For Creatinine 
Clearance of 30-70 mL/min/1.73m2, there will be a 20% dose reduction. If the Creatinine 
Clearance is less than 30mL/min/1.73m2, Fludarabine will not be administered.
Agent
Dose
Days
Fludarabine
30 mg/m2 per day
IV infusion over 30 
min,daily for 3 days
Transplant Days –4, -3, -2
Total body Irradiation
300 cGy
Transplant Day -1
3.2.3
Transplant Conditioning Regimen for Haploidentical Related Donor Transplant
a) Central line access will be required prior to the start of the preparative regimen, and a triple 
lumen Hickman catheter is recommended, however clinical determination for the most 
appropriate line type and placement will be made on a case-by-case basis.
b) Conditioning Regimen with 200 cGy TBI and Fludarabine and Cyclophosphamide for 
Haploidentical Related Donor.  
c) The dose of Fludarabine will be dose adjusted for renal dysfunction. For Creatinine 
Clearance of 30-70 mL/min/1.73m2, there will be a 20% dose reduction. 
Agent
Dose
Days
Fludarabine
30 mg/m2 per day
IV infusion over 30 
min,daily for 3 days
Transplant Days -6, -5. –
4, -3, -2
Cyclophosphamide 
14.5 mg/kg
Transplant days -6, -5
Total body Irradiation
200 cGy
Transplant Day -1
3.2.4
Transplant Conditioning Regimen for Umbilical Cord Blood
a) A triple lumen Hickman catheter will be placed by an interventional radiologist or surgeon at 
least 7 days before the start of the preparative regimen.
b) Conditioning with 200 cGy TBI, Fludarabine, and Cyclophosphamide for umbilical cord 
blood transplant will occur as follows:


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
Day - -6
Fludarabine 40 mg/m2 IV,   Cyclophosphamide 50 mg/kg IV, Equine ATG  
30mg/kg IV
Day-
-5
Fludarabine 40 mg/m2 IV, Equine ATG 30 mg/kg IV
Day-
-4
Fludarabine 40 mg/m2 IV, Equine ATG 30 mg/kg IV 
Day-
-3
Fludarabine 40 mg/m2 IV
Day-
-2
Fludarabine 40 mg/m2 IV 
Day-
-1
TBI 200 cGy 
Day 
0
Cord blood transplant
If anesthesia is required in pediatric patients, an additional consent will be obtained for 
TBI anesthesia.
Agent
Dose 
Days
Fludarabine
40 mg/m2 per day
IV infusion over 30 
min, daily for 5 days
Transplant Days 
-6, -5, -4, -3, -2
Cyclophosphamide
50 mg/kg
Transplant Day 
-6
Total body 
Irradiation
200 cGy
Transplant Day 
-1
Equine ATG
30 mg/kg IV daily 
for 3 days
Transplant Days 
-6, -5, -4
c) Equine ATG Instructions
1. Equine ATG will be administered at a dose of 30 mg/kg/day for 3 consecutive days (days 
-6, -5, -4) for a total dose of 90 mg/kg.  
2. Equine ATG will be infused IV over 4 hours.  Infusion times may be extended up to 24 
hours to improve tolerance if necessary. 
3. An epinephrine Auto-Inj 0.3 mg (EpiPen) should be kept at bedside on days of equine 
ATG administration
4. Because of risk of allergic reaction to ATGAM, at least 24 hours before the first infusion 
of ATGAM, patients will be tested with an intradermal injection of 0.1 ml of a 1:1000 
dilution (5 μg horse ATG) of ATGAM in sodium chloride injection and a contralateral 
sodium chloride injection control.  The patient should be observed every 15 to 20 min 
over the first hour of intradermal injection.  A local reaction of 10 mm or more with a 
wheal or erythema or both should be considered a positive test.  If there is a positive skin 
test, the patient will undergo ATG desensitization per standard of care guidelines or 
receive a 24-hour infusion of ATG.
5. Subjects will receive pre-medication prior to Equine ATG infusion consisting of:  
x Oral acetaminophen 650 mg
x Oral diphenhydramine 25-50 mg IV
The dosages of these drugs may be adjusted for weight based dosing if necessary 
following pediatric dosing recommendations.
Oral prednisone at 1mg/kg/day will begin on day -5 prior to the first dose of h-ATG for 
serum sickness prophylaxis, and will be continued at this dose for 10 days.  Thereafter, 
prednisone will be slowly tapered over the next 2 weeks until it is discontinued on day 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
+19.   Likewise, patients where it is clinically indicated to use a shorter course or taper 
schedule will be dosed individually as clinically indicated.  Those patients who develop 
serum sickness may require a longer tapering schedule and will be dosed individually 
as clinically indicated.  Infusion reactions will be treated symptomatically (e.g. 
antiemetics, 
IV 
fluid 
hydration, 
acetaminophen, 
antihistamines, 
inhaled 
bronchodilators, and meperedine.  In cases of moderate to severe reactions, 
hydrocortisone will be given and the infusion will be discontinued and restarted at a 
slower rate once the symptoms have subsided.  If a patient has a persistent severe 
infusion reaction that does not respond to measures to ameliorate the sings/symptoms 
associated with the infusion, the infusion will be discontinued and further study 
participation will continue as planned with the exception that no further ATG will be 
administered.
d) The dose of Fludarabine will be dose adjusted for renal dysfunction. For Creatinine 
Clearance of 30-70 mL/min/1.73m2, there will be a 20% dose reduction. If the Creatinine 
Clearance is less than 30mL/min/1.73m2, Fludarabine will not be administered.
e) Cyclophosphamide will be dosed on actual body weight. Hydration will be carried out according 
to the NIH supportive care guidelines for the prevention of hemorrhagic cystitis as outlined 
below. 
Background: 
Hemorrhagic cystitis (HC) is a well documented complication of cyclophosphamide therapy. The 
mechanism of cyclophosphamide-induced HC is secondary to bladder wall damage from contact 
with the acrolein metabolite of cyclophosphamide.  The risk of cyclophosphamide-induced HC is 
greater with high dose cyclophosphamide regimens such as those employed in hematopoetic 
stem cell transplant (HSCT) preparative regimens.  Routine prevention strategies including 
intravenous hydration, forced diuresis, and mesna are imperative to reduce the risk of HC.  This 
guideline is intended to provide a consistent approach to HC prevention in patients receiving 
high-dose cyclophosphamide in chemotherapy preparative regimens prior to HSCT at the NIH. 
Definitions: 
High-dose cyclophosphamide: There is no absolute cut off for defining a dose of 
cyclophosphamide that would necessitate an aggressive strategy for HC prevention. 
Cyclophosphamide doses employed in HSCT preparative regimens at the NIH that equal or 
exceed 50 to 60 mg/kg/dose OR 1200 mg/m2/dose should always be accompanied by the HC 
prevention strategies outlined below. 
x
Intravenous hydration should be initiated at a minimum of 12 hours prior to the first dose 
of cyclophosphamide
x
The rate of intravenous infusion for hydration is 0.9% Sodium Chloride Inj with 10 mEq / 
liter of potassium chloride infused at a rate of 90 mL/m2/hour. 
x
Continue hydration until 24 hours after last cyclophosphamide infusion. 
x
Furosemide 20mg intravenously will be given once daily - Adult Patients Only -
(preferably in the AM hours) on a scheduled basis on the days of cyclophosphamide 
administration to maintain diuresis.  Pediatric patients may receive furosemide as 
clinically indicated at a dose of 1mg/kg up to a maximum of 20 mg. (Furosemide doses 
may be adjusted based on patient weight, diuretic response or other clinical factors; 
o
Monitor intake and output closely (2 hour intervals).  Accurate documentation of 
intake and output is essential to make good clinical decisions regarding diuresis. 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
o
If fluid intake exceeds urine output by 500 ml (10 ml/kg for pediatric patients < 
50 kg) over an 8 hour period, an additional 20 mg of furosemide (1mg/kg for 
pediatric patients up to a maximum of 20 mg) will be administered intravenously. 
Notify PI/LAI when PRN doses of furosemide are administered. 
o
Additional doses of furosemide maybe administered as needed for weight gain 
due to fluid retention. In general, furosemide doses should be separated by at least 
a four hour observation interval. 
o
Notify PI/LAI if patient’s input is greater than output by 1 liter (20 ml/kg for 
pediatric patients < 50 kg) in an 8 hour period during cyclophosphamide 
hydration. 
o
Stop IV hydration (24 hours after last cyclophosphamide dose). 
x
MESNA 
For detoxification of acrolein, the urotoxic metabolite of cyclophosphamide, Mesna will
be given in a dose equal to that of cyclophosphamide. Total MESNA dose should = the 
cyclophosphamide dose. Mesna will be administered as a continuous intravenous 
infusion over 24 hours on each day that cyclophosphamide is administered. The initial 
bag of mesna should be started concurrently with the start of cyclophosphamide. 
Example: For preparative regimens that dose cyclophosphamide at 60 mg/kg/day, the 
MESNA will also be given at a dose of 60 mg/kg administered as a continuous 
intravenous infusion over 24 hours. 
The MESNA infusion should continue for a minimum of 22-24 hours after the last dose 
of cyclophosphamide. The entire MESNA dose prescribed should be administered each 
day of cyclophosphamide therapy 
3.2.5
GVHD Prophylaxis with Sirolimus
a) Patients will receive GVHD prophylaxis with sirolimus and tacrolimus.  
b) For recipients of matched related and unrelated donors, and umbilical cord blood, Sirolimus 
will be administered continuously from day –2 by mouth as Rapamune tablets at an initial 
“loading dose” of 12 mg, p.o. in adults > 18 years of age. In pediatric patients >40 kg the 
loading dose will be 6 mg. In pediatric patients <40kg, the loading dose will be 3mg/m2. 
c) For recipients of haploidentical donors, Sirolimus will be administered continuously from
day +5 by mouth as Rapamune tablets at an initial “loading dose” of 12 mg, p.o. in adults > 
18 years of age. In pediatric patients >40 kg the loading dose will be 6 mg. In pediatric 
patients <40kg, the loading dose will be 3mg/m2. 
d) Sirolimus will be administered each day in the morning.
e) From days -1 in matched related and unrelated donor transplants, and umbilical cord 
blood transplants, and continuing post-transplant, Sirolimus dosing will be Rapamune 
tablets, 4 mg, p.o., each day in adult patients.  In pediatric patients > 40 kg the initial dose 
will be 2 mg every 24 hours.  For patients < 40 kg, the initial dose will be 1 mg/m2.  This 
may be delayed or held during the peri-engraftment phase for severe oral mucositis or 
delayed platelet engraftment.
Sirolimus dose should be adjusted to maintain a target 
therapeutic concentration of 10 ng/L with a range of 5 to 15 ng/L. 
f)
In haploidentical blood recipients Sirolimus dosing will be Rapamune tablets, 4 mg, p.o., 
each day in adult patients.  In pediatric patients > 40 kg the initial dose will be 2 mg 
every 24 hours.  For patients < 40 kg, the initial dose will be 1 mg/m2.  This may be 
delayed or held during the peri-engraftment phase for severe oral mucositis or delayed 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
platelet engraftment. Sirolimus dose should be adjusted to maintain a target therapeutic 
concentration of 10 ng/L with a range of 5 to 15 ng/L
g) Sirolimus levels will be drawn on a Monday, Thursday. For sirolimus levels, 2.5 cc of 
blood will be collected into EDTA tubes and analyzed at the NIH Clinical Center.
h) Because sirolimus has a long half-life (approximately 60 hours), sirolimus levels should 
be monitored once per week beyond day 60 until levels are undetectable.  This 
information will be informative relative to the duration of time post-transplant that 
individual subjects have exposure to biologically significant levels of sirolimus.
i)
The total dose of sirolimus will continue with tapering beginning at day +180. (+/- two 
days) unless clinically indicated per PI discretion.
j)
The initial Sirolimus dosing maybe adjusted if clinically indicated for known drug 
interactions that cannot be avoided.
3.2.6
GVHD Prophylaxis with Tacrolimus
a) Tacrolimus will be used as the second agent in the immunosuppressive regimen, and in 
recipients of matched related and unrelated donors and umbilical cord blood, Tacrolimus  
will be initiated on day -3 before transplant as a continuous intravenous infusion at 0.02 
mg/kg/day for a target level of 5 to 10 ng/ml
b) For recipients of haploidentical donors, Tacrolimus will be administered continuously from 
day +5.
c) When the patient is reliably taking oral medications, tacrolimus will be converted to an 
equivalent oral dose using a 1:3 conversion from the IV form.  The total daily dose will be 
divided into two equal doses, one dose given approximately every 12 hours.
d) The total dose of tacrolimus will continue with tapering starting at day +180, unless clinically 
indicated per PI.
e) The initial Tacrolimus dosing may be adjusted if clinically indicated for known drug 
interactions that cannot be avoided.
3.2.7
GVHD Prophylaxis with Cyclophosphamide for Haploidentical Recipients
a) Cyclophosphamide will be used as the third agent in the immunosuppressive regimen for 
haploidentical recipients and will be given on days +3 and +4 after transplant as an infusion 
over 90 min. 
b) Cyclophosphamide will be accompanied by Mesna 80% of cyclophosphamide dose in 4 
divided doses on day +3, the day of high dose cyclophosphamide.
c) Tacrolimus and Sirolimus will be started on day +5 for haploidentical recipients. 
3.2.8
Post Transplant Treatment with Filgrastim (G-CSF)
Filgrastim will be administered at a dose of 5 micrograms/kg/day IV starting on day 0 for 
matched related, unrelated, and cord blood recipients, and on day +4 in haploidentical recipients, 
and continued until the ANC is greater than 1000 for 3 days or greater than 5000 for 1 day. 
3.3
TREATMENT MODIFICATIONS
3.3.1
Donor Hematopoietic Stem Cell Harvest Modifications
a) The dose of filgrastim for matched related donor stem cell mobilization will not be changed 
from a dose of 10 Pg/kg/day by subcutaneous injection.  
b) There will be no additional dose of filgrastim if a sixth day of apheresis is performed. 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
c) For apheresis an additional 12 L apheresis may be performed on day 6 if the target dose of 5 
x 106 CD34_+ cells/kg is not reached on the day 5 collection.
d) If greater than 5 x 106 CD34+ cells per kg are harvested after apheresis, then no further 
mobilization or apheresis will be performed, and the patient will be eligible to receive the 
stem cell transplant with that dose of CD34+ cells. 
e) In the event that < 3 x 106 CD34+ cells per kg are harvested, the donor will be given two 
weeks of rest, and then will be re-treated with filgrastim 8 μg/kg subcutaneously BID for five 
days followed by repeat blood stem cell harvesting.
f)
If the donor stem cells are cryopreserved, the apheresis product will be cryopreserved in 
Plasmalyte A, Pentastarch, human serum albumin, DMSO, and preservative free heparin 
(10U/ml). In the event that unrelated donor cells are to be collected and cryopreserved prior 
to transplant, permission will be obtained from the NMDP.
g) If an ABO incompatibility exists between the donor and patient, the donor erythrocytes will 
be removed from the graft in the cell-processing laboratory, according to standard DTM 
operating procedures.
h) Bone marrow may also be obtained from the donor if conditioning has already begun and the 
PBSC collection is not to be carried out or results in a suboptimal collection. 
3.3.2
Transplant Treatment Modification
a) If donor apheresis on days 5, 6, and 7 yields a toWDORI[6 CD34+ cells per kg, this level 
of CD34+ cell dose will be allowed.  
b) If PBSC cell transplant results in DMSO-related toxicities (chills, muscle aches), 
diphenhydramine 25 mg IV and meperidine 50 mg IV may be administered one time.
3.3.3
Post-transplant Rejection
This protocol uses a nonmyeloablative-conditioning regimen, thus autologous recovery is 
anticipated in patients who fail to engraft.  Patients who have less than 1% donor neutrophils 
in the peripheral blood on two occasions more than one month apart and occurring more than 
one month after transplant will be considered to have graft rejection. 
3.3.4
Dose Modification for Sirolimus
a) The total duration of sirolimus will be determined by the presence or absence of GVHD and 
the level of donor/recipient chimerism, however the schedule is to continue sirolimus until 
day +180 (+/- 2 days) and then taper as long as the severity of GVHD is less than grade II, 
and the patient is not requiring systemic steroids.  Sirolimus will subsequently be reduced by 
one-third on day +180 (+/- 2 days  as long as the severity of GVHD is less than grade II, the 
patient is not receiving systemic steroids, and the donor chimerism is 100 percent. If the 
donor chimerism is less than 100%, sirolimus will be continued without taper for up to 2 
years at the discretion of the PI.
b) Because prolonged dosing of sirolimus is associated with increased cholesterol and 
triglycerides, a lipid panel that includes cholesterol and triglycerides should be measured 
every 2 weeks during sirolimus therapy.  If elevated cholesterol and triglyceride levels are 
documented on two consecutive tests, therapy with an HMG-CoA reductase inhibitor 
(“statin” therapy) will be initiated. Since the patients will be on Fluconazole, it is 
recommended to start Pravastatin 40 mg/day. In the event that this 40 mg daily dose is not 
sufficient (elevation of cholesterol or triglycerides at a level 50% above baseline values), 
then consideration may be given to increase the dose of the Pravastatin therapy to 80 mg. 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
3.3.5
Dose Modification for Tacrolimus
a) Subsequent doses of tacrolimus will be adjusted according to levels monitored at least bi-
weekly and/or upon symptoms or alterations in renal function. The target level will be 5 to 10 
ng/ml
b) When the patient is reliably taking oral medications, tacrolimus will be converted to an 
equivalent oral dose using a 1:3 conversion from the IV form.  The total daily dose will be 
divided into two equal doses, one dose given approximately every 12 hours.
c) The total dose of tacrolimus will continue until day +180 and then begin tapering until day +
365 (+/- two days), per PI discretion as long as the severity of GVHD is less than grade II, 
and the patient is not requiring systemic steroids. 
3.4
PHARMACOKINETIC STUDIES (NOT APPLICABLE)
3.5
PROTOCOL EVALUATION
3.5.1
Recipient pre-transplant evaluation (perform within 48 hours of the initiation of pre-
transplant conditioning) 
a) CBC with differential
b) PT, and PTT
c) Acute Care Panel
d) Hepatic Panel
e) Mineral Panel
f)
Uric Acid, Serum
g) Protein, Total, Serum
h) Lactate Dehydrogenase
i)
Creatine Kinase
c) Urine EHCG in women of childbearing potential
3.5.2
Evaluation During Transplantation (see Appendix B)
The following studies will be obtained in the recipient during hospitalization for 
transplantation:
a) CBC twice daily; differential count daily
b) Acute Care Panel BID
c) Hepatic Panel
d) Mineral Panel
e) Uric Acid, Serum
f)
Protein, Total, Serum
g) Creatine Kinase
h) LDH daily
i)
Lipid panel weekly
j)
Type and screen twice a week
k) Sirolimus levels two times a week
l)
Tacrolimus levels will be evaluate twice weekly
m) Weekly CMV, Adenovirus, EBV, HHV6 PCR, Toxoplasmosis
n) Donor: Recipient Chimerism Studies: Determination of donor vs. host chimerism will be 
performed by VNTR-PCR of microsatellites. A CLIA-certified lab will perform these 
assays.  Initial baseline determination on donor and recipient DNA will be done at the 
time of study entry. Post-transplant chimerism will be determined at the discrete time 
points (+/- 2 days) starting with day 30 post-transplant to evaluate T-lymphoid, myeloid, 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
and total blood chimerism. Blood chimerism will also be evaluated at  day +100, 6 
months,  12 months, and 24 months post-transplant (+/- 3 days), and as clinically 
indicated (i.e., mixed chimerism).  Chimerism may be measured at other time-points if 
clinically indicated (e.g., to determine effect of manipulating immune suppression in 
order to increase donor chimerism). Send 5 cc blood in yellow top ACD tube to Jody 
Keary, Clinical Center Pathology.
o) A bone marrow aspirate will be collected at days 30 and 100 post-transplant (+/- 3 days) 
to help elucidate the contribution of donor hematopoietic progenitor cells to the graft, and 
to determine whether there are differences between the levels of donor chimerism in the 
peripheral blood compared to the bone marrow.  DNA chimerism will be performed by 
CLIA certified laboratories.  If MDS is present pre-transplant, then a bone marrow 
aspirate with cytogenetics will be performed on days 30, 100, 6 months and 12 months  
post-transplant.  A portion of the sample will be sent to Dr. Fran Hakim, Bldg 10, Room 
12C-216.
p) A lymphocyte phenotyping panel (T, B, NK) will be performed on days +30, +60, +100, 
6 months, 12 months, and 24 months post-transplant.  All times are +/- 3 days.  A CBC 
with absolute monocyte count will be performed at these same time points.
q) In order to determine the rate and contribution of each UCB unit or units to engraftment 
after UCB transplant, unsorted chimerism studies using quantitative polymerase chain 
reaction (PCR) for polymorphic variable number tandem repeat (VNTR) or short tandem 
repeat (STR) microsatellite regions from DNA from peripheral blood will be evaluated.  
A CLIA-certified lab will perform these assays. Initial baseline determination on donor 
and recipient DNA will be at time of study entry.  Send 5 cc of blood in purple top tube 
to Dr. Roger Kurlander, Clinical Center pathology.
r)
The patient will also be evaluated at least twice weekly during the first 100days after 
transplantation for the development of acute GVHD. Weekly CMV, Adenovirus, EBV, 
HHV6 PCR, and Toxoplasmosis will be performed.
3.5.3
Post-Transplant Evaluation (also see Appendix B)
After completion of therapy the patient will be followed for potential complications 
related to allogeneic SCT.  The patient will be seen in follow-up to evaluate disease status 
and late problems related to allogeneic HSCT at days +30, +60, and +100; and at 6, 12, 
and 24 months post-transplant.  At these times patients will have the following tests 
performed to determine clinical response (+/- 3days): 
a) CBC with differential count 
b) Acute Care Panel
c) Hepatic Panel
d) Mineral Panel
e) Uric Acid, Serum
f)
Protein, Total, Serum
g) Lactate Dehydrogenase
h) Creatine Kinase
i)
Lipid panel (weekly)
j)
Type and screen 
k) Sirolimus level
l)
Tacrolimus level


