Conditions: Myelodysplastic Syndrome Acute Lymphocytic Leukemia Acute Myelogenous Leukemia Chronic Myelogenous Leukemia Chronic Myelomonocytic Leukemia
Keywords: FLT Leuprolide Thymic Renewal Stem Cell Transplant Acute Lymphocytic Leukemia Acute Myelogenous Leukemia Myelodysplastic Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 76
Healthy volunteers: no

Brief summary:
Background:

* One way to treat certain cancers of the blood and immune system is to give a patient stem cells from the bone marrow of a donor whose genes are very similar but not identical to the patients. One problem with these transplants is that the new immune cells may not work as well in the recipient as they did in the donor. The result may be that the immune system will not work as well. This can increase the risk of severe infections and other complications.
* Researchers are studying the use of drugs that lower hormone levels and may allow the immune system to recover in a way that improves white blood cell function. In this study they will be looking at the drug leuprolide, a drug that lowers estrogen or testosterone levels, to see if it might improve the function of the newly transplanted cells.

Objectives:

* To determine whether leuprolide improves immune system function after bone marrow transplant from a donor with similarities in their immune cells (matched to each other).
* To evaluate the effectiveness of a nuclear medicine test with a radiotracer drug 3-deoxy-3 18F-fluorothymidine (FLT) in imaging studies. FLT will be used to image the immune system function in patients who have received bone marrow from the donor.

Eligibility:

* People between 15 (or as young as 9 in those who have gone through puberty) and 55 years of age. These patients must have acute myelogenous leukemia, acute lymphocytic leukemia, high-risk myelodysplastic syndrome, chronic myelomonocytic leukemia, or chronic myeloid leukemia. They must also be eligible for a bone marrow transplant.
* Genetically similar donors for the patients who are eligible for a transplant.

Design:

* People taking part in the study will be screened with a physical examination, medical history, blood and urine tests, and imaging studies. Patients who are not in remission or who require a bone marrow donor search may receive chemotherapy first.
* Donors will provide bone marrow for transplant according to standard bone marrow transplant (BMT) procedures.
* All women and half of the men will receive regular leuprolide doses 2 weeks before BMT to suppress hormone function.
* All recipients will receive 4 days of radiation followed by 2-4 days of chemotherapy before the bone marrow transplant (depending on age). Recipients will also receive other drugs to prevent transplant rejection and other complications of transplantation.
* Recipients will be monitored in the hospital for 4 weeks after transplant with blood tests and other studies.
* Some recipients will have an imaging study with FLT during the protocol. These imaging studies will take place before the transplant, on days 5 and 28 after transplant, and at a later time to be determined by the study researchers.
* Following discharge, participants will be monitored closely for up to 6 months, with regular but less frequent followup visits for at least 5 years. Study-related medications, including vaccinations for the new immune system, will be provided by the National Institutes of Health during the hospital stay and after discharge.

Detailed description:
Background:

* Impaired lymphocyte immune reconstitution is associated with morbidity and mortality following allogeneic bone marrow transplant (BMT).
* Data suggest that one of the limitations of immunity after BMT is the lack of thymus recovery and proper B cell development.
* Androgen withdrawal has been shown to enhance T and B lymphopoiesis.
* Leuprolide is an approved, safe, gonadotropin releasing hormone (GnRH) agonist/antagonist.
* Noninvasive imaging modalities to study immune reconstitution would be invaluable to predict optimal or impaired immune recovery permitting early institution of therapies.
* FLT is 3-deoxy-3 18F-fluorothymidine, a radiolabeled thymidine analogue that illustrates dividing hematopoietic cells and may predict immune recovery after allogeneic BMT.
* FLT has been used safely in patients who have received intensive chemotherapy.

Objectives:

* Primary: To determine if leuprolide improves B lymphocyte reconstitution after first BMT.
* Primary: To assess whether 18F FLT positron emission tomography (PET)/computed tomography (CT) could predict early engraftment/immune reconstitution in marrow and thymus after allogeneic BMT.
* Primary: To assess safety of leuprolide after 2nd BMT evaluated in a separate arm.

Eligibility:

* Patients \> 9 years old and pubertal and/or \>15 year and less than or equal to 55 years, with aggressive leukemia (Acute Myelogenous Leukemia (AML), myelodysplastic syndromes (MDS) with high risk cytogenetics, Acute Lymphocytic Leukemia (ALL), CMML, certain CML) requiring BMT will be enrolled at National Cancer Institute (NCI).
* At University of Oklahoma, Age \> 17 years old and less than or equal to 55 years for recipient.
* Patients \> 4 and \< 24 years with the above diseases will be enrolled at Children's National Medical Center (CNMC).

Design:

* This is a prospective pilot study, the primary aims of which are: 1) to assess whether leuprolide enhances lymphocyte recovery after first BMT, 2) whether FLT imaging can be used to predict engraftment/immune reconstitution after first transplant, and 3) whether leuprolide and FLT are tolerable for second HSCT.
* At NCI and Univ of Oklahoma, post-pubertal pediatric male patients (\<18 years) will be randomized to receive a 3 month (11.25 mg) injection and adult male patients will be randomized to receive 4-month preparation of leuprolide (30 mg) or placebo two weeks before the preparative regimen for first BMT. Women and all individuals undergoing 2nd BMT will receive leuprolide at these doses per age and be evaluated in the treated cohort. At Children's National Medical Center, the patients will not receive leuprolide outside of the context of clinical care and will receive myeloablative BMT as per standard of care with FLT imaging for engraftment as the only primary endpoint.
* A target of 68 evaluable adult patients will be enrolled on this trial, which may necessitate up to 118 patients (118 donors) enrolled to reach this target at NCI and University of Oklahoma. A total of 10 pediatric patients will be enrolled at Children's National Medical Center for FLT imaging only. Sixteen patients will be enrolled to undergo second BMT.
* At NCI, adults greater than 18 years old both female and adult male patients undergoing 2nd BMT will receive 4-month preparation of leuprolide (30 mg) two weeks before the preparative regimen. All patients will undergo FLT imaging to evaluate whether this may predict BMT response or failure (relapse). This will be a pilot arm of 16 patients total.
* The planned length of this trial is 7 years with interim analyses at day 100 and day 365.
* Some of the patients are anticipated to be evaluated using FLT (to include only patients needed for the immunological primary endpoint, not increasing total patient numbers). 23 adult NCI patients in total will undergo FLT PET/CT imaging on day -1, at day +5 or day +9, at 4 weeks, and at a future point to include evidence of graft-versus-host disease (GVHD) relapse, or immune recovery. An estimated 50 patients (including subset of the 23 patients undergoing serial scanning) will be imaged approximately at 1 year for evaluation of thymus reconstitution. The total possible numbers will include no more than 118 patients to achieve the 68 evaluable adults for the immunological primary endpoint. However, all 23 FLT PET/CT imaged NCI patients will undergo a single 1 year FLT for evaluation of thymus reconstitution. Up to 10 pediatric patients at CNMC will undergo FLT PET/CT imaging on Day -1, day+9, and day +28 (if possible). Initial images will be correlated with engraftment and other secondary endpoints.

Arms:
arm 1: Males randomized to leuprolide for first transplant.

\[18F\]fluorothymidine (FLT) imaging arm 2: Males not receiving leuprolide for first transplant

\[18F\]fluorothymidine (FLT) imaging arm 3: Females receiving leuprolide for first transplant.

\[18F\]fluorothymidine (FLT) imaging arm 4: Second transplant with leuprolide and \[18F\]fluorothymidine (FLT) imaging arm 5: Healthy Volunteer

Interventions: intervention 1: First Allogeneic Bone Marrow Transplant (BMT) intervention 2: Leuprolide intervention 3: 18F FLT intervention 4: Cyclophosphamide intervention 5: Methotrexate intervention 6: Tacrolimus intervention 7: Total Body Irradiation intervention 8: Busulfan intervention 9: Fludarabine intervention 10: Second Allogeneic Bone Marrow Transplantation
Intervention descriptions: intervention 1: First Allogeneic Bone Marrow Transplant intervention 2: Leuprolide: 30 mg intramuscular injection(for adult) or 11.25 mg (for patients \<18 years) between day -13 and day -20 pre-bone marrow transplant but definitely prior to initiation of preparative regimen as a 4 month intramuscular injection for patients \> 18 years and as a 3 month injection (adult preparation) for patients \< 18 years intervention 3: For the first 23 patients undergoing 1st bone marrow transplant (BMT):\[18F\]fluorothymidine (18F FLT): 0.07 mCi/kg with a maximum of 3 mCi On day + 28 (+/- 5 days) For 2nd BMT: 18F FLT: 0.07 mCi/kg with a maximum of 3 mCi On day -1, + 28, day 60 and at relapse (+/- 5 days) intervention 4: Cyclophosphamide: 60 mg/kg intravenous (IV) on days -4 and -3 (for Adults \> 22 years) or Cyclophosphamide: cyclophosphamide 50 mg/kg IV, Days -5, -4, -3, -2. (For Pediatric \</= 22 years) intervention 5: Methotrexate:10 mg/m(2) intravenous (IV) on day +1, and 5 mg/m(2) IV Days + 3, 6, 11 intervention 6: Tacrolimus:0.02 mg/kg/day continuous intravenous infusion (CIV) on day -1. intervention 7: Total Body Irradiation (TBI) 1200 cGy fractionate twice daily (lung block) Days -8, -7, -6, -5 (adult), -9, -8, -7, -6 (ped) intervention 8: Second choice is Busulfan (with goal steady state of 800-1000) with fludarabine or cyclophosphamide at myeloablative dosing or non-myeloablative dosing. intervention 9: Given with Busulfan as alternative to cyclophosphamide in second transplant setting only intervention 10: Second Allogeneic Bone Marrow Transplantation

Protocol document:
Prot_SAP_000.pdf: 
1
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
Abbreviated Title: Lupron &18F FLT in allo-HSCT
CC Protocol #: 11-C-0136
NCT# NCT01338987
Version Date: December 28, 2017
Amendment: T
Title of Study: Multi-institutional Prospective Pilot Study of Lupron to Enhance Lymphocyte 
Immune Reconstitution following Allogeneic Bone Marrow Transplantation in Post-pubertal 
Children and Adults with Molecular Imaging Evaluation
NIH Principal Investigator:
Christopher Kanakry, M.D. A-F
Experimental Transplantation & Immunology Branch
Center for Cancer Research,
National Cancer Institute, National Institutes of Health
10 Center Drive, Rm. 4-3142, MSC 1203
Telephone: 240-760-6171
Email: christopher.kanakry@nih.gov
Lead Associate Investigator:
Ronald Gress, M.D. A-F
Branch Chief, ETIB, CCR, NCI, NIH
Medical Advisory Investigator:
Peter Choyke, M.D. A-F
Branch Chief, Molecular Imaging, NCI, CCR, NIH
NIH Associate Investigators: 
Daniele Avila, CRNP, ETIB, CCR, NCI, NIH A-E
Meg Kenyon, CRNP, ETIB, CCR, NCI, NIH A-E
Stephanie Cotton, RN, OCD, CCR, NCI, NIH A-B
Jennifer Sadler, RN, OCD, CCR, NCI, NIH A-B
Bazetta Blacklock Schuver, RN, OCD, CCR, NCI, 
NIH A-B
Karen Kurdziel, MD, MIP, CCR, NCI, NIHA-F
Deborah Citrin, MD, ROB, CCR, NCI, NIHA-F
Seth M. Steinberg, PhD, BDMS, CCR, NCI, NIH
B, E
Kristen Cole, RN, OCD, CCR, NCI, NIH A-B
Constance Yuan, MD, PhD, LP, CC, NIH E-F
Dennis Hickstein, MD, ETIB, CCR, NCI, NIHA-F
Bonnie Yates, RN, POB, CCR, NCI, NIH A-B
Fran Hakim, PhD, ETIB, CCR, NCI, NIH E-F
Cindy Delbrook, RN, OCD, CCR, NCI, NIH A-B
James Kochenderfer, MD, ETIB, CCR, NCI, NIHA-F
Terry Fry, MD, POB, CCR, NCI, NIHA-F
Nirali Shah, MD, POB, CCR, NCI, NIHA-F
Maya Lodish, MD, NICHDA-F
Steven Z. Pavletic, MD, ETIB, CCR, NCI, NIHA-F
Jennifer Kanakry, MD, ETIB, CCR, NCI, NIHA-F


2
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
Tracey Chinn RN, ETIB, CCR, NCI, NIH A-B
David Stroncek, MD, DTM, CC, NIH E-F
Ellen Carroll, RN, OCD, CCR, NCI, NIH A-B
Maria Liza Lindenberg, MD, MIP, CCR, NIHA-F
Brenna Hansen, RN, OCD, CCR, NCI, NIH A-B
Willy Flegel, MD, DTM, CC, NIH E-F
Jennifer Mann, CRNP, ETIB, CCR, NCI, NIH A-E
Site Principal Investigator:
Jennifer Holter, M.D., University of Oklahoma
Site Principal Investigator
Kirsten Williams, MD., Children’s National Medical                                    
Center, Washington
Referral Contact:
Bazetta Blacklock Schuver, RN
Study Coordinator: 
Jennifer Sadler, RN
240-760-6175
Email: jennifer.sadler@nih.gov
Non-NIH Associate Investigators:
For each person listed above, roles are identified with the appropriate letter
A.
Obtain information by intervening or interacting with living individuals for research purposes
B.
Obtaining identifiable private information about living individuals
C.
Obtaining the voluntary informed consent of individuals to be subjects
D.
Makes decisions about subject eligibility
E.
Studying, interpreting, or analyzing identifiable private information or data/specimens for 
research purposes
F.
Studying, interpreting, or analyzing de-identified data or specimens for research purposes
G.
Some/all research activities performed outside NIH
IND Information:
IND Number:  111119
IND Sponsor:  Center for Cancer Research, NCI
Commercial Agents:                    Lupron Depot, Cyclophosphamide, Methotrexate, Tacrolimus, 
Fludarabine, Busulfan  
Jennifer Wilder, RN., Leidos Inc. A-B


3
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
Multi-institutional data:
University of Oklahoma
Principal Investigator:
Jennifer Holter, M.D.
Associate Professor of Hematology/Oncology and BMT
Associate Investigator:            George Selby, MD
Institution:
University of Oklahoma
MPA or SPA Number:
Federal-Wide Assurance program FWA#00003191.
Complete Address:
920 Stanton L. Young, WP 2040
Oklahoma City, OK 73104  
Phone Number:
405-271-4022 Ext 48397 Contact Elizabeth Cambron
E-mail:
jholter2@ouhsc.edu
Name of IRB Contact:
Meg Ribaudo, Director
Complete Address:
1000 Stanton L Young Blvd, Suite 176, Oklahoma City, OK 73117
Phone Number:
405-271-2045
E-mail of Contact:
meg-ribaudo@ouhsc.edu
Name of Pharmacy Contact: N/A
Children’s National Medical Center (CNMC)
Principal Investigator:
Kirsten Williams, M.D.
Assistant Professor of Pediatrics/Hematology/Oncology and BMT
Institution:
Children’s National Medical Center
MPA or SPA Number:
Federal-Wide Assurance program FWA# 00004487.
Complete Address:
111 Michigan Ave NW
Washington DC, 20010
Phone Number:
202-476-2694
E-mail:
kmwillia@cnmc.org
Name of IRB Contact:
Fahmida Hoq, MD
Complete Address:
111 Michigan Ave NW


4
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
Washington DC, 20010
Phone Number:
202-476-5000
E-mail of Contact: FHoq@childrensnational.org
Name of Pharmacy Contact: N/A


5
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
PRÉCIS
Background:
x Impaired lymphocyte immune reconstitution is associated with morbidity and mortality 
following allogeneic hematopoietic stem cell transplantation (HSCT).
x Data suggest that one of the limitations of immunity after HSCT is the lack of thymus 
recovery and proper B cell development. 
x Androgen withdrawal has been shown to enhance T and B lymphopoiesis. 
x Lupron is an approved, safe, gonadotropin releasing hormone (GnRH) 
agonist/antagonist. 
x Noninvasive imaging modalities to study immune reconstitution would be invaluable to 
predict optimal or impaired immune recovery permitting early institution of therapies. 
x FLT is 3’-deoxy-3 18F-fluorothymidine, a radiolabeled thymidine analogue that 
illustrates dividing hematopoietic cells and may predict immune recovery after 
allogeneic HSCT.  
x FLT has been used safely in patients who have received intensive chemotherapy.
Objectives:
x Primary: To determine if Lupron improves B lymphocyte reconstitution after HSCT.
x Primary: To assess whether 18F FLT PET/CT could predict early engraftment/immune 
reconstitution in marrow and thymus after allogeneic HSCT. 
x Primary: To assess safety of Lupron after 2nd HSCT evaluated in a separate arm. 
Eligibility:
x
Patients > 9 years old and pubertal and/or >15 year and  55 years, with aggressive 
leukemia (Acute Myelogenous Leukemia (AML), myelodysplastic syndromes (MDS) 
with high risk cytogenetics, Acute Lymphocytic Leukemia (ALL), CMML, certain CML)
requiring HSCT will be enrolled at NCI.
x
$W8QLYHUVLW\RI2NODKRPD$JH!\HDUVROGDQG\HDUVIRUUHFLSLHQW
x
Patients > 4 and < 24 years with the above diseases will be enrolled at Children’s 
National Medical Center.
Design:
x
This is a prospective pilot study, the primary aims of which are: 1) to assess whether 
Lupron enhances lymphocyte recovery after HSCT and 2) whether FLT imaging can be 
used to predict engraftment/immune reconstitution, and 3) whether Lupron and FLT are 
tolerable for second HSCT.
x
At NCI and Univ of Oklahoma, post-pubertal pediatric male patients (<18 years) will 
be randomized to receive a 3 month (11.25 mg) injection and adult male patients will 
be randomized to receive 4-month preparation of Lupron (30 mg) or placebo two weeks 
before the preparative regimen for first BMT.  Women and all individuals undergoing 


6
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
2nd BMT will receive Lupron at these doses per age and be evaluated in the treated 
cohort. At Children’s National Medical Center, the patients will not receive Lupron 
outside of the context of clinical care, and will receive myeloablative HSCT as per 
standard of care with FLT imaging for engraftment as the only primary endpoint. 
x
A target of 68 evaluable adult patients will be enrolled on this trial, which may 
necessitate up to 118 patients (118 donors) enrolled to reach this target at NCI and 
University of Oklahoma.  A total of 10 pediatric patients will be enrolled at Children’s 
National Medical Center for FLT imaging only. Sixteen of these patients will be 
enrolled to undergo second BMT.
x
At NCI, adults greater than 18 years old both female and adult male patients
undergoing 2nd BMT will receive 4-month preparation of Lupron (30 mg) two weeks 
before the preparative regimen.  All patients will undergo FLT imaging to evaluate 
whether this may predict HSCT response or failure (relapse). This will be a pilot arm 
of 16 patients total. 
x
The planned length of this trial is 7 years with interim analyses at day 100 and day 365.   
x
Some of the patients are anticipated to be evaluated using FLT (to include only patients 
needed for the immunological primary endpoint, not increasing total patient numbers).
23 adult NCI patients in total will undergo FLT PET/CT imaging on day -1, at day +5 
or day +9, at 4 weeks, and at a future point to include evidence of GVHD relapse, or 
immune recovery. An estimated 50 patients (including subset of the 23 patients 
undergoing serial scanning) will be imaged approximately at 1 year for evaluation of 
thymus reconstitution. The total possible numbers will include no more than 118 
patients to achieve the 68 evaluable adults for the immunological primary endpoint. 
However, all NCI patients will undergo a single 1 year FLT for evaluation of thymus 
reconstitution.  10 pediatric patients at CNMC will undergo FLT PET/CT imaging on 
Day -1, day+9, and day +28 (if possible). Initial images will be correlated with 
engraftment and other secondary endpoints.
x
Study endpoints to include: 1) safety of Lupron in the context of allogeneic BMT, 2) 
lymphocyte reconstitution after Lupron administration, 3) the incidence of acute and 
chronic GVHD and infectious complications, 4) remission rates after HSCT.


7
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
TABLE OF CONTENTS
PRÉCIS........................................................................................................................................... 5 
TABLE OF CONTENTS................................................................................................................ 7 
1 
INTRODUCTION ................................................................................................................ 14 
1.1 
Study Objectives ............................................................................................................ 14 
1.1.1 
Primary Objectives.................................................................................................. 14 
1.1.2 
Secondary Objectives.............................................................................................. 14 
1.2 
Background and Rationale............................................................................................. 15 
1.2.1 
Impaired Immune Reconstitution after Stem Cell Transplantation........................ 15 
1.2.2 
Androgen Withdrawal Enhances T and B Lymphopoiesis..................................... 16 
1.2.3 
Lupron for Androgen Suppression.......................................................................... 18 
1.2.4 
Lupron Safety Profile.............................................................................................. 18 
1.2.5 
Lupron Pharmacology............................................................................................. 18 
1.2.6 
FLT imaging modality............................................................................................ 19 
1.2.7 
18F FLT Safety Profile ............................................................................................ 21 
1.2.8 
18F FLT Pharmacology ........................................................................................... 21 
1.2.9 
FLT Availability ..................................................................................................... 22 
1.2.10 Trial Plan................................................................................................................. 22 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT....................................................... 23 
2.1 
Eligibility Criteria.......................................................................................................... 23 
2.1.1 
Inclusion Criteria: Transplant Recipient................................................................. 23 
2.1.2 
Exclusion Criteria: Transplant Recipient................................................................ 25 
2.1.3 
Inclusion Criteria: Matched Related Transplant Donor.......................................... 26 
2.1.4 
Exclusion Criteria: Matched Related Transplant Donor......................................... 26 
2.1.5 
Inclusion Criteria- Matched Unrelated Donor ........................................................ 27 
2.1.6 
Inclusion Criteria- 18F FLT Candidate Transplant Recipient ................................. 27 
2.1.7 
Exclusion Criteria- 18F FLT Candidate Transplant Recipient ................................ 27 
2.2 
Screening Evaluation and Criteria for HSCT ................................................................ 27 
2.2.1 
Recipient ................................................................................................................. 27 
2.2.2 
Matched Related Donor.......................................................................................... 29 
2.3 
Registration Procedures ................................................................................................. 30 
2.3.1 
Protocol Entry Date................................................................................................. 30 


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
2.3.2 
Registration............................................................................................................. 30 
2.3.3 
University of Oklahoma Donors and Recipients .................................................... 30 
2.3.4 
Children’s National Medical Center Donors and Recipients.................................. 31 
2.4 
Randomization Procedures ............................................................................................ 31 
2.4.1 
Female Recipients................................................................................................... 31 
2.4.2 
Male Recipients ...................................................................................................... 31 
3 
STUDY IMPLEMENTATION ............................................................................................ 32 
3.1 
Study Design.................................................................................................................. 32 
3.1.1 
NCI and University of Oklahoma for 1st BMT....................................................... 32 
3.1.2 
Children’s National Medical Center....................................................................... 33 
3.2 
Drug Administration...................................................................................................... 33 
3.2.1 
Lupron..................................................................................................................... 33 
3.2.2 
18F-FLT ................................................................................................................... 33 
3.3 
On Study Protocol Evaluation Pre-Transplant Work-up ............................................... 34 
3.3.1 
Within 4 weeks of Transplant Date ........................................................................ 34 
3.3.2 
FLT on Study Evaluations ...................................................................................... 34 
3.4 
Biologic Studies............................................................................................................. 35 
3.4.1 
Immune Reconstitution........................................................................................... 35 
3.4.2 
Immunologic Studies .............................................................................................. 36 
3.4.3 
Objectives/Specific Aims........................................................................................ 36 
3.4.4 
Methodology........................................................................................................... 36 
3.5 
Collaborative research Studies....................................................................................... 37 
3.6 
Donor Collection............................................................................................................ 38 
3.6.1 
Matched Unrelated Donors..................................................................................... 38 
3.6.2 
Matched Related Donors......................................................................................... 38 
3.7 
Preparative Regimen for HSCT and GVHD Prophylaxis.............................................. 39 
3.7.1 
Central Access ........................................................................................................ 39 
3.7.2 
Remission Status..................................................................................................... 39 
3.7.3 
Conditioning Regimen............................................................................................ 39 
3.7.4 
GVHD Prophylaxis................................................................................................. 41 
3.7.5 
Growth Factors (GCSF).......................................................................................... 41 
3.8 
Transplant Procedure for 1st and 2nd BMT..................................................................... 42 


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
3.8.1 
Day 0....................................................................................................................... 42 
3.8.2 
Transplant Outcome Determinations...................................................................... 42 
3.9 
Post-transplant monitoring (1st and 2nd BMT) ............................................................... 42 
3.9.1 
Day 0 to day +100................................................................................................... 42 
3.9.2 
Specific evaluation time points (1st and 2nd BMT) ................................................. 43 
3.9.3 
Long term follow-up guidelines (1st and 2nd BMT)................................................ 43 
3.9.4 
FLT on study evaluations........................................................................................ 44 
3.10 Criteria for Removal from Protocol Therapy and Off Study Criteria............................ 44 
3.10.1 Criteria for Removal from Protocol Therapy.......................................................... 44 
3.10.2 Off-Study Criteria................................................................................................... 45 
3.10.3 Off Protocol Therapy and Off Study Procedure at NCI ......................................... 45 
3.10.4 Participating Site Off-Study Notification ............................................................... 45 
4 
SUPPORTIVE CARE........................................................................................................... 46 
4.1 
Infection Prophylaxis..................................................................................................... 46 
4.1.1 
Infectious Disease Surveillance:............................................................................. 47 
4.2 
Management of Engraftment Syndrome........................................................................ 47 
4.3 
Treatment of Graft-Versus-Host Disease....................................................................... 47 
4.4 
Menses Suppression and Contraception ........................................................................ 48 
4.5 
Blood Product Support................................................................................................... 48 
4.6 
Nutritional Support ........................................................................................................ 49 
4.7 
Anti-Emetic Usage......................................................................................................... 49 
4.8 
Intravenous Immune Globulin (IVIG)........................................................................... 49 
4.9 
Hepatic Function Support .............................................................................................. 49 
4.10 Central Nervous System Prophylaxis ............................................................................ 50 
4.11 Fluid Management During First 30 Days Following Transplantation........................... 50 
4.12 Ancillary Support........................................................................................................... 50 
4.13 Supportive Care For Relapse ......................................................................................... 50 
4.14 Additional cell infusions for graft failure, impending graft failure, or poor graft 
function. .................................................................................................................................... 50 
5 
DATA COLLECTION AND EVALUATION..................................................................... 50 
5.1 
Data Collection .............................................................................................................. 50 
5.1.1 
Adverse event recording ......................................................................................... 52 


10
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
5.2 
Response Criteria........................................................................................................... 52 
5.2.1 
Primary Endpoints .................................................................................................. 52 
5.2.2 
Secondary Endpoints .............................................................................................. 52 
5.3 
Toxicity Criteria............................................................................................................. 53 
6 
STATISTICAL SECTION ................................................................................................... 53 
6.1 
Subject Accrual.............................................................................................................. 53 
6.1.1 
Statistics and Feasibility ......................................................................................... 53 
7 
HUMAN SUBJECTS PROTECTIONS ............................................................................... 56 
7.1 
Rationale For Subject Selection..................................................................................... 56 
7.2 
Participation of Children................................................................................................ 56 
7.3 
Participation of Subjects Unable to Give Consent......................................................... 57 
7.4 
Evaluation of Benefits and Risks/Discomforts.............................................................. 57 
7.4.1 
Recipient ................................................................................................................. 57 
7.4.2 
Risks in relation to benefit for Donor ..................................................................... 58 
7.4.3 
Pediatric Patients..................................................................................................... 58 
7.5 
Consent and Assent Process and Documentation.......................................................... 58 
7.5.1 
Consent for minors when they reach the age of majority....................................... 59 
7.5.2 
Telephone consent and re-consent procedure......................................................... 60 
7.5.3 
Informed consent of Spanish speaking subjects ..................................................... 60 
7.5.4 
Short form consent process for other non-English speaking patients..................... 60 
8 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
61 
8.1 
Definitions...................................................................................................................... 61 
8.1.1 
Adverse Event......................................................................................................... 61 
8.1.2 
Suspected adverse reaction ..................................................................................... 61 
8.1.3 
Unexpected adverse reaction .................................................................................. 61 
8.1.4 
Serious..................................................................................................................... 61 
8.1.5 
Serious Adverse Event............................................................................................ 61 
8.1.6 
Disability................................................................................................................. 62 
8.1.7 
Life-threatening adverse drug experience............................................................... 62 
8.1.8 
Protocol Deviation (NIH Definition)...................................................................... 62 
8.1.9 
Non-compliance (NIH Definition).......................................................................... 62 


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8.1.10 Unanticipated Problem............................................................................................ 62 
8.2 
NCI-IRB and Clinical Director Reporting..................................................................... 62 
8.2.1 
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths
62 
8.2.2 
NCI-IRB Requirements for PI Reporting at Continuing Review........................... 63 
8.2.3 
NCI-IRB Reporting of IND Safety Reports............................................................ 63 
8.3 
NCI Guidance for Reporting Expedited Adverse Events for Multi-Center Trials ........ 64 
8.4 
IND Sponsor Reporting Criteria.................................................................................... 64 
8.5 
Data Recording of Unrelated Donors from NMDP ....................................................... 64 
8.6 
Data and Safety Monitoring Plan................................................................................... 64 
8.6.1 
Principal Investigator/Research Team .................................................................... 64 
8.6.2 
Sponsor Monitoring Plan........................................................................................ 65 
8.6.3 
Safety Monitoring Committee (SMC) .................................................................... 65 
9 
Multi-Institutional Guidelines............................................................................................... 66 
9.1.1 
IRB Approvals ........................................................................................................ 66 
9.1.2 
Amendments and Consents..................................................................................... 66 
9.1.3 
Data and Specimen Collection Procedures............................................................. 66 
9.1.4 
Data Center Audits.................................................................................................. 66 
9.1.5 
Protocol Monitoring Committees ........................................................................... 66 
10 PHARMACEUTICAL INFORMATION............................................................................. 66 
10.1 Lupron depot.................................................................................................................. 66 
10.1.1 Chemical name........................................................................................................ 66 
10.1.2 Chemical structure .................................................................................................. 67 
10.1.3 Commercial Formulation........................................................................................ 67 
10.1.4 Storage .................................................................................................................... 67 
10.1.5 Stability................................................................................................................... 67 
10.1.6 Route of administration........................................................................................... 67 
10.1.7 Dose ........................................................................................................................ 67 
10.1.8 Drug Interactions .................................................................................................... 67 
10.1.9 Known toxicities for patients >18........................................................................... 67 
10.1.10 Known toxicities for patients <18........................................................................... 68 
10.2 Cyclophosphamide......................................................................................................... 69 


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10.2.1 Chemical name........................................................................................................ 69 
10.2.2 Chemical structure .................................................................................................. 69 
10.2.3 Commercial Formulation........................................................................................ 70 
10.2.4 Storage .................................................................................................................... 70 
10.2.5 Stability................................................................................................................... 70 
10.2.6 Route of administration........................................................................................... 70 
10.2.7 Dose ........................................................................................................................ 70 
10.2.8 Drug Interactions .................................................................................................... 70 
10.2.9 Known toxicities..................................................................................................... 70 
10.3 Total Body Irradiation.................................................................................................... 71 
10.3.1 Chemical name........................................................................................................ 71 
10.3.2 Known toxicities..................................................................................................... 71 
10.4 FLT ................................................................................................................................ 71 
10.4.1 Chemical Name....................................................................................................... 71 
10.4.2 Commercial Formulation........................................................................................ 71 
10.4.3 Storage .................................................................................................................... 71 
10.4.4 Chemical Structure.................................................................................................. 71 
10.4.5 Method of Administration....................................................................................... 72 
10.4.6 Availability ............................................................................................................. 72 
10.4.7 Known Toxicites..................................................................................................... 72 
10.5 Fludarabine (Fludara, Berlex Laboratories)................................................................... 72 
10.5.1 Chemical Name....................................................................................................... 72 
10.5.2 Supply ..................................................................................................................... 72 
10.5.3 Preparation.............................................................................................................. 72 
10.5.4 Storage and Stability............................................................................................... 72 
10.5.5 Administration ........................................................................................................ 72 
10.5.6 Toxicities................................................................................................................. 72 
10.6 Busulfan (Busulfex)....................................................................................................... 73 
10.6.1 Source ..................................................................................................................... 73 
10.6.2 Storage and Stability............................................................................................... 73 
10.6.3 Administration ........................................................................................................ 73 
10.6.4 Toxicities................................................................................................................. 73 


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10.6.5 Drug Interactions .................................................................................................... 73 
11 REFERENCES ..................................................................................................................... 74 
12 APPENDICES ...................................................................................................................... 78 
12.1 Appendix 1: Performance Scales................................................................................... 78 
12.2 Appendix 2A: Recipient (arm 1 and 2).......................................................................... 80 
12.3 Appendix 2B: Donor  (arm 1 and 2).............................................................................. 82 
12.4 Appendix 3a: FLT ( 1st BMT)........................................................................................ 83 
12.5 Appendix 4A: Adult (>22 years) BMT Roadmap ......................................................... 85 
12.6 Appendix 4B: Pediatric (<22 years) BMT Roadmap .................................................... 89 
12.7 Appendix 5: Research Specimens.................................................................................. 93 
12.8 Appendix 6: Immunization Post-Transplant.................................................................. 94 
12.9 Appendix 7: Management of Engraftment Syndrome................................................... 95 
12.10 Appendix 8A: Grading and Management of Acute Graft-Versus-Host-Disease........... 97 
12.11 Appendix 8B.................................................................................................................. 99 
12.12 Appendix 8C: Signs and Symptoms of cGVHD ......................................................... 102 
12.13 Appendix 8D: cGVHD Score Sheet ............................................................................ 104 
12.14 Appendix 9: ETIB Policy for Sample Handling.......................................................... 107 
12.14.1 Sample Processing ................................................................................................ 107 
12.14.2 Labeling ................................................................................................................ 107 
12.14.3 Storage/Tracking in the Preclinical Development and Clinical Monitoring Facility 
(PDCMF) ............................................................................................................................ 107 
12.14.4 Protocol Completion/Sample Destruction ............................................................ 108 
12.14.5 Handling for subjects at other Participating Institutions....................................... 109 
12.15 Appendix 10: Data Collection elements Required by Protocol................................... 110 
12.16 APPENDIX  11:  Problem Report Form...................................................................... 113 


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1
INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objectives
x
To determine whether Lupron leads to accelerated B cell recovery after allogeneic 
hematopoietic stem cell transplantation (after 1st and 2nd BMT).
x
To assess whether 18F FLT PET/CT could predict early engraftment/immune 
reconstitution in marrow and thymus after allogeneic HSCT (1st BMT only).
x
To assess safety of Lupron after 2nd HSCT and evaluate whether FLT can predict relapse 
(evaluated after 2nd BMT)
1.1.2
Secondary Objectives
x
To investigate whether Lupron will accelerate thymic reconstitution after allogeneic 
HSCT using CT scan thymic index, flow cytometric measurements of naïve T cells, 
peripheral blood TREC on sorted CD4+ and CD8+ T cells, and Spectratype analysis of T 
cell receptor diversity on sorted CD4+ and CD8+ T cells (1st BMT)
x
To assess the feasibility of 4 month Lupron in male patients after allogeneic HSCT in 
post-pubertal individuals (after 1st and 2nd BMT).
x
To investigate whether Lupron will decrease the incidence of acute or chronic graft-
versus-host disease (GVHD) after allogeneic HSCT, comparing the Lupron treated and 
untreated groups using NIH developed criterion for the definition of clinical and biopsy-
proven acute and chronic GVHD (after 1st BMT).
x
To evaluate if Lupron will decrease the incidence of infectious complications in 
recipients of allogeneic HSCT, comparing the number and clinical severity of infectious 
complications between patients who received Lupron as compared to those that did not
(after 1st BMT).
x
To evaluate if Lupron will enhance graft-versus-tumor (GVT) effects by comparing the 
remission rates of patients who did vs. did not receive Lupron (after 1st BMT). To 
compare the outcomes of the pilot patients after 2nd HSCT in terms of relapse as 
compared to historical controls. 
x
To evaluate if Lupron treatment results in other changes in immune reconstitution (e.g. 
dendritic cell reconstitution, monocyte reconstitution, and immunoglobulin recovery)
(after 1st BMT).
x
To demonstrate that 18F FLT imaging is safe in the peri-transplant period (after 1st
BMT).
FLT endpoints include: 1) Ability of 18F FLT-PET to document preparative regimen 
ablation success 2) Evaluate the potential of 18F FLT/PET imaging to predict 
engraftment at week one 3) Assessment of GVHD using 18F FLT, 4) Assess relapse 
using FLT (after 1st and 2nd BMT).


