Clinical trial NCT00719888
Conditions: Acute Biphenotypic Leukemia Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Burkitt Lymphoma Chronic Lymphocytic Leukemia Chronic Myelogenous Leukemia, BCR-ABL1 Positive Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive Follicular Lymphoma Lymphoblastic Lymphoma Lymphoplasmacytic Lymphoma Mantle Cell Lymphoma Marginal Zone Lymphoma Myelodysplastic Syndrome Myelofibrosis Non-Hodgkin Lymphoma Plasma Cell Myeloma Prolymphocytic Leukemia Refractory Anemia Small Lymphocytic Lymphoma
Sponsor: Fred Hutchinson Cancer Center
Start date: 2005-11-18; Completion date: 2024-12-19
Enrollment: 135 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well giving an umbilical cord blood transplant together with cyclophosphamide, fludarabine, and total-body irradiation (TBI) works in treating patients with hematologic disease. Giving chemotherapy, such as cyclophosphamide and fludarabine, and TBI before a donor umbilical cord blood transplant helps stop the growth of cancer and abnormal cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after transplant may stop this from happening.

Detailed description:
OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I: Patients receive myeloablative conditioning comprising fludarabine intravenously (IV) over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 and -6, and undergo high-dose TBI twice daily (BID) on days -4 to -1. Patients then undergo single- or double-unit UCBT on day 0.

ARM II: Patients receive myeloablative conditioning comprising fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 2-4 hours on days -5 and -4, and middle-intensity TBI once daily (QD) on days -2 and -1. Patients then undergo single- or double-unit UCBT on day 0.

Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours, then cyclosporine orally (PO) (if tolerated), on days -3 to 100 with taper on day 101. Patients also receive mycophenolate mofetil IV every 8 hours on days 0 to 7 and then PO (if tolerated) three times daily (TID) on days 8-30. Mycophenolate mofetil is tapered to BID on day 30 or 7 days after engraftment if there is no acute GVHD, and then tapered over 2-3 weeks beginning on day 45 (or 15 days after engraftment if engraftment occurred \> day 30) after engraftment if there continues to be no evidence of acute GVHD.

After completion of study treatment, patients are followed up at 6 months, 1 year, and 2 years.

Arms: arm 1: Patients receive myeloablative conditioning comprising fludarabine IV over 30 minutes on days -8 to -6, cyclophosphamide IV on days -7 and -6, and undergo high-dose TBI BID on days -4 to -1. Patients then undergo single- or double-unit UCBT on day 0.

Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours, then cyclosporine PO (if tolerated), on days -3 to 100 with taper on day 101. Patients also receive mycophenolate mofetil IV every 8 hours on days 0 to 7 and then PO (if tolerated) TID on days 8-30. Mycophenolate mofetil is tapered to BID on day 30 or 7 days after engraftment if there is no acute GVHD, and then tapered over 2-3 weeks beginning on day 45 (or 15 days after engraftment if engraftment occurred \> day 30) after engraftment if there continues to be no evidence of acute GVHD. arm 2: Patients receive myeloablative conditioning comprising fludarabine IV over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 2-4 hours on days -5 and -4, and middle-intensity TBI QD on days -2 and -1. Patients then undergo single- or double-unit UCBT on day 0.

Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour every 8 or 12 hours, then cyclosporine PO (if tolerated), on days -3 to 100 with taper on day 101. Patients also receive mycophenolate mofetil IV every 8 hours on days 0 to 7 and then PO (if tolerated) TID on days 8-30. Mycophenolate mofetil is tapered to BID on day 30 or 7 days after engraftment if there is no acute GVHD, and then tapered over 2-3 weeks beginning on day 45 (or 15 days after engraftment if engraftment occurred \> day 30) after engraftment if there continues to be no evidence of acute GVHD.
Interventions: intervention 1: Cyclophosphamide intervention 2: Cyclosporine intervention 3: Double-Unit Umbilical Cord Blood Transplantation intervention 4: Fludarabine intervention 5: Laboratory Biomarker Analysis intervention 6: Mycophenolate Mofetil intervention 7: Total-Body Irradiation intervention 8: Umbilical Cord Blood Transplantation intervention 9: Thiotepa
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV and PO intervention 3: Undergo double-unit UCBT intervention 4: Given IV intervention 5: Correlative studies intervention 6: Given IV and PO intervention 7: Undergo high-dose or moderate-intensity TBI intervention 8: Undergo UCBT intervention 9: Given IV

Protocol documents:
ICF_002.pdf: 
FHCRC 2010.00 Regimen B
Page 1 of 14
FRED HUTCHINSON CANCER RESEARCH CENTER
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE
SEATTLE CHILDREN’S 
Consent to Participate in:
Transplantation of Umbilical Cord Blood for Patients with Hematological Diseases 
with Cyclophosphamide/Fludarabine/Total Body Irradiation or 
Cyclophosphamide/Fludarabine/Thiotepa/Total Body Irradiation Myeloablative 
Preparative Regimen (Protocol 2010)
Consent Form for Regimen B: Middle Intensity Regimen 
(Cyclophosphamide/Fludarabine/Thiotepa/Total Body Irradiation)
NOTE:  If you are a parent or guardian of a patient younger than 18 years old and have 
been asked to sign this form, the “you” in this document refers to the patient.
Principal Investigator:  Ann Dahlberg, MD, Assistant Member, FHCRC, Assistant 
                                        Professor of Pediatrics, UW, 206-667-1959
Research Staff:  Jenna Pedersen, Clinical Research Coordinator, 206-667-6013
Emergency (24 hour) Phone (For Adults):  (206) 598-8902; Fax: (206) 598-4034 
Emergency (24 hour) Phone (For Children):  (206) 987-2032; Fax (206) 987-2764  
We would like you to join this research study.
To help you decide if you want to join this study, you should:

Read this form.

Ask your doctor or nurse questions about this study.

Have your doctor or nurse explain anything you do not understand.

Talk with your family or friends about joining.

Take time to think about joining.
After you have learned about this study, met with your doctor and asked questions, you can 
decide if you want to join this study or not. This process is called informed consent.
This informed consent form gives information to help you decide if you want to join this study 
or not. In this form, we explain why we are doing this study, the risks and benefits to you, your 
choices, and other important information. Your doctor will explain the research study to you.
If you decide to join this study, we will ask you to sign this form. After you sign the form, you will 
get a copy to keep.
The purpose of a research study is to answer questions.
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Research is not the same as treatment or medical care. The purpose of a research study is to 
answer scientific questions. 
We are inviting you to join this study because you are eligible for a cord blood transplant. The 
purpose of this study is to examine how patients respond to a cord blood transplant after doses 
of chemotherapy and radiation by collecting data throughout the transplant process, specifically 
looking to see if the disease is absent or present at six months, one year, and two-years post-
transplant. Information we learn from larger numbers of patients will allow us to make more 
accurate estimates about these outcomes.  
You do not have to be in this study.
Joining this study is up to you. You are free to say yes or no. Your regular medical care will not 
change. Even if you join this study, you do not have to stay in it. You may stop at any time. 
There is no penalty for stopping, and your regular medical care will not change. 
Background 
Blood stem cells are the “parent cells” of the blood and bone marrow. They grow inside your 
bone marrow, which is your body’s “factory” to make the cells that circulate in your blood.  
These include: red blood cells (which carry oxygen), white blood cells (which fight infection), and 
platelets (which prevent bleeding). Certain cancers can be treated by giving patients stem cells 
that come from someone else. This is called a stem cell transplant. As part of the transplant 
process, patients receive doses of chemotherapy and radiation to treat their underlying disease, 
such as cancer. As one of its effects, this treatment also kills the healthy blood stem cells that 
are already in the bone marrow and giving a patient blood stem cells from a healthy donor leads 
to recovery of the bone marrow and provides a new blood system that makes the cells that 
circulate in the blood. In the case of this study these new blood stem cells will come from 
umbilical cord blood. 
Cord blood transplants are relatively new, and we’re striving to make them even more safe and 
effective in the future. We do most transplants as part of a study; which means that we follow a 
detailed protocol to make sure it’s always done the same way and we keep careful records so 
that we can evaluate the outcomes. Therefore, we would like to transplant you on this research 
study and collect information about the outcome of your transplant. Analysis of the outcomes of 
these transplants will help us improve transplant outcomes in the future.    
How many people will take part in the study?
Approximately 135 patients will be enrolled in this study.
What research tests, procedures, and treatments are parts of this 
study?
This research program involves the use of the following drugs, treatment programs, or research 
procedures:
Cyclophosphamide
Fludarabine
Thiotepa
Total Body Irradiation
Cyclosporine A
Mycophenolate mofetil
GCSF
Cord Blood Stem Cells
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Conditioning (pre-transplant chemotherapy and radiation)
You will be receiving the Middle Intensity Regimen. The conditioning regimen is standard 
treatment and is not experimental. It will involve the following: 

Six days before the transplant, you will be admitted to the hospital on the bone marrow 
transplant unit. You will also need a central venous catheter for transplant, so if you do 
not already have one, one will be placed.

Chemotherapy (fludarabine and thiotepa and cyclophosphamide) and TBI are given with 
the intent of helping to kill cancer cells and to prepare your body for the cord blood stem 
cells by suppressing your immune system. These procedures are described in a table 
below. 
Middle Intensity Regimen
(TBI total 400 cGy (200 cGy/day x 2 days, -2 to -1))
Day
Conditioning
Supportive 
Care/Other
6 days prior to 
transplant
Fludarabine
Cyclophosphamide
5 days prior to 
transplant
Fludarabine
Thiotepa
4 days prior to 
transplant
Fludarabine
Thiotepa
3 days prior to 
transplant
Fludarabine and begin CSA (100+ days)
2 days prior to 
transplant
Fludarabine
TBI once daily 
1 days prior to 
transplant
TBI once daily
0 (TRANSPLANT 
DAY)
Unmanipulated cord blood unit(s)
Begin MMF  
1 day after transplant
Begin GCSF (daily 
until recovery of 
white blood cell 
count)
Transplant Day 
On Day 0, the transplant day, the cord blood stem cells are given intravenously through the 
central venous catheter. 
Immunosuppression Therapy
As part of the transplant procedure, you will be given two drugs to reduce the risk of graft versus 
host disease, a complication that occurs when the cord blood stem cells recognize the patient's 
body as foreign and attack it. These drugs will be started three days before the cord blood stem 
cells are given. Both drugs will initially be given through your central venous catheter and then 
changed to a pill form when you can take a capsule orally as tolerated. The first drug is called 
Cyclosporine A. Cyclosporine will be continued for at least 100 days and most probably until 
Day 180 after transplant. The second drug is called Mycophenolate Mofetil (MMF). MMF will 
continue for at least 30 days.  
Follow-up
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To speed the recovery of blood cells as much as possible, you will receive granulocyte-colony-
stimulating factor (GCSF or Neupogen). GCSF signals the bone marrow to make white blood 
cells, which are needed to fight and prevent infections. You will start receiving GCSF through 
your central line or as an injection under the skin the day after transplant. You will continue to 
receive it daily until your white blood cell count recovers.  
In order to evaluate how your new marrow is developing, you will have blood drawn and/or bone 
marrow biopsies at specific time points. You are planned to have blood drawn at Day 28, Day 
56, Day 80, 6 months, 1 year and 2 years after your transplant.  
You will be discharged from the inpatient bone marrow transplant unit when you are ready to be 
cared for as an outpatient. Initially, it will be necessary for you to have frequent visits at the 
outpatient transplant clinic, and then at specific times as determined by your physician.  
You will be followed in the study for 2 years. After you have recovered from any immediate 
transplant related complications, follow-up will be routine and according to your specific disease 
type, but we will continue to collect data on how your marrow is functioning at these follow-up 
visits.
As part of follow-up, we would like to contact you and/or your referring physician around 6 
months, 1 year, and 2 years after transplant to see how you are doing. We may contact your 
physician to request copies of blood test results and other tests and procedures done as 
standard post-transplant follow-up. This will help us learn about the long-term effects of the 
study.
How long will I be in the study?
You will be followed in the study for 2 years. Even after you are discharged from the transplant 
center, we will work with your health care provider to gather information about your general 
health status and transplant-related problems for up to 2 years.
As part of follow up, we would like to call you on the telephone around 6 months and two years 
after transplant to see how you are doing. Keeping in touch with you and checking on your 
condition at these times helps us look at the long-term effects of the study. 
The researcher may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped.
You can decide to stop at any time. It is important to tell the study doctor if you are thinking 
about stopping so any risks from the treatment can be evaluated by your doctor. Another reason 
is to discuss what follow-up care and testing could be most helpful for you. 
What side effects or risks can I expect from being in the study?
The side effects associated with transplantation can be uncomfortable, and in some cases, 
dangerous, life threatening, or fatal. Because this is a research study and the treatments are 
relatively new, there may be additional side effects which are not known or predictable at this 
time. The known or possible side effects of the treatments you will receive as part of this study 
are listed below.
Risks Associated with Conditioning, Immunosuppression and 
Supportive Therapies 
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1. 
Cyclophosphamide (Cytoxan): 
Likely Side Effects 
Less Likely Side Effects 
Rare Side Effects 

Lower white blood cell count with 
increased risk of infection

Diarrhea (loose stools)

Vomiting (throwing up)

Liver damage

Lower sperm production in men

Hair loss

Nausea (feeling sick to your 
stomach)

Loss of appetite

Missing or stopping menstrual 
cycle in women

Sores in mouth or on lips

Blood in urine

Fatigue

Lower platelet count (mild) 
with increased risk of 
bleeding, especially with an 
injury like falling

Darkening of nail beds

Fetal damage if pregnancy 
occurs while taking 
Cyclophosphamide

Lung fibrosis with 
cough and 
shortness of breath

Heart failure with 
high doses

Decrease in 
sodium level in the 
blood with high 
doses

Secondary cancers
Cyclophosphamide can cause bleeding in your bladder. Getting more fluid through a 
vein or your catheter and drinking extra liquids may prevent this. 
2.
Fludarabine: 
Likely Side Effects 
Less Likely Side Effects 
Rare Side Effects 

Low white blood cell count with 
an increased risk of infection 
(from bacteria, fungi or viruses)

Lower platelet count with and 
increased risk of bleeding

Anemia

Nausea (feeling sick to your 
stomach)

Diarrhea (loose stools)

Fatigue

Vomiting 
(throwing-up)

Trouble seeing or 
problems with your 
eyes

Numbness or 
tingling in your 
fingers or toes

Severe problems 
with your brain 
(confusion or 
coma)

Pneumonia
3. 
Mycophenolate Mofetil (MMF): 
Likely Side Effects 
Less Likely Side Effects 
Rare Side Effects 

Nausea (feeling sick to 
stomach)

Miscarriage or birth 
defects if become 
pregnant while taking 
and within 6 weeks 
after stopping MMF

Vomiting (throwing up) 

Diarrhea (loose stools) and 
abdominal discomfort

Lower red blood cell count 
that is reversible

Lower white blood cell count 
with increased risk of infection

Stomach and bowel 
bleeding (blood in stools)

Secondary cancers

Progressive multifocal 
leukoencephalopathy (a 
serious brain infection that 
can cause weakness, 
clumsiness and confusion 
and can lead to death)
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 4. 
Cyclosporine:
5. 
Thiotepa
Likely (Over 10%)
Less Likely (1-
10%)
Rare (Less than 1%)

Low white blood cell count with 
an increased risk of infection 
(from bacteria, fungi or 
viruses)

Low platelet count with 
increased risk of bleeding

Anemia

Nausea/vomiting 

Diarrhea 

Anorexia (loss of appetite)

Mouth ulcers 

Sores in mouth or on lips 

Missing or stopping of 
menstrual periods in women

Skin rash

Change in skin 
coloring

Fatigue, 
weakness

Dizziness

Headache

Permanent 
sterility 
(inability to 
have children)

Allergic reactions during 
infusion (fever, chills, 
itching, hives, flushing, 
rash, shortness of 
breath, wheezing, chest 
tightness, muscle 
stiffening) 

Confusion

Seizures

Liver damage

Secondary cancers 
Likely Side Effects 
Less Likely Side Effects 
Rare Side Effects 

Nausea (feeling sick to your 
stomach)

Vomiting (throwing up)

Loss of magnesium, calcium, 
potassium

Hypertension (high blood 
pressure)

Tremor (shaking of the 
hands) 

Increased hair growth

Pain in the hands and/or 
feet. The pain decreases or 
goes away with the 
improvement of graft-
versus-host disease 
(GVHD), with a decrease in 
the rate of infusion, or 
when the cyclosporine is 
switched from the 
intravenous (by vein) to the 
oral form.

Blood test results that show 
changes in the liver or 
kidney (the dose will be 
lowered or even stopped).

Increases in cholesterol and 
triglyceride

Changes in how clearly one 
can think

Patients have had 
seizures, but it is 
unclear whether 
cyclosporine, 
other drugs, or a 
combination of 
drugs were 
responsible.