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
m) CMV, Adenovirus, EBV, HHV6, and toxoplasmosis weekly
n) Donor: Recipient Chimerism Studies: A CLIA-certified lab will perform these assays. Initial 
baseline determination on donor and recipient DNA will be done at the time of study entry. 
Post-transplant chimerism will be determined at the discrete time points (+/- 3 days) starting 
with day 30 post-transplant to evaluate T-lymphoid, myeloid, and total blood chimerism. 
Blood chimerism will also be evaluated at day +100, 6 months, 12 months, and 24 months 
post-transplant, and as clinically indicated (i.e., mixed chimerism). Chimerism may be 
measured at other time-points if clinically indicated (e.g., to determine effect of manipulating 
immune suppression in order to increase donor chimerism).
o) In order to determine the rate and contribution of each UCB unit or units to engraftment after 
UCB transplant, unsorted chimerism studies using quantitative polymerase chain reaction 
(PCR) for polymorphic variable number tandem repeat (VNTR) or short tandem repeat 
(STR) microsatellite regions from DNA from peripheral blood will be evaluated on days +30, 
+100, 6, 12, and 24 months post-transplant.  A CLIA-certified lab will perform these assays. 
Initial baseline determination on donor and recipient DNA will be at time of study entry. 
p) A bone marrow aspirate will be collected at day 100 post-transplant (+/- 3 days) to help 
elucidate the contribution of donor hematopoietic progenitor cells to the graft, and to 
determine whether there are differences between the levels of donor chimerism in the 
peripheral blood compared to the bone marrow.  DNA chimerism will be performed by CLIA 
certified laboratories.  A sample will also be delivered to Dr. Fran Hakim, Bldg 10, Room 
12C-216.
q) If MDS is present pre-transplant, then a bone marrow aspirate with cytogenetics will be 
performed on days +30, +100, 6 months, 12 months, and 24 months post-transplant (+/- 2
days).  If the patient has normal cytogenetics at day +30 cytogenetic will not be repeated 
until day 100.
r)
A lymphocyte phenotyping panel (T, B, NK) will be performed on days +30, +100, 6 
months, 12 months, and 24 months post-transplant. All times are +/- 3 days.  A CBC with 
absolute monocyte count will be performed at these same time points. 
s) The patient will also be evaluated at least twice weekly during the first 100 days after 
transplantation for the development of acute GVHD.
3.6
CONCURRENT THERAPIES
Please see section 4.1 for concurrent therapy with anti-bacterial, anti-fungal, and anti-viral agents 
during transplant. 
3.7
SURGICAL GUIDELINES (NOT APPLICABLE)
3.8
RADIATION GUIDELINES
a) Patients receiving 10/10 matched related and 10/10 matched unrelated donor hematopoietic 
stem cells, and haploidentical donor bone marrow cells, will receive 200 cGy total body 
irradiation on day -1. Patients with 9/10 matched unrelated donors will receive 300 cGy TBI 
on day -1. Following consultation with the Radiation Oncology Branch, patients will be 
measured to determine the maximal lateral separation at the level of the hip with the patient 
lying supine.  The lateral head and neck separation will also be measured to determine the 
appropriate thickness of compensators for this treatment. On day -1 patients will receive a 
total body dose of either 200 or 300 cGy delivered to the lateral midplane at a source distance 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
of 6 meters to isocenter.  The treatment will be delivered with opposed lateral treatment 
fields with head and neck compensation to minimize dose heterogeneity.  Modifications to 
the radiation treatment palm, with the exception of the total dose, may be made to the 
treatment technique at the discretion of the treating radiation oncologist based on the 
patient’s thickness or other technical factors. Approximately one hour prior to radiation, 
patients should be given one 8mg tablet of Zofan (Ondansetron) orally with water.  Pediatric 
patients who require anesthesia will be requested to sign an additional consent for anesthesia.
3.9
OFF TREATMENT CRITERIA- NOT APPLICABLE
3.10 OFF STUDY CRITERIA 
The donor or recipient will be removed from protocol for any of the following reasons:
a) Inadequate stem cell collection from the selected donor. If this occurs, another eligible donor 
may be enrolled and may undergo filgrastim mobilization and PBSC collection as outlined in 
the donor selection criteria.  If no other eligible donor is available, or if there is insufficient 
time to arrange donor cell collection, then the recipient will be removed from the trial and 
referred back to their physician.
b) Unacceptable toxicity (> grade 3) from the initiation of G-CSF until cells are harvested, for 
the donor.
c) The donor or recipient refuses to continue therapy.
d) In addition, the patient may at any time be removed from protocol at the principal 
investigator’s discretion, if the PI deems the patient to be at unacceptable risk to remain on 
study.  Reasons for this action may include (but are not limited to): declining organ 
function/performance status before transplantation; inadequate family/caregiver support; 
noncompliance. 
e) Lost to follow-up
f)
Death
g) Off-Study Procedure: Authorized staff must notify Central Registration Office (CRO) when a 
patient 
is 
taken 
off-study. 
An 
off-study 
form 
from 
the 
web 
site 
(http://intranet.cancer.gov/ccr/welcome.htm) main page must be completed and faxed to 301-
480-0757.
*Note:  Donors will be considered “Off Study” 1 day post collection of cells or until resolution 
of a pending adverse event.
3.11 POST STUDY EVALUATION (FOLLOW-UP)
a) Patients will be followed post-therapy at least weekly in the outpatient setting until at least 
day +100 (post transplant) to evaluate disease status and problems related to allogeneic 
HSCT
b) Clinic visits will be scheduled at day’s +30, +60, and +100; and at 6, 9, 12, 18, and 24 
months post-transplant at which time the following tests will be performed to determine 
clinical response: 
x
CBC with differential count 
x
Acute Care Panel
x
Hepatic Panel
x
Mineral Panel
x
Uric Acid, Serum
x
Protein, Total, Serum


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
x
Lactate Dehydrogenase
x
Creatine Kinase
x
CMV, Adenovirus, EBV, HHV6 PCR, Toxoplasmosis
x
Donor: Recipient Chimerism Studies: 
x
Lymphocyte phenotype panel (T, B, NK). A CBC with absolute monocyte count will be 
performed at these same time points. 
c) A bone marrow aspirate will be collected at day 100 post-transplant (+/- 3 days) to help 
elucidate the contribution of donor hematopoietic progenitor cells to the graft, and to 
determine whether there are differences between the levels of donor chimerism in the 
peripheral blood compared to the bone marrow. 
d) If MDS is present pre-transplant, then a bone marrow aspirate with cytogenetics will be 
performed on days +30, +100, and 6, 9, 12, 18, and 24 months post-transplant (+/- 3days).  If 
the patient has normal cytogenetics at day +30 cytogenetics will not be repeated until day 
100.
e) The patient will also be evaluated at least twice weekly during the first 100 days after 
transplantation for the development of acute GVHD.
3.12 IMMUNOLOGIC STUDIES
a) Immune reconstitution of donor leukocyte subsets will be assessed on days +30, +100, 6 
months, 12 months, and 24 months post-transplant (+/- 2 days).  Peripheral blood (five green 
(CPT) tubes will be collected) will be sent to the Dr. Fran Hakim, ETIB, Bldg 10, Room 
12C-216. After lysis of RBC, flow sorting of T-lymphocytes (CD3+), B-lymphocytes 
(CD20+), NK cells (CD56+), and monocytes (CD14+) will be carried out.  If 10,000 to 
100,000 cells can be obtained from the individual cell population, then chimerism will be 
carried out on the individual cell populations.  Sorted cell populations will be analyzed for 
donor chimerism by the Clinical Center pathology, attn: Jodi Keary. 
3.13 RESTRICTIONS FOR BLOOD DRAWN FOR RESEARCH SAMPLES:
Research blood sample aliquot size will be minimized for patients < 18 years of age and the 
total amount restricted.  The amount of blood drawn from adult (those 18 years of age or 
older) for research purposes shall not exceed 10.5 mL/kg or 550 mL, whichever is smaller, in 
an 8 week period.
The amount of blood drawn for research purposes from pediatric patient subjects (those 
under 18 years of age) will not exceed 5 mL/kg in a single day, and no more than 9.5 mL/kg 
over an 8 week period.
In the event that blood draws are limited due to patient size, research studies will be 
performed in order of priority. Small volume apheresis collections will not be included in this 
calculation since such is performed isovolumetrically with minimal red cell loss.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
4
SUPPORTIVE CARE 
4.1
INFECTION PROPHYLAXIS 
(For a full description of infection prophylaxis please refer to the NIH BMT Consortium 
Supportive Care Guidelines at http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml).  
Infection prophylaxis for pediatric patients should follow the NIH BMT Consortium Supportive 
Care Guidelines found at http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml
4.2
MANAGEMENT OF ENGRAFTMENT SYNDROME  
Engraftment syndrome may occur at the time of neutrophil recovery.  Its clinical manifestations 
include noninfectious fever, rash, and vascular leak causing non-cardiogenic pulmonary edema, 
weight gain, and renal insufficiency (Spitzer 2001).  Diagnostic criteria and a treatment schema 
for engraftment syndrome are included in Appendix E. 
4.3
TREATMENT OF GRAFT-VERSUS-HOST DISEASE
a) In patients in whom GVHD is suspected, standard clinical criteria and biopsy findings (when 
clinically indicated) will be used to establish the diagnosis. Acute GVHD will be assessed 
according to 1994 Consensus Conference on Acute GVHD Grading criteria (Przepiorka et al. 
1995). Chronic GVHD will be assessed according to 2005 Chronic GVHD Consensus 
Project (Filipovich et al. 2005). See Appendix D for details concerning the assessment of 
acute and chronic GVHD.
b) Patients with clinical Stage 1 or 2 (Grade I) GVHD of the skin without any other organ 
involvement will be treated with a topical corticosteroid cream.
c) In general, patients with t Grade II acute GVHD will be treated with high-dose, systemic 
corticosteroids.
d) Patients who fail to respond to corticosteroids will be considered for second-line 
immunosuppressive therapy. These agents include Tacrolimus as a continuous intravenous 
infusion at 0.02 mg/kg/day; Mycophenolic acid 1 Gm po BID,  Infliximab (Remicade) 10 
mg/kg/dose IV every week for a maximum of 4 doses, Daclizumab 1mg/kg IV on Days 1, 4, 
8, 15, and 22, or  other experimental acute GVHD protocols, if they are available.
4.4
MENSES SUPPRESSION AND CONTRACEPTION
a) For a full description of menses suppression and contraception please refer to the NIH BMT 
Consortium Supportive Care Guidelines at: 
b) http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml
c) Pre-menopausal women who have not undergone hysterectomy will be placed on a 
monophasic oral contraceptive to provide both menses suppression and contraception. This 
therapy will begin upon enrollment and continue until platelet recovery after transplantation 
(> 50,000/μl without transfusion).  Treatment should be started prior to the onset of 
thrombocytopenia usually when withdrawal bleeding begins. Once thrombocytopenia occurs 
therapy is less likely to be effective. As general recommendations: Prescribe Lo-Ovral 
(300μg norgestrol and 30 μg ethinyl estradiol) 1 tablet daily. Instruct patient not to take 
placebo tablets. If the patient is on another oral contraceptive, she should be switched to Lo-
Ovral. If Lo-Ovral is started when the patient is bleeding and bleeding persists for more than 
2-3 days, increase the dose to 1 tablet twice daily. If bleeding persists for more than an 
additional 2-3 days (total 5 to 6 days after starting hormones), consult the NIH Gynecology 
Consult Service.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
d) Female transplant recipients will be advised to use an effective form of contraception for at 
least 1 year after transplantation, and to have their male partners use condoms.  
e) Male transplant recipients will be advised to use contraception, preferably condoms, for 1 
year after transplantation.
4.5
BLOOD PRODUCT SUPPORT
a) Patient’s blood counts will be monitored daily during the hospitalization. Patients will 
receive packed red blood cells and platelets as needed to maintain Hb > 8.0 gm/dl, and 
platelets > 10,000/mm3 (or higher, if clinically indicated).  
b) All blood products, with the exception of the stem cell product and DLI, will be irradiated.
c) Leukocyte filters will be utilized for all blood and platelet transfusions to decrease 
sensitization to transfused leukocytes and decrease the risk of CMV infection. The patient, 
who is seronegative for CMV and whose donor is seronegative, should receive CMV-
negative blood products whenever possible.
d) Transfusion of irradiated blood and cellular blood products will begin at a minimum of two 
weeks prior to hematopoietic cell collection. Transfusion of irradiated blood and cellular 
blood products will continue to at least one year after transplantation. Patients receiving 
immunosuppressive medication will continue to have all blood and cellular blood products 
irradiated until discontinuation of immunosuppressive treatment.
e) Patients sensitized to HLA or platelet specific antigens should receive HLA matched 
apheresis platelet collections.
4.6
NUTRITIONAL SUPPORT
If mucositis or GVHD prevent adequate PO intake, parenteral hyperalimentation will be 
instituted and discontinued with input from the Pharmacy and Nutrition Departments. Oral intake 
will resume when clinically appropriate under the supervision of the dietary service of the 
Clinical Center.
4.7
ANTI-EMETIC USAGE 
Anti-emetic usage will follow recommendations from the Pharmacy. 
4.8
INTRAVENOUS IMMUNE GLOBULIN (IVIG)
a) Will follow Guidelines for Infection Management in Allogeneic HSCT Recipients by the 
NIH Blood and Marrow Consortium standard practices.
b) IgG level will be measured only in patients who have had t 2 respiratory infections that 
required antibiotic therapy in the six months prior to transplant. 
c) IgG values less than 400 mg/dl, 500 mg/kg IVIG will be administered intravenously.
4.9
HEPATIC FUNCTION SUPPORT
All patients will receive ursodeoxycholic acid (Ursodiol) for the prevention of hepatic 
complications after allogeneic stem cell transplantation.  Ursodiol will start day -4 prior to the 
transplant and will continue until day +100 post-transplant. Patients weighing less than 90 kg 
will receive 300mg orally twice daily (600mg total dose each day). Those patients weighing 
more than 90 kg will receive 300 mg orally each morning and 600 mg orally each evening (900 
mg total dose each day).


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
4.10 CENTRAL NERVOUS SYSTEM PROPHYLAXIS
Pediatric patients < 18 years of age may receive standard intrathecal (IT) chemotherapy on a 
monthly basis on a case by case basis after conferring with the PI and the treating physician, to 
prevent meningeal dissemination in patients with select hematologic malignancies.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
5
DATA COLLECTION AND EVALUATION
5.1
DATA COLLECTION
a) Data will be prospectively collected and entered in real time into the Cancer Center Clinical 
Data System database (NCI C3D database) (information at http://ccrtrials.nci.nih.gov).  It is
expected that clinical data be entered into C3D no later than after 10 business days of the 
occurrence.  The NCI PI and research nurse will have access to these data via web access.
5.1.1
Adverse Events during the Conditioning Therapy phase:
5.1.1.1 Grade 1 and 2 adverse events will not be recorded, with the exception of All Grade 2 
events that are not in the consent form, but are possibly, probably or definitely related to 
the research; 
5.1.1.2 All expected and unexpected Grade 3 and 4 adverse events possibly, probably or 
definitely related to the research will be recorded with the exception of:
a) Blood/Marrow abnormalities (will include grade 3&4 hemolysis)
b) Coagulation abnormalities
c) Metabolic abnormalities (will include grade 3&4 LFTs and creatinine)
5.1.1.3 All grade 5 adverse events will be recorded regardless of attribution.
5.1.2
Adverse Events during the Transplant phase (Day 0 to Day 100):
5.1.2.1 Grade 1 adverse events will not be recorded.
5.1.2.2 Grade 2 adverse events that will be recorded:
a) those potentially, probably and definitely related to GVHD.
b) infection including fever in the absence of neutropenia.
c) Those unexpected potentially, probably, and definitely related to the research.
d) Any that are deemed clinically significant by the PI
5.1.2.3 All expected and unexpected Grade 3 and 4 adverse events possibly, probably or 
definitely related to the research will be recorded with the exception of:
a) Blood/Marrow abnormalities (will include grade 3 &4 hemolysis)
b) Coagulation abnormalities with the exception of TTP/HUS which will be recorded
c) Metabolic abnormalities (will include grade 3 &4 LFTs and creatinine)
5.1.2.4 All grade 5 adverse events will be recorded regardless of attribution.
5.1.3
Adverse Events during the Follow-up phase (beyond Day 100):
5.1.3.1 Grade 1 adverse events will not be recorded.
5.1.3.2 Grade 2 adverse events that will be recorded:
a) those potentially, probably and definitely related to GVHD.
b) infection including fever in the absence of neutropenia.
5.1.3.3 All expected and unexpected Grade 3 and 4 adverse events possibly, probably or 
definitely related to the research will be recorded with the exception of:
a) Electrolyte abnormalities (will include grade 3&4 LFTs and creatinine)
5.1.3.4 All grade 5 adverse events will be recorded regardless of attribution.
a) After obtaining Informed Consent, a file will be created in the database with standardized 
forms.  The NCI C3D will maintain data for described endpoints in the protocol.  The 
medical record will maintain complete records on each patient including any pertinent 
supplementary information obtained from outside laboratories, outside hospitals, radiology 
reports, laboratory reports, or other patient records.  The NCI C3D will serve as the primary 
source from which all research analyses will be performed.  