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1.2
BACKGROUND AND RATIONALE
1.2.1
Impaired Immune Reconstitution after Stem Cell Transplantation
Impaired immune reconstitution contributes to morbidity and mortality after allogeneic stem cell 
transplant.  Data suggest that this is due to the delayed and often disturbed recovery of T and B 
cells post-transplant.  Although the innate immune system regenerates functionally and quickly 
post-transplant, the recovery of T and B lymphocytes is delayed for many months to years. This 
delay in lymphocyte cell recovery compared to other leukocytes is more pronounced in adult 
patients as compared to children.  As shown in Figure 1 and Figure 2below, the two figures 
compare the percentage of normal leukocyte recovery in peripheral blood between adults and 
children.  These show that B cell recovery in children approaches 50% by day 180 and 100% by 
day 270 and CD4+ numbers approach 100% at 2 years.  In contrast, for adults, B cell recovery is 
30% at day 180 and 80% at day 270 with CD4 recovery delayed indefinitely [1]
Figure 1
Figure 2
Not only are the absolute numbers of T and B lymphocytes decreased post-transplant, the 
function of these populations remains compromised even after normal numbers are achieved.  In 
part, this is due to the mechanism of lymphoid reconstitution post-transplant.  In contrast to 
normal ontogeny where the thymus provides the vast majority of T cells to the peripheral pool, 


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post-transplant T cell regeneration relies upon the mechanism of peripheral expansion for T cell 
recovery.   In the thymus, T cells are produced de novo from marrow precursors.  These T cells 
undergo T cell receptor (TCR) rearrangement, resulting in naïve T cells with diverse TCRs, 
capable of recognizing a wide array of infectious or tumor antigens.  These developing T cells 
undergo positive and negative selection, permitting the deletion of autoreactive clones.  In 
contrast, when thymic function is poor as is often the case after adult allo-HSCT, T cell 
reconstitution is accomplished through the rapid proliferation of mature T cell clones, leading to 
a skewed, oligoclonal population of T cells with the potential for alloimmunity.[1] Poor thymic 
function has significant clinical consequences in the setting of hematopoietic stem cell 
transplantation.  Impaired thymopoiesis is associated with poor clearance of infections and 
diminished responses to vaccines (due to resulting B cell dysfunction). [2-6] Successful T cell 
reconstitution also confers significant protection from relapse of malignant disease as well. [7-9]
Furthermore, impaired thymopoiesis is linked to the development and persistence of acute and 
chronic graft-versus-host disease. [6, 10-12] Thus, improving thymopoiesis and thus 
lymphopoiesis may partially abrogate GVHD, enhance immune surveillance, and improve HSCT 
outcomes. 
Similar to the effects of peripheral expansion on T cells, mature memory B cells demonstrate a 
restricted repertoire post-HSCT. [13] In contrast, B cells produced in the marrow through de 
novo development (transitional B cells) display a diverse repertoire. [13, 14] These transitional 
B cells emerge gradually (within months) after HSCT and are not influenced by viral 
reactivations and GVHD, suggesting that this population would be best used to identify the 
influence of immunotherapy on lymphocyte reconstitution after HSCT.  In addition, studies have 
suggested that transitional B cell development is delayed and diminished in older adults, those 
with reduced intensity conditioning for HSCT, findings similar to the influence of these factors 
on thymus derived T cell development. [15] Furthermore, there are data to suggest that 
transitional de novo B cell development would be associated with enhanced tolerance that could 
translate to diminished GVHD. [16] Thus, because thymus recovery could take years in young 
adults, is likely influenced by infections and GVHD, while transitional B cell reconstitution is 
faster, less modulated by other post-transplant factors, B cells will be used for the primary 
endpoint of lymphocyte engraftment in this study.  Thymus recovery and restoration of T cell 
diversity will be included as important secondary endpoints though this will likely only be 
evaluable in the small subset of patients without relapse, GVHD, who survive greater than 2 
years after HSCT. 
At this time, there are not data to determine the best source of HSCs between marrow and 
peripheral blood stem cells.  Marrow is chosen as the stem cell source for this protocol due to: 1) 
this is the standard stem cell source in pediatrics, 2) there are evidence that marrow products lead 
to  less GVHD without compromising graft-versus-leukemia effects [17, 18], and 3) all of the 
basic science work that models the lupron and FLT effects were performed with marrow grafts.  
In many adult oncology institutions, marrow remains the preferred source as well (including 
University of Oklahoma). 
1.2.2
Androgen Withdrawal Enhances T and B Lymphopoiesis
Androgen inhibitors are excellent candidates for augmenting B lymphopoiesis and thymopoiesis.  
Many groups have demonstrated increase thymic size, weight, and thymocyte number following 
androgen withdrawal. [19-22] Murine and clinical data show that androgen withdrawal can 


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reverse age-related thymic atrophy and reconstitute normal, young thymocyte subsets with 
subsequent increased peripheral T cell numbers. [23] Similarly, B lymphopoiesis is also 
increased after androgen withdrawal. [24] Data suggest that these increases in B and T cell 
numbers following androgen suppression are due to increases in de novo production of B and T 
cells in the marrow and thymus respectively. [21, 25] As shown in Figure 3below, following 
androgen withdrawal in male mice (light grey box), B cell total numbers are dramatically 
increased in the marrow as compared to control (black box) at 1, 3, and 4 weeks (see Figure 3
below, B subsets defined as B220+).  
Figure 3
Similarly, the thymus of mice treated with lupron was increased in size and thymocytes were 
increased in number as compared to controls.  Notably, because lupron initially leads to 
androgen release, followed by suppression, the thymus first involutes then expands with 
subsequent increase in thymocyte production.  As shown in Figure 4 below, thymus weight (left) 
and thymocyte number (right) are initially decreased at 1 week after lupron (grey), then similar at 
2 weeks, then increased after 4 weeks as compared to controls (black). 
Figure 4
Additionally, recent data suggest that T and B cell reconstitution is accelerated after stem cell 
transplant in murine allogeneic transplant models after androgen withdrawal without decreasing 
graft-versus-tumor effect or worsening GVHD. [19] Our murine data demonstrate that the 
mechanism underlying the accelerated thymus recovery after androgen withdrawal involves: 1. 
0.00E+00
5.00E+06
1.00E+07
1.50E+07
2.00E+07
2.50E+07
3.00E+07
3.50E+07
4.00E+07
4.50E+07
0.00E+00
2.00E+07
4.00E+07
6.00E+07
8.00E+07
1.00E+08
1.20E+08
1.40E+08
1.60E+08
Thymus Weight (ng)
Thymocyte #
0.00E+00
5.00E+07
1.00E+08
1.50E+08
2.00E+08
2.50E+08
3.00E+08
Thymus Weight (ng)
Thymocyte #
0.00E+00
2.00E+07
4.00E+07
6.00E+07
8.00E+07
1.00E+08
1.20E+08
1.40E+08
1.60E+08
Thymus Weight (ng)
Thymocyte #


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Increase in thymus epithelial cell (TEC) proliferation, 2. Increased production of CCL25 by 
these TEC, 3. Increased early thymic progenitor entry of marrow precursors by CCL25 
interactions, 4. Accelerated development of thymocytes due to CCL25 signaling, and 5. Overall 
enhanced thymopoiesis with increased export of naïve selected diverse T cells [25].  Similarly, B 
cell increases after androgen withdrawal have also been attributed to marrow stromal influences, 
resulting in accelerated de novo B cell development (rather than expansion of peripheral clones). 
[21] Given this mechanism and these murine and clinical data, androgen withdrawal has the 
potential to enhance de novo lymphopoiesis in young adults following HSCT with possible 
benefits of: improved infection and tumor clearance and diminished GVHD.  Because of the 
timing of the androgen release and thymic involution and the possibility that these effects occur 
in marrow stroma as well, male randomized subjects will receive the lupron injection 
approximately 1-2 weeks prior to HSCT to minimize the potential additive damage of thymus 
involution and radiotherapy. 
1.2.3
Lupron for Androgen Suppression
Lupron is an FDA-approved gonadotropin-releasing hormone (GnRH) analog that has been used 
clinically for androgen suppression in prostate cancer patients for males [23, 26] and for menses 
suppression during HSCT for females [27].  In males with prostate cancer, there are data to 
suggest enhanced thymic function following this agent. [23] Notably, most of these subjects 
were older individuals in whom free testosterone is substantially lower than younger subjects 
(0.2 +/- 0.081 vs. 0.43 +/- 0.098). [28] Thus, while patients may have diminished circulating 
testosterone following chemotherapy, the levels were not lower than those of older men, and the 
subjects are likely to still exhibit immunologic changes after androgen withdrawal. [29] Because 
Lupron is an analog of GnRH, it leads to an initial burst of sex steroid release followed by 
suppression.  A study of administration and efficacy of Lupron in females for the suppression of 
menses revealed that the greatest efficacy was achieved when Lupron was given greater than 2 
weeks prior to thrombocytopenia.  Similarly, our murine data has demonstrated that optimal 
administration for Lupron with regards to marrow transplantation is approximately 1-2 weeks 
pre-transplant.  This is because the initial stimulation of GnRH leads to thymus involution and 1-
2 weeks following this will be a period of relative stabilization for the thymus, and possibly 
marrow stroma.  Thus, thymic epithelial cells will be at basal proliferation and less harmed by 
radiation damage.  Taken together, Lupron (4 month preparation) will be administered at 
approved doses 1-2 weeks prior to the preparative regimen.  
1.2.4
Lupron Safety Profile
Lupron has a very good safety profile with only 3 reported adverse events (testicular atrophy) in 
greater than 20% of 94 patients studied in two clinical trials for prostate cancer (see section 10for 
details).  There are data that HSCT alone leads to testicular atrophy in male patients, thus this 
particular AE is not likely to be unique in lupron-treated subjects after HSCT.
1.2.5
Lupron Pharmacology
Lupron (leuprolide acetate) is a synthetic nonapeptide analog of GnRH that binds more strongly 
than the endogenous hormone.  The 4 month preparation is 30 mg is dispensed in a prefilled 
dual-chamber syringe containing sterile lyophilized microspheres which, upon mixing with 
diluent become a suspension that can be given as an intramuscular injection.  Within several 
days, a marked increase in serum sex steroid (testosterone) occurs followed by equilibration to 


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
baseline levels at 1 week and suppression by 2-4 weeks that is maintained until week 12 (data 
obtained from the prescription brochure).   Although no specific drug interaction studies have 
been performed, drug interactions are unlikely to occur because the drug is only 46% plasma 
protein bound and degraded by peptidase not utilizing P-450 cytochromes.  Furthermore, the 
drug has been used in HSCT for women for menses suppression without noted drug interactions.  
The effects are reversible as normal gonadal function is restored within 1-3 months upon 
discontinuation.
1.2.6
FLT imaging modality
Nuclear medicine imaging has been invaluable to assess tumor disease burden and response to 
therapy.  PET/CT uses 18F-fluorodeoxyglucose (FDG) to identify cells that rapidly uptake 
glucose including tumor cells.   This modality has revealed: tumor metastases, responses to 
tumor after treatment cycle, tumor recurrence, and has been useful to accurately predict true 
complete response, correlating PET negativity with longterm survival [30-33].  Despite these 
data demonstrating the utility of this test for evaluation in lymphomas and cancer, FDG-PET is 
limited by lack of specificity.  Because FDG-PET relies upon glucose incorporation into cells, 
the signal will be present not only in tumor cells, but also normal tissues such as brain and heart 
that require active glucose uptake and in inflammatory lesions (due to uptake by macrophages 
and granulation tissues).
Figure 5 (from the investigator’s brochure 1-03-05)
A novel agent, FLT is 3’-deoxy-3 18F-fluorothymidine, a radiolabeled thymidine analogue that 
illustrates dividing hematopoietic cells.  FLT is derived from the drug azidovudine (AZT) that 
uses thymidine kinase 1 for uptake into cells, part of the salvage pathway for DNA synthesis.  
This enzyme is tightly controlled in normal cells and increases during cell division, permitting 
increased FLT uptake in dividing cells.  Furthermore, malignant cells have lost their regulation 
and thus have higher thymidine kinase 1 available, leading to even greater uptake of FLT than 
normal cells that divide at higher rates [34].  Thus, this imaging agent has the potential to 
distinguish rapidly dividing cells from static cells and both of these from malignant cells based 
on degree of uptake of FLT.  FLT has been used to successfully stage and evaluate 
chemotherapy response in non-hodgkins lymphoma [35-38], breast cancer [39-41], and sarcoma 
[42].  In many of these studies, high background activity was noted within the marrow 
compartment, indicative of FLT uptake by hematopoietic cells.  FLT was then used to evaluate 
acute myelogenous leukemia in a pilot study, revealing higher SUV in patients with disease 
compared to controls.[43, 44] Similarly, patients with aplastic anemia or myelofibrosis 
associated with lack of hematopoiesis had decreased uptake in the marrow compartment [44].
O
F
N
NH
HO
O
Me
O
O
OH
N
NH
HO
O
Me
O
Thymidine
FLT


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FLT has been used to document response following treatment of AML [43] and has been shown 
to be accurate and reproducible following chemotherapy in patients treated for testicular 
carcinoma [45].  It can further document changes in marrow following directed radiotherapy 
dosing, which may allow for more accurate assessment of response to therapy in marrow-borne 
malignancies [45]. These data suggest that FLT could be used to assess hematopoiesis in the 
marrow compartment, potentially illustrating empty vs. normal hematopoiesis vs. leukemia 
recurrence with greater sensitivity than single site marrow aspirates yield.
Figure 6: Normal uptake in bone marrow[44]
Figure 7: Increased uptake in patient with MDS[44]
Dr. Holter, our collaborator, has modeled FLT (3’-deoxy-3’ 18F-fluorothymidine) in rat bone 
marrow transplantation and shown that by day 4, engraftment kinetics could be predicted and 
this time point preceded peripheral blood and full histologic evidence of marrow recovery. [46]
As stated above, not only is immune reconstitution a major barriers to successful HSCT, but also 
our modalities for evaluating this are often invasive (bone marrow aspirate) or less informative 
(peripheral blood evaluation).  In cord blood transplantation, this is a clinically significant 
problem as non-engraftment and late engraftment of the donor cells is common and there are 
currently no early predictive tests for whether a patient will engraft late or require a second 
conditioning regimen and new donor products.  Furthermore, even in matched adult donor 
transplantation where graft failure rates are low, there are often periods post-transplant where the 
peripheral blood cellular counts decline and the differential includes graft loss, medication 
toxicities, infections, and relapse.  Thus, a noninvasive imaging modality that could model 
engraftment kinetics would be invaluable to clinicians, potentially predicting graft failure early 
and narrowing the differential in the setting of cytopenias. These data prompted this clinical 
evaluation of FLT to determine if FLT could be used in conjunction with PET imaging at 
scheduled time points during HSCT for evaluation of engraftment.  These data could: 1) predict 
the rate of marrow engraftment and the length of neutropenia, 2) demonstrate evidence of 
minimal residual disease at the time of transplant (the uptake should be null following 
myeloablative transplant preparative regimen), 3) predict thymus recovery.  In this current 


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
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protocol, adults and children with aggressive leukemias and MDS will have both the greatest 
opportunity for: 1) evaluation of residual disease that should be positive by FLT at the time of 
transplant, 2) a differential in uptake over time as the myeloablative negative scan increases in 
uptake corresponding with increasing hematopoiesis, and 3) the greatest chance for thymus 
recovery in adults to evaluate by FLT. 
1.2.7
18F FLT Safety Profile
18F FLT is currently in use in clinical trials and has currently been shown to be safe at the doses 
proposed in this study.  Although 18F FLT enters cells via an enzyme in the salvage pathway, it is 
not significantly incorporated into DNA due to the lack of a 3’-hydroxyl group, which is 
necessary for DNA propagation.  Thus, although the agent remains within cells long enough for 
imaging, it will not persist long term nor should it be mutagenic.   At the doses used in this study, 
several studies have been published and no adverse events reported in patients with leukemia and 
MDS [43, 44].  The planned dose is 0.07 mCi/kg with maximum dose of 3 mCi (maximum of 6.1
ug).  At higher doses exceeding a 1000 fold increase in 18F FLT from our planned dose, 18F FLT
has been associated with grade 3 hematologic toxicity (6/10 at 0.125 mg/kg q12 hours which 
equals area under the curve of 417 ng-h/mL and 5/15 patients at 200 ng-h/ml), hepatic failure 
(2/10 at dose of 200ng-h/mL and 10mg/day).  At a dose 1000 fold higher than our planned dose, 
mild peripheral neuropathy occurred (2/10 at dose of 50 ng-h/mL) [47].  No AEs attributable to 
18F FLT administered at tracer levels have been reported in the published literature. While no 
related AEs are expected, patients will be monitored very closely with regards to hepatic, 
neurologic, and hematologic parameters following radiotracer injection.
Patients on this study who receive 18 F FLT/CT will be exposed to a maximum whole body dose 
(ED) of 6.2 rem whole body dose (ED), 1.2 rem from each 18 F FLT/CT scan and 0.73 from each 
FDG PET/CT. For comparison, the average person in the United States receives a radiation 
exposure of 0.3 rem per year from natural background sources, such as from the sun, outer space, 
and from radioactive materials that are found naturally in the earth’s air and soil. The dose that a
patient will receive from this research study is about the same amount that individual would 
normally receive in 20.5 years from these natural sources. A routine clinical 18F FDG PET/CT is 
approximately 1.4 rem; for the purposes of this study, we have reduced the injected dose. 
1.2.8
18F FLT Pharmacology
18F FLT has a half life of 108 minutes [48].  The administered dose will be 0.07 mCi/kg with a 
maximum dose of 3 mCi per scan.  The drug is excreted in the liver and kidney.  Transport of 
FLT across cell membranes occurs by active transport and passive diffusion [49].  The drug 
solution is stored at room temperature in a gray butyl septum sealed, sterile, pyrogen-free glass 
vial and has an expiration time of 8 hours. The injectable dose of 18F FLT for most studies will 
EHP&LNJRIIOXRULQH-18, not to exceed 3 mCi with a specific activity greater than 200
Ci/mmol at the time of injection.  In the dose of FLT, only a small fraction of the 18F FLT 
molecules are radioactive.  The amount of injected drug is < 6.1 ug (<25 nmol per dose) of 18F
FLT. 18F FLT is administered to subjects by intravenous injection of < 10mL over 30 seconds.
There is no evidence that nonradioactive and radioactive FLT molecules display different 
biochemical behavior.  


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
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1.2.9
FLT Availability
The Investigator-sponsored IND will be held by Karen Kurdziel, MD. 18F FLT will be obtained 
from commercial sources, either from Cardinal Health, Beltsville, MD, or PETNET Solutions 
Inc., Philadelphia, PA according to the DMFs filed with the FDA respectively for both 
institutions. 
1.2.10 Trial Plan
This study addresses 2 issues in transplantation: 1) the problem of delayed lymphoid engraftment 
after allogeneic transplantation in adults, and 2) the issue of evaluating engraftment of 
hematopoietic elements after allogeneic transplantation.  Patients undergoing 1st BMT with 
aggressive leukemia and MDS who are $JH\HDUVROGDQGRU\HDUVROGDQGSXEHUWDODQG
\HDUV will be enrolled and evaluated for remission status.  If the patient is not in remission 
upon study entry, the patient will progress to a chemotherapy regimen with the goal of obtaining 
complete remission.  Once the patient meets criteria for complete remission, female patients and 
half of the male patients (randomized) will receive Lupron prior to initiation of a standard 
preparative regimen with standard GVHD prophylaxis.  Immunologic assessment of transitional 
B cells and IgM levels will be used for the primary endpoint of the issue of delayed lymphoid 
engraftment. This randomization and Lupron arm of the trial will be open at University of 
Oklahoma as well as NCI.
A subset of these patients will undergo imaging analysis with 18F FLT as part of their 
evaluations. 18F FLT enrolled patients will be imaged at day -1, day 5 or 9, day 28 and a later 
time point to be determined by clinical events such as evidence of thymus recovery or GVHD. In 
addition, all newly enrolled NCI patients will be imaged at 1 year for evaluation of thymus 
reconstitution with the exception of those in the serial scanning subset that have been imaged at a 
‘later time’ as discussed above.  Ten FLT patients enrolled at Children’s National Medical 
Center will be imaged at day -1, day +9, and if possible, day +28.  Patients will not be imaged at 
University of Oklahoma.
The primary endpoint for this element of the protocol will be toxicity with a secondary endpoint 
of imaging analysis at day 5 and day 28 and correlation or prediction of engraftment as compared 
to a null baseline scan at day -1. Important secondary endpoints will also include other elements 
of engraftment (neutrophils, T cells, and dendritic cells), relapse/remission status, presence and 
severity of acute and chronic GVHD, severe infectious complications, and whether the later 18F
FLT nuclear imaging scan may assist in these clinical diagnoses. 
Patients with aggressive leukemia and MDS who have relapsed after HSCT and are greater than 
or equal to 18 years and 55 will be enrolled and evaluated for remission status. Patients will 
undergo 2nd HSCT, after receiving Lupron and will all be evaluated with 18F FLT imaging to 
explore the relapse rates and ability of FLT to predict relapse after 2nd HSCT.  The primary 
endpoints are: To assess safety of Lupron after 2nd HSCT and evaluate whether 18F FLT can 
predict relapse.  Patients will undergo 18F FLT imaging on day -1, and FLT and FDG imaging on 
day 28 and day 60 to predict relapse.  Patients may also be imaged before and after therapy for 
relapse (to not exceed 5 scans total per patient). Note patients enrolled on this protocol who 
relapse may receive another HSCT product on this protocol but will not be eligible to undergo 
FLT imaging again.


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2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
2.1.1
Inclusion Criteria: Transplant Recipient
2.1.1.1
At NIH : Age 15 years old and/or  9 years old and pubertal and 55 years for 
recipient. Pubertal is defined by: prior menses at any time (females), documentation of   
clinical Tanner stage greater than 2 at some point pre-chemotherapy or at the current 
visit.  (At this point, sex steroids have been produced for a few years which have driven 
initial pubertal development).  Tanner 2 is defined as: breast buds for females with 
coarse pubic hair, and coarse pubic hair and testes > 2.5cm for males.
2.1.1.2
At Children’s National Medical Center only: age > 4 years old and < 24.
2.1.1.3
At University of Oklahoma: Age > 17 years old and 55 years for recipient.
2.1.1.4
A diagnosis of a hematologic malignancy for which stem cell transplant is standard of 
care:
2.1.1.4.1 Acute Lymphocytic Leukemia 
x
Adult: (>22 years) > CR2 OR CR1 with e a high risk feature:
o
Matched sibling donor for recipient treated on adult leukemia regimen [50, 51]
o
t(9:22) or bcr-abl+; t(4:11), t(1:19), t(8:14), 11q23 (MLL rearrangements)
complex cytogenetics (5 or more chromosomal abnormalities), hypodiploidy (<44 
chromosomes). Note that patients with ALL blast crisis who emerge from CML 
are also eligible.
o
Primary induction failure, defined as failure to achieve CR with primary induction 
chemotherapy 
o
High WBC (>30,000 for B-cell ALL and >100,000 for T-cell ALL) at diagnosis
o
Persistence of minimal residual disease despite induction chemotherapy
x
Pediatric (< 22 years): > CR2 OR CR1 with a high risk feature:
o
Matched sibling donor for recipient treated on adult leukemia regimen [50, 51]
o
Primary induction failure (M3 (>25% with greater 200 cells counted) marrow at 
day 29), M2 (5-25% blasts with greater than 200 cells counted) bone marrow or 
MRD > 1% at day 29 who then fail at day 43 with either an M2 or M3 BM or 
MRD > 1% 
o
Persistent leukemia and t(9;22) (MRD >1% day 29 or MRD > 0.01% end-
consolidation)
o
11q23 (MLL) rearrangements detected by cytogenetic or PCR at initial diagnosis 
who are slow early responders (M2/M3 at day 14 or MRD> 0.01% at day 29)
o
Extreme hypodiploidy (< 44 chromosomes or DNA index of <0.81) detected by 
cytogenetic/ploidy analysis 


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2.1.1.4.2 Acute Myelogenous Leukemia
x
Adult: (>22 years) > CR2 OR CR1 with one of the following high risk features:
o
Adverse or intermediate-risk cytogenetics including:

Normal cytogenetics [52]

complex karytoype (>2 abnormalities) [53]

inv (3) or t(3;3); t(11;19)(q23;p13.1); +13; -17/17p-; -18; -20; (t(6;9); 
t(6;11); -7, 7q-; -5, 5q-; trisomy 8; t(3;5); t(9:11)(p22q23) [52, 53]

monosomy karyotype (presence of an autosomal monosomy in conjuntion 
with at least one other autosomal monosomy or structural abnormality. 
[52]

Any other karyotype EXCEPT t(8;21), t(9;11), inv(16), or t(16;16), and 
M3 (17; 17) [53] unless ckit mutation present and then eligible. [52]

AML emerging from CML (blast crisis) are eligible 
o
Primary induction failure, defined as failure to achieve CR with primary induction 
chemotherapy
o
Secondary AML, defined as AML related to antecedent MDS, MPN, or cytotoxic 
chemotherapy 
o
Hyperleukocytosis (WBC > 100,000 at diagnosis) 
o
Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene (FLT3-LM; FLT-ITDs) 
[54-56]
o
Bilineage or biphenotypic leukemias are high risk features and eligible. 
x
Pediatric (< 22 years): > CR2 OR CR1 with a high risk feature including:
o
Primary induction failure (> 5% blasts in marrow after induction)
o
Persistent leukemia (>15% after first course of chemotherapy)
o
Complex karyoptype, monosomy 7, or -5/-5q, FLT3 ITD-AR (>0.4) EXCEPT if also 
inv(16)/t(16;16), t(8,21)
o
Normal cytogenetics or abnormal cytogenetics EXCEPT if also inv(16)/t(16;16), t(8,21) 
are eligible for SIBLING transplant only
o
Bilineage or biphenotypic leukemias are high risk features and eligible. 
2.1.1.4.3 Myelodysplastic Syndrome RAEB 1 or 2; cytogenetics showing complex karyotype (3 
or more abnormalities), monosomy 7/del(7q), or inv(3)/t(3q)/del(3q); or transfusion 
dependent. 
2.1.1.4.4 Chronic Myelomonocytic Leukemia
2.1.1.4.5 Chronic Myelogenous Leukemia who have failed 2G- tyrosine kinase inhibitors (TKI)


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2.1.1.4.6 Standard pediatric indications for myeloablative transplantation for patients 
undergoing HSCT at Children’s National Medical Center per institutional guidelines
2.1.1.5
Disease status 
If patients are found to not be in remission at screening, then the patient may be returned to their 
primary hematologist/oncologist or may receive chemotherapy as per standard of care for the 
malignant disease.  Patients for whom this would be their first allogeneic transplant must be in 
remission (< 5% malignant blasts in marrow and peripheral blood and no evidence of 
extramedullary disease) for transplant. Patients enrolled on this protocol for their second 
transplant do not need to have attained remission prior to transplant.
2.1.1.6
Performance status: Karnofsky or Lansky performance status > 60% AND life 
expectance of greater than 3 months.
2.1.1.7
Ability to give informed consent.  For recipients and donors < 18 years of age, their 
legal guardian must give informed consent. Pediatric patients will be included in an age 
appropriate discussion in accordance with institutional guidelines. 
2.1.1.8
Hepatic function: Patients must have evidence of adequate liver function prior to 
enrollment defined by total bilirubin < 2.5 mg/dL (unless documented Gilbert’s 
syndrome) AND transaminases < 5 x the upper limit of normal for age appropriate 
indices. 
2.1.1.9
Renal function: Patients must have evidence of adequate renal function to proceed with 
stem cell transplant, creatinine clearance > 60 ml/min/1.73 m2. GFR may also 
demonstrate adequate renal function.
2.1.1.10 Left ventricular ejection fraction > 50% OR shortening fraction of >27% demonstrated 
on 2D echocardiogram or MUGA.  
2.1.1.11 Pulmonary function of DLC0 adj/VA and FEV1 > 60% of normal indices for age and 
height unless the patient has a likely acute reversible etiology of decline and then 
DLCO adj/VA > 30% of normal. Pediatric patients unable to complete PFTs may be 
enrolled as per enrolling institution SOP for recipient guidelines. 
2.1.1.12 Patients with prior autologous stem cell transplants will be included.  Patients with prior 
allogeneic stem cell transplants will be eligible for 2nd BMT if not previously 
transplanted with FLT on 11-c-0136.
2.1.1.13 Prior experimental systemic therapies must have been completed greater than 2 weeks 
prior to study entry.
2.1.2
Exclusion Criteria: Transplant Recipient
2.1.2.1
History of psychiatric disorder which may compromise compliance with transplant 
protocol, or which does not allow for appropriate informed consent. 
2.1.2.2
Active infections not responding to therapy.  All efforts should be made to clear the 
infection prior to enrollment.  


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2.1.2.3
Clinically significant systemic illness with manifestations of significant organ 
dysfunction which in the judgment PI or AI would render the patient unlikely to tolerate 
the protocol therapy or complete the study.  
2.1.2.4
Presence of active malignancy from an organ system other than hematopoietic.
2.1.2.5
HIV infection.
2.1.2.6
Chronic active hepatitis B infection.  Patients may be hepatitis B core antibody positive 
but must be surface antigen negative and without active evidence of disease. 
2.1.2.7
Pregnant or lactating females will be excluded from this trial due to unknown risks to 
the developing fetus.  Patients of child-bearing potential must use an effective form of 
contraception while on study. 
2.1.2.8
Sexually active individuals capable of becoming pregnant who are unable or unwilling 
to use effective form(s) of contraception during time enrolled on study and for 1 year 
post-transplant (see section 4.4for details). 
2.1.2.9
History of prior Lupron intolerance.  Note: patients ARE eligible if prior or current 
lupron exposure. 
2.1.3
Inclusion Criteria: Matched Related Transplant Donor
2.1.3.1
Age 2 and 60 years old and able to give consent or assent.  For donors < 18 years old, 
the legal guardian must be able to provide informed consent and an evaluation by a 
LSW or psychiatric personnel will be needed to determine willingness to participate. 
Pediatric patients will be included in an age appropriate discussion in accordance with 
institutional guidelines.
2.1.3.2
HLA-matched related donor, excluding identical twins. Donors must be matched at 
least 7 loci out of 8 at the allele or antigen level excluding antigen DRB1 mismatch.
2.1.3.3
Donor selection will be in accordance with NIH/CC Department of Transfusion 
Medicine criteria and must be able to medically endure stem cell collection or as per 
local institutional guidelines. 
2.1.3.4
Donors must be HIV negative, HTLV negative, HBsAg negative.
2.1.3.5
Donors must be physically able to and willing to tolerate marrow harvest collection 
preferably, or in the absence of this option, able and willing to donate via peripheral 
blood pheresis.
2.1.4
Exclusion Criteria: Matched Related Transplant Donor
2.1.4.1
History of medical illness that in the estimation of the PI or DTM physician precludes 
donation of marrow. 
2.1.4.2
Anemia (Hb < 10 gm/dl) or thrombocytopenia (< 100,000/ ul). 
2.1.4.3
Pregnant females (due to risk to fetus). 
2.1.4.4
Current psychiatric diagnosis that would compromise compliance with transplant 
protocol or precludes appropriate informed consent. 


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2.1.4.5
Presence of any blood transmissible infectious disease that cannot be cleared prior to 
stem cell collection and poses an unacceptable risk for the recipient (excludes CMV). 
2.1.4.6
Active malignancy will exclude the donor.  Any malignancy less than five years post-
remission will exclude the donor. Non-hematologic malignancies greater than 5 years 
ago will not exclude the donor.  Any history of hematologic malignancy will be 
considered on a case by case basis.  
2.1.4.7
Any medical contraindication to anesthesia or marrow donation will exclude the donor. 
2.1.4.8
Donors receiving experimental therapy or investigational agents.
2.1.4.9
Active autoimmune disease that in the opinion of the PI or AI would compromise the 
success of the transplant.
2.1.5
Inclusion Criteria- Matched Unrelated Donor
2.1.5.1
Unrelated donor matched at HLA-A, B, C, and DR loci by high resolution typing (at 8/8 
or 7/8 antigen/allele match) are acceptable donors. 
2.1.5.2
The evaluation of donors shall be in accordance with existing National Marrow Donor 
Program (NMDP) Standard Policies and Procedures at all institutions.
2.1.6
Inclusion Criteria- 18F FLT Candidate Transplant Recipient
2.1.6.1
Meets criteria Sections 2.1.1 and 2.1.2
2.1.6.2
Age > 18 years old at NCI, and age > 4 years and < 24 years at Children’s National 
Medical Center
2.1.6.3
Donor who is willing to undergo bone marrow or stem cell harvest. 
2.1.7
Exclusion Criteria- 18F FLT Candidate Transplant Recipient
2.1.7.1
History of prior fluorothymidine allergy or intolerance.
2.2
SCREENING EVALUATION AND CRITERIA FOR HSCT
2.2.1
Recipient
The following clinical, laboratory, radiological assessments must be performed on the recipient 
within 45 days of initiating HSCT preparative regimen with the exception of Section 2.2.2.6
which may be performed within the preceding 3 months.  These may be performed at outside 
institutions.  
2.2.1.1
Evaluations
x
Complete history and physical examination. 
x
CT scan of head, sinus, chest, abdomen, and pelvis.  
x
An echocardiogram (2D or MUGA) an electrocardiogram.
x
Pulmonary function tests (PFTs) must be performed for eligibility and FEV1, FEV1/FEV 
ratio, DLC02 recorded for adult patients; Oxygenation > 94% on RA may be used for 
pediatric patients unable to undergo PFTs at Children’s National Medical Center.