Secondary 
cancers
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6. 
Total body irradiation (TBI): 
Likely Side Effects 
Less Likely Side Effects 

Nausea (feeling sick to 
stomach)

Fatigue (feeling tired)

The irradiation dose used will 
probably result in sterility

Temporary hair loss   

Vomiting (throwing up) 

Diarrhea (loose stools)

Painful swelling of the parotid gland (a gland under 
the chin) for a few days  

Cataracts (an opacity or whitening of the lens) may 
develop in the eye

Secondary cancers
You will also have tests such as CT scans and chest x-rays, based on medical necessity 
and to help follow your progress. These studies are routine care after a transplant and 
expose you to more radiation, but the amount of radiation from these tests are small in 
comparison to the therapy dose and are not expected to increase your health risk.
Total body irradiation (TBI) destroys both the abnormal and normal marrow, resulting in 
a loss of red blood cells, white blood cells, and platelets. The temporary absence of 
these blood cells produces a risk of anemia, infection, and/or bleeding. This continues 
until the bone marrow transplant begins to work. Blood transfusions are given as 
needed.  
7.  
Granulocyte Colony Stimulating Factor (GCSF):
Problems we anticipate to be 
common:
Problems we anticipate to be 
less common:
Problems we anticipate to be 
infrequently encountered:

Ache or pain inside the 
bones, increased levels of 
liver enzymes and uric 
acid in the blood, low 
number of platelets in the 
blood

Allergic reaction, low fever

Enlargement of the spleen 
and even splenic rupture 

Worsening of pre-existing 
skin rashes, 

Hair loss 

Inflammation of a blood 
vessel in the skin
The above tables list the side effects of the drugs individually; however, when used in 
combination (as they will be here for pre-transplant chemotherapy/radiation), there may 
be an increase in the occurrence of some side effects. For example, sores in the mouth 
(mucositis) are likely with this combination (cyclophosphamide, fludarabine and TBI) and 
may be severe.
8.  
Late Complications:

Sterility 

Hypothyroidism

Possible increased incidence of radiation or chemotherapy-induced cancer, or 
leukemia [rare]

Possible brain injury [rare]
You will be watched for these side effects and treated as they occur. Follow-up care in the 
hospital and later in the outpatient clinics will be necessary to observe your recovery and 
monitor for any possible late side effects of your transplant.
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Risks Associated with Cord Blood Transplantation
The following problems may occur as a result of the transplantation of umbilical cord blood.  
These are risks that would be present whether such a transplant was done as part of a research 
study or not.
1.
Infusion Side Effects (occurring from time of infusion to 2 days after): Cord blood 
cells are stored in a solution containing dimethyl sulfoxide (DMSO) to protect the cells 
during freezing. The following side effects may occur with infusion:
Likely (Over 10% of patients )
Rare Side Effects (Less than 1%)

Unusual taste in the mouth

Unpleasant odor from the lungs 
(and breath) for a few days after 
getting the stem cells

Temporary rise in blood pressure

Nausea, vomiting

Blood in urine

Anxiety

Itching

Hives

Rash

Shortness of breath

Wheezing, chest tightness

Drop in oxygen levels

Changes in heart rate, rhythm or function

Fever

Chills

Sweating

Headache

Stiff muscles

Kidney failure
2.
Slow bone marrow recovery:  Blood counts, including red blood cells, white blood 
cells, and platelets, may be very slow to recover after unrelated donor umbilical cord 
blood transplantation. Until the new cord blood stem cells begin to grow, you are at risk 
of developing infections or bleeding.  Infections can be treated with antibiotics but 
sometimes can be very serious. Bleeding can be corrected, at least in part, by 
transfusions. However, there are risks associated with the transfusion of red blood cells 
and platelets during the post-transplantation period. These risks include serious allergic 
reactions and infections, including hepatitis, cytomegalovirus (CMV), and human 
immunodeficiency virus (HIV; the virus that causes AIDS). All blood products, however, 
will be screened for these infections in order to reduce the chance that the blood 
contains these viruses.
3.
Graft failure:  The cord blood stem cells may fail to “take” or engraft. Past experience 
suggests that this may occur in about 10% of patients overall. It is possible that the cord 
blood stem cells will grow, but not work normally.  This will result in low blood counts for 
a long period of time. Graft failure is typically fatal in traditional transplants and may be 
fatal in this type of transplant also. Should the graft fail, you will not have access to 
additional stem cells from the same infant donor; instead, you may be able to receive a 
second transplant with stem cells from another unrelated umbilical cord blood donor or a 
mismatched parent or sibling (i.e., brother or sister) donor.
4.
Graft versus host disease (GVHD): This condition results from a reaction of the 
transplanted umbilical cord blood cells against your body and organs. This reaction 
ranges from a mild skin disorder to severe involvement of the skin, liver or gut. It may be 
fatal in some patients. You will be monitored closely for this complication and given 
specific treatment to prevent and treat it. There are 2 forms: acute (early) and chronic 
(late) GVHD. 
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Acute GVHD may produce skin rashes, liver disease, diarrhea, and an increased risk of 
infection. All of these can range in severity from mild to fatal. To confirm the diagnosis of 
acute GVHD, you may be asked to have a skin biopsy (i.e., taking a piece of tissue to 
make the diagnosis of GVHD) and possibly a liver or gut biopsy. The treatment of acute 
GVHD may require you to take high doses of methylprednisolone or prednisone and, in 
some cases, other drugs such as anti-thymocyte globulin (ATG).
Chronic GVHD may produce skin rashes, hair loss, thickened skin, dry eyes, dry mouth, 
liver disease, diarrhea and an increased risk of infection. Chronic GVHD may be mild 
and respond to agents that suppress the immune system, or it could be very severe; it 
may also last for several years.
5.
Genetic Disease Transmission:   It is very rare, but there is the potential that genetic 
diseases (such as thalassemia or Gaucher’s disease) may be passed to you through the 
transplanted cord blood stem cells. Each umbilical cord blood unit can only be tested for 
a few of the many possible genetic diseases.  We will do our best to obtain screening 
results from the cord blood banks for diseases like thalassemia and sickle cell anemia, 
but they may not always be available. The family of each umbilical cord blood donor is 
asked about the development of medical problems or known genetic diseases within the 
family to further reduce the possibility of genetic disease transmission (i.e., passage of a 
disease to you from the cord blood stem cells).
6.
Incorrect Labeling of the UCB:  Though rare, it is possible that incorrect labeling of an 
umbilical cord blood unit could occur so that you receive the wrong unit. To avoid this, 
the umbilical cord blood unit is re-typed to confirm that the tissue type of the donor is as 
previously reported when the cord blood unit was first identified. Every cord blood unit 
will undergo confirmatory tissue typing either here or at an outside lab. Every effort will 
be made to perform the confirmatory typing in our lab, but this may not be possible if the 
umbilical cord unit does not have an attached sample to use. If this is the case, there are 
several ways the unit labeling can be confirmed. 
7.
Other Complications: Other complications that can result from the transplantation 
procedure not specifically related to one specific drug or the cord blood stem cells or this 
study include:
A.
Damage to the vital organs in your body: This could result in malfunction of 
any organ in your body such as heart, lungs, liver, gut, kidneys and bladder, 
brain etc. The lungs and the liver are the most vulnerable. Some patients will 
experience severe lung problems due to infections and/or due to a reaction of the 
lungs to the chemotherapy and/or radiation. Some patients can suffer veno-
occlusive disease of the liver (VOD) also due to the chemotherapy and/or 
radiation. Patients who have VOD become jaundiced (yellowish skin), have liver 
function abnormalities, abdominal swelling, and abdominal pain. Although many 
patients recover completely, these complications may result in organ failure and 
permanent damage or even death.
B.
Serious infections:  Full and complete recovery of your immune system may 
take many months following the initial recovery of your white cell count. During 
this time, there is an increased risk of viral, fungal or bacterial infections. You will 
be prescribed certain medications to reduce the chance of those infections.  
However, preventive treatments are not always effective. If you have one of 
those infections you may have to stay in the hospital longer or be re-hospitalized 
after transplant. Infections can be fatal. The data collected from several 
transplant centers indicate that patients who have been exposed to a virus called 
cytomegalovirus (“CMV”) prior to their cord blood transplant are at high risk of 
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reactivating this virus after the transplant. CMV is a very common virus, similar to 
the chickenpox virus, that about 50 to 80% of people have been exposed to at 
some time in their life. In healthy people, the virus remains inactive and does not 
cause any harm. However, it often becomes reactivated in people with a 
weakened immune system, and it can cause serious disease in the lungs, 
digestive tract and other organs. Because we are concerned that cord blood 
transplant patients are at higher risk for reactivation of CMV,  all cord blood 
transplant patients will be monitored very closely with a special blood test that 
can detect very early reactivation of CMV. If positive, you will be given 
appropriate treatments to control the virus. This treatment can last for a long 
period of time in some patients.
C.
Recurrence of disease:  Your disease may recur even if the transplant is initially 
successful.  
D.
Risk to the unborn: The treatments in this study have NOT been proven to be 
safe at any stage of pregnancy. Some are known to cause a miscarriage and 
birth defects if a woman becomes pregnant while being treated and for some 
time after stopping the treatment. Therefore, if you are pregnant, intend to 
become pregnant, or are nursing, you are not eligible for this study. Women who 
have the potential of becoming pregnant must use a combination of two forms of 
effective birth control. Effective birth control would be defined as the following: 1) 
refraining from all acts of vaginal intercourse (ABSTINENCE); 2) consistent use 
of birth control pills; 3) injectable birth control methods (Depo-Provera, Norplant); 
4) tubal sterilization or male partner who has undergone a vasectomy; 5) 
placement of an IUD (intrauterine device); and, 6) use, with every act of 
intercourse, of a diaphragm with contraceptive jelly and/or condoms with 
contraceptive foam.
E.
Sterility and future childbearing potential for men and women: 
Chemotherapy and/or radiation may affect fertility. Male patients may become 
sterile (unable to produce sperm). Female patients may find that their menstrual 
cycle becomes irregular or stops permanently. However, this DOES NOT MEAN 
THAT YOU CANNOT BECOME PREGNANT, and you must use some effective 
method of birth control. Damage to reproductive tissue may result in birth defects 
or permanent inability to father a child or become pregnant. You should discuss 
these risks and options in detail with your doctor before entering this study.
F.
Central venous catheter: There has been considerable experience with central 
venous catheter use. The most common complications are clotting and local 
infection which sometimes leads to a generalized infection in the blood. Clotting 
may require the catheter to be removed or treatment with a fibrinolytic agent 
(medicines that dissolve blood clots). Infections will be treated with antibiotics, 
and sometimes, removal of the catheter is required. Occasionally, skin redness 
at the catheter exit site occurs, this may require antibiotic treatment. There is also 
a small risk of puncturing the lung at the time of the catheter insertion. If this 
occurs, placement of a temporary chest tube to re-inflate the lung may be 
required. There are no long-term effects once the lung puncture has resolved.
Are there Benefits to Taking Part in the Study?
There may be no direct benefit to participation in this study, although we hope that this 
treatment may control and possibly even cure your cancer with reduced side effects.    
Alternative Treatments:
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Ongoing conventional chemotherapy may be considered as an alternative to transplantation in 
treatment of your cancer or bone marrow problem. No further treatment, or comfort care only 
are also possible alternatives.
Protecting your privacy
Some people may see and/or copy your medical records. They would do this as part of their 
research, to make sure this study is being done correctly and safely, or to evaluate the results. 
These people include the following individuals and organizations:

Fred Hutchinson Cancer Research Center (FHCRC)

University of Washington (UW) 

Seattle Children’s 

Seattle Cancer Care Alliance (SCCA)

National Institutes of Health (NIH)

U.S. Office for Human Research Protections (OHRP)

Center for International Blood and Marrow Transplant Research (CIBMTR)

U.S. Food and Drug Administration (FDA)

Cord Blood Bank (that provided the units for your transplant)

Institutional Review Boards (IRB)
    Nohla Therapeutics and their agents. Nohla is a company that is 
      collaborating with FHCRC on this study
These people are interested in study data, not your personal information. Personal information 
is information that can identify you. It may include your name, date of birth, social security 
number, phone number, or other information.
Study records will be maintained indefinitely for the purpose of analysis and follow-up. We will 
do our best to keep the personal information in your medical record confidential. But we cannot 
guarantee total confidentiality. Your personal information may be given out if required by law.  
We will not use your personal information in any reports about this study, such as journal 
articles or presentations at scientific meetings.
Information about your participation in this study (including a copy of this consent form) will be 
made part of your permanent medical record. If you authorize others to see your medical record, 
they will see a copy of this consent form.
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.
This research is covered by a Certificate of Confidentiality from the U.S. government. This 
Certificate helps protect the confidentiality of information about people who join the study. If you 
join the study, the Certificate means that generally we would not have to give out identifying 
information about you even if we were asked to by a court of law. We would use the Certificate 
to resist any demands for identifying information.
We could not use the Certificate to withhold research information if you give written consent to 
give it to an insurer, employer, or other person. 
This protection has some limits. We would voluntarily provide the information:
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 To a member of the federal government who needs it in order to audit or evaluate the 
research. 
 To the funding agency and groups involved in the research, if they need the information to 
make sure the research is being done correctly.
 To the federal Food and Drug Administration (FDA), if required by the FDA.
 To someone who is accused of a crime, if he or she believes that our research records 
could be used for defense.
 To authorities, if we learn of child abuse, elder abuse, or if participants might harm 
themselves or others.  
Costs:
All medical expenses relating to, or arising from, these procedures will be paid by you and/or 
your insurance company. Taking part in this study may lead to added costs to you or your 
insurance company. Please ask about any expected added costs or insurance problems.
If you have any questions concerning your financial responsibilities, then contact your financial 
advisor at the SCCA (206-606-1113).  
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
What happens if I am injured because I took part in this study? 
For a life-threatening problem, call 911 right away or seek help immediately.  Contact your study 
doctor when the medical emergency is over or as soon as you can.   
For all other medical problems or illness related to this research, immediately contact Dr. Ann 
Dahlberg. She will treat you or refer you for treatment.  You or your health insurance will have to 
pay for the treatment. There are no funds to pay you for a research-related injury, added 
medical costs, loss of a job, or other costs to you or your family.  State or national law may give 
you rights to seek payment for some of these expenses.  You do not waive any right to seek 
payment by signing this consent form.
You or your insurer will be billed for treatment of problems or complications that result from your 
condition or from standard clinical care.
You would not lose any legal right to seek payment for treatment if you sign this form. 
Will I be paid to take part in this research study? 
You will not be paid for taking part in this study. 
Oversight and Review of Protocol Safety:
The FHCRC has guidelines for keeping patients safe in studies. There is a plan for reporting 
any event that may harm people in a study. The principal investigator, Ann Dahlberg, MD, will 
make sure this plan is followed.
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No 
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matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits. Leaving the study will not affect your medical care. You can still get your 
medical care from our institution. In the case of injury resulting from this study, you do not lose 
any of your legal rights to seek payment by signing this form. 
During the study, we may learn new information you need to know. For example, some 
information may affect your health. Other information may make you change your mind about 
being in the study. If we learn these kinds of information, we will tell you. 
Who can answer my questions about the study?
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor, Ann Dahlberg, MD, at 206-667-1959.
If you have any questions about your rights as a research participant, contact 206-667-5900 or 
email irodirector@fredhutch.org (Director of Institutional Review Office at Fred Hutchinson 
Cancer Research Center).
Where can I get more information?
You may call the National Cancer Institute’s Cancer Information Service at
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615
You may also visit the NCI Web site at http://cancer.gov/

For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/

For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
 
Signature
Before you sign this consent form, make sure of the following:

You have read this consent form, or someone has read it to you.
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
This study has been explained to you.

You had the chance to ask as many questions as you wanted.

You understand you can ask more questions anytime.

You understand you (or your insurer) will have to pay the costs of being in this study, 
including treatment for side effects.

You understand your medical records will be available to the doctors, staff, and other 
groups working on this study.

You agree to join this study.
_____________________________________________________________________
Participant (Age 14+)                                      
Date
                                                             
                                                  
Parent/Legal Guardian
      Date
Other Parent/Legal Guardian / Date
(for participants under 18 years old)
(if reasonably available)
If you served as an interpreter or impartial witness during the consent process, sign below to 
indicate you attest to the accuracy of the presentation and the participant’s apparent 
understanding of and willingness to participate in the research.
Impartial Witness or Interpreter:
_____________________________________________________________________
Printed Name                                     Signature                                 
Date
Copies to:
Participant, Medical Records, Research File
I have discussed the above research study, including the study procedures and 
possible alternatives and risks, with the person signing above.  I encouraged 
questions and have answered them to the best of my ability.  A signed and dated 
copy of the consent form will be given to the participant.
 _____________________________________________________________________
Staff Signature
Printed Name of Staff                      
Date
Current Version Date:   6/21/2021
Previous Version Date: 8/20/2019
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Prot_SAP_000.pdf: 
FHCRC 2010.00
FRED HUTCHINSON CANCER RESEARCH CENTER
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE
SEATTLE CHILDREN’S 
Current version: 06/21/2021
Previous version: 1/8/2021
Transplantation of Umbilical Cord Blood for Patients with Hematological Diseases with 
Cyclophosphamide/Fludarabine/Total Body Irradiation or 
Cyclophosphamide/Fludarabine/Thiotepa/Total Body Irradiation 
Myeloablative Preparative Regimen
Investigators   
Professional Title
Ann Dahlberg, MD
Principal Investigator
Assistant Member, FHCRC 
Assistant Professor of Pediatrics, UW
(206) 667-1959
Colleen Delaney, MD, MSc
Affiliate Member, FHCRC 
Founder and Chief Scientific Officer
Executive Vice President of Research and 
Development 
Nohla Therapeutics, Inc.
(206) 519-5304
Fred Appelbaum, MD
Member, FHCRC 
Professor of Medicine, UW
(206) 667-4412
Effie Petersdorf, MD
Member, FHCRC
Professor of Medicine, UW
(206) 667-4453
Filippo Milano, MD, PhD
Assistant Member, FHCRC
Assistant Professor of Medicine, UW 
(206) 667-5925
Biostatistician: 
Ted Gooley, Ph.D.
Member, FHCRC
(206) 667-6533
Research Staff: 
Jenna Pedersen
Research Coordinator
(206) 667-6013
Denise Ziegler
Research Coordinator
(206) 667-5762
Mary Joy Lopez
Data Coordinator
(206) 667-6139
Emergency Contacts (24 hour): 
Local Phone (For Adults): (206) 598-8902; Fax: (206) 598-4034
Local Phone (For Children): (206) 987-2032; Fax (206) 987-2764
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TABLE OF CONTENTS
1.0
OBJECTIVES
3
2.0
BACKGROUND
3
3.0
STUDY DESIGN
6
4.0
PATIENT/DONOR SELECTION
6
5.0
PATIENT REGISTRATION
8
6.0
TREATMENT PLAN
9
7.0
STUDY PARAMETERS
16
8.0
GUIDELINES FOR SERIOUS ADVERSE EVENT 
REPORTING
18
9.0
RECORDS
21
10.0
STATISTICAL CONSIDERATIONS
21
11.0
REFERENCES
23
APPENDIX I
GVHD STAGING AND GRADING 
23
APPENDIX II
HEMATOPOIETIC CELL TRANSPLANT-COMORBIDITY 
INDEX (HCT-CI)
26
APPENDIX III
POTENTIAL ADVERSE EVENTS ASSOCIATED OR 
EXPECTED WITH HSCT
27
APPENDIX IV
KARNOFSKY, LANSKY, AND ECOG PERFORMANCE 
STATUS SCALES
29
APPENDIX V
UMBILICAL CORD BLOOD GRAFT SELECTION 
30
APPENDIX VI
ADAPTED CTCAE CRITERIA
31
APPENDIX VII
FHCRC IRB POLICIES
36
APPENDIX VIII
SCHEDULE OF STUDY EVALUATIONS
37
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1.0
OBJECTIVES
1.1 Primary objective
The primary objective of this study is to estimate the one-year survival of patients undergoing 
umbilical cord blood transplantation (UCBT) after a myeloablative preparative regimen consisting of 
Regimen A: cyclophosphamide (CY), fludarabine (FLU) and fractionated total body irradiation (TBI) 
or Regimen B: cyclophosphamide (CY), fludarabine (FLU), thiotepa and fractionated total body 
irradiation (TBI).  
1.2 Secondary objectives are to estimate the:

Incidence of transplant-related mortality (TRM) at 6 months 

Incidence of neutrophil engraftment at Day 42 

Incidence of platelet engraftment at 6 months 

Incidence of disease free survival at 1 and 2 years 

Incidence of relapse at 1 and 2 years 
1.3 Exploratory objectives are to assess the:

Chimerism at multiple time points

Incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV at Day 100  

Incidence of chronic GVHD at Day 100, 1 year and 2 years

Incidence of clinically significant infections at 6 months, 1 year and 2 years 
2.0
BACKGROUND & RATIONALE
Bone marrow transplantation (BMT) is a standard treatment option for an increasing number of 
malignant and non-malignant disorders.  To reconstitute hematopoiesis after an intensive 
myeloablative therapy, the transplantation of pluripotential hematopoietic stem cells (HSCs) is 
required.  Such HSCs are typically recovered from the bone marrow of related or unrelated donors 
or the bone marrow or apheresed peripheral blood of the patients themselves [1].  Unfortunately, 
suitable marrow is frequently not available [2].  Either the patient's own marrow is contaminated with 
tumor cells or potential allogeneic marrow donors are unsuitable most often on the basis of HLA 
mismatch.   Human umbilical cord blood (UCB) is an alternative source of HSCs that is capable of 
reconstituting hematopoiesis after intensive myeloablative therapy [3-10].
2.1
Umbilical Cord Blood Transplantation (UBCT)
As a result of the early successes with umbilical cord blood transplantation (UCBT) from sibling 
donors, pilot programs for the banking of unrelated donor UCB were initiated in many countries 
around the world.  Known benefits of banked UCB include: 1) rapid availability, 2) absence of donor 
risk, 3) absence of donor attrition, and 4) very low risk of transmissible infectious diseases, such as 
CMV and EBV, and 5) low risk of acute GVHD despite HLA mismatch.  UCB is particularly beneficial 
for patients of ethnic and racial minority descent for whom adult marrow and blood donors often cannot 
be identified.
2.2    UCBT Experience at the University of Minnesota
Single Unit UCBT [11].  
Between 1994 and 2001, 102 consecutive patients (median age 7.4 years) received a single, 
unrelated UCB unit after a myeloablative conditioning for malignant (n = 65; 68% high-risk) 
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and non-malignant diseases (n = 37).  Median infused cell dose of UCB was 3.1 x 107 NC/kg 
(range 0.7-57.9), and 2.8 x 105 CD34+ cells/kg (range 0.4-39.1).  Fourteen percent had an 
HLA matched unit and 86% had a 1-3 HLA-match.  Neutrophil recovery occurred at a median 
of 23 Days (range 9-54) after UCBT with cumulative incidence of engraftment of 88% (95% 
CI: 81-95) by Day 42. Speed and likelihood of neutrophil recovery were strongly associated 
with cell dose, with markedly inferior engraftment (72% at a median of 34 Days) in patients 
receiving a CD34+ cell dose <1.7 x 105 cells/kg. 
The incidences of grade II-IV and III-IV acute GVHD were 39% (95% CI: 29-49) and 11% 
(95% CI: 5-17), respectively, at Day 100, with 10% (95% CI: 4-14) of patients having chronic 
GVHD at 1 year. One year transplant-related mortality (TRM) was 30% (95% CI: 21-39) 
which was strongly associated with CD34+ cell dose.  The probabilities of 1 and 2-year 
survival were 58% (95% CI: 49-70) and 47% (95% CI: 36-57), respectively.  Importantly, with 
a graft cell dose >1.7 x 105 CD34+ cells/kg, survival was 70% (95% CI: 49-90) at 1 year.
The principal conclusions of this study were: 1) an adequate cell dose (>1.7 x 105 CD34+ 
cells/kg or >2.5 x 107 nucleated cells/kg) consistently engraft; 2) GVHD is low despite HLA 
mismatch;  3) survival and risk of relapse are comparable to that observed after BMT,  and; 
4) cell dose significantly limits the applicability of UCB, particularly in adult size recipients.
Multi-Unit UCBT [12].  
Since cell dose has been clearly identified as a major limitation, often preventing the 
consideration of UCB for adult recipients, we have explored the possibility of infusing two 
partially HLA matched units to augment cell dose.  Between 2000 and 2005, we have 
increasingly utilized two UCB units rather than one, particularly in adults and adolescents 
who cannot find a suitable single UCB unit.  The underlying hypothesis of the original study 
(MT2000-15) was that the addition of the second unit would enhance the engraftment and 
the speed of hematopoietic recovery.
We have analyzed the results of the first 31 adult and adolescent patients [median age 24 
years (range: 13-53); median weight 73 kg (range: 48-120)] with high-risk hematologic 
malignancy who were transplanted with two partially HLA-matched UCB units after a 
myeloablative conditioning. Patient breakdown by diagnosis was: acute myelogenous 
leukemia (AML, n=15), acute lymphocytic leukemia (ALL, n=12), chronic myelogenous 
leukemia (CML, n=3) and non-Hodgkins Lymphoma (NHL, n=1). The median total infused 
dose 3.7 x 107 nucleated cells per kilogram (range 1.1-6.3) and 4.9 x 105 CD34 per kilogram 
(range, 0.9-14.5).
In this study, 100% of evaluable patients (i.e., survived for 21 Days [n=29]) engrafted at a 
median of 23 Days (range 14-41).  This compares favorably with a 65-75% incidence of 
engraftment reported for adults [9, 10].  In each case, one unit predominated.  Thus far, no 
factor (nucleated cell dose, CD34+ cell dose, HLA-match, ABO, sex, order infusion) predicts 
which unit will eventually be responsible for long term marrow recovery. The incidence of 
platelet recovery (>50,000/uL) was 73% (95% CI, 51-95) at Day 180. Incidence of grades II-
IV and III-IV acute graft-versus-host disease (GVHD) was 65% (95% CI, 42-88) and 17% 
(95% CI, 2-32) at Day 100.  Disease-free survival remains 72% at 1 year for patients 
transplanted in CR with no relapse in this cohort (median follow up: 1.2 years).
These data indicate that: 1) double unit UCBT is safe in terms of engraftment (bi-directional 
immune rejection between the units was never observed);  2) one unit always predominates 
within the first 100 Days;  3) >90% of adults will be able to identify two units that are partially 
HLA matched with the patient and each other;  4) incidence GVHD is similar to that observed 
after single UCBT; and  5) survival exceeds that of historical data with a single UCB unit.   
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As a result of these promising early data, we plan to extend this trial in order to 1) confirm the 
initial observations and 2) establish survival outcomes and relapse risk for individual disease 
groups.  Validation studies at other centers are in progress.
2.3
REGIMEN
This clinical trial will allow variation in preparative regimen but will have identical regimen for GVHD 
prophylaxis. The protocol-allowed conditioning regimens are: 
1. High-dose TBI + Fludarabine + cyclophosphamide
2. Middle-intensity TBI + Fludarabine + cyclophosphamide + thiotepa
The additional regimen (middle-intensity TBI + Fludarabine + cyclophosphamide + thiotepa) was 
chosen in addition to the more conventional high-dose TBI regimen that was used in our pilot study 
based on the extensive work published by Dr. Juliet Barker at the Memorial Sloan Kettering Cancer 
Center [14].This novel regimen was originally developed as an alternative intensive conditioning 
regimen aimed at reducing the increased risk of lethal regimen-related organ toxicity that has been 
associated with the more conventional high-dose TBI-based regimen used for myeloablative CBT 
(using 13.2 Gy TBI). In fact, the known risk of end-organ toxicity with high-dose TBI has led to 
restriction of this regimen to those 45 years and younger. Although there are nonmyeloablative 
conditioning regimens that have been used in the CBT setting for those patients older than 45 years, 
nonmyeloablative conditioning itself is limited by increased risk of graft rejection and relapse in this 
setting. Thus, there is a significant need to develop a well-tolerated middle-intensity, near-
myeloablative regimen to address the limitations of the high-dose TBI and nonmyeloablative 
regimens. This is particularly true for those patients older than 45 years or younger patients with 
significant pre-existing co-morbidities precluding them from the conventional high dose TBI regimen. 
Dr. Barker published on this regimen for the first time in 2013 which presented results for 30 patients 
with acute leukemia and MDS, with the majority having acute leukemia (n=26) [14].  The median age 
was 56 years (range 18 to 69).  The overall incidence of engraftment was 97% (1 graft failure), with 
a median time to engraftment of 26 days (range, 13 to 43).
Expanding our clinical trial to allow the option of this new conditioning regimen as an alternative to 
the conventional high-dose TBI regimen, with corresponding expanded age range, brings the 
benefits of cord blood transplant to a wider cohort.  The argument for addition of this conditioning 
regimen is strongly motivated by arguments for the importance of generalizability and for the ability 
to pool results.  The use of the same primary and secondary endpoints for both conditioning 
regimens is well motivated by the study’s primary objective to estimate the one-year survival of 
patients undergoing cord blood transplantation. Furthermore, the Barker trial results reveal time to 
engraftment, overall survival and TRM are similar between the cohorts thus supporting the pooling of 
results from the two conditioning regimens.   For these reasons, the inclusion of this new middle-
intensity regimen and the inclusion of patients up to age 65 enables a clinically well motivated 
generalization of the assessment of patients undergoing cord blood transplantation.
The regimen selection for individual patients is flexible to allow for attending physician and site 
preference. There are some absolute criteria, for example, that patients between the ages of 46 and 
65 would have to go on the middle-intensity regimen. However, outside of this, the decision of which 
conditioning regimen would be based on the underlying disease, presence of MRD, age, co-
morbidities and attending preference. Furthermore, there is also a move away from high-dose TBI 
by some physicians/centers in younger patients to avoid the long-term sequelae of high-dose TBI. In 
general, it is anticipated that younger patients would continue to accrue to the high dose TBI 
regimen, especially those with minimal residual disease and the middle-intensity regimen would 
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accrue those patients between 46 and 65 years of age and patients for whom the attending 
physician feels this is the more appropriate regimen.  
In this study, we will choose the unmanipulated CB donors per a CB selection algorithm (see 
Section 4.0 and Appendix V) allowing a single or double non-manipulated cell graft. 
3.0
STUDY DESIGN
This is a single-arm, phase II study to estimate the one-year survival of patients undergoing umbilical 
cord blood transplantation (UCBT) after a myeloablative preparative regimen consisting of Regimen 
A: cyclophosphamide, fludarabine and fractionated total body irradiation (TBI) or Regimen B: 
cyclophosphamide, fludarabine, thiotepa and fractionated total body irradiation (TBI) for the 
treatment of study specific hematological malignancies
4.0
PATIENT/DONOR SELECTION
4.1 Graft Criteria

UCB units will be selected according to current umbilical cord blood graft 
selection algorithm (Appendix V). One or 2 UCB units may be used to achieve the 
required cell dose.

The UCB graft is matched at 4-6 HLA-A, B, DRB1 antigens with the recipient. This 
may include 0-2 antigen mismatches at the A or B or DRB1 loci. Unit selection based 
on cryopreserved nucleated cell dose and HLA-A, B, DRB1 using intermediate 
resolution A, B antigen and DRB1 allele typing.

If 2 UCB units are required to reach the target cell dose, each unit must be a 4-6 
antigen match to the recipient. 
4.2 Age and Disease Criteria
1. High-dose TBI regimen: 6 months to ≤ 45 years
2. Middle-intensity TBI regimen: 6 months to ≤ 65 years
Conditioning regimen selection should be based on the underlying disease, presence of MRD, 
age, co-morbidities, and attending physician. 
Patients must have a hematological malignancy as described below:
Acute Myeloid Leukemia, including Biphenotypic Acute Leukemia or Mixed-Lineage 
Leukemia

All patients must be in CR as defined by hematologic recovery and <5% blasts by 
morphology/flow cytometry in a representative bone marrow sample with cellularity > 
15% for age. Patients who do not have high-risk features (for example preceding 
MDS, high-risk cytogenetics, ≥ 2 cycles to obtain CR, erythroblastic or 
megakaryocytic leukemia or ≥ CR2) must be discussed with the PI prior to enrollment 
and at the Patient Care Conference or equivalent group such as the pediatric 
leukemia board as an alternative. 

Patients in whom adequate marrow/biopsy specimens cannot be obtained to 
determine remission status by morphologic assessment, but have fulfilled criteria of 
remission by flow cytometry, recovery of peripheral blood counts with no circulating 
blasts, and/or normal cytogenetics (if applicable) may still be eligible. Reasonable 
attempts must be made to obtain an adequate specimen for morphologic 
assessment, including possible repeat procedures. These patients must be discussed 
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with the PI prior to enrollment.  Patients persistently aplastic for greater than one 
month since completing last chemotherapy are also eligible with PI approval.
Very high risk pediatric/young adult patients with AML.  Patients < 25 years, however, are 
eligible with (M2 marrow) with < 25% blasts in marrow after having failed one or more cycles 
of chemotherapy. This group of patients will be analyzed separately. 
Acute Lymphoblastic Leukemia, including Biphenotypic Acute Leukemia or Mixed-
Lineage Leukemia

All patients must be in CR as defined by <5% blasts by morphology.flow cytometry in 
      a representative bone marrow sample with cellularity ≥ 15% for age.  Patients who do
      not have high-risk disease (High risk CR1, greater than one cycle to obtain CR or
      ≥CR2) must be discussed with the PI prior to enrollment and at the Patient Care
      Conference or equivalent group such as the pediatric leukemia board as an
      alternative.  

Patients in whom adequate marrow/biopsy specimens cannot be obtained
to determine remission status by morphologic assessment, but have fulfilled
      criteria of remission by flow cytometry, recovery of peripheral blood counts with 
      no circulating blasts, and/or normal cytogenetics (if applicable) may still be 
      eligible. Reasonable attempts must be made to obtain an adequate specimen
      for morphologic assessment, including possible repeat procedures. These
      patients must be discussed with the Principal Investigator, Ann Dahlberg ((206) 667-     
      1959 or pager, (206) 469-3102) prior to enrollment. Patients persistently 
      aplastic for greater than one month since completing last chemotherapy are also 
      eligible with PI approval. 
Chronic myelogenous leukemia excluding refractory blast crisis. To be eligible in 
first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate.
Advanced myelofibrosis
Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e., RAEB, RAEBt) or refractory anemia with 
severe pancytopenia or high risk cytogenetics. Blasts must be < 10% by a representative bone 
marrow aspirate morphology.
Lymphoblastic lymphoma, Burkitt’s lymphoma, and other high-grade 
NHL after initial therapy if stage III/IV in PR1 or after progression if stage I/II < 1 year. 
Stage III/IV patients are eligible after progression in CR/PR. 
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-
cell lymphoma, lymphoplasmacytic lymphoma or follicular lymphoma that have progressed 
after at least two different prior therapies. Patients with bulky disease (nodal mass greater than 5 
cm) should be considered for debulking chemotherapy before transplant. These patients must be 
presented at PCC prior to enrollment, given potential competing eligibility on autotransplant 
protocols.
Mantle-cell lymphoma, prolymphocytic leukemia 
      Eligible after initial therapy in ≥CR1 or ≥PR1.
Large cell NHL > CR2/> PR2. 

Patients in CR2/PR2 with initial short remission (<6 months) are eligible.

These patients must be presented at PCC prior to enrollment, given potential 
competing eligibility on autotransplant protocols.
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Multiple myeloma beyond PR2. 

Patients with chromosome 13 abnormalities, first response lasting less than 6 
months, or β-2 microglobulin > 3 mg/L, may be considered for this protocol after initial 
therapy.
4.3 
Organ Function and Performance Status Criteria

Performance status score:  Karnofsky (for adults) ≥ 70% or ECOG 0-1
Lansky (for children)  50%            

Renal function: creatinine < 2.0 mg/dL (for adults) or creatinine clearance 
            > 60 ml/min (for children)

Hepatic function: Patients with clinical or laboratory evidence of liver disease will be 
evaluated for the cause of liver disease, its clinical severity in terms of liver function, 
histology, and the degree of portal hypertension. Patients with fulminant liver failure, 
cirrhosis with evidence of portal hypertension or bridging fibrosis, alcoholic hepatitis, 
esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, 
or correctable hepatic synthetic dysfunction evidenced by prolongation of the 
prothrombin time, ascites related to portal hypertension, bacterial or fungal abscess, 
biliary obstruction, chronic viral hepatitis with total serum bilirubin >3mg/dL, and 
symptomatic biliary disease will be excluded.

Pulmonary function: DLCOcorr > 50% normal or a pediatric patient who is unable to 
perform PFTs but has adequate pulmonary function

Cardiac function:  Left ventricular ejection fraction > 45%, or shortening fraction >26%
4.4
   Exclusion Criteria

Uncontrolled viral or bacterial infection at the time of study enrollment.

Active or recent (prior 6 month) invasive fungal infection without ID consult and 
approval.

History of HIV infection.

Pregnant or breastfeeding. 

Chemotherapy refractory large cell and high-grade NHL (i.e., progressive disease 
after > 2 salvage regimens). 

Patients with history of prior myeloablative transplant containing full dose TBI (greater 
than 8 Gy) will not be eligible for Regimen A; however, they may still enroll on 
Regimen B if they otherwise meet inclusion and exclusion criteria.

Any prior myeloablative transplant within the last 6 months.