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
b) Data collection will include the eligibility criteria checklist, patient history, , specialty forms 
for pathology, radiology, weekly toxicity monitoring, monitoring of GVHD, engraftment 
data, chimerism data, immune reconstitution and relapse data and an off-study summary 
sheet, including a final assessment by the treating physician. After patients are seen in clinic 
on day +30, +100 and 6, 9, 12, 18, and 24 months post-transplant, the NCI C3D will be 
updated in real-time. Additional data that is obtained during the transplant process may be 
utilized in the analysis of this protocol (e.g. chimerism testing performed as clinically 
indicated on dates other than those specifically required under the guidelines of the protocol). 
Please see appendix H for detailed data entry requirements for C3D.
c) Data will also be sent to the International Bone Marrow Transplant Registry (IBMTR).
d) Unrelated donor recipients will be offered to participate in a cross-institute data and 
repository sample collection protocol though NIAID which fulfills the NMDP requirements 
for data reporting as described in the Clinical Center’s Transplant Center Agreement with 
NMDP.
e) Protocol Deviations: Any protocol deviations should be directly reported to the PI or LAI.  
These deviations will be reported to the NCI IRB. 
5.2
RESPONSE CRITERIA
a) Patients will also be assessed for complete clinical and hematological response at day +30, 
+60, and +100, and 6, 12, and 24 months post-transplant.
In the unlikely events that bone marrow is used as the source of stem cells for HSCT, the 
data from these individuals will be analyzed separately for the primary and secondary end-
points, however this data will be included in the stopping point criteria.
x
Parameters to be monitored:
x
Total nucleated cell dose, CD34+ cell dose, CD3+ cell dose
x
Degrees of reconstitution of monocytes, B-lymphocytes, NK cells, T-lymphocytes, by 
lymphocyte phenotype on peripheral blood leukocytes for CD3+, CD20+, CD56+, 
and CD14+ cells 
x
Absolute neutrophil and absolute monocyte count
x
Neutrophil recovery (days to neutrophil count of 5 x 109/l
x
Platelet recovery (days to platelet count of 50 x 109/l, days to transfusion 
independence. 
x
Red cell recovery (days to RBC transfusion independence) 
x
Incidence and severity of acute GVHD
x
Incidence and severity of chronic GVHD
x
Incidence of graft rejection
x
Non-hematological effects attributable to the preparative regimen
x
Transplant related mortality
x
Incidence and type of infectious episodes
x
Disease-free and overall survival
b) Complete hematological response (CR) for GATA2 Mutation Syndrome consists of normal 
levels of T-lymphocytes, B-lymphocytes, NK cells, monocytes, and neutrophils at 100 days 
post-transplant.  CRIS order to be entered for TBNK cells by flow cytometry.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
c) A partial hematological response (PR) for GATA2 mutation syndrome consists of 
normalization at 100 days post-transplant of one or more of the leukocyte subsets which were 
severely decreased prior to transplant, i.e., B-lymphocytes, NK cells, or monocytes.  
d) No response for GATA2 mutation syndrome  consists of lack of normalization any of the 3 
leukocyte subsets that were severely decreased prior to transplant 
e) Complete response (CR) for MDS consists of  normalization of the peripheral blood counts 
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cellularity > 20% with normal maturation and fewer than 5% blasts in bone marrow 100 days 
after transplant (Schetelig et al. 2003).  The absence of specific molecular or cytogenetic 
markers of disease that were previously present further defines molecular or cytogenetic 
remission, respectively. 
f)
Partial response (PR) for MDS is defined as improvement in markers of leukemia or by 
having all criteria for complete remission satisfied, except that the bone marrow may contain 
> 5% but < 25% blasts, or < 5% blasts are present. 
g) No response for MDS is defined as bone marrow and peripheral blood morphological 
features consistent with relapse or progression, including rising blast count and re-emergence 
of specific molecular or cytogenetic markers.
h) Samples will be collected and analyzed at day’s +30, +60, and +100, and at 6 and 12 months 
post-transplant for clinical and hematological response. 
5.3
TOXICITY CRITERIA:
Adverse Events on this study will be reported using the NCI Common Terminology Criteria for 
Adverse Events version 3.0 (CTCAE v3.0).  A copy of the CTCAE v3.0 can be downloaded 
http://ctep.info.nih.gov/CTC3/default.html.
All appropriate treatment areas should have access to a copy of the CTCAE version 3.0.
5.4
STATISTICAL CONSIDERATIONS
a) The primary objectives of this feasibility study are:
1) In a pilot fashion, to determine whether reduced-intensity allogeneic HSCT results in 
engraftment and restores normal hematopoiesis by day +100 in patients with GATA2 
mutation syndrome 
2) To determine the safety of this HSCT regimen in patients with GATA2 mutation 
syndrome, including transplant related toxicity, the incidence of acute and chronic graft-
versus-host disease, immune reconstitution, overall survival, and disease-free survival 
b) Up to 15 patients in total will be prospectively recruited over a 2-year period for this HSCT 
protocol.  We currently have six patients with mutations in GATA2 who are candidates for 
transplant.  This study utilizes a matched related donor if one is present, however if no 
matched related donor is identified, but a 10/10 matched unrelated donor is available, then 
that donor will be utilized. If neither a 10/10 matched related donor nor a 10/10 matched 
unrelated donor is available, then either a 9/10 matched unrelated donor, a haploidentical 
donor or UCB units will be used if they are available and meet the dose and matching 
requirements.  The choice between a 9/10 matched unrelated donor, an UCB donor, or a 
haploidentical donor will depend upon the nature of the HLA mismatch, the clinical 
condition of the patient, and the urgency for transplant among other factors.  This decision 
whether to use a 9/10 matched unrelated donor, an UCB donor, or a haploidentical donor will 
be made by the PI or LAI.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
c) It is estimated that approximately one-quarter of the patients with GATA2 deficiency will 
have a 10/10 matched related donor, and that approximately one-quarter of  the patients will 
have a 10/10 matched unrelated donor. It is anticipated that the remaining patients will have 
9/10 matched unrelated donors, umbilical cord blood donors, or haploidentical donors. Thus, 
it is anticipated that no more than 5 patients from each donor category will be enrolled.  To 
date we have enrolled 3 matched related donor recipients, three matched unrelated donor 
recipients, and 4 umbilical cord blood recipients
d) Our goal is to learn if the approach is likely to be of beneficial and have an acceptable level 
of toxicity.  The definition of benefit is whether the patient engrafts the donor HSC and 
normal hematopoiesis is reconstituted.  For purposes of sample size calculations, we will aim 
for 50% with benefit and consider this procedure to be of less benefit if fewer than half 
(50%) may truly benefit.  As an illustration, we will aim for 50% with benefit and consider 
the results to be less promising if consistent with only 20% having benefit. If there are 15 
evaluable patients, considered without regard to type of donor, the probability of having 6 or 
more with a successful outcome is 6.1% if the true probability of benefit were 20% and the 
probability is 84.9% if the true probability of benefit were 50%. Thus, observation of benefit 
in 6 or more of 15 patients provides evidence that this method is likely to be useful for these 
patients. At the conclusion of the trial, 90% and 95% confidence intervals will be formed 
around the observed benefit results.  Given the rarity of this condition, this is intended to be a 
guideline, but findings of lesser benefit may be considered useful for further consideration if 
the toxicity profile is not excessively negative.
e) Stopping Rules: Although the patients with this disease are debilitated from the 
immunodeficiency disease and the frequency of infections, we anticipate that most will 
survive the transplant itself.  The following stopping rules will be implemented in order to 
provide patient safety: 
1) Separately within each donor category, if two patients fail to engraft, or fail to survive the 
first 100 days following HSCT, then we will stop enrollment, reevaluate the protocol, and 
present this data to the IRB.
2) If while accrual is proceeding, if 1/3 or greater of the patients have a grade 3 or higher 
GVHD, this will also pause accrual to the trial, including IRB review, prior to re-starting 
accrual or amending the trial appropriately. 
5.5
DATA AND SAFETY MONITORING PLAN
In accordance with NCI IRB policy, this pilot study will require independent monitors or review 
by a Safety Monitoring Committee (SMC).
The PI, LAI, and Scientific Chairperson will provide continuous, close monitoring, with prompt 
reporting of serious adverse events to the IRB.  On a weekly basis, the PI, LAI, Protocol 
Research Nurse, and the NCI Transplant Coordinator will review clinical and laboratory data 
from patient. A complete summary of patient outcomes will be provided every six months to the 
IRB in the form of a continuing review application.  The research nurse will verify enrollment 
data entered into the C3D for each subject within 4 weeks of signing consent.  Ongoing data 
entered into C3D will be verified by the research nurse monthly, and at the time of continuing 
review.  Documentation of data verification will be tracked in C3D.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
6
HUMAN SUBJECTS PROTECTIONS
6.1
RATIONALE FOR SUBJECT SELECTION
Subjects for this pilot and feasibility study will be males and females of all races and ethnic 
groups with mutations in GATA2 and a life-expectancy of greater than 3 months but less than 24 
months.  The GATA2 mutation syndrome is characterized by: 1) the onset of disease beyond 
infancy with least two episodes of a life-threatening opportunistic infection including MAC, 2) a 
unique T+, B-, NK-, monocyte- phenotype on flow cytometry, 3)  propensity to progress to 
MDS/AML, and 4) mutations in the GATA2 gene.  This patient group was chosen because 
allogeneic hematopoietic stem cell transplant represents a potentially effective treatment for both 
GATA2 mutations and MDS.  There are no treatment options for patients with this disease that 
provide any significant survival advantage. The approximate survival of these patients with 
conventional treatment is approximately five years. Because myeloablative preparative regimens 
are associated with a high degree of morbidity and mortality in patients with co-morbidities, such 
individuals are most likely to benefit from the reduced-intensity transplant approach used in this 
study.  Individuals with HIV disease will not be candidates for this protocol due to the high rate 
of post-transplant complications in this group.  Individuals who are pregnant or lactating will not 
be candidates for this protocol due to the risk to the fetus or newborn.
Information about this protocol will be posted on www.clinicaltrials.gov, NIH Clinical Center 
studies, and the NCI Patient recruitment websites. The protocol will also be listed in the 
physician’s data query (PDQ).
6.1.1
Inclusion of Women and Minorities
Both men and women and members of all races and ethnic groups are eligible for this trial.
6.1.2
Participation of Children
Children below the age of 12 will not be included on this protocol.  Donors less than 15 years of 
age will not be included on this protocol since the protocol involves greater than minimal risk 
without prospect of direct benefit to individual patients for this population.
Physicians, nurses, and multidisciplinary support teams of the POB, NCI, and CC will provide 
patient care.  The staff of the POB has expertise in the management of children with complex 
oncologic disorders and complications of therapy.  Full pediatric support and subspecialty 
services are available at the NIH CC.  
6.2
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS- PATIENTS
6.2.1
Related to the Transplant in General 
The patients may obtain direct benefit from the transplant.  However, the radiation and 
immunosuppression utilized in this study carry the risk of direct toxicity.  In addition, immune 
suppression is associated with an increased risk of opportunistic infections.  However, it is 
anticipated that these risks will be lower than the risks associated with traditional allogeneic 
transplantation utilizing total body irradiation in which the mortality may be as high as 40%.  
Although our data as well as that of others suggest a significant reduction in transplant related 
mortality with reduced-intensity conditioning, 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.  The 
use of 200 cGy low-dose TBI may increase both the degree of myelosuppression and 
immunosuppression without significantly altering the side effect profile.  The specific hazards of 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
this study using a reduced-intensity conditioning regimen are graft rejection, graft-versus-host 
disease, and disease relapse.  Of these complications, GVHD remains the major cause of 
morbidity and mortality.  Therefore, the patient will receive sirolimus (Rapamycin) and 
tacrolimus for GVHD prophylaxis.  It is not known whether study recipients will be protected 
against GVHD by this regimen.  The major discomforts of sirolimus and/or tacrolimus are: 
nausea, anorexia, diarrhea, fever and malaise, and intolerance of the period of confinement (see 
section 8.2 and 8.3 for full toxicity profile).  Side effects of those drugs novel to reduced-
intensity transplantation are described in detail in Section 8.
6.2.2
Risks related to matched related donor transplant
Engraftment is more predictable using a 10/10 matched donor transplant than with a 9/10-
matched unrelated donor transplant.  Treatment with both total body irradiation and fludarabine 
is designed to enhance donor engraftment to greater than 90%.  Graft-versus-host disease 
remains a formidable risk with approximately 50% of patients developing GVHD, and 25% of 
patients having GVHD requiring additional treatment.  The risk of GVHD is least with a 
matched related donor compared to the other two donor sources. 
6.2.3
Risks related to matched unrelated donor transplant
Engraftment is also predictable using a 10/10 matched unrelated donor transplant with 
approximately 90% or more of patients achieving engraftment. Treatment with both total body 
irradiation and fludarabine, and the increase to 300 cGy TBI for 9/10 matched unrelated donors,
is designed to enhance donor engraftment.  Graft-versus-host disease remains a formidable risk 
with approximately 60% of patients developing some GVHD, and 30% of patients having 
GVHD requiring additional treatment.  The risk of GVHD is greater with a matched unrelated 
donor than with a matched related donor. 
6.2.4
Risks Related to Haploidentical Transplant
Haploidentical donor transplant with this conditioning regimen results in 90% or more of 
patients achieving engraftment.  The risk of GVHD using a haploidentical donor and this 
conditioning regimen is approximately 50%, however only 10% have grade 3 to 4 GVHD.
6.2.5
Risks related to UCB transplant
Engraftment is lowest in this group compared to the other two groups.  This results in an 
increased risk of infection and bleeding.  However, the risk of GVHD is lower in this group 
compared to matched unrelated donor transplant.  
6.2.6
Related to Total Body Irradiation
The side effects of radiation have been well described. The most common include nausea and 
mucositis. There also exists a risk of hypothyroidism, cataracts, interstitial pneumonitis, 
nephropathy, and an unspecified long term risk of developing secondary malignancies (Buchali 
et al. 2000) (Deeg et al. 1983).  Importantly, the majority of the non-neoplastic effects were 
subclinical and/or reversible (Thomas et al. 2001).  Studies attempting to evaluate the risk 
induced by radiation alone suggest that there is a higher rate of solid tumors after radiation-based 
regimens.  Curtis et al. reported on 19,229 patients and found a cumulative incidence rate of 
2.2% at 10 years, and 6.7% at 15 years, with higher doses of TBI associated with a higher risk of 
solid cancers (Curtis et al. 1997).  In a study in 1999, no relationship could be found to radiation 
but the highest risk factor was felt to be the presence of chronic graft versus host disease, and 
long-term treatment with cyclosporine (Kolb et al. 1999). Pediatric patients who require sedation 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
in order to undergo TBI will be asked to sign a separate consent outlining the risk of the selected 
anesthesia.
6.2.7
Related to Cyclophosphamide (Cytoxan)
Commercially available.  See package insert for further information.
Toxicity:
Common
Occasional
Rare
Immediate:
Within 1-2 days 
of receiving 
drug
Anorexia (L), nausea 
(L), vomiting(L)
Metallic taste (L), 
Inappropriate ADH1
Transient blurred vision1
cardiac toxicity with 
arrhythmias1 myocardial 
necrosis 2(L)
Prompt:
Within 2-3
weeks, prior to 
the next course
Myelosuppression (L), 
alopecia (L)
Hemorrhagic cystitis 
(L)
Delayed:
Any time later 
during therapy, 
excluding the 
above 
conditions
Immunosuppression, 
gonadal dysfunction 
/sterility (L)
Pulmonary fibrosis3(L)
Late:
Any time after 
completion of 
treatment
Secondary malignancy, 
bladder fibrosis
Unknown Frequency and Timing:  **Fetal and teratogenic toxicities and toxicities in breast-
fed children
1 Less common with lower doses.
2Only with very high doses.
3 Risk increased with chest radiation.
(L) Toxicity may also occur later.
**Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination with 
other antineoplastic agents) have been noted in humans.  Toxicities include: chromosome 
abnormalities, multiple anomalies, pancytopenia, and low birth weight.
**Cyclophosphamide is excreted into breast milk.  Neutropenia has been reported in breast-fed 
infants.  Cyclophosphamide is considered to be contraindicated during breast feeding because of 
the reported cases of neutropenia and because of the potential adverse effects relating to immune 
suppression, growth, and carcinogenesis.
6.3
RISKS IN RELATION TO BENEFIT 
6.3.1
Recipients:
Patients on this study may be directly benefited by this treatment protocol.  Considerable clinical 
data has demonstrated long-term disease-free survival for patients with immunodeficiency 
diseases as well as high-risk hematological malignancies following allogeneic HSCT.  Thus, the 
patient on this study may be directly benefited by this treatment.  In particular, reduced-intensity 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
allogeneic stem cell transplantation may offer the patient a curative therapy for his disease while 
reducing the risks of a myeloablative transplant. This carefully defined patient cohort is a 
reasonable one in which to explore strategies to improve the results of allogeneic HSCT from 
unrelated donors, which historically has achieved prolonged remission and survival for some 
patients, but has been associated with significant morbidity and high transplant-related mortality.  
It is hypothesized that the transplant approach used in this study will result in the successful 
transfer of allogeneic stem cells with reduced morbidity and mortality from the transplant 
preparative regimen, and with reduced graft-versus-host disease. Clinically the approach is 
ethically acceptable because we are treating patients with at least one, and in some cases two, 
lethal hematological diseases that are both incurable with conventional treatments.  The protocol 
aims to decrease the risk of transplant related toxicity, thus making more patients candidates for
this potentially curative therapy.  Therefore the research involves more than a minor increase 
over minimal risk to subjects with the prospect of direct benefit (45 CFR 46.102).  The potential 
risks to the transplant recipient have been carefully considered and are felt to be significantly less 
than would otherwise occur with myeloablative allogeneic HSCT.  The risks graft rejection, 
acute and chronic GVHD, infection, and relapse will be present, as discussed previously.
6.3.2
Donors:
Healthy 10/10 matched related donors, 10/10 matched unrelated donors,9/10 matched unrelated 
donors, and haploidentical donors will be co-enrolled onto this study. The collection aspect of 
this protocol is not investigational. There is potential benefit for donors, as they may derive
psychological benefit from participating in a clinical trial designed to improve the health of the 
recipient of the prior transplant donation. Other potential benefits include the diagnosis of 
previously unknown illnesses (such as viral hepatitis) at the time of donor screening.
6.4
CONSENT AND ASSENT PROCESSES AND DOCUMENTS
a) Informed consent will be obtained from all patients, and/or the patient’s parents or legal 
guardian (if he/she is < 18 years of age), and matched related donors entered on this trial.  
The procedures and treatments involved in this protocol, with their attendant risks and 
discomforts, potential benefits, and potential alternative therapies will be carefully explained 
to the recipient and/or parent/guardian.  If applicable, the parent or guardian will sign the 
designated line on the informed consent attesting to the fact that the child has given assent.
b) The investigators are requesting a waiver from the IRB to allow only one parent to sign the 
informed consent to enter a child on the protocol. Because many patients must travel to the 
NIH from long distances at substantial expense, requiring both parents to be present for the 
consent process could be a financial hardship for many families. When necessary, the 
protocol will be reviewed by telephone with the other parent and their approval will be 
verified. When guardianship status of the child is uncertain, a social worker will be asked to 
investigate and, if necessary, seek documentation of custody status. The PI or an associate 
investigator on the trial will obtain consent. Where deemed appropriate by the clinician and 
the child’s parents or guardian, the child will also be included in all discussions about the 
trial and verbal assent will be obtained. The parent or guardian will sign the designated line 
on the informed consent attesting to the fact that the child has given assent.
c) Similarly, the procedures and treatments involved in this protocol, with their attendant risks 
and discomforts, will be carefully explained to the matched unrelated donors at the respective 
donor center as required by NMDP.  The original signed informed consent goes to Medical 
Records; a copy will be kept for the research record.  The Central Registration Office (CRO), 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
Data Management Section will also retain a copy of the informed consent document.  A copy 
of the signed informed consent document will also be given to the recipient (and matched 
related donor, when applicable).  b) The Central Registration Office (CRO) will ascertain the 
date of IRB approval before registering the first patient. 
d) The Principal Investigator and/or an authorized designee will consent the patient and 
matched related donor (when applicable) and will be available to answer all patient 
questions.
e) If any new information becomes available relating to risks, adverse events, or toxicities, 
while patients are participating in this protocol, this information will be provided orally 
and/or in writing to all enrolled and prospective patient participants.  Documentation will be 
provided to the IRB and if necessary the informed consent amended to reflect relevant 
information.
6.4.1
Telephone re-consent procedure
Reconsent on this study may be obtained via telephone according to the following procedure: the 
informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signature will 
sign and date the consent.  The original informed consent document will be sent back to the 
consenting investigator who will sign and date the consent form with the date the consent was 
obtained via telephone.  A fully executed copy will be returned via mail for the subject’s records.
The informed consent process will be documented on a progress note by the consenting 
investigator and a copy of the informed consent document and note will be kept in the subject’s 
research record.
7
DATA REPORTING
7.1
DEFINITIONS
7.1.1
Adverse Event
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form unless otherwise noted above in 
Section 5.1.
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Serious adverse 
events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of at least possibly related to the agent/intervention 
should be recorded and reported as per section 7.2.
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:
x
Results in discontinuation from the study


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
x
Is associated with clinical signs or symptoms 
x
Requires treatment or any other therapeutic intervention
x
Is associated with death or another serious adverse event, including hospitalization. 
x
Is judged by the Investigator to be of significant clinical impact
x
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
7.1.2
Suspected adverse reaction
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.
7.1.3
Unexpected adverse reaction
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.
7.1.4
Serious 
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others.
7.1.5
Serious Adverse Event
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
x
Death,
x
A life-threatening adverse drug experience
x
Inpatient hospitalization or prolongation of existing hospitalization
x
A persistent or significant disability/incapacity
x
A congenital anomaly/birth defect.
x
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
7.1.6
Disability
A substantial disruption of a person’s ability to conduct normal life functions.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
7.1.7
Life-threatening adverse drug experience
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death.
7.1.8
Protocol Deviation (NIH definition)
Any change, divergence, or departure from the IRB approved research protocol..
7.1.9
Non-compliance (NIH Definition)
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subject.
7.1.10 Unanticipated Problem
Any incident, experience, or outcome that:
x
Is unexpected in terms of nature, severity, or frequency in relation to the research risks 
that are described in the IRB-approved research protocol and informed consent 
document; Investigator’s Brochure or other study documents, and the characteristics of 
the subject population being studied; AND
x
Is related or possibly related to participation in the research; AND
x
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.
7.2
NCI-IRB REPORTING
7.2.1
NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths
The protocol PI will report to the NCI-IRB:
x
All deaths, expect deaths due to progressive disease
x
All Protocol Deviations
x
All Unanticipated Problems
x
All non-compliance
7.2.2
NCI-IRB Requirements for PI Reporting at Continuing Review
The protocol PI will report to the NCI-IRB: 
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action.
2. A summary of any instances of non-compliance
3. A tabular summary of the following adverse events:
x
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research; 
x
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research; 
x
All Grade 5 events regardless of attribution; 
x
All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be reported. 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
All Grade 4 and 5 unexpected serious adverse events that are related to commercially available 
agents will be reported directly to the FDA via Medwatch (http://www.fda.gov/medwatch).