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x
Laboratory studies: 
o
CBC with differential, ABO blood type, PT/PTT, fibrinogen, thrombin time
o
Comprehensive chemistry
o
Lipid profile with triglycerides, TSH, free T4
o
Urine pregnancy test for women of childbearing potential
o
24 hour creatinine clearance or GFR
o
Bone marrow biopsy and aspiration with studies appropriate to staging of 
malignant disease, a LP or other biopsy may be required depending upon the 
diagnosis (to include LP for all AML and ALL) 
o
Infectious disease work-up at NCI only: antibody for Hepatitis A, B, C, HIV, 
T.Cruzi, HTLV-I/II, CMV, adenovirus, varicella, EBV, HSV, Toxoplasmosis, and 
syphilis. Work-up at other institutions may follow their policy.
x
Immunology studies: Lymphocyte phenotype panel (T, B, NK), IgG, IgA, IgM for NCI 
patients only.
x
Radiation Oncology Consult (within 28 days of initiating conditioning chemotherapy for 
HSCT at NCI). At Children’s National Medical Center and University of Oklahoma, this 
is per institutional practice.
x
Nutritional assessment (initial consult) and dental consult and social work consultation 
must be performed within 3 months of initiating preparative regimen and typing for 
HLA-A, -B, -C, and DR with PCR test of DNA mini-satellite regions for future 
determination of chimerism or as per local institutional practice. Note that when 
possible, the HLA and chimerism assays require 2 separate tubes of blood at NCI.
2.2.1.2
Criteria to proceed to HSCT
x
Disease status: Remission as defined by < 5% blasts in marrow and no evidence of 
extramedullary disease for patients undergoing their first allogeneic transplant.  Patients 
undergoing their second transplant do not have to have obtained a complete remission.
x
Performance status: Karnofsky or Lansky performance status > 60% AND life 
expectance of greater than 3 months. 
x
Hepatic function: Patients must have evidence of adequate liver function prior to 
enrollment defined by total bilirubin < 2.5 mg/dL AND transaminases < 5 x the upper 
limit of normal for age appropriate indices. 
x
Renal function: Patients must have evidence of adequate renal function to proceed with 
stem cell transplant, creatinine clearance > 60 ml/min/1.73 m2.
x
Left ventricular ejection fraction > 50% demonstrated on 2D echocardiogram or MUGA.  
x
Pulmonary function of DLC0/Adj/VA and FEV1 > 60% of normal indices for height and 
weight for adults and >95% oxygenation on RA for pediatric patients.
x
Patients who have received prior chemotherapy must have had resolution of significant 
toxicities to proceed to transplant. 
x
Negative pregnancy test (females)


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
x
No evidence of an active infection (clinical assessment and review of CT) that is not 
currently being treated or responding to therapy.
x
Either a HLA-matched related or unrelated donor, excluding identical twins. Donors must 
be matched at least 5 loci out of 6 by antigen matching or at least 8 of 10 using allele 
matching who met criteria for entry onto this protocol. 
2.2.2
Matched Related Donor 
(See Section 12.3)
The following clinical, laboratory, radiological assessments must be performed on the donor 
within 4 weeks of initiating HSCT preparative regimen with the exception of Section 2.2.2.6 at 
NCI.  Note, where these differ from institutional practice at University of Oklahoma or 
Children’s National Medical Center, the SOPs at those institutions may be followed.
2.2.2.1
Complete history and physical examination. 
2.2.2.2
Laboratory studies: 
o
CBC with differential, ABO blood type, PT/PTT
o
Comprehensive chemistry
o
Urinalysis 
o
Urine pregnancy test for women of childbearing potential
o
Screening for Hemoglobinapathy at NCI only if CBC suggests anemia due to 
hemoglobinapathy
o
Infectious disease work-up: antibody for Hepatitis A, B, C, HIV, T.Cruzi, HTLV-
I/II, CMV, adenovirus, EBV, HSV, varicella, Toxoplasmosis, and syphilis (RPR)
at NIH or as per institutional practice at Children’s National Medical Center or 
University of Oklahoma.
2.2.2.3
Immunology studies: Lymphocyte phenotype panel (TBNK) at NCI only.
2.2.2.4
Electrocardiogram
2.2.2.5
Chest radiograph 
2.2.2.6
Typing for HLA-A, -B, -C, and DR with PCR test of DNA mini-satellite regions for 
future determination of chimerism (may be done at anytime prior to HSCT).
2.2.2.7
Donor Health History Screen through Dowling Apheresis Center for those undergoing 
peripheral blood stem cell collection at Dowling Apheresis Center at NCI, or as per 
institutional guidelines at: Univ of Oklahoma, or Children’s National Medical Center.
2.2.2.8
DTM venous assessment and health history screen through Dowling Apheresis Center 
for those undergoing PBSC collection at NCI or as per institutional practice.
2.2.2.9
For donors undergoing bone marrow harvest, pre-anesthesia evaluation at NCI or as per 
local institutional practice.


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
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2.3
REGISTRATION PROCEDURES
2.3.1
Protocol Entry Date
Protocol “entry date” is considered to be the day that the informed consent form has been signed 
by the recipient.
2.3.2
Registration
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://intranet.cancer.gov/ccr/welcome.htm) must be completed and sent via encrypted email to: 
NCI Central Registration Office ncicentralregistration-l@mail.nih.gov.  After confirmation of 
eligibility at Central Registration Office, CRO staff will call pharmacy to advise them of the 
acceptance of the patient on the protocol prior to the release of any investigational agents.  
Verification of Registration will be forwarded electronically via e-mail to the research team. A 
recorder is available during non-working hours. 
2.3.2.1
Donors at NIH will be registered on this study prior to stem cell collection. Donors at 
Children’s National Medical Center and University of Oklahoma need to be identified 
and eligible but may follow local institutional practice.
2.3.2.2
Unrelated donors from NMDP Centers will be consented on an approved NMDP 
consent prior to eligibility evaluation. NIH UID numbers will be generated on unrelated 
donors while maintaining the anonymity required by the NMDP. The recipient may not 
sign consent before the matched unrelated donor has been identified and cleared by 
NMDP and the patient has been determined to be eligible At other institutions, this will 
be done as per institutional practice.
2.3.3
University of Oklahoma Donors and Recipients
2.3.3.1
These patients will sign consent after meeting eligibility criteria at the University of 
Oklahoma (Site PI: Dr. Holter), may receive therapy at the National Cancer Institute or 
the University of Oklahoma.
2.3.3.2
Registration will be a two part process as patients are screened on this protocol. A 
protocol registration form will be supplied by the CCR study coordinator and updates 
will be provided as needed. Subject eligibility and demographic information is required 
for registration. To initially register a subject, after the participant has signed consent, 
complete the top portion of the form and send to CCR study coordinator.   Once 
eligibility is confirmed, after completion of screening studies, complete the remainder 
of the form which is the eligibility checklist, indicating that the patient is being 
registered for treatment and send to CCR study coordinator. In addition, source 
documents supporting the eligibility criteria must be sent to the CCR study coordinator.  
The CCR study coordinator will notify you either by e-mail or fax that the protocol 
registration form has been received which will include the unique patient/subject ID 
number. Questions about eligibility should be directed to the CCR study coordinator or 
PI.  Questions related to registration should be directed to the CCR study coordinator. 


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
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Subjects that do not meet screening criteria should be removed from the study following 
the procedure in section3.10.4.
2.3.4
Children’s National Medical Center Donors and Recipients
2.3.4.1
Patients will sign consent after meeting eligibility criteria at Children’s National 
Medical Center (Site PI: Dr. Williams), and will receive therapy at Children’s National 
Medical Center.
2.3.4.2
Registration will be a two part process as patients are screened on this protocol. A 
protocol registration form will be supplied by the CCR study coordinator and updates 
will be provided as needed. Subject eligibility and demographic information is required 
for registration. To initially register a subject, after the participant has signed consent, 
complete the top portion of the form and send to CCR study coordinator. Once 
eligibility is confirmed, after completion of screening studies, complete the remainder 
of the form which is the eligibility checklist, indicating that the patient is being 
registered for treatment and send to CCR study coordinator. In addition, source 
documents supporting the eligibility criteria must be sent to the CCR study coordinator.  
The CCR study coordinator will notify you either by e-mail or fax that the protocol 
registration form has been received which will include the unique patient/subject ID 
number. Questions about eligibility should be directed to the CCR study coordinator or 
PI.  Questions related to registration should be directed to the CCR study coordinator. 
Subjects that do not meet screening criteria should be removed from the study following 
the procedure in section 3.10.4.
2.4
RANDOMIZATION PROCEDURES
2.4.1
Female Recipients
2.4.1.1
All female recipients will receive Lupron
2.4.2
Male Recipients
2.4.2.1
The CRO will provide the randomized treatment assignment to the PI based on random 
assignments determined by the study statistician for first BMT. For 2nd BMT, all 
patients will receive Lupron.


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3
STUDY IMPLEMENTATION
3.1
STUDY DESIGN
3.1.1
NCI and University of Oklahoma for 1st BMT
(Note: FLT/FDG PET scans will not be performed at the University of Oklahoma)
Some of these patients are anticipated to be evaluated using FLT (to include only patients needed 
for the immunological primary endpoint, not increasing total patient numbers). 23 adult NCI 
patients in total will undergo FLT PET/CT imaging on day -1, at day +5 or day +9, at 4 weeks, 
and at a future point to include evidence of GVHD relapse, or immune recovery. An estimated 
50 patients (including subset of the 23 patients undergoing serial scanning) will be imaged 
Recipient consents
Yes
>18 yrs and
Consent to FLT?
No
FLT/FDG/CT
Imaging
Day-1 FLT 
Day +5 or 9 FLT
Day +28 
FLT/FDG/CT
>Day +28
FLT/FDG/CT
Preparative Regimen
1) Total Body Irradiation (TBI) 1200 cGy 
fractionate twice daily (lung block) Days  -8,
-7, -6, -5  (adult), -9, -8, -7, -6 (ped)
2) Cyclophosphamide IV, Days  -4, -3 (adult) 
or -5, -4, -3, -2 (ped) *refer to 3.6.3.1.3
GVHD Prophylaxis 
1) Methotrexate IV Days + 1, 3, 6, 11 
2) Tacrolimus Day -1 (Goal levels) 
Allogeneic HSC Transplantation
1) Marrow (Day 0); Matched Related or Unrelated Donor
2) Tacrolimus 0.02 mg/kg (IBW) continuous IV infusion from Day -1 until tolerating oral  
Identify Donor:
Available within 4 weeks
Females
Lupron at -1-2 wk
Males
No Lupron


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
approximately at 1 year for evaluation of thymus reconstitution. The total possible numbers will 
include no more than 118 patients to achieve the 64 evalauble adults for the immunological 
primary endpoint. However, as of amendment K, all NCI patients will undergo a single 1 year 
FLT for evaluation of thymus reconstitution.
For 2nd BMT, at NCI, all 16 patients will undergo FLT imaging at day -1, and FLT and FDG 
imaging on day 28, day 60 and at relapse and response to therapy (if this occurs). 
3.1.2
Children’s National Medical Center
Ten pediatric patients at CNMC will undergo FLT PET/CT imaging on Day -1, day +9, and day 
+28 (if possible). Initial images will be correlated with engraftment and other secondary 
endpoints. At Children’s National Medical Center, the patients will not receive Lupron outside 
of the context of clinical care, and will receive myeloablative HSCT as per standard of care with 
FLT imaging for engraftment as the only primary endpoint.    
3.2
DRUG ADMINISTRATION
3.2.1
Lupron
Lupron will be administered to all female patients and half of the male patients (randomized for first 
BMT) and to all patients for 2nd BMT, once optimally between day -13 and day -20 pre-HSCT but 
definitely prior to initiation of preparative regimen as a 4 month intramuscular injection for patients > 18
years and as a 3 month injection (adult preparation) for patients < 18 years.  Subsequent injections may 
be given if clinically indicated to females.  There will be no dose modifications.  Females already on 
lupron therapy will receive the 4 month injection within 2 weeks prior to the next scheduled injection
and prior to HSCT preparative regimen.
3.2.2
18F-FLT
All NCI patients will undergo PET imaging in the NCI Molecular Imaging Clinic (B3). Pediatric 
patients will undergo PET imaging in the Children’s National Medical Center clinical imaging 
department.  Patients at University of Oklahoma will not undergo PET imaging per protocol
A low dose transmission CT scan will be performed for the purpose of attenuation correction.  
18F FLT PET/CT will be performed per the described schedule to include 4 imaging sessions in 
the peri-transplant at NCI and a maximum of 3 at Children’s National Medical Center. 18F FLT 
PET/CT alone will be used to assess the marrow at a pre-HSCT baseline image and an image day 
+5 or +9 (to evaluate for early signs of engraftment).  At both institutions, for first BMT, day + 
28 (+/- 5 days) image may be performed and at NIH only, a later time point (to be obtained when 
clinically indicated either with evidence of thymus recovery or GVHD), 18F FLT and FDG 
imaging will be conducted within 48 hours.  At NIH only, all newly accrued patients will 
undergo a 18F FLT scan at 1 year post-HSCT with FDG. These will be used to distinguish 
dividing cells (18F FLT+) from cells high in glucose consumption (FDG+).  A few patients in 
relapse who are consented to this protocol arm will undergo imaging analysis with 18F FLT 
PET/CT alone for calculation of ‘positive’ control for leukemia relapse.  For 2nd BMT, patients 
will undergo 18F FLT imaging on day -1, day 28, and day 60 to predict relapse.  Patients may 
also be imaged before and after therapy for relapse (to not exceed 5 scans total per patient).  


34
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
The expected dose of [18F]FLT is 0.07 mCi/kg with a maximum of 3 mCi.  Due to potential 
unpredictable delays, the total activity administered may be reduced at the discretion of the PI.
18F FLT will be provided by Cardinal Health or PETnet pharmacies.  IND will be held by Dr. 
Karen Kurdziel, Molecular Imaging Program, CCR, NCI.
18F FLT and FDG uptake greater than surrounding background (T:B>1.2) will be considered 
positive.  For hypermetabolic lesions, an estimated smoothed maximum SUV will be reported.  
Analysis of uptake will be performed using current practice guidelines within the Molecular 
ImagingProgram, Children’s National Medical Center and University of Oklahoma (on de-
identified scans).
3.3
ON STUDY PROTOCOL EVALUATION PRE-TRANSPLANT WORK-UP 
See Sections 12.2 and 12.3
3.3.1
Within 4 weeks of Transplant Date 
x
History and Physical Examination 
x
Laboratory studies must include the following: 
o
Complete blood counts with differential.
o
Complete chemistry panel: sodium, potassium, chloride, CO2, blood urea 
nitrogen, creatinine, calcium, phosphorus, magnesium, ALT, AST, total and direct 
bilirubin.
o
Toxoplasma IGG, Varicella IGG, CMV IGG, HSV IGG.
o
Immunologic screening: Immunoglobulin levels (IgG with subclasses, IgA), 
CD4/CD8 total numbers and ratio at NCI only.
o
Flow cytometry of peripheral blood for T/B/NK and residual disease at NCI and 
Children’s National Medical Center only
o
Chest and sinus CT 
o
Pulmonary Function Tests for adult patients and oxygen saturation on room air for 
pediatric patients.
o
Echocardiogram or MUGA
o
Electrocardiogram
o
BM biopsy and aspirate with flow cytometry, and cytogenetics if previously 
positive 
o
Lumbar puncture with flow cytometry for patients with ALL and AML
o
Testosterone and Estrogen levels, LH, FSH for all adult patients.
3.3.2
FLT on Study Evaluations 
(For patients enrolled on 18F FLT arm, Section 12.4): 


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
x
Imaging Study time points, 1st BMT:
o
Day -1: 18F FLT + low dose CT 
o
Day +5 or +9: 18F FLT + low dose CT 
o
Day +28, 29: 18F FLT + low dose CT, 18F FDG(not required at Children’s 
National Medical Center) + CT
o
Day + (GVHD vs. thymus recovery): 18F FLT + low dose CT, 18F FDG + CT at 
NCI only
x
Imaging Study time points 2nd BMT:
o
Day -1: 18F FLT + low dose CT 
o
Day +28/29: 18F FLT + FDG (not required for Children’s National Medical Center site) +
low dose CT
o
Day +60/61: 18F FLT + FDG (not required for Children’s National Medical Center site) +
low dose CT
o
Day + of relapse and initial response to immunotherapy: 18F FLT + FDG + low dose CT
at NCI only
x
Laboratory studies for FLT within 24 hours prior: 
o
Creatinine < 2, ALT and AST within 5 x ULN
o
TK1 serum measurement 
x
18F FLT imaging protocol: 
o
At NCI immediately following the IV infusion of 18F FLT, a dynamic PET 
emission will be performed for 45 minutes followed by a whole body static 
image.  An additional PET emission imaging acquisition will be performed 120 
minutes (+/- 15 minutes) post infusion.  A corresponding low dose transmission 
CT will be acquired immediately before each emission scan. At Children’s 
National Medical Center, the dynamic image will be omitted. 
3.4
BIOLOGIC STUDIES
The total aliquot of phlebotomy will not exceed 3 mL/kg per draw and 7 ml/kg in a 4 week 
period for research studies.  Should the research requests exceed these restrictions, research 
studies will be done in the order of Sections 12.5,12.6 and 12.7.
3.4.1
Immune Reconstitution
Studies to elucidate difference in immune reconstitution between Lupron treated and untreated 
groups to include multiparameter flow cytometry analysis of relevant cell populations (B and T) 
and serum analysis of relevant cytokines.  If available, these will be compared with donor 
lymphocyte characteristics (whereby 5 million total donor nucleated cells of the donor product 
will be reserved for biologic studies and go to the clinical core of ETIB (Bldg 10, Room 12C-
216, (301- 402-3627)). At Univ of Oklahoma, these may be stored within CETI lab or Holter lab 
respectively, or sent directly to the Pre-Clinical Core at NCI. At Children’s National Medical 


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
Center, these may be stored within CETI lab or Bollar lab respectively, or sent directly to the 
Pre-Clinical Core at NCI. 
3.4.2
Immunologic Studies
Impaired lymphocyte reconstitution is believed to contribute to the morbidity and mortality of 
allogeneic stem cell transplantation as evidenced by poor clearance of infections, and allo-
immunity (GVHD).[57] In adult HSCT recipients, T and B cell functions can be compromised 
indefinitely due to lack of thymus function and poor B cell education.  This study will use 
immunologic studies to determine if Lupron may enhance thymus reconstitution and B cell 
development.  Exploratory studies will include immunologic evaluations of HSCT complications 
to include: relapse, GVHD, infections, and the influence of thymus reconstitution on these 
complications. For these studies, prospective collection of infections to include: HHV6, 
adenovirus, EBV, CMV.  
3.4.3
Objectives/Specific Aims
3.4.3.1
Determine the effect of Lupron on engraftment and the recovery of T and B cell subsets 
following allogeneic HSCT by enumeration of cellular subsets in patients with and 
without Lupron.  Should thymus recovery be evident in subsets, secondary analysis of 
thymus function using T cell receptor excision circle analysis on peripheral T cells and 
using spectratype techniques. 
3.4.3.2
Determine whether FLT uptake demonstrates engraftment, leukemia relapse or residual 
disease, and/or GVHD, and/or thymus recovery. FLT images will be compared as 
follows: pre-transplant image will be used for assessment of MRD (to be correlated 
with disease recurrence and histology at day 28), post infusion image will be used to 
assess homing and cellular growth at day +5 or +9 image to correlate to time to 
engraftment, and correlate with marrow stability at histological assessment day +28, 
day +28 image to be quantitatively evaluated to correlate with blast % and marrow 
repopulation with histology, and the final image to be performed at a time of new-onset 
GVHD, potential relapse, or thymus recovery.  Exploratory studies to include the 
biology of HSCT.
3.4.3.3
For arm 2, exploratory analyses will include: whether FLT uptake can predict relapse or 
response to immunotherapy and whether there is an improvement in this small number 
of patients in relapse rates (from 80% as designated in historical controls).  Immune 
studies will be undertaken to explore whether there is alterations in lymphocyte subsets 
similar to patients who remain in remission on the primary arm of the protocol.  
3.4.4
Methodology 
The following studies will be performed on peripheral blood (if available) samples.  Blood 
samples (20 cc in red/green CPT heparin and 16 cc in EDTA tubes, age adjusted for weight in
pediatric patients) will be drawn for evaluations.  Time points are listed in section 3.8.
Complete blood counts and TBNK will be collected on the same day.  Samples should be 
delivered to the lab of Dr. Fran Hakim in Building 10, Room 3E-3288 (301-402-3627) at NCI 
and may be processed and frozen and shipped in batch from Children’s National Medical Center
and University of Oklahoma.


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3.4.4.1
Peripheral blood: quantity (20mL).  Flow cytometry will be performed on peripheral 
blood samples. Commercially available antibodies will be used to characterize T cell, B 
cell, dendritic cell and monocyte recovery after HSCT.  Samples will be frozen and 
thawed in batches. 
3.4.4.1.1 Research blood sample aliquot size will be minimized for patients < 18 years of age 
and the total amount restricted to a maximum of 3 ml/kg per draw and 7 ml/kg per 6-
week period (maximum 450 ml). In the event that blood draws are limited due to 
patient size, research studies will be performed in order of priority as listed in Section
12.7. Small volume apheresis collections will not be included in this calculation since 
such is performed isovolumetrically with minimal red cell loss.
3.4.4.2
Plasma (>20 mL).  Plasma (EDTA and heparin) will be spun in refrigerated centrifuge 
and frozen immediately and subsequently utilized for cytokine studies using 
immunofluorescent technique.
3.4.4.3
Tissue, urine, and other fluid specimens (optional):  Any pathology or biopsy specimen 
or fluid that is obtained for clinical indications from the recipient and has remaining (or 
extra specimen) following the clinically indicated test may be stored and used for 
immunological characterization.  This includes any biopsies of bones obtained because 
of new onset pain, uptake of nuclear imaging scanning concerning for relapse or 
infection from the recipient.   Patients will have the opportunity to opt outin writing to 
determine if extra fluids and tissues may be used for these studies. 
3.5
COLLABORATIVE RESEARCH STUDIES
Under Amendment P, coded serum samples and human peripheral blood will be sent to 
the Children's National Medical Center to evaluate comparisons of T and B cells between 
patients who received lupron and those who did not in terms of relapse, GVHD, and infections
Rationale: Dr. Williams is a recognized expert in multicolor flow cytometry for the analysis of 
human peripheral blood from post-allogeneic-transplant patients.
Specific Aims:  To determine the effect of Lupron on engraftment and the recovery of T and B 
cell subsets following allogeneic HSCT by enumeration of cellular subsets in patients with and 
without Lupron.
Design/Procedures:
The samples will be sent to laboratories at the Children's National Medical Center to perform 
multicolor flow cytometry as per section 3.4.4.1 as well as cytokine studies as per section 3.4.4.2
after an MTA is executed between the NCI and the Children's National Medical Center. All 
excess samples will be destroyed at the conclusion of the planned studies. The serum and human 
peripheral blood samples will be sent to the following address:  
Kirsten Williams MD
Center for Cancer and Immunology Research


38
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
Program for Cell Enhancement and Technologies for Immunotherapy
Children's National Medical Center
5th Flr, Suite 5220 
111 Michigan Ave NW
Washington, DC 20010
Coded serum samples will be sent to Dr. Williams from patients participating in the 11-C-0136
clinical protocol led by primary investigator, Dr. Christopher Kanakry at NCI. Cryopreserved 
heparinized serum from up to 25 patients will be transferred through this collaboration. 
Laboratory results will be sent back to Dr.Kanakry for data compilation and analysis. Dr. 
Williams will not have access to patient identifiers or patient information.
Only the subject’s unique identifier will be used and information about the enrolling site will be 
removed.  Authorized investigators at NCI and Dr. Williams will maintain codes linking the 
laboratory specimens received to clinical information; however, Dr. Williams will not have 
access to any other patient identifiers or patient information. Sample identifiers are not derived 
from actual identifiers and Dr. Williams’s research team will not have access to the re-
identification key.
3.6
DONOR COLLECTION
3.6.1
Matched Unrelated Donors 
Matched unrelated donors will be collected as per NMDP policies and procedures.  The 
concentration of CD34+ cells will be determined by flow cytometry.  The product may be 
infused fresh or stored frozen prior to infusion.  Every attempt will be made to obtain a marrow 
product for first BMT.  Should PBSC be the only alternative, these patients will be analyzed 
separately and replaced. The target dose is > 350 million total nucleated cells per kilogram. Of 
this product, 5 million total donor nucleated cells will be reserved for biologic studies and go to 
the clinical core of ETIB (Bldg 10, Room 12C-216, 301 402 3627) at NCI. Cell selection will not 
be performed on the HSC grafts. If samples are obtained at Children’s National Medical Center
and University of Oklahoma, these may be processed, frozen, and shipped in batch, or fresh to 
Dr. Hakim (above).  MUD policies at Univ of Oklahoma and Children’s National Medical 
Center will be followed as per SOPs of institutional practice. Please refer to Section 3.4 for 
research study details. For 2nd BMT, PBSC will be preferred over marrow.  
3.6.2
Matched Related Donors 
Matched related donors will undergo marrow harvest with general anesthesia.  Subjects will 
undergo anesthesia consultation, and meet criteria for eligibility/enrollment. CD34+ fraction will 
be determined.  Subjects will also undergo the Donor Health History Screen to determine donor 
eligibility using standard DTM criteria in the Dowling Apheresis Clinic by skilled staff in the 
Blood Services Section for adult patients and age-appropriate questioning when indicated for 
pediatric subjects at NCI, the Oklahoma Blood institute, and will be evaluated and exam 
performed by a member of the Oklahoma Transplant team for both PBSC collection and marrow 
donation, and by BMT staff at Children’s National Medical Center as per institutional protocol.
Subjects will undergo follow-up history and physical examination within 1 week of donation, at 


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
NCI or as per local institutional guidelines. Donor recipient weight discrepancy with smaller 
donors placing the recipient at risk for non-engraftment will necessitate PBSC collection.  
Calculations will be performed by weight; for obese patients, an average between ideal and 
actual body weight.  PBSC collection will be done as per standard of care and local institutional 
practice; at NCI, with donors receiving 10 ug/kg of GCSF for 5 days, with first collection 
through large bore venous catheter on the 5th day and potential second collection on day 6 (for 
insufficient sample) with a 6th dose of GCSF. Should PBSC be the only alternative, these patients 
will be analyzed separately and may be replaced. The target dose is > 350 million total 
nucleated cells per kilogram; however > 100 million total nucleated cells per kilogram will be 
sufficient for marrow collections and between 3-4 million CD34/kg for PBSC products.  Of this 
product, 5 million total donor nucleated cells will be reserved for biologic studies and go to the 
clinical core of ETIB (Bldg 10, Room 12C-216, 301 402 3627) at NCI, and may be processed 
and stored and shipped frozen from outside institutions. Cell selection will not be performed on 
the HSC grafts.  Note that TTV testing sample will be drawn as per institutional practice (e.g. on
the day of marrow collection at NCI). Harvested cells will be processed in DTM at NCI, within 
the Stem Cell laboratory at Children’s National Medical Center and in the Oklahoma Stem cell 
processing center at Univ. of Oklahoma.  For all frozen samples and all fresh samples with ABO 
mismatch, the product will be depleted of red cells until less than 0.5 cc/kg or 50 cc total remain 
(whichever is smallest) when possible.  For fresh harvest products, plasma pheresis may also be 
required if indicated by ABO mismatch.  DTM at NCI, the Stem Cell laboratory at Children’s 
National Medical Center, and the Oklahoma Stem Cell processing unit  at Univ. of OK will 
notify the Adjunct PI and/or NIH PI and /or site PI and research RN of any problems in regard to 
cell number or red cell volume prior to freezing product. Note: for 2nd BMT, PBSC products 
will be preferred.  
3.7
PREPARATIVE REGIMEN FOR HSCT AND GVHD PROPHYLAXIS
(Refer to Sections 12.5 and 12.6)
3.7.1
Central Access
An appropriate form of central access will be obtained prior to HSCT procedure. Tunneled triple 
lumen catheter is preferred in thorax at NCI.  Other institutions will follow institutional 
standards.
3.7.2
Remission Status
Patients undergoing first HSCT must be in remission prior to HSCT; this may include patients 
without evidence of disease in aplasia.   
3.7.3
Conditioning Regimen 
3.7.3.1
Adults (>22 years and on ETIB service at NCI, on adult BMT at Univ of Oklahoma): 
3.7.3.1.1 TBI will be delivered to a total midplane dose of 12Gy and median lung dose of 6Gy.  
Radiation will be fractionated twice daily over 4 days (days -8, -7, -6, -5).  Opposed 
lateral fields with lung compensation will be treated to 1.5 Gy for each fraction to a 
total cumulative dose of 12Gy.  Mediastinal fields will be treated AP-PA concurrently 
with the opposed lateral fields at a dose of 75cGy twice daily to bring the mediastinal 
dose to 12Gy with a median lung dose of 6 Gy.  Fractions will be delivered with at 


40
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
least a 6 hour interfraction interval.  Gonadal shielding will not be used.  Head and 
neck compensation and other technical modifications may be made at the discretion of 
the treating radiation oncologist.  For patients with CNS positive disease at any time
after diagnosis, CNS boost may be delivered unless contraindicated by PI or AI. 
The CNS boost will be delivered as a 6 Gy boost in once daily 2 Gy fractions.  The 
boost will be delivered prior to TBI.  Patients with sites identified by nuclear imaging 
or other clinically accepted diagnostic tests may receive a boost to these areas as 
clinically indicated at any time point pre- or post transplantation.
3.7.3.1.2 Cyclophosphamide:  cyclophosphamide 60 mg/kg IV, Days -4, -3 with forced diureses 
with IV hydration to maintain urine output at 2-3ml/kg/hr and mesna 60mg/kg/dose IV 
at continuous intravenous infusion equal to the dose of cyclophosphamide. For 
patients with BMI > 35, the cyclophosphamide and mesna dosing will be based on a 
modified weight half way between the ideal and actual body weights.
3.7.3.1.3 Modifications: For adult patients with MDS who are aplastic after induction therapy, 
a modified regimen may be used as the preparative regimen including: Fludarabine 30 
mg/m2 for 3 days (day -4, -3, -2) and TBI 200cGy day -1.
For patients who have already received TBI, or exceeded the radiation maximum 
tolerated dose to preclude TBI for first or second BMT, preferred second choice is 
busulfan (with goal steady state of 800-1000) with fludarabine or cyclophosphamide at 
myeloablative dosing or non-myeloablative dosing if recommended for 2nd BMT.
3.7.3.2
Pediatric (<22 years and on POB service at NCI or at Children’s National Medical 
Center):
3.7.3.2.1 At NCI: TBI will be delivered to a total midplane dose of 12Gy and median lung dose 
of 6Gy. Radiation will be fractionated twice daily over 4 days (days -9, -8, -7, -6). 
Opposed lateral fields with lung compensation will be treated to 1.5 Gy for each 
fraction to a total cumulative dose of 12Gy.  Mediastinal fields will be treated AP-PA 
concurrently with the opposed lateral fields at a dose of 75cGy twice daily to bring the 
mediastinal dose to 12Gy with a median lung dose of 6Gy.  Fractions will be delivered 
with at least a 6 hour interfraction interval.  Gonadal shielding will not be used.  Head
and neck compensation and other technical modifications may be made at the 
discretion of the treating radiation oncologist.  For patients with CNS positive disease 
at any time after diagnosis without definitive prior cranial radiation, CNS boost may
be delivered unless contraindicated by PI or AI. Adjustments to the boost dose in 
pediatric patients may be made if contraindicated at the discretion of the PI or AI.  The 
CNS boost will be delivered as a 6 Gy boost in once daily 2 Gy fractions.  The boost 
will be delivered prior to TBI.  Patients with sites identified by nuclear imaging may 
receive a boost to these areas as clinically indicated at any time point pre- or post 
transplantation.
3.7.3.2.2 At NCI: Cyclophosphamide: cyclophosphamide 50 mg/kg IV, Days -5, -4, -3, -2 with 
forced diureses with IV hydration to maintain urine output at 2-3ml/kg/hr and mesna 


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
as 24 hour continuous intravenous infusion equal to the dose of cyclophoshamide.  For 
patients with BMI > 35, the cyclophosphamide and mesna dosing will be based on a 
modified weight half way between the ideal and actual body weights. 
3.6.3.2.3 For patients who have already received TBI, or exceeded the radiation maximum 
tolerated dose to preclude TBI for first or second BMT, preferred second choice is 
busulfan (with goal steady state of 800-1000) with fludarabine or cyclophosphamide at 
myeloablative dosing or non-myeloablative dosing if 2nd BMT.
3.6.3.2.4At Children’s National Medical Center, myeloablative transplantation for FLT imaging 
may be according to current standard practice including the regimens of: TBI   
3.7.4
GVHD Prophylaxis 
GVHD prophylaxis at NCI and Univ of Oklahoma will include: methotrexate 10 mg/m2 IV on 
day +1, and 5 mg/m2 IV Days + 3, 6, 11 and tacrolimus  starting Day -1 at dose of 0.02 
mg/kg/day continuous infusion  (with target level between 5 and 10 ng/ml though up to 15 
acceptable).  Note, methotrexate dose should be discussed with pharmacy and adjusted for renal 
or liver dysfunction.  Should either agent not be tolerated (for example, posterior reversible 
encephalopathy from tacrolimus) or other risks put patients at added risk, these may be 
substituted with standard alternatives (e.g. cyclosporine, sirolimus, cellcept). When the patient is 
tolerating orals, tacrolimus may be converted to oral administration.  Taper of tacrolimus may be 
initiated on day +100 if there is no evidence of GVHD.  Patients should be evaluated weekly 
after the initiation of tacrolimus taper and tacrolimus taper held or increased for evidence of 
GVHD (to include diarrhea, mouth sores, unexplained elevation of liver enzymes).  If taper is not 
able to be initiated at day +100, by day +180, a new evaluation should occur to attempt taper.  
Patients are at high risk of relapse and every attempt should be made in this protocol to permit 
graft-versus-leukemia effects. For patients after 2nd BMT, taper may be initiated as early as day 
45 and the plan will be to taper as rapidly as possible. 
3.7.5
Growth Factors (GCSF)
GCSF will not be administered unless clinically indicated such as life threatening infection and 
neutropenia or significantly delayed engraftment (greater than day 18) during the initial 
transplant phase (less than day 30).  A PI or AI must be involved in this clinical decision.  While 
there are data that GCSF accelerates neutrophil engraftment by several days without effects on 
GVHD and relapse in two randomized, placebo controlled studies [58, 59], there are also data 
from larger historical cohorts that suggest higher rates of GVHD and relapse without significant 
differences in neutrophil recovery times. [17, 60] In addition, GCSF has the potential to induce 
leukemic expansion in AML patients [60] and to alter the imaging evaluation by FLT studies.  
Notably, GCSF is not standard practice for pediatric patients receiving marrow grafts which are 
the primary source for pediatric transplantations currently. Given the lack of clear benefit from 
these studies and the likelihood that patients will recover neutrophils prior to life-threatening 
infections with matched marrow products, GCSF will not be part of the planned BMT support
but rather an option for the few patients who may benefit from its administration (due to delayed 
engraftment or infections). GCSF may be used after engraftment in the setting of secondary 