Patients > 45 years: comorbidity score of 5 or higher

Patients who have received Y-90 ibritumomab (Zevalin) or I-131
tostumomab (Bexxar), as part of their salvage therapy are not eligible for Regimen A.
5.0
PATIENT REGISTRATION
Informed consent must be signed prior to the performance of any study related procedures or 
assessments.
Eligible patients will be identified by the Clinical Coordinators Office. Patients will be registered with 
the Registration Office (206-667-4728) between 8:30 am and 4:00 PM Pacific Time, Monday through 
Friday.  After hours, the Registration office can be reached by paging (206) 995-7437. Questions 
regarding eligibility or protocol information should be directed to Ann Dahlberg, MD (206-667-1959).
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6.0
TREATMENT PLAN
6.1
Conditioning Regimen
There are two conditioning regimens allowed per protocol. They are: 
1.
Regimen A: High-dose TBI + Fludarabine + cyclophosphamide
2.
Regimen B: Middle-intensity TBI + Fludarabine + cyclophosphamide + thiotepa
REGIMEN A: High-Dose TBI regimen (included ages: 6 months through 45 years old)
Please refer to standard practice with input from radiation oncology as needed.
Fludarabine total 75 mg/m2 (25 mg/m2/day IV x 3 days, days -8 to -6), Cyclophosphamide total 120 
mg/kg (60 mg/kg IV x 2 days, days -7 to -6), High Dose TBI total 1320 cGy (165 cGy BID, total 8 
fractions, days -4 to -1)
Day
Preparative Regimen
Supportive 
Care/Other
-8
Fludarabine 25 mg/m2 IV over 30 minutes
-7
Fludarabine 25 mg/m2 IV over 30 minutes 
Cyclophosphamide 60 mg/kg IV
-6
Fludarabine 25 mg/m2 IV over 30 minutes 
Cyclophosphamide 60 mg/kg IV
-5
Rest
-4
TBI 165 cGy twice daily
-3
TBI 165 cGy twice daily
Begin CSA (as per 
Section 6.2)
-2
TBI 165 cGy twice daily
-1
TBI 165 cGy twice daily
0
UCBT
Begin MMF (as per 
Section 6.2)
+1
Begin G-CSF (as per 
Section 6.4)
A. Fludarabine: 25 mg/m2/day IV over 30 minutes x 3 days (days -8 to -6); total dose 75 
mg/m2. For patients > 120% of ideal weight, BSA will be calculated using adjusted weight. 
B. Cyclophosphamide 
1.
Cyclophosphamide: 60 mg/kg/Day IV x 2 days (Days -7 and -6); total dose 
120mg/kg.
2.
Preparation, administration and monitoring will be according to Institutional 
Guidelines. If patient’s actual weight is >100% of IBW, adjusted body weight 
should be used for calculating initial doses based on per kilogram weight, per 
Institutional Guidelines. MESNA will be given for bladder prophylaxis according to 
Institutional Guidelines. Continuous bladder irrigation is an alternative for bladder 
prophylaxis at the attending physician’s discretion. 
3.
Cyclophosphamide administration and hydration guidelines for outside centers will 
be reviewed and approved by FHCRC PI if varying significantly from the above. 
Monitoring for toxicities will be according to Institutional Guidelines.
C. Total Body Irradiation: TBI 165 cGy will be given twice daily for a total dose of 1320 cGy 
(days -4 to –1).
REGIMEN B:  Middle-Intensity TBI regimen (included ages: 6 months through 65 years old)
Please refer to standard practice with input from radiation oncology as needed.
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Fludarabine total 150 mg/m2 (30mg/m2 IV x 5 days, days -6 to -2), Cyclophosphamide total 50 mg/kg 
IV x 1 day, day - 6), Thiotepa total 10 mg/kg (5 mg/kg/day x 2 days, -5 to -40), TBI total 400 cGy 
(200 cGy/day x 2 days, -2 to -1) 
A. Fludarabine: 30 mg/m2/day IV over 30 minutes x 5 days (days -6 to -2); total dose 150 
mg/m2. For patients > 120% of ideal weight, BSA will be calculated using adjusted weight
B. Thiotepa: 5 mg/kg IV x 2 days (days -5 to -4); total dose 10 mg/kg. For subjects > 125% of 
ideal weight, dose will be calculated based on adjusted weight.
C. Cyclophosphamide: 
a.
50 mg/kg IV x1 day (day -6)
b.
Preparation, administration and monitoring will be according to Institutional 
Guidelines. If patient’s actual weight is >100% of IBW, adjusted body weight should 
be used for calculating initial doses based on per kilogram weight, per Institutional 
Guidelines. MESNA will be given for bladder prophylaxis according to Institutional 
Guidelines. Continuous bladder irrigation is an alternative for bladder prophylaxis at 
the attending physician’s discretion
c.
Cyclophosphamide administration and hydration guidelines for outside centers can be 
according to Institutional Guidelines. Monitoring for toxicities will be according to 
Institutional Guidelines
D. Total Body Irradiation: TBI 200 cGy will be given once daily for a total dose of 400 cGy 
(days -2 to –1)
6.2 Immunosuppressive Therapies
All patients will receive GVHD prophylaxis with 2 drugs as follows:
Cyclosporine (CSA)
  Patients will receive cyclosporine (CSA) therapy beginning Day -3 maintaining a 
      level of > 200 ng/mL. For adults the initial dose will be 2.5 mg/kg IV over 1
  hour every 12 hours.  For children < 40 kg the initial dose will be 2.5 mg/kg IV 
  over 1 hour every 8 hours.
  Dose adjustments will be made on the basis of toxicity and CSA levels with a 
      targeted trough level of 200-400ng/mL. Once the patient can tolerate oral 
Day
Preparative Regimen
Supportive Care/Other
-6
Fludarabine 30 mg/m2 IV over 30-60 minutes
Cyclophosphamide 50 mg/kg IV 
-5
Fludarabine 30 mg/m2 IV over 30-60 minutes
Thiotepa 5 mg/kg IV over 2-4 hours
-4
Fludarabine 30 mg/m2 IV over 30-60 minutes 
Thiotepa 5 mg/kg IV over 2-4 hours
-3
Fludarabine 30 mg/m2 IV over 30-60 minutes
Begin CSA (as per Section 
6.2)
-2
Fludarabine 30 mg/m2 IV over 30 minutes
    TBI 200 cGy once daily
-1
TBI 200 cGy once daily
0
UCBT
Begin MMF (as per Section 
6.2)
+1
Begin G-CSF (as per 
Section 6.4)
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      medications and has a normal gastro-intestinal transit time, CSA will be 
      be converted to an oral form. Refer to Institutional guidelines for conversion 
      from IV to PO dosing, CSA dosing will be monitored and altered as  
      clinically appropriate.
  Initial cyclosporine dose is calculated using actual body weight except for those 
patients who are greater than 100% ideal body weight in which case calculation of   
dose using adjusted body weight is recommended.
  Patients will receive CSA until Day +100.  If there is no GVHD, the dose will be 
tapered 10% per week beginning on Day 101, to discontinue no sooner than 
6months post-transplant.
Mycophenolate Mofetil (MMF)

All patients will begin mycophenolate mofetil (MMF) on Day 0, starting approximately 
4 - 6 hours after infusion of the cord blood unit(s) is completed. All patients will 
receive MMF at the dose of 15 mg/kg (based on adjusted weight) every 8 hours with 
a maximum of 1 gram/dose. If actual body weight is < ideal body weight, calculation 
based on actual weight is allowed. Rounding of the dose to the nearest 250 mg 
capsule size is also allowed. 

Use IV route between days 0 and +7; then, if tolerated, may change to PO beginning 
on day +8 three times a day. 

All patients will remain on three times a day as permitted after day 7 for a minimum 
of 30 days. At day +30 or 7 days after engraftment (defined as 1st day of 2 
consecutive days of absolute neutrophil count [ANC] ≥ 0.5 x 109 /L), whichever day 
is later, if there is no evidence of acute GVHD and donor CD3 engraftment is at 
least 50% from one donor, taper MMF to BID. At day +45 (or 15 days after 
engraftment if engraftment occurred > day +30), if there continues to be no evidence 
of acute GVHD and donor engraftment has been achieved (defined as <10% host in 
CD3, CD33 and CD56), taper MMF over the next two to three weeks.   

If there is no donor engraftment, do not stop MMF. If there is no evidence of donor 
engraftment on the day +28 bone marrow biopsy, notify the PI, Ann Dahlberg 
(pager: 206-469-3102) or the research coordinator, Jenna Pedersen ((206) 667-
6013). 
6.3       Umbilical Cord Blood Transplantation (UCBT)

Procedures for requesting, receiving and characterizing the cord blood unit for 
infusion will be according to institutional protocol.  

The cord blood unit should be thawed and infused per FHCRC Standard Practice 
Manual. Cord blood products should be infused without delay as soon as the 
product arrives on the unit.  

The thawed product (either one or two units) will be delivered to the patient           
floor/bedside where the product is double-checked by a nurse with the
technologist from the Cellular Therapy Laboratory. Visual inspection of the 
product is also made at this time. The unit(s) is verified according to 1) the 
infusion order sheets, 2) the patient’s identification number on the cell product, 
3) the product (cell) identification number and 4) the patient wrist band. 

If the cord blood unit(s) fails to pass inspection or if there is insufficient 
              information to verify the cell product for the patient, notify
the Cell Therapy Lab ((206) 606-1200) and the PI, Ann Dahlberg ((206) 667-
1959, pager (206) 469-3102) immediately.

The goal infusion time of each cord blood unit is 30 minutes, as clinically 
possible. Pre-medications (if any) prior to cord blood infusion will be at the 
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discretion of the attending. Under no circumstances is the cord blood to be 
irradiated. No medications or fluids should be given piggyback through the 
catheter lumen that is being used for cord blood infusion. 

The product is infused via IV drip directly into the central line without a needle 
or pump.

Vital signs should be monitored before beginning the infusion and periodically 
                        during administration. Notify the attending physician, fellow or PA immediately
                        if the patient exhibits signs or symptoms of a reaction. 

Benadryl, epinephrine, and hydrocortisone should be available at the bedside 
for emergency use if necessary. Oxygen with nasal prongs for standby use 
should be present in the room.

If the patient is a double cord blood recipient, the two units may be given 
sequentially with no wait between infusion of the units. However, infusion of the 
second unit will not begin until any acute toxicities from the first unit have been 
controlled. The start and stop time of each unit should be recorded on the 
infusion record. 
6.4
Growth Factor 
All patients will receive G-CSF 5 mcg/kg/day IV (pediatric patients) or SC (adult patients) (dose 
rounded to vial size) based on the actual body weight IV beginning on Day +1 after UCB infusion.  
G-CSF will be administered daily until the ANC exceeds 2.5 x 109/L for three consecutive days and 
then discontinued.  If the ANC decreases to <1.0 x 109/L, G-CSF will be reinstituted and titrated to 
maintain an ANC >1.0 x 109/L.
6.5
Supportive Care
Patients will receive transfusions, infection prophylaxis (bacterial, fungal, CMV), and other therapy 
(including GVHD) according to institutional guidelines (at FHCRC this is the FHCRC Standard 
Practice Manual). FHCRC infection guidelines are provided to outside centers as recommendations.
6.6
Management of Pre-engraftment Immune Reactions 
A well-recognized clinical entity consisting of skin rash, fever, and, often, loose stools and 
respiratory distress has been noted to occur prior to engraftment among cord blood patients, 
generally between Days +7 and +21.  This clinical syndrome likely involves cytokine activation, and 
though clinically similar to acute or hyperacute graft versus host disease, it appears to be a distinct 
entity, “pre-engraftment syndrome.”   This syndrome is often controlled with brief steroid bursts, thus 
avoiding a commitment to extended steroid exposure. Patients should be monitored carefully for this 
syndrome.
If patients have moderate to severe symptoms as described above and alternative etiologies (i.e., 
infection) have been excluded or are being appropriately evaluated, recommendations for 
management are:
1.
For patients not on steroid therapy when the syndrome occurs:  methylprednisolone 
should be given at 1 mg/kg IV q day for three days.  If symptoms have abated, 
steroids should be stopped.  If symptoms persist, 1 mg/kg can be continued through 
six days then stopped if symptoms have abated.  If symptoms persist for more than 
six days, the patient should be considered to have acute/hyperacute GVHD and 
should be treated with prolonged steroids as deemed appropriate.
2.
For patients already on steroids for other reasons when the syndrome occurs:  
methylprednisolone should be given at a dose of 3-5 mg/kg IV (max dose 500 mg) q 
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12 hours x 48 hours, followed by a rapid taper to 1 mg/kg IV q 12 hours.  Patients 
should be weaned after response as tolerated.
6.7
Treatment Related Toxicities
6.7.1
Potential toxicities associated with preparative therapies
Cyclophosphamide
Common
Occurs in 21-100 
people out of every 100
Less Frequent
Occurs in 5-20 people out of 
every 100
Uncommon
Occurs in  <5 people out of every 100
Nausea/vomiting
Mucositis
Sterility
Severe suppression of 
blood counts
Diarrhea
Fluid weight gain or 
edema
Alopecia
Hemorrhagic cystitis
Cardiomyopathy
Skin rash
SIADH (Syndrome of Inappropriate Anti-
diuretic Hormone)
Fludarabine
Common
Occurs in 21-100 
people
out of 100
Less Frequent
Occurs in 5-20 people out of 
every 100
Uncommon
Occurs in <5 people out of every 100
Severe suppression of 
blood counts
Diarrhea 
Anorexia
Mucositis
Nausea/vomiting
Stomatitis
Osteoporosis
Dysuria
Chills
Fever
GI bleeding
Peripheral edema
Neurotoxicity
Agitation and confusion
Blurred vision
Peripheral neuropathy
Hearing loss 
Headache
Cerebellar syndrome
Blindness
Coma 
Weakness
Depression
Insomnia
Hemorrhagic cystitis (except in FA)
Abnormal renal function test
Autoimmune hemolytic anemia
Deep venous thrombosis
Aneurysms
Pruritic skin rash
Abnormal liver function/Liver failure
Constipation
Transient ischemic attack
Dysphagia
Myalgia
Arthralgia
Renal failure
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Thiotepa
Likely (Over 10%)
Less Likely (1-10%)
Rare (Less than 1%)

Low white blood cell count with 
an increased risk of infection 
(from bacteria, fungi or 
viruses)

Low platelet count with 
increased risk of bleeding

Anemia

Nausea/vomiting 

Diarrhea 

Anorexia (loss of appetite)

Mouth ulcers 

Sores in mouth or on lips 

Missing or stopping of 
menstrual periods in women

Skin rash

Change in skin coloring

Fatigue, weakness

Dizziness

Headache

Permanent sterility 
(inability to have children)

Allergic reactions during 
infusion (fever, chills, 
itching, hives, flushing, 
rash, shortness of 
breath, wheezing, chest 
tightness, muscle 
stiffening) 

Confusion

Seizures

Liver damage

Secondary cancers 
Total Body Irradiation (TBI) 
Common
Occurs in 21-100 
people
out of 100
Less Frequent
Occurs in 5-20 people out of 
every 100
Uncommon
Occurs in <5 people out of every 100
Nausea and vomiting
Diarrhea
Cataracts
Sterility
Endocrinopathies
Growth failure
Intestinal cramps
Mucositis
Parotitis
Interstitial Pneumonitis
Generalized mild erythema
Veno-occlusive disease
Dysphagia
Vertebral deformities
Nephropathy
6.7.2
Toxicities potentially associated with the infusion of the UCB graft
Potential toxicities associated with the infusion include DMSO toxicity and side effects from red cells.  
DMSO toxicity and side effects of red cells may include changes in heart rate, rhythm or function, 
changes in blood pressure, changes in oxygenation, fever, chills, sweats, nausea/vomiting, diarrhea, 
abdominal cramping, headache, allergic reaction, presence of DMSO taste and odor, 
hemoglobinuria, and acute renal failure.  
6.7.3
Potential toxicities associated with Immunosuppressive therapies
Cyclosporine (CSA)
Nephrotoxicity
Thrombotic thrombocytopenic purpura
Seizures
Electrolyte imbalances
Hypertension
Paresthesias/neuropathy
Hirsutism
Gingival hyperplasia
Increased risk of relapse
Increased risk of opportunistic infection
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Mycophenolate Mofetil (MMF)
Pancytopenia
Hypertension
Headache
Dizziness
Insomnia
Hyperglycemia
Electrolyte imbalances
Rash
Leg cramps/bone pain
Nausea/diarrhea
Spontaneous abortion
Birth defects
Progressive multifocal 
leukoencephalopathy
6.7.4
Toxicities associated with Neupogen (G-CSF)
Bone pain
Insomnia
Headaches
Dyspnea
Body aches
Rash
Fatigue
Edema
Nausea/vomiting
7.0      STUDY PARAMETERS
See Appendix VIII for schedule of study evaluations.
7.1 Patient Pre-Study Screening per Standard Practice Procedures                                    
(Results of tests and/or procedures conducted as per standard of care for pre-transplant 
workups may be used for eligibility determination if conducted within an appropriate window prior 
to screening. In addition to procedures and evaluations listed below, additional clinical 
evaluations as directed by the clinical team may be captured for research purposes.)

Medical history of allergies, previous chemotherapy, prior radiotherapy and response to 
treatment

Karnofsky/ECOG/Lansky performance (Appendix IV) status

Physical examination

Complete blood count with leukocyte differential

Basic metabolic and hepatic function panels

Urinalysis

Pregnancy test (blood or urine) 

Viral titers (HSV, CMV, HIV, HBsAg, HBcAb, HCV, HTLV 1, 2).  PCR for CMV DNA must be 
done within 2 weeks prior to the start of conditioning. 

Bone marrow aspirate (+/- biopsy as clinically indicated) collected less than one month prior 
to the start of conditioning

Electrocardiogram and MUGA or echocardiography with measurement of the
      left ventricular ejection fraction (LVEF) and/or shortening fraction.  

A chest CT without contrast to exclude occult infection prior to transplant
      for patients with a history of the following:
o
MDS/CML blast crisis
o
2 or more consecutive leukemia inductions
o
prolonged neutropenia, as defined as ≥ 4 weeks of neutropenia
      within the 2 months prior to study

Chest radiograph; CXR not required if chest CT performed.

Pulmonary functions tests 

DNA specimen from cord blood unit(s) for chimerism studies (submitted to CIL)
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
Pediatric pre-transplant evaluation qualification: for children that are not able to cooperate to 
have a MUGA and/or pulmonary function tests, an echocardiogram should be attempted and 
pulse oximetry with exercise tolerance obtained. If not possible at all, it should clearly be 
documented in the physician’s note.

Quantitative immunoglobulin levels (IgG, IgA, IgM)

Immune Reconstitution Research Study (see section 7.8).

Blood samples for Host and Donor Immunologic Interaction Studies (see Section 7.7)
7.2
Patient Evaluations During Therapy Until Engraftment (Through Day 30)

Physical examinations daily 

Complete blood count with leukocyte differential daily until the absolute neutrophil count 
(ANC) > 5 X 108/L for 3 consecutive measurements. Leukocyte differential is to be performed 
daily if WBC count > 500.

Basic metabolic panel daily or as clinically indicated

Hepatic function panel as clinically indicated or per standard practice

CMV monitoring per standard practice

Urinalysis as clinically indicated

Chest radiographs as clinically indicated

Day 28 peripheral blood for chimerism studies (as possible sorted for CD3, CD14, CD33, 
CD56 cells)

For patients who received a single cord blood unit – peripheral blood for chimerism 
studies (sorted for CD3, CD14, CD33, CD56 cells) on Day 28.  For patients who received 
double cord blood units - peripheral blood for chimerism studies (sorted for CD3, CD14, 
CD33, CD56 cells) on Day 28. 

Bone marrow aspirate (+/- biopsy as clinically indicated) on Day 28 for assessment of UCB 
engraftment. Bone marrow DNA specimen for chimerism studies. 

Quantitative immunoglobulin levels (IgG, IgA, IgM) at Day 28

As possible, total T lymphocytes and subset enumeration at Day 28

GVHD evaluation (Appendix I) weekly or as clinically indicated

Other tests (e.g., x-rays and tumor markers) as clinically appropriate for assessment of 
underlying malignancy on Day 28
7.3
Patient Evaluations from Engraftment through Day 100, 6 months, 1 year and 2 years

Physical examinations weekly and/or as clinically indicated during first 100 days, 6 months, 1 
year and 2 years 

Karnofsky/ECOG/Lansky performance status (Appendix IV) once between Day 80-100, at 6 
months, 1 year and 2 years

Complete blood count with leukocyte differential weekly and/or as clinically indicated through 
Day 100 or until discharge then at 6 months, 1 year and 2 years 

Basic metabolic panel at least weekly or as clinically indicated

Hepatic function panel as clinically indicated

CMV monitoring per standard practice

Chest radiographs, EKG and pulmonary function tests as clinically indicated

Bone marrow aspirate (+/- biopsy as clinically indicated) on Day 80 and 1 year for 
assessment of UCB engraftment and evidence of recurrent disease. FHCRC: DNA specimen 
for chimerism studies (without cell sorting) 

Peripheral blood for chimerism studies as possible (sorted for CD3+, CD33+, CD56+ cells) 
on Day 56, 80, 6 months, 1 year and 2 years in both single and double cord blood unit 
recipients
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
Quantitative immunoglobulin levels (IgG, IgA, IgM) as possible at Day 56, 80, 6 months, 1 
year and 2 years

As possible, total T lymphocytes and subset enumeration on Day 56, 100, 6 months, 1 year 
and 2 years  

GVHD evaluation (Appendix I) weekly and/or as clinically indicated through Day 100 (or 
longer if clinically indicated), then at 6 months, 1 year and 2 years 

Autopsy report, if available, if death occurs before the 2-year follow-up
7.4
UCB Engraftment Evaluation
Chimerism studies will be performed on the bone marrow on Days 28, 80 and 1 year. Subsequently, 
if the patient's peripheral blood counts drop after an initial recovery, the peripheral blood and bone 
marrow should again be evaluated unless a cause has been determined (e.g., use of Ganciclovir for 
treatment of CMV).  Patients diagnosed with graft failure as defined in section 10.2 must be reported 
to the Principal Investigator (Ann Dahlberg, 206-667-1959/pgr 206-469-3102).
7.5
GVHD Evaluation
GVHD assessment, done as part of routine care, will be reviewed once weekly through Day 100.  
Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea 
and maximum bilirubin level.  Patients will be rescored at 6 months, and at 1 and 2 years with 
additional scores as events occur once discharged to home. 
7.6
Residual/Recurrent Disease Evaluation
Patients will be evaluated routinely for evidence of recurrent malignancy.  If at any time the attending 
physician suspects recurrent disease, additional analyses will be performed as clinically indicated.  
7.7
Immune Reconstitution after UCBT
Clinical Studies:

Quantitative immunoglobulin levels (IgG, IgA, IgM) will be assessed at Day 28. As possible at 
Days 56, 80, 6 months, 1 year and 2 years.