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
8
PHARMACEUTICAL INFORMATION
8.1
FLUDARABINE (FLUDARA, BERLEX LABORATORIES)
a) Supply - Fludarabine monophosphate will be purchased by the NIH Clinical Center 
Pharmacy Department from commercial sources and is supplied as a white, lyophilized 
powder.  Each vial contains 50 mg of fludarabine phosphate, 50 mg of mannitol, and sodium 
hydroxide to adjust pH.  Fludara is stored at room temperature.
b) Preparation - FLUDARA IV should be prepared for parenteral use by aseptically adding 
Sterile Water for Injection, USP.  When reconstituted with 2 ml of Sterile Water for 
Injection, each ml of the resulting solution will contain 25 mg of Fludarabine Phosphate, 25 
mg of mannitol, and sodium hydroxide to adjust the pH to 7–8.5.  Fludarabine will be diluted 
in 100 to 125ml of either 5% dextrose in water or 0.9% sodium chloride, and infused IV over 
30 minutes.
c) Storage and Stability - Reconstituted FLUDARA IV should be stored in the refrigerator 
between 36 and 46 degrees F. Because reconstituted FLUDARA IV contains no 
antimicrobial preservative, care must be taken to assure the sterility of the prepared solution; 
for this reason, reconstituted FLUDARA IV should be used or discarded within 8 hours.
d) Administration - Parenteral drug products should be inspected visually for particulate matter 
and discoloration prior to administration.
e) Toxicities – Fludarabine toxicities include myelosuppression (dose limiting toxicity), fever, 
nausea, vomiting, stomatitis, diarrhea, gastrointestinal bleeding, anorexia, edema, skin 
rashes, myalgia, headache, agitation, hearing loss, transient episodes of somnolence and 
fatigue, auto-immune hemolytic anemia, auto-immune thrombocytopenia, paresthesias, 
peripheral neuropathy, renal, and pulmonary toxicity (interstitial pneumonitis).  Severe fatal 
CNS toxicity presenting with loss of vision and progressive deterioration of mental status 
were encountered almost exclusively after very high doses of fludarabine monophosphate.  
Such toxicity has only rarely been demonstrated at the 25-30 mg/m2/day dosage of 
fludarabine.  Very rarely described complications include transfusion-associated graft-
versus-host disease, thrombotic thrombocytopenic purpura, and liver failure.  Tumor lysis 
syndrome following fludarabine administration has been observed, especially in patients with 
advanced bulky disease.  Opportunistic infections (protozoan, viral, fungal, and bacterial) 
have been observed post-fludarabine, especially in heavily pre-treated individuals, and in 
individuals receiving fludarabine combined with other agent.
f)
Dose reduction for renal impairment- For Creatinine Clearance of 30-70 mL/min/1.73m2 
there will be a 20% dose reduction. If the Creatinine Clearance is less than 
30mL/min/1.73m2, Fludarabine will not be administered.  
8.2
SIROLIMUS (RAPAMUNE®)
a) General:  Sirolimus is an immunosuppressant that is FDA approved for use in combination 
with cyclosporine and corticosteroids for prophylaxis of organ rejection after kidney 
transplant. Sirolimus is administered SIROLIMUS (Rapamycin) (Rapamune®, Wyeth-
Ayerst Laboratories)
b) Supply - For patient administration, oral tablets will be purchased by the NIH Clinical Center 
Pharmacy Department from commercial sources. 
c) Storage and Stability - Oral tablets should be stored 20-25 C° (68-77 F°). Oral solution 
should be refrigerated (2-8 C° or 36-46 F°).
d) Administration: Because fatty food can increase the absorption of sirolimus, the tablets 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
should be administered in the setting of a steady diet that is relatively constant with respect to 
fat content.
e) Toxicities: 1) Sirolimus induces immune suppression, which has been associated with 
opportunistic infection and an increased rate of malignancy, particularly skin cancer. 2) Some 
individuals may develop hypersensitivity to sirolimus.  3) May cause an increase in 
cholesterol and triglycerides, which may be associated with pancreatitis.  4) With long-term 
administration, may result in impaired renal function.  4) Co-administration of voriconazole 
is strongly discouraged on this protocol, as the combination of voriconazole and sirolimus 
results in an approximate 10-fold increase in sirolimus blood levels. 
f)
Drug Interactions: May increase the in vivo drug levels of simvastatin.
8.3
TACROLIMUS (FK506, PROGRAF)
a) Supply: Tacrolimus will be obtained by the NIH Clinical Center Pharmacy Department from 
commercial sources and is available in capsules (0.5 mg, 1mg, and 5mg), and as a parenteral 
concentrate for injection (5 mg/ml, 1 ml ampules).  
b) Preparation: For parenteral doses, tacrolimus injection concentrate (5 mg/ml) should be 
diluted to a final concentration of 0.004 to 0.02 mg/ml in dextrose 5% in water or sodium 
chloride 0.9%.   Parenteral doses of tacrolimus will be prepared in non-PVC containers and 
infused with non-PVC administration sets/tubing.  
c) Storage and Stability: Capsules and ampules of parenteral concentrate bear expiration dates 
and are stored at room temperature.  Tacrolimus concentrate for injection that has been 
diluted to a final concentration of 0.004 to 0.02 mg/ml is stable for 24 hours in 5% dextrose 
or 0.9% sodium chloride injection in glass, PVC or non-PVC plastic containers.  To 
minimize the potential for sorption to PVC plastic bags and tubing as well the leaching of 
phthalate plasticizer (DEHP) into the solution, only non-PVC plastic bags and intravenous 
administration sets should be utilized.  
d) Administration: Tacrolimus may be given intravenously over 24 hours or orally.   
e) Toxicities: Acute tacrolimus nephrotoxicity is usually manifested by a moderate decline in 
renal excretory function, which is readily reversible by a decrease in drug dosage.  Although 
some degree of transient renal dysfunction may occur in patients with therapeutic levels of 
tacrolimus, significant renal toxicity is associated with elevated trough or steady state levels.  
In addition to an increase in BUN and creatinine, hyperkalemic hyperchloremic acidosis, low 
fractional excretion of sodium and the onset of hypertension with hypomagnesemia are seen 
with tacrolimus nephrotoxicity. Insulin dependent post transplant diabetes mellitus was 
reported in 20% kidney transplant patients, which was reversible in 50% of the patients at 2 
years post transplant.  Hypertension occurs in up to 60% of patients.   Hypomagnesaemia can 
be associated with neurologic symptoms, including seizures, cerebellar ataxia and 
depression.  Dose-related hepatotoxicity, manifested by elevation of serum transaminases and 
bilirubin, has been reported. The drug carries a warning for increased susceptibility to 
infection and the possible development of lymphoma may result from resulting 
immunosuppression.      
8.4
FILGRASTIM (G-CSF; NEUPOGEN ®)
(Amgen), Filgrastim   Classification: glycoprotein  
a) Supply – Commercially available as filgrastim injection in a concentration of 300Pg/ml in 
1ml (300Pg) and 1.6ml (480Pg) vials from the Clinical Center Pharmacy Department.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
b) Preparation – For subcutaneous administration, the appropriate prescribed dose is drawn up 
from the vial with no further dilution prior to administration.  For intravenous administration, 
the commercial solution for injection should be diluted prior to administration.  It is 
recommended that the prescribed dose be diluted with dextrose 5% in water to a 
concentration greater than 5Pg/ml just prior to administration; storage of the diluted 
filgrastim is not recommended.  Dilution of filgrastim to a final concentration of less than 
5Pg/ml is not recommended at any time.  Do not dilute with saline at any time; product may 
precipitate.  Filgrastim diluted to concentrations between 5 and 15Pg/ml should be protected 
from absorption to plastic materials by the addition of Albumin (Human) to a final 
concentration of 2mg/ml.  When diluted in 5% dextrose or 5% dextrose plus Albumin 
(Human), filgrastim is compatible with glass bottles, PVC and polyolefin IV bags, and 
polypropylene syringes.  The dose may be “rounded down” to within 10% of patient’s 
calculated dose to use the drug cost-effectively.
c) Storage and Stability – Filgrastim for injection should be stored in the refrigerator at 2o to 
8oC (36o to 46oF).  Avoid shaking.  
d) Administration – Subcutaneous injection is preferred.  If clinically indicated, filgrastim may 
be administered as an intravenous infusion over 4 or 24 hours.
e) Toxicities – Medullary bone or skeletal pain is the most commonly reported toxicity.  In 
addition, reversible elevations in uric acid, lactate dehydrogenase, and alkaline phosphatase 
are common laboratory abnormalities.  Four cases of splenic rupture have been reported in 
healthy donors when given filgrastim or other myeloid growth factors for peripheral blood 
stem cell mobilization; 1 of these cases resulted in fatality.  Five additional cases of splenic 
rupture have been reported in cancer patients undergoing chemotherapy or peripheral blood 
stem cell mobilization; splenic rupture may have contributed to deaths in 2 of these cases.  
One additional death due to splenic rupture after filgrastim therapy was reported to the 
manufacturer without additional information.  According to the manufacturer, the reporting 
rate for splenic rupture with filgrastim is less than 1 in 486,000. 
8.5
DIPHENHYDRAMINE
a) Supply – Commercially available.  Diphenhydramine HCl injection is available in an 
injectable solution at a 50mg/ml concentration in single dose ampules, syringes and vials as 
well as multi-dose vials from multiple manufacturers.
b) Preparation – Diphenhydramine HCl may be given by direct intravenous injection without 
additional dilution.  Alternatively the prescribed dose may be diluted in a small volume (e.g. 
25-50ml) of 5% dextrose in water (D5W) or 0.9% sodium chloride (NS) and infused over 10-
15 minutes.
c) Storage and Stability – Store commercially available injectable product at controlled room 
temperature.
d) Administration – Diphenhydramine HCl injection may be administered by direct IV injection 
(IV push) at a rate generally not exceeding 25mg/min.  Alternatively, diphenhydramine HCl 
injection may be diluted and given over 10-15 minutes (see Preparation).
e) Toxicities – Sedation, sleepiness, dizziness, disturbed coordination, epigastric distress, and 
thickening of bronchial secretions.  Diphenhydramine can provide additive effects with 
alcohol or other CNS depressants.  Diphenhydramine can cause anticholinergic side effects 
(e.g. dry mouth, fixed or dilated pupils, flushing, urinary retention).  Diphenhydramine 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
should be used with caution in patients with a history of bronchial asthma, increased 
intraocular pressure, hyperthyroidism, cardiovascular disease or hypertension.
8.6
ACETAMINOPHEN
a) Supply: Commercially available as 325 mg or 500 mg tablets for oral administration from 
multiple manufacturers. 
b) Storage: Store at controlled room temperature. 
c) Administration: Oral.  For analgesia and antipyretic, the usual dose is 650 to 1000 milligrams 
every 4 to 6 hours, to a maximum of 4 grams/day. 
d) Toxicities: No toxicities are anticipated to result from single doses of acetaminophen 
administered as premedication for rituximab infusions.
8.7
ACYCLOVIR  
a) Supply: Commercially available.
b) Product description: Acyclovir is available in 200mg capsules, 400mg tablets, and 800mg 
tablets. It is also available in an oral suspension at a concentration of 200mg/5ml. Parenteral 
acyclovir sodium is available in vials containing 500mg or 1gm powder for injection of 
acyclovir as the sodium salt. Acyclovir sodium for injection is also available as a 50mg/ml 
solution for injection in 1gm/20ml vials.
c) Preparation: For parenteral administration, acyclovir sodium powder for injection should be 
reconstituted with sterile water for injection to a concentration of 50mg/ml (10ml of diluent 
for 500mg vial and 20ml of diluent for 1gm vial). The calculated dose should be further 
diluted in 0.9% sodium chloride or 5% dextrose in water to a concentration of < 7mg/ml 
prior to administration.
d) Storage and Stability: Oral capsules, tablets and oral solution should be stored at 15o to 25oC
(59o to 77oF). Capsules and tablets should be protected from moisture.  Acyclovir powder for 
injection and solution for injection should be stored at 15o to 25oC (59o to 77oF).  The powder 
for injection once reconstituted should be used within 12 hours. After final dilution for 
administration, the dose may be stored at room temperature; it should be used within 24 
hours.
e) Route of administration: Oral and parenteral. Parenteral doses should be administered by 
slow intravenous infusion over one hour at concentrations of 7mg/ml or less.
f)
Toxicities: Oral administration: nausea and/or vomiting, diarrhea, headache, malaise, skin 
rash, asthenia; Parenteral administration: inflammation or phlebitis at the injection site, 
transient elevations of serum creatinine or BUN, nausea and/or vomiting, itching, rash or 
hives, elevation of transaminases, and encephalopathic changes. Renal toxicity can occur and 
is secondary to precipitation of acyclovir crystals in the renal tubules. The risk of toxicity can 
be minimized by avoiding the administration of high concentrations and rapid infusions.
8.8
TRIMETHOPRIM/SULFAMETHOXAZOLE 
(TMP/SMX,
COTRIMOXAZOLE,
BACTRIM,
SEPTRA)
a) Supply: Commercially available as a single strength tablet containing trimethoprim 80mg 
and sulfamethoxazole 400mg and a double strength (DS) tablet containing trimethoprim 
160mg and sulfamethoxaole 800mg. It is also available in an oral suspension at a 
concentration of 40mg of trimethoprim and 200mg sulfamethoxazole per 5ml.  Parenteral 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
TMP/SMX is available in a solution for injection at a concentration of 80mg of trimethoprim 
and 400mg of sulfamethoxazole per 5ml. 
b) Preparation: For parenteral administration, the commercial solution for injection must be 
diluted prior to administration.  It is recommended that each 5ml of the solution for injection 
be diluted with 100-125 ml or, if fluid restriction is required, in 75ml of dextrose 5% in 
water.  0.9% NaCl may be substituted as a diluent but the resulting solutions have reduced 
stability. Consult with pharmacy for questions regarding diluent, volume, and expiration. 
c) Storage and Stability: Oral tablets and oral suspension should be stored at 15o to 30oC (59o to 
86oF) in a dry place and protected from light.  TMP/SMX for injection should be stored at 
room temperature between 15o to 30oC (59o to 86oF) and should not be refrigerated.  Stability 
of intravenous doses after final dilution is dependent on concentration and diluent.  Consult 
with pharmacy for questions regarding stability and expiration dating. 
d) Administration – Oral and parenteral.  Parenteral doses should be administered by an 
intravenous infusion over 60 to 90 minutes. 
e) Toxicities: 1) the most common adverse effects from TMP/SMX are gastrointestinal 
disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and 
urticaria).  2) Fatalities associated with the administration of sulfonamides, although rare, 
have occurred due to severe reactions, including Stevens-Johnson syndrome, toxic epidermal 
necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood 
dyscrasias.  3) For TMP/SMX injection, local reaction, pain and slight irritation upon IV 
administration are infrequent.  Thrombophlebitis has rarely been observed.
8.9
URSODEOXYCHOLIC ACID (URSODIOL, ACTIGALL®)
a) Supply – Commercially available as 300 mg capsules.
b) Pharmacology - About 90% of a therapeutic dose of Ursodiol is absorbed in the small bowel 
after oral administration. After absorption, Ursodiol enters the portal vein and undergoes 
efficient extraction from portal blood by the liver where it is conjugated with either glycine 
or taurine and is then secreted into the hepatic bile ducts. Only small quantities of Ursodiol 
appear in the systemic circulation and very small amounts are excreted into urine. The sites 
of the drug’s therapeutic actions are in the liver, bile, and gut lumen.
c) Storage and Stability – Oral capsules should be stored at 15°C-30°C (59°F-86°F).
d) Administration – Oral.
e) Toxicities – Nausea, vomiting, dyspepsia, metallic taste, abdominal pain, biliary pain, 
cholecystitis, constipation, stomatitis, flatulence, diarrhea, pruritus, rash, dry skin, urticaria, 
headache, fatigue, anxiety, depression, sleep disorders. Less common side effects include 
sweating, thinning of hair, back pain, arthralgia, myalgia, rhinitis, cough.
f)
Drug Interactions - Bile acid sequestering agents such as cholestyramine and colestipol may 
interfere with the action of Ursodiol by reducing its absorption. Aluminum-based antacids 
have been shown to adsorb bile acids in vitro and may be expected to interfere with Ursodiol 
in the same manner as the bile acid sequestering agents. Estrogens, oral contraceptives, and 
clofibrate increase hepatic cholesterol secretion, and encourage cholesterol gallstone 
formation and hence may counteract the effectiveness of Ursodiol.
8.10 CEFTAZIDIME  (FORTAZ ®)
a) Supply: Supplied frozen, sterile, iso-osmotic non-pyrogenic solution in plastic containers.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
b) Preparation: For IV infusion, reconstitute the 1- or 2 Gm infusion pack with 100 mL sterile 
water. Consult with pharmacy for questions regarding diluent, volume, and expiration. 
c) Storage and Stability: Commercially available in dry state stored between 15 and 25  degrees 
C protected from light.  Also supplied frozen in 50-mL single dose plastic containers as a 
premixed solution of ceftazidime sodium and should not be stored above -Û&
d) Administration: The usual dosage is 2 grams administered intravenously every 8 to 12 hours. 
Parenteral doses should be administered by an intravenous infusion over 20 to 30 minutes. 
e) Toxicities: 1) the most common adverse effects from ceftazidime are local reactions and 
allergic and gastrointestinal reactions. These reactions include: 1) phlebitis and inflammation 
at the site of injection, 2) pruritis, rash, and fever, 3) nausea, vomiting , and abdominal pain, 
4) headache, dizziness, and paresthesias, 
8.11 LEVOFLOXACIN  (LEVAQUIN ®)
a) Supply: Levofloxacin for injection is supplied in single-use vials with each vial containing a 
concentrated solution with the equivalent of 500 mg of levofloxacin in 20 mL vials and 750 
mg in 30 mL vials.  Levofloxacin is also supplied as a premix in 5% dextrose with each bag 
containing a dilute solution with the equivalent of 250, 500, or 750 mg respectively of 
levofloxacin. 
b) Preparation: For IV infusion, the single-use vial must be diluted to 5 mg/mL with D5W or 
0.9% Sodium Chloride prior to administration. For the levofloxacin in premixed, ready to use 
solution in D5W, no further preparation is necessary.
c) Storage and Stability:  Levofloxacin injection in Single-Use vials should be stored at 
controlled room temperature and protected for light.  Levofloxacin injection Premix should 
EHVWRUHGDWRUEHORZÛ&$YRLGH[FHVVLYHKHDWDQGSURWHFWIURPOLJKW
d) Administration: Levofloxacin injection is 250 or 500 mg administered by slow infusion over 
60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 
24 hours.  
e) Toxicities: 1) Moderate to severe photoxicity reactions have been observed in patients 
exposed to direct sunlight while receiving levofloxacin, 2) predispose to seizure, 3) 
disturbances in blood glucose, 4) peripheral neuropathies. 
8.12 CYCLOPHOSPHAMIDE  (CTX, CYTOXAN)
a) Supply – Cyclophosphamide will be purchased by the NIH Clinical Center Pharmacy 
Department from commercial sources and is supplied as a lyophilized powder in various vial 
sizes.
b) Preparation - will be reconstituted with sterile water for injection to yield a final 
concentration of 20 mg/ml as described in the package insert.
c) Storage and Stability - The vials are stored at room temperature. Following
d) reconstitutions as directed, solutions of cyclophosphamide are stable for 24 hours at room 
temperature, or 6 days when refrigerated at 2-8° C.
e) Route of Administration - The cyclophosphamide used in this regimen will be mixed in 100 
ml 0.9% sodium chloride, Inj., and given at a dose of 50 mg/kg as an IVPB over 2 hours on 
day -6. .e) Toxicities:
1) Nausea and vomiting - variable; symptomatically improved with standard antiemetics 
and/or benzodiazepines [e.g., lorazepam].
2) Water retention – cyclophosphamide may rarely provoke the syndrome of inappropriate 
antidiuretic hormone secretion and resultant hyponatremia, usually manifested 12-48 hrs 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
after IV administration, necessitating frequent accurate assessment [q 1-2 hrs] of intake, 
urine output and urine specific gravity. This effect can be counteracted by furosemide. 
Fluid restriction is not feasible during administration of high dose cyclophosphamide.
3) Cardiomyopathy - cyclophosphamide may cause severe, sometimes lethal, hemorrhagic 
myocardial necrosis or congestive cardiomyopathy. Patients may present with congestive 
cardiomyopathy as late as 2 weeks after the last dose of cyclophosphamide. The clinical 
syndrome has been observed in patients receiving the dose of cyclophosphamide used in 
this protocol. In an attempt to minimize this complication, patients with significant 
cardiac dysfunction are excluded from this protocol [see patient eligibility]. Congestive 
failure is managed according to standard medical therapeutics.
4) Hemorrhagic cystitis – this is a serious, potentially life-threatening complication related 
to injury of the bladder epithelium by cyclophosphamide metabolites.
5) Although sub-clinical hematuria is not uncommon at this dose level, clinically significant 
hematuria or serious hemorrhage can usually be avoided by maintaining a high urine 
volume and frequent voidings and the administration of Mesna. Diuresis is maintained 
for 24 hrs after completion of last dose by parenteral infusions of normal saline with 
potassium chloride. Careful monitoring of serum and urine electrolytes is mandated. 
Furosemide may be required to ensure this diuresis. Continuous bladder irrigation may be 
used for control of significant hematuria.
6) Sterility
7) Less common but serious complications include pulmonary fibrosis and secondary 
malignancies. Less common but reversible toxicities include alopecia and skin rash.
8.13 EQUINE ANTI-THYMOCYTE GLOBULIN (ATGAM)
a) Supply- Purified, concentrated sterile gamma globulin, primarily monomeric IgG, from 
hyperimmune serum of horses immunized with human thymus lymphocytes. Each ml of 
ATGAM contains 50 mg of horse gamma globulin stabilized in 0.3 molar glycine to a PH of 
approximately 6.8.  
b) Preparation- ATGAM should be reconstituted at a concentration not to exceed 4 mg/ml on 
0.9% sodium chloride.  
c) Storage and Stability- $7*$0LVVWRUHGDVPODPSXOHVLQDUHIULIJHUDWRUDWÛWRÛ&'2
NOT FREEZE.  
d) Administration- Dose of 30 mg/kg IV every day on days -6, -5, and -4, for a total dose of 90 
mg/kg. Diluted ATGAM should be allowed to reach room temperature before infusion.  The 
drug should be infused IV through an in-line filter with a pore size of 0.2 to 1.0 micron.  
ATGAM should be infused over 4 hours.  
e) Toxicities- Because of risk of allergic reaction to ATGAM, at least 24 hours before the first 
infusion of ATGAM, the manufacturer recommends that patients be tested with an 
intradermal injection of 0.1 ml of a 1:1000 dilution (5 μg horse ATG) of ATGAM in sodium 
chloride injection and a contralateral sodium chloride injection control. The patient should 
be observed every 15 to 20 min over the first hour of intradermal injection. A local reaction 
of 10 mm or more with a wheal or erythema or both should be considered a positive test. 
Additional toxicities include: leucopenia, thrombocytopenia, fever, chills, serum sickness 
like symptoms.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
9
APPENDICES
9.1
APPENDIX A: PREPARATIVE REGIMEN
Administration of Fludarabine and Total Body Irradiation (TBI) for 10/10 Matched 
Related and Unrelated Donor Transplantation 
Agent
Dose
Days
Fludarabine
30 mg/m2 per day
IV infusion over 30 minutes,
daily for 3 days
Transplant Days –4, -3, -2
TBI
200 cGy
Transplant Day -1
Administration of Fludarabine and Total Body Irradiation (TBI) for 9/10 Matched 
Unrelated Donor Transplantation 
Agent
Dose
Days
Fludarabine
30 mg/m2 per day
IV infusion over 30 minutes,
daily for 3 days
Transplant Days –4, -3, -2
TBI
300 cGy
Transplant Day -1
Administration of Fludarabine, Cyclophosphamide, Equine ATG and TBI for Umbilical 
Cord Blood Transplant
Agent
Dose
Days
Fludarabine
40 mg/m2 per day 
(25 mg/m2 per day in 
patients < 50 kg)
IV infusion over 30 
min, daily for 5 days
Transplant Days -6, -5,    
-4, -3, -2
Equine ATG
30 mg/kg per day
Transplants Days -6, -5, -
4
Cyclophosphamide
50 mg/kg
Transplant Day -6
Total body Irradiation
200 cGy
Transplant Day -1