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
neutropenia (often associated with medications administered post-transplant (e.g. 
antimicrobials).  
3.8
TRANSPLANT PROCEDURE FOR 1ST AND 2ND BMT
3.8.1
Day 0
On day 0, the patient will receive the donor product from the selected donor intravenously per 
DTM standard operating procedures or local institutional guidelines. 
.
3.8.2
Transplant Outcome Determinations
x
Neutrophil Recovery: Designated by the first of 3 consecutive days with an ANC 
above 500/mm3.
x
Platelet Recovery: Designated by the first of 7 days where the platelet count remains 
above 20,000/mm3 without transfusion support.
x
Sustained Donor Engraftment: Neutrophil recovery associated with complete donor 
chimerism at day 100.  Any patient who dies before day 28 will not be evaluated for 
engraftment but will be evaluable by FLT.
x
Primary Graft Failure: Failure to achieve sustained donor engraftment
x
Secondary Graft Failure: Documented sustained donor engraftment as defined above 
followed by:  1) severe neutropenia (ANC < 500/mm3) and bone marrow biopsy 
revealing a cellularity of less than 25% or 2) absence of donor cells in the marrow or 
blood as demonstrated by a chimerism assay without subsequent improvement occurring 
either spontaneously or after growth factor treatment.  Improvement is defined as ANC 
> 500/mm3 consistently.  Severe neutropenia with marrow cellularity > 25% is not 
secondary graft failure.
x
Aplasia: Less than 5% marrow cellularity as measured on bone marrow biopsy. 
3.9
POST-TRANSPLANT MONITORING (1ST AND 2ND BMT)
(See Sections 12.5 and 12.6)
At NCI, patients will be admitted during the preparative regimen and throughout the peri-
transplant period until engraftment has occurred and the patient is deemed stable for discharge.  
After discharge, the patient will be monitored as clinically indicated until day +100.  
3.9.1
Day 0 to day +100
x
History and physical evaluation
x
CMV, Adenovirus, EBV PCR
x
CBC with differential 
x
Acute, Hepatic and Mineral Panels, CK , Uric acid and LDH
x
Lipid panel (days +28, +60, and +100 (+/- 10 days))
x
Tacrolimus level as long as on tacrolimus
x
Monitoring for aGVHD (documented day +28, +60, +100) (see Section 12.10)


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
x
Monitoring for HHV6 in peripheral blood (all patients) and CSF (for those with leukemia 
diagnosis) at day +28, +60, +100 +/- 10 days for patients at NCI only
x
Research blood (day +5, +7, +14, +21, +28, +60, +100)
o
+/- Allowances for the drawing of research blood is +/-1 day for day +5 and +7, +/- 2
days for day +14, +/- 3 days for day +28, +/- 7 days for day +60, +/- 14 days for day 
+100, and +/- 30 days for later time points.
3.9.2
Specific evaluation time points (1st and 2nd BMT)
Patients will be followed as clinically indicated.  These evaluations should occur within 10 days 
of anticipated date for time points less than day 100 and within 1 month for time points after day 
100.
x
History and physical evaluation on day +180, +270, +365
x
Bone marrow aspirate with studies appropriate to staging of malignant disease, a LP or 
other biopsy may be required depending upon the diagnosis (to include LP for all AML 
and ALL) with chimerism on day +28, +60, +100, +365
x
Bone marrow biopsy on day +28, +60, +100, +365
x
Lymphocyte phenotyping (T,B,NK) on day +28, +60, +100, +180, +270, +365 (to be 
performed at NCI including those from outside institutions)
x
Pulmonary function tests on day + 100, +180, +270, +365
x
Chimerism of peripheral blood on day +28, +100, +180, +270, +365 for all adult 
patients
x
Immunoglobulins (IgG, IgM, IgA) on day +28, +100, +180, +270, +365
x
Acute, Hepatic and Mineral Panels, CK , Uric acid and LDH and lipid on day +28, +100, 
+180, +270, +365
x
cGVHD evaluations on day +100, +180, +270, +365 (see Sections 12.11, 12.12 and 
12.13)
x
Research blood on day +180, +270, +365, and when clinically significant events such as 
cGVHD, laboratory suspicion of relapse, or thymus recovery occur. 
x
Chest CT +100, +365
3.9.3
Long term follow-up guidelines (1st and 2nd BMT)
Ref: recommendations [61]
These guidelines are for all NIH patients.  All patients may obtain these studies within 1 month of 
desired date and these may be done in other institutions than NIH with documentation.  Please note that 
these should be performed yearly for 5 years after transplantation either as part of this protocol or in 
another setting for abnormal results. Pediatric follow-up for CNMC patients will be done as per 
Children’s National Medical Center guidelines.  
x
Dental evaluations day +180, +365
x
Ferritin and iron studies on day +180, +270, +365


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
x
Thyroid studies on day +180, +270, +365
x
FSH, LH on day +180, +270, +365
x
Ophthalomological evaluation on day +180, +365
x
DEXA scan on day +365
x
Echocardiogram on day +365
x
Pulmonary Function Test yearly for 5 years
x
GYN examination (female patients) day +365
x
Urinalysis/protein screening day +180, +365
3.9.4
FLT on study evaluations 
(For patients enrolled on FLT arm at NCI or Children’s National Medical Center)
x
Imaging Study time points 1st BMT:
o
Day -1: 18F FLT + low dose CT 
o
Day +5 or +9: 18F FLT + low dose CT 
o
Day +28/29: 18F FLT + FDG (not required for Children’s National Medical Center site) +
low dose CT
o
Day + (GVHD vs. thymus recovery): 18F FLT + FDG + low dose CT at NCI only
x
Imaging Study time points 2nd BMT:
o
Day -1: 18F FLT + low dose CT 
o
Day +28/29: 18F FLT + FDG (not required for Children’s National Medical Center site) +
low dose CT
o
Day +60/61: 18F FLT + FDG (not required for Children’s National Medical Center site) +
low dose CT
o
Day + of relapse and initial response to immunotherapy: 18F FLT + FDG + low dose CT
at NCI only
x
Laboratory studies for FLT within 24 hours prior : 
o
Creatinine < 2, ALT and AST within 5 x ULN
o
TK1 serum measurement 
x
18F FLT imaging protocol: 
o
At NCI, Immediately following the IV infusion of 18F FLT, a dynamic PET emission 
imaging will be performed for 60 minutes, immediately followed by a whole body static 
image.  An additional PET emission imaging acquisition will be performed 120 minutes 
(+/- 15 minutes) post infusion.  A corresponding transmission CT will be acquired 
immediately before each emission scan. Children’s National Medical Center will omit the 
dynamic protocol.
3.10 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
3.10.1 Criteria for Removal from Protocol Therapy 
x
Completion of 1year protocol therapy
x
Participant requests to be withdrawn from active therapy 
x
The option to treat the patient after protocol therapy with alternative therapies.
x
Investigator discretion


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Please note: The AEs as outlined in the treatment protocol will not be collected from that point 
forward.
3.10.2 Off-Study Criteria
x
Failure to meet pre-transplant eligibility criteria as defined in section 3.3.1 and 3.7.2.
x
Patients who do not have a suitable donor or patients for whom the collection product is 
deemed insufficient without opportunity for further collection of the donor (via PBSC). 
Patients may proceed on standard of care if this is deemed to be the best medical 
management by the PI or AI. 
x
The donor or recipient refuses to continue therapy
x
Patients for whom a suitable donor cannot be found
x
Donor subjects who become decisionally impaired 
x
Lost to follow-up
x
PI decision to end this study
x
Death 
x
Completed post-transplant follow up period (5 years)
In all cases, the reason(s) for withdrawal will be documented.
In addition, a patient may at anytime be removed from protocol at the principal investigator’s 
discretion, if the P.I. deems the subject to be at unacceptable risk to remain on study. Reasons for 
this action may include (but are not limited to disease progression with declining organ 
function/performance status before transplantation; inadequate family/caregiver support; 
noncompliance.
Note: Minors should remain on study until they reach the age of 18 and have an opportunity to 
be consented for the future use of their data and specimens. 
3.10.3 Off Protocol Therapy and Off Study Procedure at NCI
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
protocol therapy and when a subject is taken off-study. A Participant Status Update Form from 
the web site (http://camp.nci.nih.gov/ccr/welcome.htm) main page must be completed and sent 
via encrypted email to: NCI Central Registration Office<ncicentralregistration-l@mail.nih.gov.
3.10.4 Participating Site Off-Study Notification
The Participant Status Update Form will be supplied by the CCR study coordinator. Send the 
completed form to the CCR study coordinator.


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4
SUPPORTIVE CARE
4.1
INFECTION PROPHYLAXIS
For a full description of infection prophylaxis for NCI patients please refer to the NIH BMT 
Consortium Supportive Care Guidelines at 
http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml) which are recommended.  Infection 
prophylaxis for pediatric patients at NCI should follow the NIH BMT Consortium Supportive 
Care Guidelines found at http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml or as per 
local institutional practice.
Below is a table summarizing adult recommendations at NCI.  Please note that the numbers 
correspond to the order in which the agents should be attempted (i.e. first choice for PJP is 
trimethoprim/sulfamethoxazole and the second choice is atovaquone). Whenever possible, these 
should be followed at University of Oklahoma.  Children’s National Medical Center pediatric 
patients should follow Children’s National Medical Center guidelines (SOP). Also, please note 
that these should be followed for patients receiving chemotherapy on this protocol as well. 
Table 1
Organism
Prophylaxis Recommendations
Timing
Pneumocystis 
jiroveci pneumonia 
1) Trimethoprim/sulfamethoxazole 
DS (or pediatric dose equivalent) 
once a day three times weekly
2) Atovaquone 1500 mg daily 
3) Inhaled Pentamidine monthly
Start after immune 
reconstitution or by day 28. 
Stop > 6 months after 
immunosuppression 
withdrawal without evidence 
of GVHD and greater than 1 
year after HSCT.
Fungus 
1) Caspofungin 
2) Voriconazole or Posaconazole 
(Check levels and target dose to 
Vori > 2 for prophylaxis, >4 for 
treatment; posa > 1000)
3) Liposmal amphotericin B
Start caspofungin with 
preparative regimen for mold 
prophylaxis and continued 
until neutrophil recovery and 
not on prednisone equivalent 
exceeding 0.8mg/kg/qod.  Plan 
to switch to or add azole for 
evidence of invasive mold.  
Note: azoles will need to 
modify tacrolimus dosing.  
History of presumed or proven 
invasive fungal infection 
necessitates continuous 
antifungal coverage throughout 
HSCT until off 
immunosuppression unless 
there is a significant 
complication of therapy.


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Organism
Prophylaxis Recommendations
Timing
Virus 
1) Acyclovir 800 mg po BID or 
250mg/m2 IV q12. 
Positive HSVI/II serology, 
history of Herpes Simplex or 
varicella infection, or CMV 
infection.  Starting on day -4.
Bacteria
1) Ceftazidime 2 gm IV q 8 hrs 
2) Levofloxacin 500 mg PO or IV 
Start at neutropenia, 
discontinue after resolution of 
neutropenia.  Note: patients 
should remain on PCN 
(encapsulated organism 
prophylaxis) until off 
immunosuppression > 6 
months and without ongoing 
or cGVHD.
This study will also monitor for viral infections to include adenovirus, EBV, CMV, and HHV6.  
If the patient develops chronic GVHD, he/she will receive penicillin V for prophylaxis against 
bacterial infections.  He/she will undergo vaccination against S. pneumoniae and H. influenzae,
beginning 12 months after transplantation as per the NIH BMT Consortium Supportive Care 
Guidelines.
Administration of live vaccines will be avoided during the first 2 years after transplantation or in 
patients with ongoing chronic GVHD or immunosuppression. Immunizations with inactive 
vaccines will be administered starting 6 months after withdrawal of immunosuppression or one 
year whichever comes first with the exception of influenza vaccine and prevnar.  Response to 
vaccines is an exploratory endpoint on this trial.  Vaccine response is one of the best markers of 
T and B cell function (requiring CD4+ T cells to convert B cells to IgG).  
4.1.1
Infectious Disease Surveillance:  
Adenovirus PCR will be sent weekly during engraftment. For patients who have Toxoplasmosis 
titer positive (at any point prior to HSCT), toxoplasmosis will be monitored weekly during 
engraftment at NCI only. HHV6 will be monitored in blood and CSF at day +28, +60, +100 +/-
10 days (for those undergoing CSF evaluation at these time points at NCI only).
4.2
MANAGEMENT OF ENGRAFTMENT SYNDROME
Engraftment syndrome is characterized by noninfectious fever, rash, and vascular leak causing 
non-cardiogenic pulmonary edema, weight gain, and renal.  Diagnostic criteria and a treatment 
schema for engraftment syndrome are included in Section 12.9.
4.3
TREATMENT OF GRAFT-VERSUS-HOST DISEASE
In patients in whom GVHD is suspected, standard clinical criteria and biopsy findings (when 
clinically indicated) will be used to establish the diagnosis. Acute GVHD will be assessed 
according to 1994 Consensus Conference on Acute GVHD Grading criteria [62].  Chronic 
GVHD will be assessed according to 2005 Chronic GVHD Consensus Project [62]. See Section 
12.12 for details concerning the assessment of acute and chronic GVHD.


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Patients with clinical Stage 1 or 2 (Grade I) GVHD of the skin without any other organ 
involvement will be treated with a topical corticosteroid cream.
In general, patients with t Grade II acute GVHD will be treated with high-dose, systemic 
corticosteroids.
Patients who fail to respond to corticosteroids within 3 days will be considered for second-line 
immunosuppressive therapy.   Given that the patients in this protocol are young adults with the 
potential for rapid response to immunosuppressive agents, every effort will be made for rapid 
taper of high dose steroids and rescue with other, less immunosuppressive agents. 
As standard treatment of steroid-refractory acute GVHD and of chronic GVHD is often 
unsuccessful, treatment of either can include standard systemic or local therapies. This can 
specifically include autologous serum eye drops when recommended by ophthalmology for 
ocular GVHD per NIH Consensus Guidelines.
4.4
MENSES SUPPRESSION AND CONTRACEPTION
For a full description of menses suppression and contraception guidelines for NCI please refer to 
the NIH BMT Consortium Supportive Care Guidelines at: 
http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml
Pre-menopausal women who have not undergone hysterectomy will receive Lupron within 2 
weeks of preparative regimen. Adult women will receive the 4 month (30 mg) preparation and 
females < 18 years old will receive the 3 month (11.25 mg) preparation.  Subsequent therapy will 
continue until platelet recovery after transplantation (> 50,000/μl without transfusion) and may 
include repeat Lupron dosing or Lo-Ovral (300μg norgestrol and 30 μg ethinyl estradiol) 1 tablet 
daily without placebo tablets. If Lo-Ovral is started when the patient is bleeding and bleeding 
persists for more than 2-3 days, increase the dose to 1 tablet twice daily. If bleeding persists for 
more than an additional 2-3 days (total 5 to 6 days after starting hormones), consult the NIH 
Gynecology Consult Service.  However, Lo-Ovral will be stopped as soon as possible and 
patients who receive it may be analyzed separately from the lupron-treated female cohort.
Female transplant recipients will be advised to use an effective form of contraception for at least 
1 year after transplantation, and to have their male partners use condoms.  
Male transplant recipients will be advised to use contraception, preferably condoms, for 1 year 
after transplantation.
4.5
BLOOD PRODUCT SUPPORT
Patient’s blood counts will be monitored daily during the transplant hospitalization. Patients will 
receive packed red blood cells and platelets as needed to maintain Hb > 8.0 gm/dl at NCI and 
CNMC and Hb> 7.0 gm/dl at Univ. of OK as per institutional practice, and plts > 10,000/mm3
(or higher, if clinically indicated) unless the patient is not group 0 blood type and the donor 
is, then Hb> 9.4 until after day 15 at NCI and per institutional practice. All blood products, 
with the exception of the stem cell product and Donor Cell Infusion (DCI), will be irradiated and 
leukoreduced as per DTM protocol at NIH, and per the Blood Bank at Children’s National 
Medical Center or the University of Oklahoma. The patient, who is seronegative for CMV and 
whose donor is seronegative, should receive CMV-negative blood products whenever possible.


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Notably, all future transplant recipients should receive transfusion only of irradiated blood and 
cellular blood products. Transfusion of irradiated blood and cellular blood products will continue 
to at least one year after transplantation. Patients receiving immunosuppressive medication will 
continue to have all blood and cellular blood products irradiated until discontinuation of 
immunosuppressive treatment.
Patients sensitized to HLA or platelet specific antigens should receive HLA matched apheresis 
platelet collections.
4.6
NUTRITIONAL SUPPORT
If mucositis or GVHD prevent adequate PO intake, nasogastric tube feeds or parenteral 
hyperalimentation will be instituted and discontinued with input from the Pharmacy and 
Nutrition Departments at NCI. Oral intake will resume when clinically appropriate under the 
supervision of the dietary service of the Clinical Center. At Children’s National Medical Center
and University of Oklahoma, this should be done as per institutional practice.
4.7
ANTI-EMETIC USAGE
Anti-emetic usage will follow recommendations from the NIH CC Pharmacy or as per 
institutional practice.
4.8
INTRAVENOUS IMMUNE GLOBULIN (IVIG)
IVIG administration will follow Guidelines for Infection Management in pediatric standard 
practices due to the difficulties of avoidance of viral exposures in pediatric patients.  For an IgG 
values less than 400 mg/dl, 500 mg/kg IVIG will be administered intravenously as per 
institutional guidelines.  Administration of IVIG may also occur if clinically indicated (e.g. 
setting of severe viral infection and vascular leak). 
4.9
HEPATIC FUNCTION SUPPORT
All patients will receive ursodeoxycholic acid (Ursodiol) for the prevention of hepatic 
complications after allogeneic stem cell transplantation.  Ursodiol will start by day -4 prior to the 
transplant and will continue until day +100 post-transplant (or longer if clinically indicated).
Patients weighing less than 90 kg will receive 300mg orally twice daily (600mg total dose each 
day). Those patients weighing more than 90 kg will receive 300 mg orally each morning and 600 
mg orally each evening (900 mg total dose each day). CNMC pediatric patients will be dosed as 
per Children’s National Medical Center guidelines.
The primary hepatic complication after transplantation is sinusoidal obstructive syndrome (also 
known as veno-occlusive disease or VOD).  This has been defined using Seattle criteria as: 
unexplained weight gain, hepatic tenderness, and jaundice; these criteria have been refined by 
Baltimore to include: total bilirubin > 2, and 2 of the following: hepatomegaly, weight gain 5%, 
and ascites.  Because no drugs are approved to treat VOD, and access to defibrotide, the only 
drug that has demonstrated promise, is limited, every effort will be made to optimize 
management to minimize the severity of VOD.  Throughout the first 30 days of transplantation, 
management should include equal ins and outs without weight gain.  Salt loads should not occur 
in the absence of clear benefit to the patient (e.g. sepsis).  Close monitoring for this condition and 
immediate fluid restriction, use of oncotics and lasix (see Section 4.11), and salt removal from 
infusions should be instituted.  


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4.10 CENTRAL NERVOUS SYSTEM PROPHYLAXIS
Patients with history of CNS positive disease will receive CNS boost.  
4.11 FLUID MANAGEMENT DURING FIRST 30 DAYS FOLLOWING TRANSPLANTATION
Patients should be well-hydrated prior to stem cell infusion (within 12 hours prior).  Following 
stem cell infusion, weights and abdominal girths should be followed closely.  Patients should be 
kept EVEN in fluid status with every attempt to minimize salt and fluid loading.  High salt and 
fluid loads have been implicated in the physiology that leads to severe engraftment syndrome 
and VOD.  Lasix may be used to maintain this.  In addition, an oncotic (e.g. blood, IVIG, 
platelets, albumin) may be used followed by lasix to preserve renal function while optimizing 
fluid management. 
4.12 ANCILLARY SUPPORT
Other supportive care to include: physical therapy, occupational therapy, psychosocial therapy as 
deemed clinically appropriate. 
4.13 SUPPORTIVE CARE FOR RELAPSE
Patients who experience relapse on this protocol may receive therapy for relapse to include intrathecal or 
systemic chemotherapy, donor lymphocyte infusions or other treatments.
4.14 ADDITIONAL CELL INFUSIONS FOR GRAFT FAILURE, IMPENDING GRAFT FAILURE, OR 
POOR GRAFT FUNCTION.
Patients who experience graft failure (primary or secondary), impending graft failure (falling counts 
and/or donor chimerism after initial engraftment in the absence of relapse), or poor graft function 
posttransplant (hypoplastic bone marrow, complete or near-complete donor chimerism, absence of 
relapse or cytopenias clinically thought to be caused by medication or infection, severe cytopenias in at 
least two lines [Hb < 10 g/dL, platelet count < 30 x 109/L, neutrophil count < 1.0 x 109/L] lasting at least 
2 weeks beyond day +14 and with transfusion requirement) will be eligible to receive a CD34+-selected 
cell boost.  The same donor for the most recent BMT must be used.  The donor will have a GCSF-
mobilized peripheral blood stem cell product collected and CD34+-selected using the Miltenyi 
CliniMACS® system prior to infusion into the patient.  A fresh product will be preferred although a 
cryopreserved product will be acceptable.
5
DATA COLLECTION AND EVALUATION 
5.1
DATA COLLECTION
Data will be prospectively and entered into an NCI, CCR C3D Database from each institution.  After 
obtaining Informed Consent, a file will be created in the database with standardized forms.  The 
database will maintain complete records on each patient including any pertinent supplementary 
information obtained from outside laboratories, outside hospitals, radiology reports, laboratory reports, 
or other patient records. Patient records will be summarized at key time points in protocol visit notes at:
pre-transplant, day 28, 60, 100, 6 month, 9 month, 12 months, and yearly post-transplant. These 
protocol notes will serve as the primary source material from which data will be collected and research 


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analyses will be performed.  These will be reviewed by the Adjunct PI or site PI and research 
nurse/coordinator for accuracy and include interpretation of the events prior to this note.  This is done to 
minimize the day to day confusion that may occur (e.g. patient has diarrhea, thought initially to be 
GVHD but later determined to be CMV).  The following will be used for source data and wherever 
possible will use the interpretations from the protocol visit notes as detailed below:
x
Eligibility Checklist: To be completed at study entry and forwarded to the protocol 
research nurse. 
x
Patient history and physical examinations while on study (protocol visit notes)
x
Patient flow sheets (protocol visit notes)
x
Patient pathology, radiology, chimerism data, laboratory evaluations. (interpreted in 
protocol visit notes)
x
Relevant data will also be sent to the Center for International Bone Marrow Transplant 
Registry (CIBMTR). This will include outcome data and patient characteristics, but do 
not include adverse events.
x
Protocol Deviations/Unanticipated problems (UPs): Any protocol deviations or UPs 
should be directly reported to the PI, PC, or AI. These will be submitted to each site’s 
respective IRB. Outside institutions are required to send all protocol deviations and UPs
to the Adjunct PI to be submitted to NCI IRB.
x
Confidentiality Protection: Prior to analysis, all identifiers will be removed and a random 
number ascribed to protect patient confidentiality. 
The PI will be responsible for overseeing entry of data into an in-house password protected electronic 
system and ensuring data accuracy, consistency and timeliness. The principal investigator, associate 
investigators/research nurses and/or a contracted data manager will assist with the data management 
efforts. All data obtained during the conduct of the protocol will be kept in secure network drives or in 
approved alternative sites that comply with NIH security standards. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for at least 30 days after removal from study treatment or 
until off-study, whichever comes first.
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:
x
Results in discontinuation from the study
x
Is associated with clinical signs or symptoms 
x
Requires treatment or any other therapeutic intervention
x
Is associated with death or another serious adverse event, including hospitalization. 
x
Is judged by the Investigator to be of significant clinical impact


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x
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH Intramural 
Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject 
confidentiality and trial data has occurred, the IRB will be notified.
5.1.1
Adverse event recording
x
Grade 1 adverse events will not be recorded
x
All serious adverse events regardless of the attribution will be recorded
x
If adverse events are not serious and possibly, probably, or definitely attributable to either 
Lupron or FLT imaging then they will be recorded.
5.2
RESPONSE CRITERIA
5.2.1
Primary Endpoints
5.2.1.1
To determine whether Lupron leads to accelerated B cell recovery after allogeneic 
hematopoietic stem cell transplantation.
5.2.1.2
To determine if FLT imaging can be used safely to evaluate for engraftment of 
transplanted cells. 
5.2.1.3
B cell recovery will be assessed on day 180 for comparison between two groups: those 
who have received Lupron and those who have not.  
5.2.1.4
Patients will be evaluated for complete clinical response to primary malignancy at day 
+28, day +100, and day +365; those with and without Lupron will be compared.  
Complete response will include M1 marrow and no evidence of disease by flow 
cytometry, cytogenetics or FISH testing in all sites evaluated (lumbar puncture, bone 
marrow).  Minimal residual disease will be used to denote < 5 % blasts in marrow but 
detection of disease by one of these measures.  
5.2.2
Secondary Endpoints 
5.2.2.1
Thymus studies with CT scan thymic index, flow cytometry measurements of naïve T 
cells.
5.2.2.2
Assess feasibility and tolerability of Lupron in male HSCT recipients. Assess recovery 
of testicular and ovarian function after HSCT.
5.2.2.3
Rates and details of acute and chronic GVHD in Lupron vs. no-Lupron HSCT 
recipients. 
5.2.2.4
Rates and details of infectious episodes in Lupron vs. no-Lupron HSCT recipients.
5.2.2.5
Recovery of other populations to include: neutrophils, red blood cells, platelets, and 
other cell subsets (e.g. monocytes) will be assessed and compared between groups.


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5.2.2.6
Transplant related mortality, incidence of graft rejection, disease-free and overall 
survival will also be collected.
5.2.2.7
The FLT images will be used in exploratory fashion to determine if the day +5 or day 
+9 image can be used to predict engraftment of donor cells by comparing the uptake of 
FLT at day -1 with day +5 or day +9 and day +28 (post-engraftment) and correlating 
this will leukocyte recovery for first BMT. Difference between patients who receive 
bone marrow or peripheral blood stem cell products will also be explored. For 2nd
BMT, exploratory analyses will compare day -1 FLT image with relapse rates, and day 
+28 and +60 image abnormalities suggestive of relapse with relapse rates.
5.2.2.8
Evaluate thymic reconstitution by FLT (1st BMT).
5.2.2.9
Evaluate whether FLT vs. FDG could distinguish GVHD vs. infection and relapse vs. 
healthy donor engraftment (1st and 2nd BMT).
5.2.2.10 Evaluate the safety of FLT imaging in the peritransplant period (1st and 2nd BMT).
5.3
TOXICITY CRITERIA
Adverse events on this study will be reported using the NIH mechanism of NCI Common Terminology 
Criteria for Adverse Events.  This study will utilize the CTCAE version 4.0 for toxicity and adverse 
event reporting.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP home page 
(http://ctep.info.nih.gov) under reporting guidelines.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.
An adverse event will be defined as any novel, concerning medical condition or worsening of a 
previously existing medical condition. Please refer to section 8 for details on adverse event collection. 
6
STATISTICAL SECTION 
6.1
SUBJECT ACCRUAL
Non-pregnant female and male subjects from all racial and ethnic groups are eligible for this trial if they 
meet entry criteria.  Although every effort will be made to incorporate individuals representative of the 
national population with the eligible malignant diseases, issues of limited accrual may not permit this 
study to explore the impact of race or gender.  Should the analysis suggest that there is a difference 
observed across race or gender, accrual may be expanded or additional studies will be designed to 
address these questions. 
6.1.1
Statistics and Feasibility
The primary objectives of this study are:
1) To determine if there is a difference in the percentage of B cells which recover at 12 
months between males who are randomized to receive Lupron or not, and to estimate the 
fraction of females, all of whom will receive Lupron, who have B cells which recover at 
12 months.
2) To evaluate engraftment kinetics to estimate the relationship between level of uptake of 
FLT at a day +5 scan and the day at which neutrophils recover to >500, statistical 
analyses were performed for this secondary endpoint. 
6.1.1.1
Statistics on FLT


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This subset of the total male and female patients receiving marrow transplants will undergo pre-
transplant conditioning and FLT imaging agent.  The patients will have their level of FLT uptake 
evaluated at a day +5 scan, and will be followed until they recover their neutrophils to >500. A 
Spearman correlation coefficient will be used to estimate the degree of association between these 
two parameters. With 13 evaluable patients, who have both a day +5 scan level of uptake and a 
known number of days to recovery of neutrophils, a correlation coefficient will be estimated in a 
pilot fashion; a 0.10 one-sided Fisher’s test of whether the correlation coefficient has a value of 
0.85 rather than a null value of 0.50 can be performed with 80% power if 13 patients are 
included in the evaluation.  Fifteen patients will be studied in this cohort to obtain 13 fully 
evaluable images given that 2 may have early events that preclude day 28 evaluation.  Patients 
enrolled on this arm of the protocol who do not complete a day 28 evaluation may be substituted 
to achieve 13 evaluable patients unless the patients are not evaluable due to toxicities attributed 
to FLT.  Interim safety analysis of AEs attributed to FLT imaging will be performed on the first 
7 patients.  Should greater than 1 of these 7 patients not engraft and require a back-up product, 
the FLT arm of this protocol will be halted. Notably, patients who experience early relapse may 
be analyzed separately for some statistical evaluations as leukemia cells upregulate TK1 and may 
alter images obtained around the time of relapse.  An additional eight evaluable patients will 
permit us to evaluate the day +9 scan rather than a day +5 scan and correlate this with 
engraftment and explore differences between peripheral blood stem cell source and bone marrow 
stem cell source.  These demonstrate different kinetics of marrow recovery (with engraftment of 
neutrophils typically 14 days earlier with peripheral blood stem cells).  Finally, not only will 
these kinetics help us to understand the biology of stem cell transplantation, they will also serve 
as a critical piece of information for a future study with cord blood as the stem cell source (which 
has even greater delay in neutrophil recovery, typically engrafting 2 weeks later than a marrow 
product).  
Because the interim analysis confirmed safety in adults, up to 10 pediatric patients will now be 
enrolled at Children’s National Medical Center.  These patients will be imaged on day -1, day 
+9, and if possible, day +28.  Analyses will mirror the adult statistics and also permit exploratory 
comparisons between pediatric and adult patients.  The same safety stopping rules will apply: 
should greater than 1 of these 7 patients not engraft and require a back-up  product, the FLT arm 
of this protocol will be halted.  
In addition, because there is a suggestion that FLT may predict relapse (showing relapse in 4/4 
imaged patients to date, and prediting relapse in ¾), FLT will be incorporated into the evaluation 
of all patients in arm 2 (who are undergoing 2nd HSCT for relapse after 1st HSCT).  This will be 
exploratory analyses to use FLT to try to predict response of therapy (in the day -1 image) and 
relapse in subsequent images in this population at high risk for relapse (80% historically).  For 
patients who do relapse after this 2nd HSCT, a scan may be performed pre- and after therapies to 
treat this relapse to explore the effect of immunotherapy on FLT uptake.
6.1.1.2
Statistics on Lupron
For 1st BMT the larger cohort of patients (of which some of these patients may undergo FLT 
imaging as well) will be eligible male subjects who will be randomized in a 1:1 ratio to receive 


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Lupron vs. no Lupron prior to receiving their pre-transplant preparative regimen.  The objective 
will be to determine if there is a difference in the percentage of these subjects who recover their 
B cells by 12 months according to whether they receive Lupron or not. With 17 evaluable 
patients per arm (34 total evaluable patients), there is 80% power to detect a difference equal to 
one standard deviation (one SD effect size) between the two arms using a 0.05 two-sided two-
sample t-test (that is, that the difference in the means of the two groups differs by one SD, 
assumed to be the same in both groups).  In practice, if the data from the two groups are not 
normally distributed (p<0.05 by a Shapiro-Wilks test in either group), then a Wilcoxon rank sum 
test will be used.  Since only patients who have not relapsed by 12 months would be eligible for 
this definitive evaluation, up to 68 patients may need to be enrolled in order to obtain this 
definitive evaluation. 
For 1st BMT, a second cohort of patients (which may include FLT exposed patients) will be 
eligible female subjects who will each receive Lupron prior to receiving their pre-transplant 
preparative regimen. The objective in this cohort will be to estimate the fraction of patients who 
recover their B cells by 12 months. If there are 30 eligible female patients who have this value 
determined at 12 months, then a two-sided 95% confidence interval could have width of 
approximately +/- 4 if the standard deviation was equal to 10.  Since the female patients may also 
relapse prior to 12 months and not provide a definitive value for evaluation, up to 50 females will 
be enrolled into this cohort to try to ensure that at least 30 are evaluable.
For 1st BMT, for the female and male cohorts, all enrolled patients will be evaluated at the latest 
time point possible for a variety of immune reconstitution parameters.  Thus, even if they are 
unable to ultimately contribute information to the definitive evaluation at 12 months, the values 
that are obtained at any time point will be used to estimate the recovery at various time points 
prior to 12 months.
In order to complete accrual to these cohorts, up to 68+50=118 patients may need to be enrolled. 
If 2-3 patients per month are able to be accrued onto this trial, accrual should be completed 
within 3 to 5 years.  Patients who do not undergo allogeneic transplantation may be substituted. 
Toxicity of FLT and Lupron in this population will be evaluated in all exposed patients.  
For 1st BMT, exploratory analyses will evaluate other leukocyte subsets of immune reconstitution with 
and without Lupron (including transitional B cells, dendritic cells, recent thymus emigrants, naïve and 
memory T cells), disease control by treatments pre- and peri-transplant, whether FLT can identify 
relapse disease, or GVHD.  The effect of cell dose and age on lymphoid engraftment will also be 
explored.  In addition, evidence of functional immune recovery as per vaccine response will also be 
explored.  For patients to receive benefit from vaccines after myeloablative HSCT, the immune system 
must mount a durable response.  If the patient receives a vaccine without evidence of a rise in antibody 
titers, it is possible or even likely that the patient does not receive benefit from this vaccine.  In pediatric 
HSCT recipients in many institutions, it is standard practice to test for a vaccine response and repeat 
vaccinations when one is achieved to maximize the potential for long-lasting immunity to this pathogen.  
In adult HSCT recipients, this is not standard of care because both there is less likelihood that older 
adults can achieve this after myeloablative transplantation and high likelihood that residual plasma cells 
(of host origin) will respond after non-myeloablative transplantation which may not be meaningful for 
long-lasting immunity.  Because the immune modulation of lupron may improve the immune system of 
these young adults similar to those often achieved in pediatric patients, the optimal approach for long 