Total T lymphocytes and subset enumeration (Lymphocytes panel) will be performed at Day 
28, 56, 100, 6 months, 1 year and 2 years.
8.   Guidelines for Serious Adverse Event Reporting
8.1
Monitoring the Progress of Trial and the Safety of Participants
This is a Phase 2 clinical trial that is monitored by the principal investigator (PI), Ann Dahlberg, M.D.  
For FHCRC patients, the PI reviews the outcome of the data for each individual patient on an 
ongoing basis. The PI of the study will have primary responsibility for ensuring that the protocol is 
conducted as approved by the Scientific Review Committee and Institutional Review Board. The PI 
will ensure that the monitoring plan is followed, that all data required for oversight of monitoring are 
accurately reported to the Data and Safety Monitoring Committee, that all adverse events are 
reported according to the protocol guidelines, and that any adverse reactions reflecting patient 
safety concerns are appropriately reported. The PI will personally review with the Research Nurse 
the clinical course of all the enrolled patients at least twice monthly. 
Until October 2018, this was a multi-institution trial with FHCRC serving as the Coordinating Center.  
In this capacity, the PI obtained copies of all IRB approvals and had the responsibility for receiving 
the information required for adverse event reporting and safety monitoring and disseminating that 
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information to the appropriate Consortium committees. Written agreements were obtained from all 
participating sites acknowledging their responsibilities for data and adverse event reporting and 
agreement to provide records, files, case report forms or any other documents needed to verify 
compliance.  The PI reviewed outcome data for each individual patient at a minimum of 3 months 
after UCBT.  Clinical outcome data were summarized and transmitted from collaborating centers as 
case report forms (CRFs). When possible, primary source documents regarding patient outcomes 
were collected from the collaborating centers. The CRFs were generated from the collaborating 
centers at defined time points (day 28, day 100, day 180, 1 year and 2 years post-transplant). The 
local PI reviewed the official CRF and primary source documents. When the CRFs were verified, the 
data were entered into a central database managed by the FHCRC Coordinating Center. 
8.2.
Reporting of Adverse Events
Adverse Event Definitions
Adverse Event
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a medicinal product; the event does not necessarily have a causal relationship with 
study drug administration or usage. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product.
Serious Adverse Event 
A serious adverse event (SAE) is defined as an untoward medical occurrence that results in any of 
the following outcomes:
• Death
• Life-threatening situation (i.e., with an immediate risk of death from the event as it occurred but
  not including an event that, had it occurred in a more serious form, might have caused death).
• In-patient hospitalization or prolongation of existing hospitalization. Inpatient hospitalization       
  comprises formal admission to a hospital for medical reasons, for any length of time, whether or 
  not hospitalization extends overnight. However, hospital admissions for administration of the
  study drug, procedures required by the study protocol, or tumor-related diagnostic procedures
  are not considered serious. Hospitalizations commonly associated with transplant including, but
  not limited, to febrile neutropenia, fevers, infections, and gastrointestinal toxicities will not be
  recorded as serious adverse events as the majority of patients receiving transplants are 
  hospitalized. 
• Persistent or significant disability/incapacity or substantial disruption of the ability to conduct
  normal life functions.
• Congenital anomaly/birth defect.
• An important medical event that requires intervention to prevent one of the above outcomes.
Unexpected Adverse Event
An unexpected adverse event is defined as an event that has a nature or severity, or frequency that 
is not consistent with the applicable investigator brochure.  “Unexpected,” as used in this definition, 
refers to an adverse drug experience that has not been previously observed and reported rather 
than an experience that has not been anticipated based on the pharmacological properties of the 
study drug.
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Recording an Adverse Event and Grading of the Severity of an Adverse Event
Adverse events will be collected and graded according to the modified (for HSCT) NCI Common 
Toxicity Criteria (Appendix VI). Grade 3 or 4 adverse events (or highly unusual grade 2 adverse 
events), which occur from the start of study treatment (pre-transplant conditioning) through Day 
+100 post-transplant will be collected on the Case Report Form (CRF). These adverse events, which 
are observed by the Investigator or reported by the patient, whether or not attributed to the study, 
will be reported on the CRF. Attributes will include a description, date of onset, maximum severity, 
and assessment of relationship to the study agent or other suspect agent(s).
Adverse events will be graded according to CTCAE version 3.0 (Appendix VI). Association or 
relatedness to the study agent will be graded as follows: 1 = unrelated, 2 = unlikely, 3 = possibly 
related, 4 = probably related, and 5 = definitely related.
If a patient experiences relapse or graft failure and goes on to further treatment off protocol, adverse 
events will no longer be collected with the exception of death. The adverse event reporting in this 
clinical trial will comply with current FHCRC reporting policy (see Appendix VII). For patients being 
cared for at the FHCRC, health care providers communicate with the PI, trial coordinator or research 
nurses as events occur triggering subsequent reporting. Toxicities meeting the study stopping rule 
criteria will be reported to the IRB within 10 days of study staff awareness. All other SAEs and 
deaths, not meeting the expedited reporting criteria, will be reported to the IRB as part of the annual 
continuation review report to the IRB. For the purpose of this study, hospitalizations for 
protocol-scheduled procedures, blood product transfusions, or for social reasons (i.e., 
awaiting transport home) will not be considered serious adverse events. Hospitalization will 
be considered a serious adverse event if it is unexpected or the duration of the hospital stay 
is unexpected.
Refer to Appendix III for a list of potential adverse events associated or expected with hematopoietic 
cell transplantation. PI and the research study team have fulfilled all NIH requirements for training in 
human subjects protection.   
8.3.
Plans for assuring data accuracy and protocol compliance
For study enrollment, a signed consent form and eligibility checklist with source documents must 
demonstrate study eligibility. Fred Hutch Cord Blood Program research staff review CRFs for 
adherence to the protocol, accuracy, and completeness. The study is monitored under the FHCRC 
Monitoring Plan. The FHCRC Data and Safety Monitoring Plan details the full scope and extent of 
monitoring and provides for immediate action in the event of the discovery of major deviations.  
8.4.
Oversight and Review of Safety Monitoring
An annual review of the progress of the study with respect to the monitoring plan will be performed 
by a Data and Safety Monitoring Committee (DSMC). As part of the annual renewal process, the PI 
will submit an accounting of patient enrollment and outcomes defining the monitoring plan in 
sufficient detail as to permit verification of the report through chart audit. The IRB provides a final 
level of annual review. Approval by the DSMC is a necessary but not sufficient condition for final 
approval by the IRB. The IRB will review the same continuation application and materials that are 
reviewed by the DSMC, and make an independent assessment of the progress of the trial and 
determine whether the perceived risk-benefit ratio continues to be acceptable.
9.0
RECORDS 
Clinical Research Data Systems maintains a patient database at FHCRC to allow storage and 
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retrieval of patient data collected from a wide variety of sources.  The investigator will ensure that 
the data collected conform to all established guidelines for coding, collection, key entry and 
verification.  Each patient is assigned a unique patient number to assure patient confidentiality.  
Patients will not be referred to by this number, by name, or by any other individual identifier in any 
publication or external presentation.  The licensed medical records department, affiliated with the 
institution where the patient receives medical care, maintains all original inpatient and outpatient 
chart documents. Patient research files are kept in a locked room. Patient research files are scanned 
and stored in a secure database and maintained by the Fred Hutch data abstraction staff. Access is 
restricted to personnel authorized by the Division of Clinical Research.
10.0
STATISTICAL CONSIDERATIONS
10.1 
Objectives
Primary objective
The principal aim of this study is to estimate one-year overall survival of UCBT after a 
myeloablative preparative regimen for the combined experience of single unit UCB 
transplants and double unit UCB transplants.
Secondary objectives