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
Administration of Fludarabine, Cyclophosphamide, and TBI for Haploidentical 
Transplant
Agent
Dose
Days
Fludarabine
30 mg/m2 per day 
(25 mg/m2 per day in 
patients < 50 kg)
IV infusion over 30 
min, daily for 5 days
Transplant Days -6, -5,    
-4, -3, -2
Cyclophosphamide
14.5 mg/kg per day 
Transplant Day -6,-5
Total body Irradiation
200 cGy
Transplant Day -1
Total Body Irradiation
Patients receive irradiation given from a linear accelerator. Protocols specify the irradiation 
exposure and schedule of administration. TBI will be given at a dose of 200 cGy on day -1.
Fludarabine
Fludarabine is given as an IV infusion over 30 min.  Dosing is based on actual weight.
Cyclophosphamide dosing is based upon actual body weight. 


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Version Date: 05/18/2016
9.2
APPENDIX B: PROTOCOL EVALUATION CHECKLIST
1. Recipient pre-transplant evaluation (perform 48 hours prior to the initiation of pre-
transplant  conditioning)  
a) CBC with differential
b) PT, PTT
c) ABO Typing
d) Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine 
kinase, Lactate Dehydrogenase, Uric acid-serum 
e) Urine ß-HCG if female of childbearing potential 
2. During hospitalization for transplant
a) CBC BID with differential in am 
b) Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine 
kinase, Lactate Dehydrogenase, Uric acid-serum 
c) Lipid panel weekly
d) Type and screen twice a week 
e) Sirolimus levels twice a week
f)
Tacrolimus levels twice a week
g) Weekly CMV PCR Adenovirus, EBV, HHV6 PCR, toxoplasmosis
3. Post-transplant evaluation
a) CBC with diff twice weekly or weekly at the discretion of the PI. 
b) Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine 
kinase, Lactate Dehydrogenase, Uric acid-serum weekly or weekly at the discretion 
of the PI 
c) Lipid panel weekly or weekly at the discretion of the PI 
d) Type and screen twice weekly or weekly at the discretion of the PI 
e) Sirolimus levels twice weekly or weekly at the discretion of the PI 
f)
Tacrolimus levels twice weekly or weekly at the discretion of the PI 
g) Weekly CMV, Adenovirus, EBV, HHV6 PCR, Toxoplasmosis or weekly at the 
discretion of the PI 
4. Day + 14
a) CBC with differential, 
b)
Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine 
kinase, Lactate Dehydrogenase, Uric acid-serum 
5. Day + 30
a) CBC with differential, 
b) Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine 
kinase, Lactate Dehydrogenase, Uric acid-serum 
c) Peripheral Blood Lymphocyte Phenotyping (T, B, NK). Send 5 cc blood in purple top 
tube to Clinical Center pathology. 
d) CMV, Adenovirus, EBV, HHV6 PCR, Toxoplasmosis
e) Donor: Recipient Chimerism Studies to evaluate T-lymphoid, myeloid, and total 
blood chimerism. Send yellow top ACD tube to Clinical Center pathology, attn; Jody 
Keary.


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Version Date: 05/18/2016
f)
Leukocyte subset donor chimerism. Blood (Five green CPT tubes) will be sent to Dr. 
Fran Hakim, ETIB, Bldg 10, Room 12-C-216. After lysis of RBC, flow sorting of T-
lymphocytes (CD3+), B-lymphocytes (CD20+), NK cells (CD56+), and monocytes 
(CD14+) will be carried out.  If 10,000 to 100,000 cells can be obtained from the 
individual cell population, then chimerism will be carried out on the individual cell 
populations.  Sorted cell populations will be analyzed for donor chimerism by the 
Clinical Center pathology, attn: Dr. Roger Kurlander. 
g) If MDS is present pre-transplant, then a bone marrow aspirate with cytogenetics will 
be performed (5mLs will be sent to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-
216).
6. Day + 60 
a) CBC with differential
b) Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine 
kinase, Lactate Dehydrogenase, Uric acid-serum 
7. Day + 100
a) CBC with differential
b) Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine 
kinase, Lactate Dehydrogenase, Uric acid-serum 
c) Peripheral Blood Lymphocyte Phenotyping (T, B, NK). Send 5 cc blood in purple top 
tube to Clinical Center pathology. 
d) CMV, Adenovirus, EBV, HHV6 PCR, Toxoplasmosis
e) Donor: Recipient Chimerism Studies to evaluate T-lymphoid, myeloid, and total 
blood chimerism. Send yellow top ACD tube to Clinical Center pathology, attn; Jody 
Keary. Leukocyte subset donor chimerism. Blood (five green CPT tubes) will be sent 
to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-216.  After lysis of RBC, flow sorting 
of T-lymphocytes (CD3+), B-lymphocytes (CD20+), NK cells (CD56+), and 
monocytes (CD14+) will be carried out.  If 10,000 to 100,000 cells can be obtained 
from the individual cell population, then chimerism will be carried out on the 
individual cell populations.  Sorted cell populations will be analyzed for donor 
chimerism by the Clinical Center pathology, attn: Dr. Roger Kurlander. 
f)
A bone marrow aspirate with cytogenetics will be performed on all patients (5mLs 
will be sent to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-216).
8. 6 Months Post-Transplant
a) CBC with differential
b) Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine 
kinase, Lactate Dehydrogenase, Uric acid-serum 
c) Peripheral Blood Lymphocyte Phenotyping (T, B, NK). Send 5 cc blood in purple top 
tube to Clinical Center pathology. 
d) CMV, Adenovirus, EBV, HHV6 PCR, Toxoplasmosis
e) Donor: Recipient Chimerism Studies to evaluate T-lymphoid, myeloid, and total 
blood chimerism. Send yellow top ACD tube to Clinical Center pathology, attn; Jody 
Keary. Leukocyte subset donor chimerism. Blood (Five green CPT tubes) will be sent 
to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-216.  After lysis of RBC, flow sorting 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
of T-lymphocytes (CD3+), B-lymphocytes (CD20+), NK cells (CD56+), and 
monocytes (CD14+) will be carried out.  If 10,000 to 100,000 cells can be obtained 
from the individual cell population, then chimerism will be carried out on the 
individual cell populations.  Sorted cell populations will be analyzed for donor 
chimerism by the Clinical Center pathology, attn: Dr. Roger Kurlander. 
f)
If MDS is present pre-transplant, then a bone marrow aspirate with cytogenetics will 
be performed (5mLs will be sent to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-
216).
9. 12 Months Post –Transplant
a) CBC with differential
b) Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine 
kinase, Lactate Dehydrogenase, Uric acid-serum 
c) Peripheral Blood Lymphocyte Phenotyping (T, B, NK). Send 5 cc blood in purple top 
tube to Clinical Center pathology. 
d) CMV, Adenovirus, EBV, HHV6 PCR, Toxoplasmosis
e) Donor: Recipient Chimerism Studies to evaluate T-lymphoid, myeloid, and total 
blood chimerism. Send yellow top ACD tube to Clinical Center pathology, attn; Jody 
Keary. Leukocyte subset donor chimerism. Blood (Five green CPT tubes) will be sent 
to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-216. After lysis of RBC, flow sorting 
of T-lymphocytes (CD3+), B-lymphocytes (CD20+), NK cells (CD56+), and 
monocytes (CD14+) will be carried out.  If 10,000 to 100,000 cells can be obtained
from the individual cell population, then chimerism will be carried out on the 
individual cell populations.  Sorted cell populations will be analyzed for donor 
chimerism by the Clinical Center pathology, attn: Dr. Roger Kurlander.If MDS is 
present pre-transplant, then a bone marrow aspirate with cytogenetics will be 
performed (5mLs will be sent to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-216).
10. 18 Months Post –Transplant
a) CBC with differential
b) Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine kinase, 
Lactate Dehydrogenase, Uric acid-serum 
f)
Peripheral Blood Lymphocyte Phenotyping (T, B, NK). Send 5 cc blood in purple top 
tube to Clinical Center pathology. 
c)CMV, Adenovirus, EBV, HHV6 PCR, Toxoplasmosis
d0 Donor: Recipient Chimerism Studies to evaluate T-lymphoid, myeloid, and total blood 
chimerism. Send yellow top ACD tube to Clinical Center pathology, attn; Jody 
Keary. Leukocyte subset donor chimerism. Blood (Five green CPT tubes) will be sent 
to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-216.. After lysis of RBC, flow sorting 
of T-lymphocytes (CD3+), B-lymphocytes (CD20+), NK cells (CD56+), and 
monocytes (CD14+) will be carried out.  If 10,000 to 100,000 cells can be obtained 
from the individual cell population, then chimerism will be carried out on the 
individual cell populations.  Sorted cell populations will be analyzed for donor 
chimerism by the Clinical Center pathology, attn: Dr. Roger Kurlander. 


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
e) If MDS is present pre-transplant, then a bone marrow aspirate with cytogenetics will 
be performed (5mLs will be sent to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-
216).
11.  24 Month Post-Transplant
a)  CBC with differential
b)  Acute care panel, Hepatic panel, Mineral panel, Protein-total serum, Creatinine 
kinase, Lactate Dehydrogenase, Uric acid-serum  
c) Peripheral Blood Lymphocyte Phenotyping (T, B, NK). Send 5 cc blood in purple 
top tube to Clinical Center pathology. 
d) CMV, Adenovirus, EBV, HHV6 PCR, Toxoplasmosis
e) Donor: Recipient Chimerism Studies to evaluate T-lymphoid, myeloid, and total 
blood chimerism. Send yellow top ACD tube to Clinical Center pathology, attn; Jody 
Keary. Leukocyte subset donor chimerism. Blood (Five green CPT tubes) will be sent 
to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-216. After lysis of RBC, flow sorting 
of T-lymphocytes (CD3+), B-lymphocytes (CD20+), NK cells (CD56+), and 
monocytes (CD14+) will be carried out.  If 10,000 to 100,000 cells can be obtained 
from the individual cell population, then chimerism will be carried out on the 
individual cell populations.  Sorted cell populations will be analyzed for donor 
chimerism by the Clinical Center pathology, attn: Dr. Roger Kurlander. 
f) If MDS is present pre-transplant, then a bone marrow aspirate with cytogenetics will be 
performed (5mLs will be sent to Dr. Fran Hakim, ETIB, Bldg 10, Room 12-C-216).
9.3
APPENDIX C: IMMUNIZATIONS POST-TRANSPLANT
Immunizations:  All recipients will receive immunizations after transplant, according to the 
following table (http://intranet.cc.nih.gov/bmt/_pdf/table_II.pdf):


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Version Date: 05/18/2016
9.4
APPENDIX D: GRADING AND MANAGEMENT OF ACUTE GRAFT-VERSUS-HOST DISEASE
Clinical Staging of Acute GVHD
Stage
Skin
Liver
Gut
+
Rash < 25% BSA
Total bilirubin 2-3 mg/dl
Diarrhea 
500-
1000ml/d
++
Rash 25-50% BSA
Total bilirubin 3-6 mg/dl
Diarrhea 
1000-
1500ml/d
+++
Generalized 
erythoderma
Total bilirubin 6-15 mg/dl
Diarrhea >1500ml/d
++++
Desquamation 
and 
bullae
Total bilirubin > 15 mg/dl
Pain +/- ileus
BSA = body surface area; use “rule of nines” or burn chart to determine extent of rash.
Clinical Grading of Acute GVHD 
Stage
Grade
Skin
Liver
Gut
PS
0 (none)
0
0
0
0
I
+ to ++
0
0
0
II
+ to +++
+
+
+
III
++ to +++
++ to +++
++ to +++
++
IV
++ to ++++
++ to ++++
++ to ++++
+++
Treatment of Acute GVHD
This schema is intended to serve as a guideline and to promote consistency in our clinical 
practice; it may be modified for individual patients as clinical circumstances warrant.
Grade 0-I GVHD: 
1) Topical corticosteroids (usually 0.1% triamcinolone; 1% hydrocortisone to face) applied to 
rash BID.
Grade II-IV GVHD:
1) Methylprednisolone (MP) 1 mg/kg per dose IV, BID for 4 consecutive days.
2) If no response after 4 days, continue until response (7-day maximum trial); the dose may be 
doubled (4 mg/kg/day).
3) If response within 7 days, taper as follows:
a) 0.75 mg/kg per dose IV BID for 2 days.
b) 0.5 mg/kg per dose IV BID for 2 days.
c) 0.375 mg/kg per dose IV BID for 2 days.
d) If clinically appropriate, change MP to oral prednisone to equivalent of IV dose) daily for 
2 days.  MP may be converted to prednisone later in the taper at the investigators’ 
discretion.
e) After this, steroids will be reduced by 10% of starting oral dose each week until a dose of 
10 mg/day is reached.  Subsequent reductions will be made at the investigators’ 
discretion.