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lasting immunity is to attempt to determine a functional benefit to the vaccines, to give the vaccine to 
the patient when they can respond and develop durable benefit (prophylaxis from infections). 
Interim analyses will be conducted on FLT treated patients after 7 patients have completed day 28 
imaging and on the lupron treated vs. untreated male subjects after 15 have been enrolled to each arm to 
evaluate for safety (lupron and FLT) and efficacy (lupron). 
Using the CIBMTR (international registry data), the expected survival is <30% for acute myelogenous 
leukemia and 30% for acute lymphoid leukemia at 2 years.   Because 10% of these patients die of non-
relapse causes, this means that the expected relapse rate is 60% for similar patients, suggesting that our 
relapse rate of less than half this is considerably better.  The relapse rate for patients after 2nd BMT is 
even higher, so these patients will need to be analyzed separately from patients who have only 
undergone 1 BMT.  These patients will be added via amendment L, which will have the following 
characteristics: males and females who have previously failed a transplant will be enrolled onto the trial 
and receive Lupron. The patients will be followed for progression and for survival. With 16 patients, 
there would be 82% power to detect an improvement from 60% who relapse by one year to 30% who 
relapse by one year (using data for 2nd BMT where the relapse rates exceed 60%), using an exact 
binomial test with a 0.10 one-sided significance level. In practice, the fraction of the 16 evaluable 
patients who survive without relapse to one year will be estimated; this fraction will be reported along 
with appropriate confidence intervals, such as a one-sided 90% interval to show if the fraction is below 
60%, as well as a two-sided 95% confidence interval to help describe the observed fraction of patients 
who are relapse free at one year. In addition, a Kaplan-Meier curve of relapse free survival will be 
constructed to estimate the relapse free probabilities at various time points. 
To ensure that patients are not continued to enroll onto this arm in the event that results are not adequate, 
the following early stopping rule will apply: if among the first 8 patients enrolled, 0 of 8 are able to 
survive to one year, then no further patients will be enrolled onto this trial as soon as this can be 
determined, as this will indicate worse than expected results: the upper one sided 90% Confidence 
interval on 0/8 is 0.25, which would indicate that this result would not be consistent with tolerable 
results.
7
HUMAN SUBJECTS PROTECTIONS 
7.1
RATIONALE FOR SUBJECT SELECTION
All patients with eligible malignant diseases who may benefit from allogeneic stem cell 
transplantation are eligible for this trial. All ethnic groups and both sexes may be enrolled.  Ethnic 
enrollment may vary as ethnic groups afflicted by these diseases may vary.  Pregnant females will 
be excluded from this trial.  It is unlikely that our patient numbers will permit statistics of 
individual ethnic or age groups, however this will be attempted should numbers permit. 
7.2
PARTICIPATION OF CHILDREN
In addition, this trial is open to pediatric as well as adult patients; however, at Univ of Oklahoma
only adult patients will be enrolled and at Children’s National Medical Center only pediatric 
patients will be enrolled.  Patients > 15 years old and/or > 9 years and after Tanner stage 2 are 


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eligible at NCI, because these; patients who are pre-pubertal are unlikely to receive benefit (and 
may be harmed) by exposure to Lupron. At Children’s National Medical Center pediatric patients 
> 4 years of age will be eligible. Donors less than 2 years of age will not be included on this 
protocol.  Physicians, nurses, and multidisciplinary support teams of the POB, NCI, and CC at 
NIH, and Oklahoma Transplant Team, Children’s Hospital, Stephenson Cancer Center, and HCA 
at Univ of Oklahoma, and the BMT team, Blood Bank at Children’s National Medical Center will 
provide patient care.  The staff of the POB has expertise in the management of children with 
complex oncologic disorders and complications of therapy.  Full pediatric support and 
subspecialty services are available at the NIH CC.  Note: arm 2 is for adults only at NIH.
7.3
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT
.Re-consent may be necessary and there is a possibility, though unlikely, that subjects could 
become decisionally impaired. For this reason and because there is a prospect of direct benefit
from research participation (section 7.4), all recipients VXEMHFWV  DJH  ZLOO EH RIIHUHG WKH
opportunity to fill in their wishes for research and care, and assign a substitute decision maker on 
the “NIH Advance Directive for Health Care and Medical Research Participation” form so that 
another person can make decisions about their medical care in the event that they become 
incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will 
contact the NIH Ability to Consent Assessment Team for evaluation.  For those subjects that 
become incapacitated and do not have pre-determined substitute decision maker, the procedures
described in MAS Policy 87-4 for appointing a surrogate decision maker for adult subjects who
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed.
Donor subjects who become incapacitated or cognitively impaired during the course of the study
will come off study since there are no direct benefit to the donor subjects.
7.4
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
7.4.1
Recipient
Patients are likely to obtain direct benefit from the HSCT as the eligible diseases for this protocol 
are aggressive and likely to lead to death without HSCT.  The transplantation preparative 
regimen and GVHD prophylaxis are standard of care for patients of these ages with these 
diseases.  These regimens carry an acceptable risk of direct toxicities including: organ toxicity 
(lung, heart, kidney, endocrinological, neurological, and liver), immunosuppression with 
increased risk of infections, potential for graft versus host disease.  The patients will be 
monitored for toxicities using the current best practice guidelines and will receive prophylaxis 
for those complications that we can prevent (e.g. infectious, mesna for cyclophosphamide to 
minimize kidney toxicity).   See section 10 for details.  The greatest risk to mortality remains 
relapse in this population.  Thus, a myeloablative regimen has been chosen that confers the 
greatest potential for disease control.  Lupron may not impact on disease control, or it may 
improve disease control by decreasing androgen levels (leukemias often have androgen receptor 
and may respond to this substrate) and through enhanced post-transplant lymphocyte 
reconstitution (with potential to improve GVL).  
7.4.1.1
FLT risks to exposed recipient


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The greatest risks of clinical FLT scans to patients enrolled on imaging studies to date have 
included bruising at the injection site; no significant adverse events were reported in the 
literature.  Please see section 1.2.7 for details and toxicities at much higher doses of FLT than 
patients on this protocol will receive, none of which are expected.  The one theoretical risk to 
patients undergoing HSCT is that the newly dividing hematopoietic stem cells could be affected 
by FLT delaying engraftment or contributing to failure to engraft.  However, the actual radiation 
dose to which the bone marrow is exposed is equivalent to the dose received in an abdominal CT 
with contrast, a test routinely performed for clinical indications without adverse effects on 
engraftment.  Stopping rules are in place for nonengraftment. 
7.4.2
Risks in relation to benefit for Donor
Healthy HLA-matched donors will be co-enrolled onto this study. The collection aspect of this 
protocol is not investigational. There is potential benefit for donors, as they may derive 
psychological benefit from participating in a clinical trial designed to improve the health of the 
recipient of the prior transplant donation. Other potential benefits include the diagnosis of 
previously unknown illnesses (such as viral hepatitis) at the time of donor screening. 
7.4.3
Pediatric Patients
Pediatric patients are eligible to participate in this trial if they meet criteria including a disease 
for which BMT is the recommended therapy. The diseases addressed in this protocol are the 
current diseases recommended for transplantation by the national cooperative groups (Children’s 
Oncology Group). The preparative regimen is one of the standard recommended 
regimens. Pediatric patients at Children’s National Medical Center are now eligible for FLT,
because this testing did not increase the risk to recipients in the adult study (14 adult patients 
have undergone FLT without attributable toxicities at NCI). Female patients who have begun 
puberty will receive the standard of care for menses prophylaxis, lupron at the dose of 11.25 mg 
for patients < 18 years. Thus, the only additive risk to pediatric patients beyond standard of care 
is the exposure of male patients to lupron. Given that female children have tolerated this agent 
well, the risks of lupron in male subjects are expected to be mild and reversible (the drug will 
clear in 3 months and not redosed in this study in male subjects). The potential benefits include: 
1) improved immune reconstitution, 2) potential anti-tumor effects, and 3) possible benefit for 
preservation of fertility. 
7.5
CONSENT AND ASSENT PROCESS AND DOCUMENTATION
Informed consent will be obtained from all patients, and/or the patient’s parents or legal guardian 
(if he/she is < 18 years of age) and matched related donors prior to entry..  The procedures and 
treatments involved in this protocol, with their attendant risks and discomforts, potential benefits, 
and potential alternative therapies will be carefully explained to the recipient and/or 
parent/guardian.  Where deemed appropriate by the clinician and the child’s parent(s) or 
guardian, the child will also be included in all discussions about the trial and age-appropriate 
language will be used to describe the procedures and tests involved in this study, along with the 
risks, discomforts and benefits of participation.  Verbal assent will be obtained as appropriate for 
children ages (12 years and older) and the parent or guardian will sign the designated line on the 
informed consent attesting to the fact that the child has given assent.  Children under the age of 
12 years will not be required to provide assent as they typically do not have the cognitive ability 
to fully understand the nature of research. The consent/assent process will be documented in the 


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child’s medical record, including the assessment of the child’s ability to provide verbal assent. 
All children will be contacted after they have reached the age of 18 to determine whether they 
wish to continue on the trial and informed consent will be obtained from them at that time. Note 
that NMDP consents will be used for unrelated donor patients. 
The investigators are requesting a waiver from the IRB to allow only one parent to sign the 
informed consent to enter a child on the protocol. Because many patients must travel to the NIH 
from long distances at substantial expense, requiring both parents to be present for the consent 
process could be a financial hardship for many families. When guardianship status of the child is 
uncertain, a social worker will be asked to investigate and, if necessary, seek documentation of 
custody status. In situations where there is joint custody of a child, both parents must sign 
consent. If only one parent can be present at NIH, the other parent’s consent can be obtained by 
telephone via the procedure described in section 7.5.1 Similarly, the procedures and treatments 
involved in this protocol, with their attendant risks and discomforts, will be carefully explained 
to the matched unrelated donors at the respective donor center as required by NMDP.  The 
original signed informed consent goes to Medical Records; a copy will be kept for the research 
record.  The Central Registration Office (CRO), Data Management Section will also retain a 
copy of the informed consent document.  A copy of the signed informed consent document will 
also be given to the recipient (and matched related donor, when applicable).  b) The Central 
Registration Office (CRO) will ascertain the date of IRB approval before registering the first 
patient.
The Principal Investigator and/or an authorized designee will consent the patient and matched 
related donor (when applicable) and will be available to answer all patient questions.
If any new information becomes available relating to risks, adverse events, or toxicities, while 
patients are participating in this protocol, this information will be provided orally and/or in 
writing to all enrolled and prospective patient participants.  Documentation will be provided to 
the IRB and if necessary the informed consent amended to reflect relevant information.
The possible risks and benefits of this trial will be explained in layman’s terms for patients and 
guardians.  For patients who elect to enroll, consent will be obtained.  A signed consent must be 
obtained by patient or legal guardian prior to study entry.  The PI, an Associate investigator, or 
an appropriate designee will answer all questions regarding this medication and the purpose of 
the trial prior to obtaining consent
7.5.1
Consent for minors when they reach the age of majority 
When a pediatric subject reaches age 18, continued participation (including ongoing interactions 
with the subject or continued analysis of identifiable data) will require consenting of the now 
adult with the standard protocol consent document to ensure legally effective informed consent 
has been obtained. We request waiver of informed consent for those individuals who have 
completed their participation in the research study and subjects who have been lost to follow-up
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d): 
1) The research involves no more than minimal risk to the subjects. a. Analysis of samples 
and data from this study involves no additional risks to subjects. 
2) The waiver or alteration will not adversely affect the rights and welfare of the subjects. a. 
Retention of these samples or data does not affect the welfare of subjects. 


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3) The research could not practicably be carried out without the waiver or alteration. a. 
Considering the length of time between the minor’s last contact with the research team 
and their age of majority, it will likely be very difficult to locate them again. A significant 
reduction in the number of samples analyzed is likely to impact the quality of the 
research. 
4) Whenever appropriate, the subjects will be provided with additional pertinent information 
after participation. a. We only plan to request a waiver of reconsent for those subjects 
who have been lost to follow-up or prior to amendment T, have been taken off study prior 
to reaching the age of majority. 
7.5.2
Telephone consent and re-consent procedure
The following procedure may be used in cases of re-consent or for intial consent in cases where 
the consent of both parents of a minor participant is required as discussed in section 7.5. the 
informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent. A witness to the subject’s signaturewill sign 
and date the consent.  The original informed consent document will be sent back to the 
consenting investigator who will sign and date the consent form with the date the consent was
obtained via telephone.  A fully executed copy will be returned via mail for the subject’s records.  
The informed consent process will be documented on a progress note by the consenting 
investigator.
7.5.3
Informed consent of Spanish speaking subjects
We anticipate the enrollment of Spanish speaking research participants into our study. The IRB 
approved full consent document will be translated into that language in accordance with the 
Clinical MAS Policy M77-2.
7.5.4
Short form consent process for other non-English speaking patients
If there is an unexpected enrollment of a research participant for whom there is no translated extant 
IRB approved consent document, the principal investigator and/or those authorized to obtain 
informed consent will use the Short Form Oral Consent Process as described in MAS Policy M77-
2, OHSRP SOP 12, 45 CFR 46.117 (b) (2).  The summary that will be used is the English version 
of the extant IRB approved consent document.  Signed copies of both the English version of the 
consent and the translated short form will be given to the subject or their legally authorized 
representative and the signed original will be filed in the medical record.
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a family 
member) will assist in presenting information and obtaining consent. Whenever possible, 
interpreters will be provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible). 
We request prospective IRB approval of the use of the short form process and will notify the IRB 
at the time of continuing review of the frequency of the use of the Short Form.


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8
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN
8.1
DEFINITIONS
8.1.1
Adverse Event
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research.
8.1.2
This study incorporates a standard myeloablative bone marrow transplantation platform 
that has been in use for ~50 years and has many expected adverse events.  As the purpose 
of this study is to assess the integration of lupron and FLT imaging with this 
transplantation platform, only 1) serious adverse events and 2) adverse events not 
attributable to the standard BMT platform and either possibly, probably, or definitely 
attributable to either lupron or FLT imaging will be reportedSuspected adverse reaction
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug.
8.1.3
Unexpected adverse reaction
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation.
8.1.4
Serious
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others.
8.1.5
Serious Adverse Event
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
x
Death,
x
A life-threatening adverse drug experience
x
Inpatient hospitalization or prolongation of existing hospitalization
x
A significant disability/incapacity


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x
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
8.1.6
Disability
A substantial disruption of a person’s ability to conduct normal life functions.
8.1.7
Life-threatening adverse drug experience
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death.
8.1.8
Protocol Deviation (NIH Definition)
Any change, divergence, or departure from the IRB approved research protocol
8.1.9
Non-compliance (NIH Definition)
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subject.
8.1.10 Unanticipated Problem
Any incident, experience, or outcome that:
x
Is unexpected in terms of nature, severity, or frequency in relation to 
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and
(b) the characteristics of the subject population being studied; AND
x
Is related or possibly related to participation in the research; AND
x
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.
8.2
NCI-IRB AND CLINICAL DIRECTOR REPORTING
8.2.1
NCI-IRB and NCI CD Expedited Reporting of Unanticipated Problems and Deaths
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director:
x
All deaths, except deaths due to progressive disease
x
All Protocol Deviations
x
All Unanticipated Problems
x
All non-compliance


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Reports must be received within 7 days of PI awareness via iRIS.
8.2.2
NCI-IRB Requirements for PI Reporting at Continuing Review
The protocol PI will report to the NCI-IRB: 
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action.
2. A summary of any instances of non-compliance
3. A tabular summary of the following adverse events:
x
All Grade 2 unexpected events that are possibly, probably, or definitely related to 
lupron or the IND;
x
All Grade 3 and 4 events that are possibly, probably, or definitely related to the 
lupron or the IND;
x
All Grade 5 events regardless of attribution; 
x
All Serious Events regardless of attribution. 
NOTE: Grade 1 events are not required to be collected or reported. 
Note: With the exception of severe adverse events, AE that occur prior to the initiation of 
protocol directed therapy (to include standard of care chemotherapy that could be given 
due to delay in donor availability or for other reasons) will not be collected or reported.
NOTE: Expected AE of transplantation that will be exempt from reporting (because they 
will not be related to research) include: 
-
Leukopenia, anemia, and thrombocytopenia until engraftment of these cellular 
populations.  Should a patient not engraft, this will be captured as an AE.
-
Coagulation abnormalities
-
Electrolyte abnormalities including sodium, potassium, chloride, magnesium, 
calcium, phosphorus, bicarb, blood urea nitrogen, lactate dehydrogenase, 
creatinine kinase.
-
Endocrine abnormalities, bone mineralization abnormalities, avascular 
necrosis, delay in growth/development, and nutritional data (to include lipid 
levels, prealbumin, albumin).  
-
Dermatology abnormalities (to include changes in nails, pigmentation)
-
Mucositis
8.2.3
NCI-IRB Reporting of IND Safety Reports
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB.


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8.3
NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR MULTI-CENTER 
TRIALS
The site PI must immediately report to the coordinating center PI any serious adverse event, 
whether or not considered drug related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the 
drug caused the event within 24 hours of PI awareness of the event. The Site PI must also report 
any protocol deviations to the coordinating center PI within 7 days of PI awareness. Participating 
centers must also submit the report to their IRB in accordance with their institutional policies. 
A participating site problem form (available in section 12.16) is to be filled out and sent to the 
Coordinating Center’s PI.
8.4
IND SPONSOR REPORTING CRITERIA
During the first 30 days after the subject receives investigational agent/intervention, the
investigator must immediately report to the sponsor using the mandatory MedWatch form 3500a,
or equivalent any serious adverse event, whether or not considered drug related, including those 
listed in the protocol or investigator brochure and must include an assessment of whether there is 
a reasonable possibility that the drug caused the event. For serious adverse events that occur 
more than 30 days after the last administration of investigational agent/intervention, only report 
those that have an attribution of at least possibly related to the agent/intervention.
Required timing for reporting per the above guideline:
x
Deaths (except death due to progressive disease) must be reported via email within 
24 hours.  A complete report must be submitted within one business day. 
x
Other serious adverse events as well as deaths due to progressive disease must be 
reported within one business day
.
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov
and to the CCR PI and study coordinator.
8.5
DATA RECORDING OF UNRELATED DONORS FROM NMDP
Per NMDP regulations, and to maintain donor confidentiality, unrelated donor source documents 
will not be sent to the NIH. The NMDP will maintain all required source documents in accordance 
with NMDP policies and procedures. The NMDP will confirm donor eligibility and will notify the 
NIH of any deviations in regard to protocol requirements.
The National Marrow Donor Program (NMDP) IRB will be responsible for the review and
continuing oversight of protocol procedures that relate only to NMDP unrelated donors.
8.6
DATA AND SAFETY MONITORING PLAN
8.6.1
Principal Investigator/Research Team 
The clinical research team will meet on a regular basis weekly when patients are being actively 
treated on the trial to discuss each patient. 


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All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Pertinent data includes: GVHD acute or chronic and characterization as 
per appendices and medications to treat this documented at day 30, 60, 100, 180, 270, 365, and 
yearly after this, infections and medications and disease response and therapies for recurrent 
disease also collected at these key time points.  Ancillary medications taken at the time of these 
time points needs to be collected, however, ancillary medications not associated with the 
aforementioned that are started and stopped between key time points need not to be 
collected/recorded unless associated with adverse events.  Adverse events will be reported as 
required above. Any safety concerns, new information that might affect either the ethical and or 
scientific conduct of the trial, or protocol deviations will be immediately reported to the IRB 
using iRIS.
The site principal investigator will review adverse event and response data on each patient to 
ensure safety and data accuracy. The site principal investigator will personally conduct or 
supervise the investigation and provide appropriate delegation of responsibilities to other 
members of the research staff. 
8.6.2
Sponsor Monitoring Plan
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study data 
with source documentation focusing on:
•
Informed consent process
•
Eligibility confirmation
•
Drug administration and accountability
•
Adverse events monitoring
•
Response assessment.
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center.
8.6.3
This trial will be monitored by personnel employed by an NCI contractor. Monitors are 
qualified by training and experience to monitor the progress of clinical trials. Personnel 
monitoring this study will not be affiliated in any way with the trial conductSafety 
Monitoring Committee (SMC)
This protocol will require oversight from the Safety Monitoring Committee (SMC).  Initial 
review will occur as soon as possible after the annual NCI-IRB continuing review date.   
Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting 
schedule permits or more frequently as may be required by the SMC.   For initial and subsequent 
reviews, protocols will not be reviewed if there is no accrual within the review period. Written 
outcome letters will be generated in response to the monitoring activities and submitted to the 
Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.


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9
MULTI-INSTITUTIONAL GUIDELINES
This is a multi-institutional trial with University of Oklahoma and National Institutes of Health, 
National Cancer Institute, and Children’s National Medical Center.
Children’s National Medical Center will enroll only children and open only the FLT arm of the 
study.  Univ. of Oklahoma will enroll only adults and open only the Lupron arm.  
9.1.1
IRB Approvals 
The PI will provide the NCI IRB and Central Registration Office with a copy of the participating 
institution’s approved yearly continuing review.  Registration will be halted at any participating 
institution in which a current continuing approval is not on file at the NCI IRB.
9.1.2
Amendments and Consents
The PI will provide NIH IRB with any and all documentation of amendments, consents, and approvals 
from IRB reviews at all participating institutions.  All amendments to the protocol or the NCI consent 
are to be approved by the NCI PI and the NCI IRB and then submitted to the participating institution’s 
IRB for approval.  
9.1.3
Data and Specimen Collection Procedures
The NCI C3D data base will be utilized; data will only be collected at the time points specified in 
this trial.  Participating sites will be trained in the use of C3D and directly enter data at these sites 
into C3D.  Any questions or concerns should elicit immediate contact of the NCI PI or AI.  .
9.1.4
Data Center Audits
All participating sites will be monitored as per section 8.7.2. Scans and data may also be reviewed of 
primary NIH or Children’s National Medical Center patients at Univ of Oklahoma after de-identification
for exploratory analyses. The NCI PI or AI will oversee the implementation of any necessary quality 
improvement measures that may be indicated as a result of these quality assurance activities.
9.1.5
Protocol Monitoring Committees
The NCI PI or AI will have either a meeting or phone conversation with all IRB-approved participating 
institution PIs to discuss protocol progress at least monthly after the outside site as begun accrual.
10 PHARMACEUTICAL INFORMATION  
10.1 LUPRON DEPOT
10.1.1 Chemical name
5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-D-leucyl-L-leucyl-Larginyl-N-ethyl-L-
prolinamide acetate
Lupron is a synthetic nonapeptide analog of naturally produced gonadotropin-releasing hormone 
(GnRH).


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10.1.2 Chemical structure 
Figure 8: Chemical Structure of Lupron Depot
10.1.3 Commercial Formulation
Supplied either daily or extended release injections.  Daily formulation is a 2.8 mL multi-dose 
vial with 5 mg/mL Lupron, administered as 1 mg (0.2 mL) subcutaneously per day.  Lupron also 
is supplied as Lupron Depot in either a 1, 3, or 4 month preparation with 3.75, 22.5 mg, or 30 mg
leuprolide acetate respectively for adults and as 11.25 mg 3 month preparation for children.
Lupron Depot is given as an intramuscular injection in a dual chamber syringe system that 
contains sterile lyophilized microspheres which become suspended in the carrier solution upon 
injection and continue drug release for the recommended timeframe. 
10.1.4 Storage
Room temperature 
10.1.5 Stability
Lupron remains stable when stored at 15-30 deg. Celsius.  The product should be stored in the 
original container and away from light sources. 
10.1.6 Route of administration
Intramuscular injection.  Emla may be given prior to injection to minimize discomfort at 
injection site. 
10.1.7 Dose
Lupron will be administered as 30 mg intramuscular injection once prior to stem cell transplant
for adult patients and as an adult preparation 3 month extended release 11.25 mg intramusclular 
injection once prior to stem cell transplant for patients <18 years.
10.1.8 Drug Interactions
There are no reported drug interactions with Lupron.  It is metabolized by peptidases and does 
not involve the P450 enzyme system.  However, given the mechanism of action of sex hormone 
suppression, all sex hormones are contraindicated (including: testosterone, progesterone, and 
estrogen) in all preparations. 
10.1.9 Known toxicities for patients >18
(see table below)


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Please utilize the table for the most accurate assessment of Lupron toxicities.  The most common 
side effects in large trials include headache and fatigue.  A toxicity table from the Lupron insert 
is included here: 
Table 2: Adverse Events in ≥5% of Patients Regardless of Causality
10.1.10Known toxicities for patients <18
(see table below)
In two studies of children with central precocious puberty, in 2% or more of the patients 
receiving the drug, the following adverse reactions were reported to have a possible or probable 
relationship to drug as ascribed by the treating physician. Reactions which are not considered 
drug related are excluded.


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Table 3
10.2 CYCLOPHOSPHAMIDE
10.2.1 Chemical name
2-[bis(2-chloroethyl)amino] tetrahydro-2H-1,3,2-orxazaphosphorine 2-oxide monohydrate.
Cyclophosphamide is a chemotherapy metabolized in the liver to an active alkylator that 
interferes with cell division through cross-linking of DNA.
10.2.2 Chemical structure 
Figure 9: Chemical Structure of Cyclophosphamide


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10.2.3 Commercial Formulation
Supplied as lyophilized powder that will be reconstituted with normal saline prior to intravenous 
administration.  Oral tablets are available but not relevant to this trial.  
10.2.4 Storage
Room temperature 
10.2.5 Stability
Cyclophosphamide reconstituted is stable for 24 hours at room temperature or for 6 days in the 
refrigerator.    
10.2.6 Route of administration
Intravenous injection 
10.2.7 Dose
Cyclophosphamide will be administered as per Section 12.4.
10.2.8 Drug Interactions
The rate of metabolism and the activity of cyclophosphamide are increased with concomitant 
administration of Phenobarbital.  Cyclophosphamide also increases the activity of 
succinylcholine chloride.  If the patient has been treated with cyclophosphamide within 10 days 
of general anesthesia, the anesthesiologist should be alerted.  
10.2.9 Known toxicities 
(see table below)
Table 4: Toxicity
Common
Occasional
Rare
Immediate:
Within 1-2 days of receiving drug
Anorexia (L), nausea 
(L), vomiting(L)
Metallic taste (L), 
Inappropriate ADH1
Transient blurred vision1 cardiac 
toxicity with arrhythmias1
myocardial necrosis 2(L)
Prompt:
Within 2-3 weeks, prior to the next 
course
Myelosuppression (L), 
alopecia (L)
Hemorrhagic cystitis (L)
Delayed:
Any time later during therapy, 
excluding the above conditions
Immunosuppression, 
gonadal dysfunction 
/sterility (L)
Pulmonary fibrosis3(L)
Late:
Any time after completion of 
treatment
Secondary malignancy, bladder 
fibrosis
Unknown Frequency and Timing:  **Fetal and teratogenic toxicities and toxicities in breast-fed children
1 Less common with lower doses.
2Only with very high doses.
3 Risk increased with chest radiation.
(L) Toxicity may also occur later.


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**Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination 
with other antineoplastic agents) have been noted in humans.  Toxicities include: 
chromosome abnormalities, multiple anomalies, pancytopenia, and low birth weight.
**Cyclophosphamide is excreted into breast milk.  Neutropenia has been reported in 
breast-fed infants. Cyclophosphamide is considered to be contraindicated during breast 
feeding because of the reported cases of neutropenia and because of the potential adverse 
effects relating to immune suppression, growth, and carcinogenesis.
10.3 TOTAL BODY IRRADIATION
10.3.1 Chemical name
Not applicable
10.3.2 Known toxicities
The side effects of radiation have been well described. The most common include nausea and 
mucositis. There also exists a risk of hypothyroidism, cataracts, interstitial pneumonitis, 
nephropathy, and an unspecified long-term risk of developing secondary malignancies [63].
Importantly, the majority of the non-neoplastic effects were subclinical and/or reversible [64].
Studies attempting to evaluate the risk attributed to radiation within a preparative regimen have 
implicated secondary malignancies, however this is difficult to ascribe since secondary 
malignancies are also increased with cGVHD and other post-transplant complications [65] [66].
Pediatric patients who require sedation in order to undergo TBI will be asked to sign a separate 
consent outlining the risk of the selected anesthesia.
10.4
FLT
10.4.1 Chemical Name
3’-deoxy-3 18F-fluorothymidine
10.4.2 Commercial Formulation
FLT is supplied as a unit dose by intravenous injection.
10.4.3 Storage
Room Temperature
10.4.4 Chemical Structure
Figure 10: Chemical Structure of FLT
O
F
N
N H
H O
O
M
e
O
F L T


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10.4.5 Method of Administration
[18F] FLT is administered by intravenous injection over 15 seconds with a saline flush.  
Appropriate shielding will meet the Radiation Safety Guidelines of NIH. 
10.4.6 Availability
[18F] FLT will be synthesized and delivered to Building 21 by Cardinal Health, or PETnet 
Pharmacies. [18F] FLT will be synthesized and delivered Radiology Department located on 2nd
floor of hospital at Children’s National Medical Center by Cardinal Health or PETnet 
Pharmacies.
10.4.7 Known Toxicites
No AEs attributable to 18F FLT administered at tracer levels have been reported in the published 
literature. While no related AEs are expected, patients will be monitored very closely with 
regards to hepatic, neurologic, and hematologic parameters following radiotracer injection.
10.5 FLUDARABINE (FLUDARA, BERLEX LABORATORIES)
10.5.1 Chemical Name
Fludarabine monophosphate 
10.5.2 Supply
Fludarabine monophosphate will be purchased by the NIH Clinical Center Pharmacy Department 
from commercial sources and is supplied as a white, lyophilized powder.  Each vial contains 50 
mg of fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH.  Fludara is 
stored at room temperature.
10.5.3 Preparation
FLUDARA IV should be prepared for parenteral use by aseptically adding Sterile Water for 
Injection, USP.  When reconstituted with 2 ml of Sterile Water for Injection, each ml of the 
resulting solution will contain 25 mg of Fludarabine Phosphate, 25 mg of mannitol, and sodium 
hydroxide to adjust the pH to 7–8.5.  Fludarabine will be diluted in 100 to 125ml of either 5% 
dextrose in water or 0.9% sodium chloride, and infused IV over 30 minutes.
10.5.4 Storage and Stability
Reconstituted FLUDARA IV is chemically and physically stable for 24 hours at room 
temperature or for 48 hours if refrigerated.  Because reconstituted FLUDARA IV contains no 
antimicrobial preservative, care must be taken to assure the sterility of the prepared solution; for 
this reason, reconstituted FLUDARA IV should be used or discarded within 8 hours.
10.5.5 Administration 
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration.
10.5.6 Toxicities 
Fludarabine toxicities include myelosuppression (dose limiting toxicity), fever, nausea, vomiting, 
stomatitis, diarrhea, gastrointestinal bleeding, anorexia, edema, skin rashes, myalgia, headache, 


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agitation, hearing loss, transient episodes of somnolence and fatigue, auto-immune hemolytic 
anemia, auto-immune thrombocytopenia, paresthesias, peripheral neuropathy, renal, and 
pulmonary toxicity (interstitial pneumonitis).  Severe fatal CNS toxicity presenting with loss of 
vision and progressive deterioration of mental status were encountered almost exclusively after 
very high doses of fludarabine monophosphate.  Such toxicity has only rarely been demonstrated 
at the 25-30 mg/m2/day dosage of fludarabine.  Very rarely described complications include 
transfusion-associated graft-versus-host disease, thrombotic thrombocytopenic purpura, and liver 
failure.  Tumor lysis syndrome following fludarabine administration has been observed, 
especially in patients with advanced bulky disease.  Opportunistic infections (protozoan, viral, 
fungal, and bacterial) have been observed post-fludarabine, especially in heavily pre-treated 
individuals, and in individuals receiving fludarabine combined with other agents.
10.6 BUSULFAN (BUSULFEX)
Busulfan is a bifunctional alkylating agent approved for use as a conditioning agent prior to 
allogeneic hematopoieitc stem cell transplantation at NCI on protocol 10-c-0174 amendment
M.The IV formulation is administered as Busulfan (Busulfex, Otsuka America Pharmaceutical, 
Inc.)
10.6.1 Source
For patient administration, IV Busulfan is purchased by the NIH Clinical Center Pharmacy 
Department from commercial sources. The drug is supplied as a clear, colorless sterile solution in 
10ml single use vials. Each vial of Busulfan contains 60 mg (6mg/ml) of busulfan.
10.6.2 Storage and Stability
Unopened vials of Busulfan are stable until the date indicated on the package when stored under 
refrigeration at 2-6 degrees C (36-46 degrees F).
10.6.3 Administration
Busulfan must be diluted prior to use with either 0.9% Sodium chloride or 5% Dextrose   Injection. 
The diluent quantity should be 10 times the volume of Busulfan so that the final concentration of 
busulfan is approximately 0.5 mg/ml. Busulfan should be administered intravenously via a central 
venous catheter as a two-hour infusion every 24 hours for a total of 4 doses over four days.  
10.6.4 Toxicities
At the indicated dose and schedule Busulfan induces profound myelosuppression; 2) All patients 
should be given a seizure prophylaxis regimen (e.g. Clonazepam plus levetiracetam) since 
busulfan is known to cross the blood brain barrier and induce seizures; 3) Nausea, vomiting, and 
stomatitis are common side effects of busulfan.  
10.6.5 Drug Interactions 
Itraconazole increases the clearance of busulfan by up to 25%. Phenytoin increases the clearance 
of busulfan by 15%.