Transplant related mortality at 6 months

Chimerism at multiple time points

Neutrophil engraftment at Day 42

Platelet recovery at 6 months

  Acute GvHD

Chronic GvHD

Clinically significant infections at multiple time points

Relapse at one and two years 

Progression-free survival at one and two years

Comparison of single unit UCB transplants with historical controls

  Comparison of single unit UCB transplants with double unit UCB transplants
10.2
Statistical Analysis
The primary objective of this study is to gain experience with both double- and single-unit UCBT’s 
and to estimate the one-year overall survival among patients treated on this study.  A non-statistical 
comparison with historical controls will be made for the endpoints survival and progression-free 
survival, and the doubles and singles will be assessed separately for these purposes.  In addition, 
we have added a middle-intensity conditioning regimen as described above, this allowing for 
inclusion of patients > 45 years of age.  In addition to assessing results by double vs. single, results 
will also be examined according to conditioning intensity.  Historically, the survival at two years for 
single-unit UCBT’s has ranged from 26-74% [13].  At FHCRC, patients transplanted for CML, acute 
leukemia, or MDS from an unrelated donor and matched for 10 of 10 alleles have an estimated 2-
year survival of 57%; those matched for 9/10 alleles have an estimated 2-year survival of 49%, and 
those matched for 8/10 alleles have an estimated 2-year survival of 46%.  Based on the numbers, 
we shall use 50% survival at 1 year as the rough benchmark for the current study.  We plan to enroll 
135 patients, and we expect that approximately 2/3 of these will be double-unit UCBT’s.  The first 75 
patients (or so) received the high-intensity regimen, and we expect the remaining 60 to be 
distributed equally between the high-dose and middle-intensity regimens.  This would result in 
roughly 105 high-dose and 30 middle-intensity patients, and approximately 90 double-cord recipients 
and 45 single-cord recipients.  Combining each of these, we expect approximately 70 patients to 
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receive high-dose TBI and a double cord, 35 to receive high-dose TBI and a single cord, 20 to 
receive middle-dose TBI and a double cord, and 10 to receive middle-dose TBI and a single cord.  If 
the observed 1-year survival for a particular arm is at least 10 percentage points better than the 
historical benchmark, that arm will be considered to be worthy of further study.  The table below 
shows the probability of observing a 1-year survival that is at least 10 percentage points higher than 
the benchmark of 50%.  The table contains various sample sizes and various assumed-true 1-year 
survival rates (the varying sample sizes correspond to the expected numbers based on distributions 
conditioning and number of cords).  
N
Group
True 1-year OS
Probability observe > 50% OS
105
High-dose TBI
.65
.88
30
Medium-intensity TBI
.70
.92
90
Double cords
.65
.86
45
Single cords
.65
.81
70
High-dose, doubles
.65
.84
35
High-dose, singles
.70
.93
20
Med-intensity, doubles
.70
.89
10
Med-intensity, singles
.75
.92
Graft failure by Day 42 and transplant-related mortality by day 100 will be carefully monitored 
throughout the study, and if reasonable evidence exists suggesting that failure for either of these 
endpoints is excessive, the study will be stopped.  Monitoring will take place separately for the single 
and double UCBT cohorts.  Patients will be considered primary graft failure/rejections provided they 
meet any criteria listed below:
i.
Absence of 3 consecutive days with neutrophils ≥500/ul combined with host CD3 
peripheral blood chimerism ≥ 50% at day 42
ii.
Absence of 3 consecutive days with neutrophils ≥500/ul under any circumstances 
at day 55
iii.
Death after day 28 with neutrophil count <100/ul without any evidence of 
engraftment (< 5% donor CD3)
iv.
Primary autologous count recovery with < 5% donor CD3 peripheral blood 
chimerism at count recovery and without relapse
A true graft failure rate of 15% will be considered excessive, and a true Day 100 TRM rate of 20% 
will be considered excessive, and reasonable evidence will be taken to be a ratio of failures to 
patients treated with a lower limit to the corresponding 80% confidence interval in excess of these 
rates.  These ratios will be assessed after every 5th enrolled patient becomes evaluable and will be 
assessed separately between the four conditioning/cord-number groups.  
Operationally, the stopping limits will be met if any of the following ratios occur:
Graft Failure: 2/5, 3/10, 4/15, 5/20, 6/25, 7/30, 8/35, 9/40, 10/45, 11/50, 11/55, 12/60, 13/65, 
14/70
TRM: 3/5, 4/10, 5/15, 6/20, 8/25, 9/30, 10/35, 11/40, 12/45, 13/50, 14/55, 16/60, 17/65, 18/70
If the true probability of graft failure is 5%, then the probability of stopping the study after 20, 40, or 
60 patients is approximately 0.03, 0.03, and 0.03, respectively.  If the true probability is 25%, these 
stopping probabilities are approximately 0.70, 0.84, and 0.91, respectively.  (It is not expected that 
60 patients will be enrolled in either arm, but theoretically it is possible.)  If the true probability of 
TRM is 15%, then the probability of stopping after 20, 40, or 60 patients is 0.11, 0.12, and 0.13, 
respectively, while a true probability of 30% leads to stopping probabilities of 0.66, 0.81, and 0.89.  
Secondary endpoints listed in Section 10.1 will also be evaluated.  Cumulative incidence estimates 
will be used to summarize the time-to-event outcomes.
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We anticipate that the data from this study will be useful in the design of future studies, these future 
studies hopefully culminating in a Phase III trial comparing UCBT to some other alternative source of 
stem cells.  If the data from this trial suggest favorable outcomes as detailed above, then the 
appropriate groups will be considered for potential inclusion on the clinical trial(s) as appropriate.
10.3
Gender and Ethnicity Statement
This study is open to both males and females and to all racial/ethnic groups. The patient enrollment 
pattern is expected to be similar to that of other hematological malignancy studies. It is not 
anticipated that the outcome will be affected by either race or gender.  The study will not have 
separate accrual targets for different subgroups. 
11.0
REFERENCES
1.
Blume, K., S.J. Forman, and F.R. Appelbaum, Thoma's Hematopoietic Cell Transplantation. 
3nd ed. 2004, Malden, MA: Blackwell Science, Inc.
2.
Confer, D.L., Unrelated marrow donor registries. Curr Opin Hematol, 1997. 4(6): 408-12.
3.
Wagner, J.E., N.A. Kernan, M. Steinbuch, et al., Allogeneic sibling umbilical-cord-blood 
transplantation in children with malignant and non-malignant disease. Lancet, 1995. 
346(8969): 214-9.
4.
Wagner, J.E., J. Rosenthal, R. Sweetman, et al., Successful transplantation of HLA-matched 
and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment 
and acute graft-versus-host disease. Blood, 1996. 88(3): 795-802.
5.
Kurtzberg, J., M. Laughlin, M.L. Graham, et al., Placental blood as a source of hematopoietic 
stem cells for transplantation into unrelated recipients. N Engl J Med, 1996. 335(3): 157-66.
6.
Gluckman, E., V. Rocha, A. Boyer-Chammard, et al., Outcome of cord-blood transplantation 
from related and unrelated donors. Eurocord Transplant Group and the European Blood and 
Marrow Transplantation Group. N Engl J Med, 1997. 337(6): 373-81.
7.
Rubinstein, P., C. Carrier, A. Scaradavou, et al., Outcomes among 562 recipients of 
placental-blood transplants from unrelated donors. N Engl J Med, 1998. 339(22): 1565-77.
8.
Laughlin, M.J., J. Barker, B. Bambach, et al., Hematopoietic engraftment and survival in adult 
recipients of umbilical-cord blood from unrelated donors. N Engl J Med, 2001. 344(24): 1815-
22.
9.
Laughlin, M.J., M. Eapen, P. Rubinstein, et al., Outcomes after transplantation of cord blood 
or bone marrow from unrelated donors in adults with leukemia. N Engl J Med, 2004. 351(22): 
2265-75.
10.
Rocha, V., M. Labopin, G. Sanz, et al., Transplants of umbilical-cord blood or bone marrow 
from unrelated donors in adults with acute leukemia. N Engl J Med, 2004. 351(22): 2276-85.
11.
Wagner, J.E., J.N. Barker, T.E. DeFor, et al., Transplantation of unrelated donor umbilical 
cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell 
dose and HLA disparity on treatment-related mortality and survival. Blood, 2002. 100(5): 
1611-8.
12.
Barker, J.N., D.J. Weisdorf, T.E. DeFor, et al., Transplantation of 2 partially HLA-matched 
umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. 
Blood, 2005. 105(3): 1343-7.
13.
Schoemans, H., et al., Adult umbilical cord blood transplantation: a comprehensive review, 
Bone Marrow Transplantation, 2006. 38(2): 83-93.
14.
Ponce D, Sauter C, Devlin S, Lubin M, Gonzales A, Kernan N, Scaradavou A, Giralt S, 
Goldberg J, Koehne G, Perales M, Young J, Castro-Malaspina H, Jakubowski A, 
Papadopoulos E, Barker J. A Novel Reduced-Intensity Conditioning Regimen Induces a High 
Incidence of Sustained Donor-Derived Neutrophil and Platelet Engraftment afterDouble-Unit 
Cord Blood Transplantation. BBMT, Feb 2013; 19: 799-803.
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Appendix I
GVHD Staging and Grading 
ACUTE GVHD ASSESSMENT
Staging by Individual Organ Involvement
SKIN:
measured by rash first appearing generally between 10 and 70 days after transplant. (excludes 
rashes of known viral or other origin)
Stage
Description
1
Maculopapular rash  <25% BSA
2
Maculopapular rash 25 – 50% BSA
3
Generalized erythroderma 
4
Generalized erythroderma with
bullous formation and desquamation
LIVER*:
measured by total serum bilirubin
Stage
Description
1
2.0 – 2.9 mg/dL
2
3.0 – 5.9 mg/dL
3
6.0 – 14.9 mg/dL
4
> 15.0 mg/dL
GUT**:
includes only diarrhea occurring after Day +21
Score
Adult
Pediatric***
1
upper GI (anorexia, nausea, 
vomiting) with diarrhea of <1000 
mL/day
upper GI (anorexia, nausea, 
vomiting) with diarrhea of <555 
mL/m2/day
2
1000 – 1499 mL/day diarrhea
556-833 mL/m2/day diarrhea
3
> 1500 mL/day diarrhea
>833 mL/m2/day diarrhea
4
severe abdominal cramping, bleeding or ileus caused by GVHD
*
In cases where another cause of hyperbilirubinemia antedated the onset of rash, the liver score 
should be decreased by one stage.
**
In cases where peak GI symptoms are exacerbated by a cause other than GVHD, the gut score 
should be decreased by one stage.
***  Pediatric patients <17 years of age
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APPENDIX I (continued)
GVHD Staging and Grading 
ACUTE GVHD ASSESSMENT
Overall Grade
The determination of an overall GVHD grade should be based on the organ stage, response to treatment 
and whether GVHD was a major cause of death.
Overall 
Grade
 Organ Stage
Qualifying Conditions
Additional Qualifying Conditions
I
Stage 1 -2 skin 
No liver or gut
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD.
II
Stage 3 skin 
or 
Stage 1 liver 
or 
Stage 1 gut
N/A
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD, but glucocorticoid treatment 
after the onset of GVHD was generally 
sufficient to control the disease.
III
Stage 4 skin 
or 
Stage 2-4 liver 
or 
Stage 2-4 gut 
without GVHD as a 
major contributing cause 
of death
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD and that additional treatment 
after the onset of GVHD did not readily 
control the disease.
IV
Stage 4 skin 
or 
Stage 2-4 liver 
or 
Stage 2-4 gut 
with GVHD as a major 
contributing cause of 
death
GVHD was resistant to both the 
prophylactic immunosuppressive 
regimen and any additional treatment 
after the onset of the disease.
References:  
1.
Leisenring, WM, Martin, PJ, Petersdorf, EW, et al. An acute graft-versus-host-disease activity index to predict 
survival after hematopoietic cell transplantation with myeloablative conditioning regimens, Blood, 2006:108: 
749-755.
2.
Przepiorka D, Weisdorf D, Martin PJ, et al. 1994 Consensus Conference on Acute GVHD Grading.  Bone 
Marrow Transplant. 1995:15: 825-828.
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 APPENDIX I (continued)
GVHD Staging and Grading
CHRONIC GVHD
Patients who develop clinical and laboratory findings of chronic GVHD will be classified according to the 
schema outlined below:
Clinical Limited cGVHD
1. 
Oral abnormalities consistent with cGVHD, a positive skin or lip biopsy, and no other manifestations 
of cGVHD.
2.
Mild liver test abnormalities (alkaline phosphatase <2 x upper limit of normal, AST or ALT <3 x upper 
limit of normal and total bilirubin <1.6) with positive skin or lip biopsy, and no other manifestations of 
cGVHD. 
3.
Less than 6 papulosquamous plaques, macular-papular or lichenoid rash involving <20% of body 
surface area (BSA), dyspigmentation involving <20% BSA, or erythema involving <50% BSA, 
positive skin biopsy, and no other manifestations of cGVHD. 
4.
Ocular sicca (Schirmer’s test <5mm with no more than minimal ocular symptoms), positive skin or lip 
biopsy, and no other manifestations of cGVHD.  
5. 
Vaginal or vulvar abnormalities with positive biopsy, and no other manifestations of cGVHD.
Clinical Extensive cGVHD
1.
Involvement of two or more organs with symptoms or signs of cGVHD, with biopsy documentation of 
cGVHD in any organ.
2.
 More than 15% loss of base line body weight not due to other causes, with biopsy documentation of 
cGVHD in any organ.  
3.
Skin involvement more extensive than defined for clinical limited cGVHD, confirmed by biopsy.
4.
Scleroderma or morphea. 
5. 
Onycholysis or onychodystrophy thought to represent cGVHD, with documentation of 
cGVHD in any organ 
6. 
Decreased range of motion in wrist or ankle extension due to fasciitis caused by cGVHD. 
7.
Contractures thought to represent cGVHD.
8.
Oral involvement with functional impairment, refractory to topical treatment. 
9.
Vaginal involvement with functional impairment, refractory to topical treatment.
10.
Bronchiolitis obliterans not due to other causes. 
11.
Positive liver biopsy; or abnormal liver function tests not due to other causes with 
alkaline phosphatase >2 x upper limit of normal, AST or  ALT >3 x upper limit of normal, or total 
bilirubin  >1.6, and documentation of cGVHD in any organ. 
12.
Positive upper or lower GI biopsy 
13.       Fasciitis or serositis thought to represent cGVHD and not due to other causes
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APPENDIX II: The Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI)
Instructions: Circle applicable scores and provide actual value or cause of' co-morbidity.
Comorbidities 
Definitions
HCT-CI 
weighted 
scores 
Actual Lab 
Values/Comments
Arrhythmia
Atrial fibrillation or flutter, sick sinus  syndrome, and 
ventriuclar arrhythmias
1
Cardiac
Coronary artery disease, congestive heart failure, 
myocardial infarction, or EF<50%
1
Inflammatory 
bowel disease
Crohn's disease or ulcerative colitis
1
Diabetes*
Requiring treatment with insulin or oral 
hypoglycemics, but not diet alone
1
Cerebro-vascular 
disease
Transient ischemic attack or cerebro-vascular a 
ccident
1
Psychiatric
Disturbance
Depression anxiety requiring psychiatric consult or 
treatment
1
Hepatic -mild*
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN,or 
AST/ALT >ULN-2.5XULN
1
Obesity*
Patients with a body mass index > 35kg/ m2
1
Infection*
Requiring continuation of anti-microbial
Treatment after day 0
1
Rheumatologic
SLE, RA, polymyositis, mixed CTD
Polymyalgia rheumatica
2
Peptic ulcer*
Requiring treatment
2
Moderate/severe
renal*
serum creatinine>2mg/dl, on dialysis, or prior renal 
transplantation
2
Moderate
pulmonary*
DLCO and/or FEV1, 66%-80% or
Dyspnea on slight activity
2
Prior solid tumor
Treated at any time point in the patient's past
history, excluding non-melanoma skin cancer
3
Heart valve 
disease*
Except mitral valve prolapse
3
Severe 
pulmonary*
DLCO and/or FEV1 ≤65% or
dyspnea at rest requiring oxygen
3
Moderate/severe
Hepatic
Liver cirrhosis, Bilirubin>1.5XULN or
AST/ALT>2.5XULN
3
Please provide         Karnofksy performance Score (KPS) 
=______________%
Total 
Score
=______
Completed by (Print ): _____________________________________   Date: ________________
Signature: ________________________________________________
*Comorbidity is currently active or patient requires medical treatment +
One or more vessel-coronary artery stenosis, requiring medical treatment, stent, or bypass graft 
EF indicates ejection fraction; ULN, upper limit of normal; SLE, systemic lupus erythematosus;  RA, rheumatoid arthritis; CTD, connective tissue disease;
DLCO, diffusion capacity of carbon monoxide; FEV1, forced expiratory volume in one second; AST, aspartate aminotransfcrase; ALT, alanine aminotransferas
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APPENDIX III
Potential Adverse Events Associated or Expected with Hematopoietic Cell Transplantation
1. Graft versus host disease:  GVHD is a major toxicity associated with the infusion of allogeneic donor 
stem cells.  GVHD may be acute or chronic and may affect multiple organ systems, including the skin, liver, 
and GI tract.
2. Opportunistic infections, including viral and fungal infections, can results in severe pulmonary, neurologic, 
hepatic and other organ dysfunction, and possible death.
3. Gastrointestinal toxicity. Nausea and vomiting can be anticipated during the entire course of ablative 
therapy. Mucositis and diarrhea should be expected. Prednisone can cause GI bleeding.
4. Cardiac toxicity. Cardiac toxicity (congestive heart failure, pericardial effusion, EKG changes) is 
uncommonly associated with the chemotherapy agents and TBI used in the regimen and these sequelae 
may prove lethal.
5. Pulmonary toxicity. Diffuse interstitial pneumonitis of unknown etiology occurs with some regularity after 
BMT and interstitial fibrosis occurs much more rarely. Both are well-described complications of intensive 
chemotherapy and TBI regimens and may prove lethal.
6. Hepatic toxicity. Veno-occlusive disease of the liver is a common toxicity of high-dose chemoradiotherapy 
and may result in death. Cyclosporine may cause elevation of ALT/AST.
7. Renal dysfunction. Chemoradiotherapy may uncommonly cause renal dysfunction. More commonly, 
nephrotoxicity results from cyclosporine and generally responds to dose reduction. Rarely, idiopathic or 
calcineurin inhibitor-associated hemolytic-uremic syndrome may occur and may be progressive and fatal. A 
syndrome of moderate renal insufficiency and hemolysis has been seen 5-7 months post HSCT after 
intensive multi-agent conditioning plus TBI.
8. Hemorrhagic cystitis, manifested either as gross or microscopic hematuria, is a common toxicity after 
high-dose chemoradiotherapy, but usually associated with regimens that include cyclophosphamide. 
Hemorrhagic cystitis may predispose to a long-term increased risk of bladder cancer.
9. Central nervous system toxicity. Radiation and chemotherapy can cause CNS toxicity, including seizures, 
depressed mental status, or leukoencephalopathy. Calcineurin inhibitors can cause seizures or other CNS 
toxicity.
10. Marrow aplasia. Severe neutropenia, thrombocytopenia, and anemia, is expected to occur for a period 
of 7 to 42 days following infusion of marrow. Transfusion of platelets and red blood cells is expected as 
supportive care. Transfusion of blood products may be associated with acquisition of HIV or a hepatitis 
virus. Neutropenia may increase the risk for acquiring serious infection. Thrombocytopenia may increase 
the risk of life-threatening hemorrhage. Hemorrhagic or infectious complications during the expected period 
of aplasia may result in death.
11. Miscellaneous. Alopecia and sterility are expected complications of the program as a whole. Cataract 
development is possible after TBI and/or steroids. Deficiencies of growth hormone, thyroid hormone, and 
sex hormones are possible after TBI. Calcineurin inhibitors can cause transient gingival hyperplasia, tremor, 
seizure, hypertension, headache, dysesthesia and hirsutism. Steroid therapy can also contribute to fluid 
retention, easy bruising, hypertension, aseptic necrosis of bone and increased susceptibility to infection. 
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MMF can cause spontaneous abortions and birth defects. Hospitalization during conditioning and recovery 
period is expected to be 5-9 weeks in duration.
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APPENDIX IV - Karnofsky and Lansky Performance Status Scales
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In bed <50% of the time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.
LANSKY PLAY PERFORMANCE STATUS SCALE
Percentage
100
Fully active, normal
90
Minor restrictions in physically strenuous activity
80
Active, but tires more quickly
70
Both greater restriction of, and less time spent in, play activities
60
Up and around, but  minimal active play; keeps busy with quieter activities
50
Gets dressed but lies around much of the day, no active play; able to participate in all 
quiet play and activities
40
Mostly in bed; participates in quiet activities
30
In bed; needs assistance even for quiet play
20
Often sleeping; play entirely limited to very passive activities
10
Unresponsive
0
Dead
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 APPENDIX V
Umbilical Cord Blood Graft Selection 
CB donor selection will be based on institutional guidelines and in general should be selected to optimize 
both HLA match and cell dose. Additionally, CB grafts shall consist of one or two CB donors based on, but 
not exclusively determined by, cell dose (TNC/kg and CD34/kg), HLA matching and disease status and 
indication for transplant. Attending preference will be allowed for single versus double unit as well as the 
degree of mismatching based on patient specific factors, as long as the following minimum criteria are met:
A. HLA matching:
i.
Minimum requirement: The CB graft(s) must be matched at a minimum at 4/6 HLA-A, B, 
DRB1 loci with the recipient. Therefore 0-2 mismatches at the A or B or DRB1 loci based on 
intermediate resolution A, B antigen and DRB1 allele typing for determination of HLA-match 
is allowed. 
ii.
HLA-matching determined by high resolution typing is allowed per institutional guidelines as 
long as the minimum criteria (#A.i., above) are met. 
B. Selection of two CB units is mandatory when a single cord blood unit does not meet the following 
criteria in the table below.  
Single Unit Allowed for:
Match 
Grade
TNC Dose
6/6
≥ 2.5 x 107/kg
5/6, 4/6
≥ 4.0 (± 0.5) x 107/kg
If two CB units are used, the total cell dose of the combined units must be at least 3.0 x 107 TNC 
per kilogram recipient weight based on pre-cryopreservation numbers, with each CB unit 
containing a MINIMUM of 1.5 x 107 TNC/kg. 
C. The minimum recommended CD34/kg cell dose should be 2 x 105 CD34/kg, total dose from a 
single or combined double. 
D. The unmanipulated CB unit(s) will be FDA licensed or will be obtained under a separate IND, such 
as the National Marrow Donor Program (NMDP) Protocol 10-CBA conducted under BB IND-7555 
or another IND sponsored by (1) a participating institution or (2) an investigator at FHCRC or one 
of the participating institutions. 
E. FHCRC only: Up to 5% of the unmanipulated cord blood product (s), when ready for infusion, may 
be withheld for research purposes as long as thresholds for infused TNC dose are met.  These 
products will be used to conduct studies involving the kinetics of engraftment and immunobiology 
of double cord transplantation.
  
UCB Unit Exclusions
1. Any cord blood units with <1.5 x 107 total nucleated cells per kilogram recipient weight.
2. Any cord blood units without full maternal testing and negative results for hepatitis B, C, HIV, and HTLV-1 
viruses. Any additional available virology results on the unit itself will be reviewed but are not mandated, 
complete or always available. Cord blood units are presumed to be CMV negative regardless of serologic 
testing due to passive transmission of maternal CMV antibodies. 
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APPENDIX VI:  Adapted from COMMON TOXICITY CRITERIA (CTC)
ALLERGY/IMMUNOLOGY
Adverse Event
Grade 3
Grade 4
Allergic reaction/ hypersensitivity 
(including drug fever)
Symptomatic bronchospasm, requiring 
parenteral medication(s), with or 
without urticaria; allergy related 
edema/angioedema
Anaphylaxis
Vasculitis Requiring steroids 
 