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Version Date: 05/18/2016
f)
If GVHD worsens during taper, steroids should be increased to previous dose.
g) During steroid taper, maintain cyclosporine at therapeutic levels (Section 3.5.1).
4) If no response is observed within 7 days of MP treatment:
a) Increase Methylprednisolone to 10 mg/kg per dose IV, BID for 2 days.
b)
If there is no improvement, consideration will be given to using second-line 
immunosuppressive therapy, e.g., tacrolimus, mycophenolic acid, monoclonal antibodies, 
or studies of investigational agents for acute GVHD, if they are available.
5) Antifungal prophylaxis with agents effective against mould will be started when it is 
anticipated that the patient will be receiving steroids at > 1 mg/kg/day of methylprednisolone 
(or equivalent) for > 2 weeks. Voriconazole, caspofungin, liposomal amphotericin B 
(Ambisome), posaconazole or amphotericin B lipid complex (Abelcet) are valid alternatives.  
During prophylaxis with any of the above agents, fluconazole should be discontinued.  In 
patients with therapeutic cyclosporine levels at the initiation of voriconazole therapy, the 
cyclosporine or tacrolimus dose should be decreased by approximately 50%. In patients with 
therapeutic sirolimus levels at the initiation of voriconazole therapy, the sirolimus dose 
should be decreased by approximately 90%.
6) Determination of GVHD treatment response should be made within 96 hours of starting the 
treatment.  The following are criteria to determine definitions of response to GVHD 
treatment:
a) Complete response:  Complete resolution of all clinical signs and symptoms of acute 
GVHD.
b) Partial Response: 50% reduction in skin rash, stool volume or frequency, and/or total 
bilirubin.  Maintenance of adequate performance status (Karnofsky Score > 70%).
c) Non-responder: < 50% reduction in skin rash, stool volume or frequency, and/or total 
bilirubin.  Failure to maintain adequate performance status (Karnofsky Score d 70%).
d) Progressive disease:  Further progression of signs and symptoms of acute GVHD, and/or 
decline in performance status after the initiation of therapy.
Treatment 
This schema is intended to serve as a guideline and to promote consistency in our clinical 
practice; it may be modified for individual patients as clinical circumstances warrant.


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9.5
APPENDIX E: MANAGEMENT OF ENGRAFTMENT SYNDROME
Clinical Definition of Engraftment Syndrome
A constellation of clinical symptoms and signs has been observed during neutrophil recovery 
following HSCT, most commonly termed “engraftment syndrome” (ES), but interchangeably 
termed “capillary leak syndrome” and “autoaggression syndrome”.  Engraftment syndromes 
have been observed after both autologous and allogeneic HSCT; in the latter setting, the clinical 
sequelae of neutrophil recovery were historically attributed to an early, sometimes “hyperacute” 
graft-versus-host reaction.  Our current understanding of ES holds the overproduction of pro-
inflammatory cytokines at the time of neutrophil recovery to be the initiating event.  The study of 
ES has been somewhat hindered by the lack of uniform definition for this clinical entity; 
therefore, the following criteria have been propose (Spitzer 2001):
Major criteria:
x
Fever > 38.3q with no identifiable infectious etiology
x
Erythrodermatous rash involving more than 25% of body 
surface area and not attributable to a medication
x
Noncardiogenic pulmonary edema, manifested by diffuse 
pulmonary infiltrates and hypoxia
Minor criteria
x
Hepatic dysfunction with either total bilirubin > 2 mg/dl or 
transaminases levels > two times normal
x
Renal insufficiency (serum creatinine > two times baseline)
x
Weight gain > 2.5% of baseline body weight
x
Transient encephalopathy unexplainable by other causes
A diagnosis of ES is established by the presence of all three major criteria, or two major criteria 
and one or more minor criteria; the clinical signs and symptoms should appear within 96 hours of 
neutrophil recovery, according to the above proposed definition.

Neutrophil recovery after transplantation may result in “engraftment syndrome” (which 
may include fever, rash, edema, hypoxia)

The following criteria will be utilized to diagnose engraftment syndrome (must have 3 
major criteria or 2 major + 1 minor criteria):

To promote consistency of our clinical practice, the following will be the recommended 
therapy for engraftment syndrome.  However, this schedule may be modified (taper either 
accelerated or delayed) for individual patients as clinical circumstances warrant.
Treatment of Engraftment Syndrome
The mainstay of therapy for ES is high-dose corticosteroids, based upon the literature on diffuse 
alveolar hemorrhage in the setting of bone marrow transplantation – a complication that many 
investigators now believe to be part of the spectrum of ES (Metcalf et al. 1994).  Our group has 
adopted the following treatment schema for patients diagnosed with ES, with satisfactory results:
Day 1:
Methylprednisolone 250 mg IV Q6 hours x 4 doses
Day 2:
Methylprednisolone 250 mg IV Q8 hours x 3 doses
Day 3:
Methylprednisolone 250 mg IV Q12 hours x 2 doses
Day 4:
Methylprednisolone 125 mg IV Q12 hours x 2 doses


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Version Date: 05/18/2016
Day 5:
Methylprednisolone 60 mg IV Q12 hours x 2 doses
Day 6:
Methylprednisolone 30 mg IV Q12 hours x 2 doses
Days 7-8:
Prednisone 60 mg PO QD x 2 days
Days 9-10:
Prednisone 50 mg PO QD x 2 days
Days 11-12:
Prednisone 40 mg PO QD x 2 days
Days 13-14:
Prednisone 30 mg PO QD x 2 days
Days 15-16:
Prednisone 20 mg PO QD x 2 days
Days 17-18:
Prednisone 10 mg PO QD x 2 days
Day 19:
Discontinue prednisone
In the event that symptoms or clinical signs of ES recur during the steroid taper, patients should 
be retreated with methylprednisolone at a minimum dose of 60 mg IV QD.  This schema is 
intended to serve as a guideline and to promote consistency in our clinical practice; it may be 
modified for individual patients as clinical circumstances warrant. In particular, steroid dosing 
for pediatric patients (< 18) will be determined on a case-by-case basis.


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Version Date: 05/18/2016
9.6
APPENDIX F- NMDP CRITERIA FOR MATCHED UNRELATED DONOR
a) HLA-testing performed by high resolution typing, and donors matched at HLA (matched 
10/10) -A, B, C, and DRB1 and DQ loci  or 9/10 loci are acceptable donors.
b) An NMDP designated physician, in accordance with the most recent NMDP Standards 
and FDA Guidance, will perform unrelated donor eligibility determination.  In general, 
the following inclusion criteria apply:
a.
Age 18 – 60
b. Ability to give informed consent
c) Determination of Medical Suitability
a.
Medical suitability will be determined as specified in the 19th Edition NMDP 
Standards, section 9.3000, and according to the NMDP standard operating 
procedure A00220.  The NMDP adheres to the strictest interpretation of the FDA 
Guidance for Industry “Eligibility Determination for Donors of Human Cells, 
Tissue, and Cellular and Tissue-Based Products (HCT/P’s)”, February 2007. 
b. Per NMDP Standards, a physical exam is performed on all potential marrow and 
PBSC donors.  The assessment includes, but is not limited to:
i. Complete medical history and physical exam with special note of:
1. Deferral of voluntary blood donation, prior experience or problems 
with anesthetic agents, or other possible contraindications to 
donation for the prospective donor
2. Vital signs, including height and weight
3. List of medications
4. Venous access for potential apheresis donors
5. If information provided in the health history screening 
questionnaire or other relevant medical records indicates a 
potential risk for transmission of a communicable disease, the 
donor may be deferred or a physical examination including 
specific assessment for signs or symptoms of a communicable 
infection will be performed.
ii. Examinations including but not limited to:
1. Chest X-Ray
2. Urinalysis
3. Electrocardiogram
4. Labs
a.
Hemoglobin and Hematocrit 
b. CBC with differential
c.
Platelet Count
d. ABO and RH
e.
Screening for Hemoglobin S
f.
Electrolytes
g. Alkaline Phosphatase
h. BUN and Creatinine
i.
LDH
j.
Bilirubin


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Version Date: 05/18/2016
k. ALT,SBPT
l.
Glucose
m. Serum Total Protein plus albumin or serum protein 
electrophoresis
n. Serum Beta-HCG Pregnancy
c.
Infectious Disease Testing
i. Donor Infectious Disease Markers are tested at the time of donor’s 
confirmatory typing, within 30 days of collection, and again on the day of 
collection according to FDA regulations.  Interpretation of infectious 
disease markers is performed by the donor center physician according to 
NMDP Standard A00223 version 2.0 “IDM Eligibility and Labeling 
Guide” 
ii. The following markers are tested
1. Hepatitis B surface antigen (HBsAg)
2. Hepatitis B core antibody (Anti HBc)
3. Hepatitis C antibody (Anti-HCV)
4. Anti-HTLV I/II
5. Antibody to T.cruzi
6. NAT testing for HIV-1/HCV
7. Anti-HIV 1 and Anti-HIV 2
8. Syphilis serologic screening test (STS)
9. Anti-CMV (IgG or total)
10. WNV-NAT testing (only required on day of collection during 
optional testing period)
iii. Any abnormal findings that may increase the risk of transmitting a 
communicable disease or that could increase the risk of transplant for the 
recipient are disclosed to the transplant center.  The patient’s physician 
will be notified, and a determination will be made whether or not to 
proceed with the collection.  In the event the donation process continues a 
Letter of Urgent Medical Need will be generated.
d) Documentation of donor clearance and consent will be provided to NIH through the 
search-coordinating unit at the NMDP.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
9.7
APPENDIX G:
EXPERIMENTAL TRANSPLANTATION 
AND IMMUNOLOGY BRANCH 
PRECLINICAL SERVICE POLICY FOR SAMPLE HANDLING  
Storage/Tracking in the Preclinical Development and Clinical Monitoring Facility 
(PDCMF)
x
Normal patient blood and tissue samples, collected for the purpose of research under IRB 
approved protocols of the Experimental Transplantation and Immunology Branch (ETIB)
may be archived by the ETIB Preclinical Development and Clinical Monitoring Facility 
(PDCMF). All data associated with archived clinical research samples is entered into the 
ETIB PDCMF’s Microsoft Excel databases on frozen cells and plasma. These databases 
are stored on the NCI group drive in the ETIB ‘PRECLINSERVICE’ folder. Access to 
this folder is limited to PDCMF staff and ETIB clinical staff, requiring individual login 
and password. All staff in the PDCMF laboratory receives annually updated NIH/CIT 
training and maintains standards of computer security.
x
The data recorded for each sample includes the patient ID, trial name/protocol number, 
date drawn, treatment cycle/post-transplant time point, cell source (e. g. peripheral blood, 
lymphapheresis, mobilized peripheral blood stem cells, marrow, urine, skin or oral biopsy
as well as box and freezer location. Patient demographics that correlate treatment 
outcomes and therapies with the samples can be obtained only through the NCI/ETIB 
clinical records. As of January 2007, all newly received samples receive a unique bar 
code number, which is included in the sample record in the PDCMF database. Only this 
bar code is recorded on the sample vial and the vials will not be traceable back to patients 
without authorized access to the PDCMF database. All non-coded samples previously 
archived will be stripped of identifiers prior to distribution for any use other than as a 
primary objective of the protocol under which they were collected.
x
Samples are stored in locked freezers. All samples will be labeled solely with a bar code 
(which includes the date, and serially determined individual sample identifier). The key 
will be available to a restricted number of ETIB investigators and associate investigators 
on the protocol. Coded samples will be stored frozen at -20°, -80° or liquid nitrogen 
vapor phase to -180 C according to the stability requirements in a single location under 
the restricted control of the PDCMF of ETIB.
x
Access to samples from a protocol for research purposes will be by permission of the 
Principal Investigator of that protocol in order to be used (1) for research purposes 
associated with protocol objectives for which the samples were collected, or (2) for a new 
research activity following submission and IRB approval of a new protocol and consent, 
or (3) for use only as unlinked or coded samples under the OHSRP Exemption Form 
guidelines stipulating that the activity is exempt from IRB review. Unused samples must 
be returned to the PDCMF laboratory.
x
Samples and associated data will be stored permanently unless the patient withdraws 
consent. If researchers have samples remaining once they have completed all studies 
associated with the protocol, they must be returned to the PDCMF laboratory.
x
These freezers are located onsite at the Preclinical Service laboratory (12C216) (-85° 
freezer) or in ETIB common equipment space (CRC/3-3273).


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Version Date: 05/18/2016
Protocol Completion/Sample Destruction 
x
Once research objectives for the protocol are achieved, researchers can request access to 
remaining samples, providing they have both approval of the Principal Investigator of the 
original protocol under which the samples or data were collected and either an IRB 
approved protocol and patient consent or the OHSRP Exemption Form stipulating that 
the activity is exempt from IRB review.
x
The PDCMF staff will report to the Principal Investigators any destroyed samples, if 
samples become unsalvageable because of environmental factors (ex. broken freezer or 
lack of dry ice in a shipping container), lost in transit between facilities or misplaced by a 
researcher. 
x
The PI will report destroyed samples to the IRB if samples become unsalvageable 
because of environmental factors (ex. broken freezer or lack of dry ice in a shipping 
container) or if a patient withdraws consent.  Samples will also be reported as lost if they 
are lost in transit between facilities or misplaced by a researcher.  Freezer problems, lost 
samples or other problems associated with samples will also be reported to the IRB, the 
NCI Clinical Director, and the office of the CCR, NCI.


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
9.8 Appendix H: Data Collection Elements Required By Protocol 
All of the following elements will be recorded in the C3D database.
A. Patient Enrollment 
Recipient
x
Date of birth, age, gender, race, ethnicity
x
Performance Status
x
Date of original diagnosis
x
Date of Informed Consent signature, consent version and date of registration
x
Baseline History/Physical
x
Baseline Symptoms 
Donor
x
Date of birth, age, gender, race, ethnicity
x
Height
x
Weight
x
Baseline History/Physical (Y/N)
B. Study Drug administration and response for each course of therapy given
x
Dates study drugs given
x
Dose level, actual dose, schedule and route given
x
Response assessment for each restaging performed
C. Laboratory and Diagnostic Test Data
x
All Clinical laboratory and diagnostic test results done at screening(recipient and 
donor) and until day 100 post transplant with the following exceptions:
x
Screening labs that are not automatically loaded for example (HIV, anti hep B and C). 
x
Diagnostic tests which are not specified in the protocol, and if the results are not 
needed to document the start or end of an adverse event that requires reporting (all 
CTs should be recorded).
x
All clinical laboratory and diagnostic tests done after day 100 that support a possible, 
probable or definite diagnosis of GVHD, infection or secondary malignancy and 
those done to document a change in grade and the end of these adverse events.
x
All tests done to document resolution of adverse events that occurred in the first 100 
days post transplant
x
HLA data (patient and donor).
x
Blood, bone marrow, and tumor chimerism data 
D. Adverse Events Recorded per section 5.1
E. Concomitant Measures
x
GVHD prophylaxis and treatment (start and stop dates)
x
All immunosuppressive  agents
F. Treatment of Persistent/Progressive Disease with Standard Therapy


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
x
Chemotherapy
x
Immunotherapy
x
Radiation therapy
x
Donor Lymphocyte Infusion
G. Response 
Restaging studies performed at protocol specified time points and as clinically indicated.
H. Off study
x
Date and reason for off study
x
Date and cause of death
x
Autopsy findings


Abbreviated Title: HSCT for GATA2 Mutation
Version Date: 05/18/2016
10 REFERENCES
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total-body, 
irradiation-based 
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and 
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Abbreviated Title: HSCT for GATA2 Mutation
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fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or 


Abbreviated Title: HSCT for GATA2 Mutation
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ICF_001.pdf: 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient 
 
 
INSTITUTE: 
National Cancer Institute 
 
 
STUDY NUMBER: 
09-C-0096 
PRINCIPAL INVESTIGATOR: Dennis D.  Hickstein, M.D. 
 
 
STUDY TITLE: 
Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem Cell Transplant 
for Patients with GATA2 Mutations 
 
 
Continuing Review Approval by the IRB on 06/30/15 
Amendment Approved by the IRB on 06/10/16 (T) 
 
 
Date Posted to Web: 06/11/16 
Recipient 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient 
 
NIH-2514-1 (7-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
 
INTRODUCTION 
 
We are asking you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional. 
 
If you are signing this consent for a minor child, “you” refers to “your child” throughout the 
consent document. 
 
Why is this study being done? 
We are conducting an experimental research study of allogeneic stem cell transplantation (SCT) 
from HLA-matched related or unrelated donors for patients with mutations in GATA2. This 
testing will be done in the laboratory of Dr. Steven Holland at the NIH, and you will be informed 
of the results and counseled as to the significance of the testing by Dr. Holland and his 
associates.  Another purpose of this study is to test if the treatment with allogeneic SCT is safe.    


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  2  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Why are you being asked to take part in this study? 
Because you have this disease (GATA2 deficiency), we are inviting you to participate in this 
research study, called: “Pilot and Feasibility Study of Reduced-Intensity Hematopoietic Stem 
Cell Transplant for Patients with GATA2 Mutations."  This research study is for patients with 
this newly described disease that has a relative donor, unrelated donor, or umbilical cord blood 
donor, identified through one of the bone marrow donor registries such as the National Marrow 
Donor Program. To be eligible to participate on this study you be 12-60 years of age and must 
match on 10 out of 10 or 5 out of 10 HLA markers with your potential related donor, match 
10/10 or 9/10 HLA markers with your potential unrelated donor, or match 4 out of /6 HLA 
markers with your umbilical cord blood donor. Human Leukocyte Antigen (HLA) are proteins 
(or markers), found on most cells in your body. Your immune system uses these markers to 
recognize which cells belong in your body and which do not.  The better the match between the 
donor’s HLA markers and your HLA markers, there may be less risk of some types of side 
effects.  This is explained in more detail below.  In this study, we will accept patients 12 to 60 
years of age, however, individuals that are 12-17 years of age must have myelodysplastic or pre-
leukemic changes to the bone marrow along with changes in the chromosomes of the bone 
marrow cells.  
 
How many people will take part in this study? 
Up to 15 patients and their donors will take part in this research study. 
 
Description of Research Study 
 “Stem cells” are immature blood cells, like seeds; they grow in the bone marrow and produce all 
of the cells needed for normal blood and immunity.  When these stem cells are taken from one 
person (called the “donor”) and given to another person (called the “recipient”), it is known as 
“allogeneic” stem cell transplantation.  Originally, stem cells were collected for transplantation 
by taking samples of bone marrow from the donor.  This was commonly called “bone marrow 
transplantation.”  Now, most allogeneic transplants use stem cells collected from the donor’s 
blood.  This is often called “peripheral blood stem cell transplantation.” 
 
Allogeneic stem cell transplantation (SCT) has been used successfully to treat, and sometimes 
cure, many kinds of immune diseases, cancer, or pre-cancerous conditions that develop in blood 
or immune system cells.  Large doses of chemotherapy drugs and/or radiation were traditionally 
used to eliminate most of the cancerous or abnormal cells from the recipient’s system, along with 
most of his or her own stem cells and immune cells.  Donor stem cells can then replace the 
recipient’s stem cells in the bone marrow, restoring the normal jobs of the bone marrow – 
growing blood cells and immune cells; this process is called “engraftment”.  In this way, an 
allogeneic SCT provides not only new blood cells but an entirely new immune system.  Immune 
cells from the donor are important not only to protect the transplant recipient from infections; 
these transplanted cells can sometimes destroy the abnormal cells that caused the patient’s 
disease.  This type of immune attack is called the “graft-versus-tumor” (GVT) effect, and it is 
thought to be the main reason that allogeneic SCT cures some patients of these conditions. 


 
  
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If the recipient’s immune system remains strong enough after large doses of chemotherapy or 
radiation, it may attack and destroy the donor’s cells after the transplant.  This is called “graft 
rejection.”  When this happens, the transplant recipient’s own stem cells may be so severely 
damaged after chemotherapy or radiation that they cannot produce blood cells, usually leading to 
death. Another serious complication can occur if donor immune cells recognize and attack the 
recipient’s normal tissues, damaging the liver, intestinal tract, and skin.  This type of immune 
attack is called “graft-versus-host disease”, or GVHD. 
 