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64.
Thomas, O., et al., Long-term complications of total body irradiation in adults. Int J 
Radiat Oncol Biol Phys, 2001. 49(1): p. 125-31.
65.
Curtis, R.E., et al., Solid cancers after bone marrow transplantation. N Engl J Med, 
1997. 336(13): p. 897-904.
66.
Kolb, H.J., et al., Malignant neoplasms in long-term survivors of bone marrow 
transplantation. Late Effects Working Party of the European Cooperative Group for 
Blood and Marrow Transplantation and the European Late Effect Project Group. Ann 
Intern Med, 1999. 131(10): p. 738-44.
12 APPENDICES
12.1 APPENDIX 1: PERFORMANCE SCALES
%
Karnofsky†
Status
Lansky Scale#
100
Normal; no complaints/ no 
evidence of disease
100
Fully Active
90
Able to carry on normal 
activity; minor signs or 
symptoms of disease
90
Minor restrictions in 
physically strenuous play


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Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
†     Karnofsky =  D.A., et al., Cancer 1: 634-656, 1948
#
Lansky Scale = Lansky, et. al., Cancer Oct 1; 60(7): 1651-1656, 1987
80
Normal activity with effort; 
some signs or symptoms of 
disease
80
Restricted in strenuous 
play, tires more easily, 
otherwise active
70
Cares for self; unable to 
carry on normal activity or 
do active work
70
Both greater restrictions of 
and less time spent in 
active play
60
Requires occasional 
assistance but is able to care 
for most of his needs
60
Ambulatory up to 50% of 
time, limited active play 
with assistance / 
supervision
50
Requires considerable 
assistance and frequent 
medical care
50
Considerable assistance 
required for any active 
play; fully able to engage 
in quiet play
40
Disabled, requires special 
care and assistance
40
Able to initiate quiet 
activities
30
Severely disabled; 
hospitalization is indicated 
though death not imminent
30
Needs considerable 
assistance for quiet activity
20
Very sick; hospitalization is 
necessary
20
Limited to very passive 
activity initiated by others 
e.g. TV
10
Moribund; fatal process 
progressing rapidly
10
Completely disabled, not 
even passive play
0
Unresponsive, coma


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Version Date: December 28, 2017
12.2 APPENDIX 2A: RECIPIENT (ARM 1 AND 2)
Name: ______________
Donor: _______________
DOB: ___/___/______
MR#______________
Tentative Transplant Date ___/___/______
Pre-Tx W/u: Scheduled   Date Done    Comments
H/P:   
__/__/__     __/__/__
CT Scans: 
Head 
__/__/__     __/__/__
Sinus
__/__/__     __/__/__
Chest
__/__/__     __/__/__
Abd/Pel
__/__/__     __/__/__
Echo 
__/__/__     __/__/__
EKG
__/__/__     __/__/__
PFT
DLCO
__/__/__     __/__/__
FEV1
__/__/__     __/__/__
Dental Ex
__/__/__      __/__/__
Broviac p.
__/__/__      __/__/__
Radiation 
__/__/__
__/__/__
BM/LP 
__/__/__      __/__/__
Nutrition 
__/__/__      __/__/__
Date Done     Result
CBC
__/__/__
ABO Type
__/__/__
_______
PT/PTT             __/__/__
Acute care panel __/__/__
_______
Hepatic panel    __/__/__      _______
Mineral Panel   __/__/__
_______
CK and LDH __/__/__            _______
Uric Acid
_/__/__             _______
Lipid/TRI
__/__/__
_______
U Preg (F)
__/__/__
_______
Hep A Ab
__/__/__
_______
Hep B Ab
__/__/__
_______
Hep C Ab
__/__/__
_______
HIV Ab
__/__/__
_______
Toxo IgG/IgM  __/__/__
_______
CMV IgG/IgM  __/__/__
_______
HTLV I/II IgG  __/__/__
_______
HSV1,2 IgG/IgM  __/__/__
_______
Testosterone and Estrogen level 
Adenovirus IgG __/__/__
_______
Pre-Lupron for females and males. 
EBV IgM/IgG  __/__/__
_______
Syphilis 
__/__/__
_______
Radiation records (prior)? 
Varicella IgG  __/__/__
_______
T/B/NK
__/__/__
_______
Disease diagnosis:
CNS+ ever? ______________
Cytogenetics:
Flow:
Extra evaluations based on hx:
Social work?
Ophtho?
ID?
Should be completed within 45 days of BMT.
May need to repeated if chemo required.


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Version Date: December 28, 2017
24 hr CCL/GFR__/__/__
_______
NMDP sample __/__/__
IgG, IgA, IgM__/__/__
RFLP
__/__/__
TSH/FreeT4
__/__/__
_______
Urinalysis
__/__/__
_______


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Version Date: December 28, 2017
12.3 APPENDIX 2B: DONOR (ARM 1 AND 2)
Name: ______________
Recipient: _______________
DOB: ___/___/______
MR#______________
Diagnosis: ___________
Tentative Transplant Date ___/___/______
Pre-Tx W/u: Scheduled   Date Done    Comments
H/P:   
__/__/__     __/__/__
EKG
__/__/__     __/__/__
CXR
__/__/__     __/__/__
Anesthesia
__/__/__      __/__/__
Date Done     Result
CBC
__/__/__
_______
ABO Type
__/__/__
_______
PT/PTT
__/__/__
Acute care, hepatic, and mineral panel plus LDH
__/__/__
_______
Lipid/TRI
__/__/__
_______
U Preg (F)
__/__/__
_______
Hep A Ab
__/__/__
_______
Hep B Ab
__/__/__
_______
Hep C Ab
__/__/__
_______
HIV Ab
__/__/__
_______
Toxo IgG/IgM  __/__/__
_______
CMV IgG/IgM  __/__/__
_______
HTLV I/II IgG  __/__/__
_______
HSV1,2 IgG/IgM  __/__/__
_______
Adenovirus IgG __/__/__
_______
EBV IgM/IgG  __/__/__
_______
Syphilis 
__/__/__
_______
Varicella IgG  __/__/__
_______
T/B/NK
__/__/__
_______
NMDP sample __/__/__
_______
RFLP
__/__/__
_______
Urinalysis
__/__/__
_______
Should be completed within 30 days of BMT.
May need to repeated if chemo required.


83
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
83
12.4 APPENDIX 3A: FLT ( 1ST BMT)
PATIENT Name _______________
MR#________________
DOB_________________
Date 
Due
Date 
Given
Week
Day
18F 
FLT
18F 
FDG
Pre-Eval
Post-Eval
Comments
-1
Cr, ALT, AST, TK
F18 1,2hr
0
1
1
2
3
4
5/9
CR, ALT, AST, TK
F18 1,2hr
6
7
2
8
3
15
4
28
CR, ALT, AST, TK
F18 1,2hr
29
+
CR, ALT, AST, TK
F18 1,2hr
To occur with GVHD, or thymus recovery


84
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Version Date: December 28, 2017
84
Appendix 3B: FLT (2nd BMT)
Patient Name_____________
MR#____________________   
DOB ____________________      
Date 
Due
Date 
Given
Week
Day
18F FLT
18F 
FDG
Pre-Eval
Post-Eval
Comments
-1
Cr, ALT, AST, TK
F18 1,2hr
0
1
1
2
3
4
28
_______
CR, ALT, AST, TK
F18 1,2hr
29
_______
5-7
8
60
_______
CR, ALT, AST, TK
F18 1,2hr
61
_______
+
PD
CR, ALT, AST, TK
F18 1,2hr
P+1
+
TX
CR, ALT, AST, TK
F18 1,2hr
To occur with progressive disease
T+1
To occur with immunotherapy 


85
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
85
12.5 APPENDIX 4A: ADULT (>22 YEARS) BMT ROADMAP
Bone Marrow Transplant with Total Body Irradiation and Cyclophosphamide
This roadmap represents the general plan of care for this patient during the bone marrow transplant 
process. This is not an order sheet. Transplant Date:____________
Patient/Diagnosis
Basis for Dose 
Calculations
Transplant
Donor
Name:
Ht (cm):
Type of 
Match:
Name:
MR#:
Wt (kg):
Prep 
Regimen:
TBI, Cytoxan
NMDP/MR#:
Sex:
BSA(m2):
Product:
Marrow 
Sex:
DOB:
/
/
IBW 
(kg):
GVH 
Regimen:
Methotrexate
, Tacrolimus
Age:
Age:
y/o
Allergies:
Day 0:
/    /
Relationship:
ABO/Rh:
Wt (kg):
CMV IgG:
ABO/Rh:
HSV (I/II):
CMV IgG:
Toxo IgG:
HLA:
A (     ,      
), Cw (     ,  
), B (      ,
), Bw (  ,    
), DRB1 (    
,     ), 
DRB3 (     
), DQB1 (    
,      )
HLA:
A (        ,      ), 
Cw (     ,        ), 
B (      ,      ), 
Bw (   ,   ), 
DRB1 (      ,      ), 
DRB3 (    ), 
DQB1 (     ,       )
Diagnosis:
Status:
Cytogenetics:
Risk Factors:
Performance 
Score:
Chemotherapy started on: (write in date) ______Was dose of prep regimen modified? If yes, explain:
___________________________


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Version Date: December 28, 2017
86
Ht (cm):
Dx:
                
Prep Regimen: TBI/Cytoxan
Type of Match: 
Wt (kg):
Status:
                
Product: Marrow
Donor CMV: 
IBW (kg):
Risk Factors: 
GVH Regimen: MTX/tacro
Donor ABO/Rh: 
BSA (m2):
Day 0:   /  /
Age:
ABO/Rh: 
Day#:
Date:
Regimen:
Medications/Interventions:
Notes:
-14 to day -7
/   /
+/- male LUPRON (+females) 
One injection of 4 month 
preparation. 
-8
TBI 
Start Pneumocystis carinii (PCP) 
and Caspofungin prophylaxis
Weekly Fungitall, Asp ag, Adeno 
+/- Toxo (for positive patients).  
-7
TBI
-6
TBI
-5
TBI
-4
CY
Mesna
Forced diuresis with IV hydration 
to maintain UOP volume of 2-
3ml/kg/hr
-3
CY
Mesna
Discontinue PCP prophylaxis
Forced diuresis with IV hydration 
to maintain UOP volume of 2-
3ml/kg/hr
-1
+/- FLT (1st or 
2nd BMT)
Tacro 0.02mg/kg/day IBW 
continuous infusion 
TAC trough at least weekly, adjust 
to goal of 5-10ng/ml.
0
TX
Start prophylactic antibiotics
TAC trough at least weekly, adjust 
to goal of 5-10ng/ml.
+1
Methotrexate 
10mg/m2 IV
+3
Methotrexate 
5mg/m2 IV 
TAC trough at least weekly, adjust 
to goal  of 5-10ng/ml.
+5
+/- FLT  (1st
BMT)
FLT can be on either day 5 or day 9 
(BMT# 1 only)
+6
Methotrexate 
5mg/m2 IV 
+11
Methotrexate 
5mg/m2 IV 
TAC trough at least weekly, 
adjust to goal of 5-10ng/ml.
+14
- Research Blood


87
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Version Date: December 28, 2017
87
+28
+/- FLT (1st or 
2nd BMT)
Restart PCP prophylaxis
-BMB, BMA morphology, RFLP, 
-BMA FISH, flow 
-diagnostic LP, Research Pl/BM
-Chimerism Bl/BM,
-H/P aGVHD, IgGs, TBNK
+29
+/- FDG (1st
or 2nd BMT)
+30
+/- FLT When 
GVHD or 
thymus 
+60
+/- FLT &
FDG (2nd BMT 
only)
-BMB, BMA morphology, RFLP, 
-BMA cytogenetics, FISH, flow 
-diagnostic LP
-Chimerism Bl/BM,  
- Research blood/BM 
-TBNK, H/p w/ AGVHD eval. 
+100
Taper Tacrolimus if no signs of 
GVHD
-H/P w/a or cGVHD, 
-BMB, BMA morphology, RFLP 
-BMA cytogenetics, FISH, flow 
- diagnostic LP
- Chimerism Bl/BM,
- Research blood/BM, TBNK
- LDH,  IGs,
- PFTs, CHEST CT.  
+180
Taper Tacrolimus if no signs of 
GVHD
-H/P w/ cGVHD, 
- Chimerism Bl,
- Research blood, TBNK
- Ferritin, Fe, LDH,  IGs,
- PFTs.
- Ophthalmology
- Dental
- LH/FSH, TSH/T4, U/A, Chem20
+270
-H/P w/ cGVHD, 
- Chimerism Bl,
- Research blood, TBNK
- Ferritin, Fe, LDH,  IGs,
- PFTs.
- LH/FSH, TSH/T4, Chem20
+365
Consider Immunizations 6 months 
after withdrawal of 
immunosuppression.  
-H/P w/a or cGVHD, 
-BMB, BMA morphology, RFLP 
-BMA cytogenetics, FISH, flow 
- diagnostic LP


88
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
88
TBI twice daily fractionated with lung block on days -7, -6, -5, and -4. Cumulative dose = 1200 
cGy/course. CNS boost if CNS positive at any time prior to HSCT. 
Cyclophosphamide 60mg/kg IV over 1 hour on days -3, -2.  Cumulative dose =120mg/kg.
***Note: Use a modified dose in obese patients that is defined as BMI > 35 and modified weight is half way 
between  actual and ideal body weight for Cyclophosphamide and Mesna dosing
Mesna IV 24 hour infusion = to total Cyclophosphamide dose on days -3, -2.
- Chimerism Bl/BM,
- Research blood/BM, TBNK
- Ferritin, LDH,  IGs,
- PFTs, CHEST CT.
- Ophthalmology
- Dental
- LH/FSH, TSH/T4, U/A, Chem20
- Echo
- Dexa
- GYN (female)


89
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
89
12.6 APPENDIX 4B: PEDIATRIC (<22 YEARS) BMT ROADMAP
Bone Marrow Transplant with Total Body Irradiation and Cyclophosphamide
This roadmap represents the general plan of care for this patient during the bone marrow 
transplant process. This is not an order sheet. 
Transplant Date:____________
Patient/Diagnosis
Basis for Dose 
Calculations
Transplant
Donor
Name:
Ht (cm):
Type of 
Match:
Name:
MR#:
Wt (kg):
Prep 
Regimen:
TBI, 
Cytoxan
NMDP/MR#
:
Sex:
BSA(m2)
:
Product:
Marrow 
Sex:
DOB:
/    /
IBW 
(kg):
GVH 
Regimen:
Methotrexate
, Tacrolimus
Age:
Age:
y/o
Allergies:
Day 0:
/    /
Relationship
:
ABO/Rh:
Wt (kg):
CMV IgG:
ABO/Rh:
HSV (I/II):
CMV IgG:
Toxo IgG:
HLA:
A (     ,      ), 
Cw (     ,     ), 
B (       ,        
), Bw (  ,    ), 
DRB1 (     ,     
), DRB3 (     
), DQB1 (     ,  
)
HLA:
A (        ,      ), 
Cw (     ,        
), B (      ,      
), Bw (   ,   ), 
DRB1 (      ,      
), DRB3 (    ), 
DQB1 (     ,       
)
Diagnosis:
Status:
Cytogenetics:
Risk Factors:
Performance 
Score:
Chemotherapy started on: (write in date) _________________________________________
Was dose of prep regimen modified? If yes, explain:
____________________________________________________________________


90
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
90
Ht (cm):
Dx:
                
Prep Regimen: TBI/Cytoxan
Type of Match: 
Wt (kg):
Status:
                
Product: Marrow
Donor CMV: 
IBW (kg):
Risk Factors: 
GVH Regimen: MTX/tacro
Donor ABO/Rh: 
BSA (m2):
Day 0:   /  /
Age:
ABO/Rh: 


91
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
91
Day#:
Date:
Regimen:
Medications/Interventions:
Notes:
-14 to day -7
/   /
+/- male 
LUPRON (+females) 
One injection of 4 month preparation. 
-9
TBI 
Start Pneumocystis carinii (PCP) 
and Caspofungin prophylaxis
Weekly Fungitall, Asp ag, Adeno +/-
Toxo (for positive patients).  
-8
TBI
-7
TBI
-6
TBI
-5
CY
Mesna
Forced diuresis with IV hydration to maintain 
UOP volume of 2-3ml/kg/hr
-4
CY
Mesna
Forced diuresis with IV hydration to maintain 
UOP volume of 2-3ml/kg/hr
-3
CY
Mesna
Forced diuresis with IV hydration to maintain 
UOP volume of 2-3ml/kg/hr
-2
CY
Mesna
Discontinue PCP prophylaxis
Forced diuresis with IV hydration to maintain 
UOP volume of 2-3ml/kg/hr
-1
+/- FLT*
Tacro 0.02mg/kg/day IBW 
continuous infusion 
TAC trough at least weekly, adjust to goal 
of 5-10ng/ml.
0
TX
Start prophylactic antibiotics
TAC trough at least weekly, adjust to goal 
of 5-10ng/ml.
+1
Methotrexate 
10mg/m2 IV
+3
Methotrexate 
5mg/m2 IV 
TAC trough at least weekly, adjust to 
goal  of 5-10ng/ml.
+5
+/- FLT  
+6
Methotrexate 
5mg/m2 IV 
+11
Methotrexate 
5mg/m2 IV 
TAC trough at least weekly, adjust to 
goal of 5-10ng/ml.
+14
- Research Blood
+28
+/- FLT
Restart PCP prophylaxis
-BMB, BMA morphology, RFLP, 
-BMA cytogenetics, FISH, flow 
-diagnostic LP, Research Pl/BM
-Chimerism Bl/BM,
-H/P aGVHD, IgGs, TBNK
+29
+/- FDG
+30
+/- FLT When 
GVHD or 
thymus 
+60
-BMB, BMA morphology, RFLP, 
-BMA cytogenetics, FISH, flow 
-diagnostic LP
-Chimerism Bl/BM,  
- Research blood/BM 
-TBNK, H/p w/ AGVHD eval. 
+100
Taper Tacrolimus if no signs of 
GVHD
-H/P w/a or cGVHD, 
-BMB, BMA morphology, RFLP 
-BMA cytogenetics, FISH, flow 
- diagnostic LP
- Chimerism Bl/BM,
- Research blood/BM, TBNK


92
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
92
TBI twice daily fractionated with lung block on days -8, -7, -6, -5.  Cumulative dose = 1200 cGy/course. CNS boost if 
CNS positive at any time prior to HSCT. 
Cyclophosphamide 50mg/kg IV over 1 hour on days -5, -4,-3, -2.  Cumulative dose =200mg/kg.
***Note: Use a modified dose in obese patients that is defined as BMI > 35 and modified weight is half way 
between actual and ideal body weight for Cyclophosphamide and Mesna dosing
Mesna IV 24 hour infusion = to total Cyclophosphamide dose on days -5,-4, -3, -2.
- Ferritin, LDH,  IGs,
- PFTs, CHEST CT.  
+180
Taper Tacrolimus if no signs of 
GVHD
-H/P w/ cGVHD, 
- Chimerism Bl,
- Research blood, TBNK
- Ferritin, Fe, LDH,  IGs,
- PFTs.
- Ophthalmology
- Dental
- LH/FSH, TSH/T4, U/A, Chem20
+270
-H/P w/ cGVHD, 
- Chimerism Bl,
- Research blood, TBNK
- Ferritin, Fe, LDH,  IGs,
- PFTs.
- LH/FSH, TSH/T4, Chem20
+365
Consider Immunizations 6 
months after withdrawal of 
immunosuppression.  
-H/P w/a or cGVHD, 
-BMB, BMA morphology, RFLP 
-BMA cytogenetics, FISH, flow 
- diagnostic LP
- Chimerism Bl/BM,
- Research blood/BM, TBNK
- Ferritin, LDH,  IGs,
- PFTs, CHEST CT.
- Ophthalmology
- Dental
- LH/FSH, TSH/T4, U/A, Chem20
- Echo
- Dexa
- GYN (female)


93
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
93
12.7 APPENDIX 5: RESEARCH SPECIMENS
Please note that any extra clinical specimen taken from the patient on protocol may become a research specimen if 
the patient has agreed to this, to include: BAL, biopsies of lung, bone, or liver etc. 
Note total aliquot will not exceed 3 ml/kg/draw nor 7 ml/kg in 4 week period for research.
Day#:
From: 
Source:
Notes:
-
DONOR
Donor marrow product  
5 million total nucleated donor cells 
(of marrow product) 
-1
HOST
Peripheral Blood – FLT patients
TK for FLT 1st or 2nd BMT
patients. 3 cc EDTA PB
+5
HOST
Peripheral Blood – FLT patients
Peripheral Blood – cells, EDTA, 
HEP pl, TBNK
TK 3 cc EDTA PB for FLT 1st BMT 
only patients.
20cc in red/green CPT PB
16 cc in EDTA PB
+7, 14, 21
HOST
Peripheral Blood – cells, EDTA, 
HEP pl, TBNK
20cc in red/green CPT PB
16 cc in EDTA PB
+28
HOST
Peripheral Blood – cells, EDTA, 
HEP pl
Bone marrow aspirate
Bone marrow biopsy 
Peripheral Blood – FLT patients
20cc in red/green CPT PB
16 cc in EDTA PB
+ TK 3 cc EDTA PB for FLT 1st or 
2nd BMT patients 
+45
HOST
Peripheral Blood – cells, EDTA, 
HEP pl, TBNK
+ 60
HOST
Peripheral Blood – cells, EDTA, 
HEP pl
Bone marrow aspirate
Bone marrow biopsy
20cc in red/green CPT PB
16 cc in EDTA PB
+ TK 3 cc EDTA PB for FLT 2nd
BMT patients 
+ONSET 
AGVHD  
HOST
Peripheral Blood – cells, EDTA, 
HEP pl
20cc in red/green CPT PB
16 cc in EDTA PB
+100 
HOST
Peripheral Blood – cells, EDTA, 
HEP pl
Bone marrow aspirate
Bone marrow biopsy
20cc in red/green CPT PB
16 cc in EDTA PB
+ONSET 
cGVHD
HOST
Peripheral Blood – cells, EDTA, 
HEP pl
20cc in red/green CPT PB
16 cc in EDTA PB
+180
HOST
Peripheral Blood – cells, EDTA, 
HEP pl
20cc in red/green CPT PB
16 cc in EDTA PB
+270
HOST
Peripheral Blood – cells, EDTA, 
HEP pl
+365
HOST
Peripheral Blood – cells, EDTA, 
HEP pl
Bone marrow aspirate
Bone marrow biopsy
+yearly on 
study until 5 
years
HOST
Peripheral Blood – cells, EDTA, 
HEP pl


94
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
94
12.8 APPENDIX 6: IMMUNIZATION POST-TRANSPLANT
Immunizations:  All recipients will receive immunizations after transplant, according to the BMT 
consortium guidelines 
(https://cccasper.cc.nih.gov/cvpn/aHR0cDovL2ludHJhbmV0LmNjLm5paC5nb3Y/bmt/clinicalc
are/pdf/Table_II.pdf)


95
Abbreviated Title: Lupron & 18F FLT in allo-HSCT
Version Date: December 28, 2017
95
12.9 APPENDIX 7: MANAGEMENT OF ENGRAFTMENT SYNDROME
Clinical Definition of Engraftment Syndrome
A constellation of clinical symptoms and signs has been observed during neutrophil recovery 
following HSCT, most commonly termed “engraftment syndrome” (ES), sometimes 
“hyperacute” graft-versus-host reaction.  Below are guidelines for diagnosis and treatment.
Major criteria:
x
Fever > 38.3q with no identifiable infectious etiology
x
Erythrodermatous rash involving more than 25% of body 
surface area and not attributable to a medication
x
Noncardiogenic pulmonary edema, manifested by diffuse 
pulmonary infiltrates and hypoxia
Minor criteria
x
Hepatic dysfunction with either total bilirubin > 2 mg/dl or 
transaminases levels > two times normal
x
Renal insufficiency (serum creatinine > two times 
baseline)
x
Weight gain > 2.5% of baseline body weight
x
Transient encephalopathy unexplainable by other causes
A diagnosis of ES is established by the presence of all three major criteria, or two major criteria 
and one or more minor criteria; the clinical signs and symptoms should appear within 96 hours 
of neutrophil recovery, according to the above proposed definition.

Neutrophil recovery after transplantation may result in “engraftment syndrome” (which 
may include fever, rash, edema, hypoxia)

The following criteria will be utilized to diagnose engraftment syndrome (must have 3 
major criteria or 2 major + 1 minor criteria):

To promote consistency of our clinical practice, the following will be the recommended 
therapy for engraftment syndrome.  However, this schedule may be modified (taper either 
accelerated or delayed) for individual patients as clinical circumstances warrant.  In 
particular, every attempt should be made to rapidly wean steroids due to infection and 
disease control issues in our patient population. 
Treatment of Engraftment Syndrome without pulmonary edema: 
-
attempt to use diuretics first.
-
If progression of edema, consider methylprednisolone at 0.5mg/kg/day x 3 
days.
Treatment of Engraftment Syndrome if pulmonary edema is present
Day 1:
Methylprednisolone 250 mg IV Q6 hours x 4 doses
Day 2:
Methylprednisolone 250 mg IV Q8 hours x 3 doses
Day 3:
Methylprednisolone 250 mg IV Q12 hours x 2 doses
Day 4:
Methylprednisolone 125 mg IV Q12 hours x 2 doses
Day 5:
Methylprednisolone 60 mg IV Q12 hours x 2 doses
Day 6:
Methylprednisolone 30 mg IV Q12 hours x 2 doses
Days 7-8:
Prednisone 60 mg PO QD x 2 days
Days 9-10:
Prednisone 50 mg PO QD x 2 days


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


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12.10 APPENDIX 8A: GRADING AND MANAGEMENT OF ACUTE GRAFT-VERSUS-HOST-DISEASE
Clinical Staging of Acute GVHD to be done/documented day +28, +60, +100 at minimum
Stage
Skin
Liver
Gut
1
Rash < 25% BSA
Total bilirubin 2-3 mg/dl
Diarrhea 500-999ml/d
2
Rash 25-50% BSA
Total bilirubin 3-6 mg/dl
Diarrhea 
1000-
1499ml/d
3
Rash > 50% BSA
Total bilirubin 6-15 mg/dl
Diarrhea 1500ml/d
4
Generalized 
erythoderma 
with 
desquamation and bullae
Total bilirubin > 15 mg/dl
Severe abdominal pain 
+/- ileus
BSA = body surface area; use “rule of nines” or burn chart to determine extent of rash.
Clinical Grading of Acute GVHD 
Stage
Grade
Skin
Liver
Gut
0 (none)
0
0
0
I
1-2
0
0
II
3 or
1 or
1
III
2-3 or
2-4
IV
4 or
4
Grade IV may also include lesser organ involvement but with an extreme decrease in 
performance status.
Treatment of Acute GVHD
This schema is intended to serve as a guideline and to promote consistency in our clinical 
practice; it may be modified for individual patients as clinical circumstances warrant.
Grade I GVHD: 
1) Supportive care or topical corticosteroids (usually 0.1% triamcinolone; 1% hydrocortisone to 
face) applied to rash BID.
Grade II GVHD
1)   Supportive care or topical corticosteroids or oral/IV corticosteroids as deemed necessary by the clinical 
providers.
Grade III-IV GVHD:
1) Methylprednisolone (MP) 1 mg/kg per dose IV, BID for 3 consecutive days.
2) If no response after 4 days, continue until response (7-day maximum trial) add second line 
therapy which could include: MMF, ECP, rituximab, sirolimus, and will be directed based on 


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organ and severity and patient co-morbidities. 3)Regardless of response within 7 days, taper 
as follows (note add other agents prior to taper for non-responders):
a) 0.75 mg/kg per dose IV BID for 7 days.
b) 0.5 mg/kg per dose IV BID for 7 days.
c) 0.375 mg/kg per dose IV BID for 7 days.
d) If clinically appropriate, change MP to oral prednisone to equivalent of IV dose) daily for 
2 days.  MP may be converted to prednisone later in the taper at the investigators’ 
discretion.
e) After this, steroids will be reduced by 10% of starting oral dose each week until a dose of 
10 mg/day is reached.  Subsequent reductions will be made at the investigators’ discretion.
f)
If GVHD worsens during taper, steroids should be increased to previous dose.
g) During steroid taper, maintain tacrolimus at therapeutic levels.
5) Antifungal prophylaxis with agents effective against muld will be started when it is 
anticipated that the patient will be receiving steroids at > 1 mg/kg/day of methylprednisolone 
(or equivalent) for > 2 weeks. Voriconazole, caspofungin, liposomal amphotericin B 
(Ambisome), posaconazole, or amphotericin B lipid complex (Abelcet) are valid alternatives.  
During prophylaxis with any of the above agents, fluconazole should be discontinued.  In 
patients with therapeutic cyclosporine levels at the initiation of voriconazole therapy, the 
cyclosporine or tacrolimus dose should be decreased by approximately 50%. In patients with 
therapeutic sirolimus levels at the initiation of voriconazole therapy, the sirolimus dose 
should be decreased by approximately 90%.
6) Determination of GVHD treatment response should be made within 96 hours of starting the 
treatment.  The following are criteria to determine definitions of response to GVHD treatment:
a) Complete response:  Complete resolution of all clinical signs and symptoms of acute 
GVHD.
b) Partial Response: 50% reduction in skin rash, stool volume or frequency, and/or total 
bilirubin.  Maintenance of adequate performance status (Karnofsky Score > 70%).
c) Non-responder: < 50% reduction in skin rash, stool volume or frequency, and/or total 
bilirubin.  Failure to maintain adequate performance status (Karnofsky Score d 70%).
d) Progressive disease:  Further progression of signs and symptoms of acute GVHD, and/or 
decline in performance status after the initiation of therapy.
Treatment 
This schema is intended to serve as a guideline and to promote consistency in our clinical 
practice; it may be modified for individual patients as clinical circumstances warrant.


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12.11
APPENDIX 8B
Please complete for new diagnosis and follow-up with cGVHD (and/or day +100, 180, 270, 365)
Current Patient Weight: ___________________
Today’s Date: ________________________
MR#/Name: ____________________   
CHRONIC GVHD ACTIVITY ASSESSMENT- CLINICIAN
Component
Findings
Scoring (see skin score worksheet)
Skin
Erythematous rash of any sort
                        % BSA (max 100%)
Moveable sclerosis 
                        % BSA (max 100%)
Non-moveable sclerosis (hidebound/non-pinchable) or subcutaneous sclerosis/fasciitis
                        % BSA (max 100%)
Ulcer(s): select the largest ulcerative lesion, and measure its largest dimension in cm and mark 
location of ulcer
Location: ___________________
Largest dimension: __________cm
Eyes
Bilateral Schirmer’s Tear Test
(without anesthesia) 
in persons 9 years or older
Right Eye:                                        mm of wetting
Left Eye:                                                      mm of wetting
Mouth
Mucosal 
change
No evidence 
of cGvHD
Mild
Moderate
Severe
Erythema
None
0
Mild erythema or 
moderate erythema 
(<25%)
1
˜ o˜ erate (≥25%) or 
Severe erythema 
(<25˜ )
2
Severe erythema 
(≥25%) 
3
Lichenoid
None
0
Hyperkeratotic 
changes(<25%)
1
Hyper˜ eratotic 
chan˜ es(˜˜˜
50%)
2
Hyperkeratotic cha˜ ges 
(>5˜ %)
3
U˜ cers
˜ one
0
Non
Ulcers involving (≤20%)
3
Seve˜ e ˜ lcerations 
(>20
Mucoceles*
None
0
1-5 mucoceles
1
6-10 scattered 
mucoceles
2
Over 10 mucoceles
3
           
*Mucoceles score˜  for lower 
la˜ ial˜˜˜
d sof˜  palate only
Total˜ score for all 
m˜ cosal˜ change
s


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Blood Counts
Platelet Count                               
                                         K/uL
ULN    
                             K/uL
Total WBC
                                                   K/uL
ULN
                                          K/uL
% Eosinophils
                                                  
%
Liver Function Tests
Total serum bilirubin
                           mg/dL
ULN
                           
                        mg/dL
ALT
                           U/L
ULN
                            
                             U/L
Alkaline Phosphatase        
                            U/L
ULN
                           U/L
Gastrointestinal-Upper GI 
x
Early satiety  OR
x
Anorexia     OR
x
Nausea & Vomiting
0= no symptoms
1=mild, occasional symptoms, with little reduction in oral intake during the past week
2=moderate, intermittent symptoms, with some reduction in oral intake during the past week
3=more severe or persistent symptoms throughout the day, with marked reduction in oral intake, on almost every day of the past week
Gastrointestinal-Esophageal
x
Dysphagia     OR
x
Odynophagia
0= no esophageal symptoms
1=Occasional dysphagia or odynophagia with solid food or pills during the past week
2=Intermittent dysphagia or odynophagia with solid foods or pills, but not for liquids or soft foods, during the past week
3=Dysphagia or odynophagia for almost all oral intake, on almost every day of the past week
Gastrointestinal-Lower GI
x
Diarrhea
0= no loose or liquid stools during the past week
1= occasional  loose or liquid stools, on some days during the past week
2=intermittent loose or liquid stools throughout the day, on almost every day of the past week, without requiring intervention to prevent or correct 
volume depletion
3=voluminous diarrhea on almost every day of the past week, requiring intervention to prevent or correct volume depletion
Lungs
x
Bronchiolitis Obliterans
Pulmonary Function Tests with Diffusing 
Capacity   (attach report for person> 5 yrs old)
FEV-1
% Predicted
Single Breath DLCO (adjusted for hemoglobin)
                                                     % Predicted
Health Care Provider 
Global Ratings:
In your opinion, do you 
think that this patient’s 
chronic GvHD is mild, 
moderate or severe?
0=none
1= mild
2=moderate
3=severe
Where would you rate the severity  of this patient’s chronic GvHD symptoms on the following 
scale, where 0 is cGVHD symptoms that are not at all severe and 10 is the most severe cGVHD 
symptoms possible:
             0       1         2         3         4         5         6    
7         8          9         10
cGvHD symptoms
                                                                                                                     Most severe cGvHD
not at all severe                                                                                                                                     symptoms
                                                                                                                                                                 possible
Over the past month would you say that this patient’s cGvHD is
+3= Very much better 
+2= Moderately better
+1= A little better
0= About the same
-1=A little worse
-2=Moderately worse 
-3=Very much worse
Functional Performance (in 
persons >4 years old)
x
Walk Time
x
Grip Strength
Total Distance Walked in 2 Minutes:
Number of laps: _______ (x 50 feet) + final partial 
lap: _____ feet  = ______ feet walked in 2 minutes,
6min                                          
Grip Strength (Dominant Hand)
Range of Motion: 
o
Not performed
o
Physical Therapy Report Attached
Trial #1
            psi
Trial #2
           psi
Trial #3
            psi
             Score
Lansky Performance Status Scale Definitions (circle from 0-100) (persons < 16 years 
old)
Karnofsky Performance Status Scale Definitions (circle 
from 0-100) (persons 16 years or older)
100
Fully active, normal
Normal no complaints; no evidence of disease
90
Minor restrictions in physically strenuous activity
Able to carry on normal activity; minor signs or symptoms of disease
80
Active, but tires more quickly
Normal activity with effort; some signs or symptoms of disease


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70
Both greater restriction of and less time spent in play activity
Cares for self; unable to carry on normal activity or to do active work
60
Up and around, but minimal active play; keeps busy with quieter activities
Requires occasional assistance but is able to care for most personal needs
50
Gets dressed but lies around much of the day, no active play but able to participate in all quiet play and activities
Requires considerable assistance and frequent medical care
40
Mostly in bed; participates in quiet activities
Disabled; requires special care and assistance
30
In bed; needs assistance even for quiet play
Severely disabled; hospital admission is indicated although death not 
imminent
20
Often sleeping; play entirely limited to very passive activities
Very sick; hospital admission necessary; active supportive treatment 
necessary
10
No play; does not get out of bed
Moribund; fatal processes progressing rapidly
0
Unresponsive
Dead