Requiring steroids
Ischemic changes or requiring amputation
Allergy/Immunology – Other
(specify):________________
Severe
Life-threatening or disabling
BLOOD/BONE MARROW
Adverse Event
Grade 3
Grade 4
Hemolysis (e.g., immune
hemolytic anemia, drug related
hemolysis, other)
Requiring transfusion and/or
medical intervention (e.g.,
steroids)
Catastrophic consequences of hemolysis 
(e.g., renal failure, hypotension,
bronchospasm, emergency
splenectomy)
For BMT studies, if specified
in the protocol.
For pediatric BMT studies, if
specified in the protocol.
>4 u pRBC in 24 hours
>30mL/kg in 24 hours
Hemorrhage or hemolysis associated with 
life-threatening anemia; medical
intervention required to improve 
hemoglobin
Hemorrhage or hemolysis associated with 
life-threatening anemia; medical
intervention required to improve 
hemoglobin
CARDIOVASCULAR - ARRHYTHMIA
Adverse Event
Grade 3
Grade 4
Cardiovascular/Arrhythmia -
Other (specify): __________
_______________________
Symptomatic, and requiring
treatment of underlying cause
Life-threatening (e.g., arrhythmia 
associated with CHF, hypotension, 
syncope, shock)
CARDIOVASCULAR – GENERAL
Adverse Event
Grade 3
Grade 4
Cardiac left ventricular function
CHF responsive to treatment
Severe or refractory CHF or requiring 
intubation
Cardiac troponin I (cTnI) 
Levels consistent with unstable
angina as defined by the
manufacturer
Levels consistent with myocardial
infarction as defined
Cardiac troponin T (cTnT)
≥ 0.1 - <0.2ng/mL
≥ 0.2ng/mL
Hypotension
Requiring therapy and sustained
medical attention, but resolves
without persisting physiologic
consequences
 Shock (associated with acidemia and
impairing vital organ function due to
tissue hypoperfusion)
Myocarditis
CHF responsive to treatment
Severe or refractory CHF
Pericardial effusion/ pericarditis
With physiologic consequences
Tamponade (drainage or pericardial 
window required)
Syncope (fainting) is graded in the 
Neurology category.
-
-
Thrombosis/embolism
Deep vain thrombosis, requiring
anticoagulant therapy
Embolic event including 
pulmonaryembolism
Vein/artery operative injury is
graded as Operative injury of
vein/artery in the
Cardiovascular (general)
category.
Other (specify):___________
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Cardiovascular/General –
Severe
Life-threatening or disabling
COAGULATION
Adverse Event
Grade 3
Grade 4
DIC (disseminated intravascular
coagulation)
Also consider
Platelets.
Note: Must have increased fibrin
split products or D-dimer in order 
to grade as DIC
Laboratory findings present with
no bleeding
Laboratory findings and bleeding
Thrombotic microangiopathy
(e.g., thrombotic thrombocytopenic 
purpura/TTA or
hemolytic uremic syndrome/HUS)
Also consider
Hemoglobin, platelets, creatinine.
Note: Must have microangiopathic
changes on blood smear (e.g., 
schistocytes, helmet cells, red cell 
fragments).
Laboratory findings present
without clinical consequences
Evidence of RBC destruction with 
creatinine (>3 x ULN) not
requiring dialysis
Laboratory findings and clinical 
consequences, (e.g., CNS 
hemorrhage/bleeding or
thrombosis/embolism or renal failure) 
requiring therapeutic intervention
Evidence of RBC destruction with renal 
failure requiring dialysis and/or 
encephalopathy.
Coagulation - Other (specify):
_________________________
Severe
Life-threatening or disabling
CONSTITUTIONAL SYMPTOMS
Adverse Event
Grade 3
Grade 4
Weight gain associated with
Veno-Occlusive Disease (VOD)
for BMT studies, if specified in
the protocol.
Also consider
Ascites Edema, Pleural effusion
(non-malignant).
>10% or as ascites
>10% or fluid retention resulting in 
pulmonary failure
DERMATOLOGY/SKIN
Adverse Event
Grade 3
Grade 4
Erythema multiforme (e.g.,
Stevens-Johnson syndrome, toxic
epidermal necrolysis)
Severe or requiring IV fluids (e.g., 
generalized rash or painful
stomatitis)
Life-threatening (e.g., exfoliative or 
ulcerating dermatitis or requiring
enteral or parenteral nutritional support)
Rash/desquamation associated
with graft versus host disease
(GVHD) for BMT studies, if
specified in the protocol.
Symptomatic generalized
erythroderma or symptomatic
macular, papular or vesicular
eruption, with bullous formation,
or desquamation covering ≥50% of 
body surface area.
Generalized exfoliative dermatitis or 
ulcerative dermatitis or bullous formation
GASTROINTESTINAL
Adverse Event
Grade 3
Grade 4
Ascites (none-malignant)
Symptomatic, requiring therapeutic 
paracentesis
Life-threatening physiologic
consequences
Colitis
Also consider
Hemorrhage/ bleeding with grade
3 or 4 thrombocytopenia,
Abdominal pain, fever, change in 
bowel habits with ileus or
peritoneal signs, and radiographic or 
biopsy documentation
Perforation or requiring surgery or toxic 
megacolon
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hemorrhage/bleeding without
grade 3 or 4 thrombocytopenia,
melena/GI bleeding, rectal
bleeding/hematochezia, 
hypotension.
Diarrhea associated with graft
versus host disease (GVHD) for
BMT studies, if specified in the
protocol.
For pediatric BMT studies, if
specified in the protocol.
Also consider
Hemorrhage/ bleeding with grade
3 or 4 thrombocytopenia,
hemorrhage/bleeding without
grade 3 or 4 thrombocytopenia,
pain, dehydration, hypotension.
>1500mL of diarrhea/day
>15mL/kg of diarrhea/day
Severe abdominal pain with or without 
ileus
Duodenal ulcer (requires
radiographic or endoscopic 
documentation)
Uncontrolled by outpatient
medical management; requiring
hospitalization
Perforation or bleeding, requiring 
emergency surgery
Gastric ulcer (requires
radiographic or endoscopic
documentation)
Also consider
Hemorrhage/bleeding with grade
3 or 4 thrombocytopenia,
hemorrhage/bleeding without
grade 3 or 4 thrombocytopenia.
Bleeding without perforation,
uncontrolled by outpatient medical 
management; requiring
hospitalization or surgery
Perforation or bleeding, requiring 
emergency surgeryv
Gastritis
Also consider
Hemorrhage/bleeding with grade
3 or 4 thrombocytopenia,
hemorrhage/bleeding without
grade 3 or 4 thrombocytopenia.
Uncontrolled by out-patient
medical management; requiring
hospitalization or surgery
Life-threatening bleeding, requiring 
emergency surgery
Pancreatitis
Also consider
Hypotension.
Note: Amylase is graded in
theMETABOLIC/LABORATORY
category.
Abdominal pain with pancreatic
enzyme elevation
Complicated by shock (acute
circulatory failure)
Mucositis
Note: Radiation-related mucositis
is graded as Mucositis due to
radiation.
Painless erythema, edema, or
ulcers preventing swallowing or
requiring hydration or parenteral
(or enteral) nutritional support
Severe ulceration requiring
prophylactic intubation or resulting in 
documented aspiration pneumonia
Typhlitis
(inflammation of the cecum)
Also consider
Hemorrhage/bleeding with grade
3 or 4 thrombocytopenia,
hemorrhage/bleeding without
Abdominal pain, diarrhea, fever,
and radiographic or biopsy
documentation
Perforation, bleeding or necrosis or other 
life-threatening complication
requiring surgical intervention (e.g., 
colostomy)
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grade 3 or 4 thrombocytopenia,
hypotension, febrile neutropenia.
HEMORRHAGE
Notes:
Transfusion in this section refers to pRBC infusion.
For any bleeding with grade 3 or 4 platelets (<50,000), always grade Hemorrhage/bleeding with grade 3 or 4 
thrombocytopenia. Also consider Platelets, Transfusion: pRBCs, and Transfusion: platelets in addition to grading severity 
by grading the site or type of bleeding.
If the site or type of Hemorrhage/bleeding is listed, also use the grading that incorporates the site of bleeding: NS 
Hemorrhage/bleeding, Hematuria, Hematemesis, Hemoptysis, Hemorrhage/bleeding with surgery, Melena/lower GI 
bleeding, Petechiae/purpura (Hemorrhage/bleeding into skin), Rectal bleeding/ hematochezia, Vaginal bleeding.
Adverse Event
Grade 3
Grade 4
Hemorrhage/bleeding with grade
3 or 4 theombocytopenia
Also consider
Platelets, hemoglobin, transfusion:
platelets, transfusion: pRBCs, site
or type of bleeding.
If the site is not listed, grade as
Hemorrhage – Other (specify
site):___________
Note: This adverse event must be
graded for any bleeding with
grade 3 or 4 thrombocytopenia.
Requiring transfusion
Catastrophic bleeding, requiring major 
non-elective intervention
CNS hemorrhage/bleeding
Bleeding noted on CT or other
scan with no clinical consequences
Hemorrhagic stroke or hemorrhagic 
vascular event (CVA) with neurologic 
signs and symptoms
Hemoptysis
Requiring transfusion
Catastrophic bleeding, requiring major 
non-elective intervention
Melena/GI bleeding
Requiring transfusion
Catastrophic bleeding, requiring major 
non-elective intervention
Rectal bleeding/hematochezia
Requiring transfusion
Catastrophic bleeding, requiring major 
non-elective intervention
Vaginal bleeding
Requiring transfusion
Catastrophic bleeding, requiring major 
non-elective intervention
Hemorrhage – Other (specify
site): _____________________
Requiring transfusion
Catastrophic bleeding, requiring major 
non-elective intervention
HEPATIC
Adverse Event
Grade 3
Grade 4
Bilirubin
Bilirubin associated with graft
versus host disease (GVHD) for
BMT studies, if specified in the
protocol.
>3.0 – 10.0 x ULN
>6 - <15mg/100mL
>10.0 x ULN
>15mg/100mL
INFECTION/FEBRILE NEUTROPENIA
Adverse Event
Grade 3
Grade 4
Febrile neutropenia (fever or
unknown origin without clinically
or microbiologically documented
infection).
Present
Life-threatening sepsis (e.g., septic shock)
Infection/Febrile Neutropenia –
Severe
Life-threatening or disabling
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Other (specify): ______________
NEUROLOGY
Aphasia, receptive and/or expressive, is graded under Speech impairment in the NEUROLOGY category.
Adverse Event
Grade 3
Grade 4
CNS cerebrovascular ischemia
Transient ischemic event or attack 
(TIA)
Permanent event (e.g.,
cerebral vascular accident)
Leukoencephalopathy associated
radiological findings
Severe increase in SAS; severe
ventriculomegaly; near total white 
matter T2 hyperintensities or diffuse 
low attenuation (CT); focal white 
matter necrosis (cystic)
Severe increase in SAS;
severe ventriculomegaly;
diffuse low attenuation with
calcification (CT); diffuse
white matter necrosis (MRI)
Seizure(s)
Seizure(s) in which consciousness is 
altered
Seizures of any type which
are prolonged, repetitive, or
difficult to control (e.g.,
status epilepticus, intractable
epilepsy)
PULMONARY
Adverse Event
Grade 3
Grade 4
Adult Respiratory Distress 
Syndrome
(ARDS)
-
Present
Apnea
Present
Requiring intubation
Carbon monoxide diffusion capacity 
(DLCO)
>25 - <50% of pretreatment or
normal value
<25% of pretreatment or
normal value
FEV1
>25 - <50% of pretreatment or
normal value
<25% of pretreatment or
normal value
Hypoxia
Decreased O2 saturation at rest,
requiring supplemental oxygen
Decreased O2 saturation,
requiring pressure support
(CPAP) or assisted
ventilation
RENAL/GENITOURINARY
Adverse Event
Grade 3
Grade 4
Creatinine
Note: Adjust to age-appropriate
levels for pediatric patients
>3.0- 6.0 x ULN
>6.0 x ULN
Renal failure
Requiring dialysis, but reversible
Requiring dialysis and irreversible
SECONDARY MALIGNANCY
Adverse Event
Grade 3
Grade 4
Secondary Malignancy – Other
(specify type): _______________
Excludes metastasis from initial
primary.
-
Present
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APPENDIX VII:   FHCRC IRB Policies
http://extranet.fhcrc.org/EN/sections/iro/irb/policy/index.html
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APPENDIX VIII Schedule of Study Evaluations
Day 1 to engraftment
Days 31-100
Long-Term Follow-up
Screen
daily
weekly
Day 28 
(± 3 days)
weekly
Day 56
(± 7 days)
Day 80
(± 7 days)
Day 100
(± 7 days)
6 months
(± 30 days)
1 year
2 years
Informed consent
X
Medical history
X
Physical exam
X
X
X
X
X
X
Performance status
X
X Day 80-100
X
X
X
Height/Weight
X
X
GVHD evaluation
X
X
X
X
X
X
Adverse events 
X
X
CBC with diff 
X
X
X
X
X
X
Basic Metabolic Panel
X
X
X
X
X
X
Hepatic Function Panel
X
As clinically indicated or per standard practice
Viral screening including 
CMV PCR 
X
CMV Surveillance by
PCR
per standard practice
Pregnancy test
X
Urinalysis
X
As clinically indicated or per standard practice
EKG
X
As clinically indicated or per standard practice
MUGA or echo
X
As clinically indicated or per standard practice
Chest x-ray or CT
X
As clinically indicated or per standard practice
PFT
X
As clinically indicated or per standard practice
Bone marrow asp/bx**
X
X
X
X
Chimerism – BM
X
X
X
Chimerism – PB
X
X
X
X
X
X
Disease evaluation
X
X
X
X
X
IgG, IgA, IgM*
X
X
X
X
X
X
X
Lymphocyte panel as 
possible
X
X
X
X
X
X
HCT-CI (for patients >45)
X
Check Section 7.0:  Study Parameters for details.   NOTE:  In certain circumstances (e.g., relapse or terminal illness), study evaluations may be omitted at the physician’s or PI’s discretion. 
Every effort will be made to complete the 1- and 2-year evaluations as close to these dates as possible, taking into consideration patient’s circumstances at these timepoints.* Per Section 7.3,  
Quantitative immunoglobulin levels (IgG, IgA, IgM) as possible at Days 56, 80, 6 months, 1 year and 2 years. **Bone marrow biopsy as clinically indicated. 

ICF_001.pdf: 
FHCRC 2010.00 Regimen A
Page 1 of 13
FRED HUTCHINSON CANCER RESEARCH CENTER
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE
SEATTLE CHILDREN’S 
Consent to Participate in:
Transplantation of Umbilical Cord Blood for Patients with Hematological Diseases 
with Cyclophosphamide/Fludarabine/Total Body Irradiation or 
Cyclophosphamide/Fludarabine/Thiotepa/Total Body Irradiation Myeloablative 
Preparative Regimen (Protocol 2010)
Consent Form for Regimen A: High Intensity Regimen 
(Cyclophosphamide/Fludarabine/Total Body Irradiation)
NOTE:  If you are a parent or guardian of a patient younger than 18 years old and have 
been asked to sign this form, the “you” in this document refers to the patient.
Principal Investigator:  Ann Dahlberg, MD, Assistant Member, FHCRC, Assistant 
                                        Professor of Pediatrics, UW, 206-667-1959
Research Staff:  Jenna Pedersen, Clinical Research Coordinator, 206-667-6013
                           
Emergency (24 hour) Phone (For Adults):  (206) 598-8902; Fax: (206) 598-4034 
Emergency (24 hour) Phone (For Children):  (206) 987-2032; Fax (206) 987-2764  
We would like you to join this research study.
To help you decide if you want to join this study, you should:

Read this form.

Ask your doctor or nurse questions about this study.

Have your doctor or nurse explain anything you do not understand.

Talk with your family or friends about joining.

Take time to think about joining.
After you have learned about this study, met with your doctor and asked questions, you can 
decide if you want to join this study or not. This process is called informed consent.
This informed consent form gives information to help you decide if you want to join this study 
or not. In this form, we explain why we are doing this study, the risks and benefits to you, your 
choices, and other important information. Your doctor will explain the research study to you.
If you decide to join this study, we will ask you to sign this form. After you sign the form, you will 
get a copy to keep.
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The purpose of a research study is to answer questions.
Research is not the same as treatment or medical care. The purpose of a research study is to 
answer scientific questions. 
We are inviting you to join this study because you are eligible for a cord blood transplant. The 
purpose of this study is to examine how patients respond to a cord blood transplant after doses 
of chemotherapy and radiation by collecting data throughout the transplant process, specifically 
looking to see if the disease is absent or present at six months, one year, and two-years post-
transplant. Information we learn from larger numbers of patients will allow us to make more 
accurate estimates about these outcomes.  
You do not have to be in this study.
Joining this study is up to you. You are free to say yes or no. Your regular medical care will not 
change. Even if you join this study, you do not have to stay in it. You may stop at any time. 
There is no penalty for stopping, and your regular medical care will not change. 
Background 
Blood stem cells are the “parent cells” of the blood and bone marrow. They grow inside your 
bone marrow, which is your body’s “factory” to make the cells that circulate in your blood.  
These include: red blood cells (which carry oxygen), white blood cells (which fight infection), and 
platelets (which prevent bleeding). Certain cancers can be treated by giving patients stem cells 
that come from someone else. This is called a stem cell transplant. As part of the transplant 
process, patients receive doses of chemotherapy and radiation to treat their underlying disease, 
such as cancer. As one of its effects, this treatment also kills the healthy blood stem cells that 
are already in the bone marrow and giving a patient blood stem cells from a healthy donor leads 
to recovery of the bone marrow and provides a new blood system that makes the cells that 
circulate in the blood. In the case of this study these new blood stem cells will come from 
umbilical cord blood. 
Cord blood transplants are relatively new, and we’re striving to make them even more safe and 
effective in the future. We do most transplants as part of a study; which means that we follow a 
detailed protocol to make sure it’s always done the same way and we keep careful records so 
that we can evaluate the outcomes. Therefore, we would like to transplant you on this research 
study and collect information about the outcome of your transplant. Analysis of the outcomes of 
these transplants will help us improve transplant outcomes in the future.    
How many people will take part in the study?
Approximately 135 patients will be enrolled in this study.
What research tests, procedures, and treatments are parts of this 
study?
This research program involves the use of the following drugs, treatment programs, or research 
procedures:
Cyclophosphamide
Fludarabine
Total Body Irradiation
Cyclosporine A
Mycophenolate mofetil
GCSF
Cord Blood Stem Cells
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Conditioning (pre-transplant chemotherapy and radiation)
You will be receiving the High Intensity Regimen. The conditioning regimen is standard 
treatment and is not experimental. It will involve the following: 

Seven or eight days before the transplant, you will be admitted to the hospital on the 
bone marrow transplant unit. You will also need a central venous catheter for transplant, 
so if you do not already have one, one will be placed.

Chemotherapy (cyclophosphamide and fludarabine) and total body radiation (TBI) are 
given with the intent of helping to kill cancer cells and to prepare your body for the cord 
blood stem cells by suppressing your immune system. These procedures are 
summarized in a table below.
High Intensity Regimen
(High Dose TBI total 1320 cGy (165 cGy BID, total 8 fractions, days -4 to -1))
Day
Conditioning
Supportive 
Care/Other
8 days prior to 
transplant
Fludarabine
7 days prior to 
transplant
Fludarabine
Cyclophosphamide
6 days prior to 
transplant
Fludarabine
Cyclophosphamide
5 days prior to 
transplant
Rest
4 days prior to 
transplant
TBI twice daily
3 days prior to 
transplant
TBI twice daily
Begin CSA (100+ 
days)
2 days prior to 
transplant
TBI twice daily
1 day prior to 
transplant
TBI twice daily
0 (TRANSPLANT 
DAY)
Unmanipulated cord blood unit(s)
Begin MMF  
1 day after transplant
Begin GCSF (daily 
until recovery of 
white blood cell 
count)
Transplant Day 
On Day 0, the transplant day, the cord blood stem cells are given intravenously through the 
central venous catheter. 
Immunosuppression Therapy
As part of the transplant procedure, you will be given two drugs to reduce the risk of graft versus 
host disease, a complication that occurs when the cord blood stem cells recognize the patient's 
body as foreign and attack it. These drugs will be started three days before the cord blood stem 
cells are given. Both drugs will initially be given through your central venous catheter and then 
changed to a pill form when you can take a capsule orally as tolerated. The first drug is called 
Cyclosporine A. Cyclosporine will be continued for at least 100 days and most probably until 
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Day 180 after transplant. The second drug is called Mycophenolate Mofetil (MMF). MMF will 
continue for at least 30 days.  
Follow-up
To speed the recovery of blood cells as much as possible, you will receive granulocyte-colony-
stimulating factor (GCSF or Neupogen). GCSF signals the bone marrow to make white blood 
cells, which are needed to fight and prevent infections. You will start receiving GCSF through 
your central line or as an injection under the skin the day after transplant. You will continue to 
receive it daily until your white blood cell count recovers.  
In order to evaluate how your new marrow is developing, you will have blood drawn and/or bone 
marrow biopsies at specific time points. You are planned to have blood drawn at Day 28, Day 
56, Day 80, 6 months, 1 year and 2 years after your transplant.  
You will be discharged from the inpatient bone marrow transplant unit when you are ready to be 
cared for as an outpatient. Initially, it will be necessary for you to have frequent visits at the 
outpatient transplant clinic, and then at specific times as determined by your physician.  
You will be followed in the study for 2 years. After you have recovered from any immediate 
transplant related complications, follow-up will be routine and according to your specific disease 
type, but we will continue to collect data on how your marrow is functioning at these follow-up 
visits.
As part of follow-up, we would like to contact you and/or your referring physician around 6 
months, 1 year, and 2 years after transplant to see how you are doing. We may contact your 
physician to request copies of blood test results and other tests and procedures done as 
standard post-transplant follow-up. This will help us learn about the long-term effects of the 
study.
How long will I be in the study?
You will be followed in the study for 2 years. Even after you are discharged from the transplant 
center, we will work with your health care provider to gather information about your general 
health status and transplant-related problems for up to 2 years.
As part of follow up, we would like to call you on the telephone around 6 months and two years 
after transplant to see how you are doing. Keeping in touch with you and checking on your 
condition at these times helps us look at the long-term effects of the study. 
The researcher may stop you from taking part in this study at any time if he/she believes it is in 
your best interest; if you do not follow the study rules; or if the study is stopped.
You can decide to stop at any time. It is important to tell the study doctor if you are thinking 
about stopping so any risks from the treatment can be evaluated by your doctor. Another reason 
is to discuss what follow-up care and testing could be most helpful for you. 
What side effects or risks can I expect from being in the study?
The side effects associated with transplantation can be uncomfortable, and in some cases, 
dangerous, life threatening, or fatal. Because this is a research study and the treatments are 
relatively new, there may be additional side effects which are not known or predictable at this 
time. The known or possible side effects of the treatments you will receive as part of this study 
are listed below.
Risks Associated with Conditioning, Immunosuppression and 
Supportive Therapies 
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1. 
Cyclophosphamide (Cytoxan): 
Likely Side Effects 
Less Likely Side Effects 
Rare Side Effects 

Lower white blood cell count with 
increased risk of infection

Diarrhea (loose stools)

Vomiting (throwing up)

Liver damage

Lower sperm production in men

Hair loss

Nausea (feeling sick to your 
stomach)

Loss of appetite

Missing or stopping menstrual 
cycle in women

Sores in mouth or on lips

Blood in urine

Fatigue

Lower platelet count (mild) 
with increased risk of 
bleeding, especially with an 
injury like falling

Darkening of nail beds

Fetal damage if pregnancy 
occurs while taking 
Cyclophosphamide

Lung fibrosis with 
cough and 
shortness of breath

Heart failure with 
high doses

Decrease in 
sodium level in the 
blood with high 
doses

Secondary cancers
Cyclophosphamide can cause bleeding in your bladder. Getting more fluid through a 
vein or your catheter and drinking extra liquids may prevent this. 
2.
Fludarabine: 
Likely Side Effects 
Less Likely Side Effects 
Rare Side Effects 

Low white blood cell count with 
an increased risk of infection 
(from bacteria, fungi or viruses)

Lower platelet count with and 
increased risk of bleeding

Anemia

Nausea (feeling sick to your 
stomach)

Diarrhea (loose stools)

Fatigue

Vomiting 
(throwing-up)

Trouble seeing or 
problems with your 
eyes

Numbness or 
tingling in your 
fingers or toes

Severe problems 
with your brain 
(confusion or 
coma)

Pneumonia
3. 
Mycophenolate Mofetil (MMF): 
Likely Side Effects 
Less Likely Side Effects 
Rare Side Effects 

Nausea (feeling sick to 
stomach)

Miscarriage or birth 
defects if become 
pregnant while taking 
and within 6 weeks 
after stopping MMF

Vomiting (throwing up) 

Diarrhea (loose stools) and 
abdominal discomfort

Lower red blood cell count 
that is reversible

Lower white blood cell count 
with increased risk of infection

Stomach and bowel 
bleeding (blood in stools)

Secondary cancers

Progressive multifocal 
leukoencephalopathy (a 
serious brain infection that 
can cause weakness, 
clumsiness and confusion 
and can lead to death)
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 4. 
Cyclosporine:
5. 
Total body irradiation (TBI): 
Likely Side Effects 
Less Likely Side Effects 

Nausea (feeling sick to 
stomach)

Fatigue (feeling tired)

The irradiation dose used will 
probably result in sterility

Temporary hair loss   

Vomiting (throwing up) 

Diarrhea (loose stools)

Painful swelling of the parotid gland (a gland under 
the chin) for a few days  

Cataracts (an opacity or whitening of the lens) may 
develop in the eye

Secondary cancers
You will also have tests such as CT scans and chest x-rays, based on medical necessity 
and to help follow your progress. These studies are routine care after a transplant and 
expose you to more radiation, but the amount of radiation from these tests are small in 
comparison to the therapy dose and are not expected to increase your health risk.
Total body irradiation (TBI) destroys both the abnormal and normal marrow, resulting in 
a loss of red blood cells, white blood cells, and platelets. The temporary absence of 
these blood cells produces a risk of anemia, infection, and/or bleeding. This continues 
until the bone marrow transplant begins to work. Blood transfusions are given as 
needed.  
Likely Side Effects 
Less Likely Side Effects 
Rare Side Effects 

Nausea (feeling sick to your 
stomach)

Vomiting (throwing up)

Loss of magnesium, calcium, 
potassium

Hypertension (high blood 
pressure)

Tremor (shaking of the 
hands) 

Increased hair growth

Pain in the hands and/or 
feet. The pain decreases or 
goes away with the 
improvement of graft-
versus-host disease 
(GVHD), with a decrease in 
the rate of infusion, or 
when the cyclosporine is 
switched from the 
intravenous (by vein) to the 
oral form.