Graft rejection or GVHD after allogeneic SCT are less likely when the transplant recipient and 
donor are very similar genetically.  To measure how genetically similar a recipient and donor 
are, both persons are tested to identify protein markers on the surface of their blood cells and 
other body tissues.  As described previously, these markers are called “human leukocyte 
antigens”, or HLA.  A person inherits half of his or her HLA markers from each parent.  Your 
immune system uses HLA proteins on your body’s cells to tell the difference between normal, 
healthy tissues and foreign organisms like bacteria or viruses.  Differences in HLA proteins 
between a donor and recipient make it more likely that one person’s immune system will 
recognize the other person’s cells as foreign, causing graft rejection or GVHD.  A donor and 
recipient who share all 10 of their HLA markers are called “HLA-identical”.  A transplant from 
an HLA-identical sibling (brother or sister) has a lower chance of graft rejection or GVHD, 
compared with other donors for allogeneic SCT.  Many people have diseases that could be 
treated with allogeneic SCT, but only 20-30% of people have HLA-identical sibling donors.  For 
some people without HLA-identical sibling donors, a partially matched related donor or a HLA-
matched unrelated donor can be used, but the risk of graft rejection and GVHD is higher. If a 
10/10 matched related donor, a 5/10 matched related donor, or a 10/10 matched unrelated donor 
cannot be identified, a 9/10 matched unrelated donor or a closely compatible umbilical cord 
blood donor may be used.  The risk of graft rejection using a 9/10-matched unrelated donor, a 
partially matched related donor or umbilical cord blood donors is higher. The risk of GVHD is 
higher with a 9/10 matched unrelated donor or a partially matched related donor, but the risk of 
GVHD is lower with umbilical cord blood when compared to a matched unrelated donor.  In this 
research study, we will use the best match to perform an allogeneic SCT to help treat your 
disease.   
 
Reduced-Intensity Allogeneic Stem Cell Transplantation (RIST) 
In the past, allogeneic SCT was done after giving very high doses of chemotherapy and/or 
radiation.  This intensive treatment was used to destroy as much of the recipient’s disease as 
possible, and it also helped to prevent graft rejection by weakening the recipient’s immune 
system.  However, such intensive chemotherapy or radiation can cause serious or even fatal side 
effects.  Because of these risks, only relatively young and healthy patients were considered for 
this form of treatment.  A newer method uses smaller, less toxic doses of chemotherapy and/or 
radiation before allogeneic SCT.  This method is often called “reduced-intensity”, or 
“nonmyeloablative”.  It was first studied in patients who could not receive high-intensity 
(“myeloablative”) allogeneic SCT because of their age or other medical conditions.  In reduced-
intensity stem cell transplants (RIST), the recipient’s stem cells and immunity are not completely 


 
  
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eliminated, but they are weakened enough to prevent the donor’s cells from being rejected.  In 
most studies of RIST, serious complications are less common than for myeloablative allogeneic 
SCT.  However, GVHD can still be a significant problem with RIST.  Also, graft rejection and 
relapses of disease have happened more often in some studies of RIST than with myeloablative 
transplants. These problems may have occurred because the lower doses of treatment in RIST 
can leave the recipient’s immune system strong enough to resist being replaced completely by 
the donor’s cells, and the disease may survive after reduced-intensity chemotherapy or radiation 
than after myeloablative treatment. 
 
We have been studying RIST to try to improve the results of allogeneic SCT for patients with 
hematologic (blood-related) cancers and pre-cancerous conditions.  In animal models we have 
used a low dose of radiation therapy before transplantation to help the donor cells to engraft.  
 
This experimental research study will use chemotherapy and low dose radiation therapy to 
decrease the chance of graft rejection after RIST from a matched related or unrelated donor and 
to try to decrease the overall side effects of the transplant.  
 
UPrevention of Graft-Versus-Host Disease 
A clearly superior combination of drugs to prevent GVHD regimen has not been established in 
patients who have received SCT from HLA-matched related or unrelated donors. Preliminary 
studies indicate that a drug called sirolimus is beneficial in matched related donors. The best 
results for matched unrelated donors that have been reported in the medical literature are with the 
combination of drugs called tacrolimus, methotrexate, and sirolimus.  In this study, we will use 
the combination of tacrolimus and sirolimus to try to prevent GVHD. Partially matched related 
donor recipients will also receive a Chemotherapy drug called cyclophosphamide post-
transplant. 
What will happen if you take part in this research study? 
 
Participation on this study will take place as follows (details are included in later sections): 
 
• First, we must establish proof of a genetic match (at least 10 out of 10 HLA genes for 
matched related donors; at least 9/10 HLA genes for matched unrelated donors; at least 5/10 
HLA genes for a partially matched related donor; at least a 4/6 match for umbilical cord 
blood units) between you and your potential related donor or unrelated donor. Approximately 
5-10 tablespoons of blood will be drawn, often this has already been performed at your home 
medical office, prior to a visit to the NIH, or it will be performed at the NIH Clinical Center. 
• If you are going to receive matched related donor stem cells, we will arrange for the 
collection of the stem cells from your donor.  Because pediatric donors will not be eligible to 
participate in this study, pediatric subjects will not receive their transplant from a pediatric 
sibling.  This may result in a small increase in the incidence of GVHD.   
• If you are going to receive matched unrelated donor stem cells, we will arrange to have your 
donor’s stem cells collected at a center in cooperation with the National Marrow Donor 
Program, and shipped to the NIH. 


 
  
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• If you are going to receive umbilical cord blood cells, we will arrange to have the umbilical 
cord blood donor stem cells shipped to the NIH. 
• Depending on the source of your donor cells, you will receive several doses of pre-transplant 
chemotherapy and radiation therapy.  This combination is called “conditioning regimen” and 
it is given to prepare you for the transplant. The various “conditioning regimens” are 
described below: 
o If you are going to receive umbilical cord blood cells, you will receive one infusion 
into your vein (IV) of a chemotherapy drug called cyclophosphamide 6 days before 
the transplant. You will receive infusions of another chemotherapy drug called 
Fludarabine on days -6, -5, -4, -3, and -2 before the transplant. 
o If you are receiving a matched related or unrelated donor cells, you will receive 
infusions through the vein of a chemotherapy drug named Fludarabine on days -4, -3, 
and -2 before transplant.  
o If you are receiving a partially matched related donor cells, you will receive infusions 
through the vein of a chemotherapy drug named Fludarabine on days -6, -5, -4, -3, 
and -2 before transplant.  You will also receive two infusions into your vein (IV) of a 
chemotherapy drug called cyclophosphamide on days -6 and -5 before the transplant. 
o All patients will receive a single dose of radiation therapy one day before the 
transplant. 
• One day later, you will receive the transplant with your donor stem cells. 
• Starting a few days before transplant, and continuing for 3 months after transplant, you will 
receive two drugs, tacrolimus and sirolimus, to help prevent GVHD.  
• Patients receiving a partially matched related donor transplant will also receive a 
chemotherapy called cyclophosphamide on day +3 and +4 following the transplant. 
• When your condition is stable, you will be discharged from the hospital and be seen 
frequently as an outpatient. 
• You will continue on medications to lower the risk of GVHD and infections. 
• You may receive additional donor immune cells, called a “donor lymphocyte infusion”, after 
the transplant to treat your disease. 
• You will visit the NCI clinic regularly for the first six months after the transplant, and then 
less often for at least five years. 
 
Pre-Transplant Evaluation 
Once it is determined that you have a potential donor, you will be seen at the NIH Clinical 
Center, at which time you will have a complete medical history and physical examination in the 
NCI Oncology Clinic.  Members of the transplant team will review your medical history and 
explain the transplant procedure.  A blood sample will also be used to check the health of your 
kidneys and liver.  We will also test for exposure to a variety of infections, including hepatitis B 
and C, T. Cruzi (Chagas agent), and a virus called cytomegalovirus (CMV).  As part of this 
study, we will test you for infection with the human immunodeficiency virus (HIV), the virus 
that causes AIDS.  If you are infected with HIV you will not be able to participate in this study.  
We will tell you what the results mean, how to find care, how to avoid infecting others, how we 
report HIV infection, and the importance of informing your partners at possible risk because of 


 
  
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your HIV infection.  You will also be tested for the viruses for hepatitis A, HTLV-1 and -2, 
adenovirus, Epstein-Barr virus, herpes simplex virus, and the parasite Toxoplasma.  If you are a 
woman, you will have a urine pregnancy test.  You will be asked to collect 24 hours of your 
urine to measure your kidney function.  In addition, you will have a special breathing test, a test 
for heart health, several X-ray studies, and/or an MRI. You may have a PPD skin test if you are 
considered high risk by the study doctor.  You may also have a bone marrow aspiration and 
biopsy.  This test is performed by numbing the hip bone with a local anesthetic called lidocaine.  
A small cut will be made in the skin, a needle is inserted into the hip bone, and about two 
tablespoons of liquid samples are removed from the bone marrow through the needle.  A small 
fragment of the bone marrow may also be removed with the needle.  You will also undergo a 
dental evaluation and meet with a social worker.  You will be encouraged to name someone as 
your “durable power of attorney”.  This should be someone whom you trust to make medical 
decisions for you if you become physically or mentally unable to make your own treatment 
decisions.  You should know that being in this study may keep you from being in other research 
studies that limit the number or types of treatments that you are allowed to have received 
previously. 
 
Birth Control 
If you are a woman of child-bearing potential, you will be placed on an oral contraceptive (birth 
control pill) when you enroll in this study and continue taking the pills until your blood counts 
recover after the transplant.  Men and women who are sexually active on this study must agree to 
use an effective form of contraception (examples include: intrauterine device (IUD), hormonal 
(birth control pills, injections, or implants), tubal ligation/hysterectomy, partner’s vasectomy, 
barrier methods (condom, diaphragm, or cervical cap), or abstinence while participating in this 
study and for 1 year after transplant.  If you think you or your partner is pregnant, you should tell 
your study doctor or nurse immediately. 
 
The Central Venous Catheter 
If you do not already have one before you enroll in this study, you will receive an intravenous 
(I.V.) line called a central venous catheter that can be used throughout your transplant procedure 
and follow-up treatment.  This kind of catheter is sometimes called a “Hickman catheter”.  It will 
be used to give you chemotherapy, DLI (if needed), transfusions (if needed), and other 
medications such as antibiotics.  It can also be used for drawing blood samples for tests.  Since 
blood will be drawn often during your treatment (about 4 to 10 teaspoons of blood, at least once 
daily during your hospitalization for transplantation and about 2 to 3 times per week at other 
times), the catheter will make it easier and less painful.  Most of the blood will be used to check 
on your health during and after your treatment.  Some blood will be drawn for research.  In 
general, 3 to 4 tablespoons of blood will be drawn for research on average of once per week. 
The maximum amount of blood taken from you is based on your age and will not be more than 
the strict blood volume limit set for research by the NIH.  In adults that limit is 37 tablespoons in 
an 8 week period.  If you are under age 18, we will not draw more than 2 teaspoons of blood for 
every kilogram (2.2 pounds) of your body weight in an 8 week period.  For example, if you 
weigh 85 pounds (weight of some 12 year olds), your weight in kilograms is about 38 kg; 


 
  
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therefore, we would not draw more than 76 teaspoons (or 25 tablespoons) of blood in an 8 week 
period. 
Your catheter will be placed in the upper part of your chest and tunneled under the skin into a 
neck vein.  If the catheter becomes infected or clogged, it can be replaced.  It will be flushed 
once daily to prevent clogging.  The nursing staff will teach you how to do this yourself. 
 
Transplantation of the Blood Stem Cells from Your Donor 
Matched related donor transplant 
If you are undergoing a matched related donor transplant, prior to transplant your related donor 
will have a medical examination by a physician in the Experimental Transplantation and 
Immunology Branch at the National Cancer Institute. This includes testing for evidence of 
infection with HIV, Hepatitis B, Hepatitis C, and possible infectious diseases that may be 
transmitted by stem cell donation.  The donor’s exam will also ensure that they remain available 
and are physically well enough to undergo the donation procedure. The donor’s medical 
clearance will be verified before you receive any pre-transplant chemotherapy or radiation 
therapy. 
 
Partially matched related donor (Haploidentical) transplant 
If you are undergoing a partially matched related donor transplant, prior to transplant your 
related donor will have a medical examination by a physician in the Experimental 
Transplantation and Immunology Branch at the National Cancer Institute. This includes testing 
for evidence of infection with HIV, Hepatitis B, Hepatitis C, and possible infectious diseases that 
may be transmitted by stem cell donation.  The donor’s exam will also ensure that they remain 
available and are physically well enough to undergo the donation procedure. The donor’s 
medical clearance will be verified before you receive any pre-transplant chemotherapy or 
radiation therapy. 
 
Matched unrelated donor transplant 
If you are undergoing a matched unrelated donor transplant because you do not have a matched 
related donor, before you begin the pre-transplant chemotherapy and radiation therapy, your 
unrelated donor will have a medical examination by a physician in the National Marrow Donor 
Program (NMDP) network that includes extensive testing for evidence of infection with HIV, 
Hepatitis B, Hepatitis C, and possible infectious diseases that may be transmitted by stem cell 
donation.  The donor’s exam will also ensure that they remain available and are physically well 
enough to undergo the donation procedure.  If you receive unrelated donor stem cells, the NMDP 
will notify NIH if there are any abnormalities that increase the risk of transmitting infectious 
diseases to you.  These findings will be discussed with you.  The donor’s medical clearance will 
be verified before you receive any chemotherapy. 
 
Unrelated donors are confidential, and the identity of the donor will be anonymous.  This means 
that you will not know who your donor is or where they are located.  You will know the age and 
gender of the donor and any history or medical exam findings that could possibly change the risk 
of your transplant.  Likewise, the donor will not know who you are or where you are located.  


 
  
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He/she will know your age, gender, and the type of disease that you have.  The donor will be 
given basic updates about your condition 30 days, 6 months, and 1 year after your transplant.  
The only information they will receive is whether or not the stem cells engrafted and if you have 
been discharged from the hospital.  The donor will also be notified in the event of your death.  
 
Depending on the policy of the particular donor center, you may be able to communicate without 
revealing your identities in an anonymous manner with your donor beginning at the time of your 
transplant.  In some cases, if both you and the donor agree, you may be able to learn who your 
donor is after one year.  There are some cases when a donor and patient may never communicate 
or meet.  Your transplant coordinator will tell you the details of if and how you may contact the 
donor once the donor has completed his or her medical exam. 
 
Your matched related or unrelated donor will receive daily injections of a medication that 
stimulates the stem cells to be released from the bone marrow and into the bloodstream.  The 
donor will have these cells removed through a process called apheresis.  To perform apheresis, 
the donor’s blood is removed through an intravenous catheter and circulated through a machine 
which separates the peripheral blood stem cells.  These cells are removed, and the rest of the 
blood is returned through the catheter.  This collection occurs at the NIH Clinical Center or at the 
NMDP apheresis center closest to the donor.  The cells are hand-carried by a trained courier to 
NIH.  Once they arrive at NIH, the cells will be given via I.V. through your central line within 24 
hours. 
 
Umbilical cord blood transplant 
If a matched related donor or matched unrelated donor cannot be identified, you may receive a 
partially matched umbilical cord blood transplant.   You will begin two pre-transplant 
chemotherapy drugs along with radiation therapy.  Umbilical cord blood units are collected and 
stored in a national cord blood registry.  The partially matched units of cord blood are sent to 
NIH prior to the transplant.  On the day of the transplant, the units are thawed and given to you 
via I.V. through your central line within a few hours of thawing. 
 
Rarely, your matched related donor or matched unrelated donor may become unavailable, or the 
donor apheresis center is unable to collect enough stem cells to perform the transplant.  If this 
happens, you will be removed from the study before transplantation unless we are able to 
identify another suitable unrelated donor or partially matched umbilical cord blood units.  
 
Transplant Procedure: 
You will be admitted approximately seven days before transplantation to the NCI’s Patient Care 
Unit at the NIH Clinical Center.  If you are receiving matched related or unrelated cells from a 
donor, you will receive 3 days of pre-transplant chemotherapy with Fludarabine and one day of 
radiation therapy.  If you are receiving umbilical cord blood cells, you will receive 5 days of pre-
transplant chemotherapy with Fludarabine, one day of pre-transplant chemotherapy with 
Cyclophosphamide, three days of horse antithymocyte globulin and one day of radiation therapy. 
If you are receiving a partially matched related donor transplant, you will receive 6 days of pre-
transplant chemotherapy with Fludarabine, two days of pre-transplant chemotherapy with 


 
  
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Cyclophosphamide, and one day of radiation therapy.  This is called the “conditioning regimen,” 
which will prepare your body to accept your donor’s stem cells because it lowers your immune 
system. One day after completing the radiation, you will receive the stem cell transplant.  Your 
donor’s stem cells will be given to you through an I.V. (central venous catheter).  This is referred 
to as “day 0”. 
 
While you are in the hospital for your transplant, you will be watched very closely for possible 
complications, which are described below.  You will receive standard supportive care such as 
antibiotics, growth factors (a drug called G-CSF), transfusions, and I.V. nutrition to prevent or 
treat any problems.  Blood will be drawn frequently during your treatment.  Most of the blood 
drawn will be to watch your health during and after the chemotherapy and transplant procedure.  
In addition, some blood samples will be drawn for research purposes.  These samples will be 
used to study how your immune system is affected by the transplant chemotherapy, the stem cell 
transplant itself, and graft-versus-host disease (if it occurs).  In general, 4 to 10 teaspoons of 
blood will be drawn an average of 2 to 3 times per week.  The average time in the hospital is 
three to four weeks, but it could be longer if there any complications. 
 
Beginning three days before you receive the stem cell transplant, you will receive the drugs 
tacrolimus and sirolimus to help prevent GVHD. Sirolimus is given by mouth one time a day 
between lunch and dinner for approximately six months after transplant. Tacrolimus is given 
either in your I.V. or by mouth (taken twice a day) for approximately six months after transplant.  
Partially matched related donor recipients will receive cyclophosphamide on days +3 and +4 
following transplant, as well as Sirolimus and tacrolimus starting 5 days after transplant. If you 
develop GVHD, you may be given additional medications to treat GVHD.  The study doctor will 
discuss these medications with you, if they become needed.  Before the transplant and continuing 
until day +100 after the transplant, you will also take a drug by mouth twice a day called ursodiol 
to help protect your liver.  After the transplant you may receive injections (shots) of a drug called 
G-CSF to raise your white blood cell count which will help your body fight infections.  The 
study team will show you or a family member how to give these shots at home. 
 
Once the stem cells have engrafted (become part of your body) and you are strong enough, you 
will be discharged from the hospital and followed closely as an outpatient.  The average hospital 
stay is three to four weeks, but this varies from person to person.  You will be required to remain 
in the Washington, D.C. area for approximately three months after transplantation to watch for 
complications.  You may require re-admission to the hospital if you have complications.  You 
will be seen frequently in the NCI clinic for the first six months after transplant, and then you 
will be seen less frequently for at least five years.  
 
After the transplant, if tests show that your blood and immune cells have not fully converted to 
your donor’s type (called “mixed chimerism”), then your sirolimus and/or tacrolimus dose will 
be lowered to help change your blood and immunity to help convert your blood and immune 
cells to that of your donor’s, this is called “full donor chimerism.”  Sometimes a donor 
lymphocyte infusion (DLI) may be given IV to reach a state of full donor chimerism. A DLI 
takes the immune cells collected from your donor and gives them to you to help convert your 


 
  
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blood and immune system to full donor chimerism. If your disease is still present after the 
transplant, tacrolimus or sirolimus may be reduced in an attempt to permit a stronger graft-
versus-tumor effect.  After this, if there are no signs of significant GVHD, then you may receive 
one or more DLI at increasing doses.  These DLI are intended to “boost” your new immune 
system and can enhance the graft-versus-tumor effect in some, but not all, patients.  DLI can 
sometimes lead to the development of GVHD, so we will watch you very closely for signs of 
GVHD after these infusions.  If you develop severe GVHD after a DLI, we will give you 
treatment for GVHD, but you will not receive any further DLI.  You may also be eligible to 
receive chemotherapy or other standard therapy after the transplant if your disease requires 
further treatment.  This therapy can be given alone or combined with DLI. 
 