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12.12 APPENDIX 8C: SIGNS AND SYMPTOMS OF CGVHD
ORGAN OR 
SITE
DIAGNOSTIC 
(Sufficient to 
establish the 
diagnosis of chronic 
GVHD)
DISTINCTIVE 
(Seen in chronic GVHD, but 
insufficient alone to establish a 
diagnosis of chronic GVHD)
OTHER 
FEATURES*
COMMON
(Seen with both 
acute and 
chronic GVHD)
Skin
Ɣ Poikiloderma 
Ɣ Lichen planus-like 
features 
Ɣ Sclerotic features
Ɣ Morphea-like 
features
Ɣ Lichen sclerosus-
like features
Ɣ Depigmentation
ƔSweat impairment
Ɣ Ichthyosis
ƔKeratosis pilaris
ƔHypopigmentation
ƔHyperpigmentation
Ɣ Erythema
Ɣ Maculopapular 
rash
Ɣ Pruritus
Nails
Ɣ Dystrophy
Ɣ Longitudinal ridging, 
splitting or brittle features
Ɣ Onycholysis
Ɣ Pterygium unguis
Ɣ Nail loss** (usually 
symmetric, affects most nails)
Scalp and 
Body Hair
Ɣ New onset of scarring or non-
scarring scalp alopecia, (after 
recovery from 
chemoradiotherapy)
Ɣ6FDOLQJSDSXORVTXDPRXV
lesions
Ɣ Thinning scalp 
hair, typically 
patchy, coarse or 
dull (not explained 
by endocrine or 
other causes), 
Ɣ Premature gray hair
Mouth
Ɣ Lichen-type 
features
Ɣ Hyperkeratotic 
plaques
Ɣ Restriction of 
mouth opening
from sclerosis
Ɣ Xerostomia
Ɣ Mucocele
Ɣ Mucosal Atrophy
Ɣ Pseudomembranes**
Ɣ Ulcers**
Ɣ Gingivitis
Ɣ Mucositis
Ɣ Erythema
Ɣ Pain
Eyes
Ɣ New onset dry, gritty, or 
painful eyes†
Ɣ Cicatricial conjunctivitis
Ɣ Keratoconjunctivitis sicca†
x Confluent areas of punctate 
keratopathy
Ɣ Photophobia
Ɣ Periorbital 
hyperpigmentation
Ɣ Blepharitis 
(erythema of the 
eye lids with 
edema)
Genitalia
Ɣ Lichen planus-like 
features
Ɣ Vaginal scarring 
or stenosis
x Erosions**
x Fissures**
x Ulcers**
GI Tract
x Esophageal web
x Strictures or stenosis 
in the upper to mid
third of the 
esophagus**
x
Exocrine 
pancreatic 
insufficiency
x Anorexia
x Nausea
x Vomiting
x Diarrhea
x Weight loss


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ORGAN OR 
SITE
DIAGNOSTIC 
(Sufficient to 
establish the 
diagnosis of chronic 
GVHD)
DISTINCTIVE 
(Seen in chronic GVHD, but 
insufficient alone to establish a 
diagnosis of chronic GVHD)
OTHER 
FEATURES*
COMMON
(Seen with both 
acute and 
chronic GVHD)
x Failure to 
thrive (infants 
and children
Liver
x Total bilirubin, 
alkaline 
phosphatase > 
2 x upper limit 
of normal†
ƔALT or AST > 
2x upper limit of 
normal†
Lung
Ɣ Bronchiolitis 
obliterans diagnosed 
with lung biopsy
x Bronchiolitis obliterans 
diagnosed with PFTs and 
radiology†
x BOOP
Muscles, 
Fascia, Joints
x Fasciitis
x Joint stiffness or 
contractures 
secondary to sclerosis
x Myositis or 
polymyositis †
x Edema
x Muscle cramps
x Arthralgia or 
arthritis
Hematopoietic
and Immune
x Thrombocytopenia
x Eosinophilia
x Lymphopenia
x Hypo- or hyper-
gammaglobulinemi
a
x Autoantibodies 
(AIHA, ITP)
Other
x Pericardial or 
pleural effusions
x Ascites
x Peripheral 
neuropathy
x Nephrotic 
syndrome
x Myasthenia gravis
x Cardiac conduction 
abnormality or 
cardiomyopathy
*Can be acknowledged as part of the chronic GVHD symptomatology if diagnosis is confirmed
**In all cases, infection, drug effect, malignancy or other causes must be excluded.
†Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer’s test foreyes). 
GVHD (graft versus host disease); ALT (alanine aminotransferase); AST (aspartate aminotransferase); 
BOOP (bronchiolitis obliterans organizing pneumonia); PFTs (pulmonary function tests); AIHA 
(autoimmune hemolytic anemia)


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12.13 APPENDIX 8D:CGVHD SCORE SHEET
Please complete for new diagnosis and follow-up with cGVHD (and/or day +100, 180, 270, 365)
SCORE 0
SCORE 1 
SCORE 2
SCORE 3
PERFORMANCE 
SCORE:
KPS   ECOG   LPS
Asymptomatic 
and fully active 
(ECOG 0; KPS or 
LPS 100%)
Symptomatic, 
fully ambulatory, 
restricted only in 
physically strenuous 
activity (ECOG 1, 
KPS or LPS 80-
90%)
Symptomatic, 
ambulatory, 
capable of self-
care, >50% of 
waking hours out 
of bed (ECOG 2, 
KPS or LPS 60-
70%) 
Symptomatic, 
limited self-care, 
>50% of waking 
hours in bed (ECOG 
3-4, KPS or LPS 
<60%)
SKIN
Clinical features:
Maculopapular 
rash
Lichen planus-like 
features
Papulosquamous 
lesions or ichthyosis
Hyperpigmentation
Hypopigmentation
Keratosis pilaris
Erythema
Erythroderma 
Poikiloderma
Sclerotic features 
Pruritus
Hair involvement
Nail involvement
% BSA 
involved
No Symptoms 
<18% BSA with 
disease signs but 
NOsclerotic 
features
19-50% BSA 
OR involvement 
with superficial 
sclerotic features 
“not hidebound” 
(able to pinch)
>50% BSA OR
deep sclerotic 
features “hidebound” 
(unable to pinch) OR
impaired mobility, 
ulceration or severe 
pruritus 
MOUTH
No symptoms 
Mild symptoms 
with disease signs 
but not limiting oral 
intake significantly
Moderate 
symptoms with 
disease signs with
partial limitation 
of oral intake
Severe symptoms 
with disease signs on 
examination with
major limitation of 
oral intake
EYES
Mean tear test (mm):
>10
6-10
<5
Not done
No symptoms 
Mild dry eye 
symptoms not 
affecting ADL 
(requiring eyedrops 
< 3 x per day) OR
asymptomatic signs 
of  
keratoconjunctivitis 
sicca
Moderate dry 
eye symptoms 
partially affecting 
ADL (requiring 
drops > 3 x per 
day or punctal 
plugs), 
WITHOUT
vision impairment
Severe dry eye 
symptoms 
significantly 
affecting ADL 
(special eyeware to 
relieve pain) OR
unable to work 
because of ocular 
symptoms ORloss 
of vision caused by 
keratoconjunctivitis 
sicca


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SCORE 0
SCORE 1 
SCORE 2
SCORE 3
GI TRACT
No symptoms
Symptoms such 
as dysphagia, 
anorexia, nausea, 
vomiting, abdominal 
pain or diarrhea 
without significant 
weight loss (<5%)
Symptoms 
associated with 
mild to moderate 
weight loss (5-
15%)
Symptoms 
associated with 
significant weight 
loss >15%, requires 
nutritional 
supplement for most 
calorie needs OR
esophageal dilation
LIVER
Normal LFT
Elevated 
Bilirubin, AP*, AST 
or ALT <2 x ULN
Bilirubin >3 
mg/dl or Bilirubin, 
enzymes 2-5 x 
ULN 
Bilirubin or 
enzymes > 5 x ULN
LUNGS*
FEV1
DLCO
No symptoms
FEV1 > 80% 
ORLFS=2
Mild symptoms 
(shortness of breath 
after climbing one 
flight of steps)
FEV1 60-79% 
ORLFS 3-5
Moderate 
symptoms 
(shortness of 
breath after 
walking on flat 
ground)
FEV1 40-59% 
ORLFS 6-9
Severe symptoms 
(shortness of breath  
at rest; requiring 0
2)
FEV1 <39% OR
LFS 10-12
JOINTS AND FASCIA
No symptoms
Mild tightness of 
arms or legs, normal 
or mild decreased 
range of motion 
(ROM) ANDnot 
affecting ADL
Tightness of 
arms or legs OR
joint contractures, 
erythema due to 
fasciitis, moderate 
decrease ROM 
ANDmild to 
moderate 
limitation of ADL
Contractures 
WITH significant 
decrease of ROM
AND significant 
limitation of ADL 
(unable to tie shoes, 
button shirts, dress 
self etc.) 
GENITAL TRACT
No symptoms 
Symptomatic with 
mild signs on exam 
ANDno effect on 
coitus and minimal 
discomfort with 
gynecologic exam
Symptomatic 
with moderate 
signs on exam 
ANDwith mild 
dyspareunia or 
discomfort with 
gynecologic exam
Symptomatic 
WITH advanced 
signs (stricture, 
labial agglutination 
or severe ulceration) 
ANDsevere pain 
with coitus or 
inability to insert 
vaginal speculum
*AP may be elevated in growing children, and not reflective of liver dysfunction
Other indicators, clinical manifestations or complications related to cGVHD (check all that apply and assign 
a score to its severity (0-3) based on its functional impact (none – 0,mild -1, moderate -2, severe – 3)
Esophageal stricture or web___
Pericardial Effusion___
Pleural Effusion(s)___
Ascites (serositis)___
Nephrotic syndrome___
Peripheral Neuropathy___
Myasthenia Gravis___
Cardiomyopathy___
Eosinophilia > 
l___
Polymyositis___               
Cardiac conduction defects___
Coronary artery involvement___
Platelets <100,000/l ___Progressive onset


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Լ OTHERS: ___________


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12.14 APPENDIX 9: ETIB POLICY FOR SAMPLE HANDLING
Experimental Transplantation and Immunology Branch 
Preclinical Service Policy for Sample Handling
12.14.1Sample Processing 
EDTA plasma:
Spin down cells at 1500 rpm, 10 min, 10°C. Draw off plasma. Store >6 ml of plasma in 1ml 
conical tubes, labeled as EDTA plasma. Store at -80°C.Heparinized Blood:
Heparinized whole blood is collected for analysis of relevant cytokine/chemokines content. 
Separate plasma by centrifugation and freeze > 6ml samples in 1ml conical tubes, labeled as 
heparinized plasma. Store at   –80°C.
If whole blood is being processed for flow cytometry:
Place 1 ml of well mixed whole blood in a 15ml tube. Add 10ml ACK. Mix well by repeatedly 
inverting tube. Hold 5 min RT. Spin down (1500 rpm, 10 min, 10°C), Resuspend in 0.5ml FACS 
buffer. Distribute to staining tubes.
If whole blood is cryopreserved
Ficoll blood and cryopreserve cells, divided into two 1ml aliquots. Store in LN2.
Our freezing protocol is attached, but any commercial cryopreserve media will suffice.
12.14.2Labeling
All samples are to be labeled with an anonymized Patient identifier such as the patient # in the 
protocol#), date, content (EDTA or heparinized plasma, PBMC with cell number,) and 
preferably stage (pre, 3m, 6m).  We need to be able to link all timepoints collected on a single 
patient but not an identity.
12.14.3Storage/Tracking in the Preclinical Development and Clinical Monitoring Facility 
(PDCMF)
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.
Samples will not be sent outside NIH without IRB notification and an executed MTA. Normal 
donor and patient blood and tissue samples, collected for the purpose of research under IRB 
approved protocols of the Experimental Transplantation and Immunology Branch, may be 
archived by the ETIB Preclinical Service. All data associated with archived clinical research 
samples is entered into the ETIB Preclinical Services’s Microsoft Excel databases on frozen cells 
and plasma. These databases are stored on the NCI group drive in the ETIB Preclinical Service 
folder. Access to this folder is limited to ETIB clinical staff, requiring individual login and 
password. All staff in the Preclinical Service laboratory have received annually updated 


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NIH/CIT training and maintain standards of computer security. Only NIH PI and Adjunct PI 
may appropriate samples for use and interpret data in the context of the endpoints of this trial.  
The data recorded for each sample includes the patient ID, name, trial name/protocol number, 
date drawn, treatment cycle/post transplant time point, cell source (e. g. peripheral blood, 
lymphapheresis, mobilized peripheral blood stem cells, marrow, pleural fluid) as well as box and 
freezer location. Patient demographics that correlate treatment outcomes and therapies with the 
samples can be obtained only through the NCI/ETIB clinical records or NCI C3D. As of January 
2007, all newly received samples will receive a unique bar code number, which will be added to 
the sample Preclinical Service database. Only this bar code will be recorded on the sample vial 
and the vials will not be traceable back to patients without authorized access to the Preclinical 
Service database. All non-coded samples previously archived will be stripped of identifiers prior 
to distribution for any use other than as a primary objective of the protocol under which they 
were collected.
Samples are stored in locked freezers. All samples will be labeled solely with a bar code (which 
includes the date, and serially determined individual sample identifier). The key will be available 
to a restricted number of ETIB investigators and associate investigators on the protocol. Coded 
samples will be stored frozen at -20°, -80° or liquid nitrogen vapor phase according to the 
stability requirements under the restricted control of the PDCM Facility of ETIB..
Access to samples from a protocol for research purposes will be by permission of the Principal 
Investigator of that protocol in order to be used (1) for research purposes associated with 
protocol objectives for which the samples were collected, or (2) for a new research activity 
following submission and IRB approval of a new protocol and consent, or (3) for use only as 
unlinked or coded samples under the OHSRP Exemption Form guidelines stipulating that the 
activity is exempt from IRB review. Unused samples must be returned to the PDCMF laboratory.
Samples, and associated data, will be stored permanently unless the patient withdraws consent. If 
researchers have samples remaining once they have completed all studies associated with the 
protocol, they must be returned to the PDCMF laboratory.
These freezers are located onsite at the PDCMF laboratory (12C216) or in ETIB common 
equipment space (CRC/3-3273).
12.14.4Protocol Completion/Sample Destruction 
Once primary research objectives for the protocol are achieved, researchers can request access to 
remaining samples, providing they have both approval of the Principal Investigator of the 
original protocol under which the samples or data were collected and either an IRB approved 
protocol and patient consent or the OHSRP Exemption Form stipulating that the activity is 
exempt from IRB review..


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The PDCMF staff will report to the Principal Investigators any destroyed samples, if samples 
become unsalvageable because of environmental factors (ex. broken freezer or lack of dry ice in 
a shipping container), lost in transit between facilities or misplaced by a researcher. 
The PI will report destroyed samples to the IRB if samples become unsalvageable because of 
environmental factors (ex. broken freezer or lack of dry ice in a shipping container) or if a patient 
withdraws consent.  Samples will also be reported as lost if they are lost in transit between 
facilities or misplaced by a researcher.  Freezer problems, lost samples or other problems 
associated with samples will also be reported to the IRB, the NCI Clinical Director, and the 
office of the CCR, NCI.
12.14.5Handling for subjects at other Participating Institutions
x
Blood speciman obtained from University of Oklahoma and Children’s National Medical 
Center may be frozen as above, stored, and shipped in batch to NCI. The specimens should be 
shipped to arrive Monday-Friday, to Dr.  Fran Hakim’s ETIB Core lab (Bldg 10, room 12C216.
Attention Jeremy Rose phone: 301-594 5339, 10 Center Drive, CRC 3-3330, Bethesda, MD 
20892.


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12.15 APPENDIX 10: DATA COLLECTION ELEMENTS REQUIRED BY PROTOCOL
All of the following elements will be recorded in the C3D database.
A. Patient Enrollment 
Recipient
x
Date of birth, age, gender, race, ethnicity
x
Height
x
Weight
x
Performance Status
x
Date of original diagnosis
x
Stage at diagnosis
x
Stage at study entry
x
Sites of disease at diagnosis and study entry
x
Tumor Histology and date of confirmation
x
Date of Informed Consent signature, consent version and date of registration
x
Baseline History/Physical
x
Baseline Symptoms 
x
Prior therapy
x
Prior surgery
x
Findings of consultations done at screening
x
ABO
Donor
x
Date of birth, age, gender, race, ethnicity
x
Height
x
Weight
x
Baseline History/Physical (Y/N)
x
Serology (CMV)
x
ABO
B. Study Drug administration and response for each course of therapy given
x
Dates study drugs given
x
Dose level, actual dose, schedule and route given
x
Height, weight, and body surface area at start of each course
x
Response assessment for each restaging performed
x
For women, the administration of estrogen supplementation will be captured.
C. Laboratory and Diagnostic Test Data
x
All Clinical laboratory and diagnostic test results done at screening  (recipient and 
donor) and until day 365 post transplant with the following exceptions:


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o Diagnostic tests which are not specified in the protocol, and if the results 
are not needed to document the start or end of an adverse event that 
requires reporting.
x
All clinical laboratory and diagnostic tests done after day 100 that support a 
possible, probable or definite diagnosis of GVHD, infection or secondary 
malignancy and those done to document a change in grade and the end of these 
adverse events.
x
All tests done to document resolution of adverse events that occurred in the first 
100 days post transplant
x
HLA data (patient and donor).
x
Serologies-CMV, HSV, EBV, toxoplasmosis, adenovirus (patient and donor)
x
TTV data (patient and donor)
x
Blood, bone marrow, and tumor chimerism data 
x
FEV1, DLCO (adjusted but not /VA) pre-transplant
x
EF pre-transplant
x
Acute care, hepatic, and mineral panel plus LDH at transplant 
x
GFR or CrCL pre-transplant 
x
Complete blood count pre-transplant
x
Lymphocyte total number, % CBC, and TBNK at research time points for primary 
endpoint
x
IgA, IgM, IGG at research primary endpoints
x
Engraftment endpoints: neutrophil, plt, hbg
x
LH/FSH/sex hormone levels
x
Vaccine serologies.
D. Adverse Events
x
All grade 2, 3, or 4 adverse events possibly, probably, or definitely attributable to 
lupron or the IND and all serious adverse events will be recorded.
x
Data will also be reported to the Center for International Bone Marrow Transplant 
Registry
E. Concomitant Measures
x
Baseline medications 
x
Antibiotics
x
GVHD prophylaxis and treatment
x
Other therapy for recorded adverse events
F. Treatment of Persistent/Progressive Disease with Standard Therapy
x
Chemotherapy
x
Immunotherapy
x
Radiation therapy


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112
x
Donor Lymphocyte Infusion
G. Tumor response and measurements
x
Restaging studies performed at protocol specified time points and as clinically 
indicated.
H. Off study
x
Date and reason for off study
x
Date and cause of death
x
Autopsy findings
x
PI decision to end this study


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12.16 APPENDIX 11: PROBLEM REPORT FORM
NCI Protocol #: 
Protocol Title: 
Report version: (select one)
____Initial Report 
____Revised Report
____Follow-up
Site Principal Investigator:
Date of problem:    
Location of problem: (e.g.,  patient’s home, 
doctor’s office )
Who identified the problem? (provide role (not name of person): nurse, investigator, 
monitor, etc…)
Brief Description of Subject (if 
applicable)
(Do NOT include personal 
identifiers)
Sex: ___ Male  ___ Female
Age:
___ Not applicable (more than subject is involved)
Diagnosis under study:  
Name the problem: (select all that apply)
[  ] Adverse drug reaction  
[  ] Abnormal lab value  
[  ] Death  
[  ] Cardiac Arrest/ code 
[  ] Anaphylaxis 
[  ] Sepsis/Infection  
[  ] Blood product reaction
[  ] Unanticipated surgery/procedure  
[  ] Change in status (e.g. increased level of care required)   
[  ] Allergy (non-medication) 
[  ] Fall 
[  ] Injury/Accident (not fall) 
[  ] Specimen collection issue  
[  ] Informed consent issue  
[  ] Ineligible for enrollment  
[  ] Breach of PII 


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114
[  ] Tests/procedures not performed on schedule 
[  ] Other, brief  1-2 word description: _________________________
Detailed Description of the problem: (Include any relevant treatment, outcomes or 
pertinent history):
*Is this problem unexpected? (see the definition of unexpected in the protocol))
__YES __NO  Please explain:
*Is this problem related or possibly related to participation in the research?  
__YES __NO  Please explain:
*Does the problem suggest the research places subjects or others at a greater 
risk of harm than was previously known or recognized?    __YES __NO      
Please explain:
Is this problem? (select all that apply)
[  ] An Unanticipated Problem* that is:       [  ] Serious        [  ] Not Serious 
[  ] A Protocol Deviation that is:                [  ] Serious        [  ] Not Serious
[  ] Non-compliance
*Note if the 3 criteria starred above are answered, “YES”, then this event is also a UP.
Is the problem also (select one) [  ] AE [  ] Non-AE
Have similar problems occurred on this protocol at your site? __YES __NO      
If “Yes”, how many? ____      Please describe:
Describe what steps you have already taken as a result of this problem:
In addition to the NCI IRB, this problem is also being reported to: (select all that 
apply)
[  ] Local IRB
[  ] Study Sponsor
[  ] Manufacturer : ____________________
[  ] Institutional Biosafety Committee 
[  ] Data Safety Monitoring Board
[  ] Other: ____________________________________
[  ] None of the above, not applicable


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INVESTIGATOR’S SIGNATURE:
DATE:  

ICF_003.pdf: 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
  MEDICAL RECORD 
• Adult Patient or     •  Parent, for Minor Patient
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
11-C-0136
  PRINCIPAL INVESTIGATOR:  Christopher Kanakry, M.D. 
STUDY TITLE: 
Multi-institutional Prospective Pilot Study of Lupron to Enhance Lymphocyte 
Immune Reconstitution Following Allogeneic Bone Marrow Transplantation in 
Post Pubertal Adults with Molecular Imaging Evaluation 
Continuing Review Approved by the IRB on 06/05/20 
Amendment Approved by the IRB on 06/0/20 (U) 
 Date Posted to Web:  06/1/20 
Donor 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
RESEARCH STUDY 
• Adult Patient or    •   Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.: 09-25-0099
File in Section 4:  Protocol Consent (1)
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional. 
If you are signing for a minor child, “you” refers to “your child” throughout the consent 
document. 
Description of Research Study 
Your Evaluation for Donation of Cells 
On your first visit to the NIH Clinical Center, you will see a physician and other members of the 
transplant team.  The doctor will take your medical history, perform a physical exam, and 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  2  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
explain the procedure.  Approximately 4 to 10 teaspoons of your blood will be drawn to see if 
you and your relative are a good match.  You and your relative must be a match on six of six 
genetic (hereditary) tests. 
To donate cells, you must be in good health.  If you have symptoms of heart disease, you cannot 
be a donor.  If you have had any heart operations such as a bypass graft or angioplasty, a 
cardiologist must evaluate you and state that you are not putting yourself at risk by donating 
cells.  If you have had cancer you may not be eligible to donate your stem cells. You must not 
have any infection in order to be a donor. 
We will also test your kidneys and liver.  As mentioned above, your blood will also be tested for 
Hepatitis B and C, syphilis, and a virus called cytomegalovirus (CMV).  As part of this study, we 
will test you for infection with the human immunodeficiency virus (HIV), the virus that causes 
AIDS.  If you are infected with HIV you will not be able to participate in this study.  We will tell 
you what the results mean, how to find care, how to avoid infecting others, how we report HIV 
infection, and the importance of informing your partners at possible risk because of your HIV 
infection.  Approximately 6-10 teaspoons of blood will be collected to perform these tests. The 
HIV, T. Cruzi (Chagas agent), and syphilis must be negative to be a donor.  If you have a 
positive Hepatitis B or C test the study doctor will determine if you are allowed to be a donor.  If 
you are a female able to have children, you will have a urine pregnancy test.  Because of health 
risks to the fetus or newborns, pregnant or breastfeeding women cannot be donors. 
We will also schedule an appointment to discuss the anesthesia for the marrow harvest.   
How Stem Cells Are Collected: Your relative can receive the bone marrow of others to help 
them fight their cancer.  That is why we are inviting you to donate cells from your bone marrow 
(called stem cells).  If accepted by your relative’s body, your stem cells will help their body 
begin to grow normal bone marrow cells. 
The stem cells will be collected from the bone marrow in the operating room using anesthesia. 
Bone marrow will be obtained from the pelvis bones in the same way that a standard bone 
marrow test is performed. Needles will be inserted into the pelvis bones and liquid bone marrow 
will be drawn into syringes. The amount that will be collected will be based on the size of the 
transplant recipient and the white blood cell count performed on the bone marrow during 
collection. Approximately 1-2 teaspoons of marrow is required for every pound of recipient body 
weight. As much as 1500 mL (approximately 3 pints) may be needed. The anesthesia options 
(general anesthesia vs. spinal anesthesia), risks, and procedures will be discussed with you prior 
to the bone marrow collection and a separate consent will be obtained at that time. You may be 
admitted to the hospital the night before the bone marrow harvest depending on the scheduled 
time of the collection. You will remain in the hospital for 1 night after the harvest. 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  3  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
The Donation: 
Once it is decided that you can be a donor, we will perform the procedure for immune cell 
collection under anesthesia.  
Within one week after the bone marrow harvest or apheresis procedure(s), you will be checked 
for any side effects at the Outpatient NCI Clinic. 
Research Performed on Donor Cells:  
A small sample of the cell product that we collect will be tested for research purposes.  We will 
remove approximately 5 million cells (less than 1% of the total) and study them to see what 
kinds of cells are in the donation product (for instance how many cells will become T cells or B 
cells).  This will be compared with the cells that the recipient makes after the bone marrow 
transplant.  
Birth Control: 
Men and women who are sexually active on this study must agree to use an effective form of 
contraception (examples include: intrauterine device (IUD), hormonal (birth control pills, 
injections, or implants), tubal ligation/hysterectomy, partner’s vasectomy, barrier methods 
(condom, diaphragm, or cervical cap), or abstinence while participating in this study. 
Alternative Collection of Stem Cells  
If it is not possible to perform the marrow harvest, donor stem cell collection may be performed 
by G-CSF stimulation.  Such cases may involve donors who are medically not eligible to receive 
G-CSF or donors who prefer the marrow procedure relative to the apheresis procedure.  
Risks or Discomforts of Participation 
The main risk of bone marrow harvest relates to the need for anesthesia, which will involve 
either general anesthesia or spinal anesthesia.  The specific risks of these procedures will be 
discussed in a separate consent procedure performed by the anesthesiology department. Bone 
marrow donation is very safe. The procedure commonly causes temporary pain and bruising over 
the sites where the marrow was collected. This usually can be managed with acetaminophen 
(e.g., Tylenol) alone. Occasionally, stronger pain medicines like codeine are required. Rarely, 
infection or bleeding at the needle sites may occur. Anemia due to removal of large amounts of 
bone marrow may require treatment with iron or a blood transfusion. Serious side effects of bone 
marrow harvest are extremely rare and include fat embolism (like blood clots in the lungs) and 
risks of anesthesia. 
For patients who donate cells via apheresis or collection through the vein, there are different 
risks as detailed below. 
G-CSF can cause the following side effects (these side effects stop once G-CSF has been 
stopped): 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  4  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
Likely: 
Less Likely: 
Rare: 
x bone pain,  
x muscle aches,  
x headache  
x Some people who receive G-CSF 
shots and apheresis have a low 
number of blood platelets for a short 
period of time.  Platelets help your 
blood to clot.  However, low platelet 
count from G-CSF has not caused an 
increased amount of bleeding.  To be 
safe, your platelet count will be 
checked during and after the 
apheresis procedure.   
x Other common lab abnormalities 
have been seen but are reversible 
once G-CSF is stopped.   
x allergic reactions,  
x chest pain,  
x lowering of the 
blood pressure     
x There is a very rare 
side effect (1 in 
486,000 people) of 
one’s spleen 
rupturing due to G-
CSF. 
Side effects of blood being drawn include pain and bruising in the area where the needle was 
placed, lightheadedness, or rarely, fainting.  When too much blood is taken, one’s red blood cell 
count may drop causing anemia.  However, the amount of blood that you will donate in this 
study (a total of 20 teaspoons) should not cause anemia.  To be safe, we will check your red 
blood cell level.  If we find that you have anemia, we will give you treatment for this condition 
(in the form of iron tablets). 
Side effects of the apheresis procedure may include low blood pressure.  If this happens, we will 
adjust the apheresis machine to correct this problem.  Other side effects include tingling in the 
mouth, fingers and toes, and mild muscle cramps.  These discomforts can be stopped by 
adjusting or stopping the procedure.  A rare, but potentially severe reaction may occur when 
calcium in the blood is low.  Symptoms include: muscle spasm, facial twitching, abdominal pain, 
and severe feeling of “pins and needles”.  If this occurs, you will be treated immediately with IV 
calcium and the apheresis procedure will stop temporarily.   
Side effects of a temporary I.V. in the femoral vein of the groin (if required) include bleeding, 
bruising, blood clot, or pain where the I.V. was placed.  The I.V. will be placed only by 
physicians with experience in this procedure.  They will discuss the risks with you before the 
procedure. 
Potential Benefits of Participation 
By being a donor, you will provide a source of stem cells and immune cells for your relative.  
Hopefully, your donation of cells will help his or her cancer treatment.  Your participation may 
also help advance our understanding of stem cell transplants and improve the way that we treat 
cancer. 
 
 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  5  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
Alternative Approaches or Treatments 
Collection through your veins after receiving a medication is an alternative approach to 
collection.  For this, we will give you an injection (shot) of a drug called filgrastim or G-CSF for 
short. G-CSF is a protein normally produced by your body in small amounts.  The U.S. Food and 
Drug Administration and the National Marrow Donor Program have both approved G-CSF for 
use in stem cell collection.  It causes your stem cells to travel from your bone marrow into your 
blood. You will receive them in the arm or thigh.  We will teach you or a family member how to 
give you these shots at home.  They will be given for a period of 5, 6, or 7 days.  Usually, you 
will be ready for the apheresis procedure for stem cell collection on day 5.  Once the stem cells 
are in your blood, they can be taken from your veins using a process called apheresis.   An I.V. 
(intravenous catheter) is placed into a vein in each of your arms.  This will mean two 
needlesticks.  Your blood will circulate through a machine that will collect and save your white 
blood cells and stem cells.  The rest of your blood will go back into your body.  The I.V. will be 
removed after the cells are collected.  The whole procedure usually takes 4 to 6 hours.  Apheresis 
avoids the need for an operation that would take the stem cells from your pelvis bone.  It will be 
performed by trained personnel from the NIH Department of Transfusion Medicine. 
Stopping Participation 
The study doctor may decide to stop your participation in this study for the following reasons: 
x If your doctor believes that it is in your best interest 
x If you have request to be withdrawn 
x If new information shows that another treatment would be better for your relative. 
If this occurs, you will be informed of the reason therapy is being stopped. 
What are the costs of taking part in this study? 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
x 
You will receive study treatment at no charge to you. This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, National 
Institutes of Health (NIH), or arranged for you by the research team to be done 
outside the Clinical Center, NIH if the study related treatment is not available at the 
NIH.  
x 
There are limited funds available to cover the cost of some tests and procedures 
performed outside the Clinical Center, NIH.  You may have to pay for these costs 
even if they are not covered by your insurance company. 
x 
Medicines that are not part of the study treatment will not be provided or paid for by 
the Clinical Center, NIH. 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  6  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
Once you have completed taking part in the study, medical care will no longer be provided by 
the Clinical Center, NIH. 
 
Research Subject’s Rights 
It is your choice to participate in this research study.  You may quit the study at any time.  There 
are no penalties for quitting the study.  We encourage you to ask our staff any questions that you 
might have. 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
x will be used for auditing or program evaluation internally by the NIH; or  
x must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
x is necessary for your medical treatment and you have consented to this disclosure;  
x is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
 
Use of Specimens and Data for Future Research  
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 


  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  7  of  9  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that it may be used for future research on any topic and shared broadly for 
research purposes. Your specimens and data will be used for research purposes only and will not 
benefit you.  It is also possible that the stored specimens and data may never be used.  Results of 
research done on your specimens and data will not be available to you or your doctor.  It might 
help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  8  of  9  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
OTHER PERTINENT INFORMATION 
 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Christopher Kanakry, M.D., Telephone: 240-760-6171. You may also call 
the Clinical Center Patient Representative at (301) 496-2626. If you have any questions about the 
use of your specimens or data for future research studies, you may also contact the Office of the 
Clinical Director, Telephone:  240-760-6070.  
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  9  of  9  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 05, 2020 THROUGH JUNE 04, 2021. 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name 
 

ICF_004.pdf: 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
  MEDICAL RECORD 
• Adult Patient or     •  Parent, for Minor Patient
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
11-C-0136       PRINCIPAL INVESTIGATOR: Christopher Kanakry  , M.D.
STUDY TITLE: 
Multi-institutional Prospective Pilot Study of Lupron to Enhance Lymphocyte 
Immune Reconstitution Following Allogeneic Bone Marrow Transplantation in 
Post Pubertal Adults with Molecular Imaging Evaluation 
Continuing Review Approved by the IRB on 06/05/20 
Amendment Approved by the IRB on 06/0/20 (U) 
 Date Posted to Web:  06/1/20 
Recipient 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
•
Adult Patient or
•
Parent, for Minor Patient
NIH-2514-1 (07-09)
P.A.:  09-25-0099
File in Section 4:  Protocol Consent (2)
INTRODUCTION 
We are asking you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
x
Taking part in NIH research is entirely voluntary.
x
You may choose not to take part, or you may withdraw from the study at any time.  In
either case, you will not lose any benefits to which you are otherwise entitled.  However,
to receive care at the NIH, you must be taking part in a study or be under evaluation for
study participation.
x
You may receive no benefit from taking part.  The research may give us knowledge that
may help people in the future.
 Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  
If you have such beliefs, please discuss them with your NIH doctors or research team 
before you agree to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional. 
If you are signing for a minor child, “you” refers to “your child” throughout the consent 
document. 
Why is this study being done? 
We are conducting a study of allogeneic stem cell transplantation from HLA-matched related 
and unrelated volunteer donors for cancers of the blood and immune system.  Because you have 
one of the cancers with which we are concerned and for which transplantation is a possible cure, 
we are inviting you to participate in this pilot trial of lupron to enhance lymphocyte immune 
reconstitution following allogeneic bone marrow transplantation (BMT) in post-pubertal adults 


 
  
CONTINUATION SHEET for either: 
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STUDY NUMBER: 
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CONTINUATION:  page  2  of  23  pages 
 
 
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with molecular imaging evaluation. The cancers with which we are concerned include acute 
myelogenous leukemia, acute lymphocytic leukemia, and high-risk myelodysplastic syndrome.  
One of the issues that often develop after BMT is that the new immune cells don’t work as well 
after transplant in the new host (the recipient of the BMT) as they did before in the donor.  This 
can lead to increased risk for severe infections and a disease called graft-versus-host disease 
whereby the new donor cells can attack and harm healthy organs in the recipient.  This study 
tests whether androgen withdrawal with a medicine called lupron might improve the function of 
the newly transplanted cells.  In addition, some participants in this study may also undergo a type 
of nuclear medicine imaging (similar to a PET scan) called FLT that may reveal how well the 
transplant is progressing and whether the cells are growing properly inside the bone marrow.   
 