Blood test results that show 
changes in the liver or 
kidney (the dose will be 
lowered or even stopped).

Increases in cholesterol and 
triglyceride

Changes in how clearly one 
can think

Patients have had 
seizures, but it is 
unclear whether 
cyclosporine, 
other drugs, or a 
combination of 
drugs were 
responsible.

Secondary 
cancers
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6.  
Granulocyte Colony Stimulating Factor (GCSF):
Problems we anticipate to be 
common:
Problems we anticipate to be 
less common:
Problems we anticipate to be 
infrequently encountered:

Ache or pain inside the 
bones, increased levels of 
liver enzymes and uric 
acid in the blood, low 
number of platelets in the 
blood

Allergic reaction, low fever

Enlargement of the spleen 
and even splenic rupture 

Worsening of pre-existing 
skin rashes, 

Hair loss 

Inflammation of a blood 
vessel in the skin
The above tables list the side effects of the drugs individually; however, when used in 
combination (as they will be here for pre-transplant chemotherapy/radiation), there may 
be an increase in the occurrence of some side effects. For example, sores in the mouth 
(mucositis) are likely with this combination (cyclophosphamide, fludarabine and TBI) and 
may be severe.
7.  
Late Complications:

Sterility 

Hypothyroidism

Possible increased incidence of radiation or chemotherapy-induced cancer, or 
leukemia [rare]

Possible brain injury [rare]
You will be watched for these side effects and treated as they occur. Follow-up care in the 
hospital and later in the outpatient clinics will be necessary to observe your recovery and 
monitor for any possible late side effects of your transplant.
Risks Associated with Cord Blood Transplantation
The following problems may occur as a result of the transplantation of umbilical cord blood.  
These are risks that would be present whether such a transplant was done as part of a research 
study or not.
1.
Infusion Side Effects (occurring from time of infusion to 2 days after): Cord blood 
cells are stored in a solution containing dimethyl sulfoxide (DMSO) to protect the cells 
during freezing. The following side effects may occur with infusion:
Likely (Over 10% of patients)
Rare Side Effects (Less than 1%)

Unusual taste in the mouth

Unpleasant odor from the lungs 
(and breath) for a few days after 
getting the stem cells

Temporary rise in blood pressure

Nausea, vomiting

Blood in urine

Anxiety

Itching

Hives

Rash

Shortness of breath

Wheezing, chest tightness

Drop in oxygen levels

Changes in heart rate, rhythm or function

Fever

Chills

Sweating

Headache

Stiff muscles

Kidney failure
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2.
Slow bone marrow recovery:  Blood counts, including red blood cells, white blood 
cells, and platelets, may be very slow to recover after unrelated donor umbilical cord 
blood transplantation. Until the new cord blood stem cells begin to grow, you are at risk 
of developing infections or bleeding.  Infections can be treated with antibiotics but 
sometimes can be very serious. Bleeding can be corrected, at least in part, by 
transfusions. However, there are risks associated with the transfusion of red blood cells 
and platelets during the post-transplantation period. These risks include serious allergic 
reactions and infections, including hepatitis, cytomegalovirus (CMV), and human 
immunodeficiency virus (HIV; the virus that causes AIDS). All blood products, however, 
will be screened for these infections in order to reduce the chance that the blood 
contains these viruses.
3.
Graft failure:  The cord blood stem cells may fail to “take” or engraft. Past experience 
suggests that this may occur in about 10% of patients overall. It is possible that the cord 
blood stem cells will grow, but not work normally.  This will result in low blood counts for 
a long period of time. Graft failure is typically fatal in traditional transplants and may be 
fatal in this type of transplant also. Should the graft fail, you will not have access to 
additional stem cells from the same infant donor; instead, you may be able to receive a 
second transplant with stem cells from another unrelated umbilical cord blood donor or a 
mismatched parent or sibling (i.e., brother or sister) donor.
4.
Graft versus host disease (GVHD): This condition results from a reaction of the 
transplanted umbilical cord blood cells against your body and organs. This reaction 
ranges from a mild skin disorder to severe involvement of the skin, liver or gut. It may be 
fatal in some patients. You will be monitored closely for this complication and given 
specific treatment to prevent and treat it. There are 2 forms: acute (early) and chronic 
(late) GVHD. 
Acute GVHD may produce skin rashes, liver disease, diarrhea, and an increased risk of 
infection. All of these can range in severity from mild to fatal. To confirm the diagnosis of 
acute GVHD, you may be asked to have a skin biopsy (i.e., taking a piece of tissue to 
make the diagnosis of GVHD) and possibly a liver or gut biopsy. The treatment of acute 
GVHD may require you to take high doses of methylprednisolone or prednisone and, in 
some cases, other drugs such as anti-thymocyte globulin (ATG).
Chronic GVHD may produce skin rashes, hair loss, thickened skin, dry eyes, dry mouth, 
liver disease, diarrhea and an increased risk of infection. Chronic GVHD may be mild 
and respond to agents that suppress the immune system, or it could be very severe; it 
may also last for several years.
5.
Genetic Disease Transmission:   It is very rare, but there is the potential that genetic 
diseases (such as thalassemia or Gaucher’s disease) may be passed to you through the 
transplanted cord blood stem cells. Each umbilical cord blood unit can only be tested for 
a few of the many possible genetic diseases.  We will do our best to obtain screening 
results from the cord blood banks for diseases like thalassemia and sickle cell anemia, 
but they may not always be available. The family of each umbilical cord blood donor is 
asked about the development of medical problems or known genetic diseases within the 
family to further reduce the possibility of genetic disease transmission (i.e., passage of a 
disease to you from the cord blood stem cells).
6.
Incorrect Labeling of the UCB:  Though rare, it is possible that incorrect labeling of an 
umbilical cord blood unit could occur so that you receive the wrong unit. To avoid this, 
the umbilical cord blood unit is re-typed to confirm that the tissue type of the donor is as 
previously reported when the cord blood unit was first identified. Every cord blood unit 
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will undergo confirmatory tissue typing either here or at an outside lab. Every effort will 
be made to perform the confirmatory typing in our lab, but this may not be possible if the 
umbilical cord unit does not have an attached sample to use. If this is the case, there are 
several ways the unit labeling can be confirmed. 
7.
Other Complications: Other complications that can result from the transplantation 
procedure not specifically related to one specific drug or the cord blood stem cells or this 
study include:
A.
Damage to the vital organs in your body: This could result in malfunction of 
any organ in your body such as heart, lungs, liver, gut, kidneys and bladder, 
brain etc. The lungs and the liver are the most vulnerable. Some patients will 
experience severe lung problems due to infections and/or due to a reaction of the 
lungs to the chemotherapy and/or radiation. Some patients can suffer veno-
occlusive disease of the liver (VOD) also due to the chemotherapy and/or 
radiation. Patients who have VOD become jaundiced (yellowish skin), have liver 
function abnormalities, abdominal swelling, and abdominal pain. Although many 
patients recover completely, these complications may result in organ failure and 
permanent damage or even death.
B.
Serious infections:  Full and complete recovery of your immune system may 
take many months following the initial recovery of your white cell count. During 
this time, there is an increased risk of viral, fungal or bacterial infections. You will 
be prescribed certain medications to reduce the chance of those infections.  
However, preventive treatments are not always effective. If you have one of 
those infections you may have to stay in the hospital longer or be re-hospitalized 
after transplant. Infections can be fatal. The data collected from several 
transplant centers indicate that patients who have been exposed to a virus called 
cytomegalovirus (“CMV”) prior to their cord blood transplant are at high risk of 
reactivating this virus after the transplant. CMV is a very common virus, similar to 
the chickenpox virus, that about 50 to 80% of people have been exposed to at 
some time in their life. In healthy people, the virus remains inactive and does not 
cause any harm. However, it often becomes reactivated in people with a 
weakened immune system, and it can cause serious disease in the lungs, 
digestive tract and other organs. Because we are concerned that cord blood 
transplant patients are at higher risk for reactivation of CMV,  all cord blood 
transplant patients will be monitored very closely with a special blood test that 
can detect very early reactivation of CMV. If positive, you will be given 
appropriate treatments to control the virus. This treatment can last for a long 
period of time in some patients.
C.
Recurrence of disease:  Your disease may recur even if the transplant is initially 
successful.  
D.
Risk to the unborn: The treatments in this study have NOT been proven to be 
safe at any stage of pregnancy. Some are known to cause a miscarriage and 
birth defects if a woman becomes pregnant while being treated and for some 
time after stopping the treatment. Therefore, if you are pregnant, intend to 
become pregnant, or are nursing, you are not eligible for this study. Women who 
have the potential of becoming pregnant must use a combination of two forms of 
effective birth control. Effective birth control would be defined as the following: 1) 
refraining from all acts of vaginal intercourse (ABSTINENCE); 2) consistent use 
of birth control pills; 3) injectable birth control methods (Depo-Provera, Norplant); 
4) tubal sterilization or male partner who has undergone a vasectomy; 5) 
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placement of an IUD (intrauterine device); and, 6) use, with every act of 
intercourse, of a diaphragm with contraceptive jelly and/or condoms with 
contraceptive foam.
E.
Sterility and future childbearing potential for men and women: 
Chemotherapy and/or radiation may affect fertility. Male patients may become 
sterile (unable to produce sperm). Female patients may find that their menstrual 
cycle becomes irregular or stops permanently. However, this DOES NOT MEAN 
THAT YOU CANNOT BECOME PREGNANT, and you must use some effective 
method of birth control. Damage to reproductive tissue may result in birth defects 
or permanent inability to father a child or become pregnant. You should discuss 
these risks and options in detail with your doctor before entering this study.
F.
Central venous catheter: There has been considerable experience with central 
venous catheter use. The most common complications are clotting and local 
infection which sometimes leads to a generalized infection in the blood. Clotting 
may require the catheter to be removed or treatment with a fibrinolytic agent 
(medicines that dissolve blood clots). Infections will be treated with antibiotics, 
and sometimes, removal of the catheter is required. Occasionally, skin redness 
at the catheter exit site occurs, this may require antibiotic treatment. There is also 
a small risk of puncturing the lung at the time of the catheter insertion. If this 
occurs, placement of a temporary chest tube to re-inflate the lung may be 
required. There are no long-term effects once the lung puncture has resolved.
Are there Benefits to Taking Part in the Study?
There may be no direct benefit to participation in this study, although we hope that this 
treatment may control and possibly even cure your cancer with reduced side effects.    
Alternative Treatments:
Ongoing conventional chemotherapy may be considered as an alternative to transplantation in 
treatment of your cancer or bone marrow problem. No further treatment, or comfort care only 
are also possible alternatives.
Protecting your privacy
Some people may see and/or copy your medical records. They would do this as part of their 
research, to make sure this study is being done correctly and safely, or to evaluate the results. 
These people include the following individuals and organizations:

Fred Hutchinson Cancer Research Center (FHCRC)

University of Washington (UW) 

Seattle Children’s 

Seattle Cancer Care Alliance (SCCA)

National Institutes of Health (NIH)

U.S. Office for Human Research Protections (OHRP)

Center for International Blood and Marrow Transplant Research (CIBMTR)

U.S. Food and Drug Administration (FDA)

Cord Blood Bank (that provided the units for your transplant)

Institutional Review Boards (IRB)
    Nohla Therapeutics and their agents. Nohla is a company that is 
      collaborating with FHCRC on this study
These people are interested in study data, not your personal information. Personal information 
is information that can identify you. It may include your name, date of birth, social security 
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number, phone number, or other information.
Study records will be maintained indefinitely for the purpose of analysis and follow-up. We will 
do our best to keep the personal information in your medical record confidential. But we cannot 
guarantee total confidentiality. Your personal information may be given out if required by law.  
We will not use your personal information in any reports about this study, such as journal 
articles or presentations at scientific meetings.
Information about your participation in this study (including a copy of this consent form) will be 
made part of your permanent medical record. If you authorize others to see your medical record, 
they will see a copy of this consent form.
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time.
This research is covered by a Certificate of Confidentiality from the U.S. government. This 
Certificate helps protect the confidentiality of information about people who join the study. If you 
join the study, the Certificate means that generally we would not have to give out identifying 
information about you even if we were asked to by a court of law. We would use the Certificate 
to resist any demands for identifying information.
We could not use the Certificate to withhold research information if you give written consent to 
give it to an insurer, employer, or other person. 
This protection has some limits. We would voluntarily provide the information:
 To a member of the federal government who needs it in order to audit or evaluate the 
research. 
 To the funding agency and groups involved in the research, if they need the information to 
make sure the research is being done correctly.
 To the federal Food and Drug Administration (FDA), if required by the FDA.
 To someone who is accused of a crime, if he or she believes that our research records 
could be used for defense.
 To authorities, if we learn of child abuse, elder abuse, or if participants might harm 
themselves or others.  
Costs:
All medical expenses relating to, or arising from, these procedures will be paid by you and/or 
your insurance company. Taking part in this study may lead to added costs to you or your 
insurance company. Please ask about any expected added costs or insurance problems.
If you have any questions concerning your financial responsibilities, then contact your financial 
advisor at the SCCA (206-606-1113).  
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this web site. 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
What happens if I am injured because I took part in this study? 
For a life-threatening problem, call 911 right away or seek help immediately.  Contact your study 
doctor when the medical emergency is over or as soon as you can.   
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For all other medical problems or illness related to this research, immediately contact Dr. Ann 
Dahlberg. She will treat you or refer you for treatment.  You or your health insurance will have to 
pay for the treatment. There are no funds to pay you for a research-related injury, added 
medical costs, loss of a job, or other costs to you or your family.  State or national law may give 
you rights to seek payment for some of these expenses.  You do not waive any right to seek 
payment by signing this consent form.
You or your insurer will be billed for treatment of problems or complications that result from your 
condition or from standard clinical care.
You would not lose any legal right to seek payment for treatment if you sign this form. 
Will I be paid to take part in this research study? 
You will not be paid for taking part in this study. 
Oversight and Review of Protocol Safety:
The FHCRC has guidelines for keeping patients safe in studies. There is a plan for reporting 
any event that may harm people in a study. The principal investigator, Ann Dahlberg, MD, will 
make sure this plan is followed.
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No 
matter what decision you make, there will be no penalty to you and you will not lose any of your 
regular benefits. Leaving the study will not affect your medical care. You can still get your 
medical care from our institution. In the case of injury resulting from this study, you do not lose 
any of your legal rights to seek payment by signing this form. 
During the study, we may learn new information you need to know. For example, some 
information may affect your health. Other information may make you change your mind about 
being in the study. If we learn these kinds of information, we will tell you. 
Who can answer my questions about the study?
You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor, Ann Dahlberg, MD, at 206-667-1959.
If you have any questions about your rights as a research participant, contact 206-667-5900 or 
email irodirector@fredhutch.org (Director of Institutional Review Office at Fred Hutchinson 
Cancer Research Center).
Where can I get more information?
You may call the National Cancer Institute’s Cancer Information Service at
1–800–4–CANCER (1–800–422–6237) or TTY: 1–800–332–8615
You may also visit the NCI Web site at http://cancer.gov/

For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/

For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
 
Signature
Before you sign this consent form, make sure of the following:

You have read this consent form, or someone has read it to you.

This study has been explained to you.
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FHCRC 2010.00 Regimen A
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
You had the chance to ask as many questions as you wanted.

You understand you can ask more questions anytime.

You understand you (or your insurer) will have to pay the costs of being in this study, 
including treatment for side effects.

You understand your medical records will be available to the doctors, staff, and other 
groups working on this study.

You agree to join this study.
_____________________________________________________________________
Participant (Age 14+)                                      
Date
                                                             
                                                  
Parent/Legal Guardian
      Date
Other Parent/Legal Guardian / Date
(for participants under 18 years old)
(if reasonably available)
If you served as an interpreter or impartial witness during the consent process, sign below to 
indicate you attest to the accuracy of the presentation and the participant’s apparent 
understanding of and willingness to participate in the research.
Impartial Witness or Interpreter:
_____________________________________________________________________
Printed Name                                     Signature                                 
Date
Copies to:
Participant, Medical Records, Research File
I have discussed the above research study, including the study procedures and 
possible alternatives and risks, with the person signing above.  I encouraged 
questions and have answered them to the best of my ability.  A signed and dated 
copy of the consent form will be given to the participant.
 _____________________________________________________________________
Staff Signature
Printed Name of Staff                      
Date
Current Version Date:   6/21/2021
Previous Version Date: 9/19/2019
Fred Hutch IRB
Approved 
2/14/2024