Frequent Follow-up at the NCI in the First Year After Transplant 
If you are in good health after the three month post-transplant period, you will then be allowed to 
return home to the care of your primary physician.  You will be required to return to the NCI 
clinic monthly until approximately six months after transplantation to monitor for late transplant 
complications including GVHD and infection.  Thereafter you will be seen here every three 
months until two years after your transplant.  During some visits you will have bone marrow 
aspirates and biopsies, blood draws, and other appropriate tests to check your disease status.  
You will also have blood drawn for research to test how your immune system recovers after the 
transplant. 
 
Alternative Treatment 
There are options you may consider other than participating on this trial, including: 
• Continuing to receive medications for your current infections as they arise. 
• Instead of participating in a research study such as this, you may also be eligible to 
receive an allogeneic transplant with high dose chemotherapy and/or radiation to 
completely wipe out your bone marrow before donor cells are transplanted. 
• Taking part in another study 
• Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by your disease. It does not treat 
the disease directly, but instead tries to improve how you feel. Comfort care tries to keep 
you as active and comfortable as possible. 
• Another option is not to receive any further treatment at all.  
• You should discuss with your referring doctor and your doctors at the NCI whether or not 
any of these other treatments might be a reasonable choice for your disease. 
 
Risks or Discomforts of Participation 
Risk of Death from Allogeneic SCT:  Patients undergoing allogeneic SCT are at risk of dying 
from the transplant procedure and its possible complications.  There is about a 20 percent chance 
of death from complications of conventional allogeneic bone marrow transplants. Based upon 
our previous results, we hope that the risk of death related to the transplant will be less than 20% 
in this study.   The risk of death or other complications can vary greatly, depending on the age of 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  11  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
the patient, the way the transplant is performed, and other factors. Deterioration of pulmonary 
function is a risk of allogeneic stem cell transplantation, including transplants from umbilical 
cord blood donors. Because patients with GATA2 deficiency often have reduced lung function as 
part of their underlying disease, they may be at greater risk of this complication.  There is also 
the risk of complications that cannot be predicted. 
 
Bone Marrow Aspiration and Biopsy:  This procedure usually causes only mild pain for a short 
time at the biopsy site.  Very rarely, bleeding or an infection may occur at the biopsy site.  
 
Blood Draws:  Blood will be drawn frequently during your treatment.  Most of the blood draws 
will be to check your health during and after the chemotherapy and transplant procedure.  In 
addition, some blood samples will be drawn for research purposes.  These samples will be used 
to study how your immune system is affected by the transplant chemotherapy, the stem cell 
transplant itself, and GVHD (if it occurs). 
 
Central Venous Catheter:  Side effects of placing a central venous line in your chest wall include 
bleeding, bruising, blood clot, or pain in the area of insertion.  This line will be placed by 
physicians with experience in this procedure.   These physicians will discuss the above risks at 
the time of the line insertion.  Rarely, putting in a central venous catheter can result in a 
collapsed lung.  If a collapsed lung occurs, it may require hospitalization and putting a plastic 
tube in your chest temporarily to re-expand the lung. 
 
Reproductive Risks:  This treatment is likely to result in sterility (the inability to have children).  
However, we cannot predict for certain that you will become sterile during this treatment.  It is 
unknown what effects the pre-transplant chemotherapy, radiation therapy, and other drugs 
included in this treatment may have on an unborn child, but they would most likely be harmful.  
Women should not breastfeed a baby while participating in this study. 
 
Treatment with Fludarabine, Cyclophosphamide and Radiation therapy:  The drugs and radiation 
that you will receive on this protocol are likely to lower the number of white blood cells in your 
blood for many days.  This will increase your risk of infection.  If you develop an infection, it 
can be very serious and may result in death.  For this reason, if you develop a fever higher than 
101° F, you must see your doctor immediately.  If necessary, you will be treated with antibiotics.  
Also, these drugs and radiation are likely to cause your platelet count to fall.  This will increase 
your risk of bleeding.  If your platelet count becomes dangerously low, you will receive platelet 
transfusions.  These chemotherapies may also cause you to develop a low red blood cell count, 
called anemia.  Anemia can cause a lack of energy and other symptoms.  Transfusions of red 
blood cells are sometimes needed to treat anemia.  The following are known specific risks of 
each drug used within the specific regimen that you will receive: 
 
UFludarabine: 
Likely: 
Less likely: 
Rare: 
• low blood counts,  
• lowered level of 
• nausea and vomiting;  
• diarrhea,  
• GI bleeding,  
• lung damage,  


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  12  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
immune cells and 
increased risk of 
infection 
 
• fever,  
• mouth sores,  
• loss of appetite,  
• swelling (edema),  
• skin rash,  
• muscle aches,  
• headache,  
• agitation,  
• hearing loss,  
• fatigue,  
• weakness,  
• numbness / tingling 
(“pins and needles”) 
• kidney damage,  
• severe neurologic 
(brain and/or spinal 
cord) toxicity has 
occurred after very 
high doses including 
blindness, 
deterioration of 
mental status, and 
death. 
 
 
UCyclophosphamide: 
If you receive partially matched related donor cells or umbilical cord blood donor cells, you will 
also receive a drug called cyclophosphamide. The potential side-effects of cyclophosphamide are 
listed below: 
 
 
 
 
Likely: 
Less Likely: 
Rare: 
• low blood counts,  
• hair loss 
• nausea and vomiting,  
• painful and bloody 
urination,  
• sterility,  
• water retention 
• heart damage,  
• secondary leukemia 
(a different type of 
cancer),  
• skin rash 
• retention of too 
much water in the 
body 
• pulmonary fibrosis 
 
 
URadiation 
Radiation therapy can reduce your immune T cells and increase your risk of developing 
infection.  The radiation can also cause nausea, vomiting, diarrhea, loss of appetite, swelling, 
skin rashes, internal bleeding, headache, fatigue, nervous system toxicity, and lung injury.  
These side effects are uncommon at the dose of radiation used in this study. 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  13  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
UFilgrastim (called G-CSF):U  
Likely: 
Less likely: 
Rare: 
• bone pain,  
• reversible lab changes 
in your blood test 
results 
 
• headache;  
• pain at the needle site,  
• fevers,  
• tiredness 
• G-CSF can cause 
rupture of the 
spleen, which can 
cause death 
 
UUrsodeoxycholic acid, also known as ursodiol: 
Likely: 
Less likely: 
Rare: 
• nausea,  
• vomiting,  
• heartburn,  
• a metallic taste,  
• abdominal pain,  
• an inflamed 
gallbladder,  
• constipation,  
• mouth pain,  
• flatulence,  
• diarrhea,  
• itching,  
• rash,  
• dry skin,  
• hives,  
• headache,  
• fatigue,  
• anxiety,  
• depression, and  
• sleep disorders. 
• sweating,  
• thinning of hair,  
• back pain,  
• muscle and joint pains,  
• runny nose, and  
• cough. 
• None 
 
Graft-versus-Host Disease Prevention: 
 As described above, you will receive two drugs to 
prevent GVHD.  They are called:  tacrolimus and sirolimus.  
 
 
UTacrolimus:  
Likely: 
Less likely: 
Rare: 
• headache,  
• tremor,  
• changes in mental 
status,  
• increase in blood tests 
of liver function,  
• diabetes,  
• anemia,  
• Seizure 
• Coma 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  14  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
• high blood pressure,  
• abnormal kidney 
function,  
• constipation,  
• diarrhea,  
• abdominal pain and  
• difficulty sleeping 
(insomnia)  
• Mild to severe increase 
in a blood electrolyte 
called potassium, 
which will be carefully 
monitored, had been 
observed following 
tacrolimus 
administration.  
• an allergic reaction, 
and  
• sensitivity reaction to 
light.  
 
 
USirolimus:    
Likely: 
Less likely: 
Rare: 
• Because sirolimus is 
an immune 
suppression drug, it is 
likely that the risk for 
some infections may 
be increased. 
• very high levels of 
fats (triglycerides) 
and increase in 
cholesterol (increased 
lipid blood levels),  
 
• diarrhea,  
• nausea,  
• damage to the liver,  
• low blood counts,  
• mouth ulcers,  
• headache;  
• increased risk of 
infection,  
• red blood cell 
breakdown with 
abnormal kidney 
function. 
• severe swelling of the 
pancreas,  
• secondary cancers (a 
different type of 
cancer) 
 
UEquine ATG   
Likely: 
Less likely: 
Rare: 
• fevers and chills 
• allergic reactions 
• skin rash  
• aching in muscles 
• aching in joints 
• reactivation of viruses 
that have been 
dormant in the patient 
• serum sickness with 
skin rashes, itching, 
fever, aching the 
muscles and joints, 
chest pain, difficulty 
breathing, enlargement 
of lymph nodes  
• infection with viruses 
• bleeding 
• lung injury 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  15  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
prior to ATG 
 
• new cancers  
•  
 
Stem Cell Infusion:  The donor cells are frozen with a chemical called DMSO to protect them 
from the effects of freezing.  Patients receiving thawed cells often develop side effects from the 
DMSO.  DMSO side effects may include headache, upset stomach, fever and allergic reactions, 
such as skin rash, itching, difficulty breathing, and low blood pressure.  These reactions are 
usually mild and temporary, and they can be easily treated with IV fluids and medications.  
DSMO frequently causes a ‘garlic-like’ breath and body odor. 
Veno-Occlusive Disease (VOD): A severe liver complication known as VOD occurs in less than 
5 percent of allogeneic transplants.  VOD is a chemotherapy side effect that causes blood vessels 
in the liver to be blocked.  Severe VOD can lead to liver failure and death. 
 
Graft Rejection:  There is a chance that you may reject your donor’s stem cells.  If that were to 
happen, you would most likely recover your own blood cells.  However, there is the rare 
possibility that your own cells may not recover.  This may result in prolonged low blood counts, 
which may result in infection or bleeding and may lead to death.  In this event, we would attempt 
to support you with transfusions, growth factors and antibiotics until your own blood counts 
recover.  A blood test will be performed at 30, 60, 100 days and 6, 12, and 24 months after your 
transplant to find out if your body has accepted the donor cells.  If no donor cells can be found, 
then we will conclude that you rejected them.  In that case, your blood counts will probably 
return to the same levels as before the transplant in about 2 to 3 weeks.  You will receive a drug 
called G-CSF to help the cells engraft (help your body accept the donor cells).  In the event that 
your cells do not engraft, we may ask your donor to donate more cells. 
 
We have specifically added ATG for recipients of umbilical cord blood to prevent graft rejection. 
One patient who received an umbilical cord blood transplant without receiving ATG rejected the 
umbilical cord blood units and required a second transplant. 
 
Immune reactivation: In two cases we have observed an immune reactivation syndrome in which 
the new immune system from the transplant reacted with the residual recipient cells in the blood 
system and kidney resulting in both blood and kidney problems requiring treatment with high 
doses of steroids.  
 
Graft-Versus-Host Disease (GVHD):  You will be at risk for the development of GVHD for the 
rest of your life after transplantation.  GVHD occurring within the first 100 days after 
transplantation is referred to as acute GVHD.  Acute GVHD most commonly attacks the liver, 
intestines, and skin.  Symptoms of skin GVHD may be as mild as a rash with itching, or as 
severe as blistering and loss of the skin.  Symptoms of intestinal GVHD may be as mild as 
heartburn and mild diarrhea, or as severe as cramping abdominal pain and bloody diarrhea.  
Liver GVHD may be as mild as slight disturbances in liver function, or severe as yellowing of 
the skin with liver failure.  Mild acute GVHD (skin rash only) can be managed with topical 
steroid creams.  Severe acute GVHD can be lethal and needs to be treated aggressively.  


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  16  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Treatment of severe GVHD initially includes slowing down the immune system, usually with 
I.V. steroids/medications.  Slowing down the immune system increases the risk of infection. 
 
A delayed form of GVHD, known as chronic GVHD, may occur after day 100 post-transplant.  
Some degree of chronic GVHD affects about half of patients after transplantation.  It most 
commonly attacks the skin, the liver and the intestines, but it may also affect other organs such 
as the lungs, eyes, muscles, joints, and the bone marrow.  Symptoms of chronic GVHD may 
include dryness of the mouth and eyes, a loss of appetite, weakness, hair loss, weight loss, liver 
damage (including yellowing of the skin), and lung damage leading to shortness of breath and 
cough.  Patients with severe chronic GVHD are also at increased risk of infection and dying.  
Chronic GVHD is also treated with drugs that slow down the immune system such as steroids.  
This again increases the risk of infection. 
 
Because of the risk of infections, and the possibility of adverse effects such as return your own 
blood cells due to continuing immune suppression, both Sirolimus and Tacrolimus will be 
tapered starting 6 months post-transplant providing that there is no evidence of GVHD. The goal 
will be to completely stop both drugs by one year post-transplant. 
 
Late Transplant Complications:  There are other potential complications that can occur long after 
transplantation.  These complications could affect any organ in the body including the heart, 
lungs, kidneys, liver, muscles, and brain.  Rarely, patients who receive an allogeneic SCT are at 
risk for developing a type of cancer such as leukemia or lung cancer. 
 
Other complications are also possible following your transplant.  The most common 
complication is infections.  Because you will be receiving drugs (e.g. fludarabine and 
cyclophosphamide) that slow down the immune system, you are at greater risk to develop 
infections from uncommon organisms.  These infections can be life-threatening, and may cause 
death. Less common complications after transplant include organ damage in the heart, liver, 
kidney, lungs, and brain.   
Other Medications:  Patients will routinely receive several other drugs to prevent or treat various 
infections and other transplant-related complications.  These medications and their common side 
effects are listed as follows: 
 
• Diphenhydramine may cause tiredness, dizziness, upset stomach, disturbed coordination, 
dry mouth, flushing, or difficulty urinating. 
 
• Valacyclovir can cause nausea, vomiting, headache, dizziness, abdominal pain, bone 
pain, allergic reactions, mild liver inflammation, kidney injury, and abnormal nervous 
system function. 
 
• Fluconazole can cause nausea, vomiting, headache, skin rash, abdominal pain, and 
diarrhea.  Rare but sometimes serious liver toxicity has also been reported.  Fluconazole 
can increase the blood levels of other drugs, which can increase their effectiveness and/or 
their side effects. 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  17  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• Trimethoprim/sulfamethoxazole (Bactrim) may cause nausea, vomiting, loss of appetite, 
allergic skin rashes, and suppression of bone marrow function.  Rare but severe reactions 
may affect the skin and bone marrow; these have sometimes been fatal. 
 
Potential Benefits of Participation 
The allogeneic SCT may improve the chance that your disease will enter into a long remission 
and possibly be cured.  However, you should understand that this cannot be guaranteed.  In 
addition, your participation in this experimental study may contribute to understanding and 
developing new ways of using allogeneic SCT for the treatment of blood diseases.  Knowledge 
gained from this study may help others in the future who have this disease. 
 
Interim Results from First 10 Patients Enrolled in Study 
Ten patients have been enrolled on this study to date. In brief, three patients received a matched 
related donor hematopoietic stem cell transplant (HSCT), three patients received matched 
unrelated donor HSCT, and four patients received umbilical cord transplants:   
 
Patient # 1:  Received his peripheral blood stem cell (PBSC) transplant and is now more than 
two and a half years from transplant with a normal blood cell counts.  He had one episode of late 
GVHD and has chronic GVHD. 
 
Patient #2:  Received PBSC from an unrelated donor and is now two and a half years after 
transplant with normal blood cell counts. He is not taking any immunosuppressive medications. 
He has no GVHD.  
 
Patient #3:  Underwent a single umbilical cord hematopoietic stem cell transplant and is now 
two years post-transplant and living at home.  She is not taking any immunosuppressive 
medications. She has no GVHD.  
 
Patient #4:  Received a 10/10 matched unrelated donor transplant and is now one and a half 
years after transplant with normal blood cell counts. She takes immunosuppressive medication 
for GVHD. 
 
Patient #5:  Transplanted with a double umbilical cord blood units and is now one and a half 
years post-transplant. He does not require blood or platelet transfusions and has no GVHD.  
 
Patient #6:  Transplanted with a matched related donor is now 14 months post-transplant 
tapering off immunosuppression. She has no GVHD although she had recurrence of her pre-
transplant abnormal cytogenetics. 
 
Patient #7:  Transplanted with a double umbilical cord blood unit and died 5 days after 
transplant of massive infection. 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  18  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Patient #8:  Transplanted with a double umbilical cord blood and had graft rejection.  She was 
re-transplanted with her father's stem cells and subsequently died from a serious infection. 
 
Patient #9:  Transplanted with a matched related donor and is now 120 days post-transplant with 
no medical issues.  
 
Patient #10:  Transplanted with a matched unrelated donor and is now 10 days post-transplant 
with no medical issues. 
 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
 
In this case, you will be informed of the reason therapy is being stopped. 
 
Participation in this research study is voluntary.  You may stop your participation in the study at 
any time; however, if you decide to stop taking part in the study, we would like you to talk to the 
study doctor and your regular doctor first.  There are no penalties for withdrawing from the 
study.  However, if you withdraw after the transplant chemotherapy (“conditioning regimen”) 
without receiving the infusion of donor stem cells, you would be at high risk for serious 
complications, including death. 
 
You will be given a copy of the consent for your records.  We encourage you to ask our staff any 
questions that you have. 
 
You will be told about new findings that pertain to this research study.  If we are required to stop 
this study because of serious side effects, we will continue to provide care for you according to 
the study protocol. 
 
Research Subject’s Rights 
UWhat are the costs of taking part in this study? 
 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include surgery, 
transplant, medicines, laboratory testing, x-rays or scans done at the Clinical Center, 
National Institutes of Health (NIH), or arranged for you by the research team to be 
done outside the Clinical Center, NIH if the study related treatment is not available at 
the NIH.  


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  19  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
• 
There are limited funds available to cover the cost of some tests and procedures 
performed outside the Clinical Center, NIH.  You may have to pay for these costs 
even if they are not covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or paid for by 
the Clinical Center, NIH. 
Once you have completed taking part in the study, medical care will no longer be provided by 
the Clinical Center, NIH. 
 
 
Additional Therapies 
Treatments covered under this protocol that are standard therapies given for disease control may 
include a single medication or a combination of medications, surgery or radiation. The treatment 
to be used will be determined by your NIH doctors based on your diagnosis, the type and extent 
of your illness, your prior treatments, and your ability to tolerate additional treatment. These 
treatments will not be experimental. Your doctors will describe their treatment plan to you in 
detail including the name of the treatment(s), the schedule, the possible harmful effects, the 
potential benefit, and possible alternatives to you before having you sign this consent form. If 
surgery or radiation therapy is required to treat your illness, you may be asked to sign a separate 
consent form by the surgeon or radiation therapist. 
 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a Protocol Review Guide. You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
Use of Specimens and Data for Future Research: 
 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  20  of  22  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  21  of  22  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (7-09) 
 
P.A.: 09-25-0099 
 
 
 
 
File in Section 4:  Protocol Consent 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or 
at scientific meetings, the people who take part are not named and identified.  In most cases, the 
NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or other authorized hospital accreditation 
organizations.  
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term 
medical care for any injury resulting from your participation in research here.  In general, no 
long-term medical care or financial compensation for research-related injuries will be provided 
by the National Institutes of Health, the Clinical Center, or the Federal Government.  However, 
you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
 
4. Problems or Questions.  If you have any problems or questions about this study, or about 
your rights as a research participant, or about any research-related injury, contact the Principal 
Investigator, Dennis D. Hickstein, M.D., Building 10/Clinical Research Center, Room 3-3142; 
Telephone: (301) 594-1718; Blackberry: 301-795-8778.  Other researchers you may call are:  Dr. 
Mark Parta 240-409-4120. For questions about the use of your specimens, or data for future 
research studies, you may contact the Clinical Director, NCI at 301-496-4251.   
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
 
 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
09-C-0096 
CONTINUATION:  page  22  of  22  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (7-09) 
 
P.A.: 09-25-0099 
 
 
 
 
File in Section 4:  Protocol Consent 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have 
been given the opportunity to discuss it and to ask 
questions.  I hereby consent to take part in this study. 
I have read the explanation about this study and have 
been given the opportunity to discuss it and to ask 
questions.  I hereby give permission for my child to 
take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
 
 
 
 
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian 
Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 30, 2015 THROUGH JUNE 29, 2016.  
 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name