Why are you being asked to take part in this study? 
 
You are being asked to participate in this study because you have acute myelogenous leukemia, 
acute lymphocytic leukemia, or high risk myelodysplastic syndrome for which transplantation is 
a potential cure and you meet the criteria for enrollment.  You may receive chemotherapy on this 
protocol first if either: 1) you are not in remission or 2) if you require a donor search and it is 
likely that your disease will come back before we can identify a donor.  If your doctors have not 
previously identified an HLA-matched donor, we will perform a search to identify a match.  If 
you have siblings, we will test these individuals first.  If you do not have siblings, or they are not 
a match, we will search the bone marrow donor registries such as the National Marrow Donor 
Program.  To be eligible to proceed to BMT on this study, you must match a relation or an 
unrelated donor on 8/8 or 7/8 HLA markers.  
  
How many people will take part in this study? 
 
Up to 236 people (118 patients/118 donors) will take part in this research study. 
 
Description of Research Study 
Bone Marrow Transplantation and Donor Search  
Donor Search 
It is first necessary for us to find a suitable (HLA-matched) donor.  About 5 to 10 tablespoons of 
blood will be drawn to check how closely you and your potential donor are genetically matched. 
Often this blood test has already been performed at your home medical office prior to a visit to 
the NIH or it will be performed at the NIH Clinical Center.  In this study, we will accept 
recipient patients 9 to 55 years of age. 
Rarely, a volunteer donor may become unavailable or the donor center is unable to collect 
enough stem cells to perform the transplant.  If this happens, you will be removed from the study 


 
  
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CONTINUATION:  page  3  of  23  pages 
 
 
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before transplantation unless we are able to identify another suitable unrelated donor.  If you 
have already received the conditioning chemotherapy, you will still be removed from the study, 
but we will continue to care for you. 
  
We will explain to you the choice of your donor once we have this information.  
 
Bone marrow transplantation  
The process of bone marrow transplantation involves killing your own bone marrow cells and 
then receiving matched cells from another individual.  Bone marrow cells are called 
hematopoietic (meaning blood) stem cells (meaning immature).  These cells live within our bone 
marrow and produce white blood cells that fight infections, red blood cells that carry oxygen, 
and platelets that help us clot.  When these bone marrow cells are taken from one person (called 
the “donor”) and given to another person (called the “recipient”), it is known as “allogeneic” 
stem cell or bone marrow transplantation (BMT).  Allogeneic BMT benefits many patients with 
high risk leukemias because: 1) we can rid the body of most of the leukemia cells, 2) the new 
donor cells may recognize and kill cancer cells, termed graft-versus-leukemia effects.  
  
BMT Preparative regimen  
Allogeneic stem cell transplantation (SCT) has been used successfully to treat, and sometimes 
cure, many kinds of cancer or pre-cancerous conditions that develop in blood or immune system 
cells.  For patients who are receiving a SCT for the first time, to deplete your own cells, we will 
use a standard preparative regimen including radiation and chemotherapy.  The radiation is total 
body irradiation, meaning that the whole body is exposed to the radiation.  The lungs will be 
protected during this process.  The chemotherapy for the BMT will be cyclophosphamide.  For 
patients who have received SCT before and those who can’t tolerate radiation therapy, we may 
use a combination of chemotherapy agents such as busulfan and fludarabine or 
cyclophosphamide.  In this way, your bone marrow cells will die.  Then, we will give you new 
healthy cells from your donor in a blood transfusion that will find their way into your bones and 
begin to grow into white blood cells, red blood cells and platelets.  We call this engraftment.  
 
The side effects of cyclophosphamide chemotherapy as part of BMT are: immediate (within 1-2 
days) anorexia, nausea, vomiting, metallic taste, difficulty with salt management and rarely 
transient blurred visions and heart problems; within 2-3 weeks, lower white blood cell counts, 
hair loss, and occasionally red blood in the urine can occur; delayed reactions can include 
gonadal dysfunction (sterility), occasionally lung problems called pulmonary fibrosis, and rarely 
second cancers and bladder fibrosis.  
 
The side effects of radiation are usually nausea, mucositis, pain with eating, occasionally, 
hypothyroidism, cataracts, lung problems, kidney problems, and rarely secondary cancers.   
 


 
  
CONTINUATION SHEET for either: 
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STUDY NUMBER: 
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CONTINUATION:  page  4  of  23  pages 
 
 
PATIENT IDENTIFICATION 
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BMT Complications  
The number one risk of death after BMT is your cancer.  If your cancer comes back after BMT, 
we will try to treat it by either helping the new immune cells work better to kill the cancer or 
giving other therapies.  However, this remains a significant risk even with the BMT.  
 
Rarely, the new cells do not engraft or continue to grow within the recipient.  This is called graft 
rejection.  When this happens, one of two things occurs.  Either your own cells will manage to 
grow back, or you will require new donor cells and possibly more chemotherapy to survive.  
 
More commonly, we observe a problem termed graft versus host disease (GVHD).  In this 
disease, the new donor cells recognize pieces of you as foreign and attack your healthy tissues.  
This can occur early after transplant with one type of disease, and later after BMT with different 
kinds of problems.  Most often when this occurs early after BMT, termed acute GVHD, the 
donor cells attack the gut leading to diarrhea and weight loss, the skin leading to a rash, or the 
liver with elevated liver enzymes.  When GVHD occurs later after BMT, termed chronic GVHD, 
patients can develop many symptoms including: dry eyes, dry mouth, rashes and skin changes, 
liver enzyme elevation, mouth ulcers, diarrhea.  Rarely, chronic GVHD can lead to life-
threatening complications such as lung GVHD, sclerotic skin GVHD, and liver failure.   
 
The risk of GVHD increases when the donor and recipient are not matched perfectly.  Cells are 
matched by markers are called “human leukocyte antigens”, or HLA.  A person inherits half of 
his or her HLA markers from each parent.  Your immune system uses HLA proteins on your 
body’s cells to tell the difference between normal, healthy tissues and foreign organisms like 
bacteria or viruses.  Differences in HLA proteins between a donor and recipient make it more 
likely that one person’s immune system will recognize the other person’s cells as foreign, 
causing graft rejection or GVHD.  A donor and recipient who share all 8 of their HLA markers 
are called “HLA-identical”.  A transplant from an HLA-identical sibling (brother or sister) has a 
lower chance of graft rejection or GVHD, compared with other donors for allogeneic SCT.  
Many people have cancers that could be treated with allogeneic SCT, but only 20-30% of people 
have HLA-identical sibling donors.  For some people without HLA-identical sibling donors, an 
HLA-matched unrelated donor can be used, but the risk of graft rejection and GVHD is higher.  
Patients on this study with a partial genetic match (7/8 HLA genes) with their unrelated donor 
may have a modestly higher risk of complications compared to subjects with a full genetic match 
with their unrelated donor (8/8 HLA genes).   
  
Drugs can prevent GVHD after allogeneic BMT, but they do not work all the time. 
 
 
 


 
  
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Prevention of Graft-Versus-Host Disease 
This study will use standard GVHD prophylaxis for myeloablative BMT: methotrexate and 
tacrolimus.  Methotrexate is a chemotherapy agent that is used to diminish rapidly dividing T 
cells, the cells that have been shown to cause GVHD.  Patients will receive 4 doses on 4 days of 
this medication after BMT.  Side effects of methotrexate include: sore throat, chills, fever, signs 
of infection, unusual bruising or bleeding, excessive tiredness, pale skin, shortness of breath, 
liver damage, lung damage, mucositis, stomach ulcers, diarrhea, black tarry stools, vomiting, 
rash, peeling skin, dizziness, drowsiness, headache, swollen tender gums, decreased appetite, 
reddened eyes, hair loss, blurred vision or sudden loss of vision, seizures, confusion, weakness or 
difficulty moving one or both sides of the body, loss of consciousness.   Tacrolimus is a 
medication that prevents T cells from attacking foreign organs (GVHD).  It may cause: fever, 
sore throat, cough, extreme tiredness, warm, red, painful skin, increase the rate of infections, 
headache, uncontrollable shaking in a part of the body, diarrhea, constipation, nausea, vomiting, 
heartburn, stomach pain, loss of appetite, difficulty falling asleep or staying asleep, dizziness, 
weakness, back or joint pain, burning, numbness, pain or tingling in hands or feet, hives, rash, 
itching, difficulty breathing or swallowing, decreased urination, pain or burning on urination, 
swelling of arms, hands, feet, ankles or lower legs, weight gain, unusual bleeding or bruising, 
seizures, coma.  
BMT Research Design 
We are trying to improve the results of allogeneic BMT by improving: 1) the new donor immune 
system’s function; and 2) ways that we identify how well the transplant worked.  
The methods we are testing in this research study include: 
x Lupron is a drug that suppresses androgen production for a period of time.  For females, 
this means that you will have less estrogen in the blood.  For males, this drug lowers 
testosterone levels.  Lupron is already used for females undergoing chemotherapy and 
BMT.  During BMT when the platelet count is lower, it is not safe to have a period.  
Lupron is one of the agents we use to prevent menses.  Lupron also affects the immune 
system.  In mice and men, lupron has been shown to improve the development and 
function of T cells, a white blood cell that is important for graft-versus-tumor effects, 
graft-versus-host disease, and to fight infections.  All females on this protocol will 
receive lupron 2 weeks prior to BMT.  For first SCT, half of the men will receive lupron 
2 weeks prior to BMT.  For 2nd SCT, all of the men will receive Lupron.  This is 
delivered as a single shot that lasts for 3 months for men and women younger than 18 and 
4 months for those older than 18.  We will then perform blood tests and monitor for 
GVHD to determine whether lupron was helpful in the recovery of the immune system 
and led to fewer complications of BMT.  Patients may receive further doses of lupron if 
clinically indicated.  


 
  
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STUDY NUMBER: 
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CONTINUATION:  page  6  of  23  pages 
 
 
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x For patients >18 years of age; FLT is a nuclear medicine imaging test; it stands for 3’-
deoxy-3 18F-fluorothymidine, the scientific name of the reagent.  During this test, patients 
will receive an injection of a FLT and undergo imaging on a special machine.  The 
pictures will reveal what the cells inside the marrow look like, letting us ‘see’ whether the 
new cells are engrafting and recovering after the BMT.  This test would be very useful 
for patients who engraft slowly, to tell us if they are engrafting slowly or not at all.  In 
addition, some patients who are not in remission will be asked to undergo this test to help 
us learn if we can detect leukemia using this test too.  This test has been used in patients 
who received high doses of chemotherapy and radiation for other cancers.   
1. For BMT whether first or 2nd: 23 patients for first BMT and 16 for 2nd SCT, who 
are >18, will undergo FLT will receive up to 5 FLT images of which 2 will be 
accompanied by PET/CT.  Images will be performed for 1st BMT: on day -1, day 
+5 or +9 with FLT alone.  On day 28 and another time point to be determined by 
evidence of immunologically important events (such as thymus immune recovery 
or GVHD), FLT and PET/CT will be performed.  After these 23 patients, newly 
accrued patients will undergo a single FLT scan greater than 1 year after 
transplant.  For 2nd BMT: 2, FLT images will be performed alone on day -1, and 
include day +28 and +60 with PET/CT as well.  If you relapse after the 2nd BMT, 
we will image at the time of relapse and after immunotherapy (if you receive it) 
with FLT and PET/CT.  
2. The PET scan is a clinical test that is used to monitor for certain cancers.  It 
requires patients to fast several hours before and then gives a radioactive glucose 
(sugar) through an IV followed by imaging in a scanner.  Because cancer and 
inflammatory cells have increased metabolism and use more glucose than 
neighboring cells, these cells will take up more of the radioactive glucose and be 
easily seen on PET scan.  Patients who undergo this PET scan will receive the IV 
radioactive glucose and then be asked to lie quietly in a darkened room for 30 
minutes.  Then, the patient will be asked to urinate.  After this, we will perform 
the scan.  The scan takes approximately 1 hour and is painless, but you may feel 
sore after lying in the scan.  You will be asked to urinate approximately 90 
minutes after the radioactive sugar is given. 
3. The FLT scans are performed in a similar way.  This scan involves the use of a 
radioactive chemical (fluoro-thymidine) injected into an IV, followed by a scan 
similar to a CT scan.  Thymidine is normally found in DNA.  Dividing cells will 
take up the radioactive thymidine, and cells that are not dividing should not take 
up any thymidine.  Because more cancer cells are dividing and new bone marrow 
transplant cells should also be dividing, these should take up radioactive 
thymidine more than surrounding cells, and should be easily seen on the FLT PET 
scan.  Patients who undergo this test will receive a dose of FLT through an IV, 
and then be asked to lie in a darkened room for 30 minutes.  After 30 minutes, we 


 
  
CONTINUATION SHEET for either: 
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NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
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STUDY NUMBER: 
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CONTINUATION:  page  7  of  23  pages 
 
 
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File in Section 4:  Protocol Consent 
 
will ask you to urinate.  This will help reduce the dose to the bladder.  We will 
then begin the scan.  The scan takes approximately 1 hour and is painless, but you 
may feel sore after lying on the scanner.  We will ask you to urinate 
approximately 90 minutes after the IV dose.   Side effects are discussed below (in 
the side effects section of this document).  
What will happen if you take part in this research study? 
 The following will be done as part of this research study (details are included in later sections): 
x First, we will determine if you are in remission and initiate chemotherapy if needed.  Some 
patients may undergo FLT imaging of relapsed leukemia.  
x Next, we must establish proof of a full genetic match (8/8 HLA genes) or partial genetic 
match (7/8 HLA genes) between you and your potential related or unrelated donor. 
x We will arrange to have your donor’s stem cells collected here if you have a sibling or at a 
center in cooperation with the National Marrow Donor Program. 
x After you have a match and are in remission, you will receive lupron if you are a female or 
have been randomized to do so as a male.  
x Then, all patients will receive the “conditioning regimen,” to prepare you for the transplant, 
which includes cyclophosphamide and total body irradiation.  
x If you are a patient with MDS and your counts did not recover after receiving chemotherapy 
you will receive a lower dose “conditioning regimen” to prepare you for transplant, which 
includes fludarabine and total body irradiation. 
x After this transplant chemotherapy, you will receive the transplant with your unrelated 
donor’s stem cells and immune cells. 
x All patients will receive GVHD prophylaxis.  Some patients may receive intrathecal 
chemotherapy (if there was evidence of the leukemia in the spinal fluid).  
x Patients who have agreed to undergo FLT imaging will be imaged before the cells are given 
(BMT) and at 3 time points after.   
x You will be hospitalized approximately 4 weeks after your transplant. 
x When the study doctors think your condition is stable, you will be discharged from the 
hospital and be seen frequently at the NIH as an outpatient. 
x You will continue on medications at home to lower the risk of GVHD and infections. 
x You may receive additional cells from the donor after the transplant; these additional cells 
are given to help to rebuild or enhance your immune system. 
x You will visit our clinic regularly for the first six months after the transplant, and then less 
often for at least five years. 
  


 
  
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Pre-Transplant Evaluation 
 Once it is determined that you have a potential donor, you will be seen at the NIH Clinical 
Center, at which time you will have a complete medical history and physical examination in the 
NCI Medical Oncology Clinic.  Members of the transplant team will review your medical history 
and explain the transplant procedure.  A blood sample will also be used to check the health of 
your kidneys and liver.  We will also test for exposure to a variety of infections, including 
hepatitis B and C, syphilis, and a virus called cytomegalovirus (CMV).  As part of this study, we 
will test you for infection with the human immunodeficiency virus (HIV), the virus that causes 
AIDS.  If you are infected with HIV you will not be able to participate in this study.  We will tell 
you what the results mean, how to find care, how to avoid infecting others, how we report HIV 
infection, and the importance of informing your partners at possible risk because of your HIV 
infection.  You will also be tested for the following viruses: hepatitis A, HTLV-1 and -2, 
adenovirus, Epstein-Barr virus, herpes simplex virus, and the parasite Toxoplasma. A total of 
approximately 4-12 teaspoons of blood will be collected.  If the study doctor feels it is necessary, 
you will have a PPD skin test (to test for tuberculosis).  You will be asked to collect your urine 
for 24 hours to measure your kidney function.  If you are a woman, you will have a urine test for 
pregnancy. If you are a woman who is breast-feeding or pregnant, you may not take part in this 
study because we don’t know how the transplant will affect your baby or unborn child.  If you 
think that you or your partner is pregnant, you should tell your study doctor or nurse 
immediately.   
  
In addition, you will have a special breathing test, a test for heart health, and several X-ray 
studies, including a CT scan of your chest, abdomen, pelvis, and possibly your neck.  You will 
have a CT scan or MRI of your head. You will also have a bone marrow aspiration and biopsy.  
This test is performed by numbing the iliac (pelvis) bone with a local numbing medicine called 
lidocaine.  A small cut will be made in the skin, a needle is inserted into the pelvis bone, and 
about two tablespoons of liquid samples are removed from the bone marrow through the needle.  
A small fragment of the bone marrow may also be removed with the needle. If you are at risk of 
having your cancer involve the brain or central nervous system, you may also have a spinal tap 
(also known as a lumbar puncture). A thin needle is then inserted into your spinal canal and a 
small amount (about 5 tablespoons) of spinal fluid is removed. You will also be seen by a 
dentist, and meet with a social worker.  You will be encouraged to name someone as your 
“durable power of attorney”.  This should be someone whom you trust to make medical 
decisions for you if you become physically or mentally unable to make your own treatment 
decisions.  You should know that being in this study may keep you from being in other research 
studies that limit the number or types of treatments that you are allowed to have received 
previously. 
 


 
  
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The Central Venous Catheter 
If you do not already have one before you enroll in this study, you will receive an intravenous 
(I.V.) line placed in the upper part of your chest and tunneled under the skin into a neck vein.  
This line is called a central venous catheter that can be used throughout your transplant 
procedure and follow-up treatment.  This kind of catheter is sometimes called a “Hickman 
catheter”.  If the catheter becomes infected or clogged, it can be replaced.  It will be flushed once 
daily to prevent clogging.  The nursing staff will teach you how to do this yourself. 
 The catheter will be used to give you chemotherapy, your transplant, blood transfusions (if 
needed), and other medications such as antibiotics.  It can also be used for drawing blood 
samples for tests.  Since blood will be drawn often during your treatment, the catheter will make 
it easier and less painful.   
  
Transplantation of the Blood Stem Cells from Your Donor 
Before you begin your induction chemotherapy, your related or unrelated donor will have had a 
medical examination by a doctor at NIH or in the National Marrow Donor Program (NMDP) 
network and laboratory studies that include extensive testing to make sure they do not have any 
of the following: HIV, Hepatitis B, Hepatitis C, and possible infectious diseases that may be 
transmitted by stem cell donation.  The donor’s exam will also ensure that they remain available 
and are physically well enough to undergo the donation procedure.  The NMDP will notify NIH 
if there are any abnormalities that increase the risk of transmitting infectious diseases to you 
during the transplant.  These findings will be discussed with you.  The donor’s medical clearance 
will be verified by the NIH study doctor before you receive any chemotherapy.  
If you have an unrelated donor, the identity of the donor is confidential and the donor will be 
anonymous.  This means that you will not know who your donor is or where they are.  You will 
know the age and gender of the donor and any history or medical exam findings that could 
possibly change the risk of your transplant.  Likewise, the donor will not know who you are or 
where you are.  He/she will know your age, gender, and the type of disease that you have.  The 
donor will be given basic updates about your condition 30 days, 6 months, and 1 year after your 
transplant.  The only information they will receive is whether or not the stem cells “engrafted” 
(taken hold), and if you have been discharged from the hospital.  The donor will also be notified 
in the event of your death.  
 
Depending on the policy of the particular donor center, you may be able to communicate without 
revealing your identities in an anonymous manner with your donor beginning at the time of your 
transplant.  In some cases, if both you and the donor agree, you may be able to learn who your 
donor is after one year.   There are some cases when a donor and patient may never communicate 
or meet.  Your transplant coordinator will tell you the details of if and how you may contact the 
donor once the donor has completed his or her medical exam. 


 
  
CONTINUATION SHEET for either: 
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STUDY NUMBER: 
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CONTINUATION:  page  10  of  23  pages 
 
 
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File in Section 4:  Protocol Consent 
 
  
Transplant Procedures 
 All females and ½ of the male (randomized) will receive lupron 2 weeks prior to BMT.   
 
You will be admitted into the hospital approximately seven days before transplantation.  You 
will receive either 4 days of irradiation followed by 2 days of cyclophosphamide transplant 
chemotherapy or 3 days of Fludarabine followed by 1 day of irradiation. Two days after 
completing this chemotherapy you will receive the stem cell transplant.  Your donor’s stem cells 
will be infused through your central venous catheter.  This is referred to as “day 0”. 
  
While you are in the hospital for your transplant, you will be monitored very closely for possible 
complications, which are described below.  You will receive drugs to help prevent and/or treat 
infections, blood transfusions, and intravenous nutrition (if needed).  Blood will be drawn 
frequently during your treatment.  Your blood will be tested to monitor your health during and 
after the chemotherapy and transplant procedure.   In general, 4 to 10 teaspoons of blood will be 
drawn an average of 2 to 3 times per week.  Some blood will be drawn for research purposes.  In 
general, 3 to 4 tablespoons of blood will be drawn for research on average of once per week for 
the first 100 days after transplant. 
  
The average time you will stay in the hospital is four weeks after transplant, but it could be 
longer if there any complications. 
  
You will receive methotrexate and tacrolimus to prevent GVHD before and after your transplant. 
Beginning three days before you receive the stem cell transplant, you will receive tacrolimus to 
help prevent GVHD. Tacrolimus is given either through an I.V. or by mouth once a day for 
approximately six months after transplant.  Methotrexate is given for four doses intravenously 
(through the vein) before you are discharged from the hospital, shortly after the transplant.   
 
Some patients will undergo FLT and PET imaging during the preparative regimen, at day 5 post-
transplant, at day 28 post-transplant, and at a later time point to correspond with the development 
of immune system (thymus) or GVHD.  
   
Once the stem cells have taken hold and you are strong enough, you will be discharged from the 
hospital and followed closely as an outpatient.    You will be required to remain in the 
Washington, D.C. area for approximately three months after transplantation so the NIH doctors 
can monitor you in case of any complications.  You may require re-admission to the hospital for 
complications.  You will be followed by the doctors in the NCI clinic for the first six months 
after transplant, and then you will be followed less frequently for at least five years.  


 
  
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After the transplant, if tests show that your blood and immune cells have not fully converted to 
your donor’s type (“mixed chimerism”), then the drugs you are taking to prevent GVHD will be 
lowered to help change your blood and immunity to full donor chimerism. If your cancer is still 
present or grows after the transplant, tacrolimus may be reduced in an attempt to permit a 
stronger graft-versus-leukemia effect. 
 
Frequent Follow-up at the NCI in the First Year after Transplant 
If you are in good health after the three month period after your transplant, you will then be 
allowed to return home to the care of your primary physician.  You will be required to return to 
the NIH monthly until approximately six months after transplantation so you can be monitored 
for late transplant complications including GVHD and infection.  Thereafter you will be seen at 
NIH every three months until you are two years after transplant.  At each visit when you return 
to NIH, you will have a physical exam and blood draws (approximately 4-10 teaspoons of blood 
will be taken).  During some visits you may have a bone marrow aspirate and biopsies, and other 
appropriate tests (for example:  CT, MRI, PET scan) to monitor disease status.  Study-related 
medications will be provided by the NIH during your hospital stay and after you leave the NIH.  
As part of your post-BMT care, you will be given vaccinations.  Because your old immune 
system is gone, we will need to vaccinate the new immune system which is standard of care. As 
part of this process, we will test to be sure that your new immune system is mature enough to 
benefit from the vaccines and we may give another vaccine if the new immune system is not yet 
mature enough to respond.  
 
Risks or Discomforts of Participation 
 Risks of Lupron  
 
Lupron has been used in female patients receiving BMT.  Male patients will be randomized in 
this study to receive lupron or not. It is administered as a single intramuscular injection 2 weeks 
prior to BMT.   
 
Side effects include:  
Likely  
Less Likely 
Rare but Serious 
x Testicular Atrophy 
x Hot flashes/sweats 
x  Generalized pain 
 
x Headache 
x Weakness 
x Injection site reaction 
x Stomach complaints 
x Joint problems 
x Abscess 
x Allergic reaction  
x Blood clot 
x Abnormal heart beat 
x Gastrointestinal bleeding 


 
  
CONTINUATION SHEET for either: 
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STUDY NUMBER: 
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CONTINUATION:  page  12  of  23  pages 
 
 
PATIENT IDENTIFICATION 
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File in Section 4:  Protocol Consent 
 
Likely  
Less Likely 
Rare but Serious 
x Dizziness 
x Flu syndrome 
x Dehydration 
x Pins and needles feeling  
x Breathing issues  
x Neuromuscular disorders 
x Skin reaction  
x Urinary problems  
x Low oxygen 
x Confusion  
x Neurological problems 
 
 
Risks of Fludarabine:  
Likely 
Less Likely 
Rare 
x low blood counts  
x lowered level of 
immune cells   
x increased risk of 
infection 
x nausea and vomiting  
x diarrhea  
x fever  
x mouth sores  
x loss of appetite  
x swelling (edema)  
x skin rash  
x muscle aches  
x headache 
x agitation  
x hearing loss 
x fatigue  
x weakness  
x numbness / tingling (“pins and 
needles”) 
x GI bleeding  
x lung damage  
x kidney damage 
x severe neurologic (brain 
and/or spinal cord) toxicity 
has occurred after very 
high doses including: 
blindness, deterioration of 
mental status, and death. 
 
Risks of Cyclophosphamide:  
Likely 
Less Likely 
Rare 
x low blood counts  
x hair loss 
x nausea and vomiting  
x painful 
and 
bloody 
urination 
x sterility 
x water retention 
x heart damage  
x secondary leukemia (a 
different 
type 
of 
cancer) 
x skin rash 


 
  
CONTINUATION SHEET for either: 
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NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
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CONTINUATION:  page  13  of  23  pages 
 
 
PATIENT IDENTIFICATION 
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NIH-2514-1 (10-84) 
 
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P.A.: 09-25-0099 
 
 
File in Section 4:  Protocol Consent 
 
 
Risks of Busulfan: 
Likely 
Less Likely 
Rare 
x Low blood counts  
x Hair loss 
x Nausea and vomiting  
x Sterility 
 
x Secondary leukemia (a 
different type of 
cancer) 
x Skin rash 
 
Risk of Radiation (not including the Total Body Irradiation from BMT)  
The risks of FLT and FDG scanning are primarily risks of radiation.  The radiation exposure that 
is for research purposes is from PET/CT scanning with FLT and FDG.  The maximal amount of 
radiation you will receive in this study is from 5 injections (maximum 3 mCi per injection) FLT 
and 2 injections FDG (maximum 5 mCi per injection).  The NIH Radiation Safety Committee 
has reviewed the use of radiation in this research study, and although the radiation exposure 
exceeds the annual guideline of 5 rem, has approved its use as involving acceptable risk to obtain 
the information desired.  Although each organ will receive a different dose, the maximum 
amount of radiation exposure that you will receive is equal to a uniform whole-body exposure of 
6.2 rem.  The average person in the United States receives an annual radiation exposure of 0.3 
rem from natural sources such as the sun, outer space and the earth’s air and soil.  If you would 
like more information about radiation, please ask the investigator for a copy of the pamphlet an 
Introduction to Radiation for NIH Research Subjects. 
 
While there is no direct evidence that the amount of research radiation exposure received in this 
study is harmful, there is indirect evidence that it might not be completely safe.  There may be a 
very slight risk of cancer; which is less than the risk for the BMT itself. 
 
Please tell your doctor if you have taken part in other research studies or received care at the NIH 
or other places/hospitals where radiation was used.  This way we can make sure that you do not 
receive too much radiation.  Consider x-rays taken in radiology departments, cardiac 
catheterization and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body. 
 
If you are pregnant or breastfeeding, you will not be permitted to participate in this research 
study.  It is best to avoid radiation exposure to unborn or nursing children, since they are more 
sensitive to radiation than adults.   
 


 
  
CONTINUATION SHEET for either: 
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STUDY NUMBER: 
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CONTINUATION:  page  14  of  23  pages 
 
 
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Risk of Death from Allogeneic SCT:   
Patients undergoing allogeneic SCT are at risk of dying from the transplant procedure and its 
possible complications.  In some studies of allogeneic SCT, as many as half of the patients died 
as a direct result of the transplant or its complications.  In transplant studies similar to this one, 
up to 50 percent of patients have died from the transplant procedure.  The risk of death or other 
complications can vary greatly, depending on the age of the patient, the way the transplant is 
performed, and other factors.   
 
Other risks from allogeneic SCT include: 
Veno-Occlusive Disease (VOD) - A severe liver complication known as VOD occurs in 
less than 5 percent of allogeneic transplants.  VOD is a chemotherapy side effect that 
causes blood vessels in the liver to be blocked.  Severe VOD can lead to liver failure and 
death. 
  
Graft Rejection:  There is a chance that you may reject your donor’s stem cells. There is 
the rare possibility that your own cells may recover.  This may result in prolonged low 
blood counts, which may result in infection or bleeding and may lead to death.  In this 
event, we would attempt to re-transplant you.   
  
Graft-Versus-Host Disease (GVHD):  You will be at risk for the development of 
GVHD for the rest of your life after transplantation.  GVHD occurring within the first 
100 days after transplantation is referred to as acute GVHD.  Acute GVHD most 
commonly attacks the liver, intestines, and skin.  Symptoms of skin GVHD may be as 
mild as a rash with itching, or as severe as blistering and loss of the skin.  Symptoms of 
intestinal GVHD may be as mild as heartburn and mild diarrhea, or as severe as cramping 
abdominal pain and bloody diarrhea.  Liver GVHD may be as mild as slight disturbances 
in liver function, or severe as jaundice (yellowing of the skin) with liver failure.  Mild 
GVHD (skin rash only) can be treated with steroid creams that you apply on your skin.  
Severe GVHD can be very dangerous and needs to be treated aggressively.  Treatment of 
severe GVHD initially includes weakening of the immune system, usually with 
intravenous (I.V.) steroids.  Weakening of the immune system increases the risk of 
infection. 
  
A delayed form of GVHD, known as chronic GVHD, may occur after day 100 post-
transplant.  Some degree of chronic GVHD affects about half of patients after 
transplantation.  It most commonly attacks the skin, the liver and the intestines, but it may 
also affect other organs such as the lungs, eyes, muscles, joints, and the bone marrow.  
Symptoms of chronic GVHD may include dryness of the mouth and eyes, a loss of 


 
  
CONTINUATION SHEET for either: 
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STUDY NUMBER: 
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CONTINUATION:  page  15  of  23  pages 
 
 
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File in Section 4:  Protocol Consent 
 
appetite, weakness, hair loss, weight loss, liver damage (including yellowing of the skin), 
and lung damage leading to shortness of breath and cough.  Patients with severe chronic 
GVHD are also at increased risk of infection and death.  Chronic GVHD is also treated 
with drugs that weaken the immune system such as steroids.  Taking steroids may 
increase your risk of infection. 
  
Late Transplant Complications:  There are other potential complications that can occur 
long after transplantation.  These complications could affect any organ in the body 
including the heart, lungs, kidneys, liver, muscles, and brain.  Rarely, patients who 
receive an allogeneic SCT are at risk for developing a second cancer such as leukemia or 
lung cancer. 
  
Other complications are also possible following your transplant.  The most common 
complication is infections.  Because you will be receiving drugs (e.g. cyclosporine) that 
weaken the immune system, you are at greater risk to develop infections from uncommon 
organisms.  These infections can be life-threatening, and could cause death. 
  
There is about a 40 percent chance of death from complications of conventional 
allogeneic bone marrow transplants. There is also the risk of complications that cannot be 
predicted. 
  
Bone Marrow Aspiration and Biopsy:  This procedure usually causes only mild pain for a 
short time at the biopsy site.  Very rarely, bleeding or an infection may occur at the biopsy site. 
Blood Draws: Side effects of blood draws include pain and bruising in the area where the needle 
was placed, lightheadedness and rarely, fainting.  When a large amount of blood is drawn, your 
red blood cell count may drop causing anemia. Anemia can cause a lack of energy and other 
symptoms.  Transfusions of red blood cells are sometimes needed to treat anemia.     
 
Central Venous Catheter:  Side effects of placing a central venous line in your chest wall 
include bleeding, bruising, blood clot, or pain in the area of insertion.  This line will be placed by 
physicians with experience in this procedure.   These physicians will discuss the above risks at 
the time of the line insertion.  Rarely, placement of a central venous catheter can result in a 
collapsed lung.  If a collapsed lung occurs, it may require hospitalization and temporary insertion 
of a plastic tube in your chest to re-expand the lung. 
  
Transplantation Chemotherapy: Potential side effects of chemotherapy and TBI are described 
above. 
  
Graft-versus-Host Disease Prevention: As described above, you will receive tacrolimus and 
methotrexate, to prevent GVHD.  Side effects are described above. 


 
  
CONTINUATION SHEET for either: 
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STUDY NUMBER: 
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CONTINUATION:  page  16  of  23  pages 
 
 
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File in Section 4:  Protocol Consent 
 
   
Stem Cell Infusion:  The donor cells may be frozen with a chemical called DMSO to protect 
them from the effects of freezing.  Patients receiving thawed cells often develop side effects from 
the DMSO.  DMSO side effects may include fever and allergic reactions, such as skin rash, 
itching, difficulty breathing, and low blood pressure.  Although not harmful, this agent does have 
an odor similar to garlic that dissipates in 24 hours.  These reactions are usually mild and 
temporary, and they can be easily treated with IV fluids and medications. Products may also be 
contaminated with bacteria or red blood cells.  Every effort is made to collect cells in sterile 
fashion and reduce red blood cells (if needed); however, you may need to receive fluids or 
antibiotics should this be needed.   
  
Other Medications:  You will routinely receive several other drugs to prevent or treat various 
infections and other transplant-related complications.  These medications and their common side 
effects are listed as follows: 
  
Ursodeoxycholic acid: Ursodeoxycholic acid, also known as ursodiol, can cause nausea, 
vomiting, “heartburn”, a metallic taste, abdominal pain, an inflamed gallbladder, constipation, 
mouth pain, flatulence, diarrhea, itching, rash, dry skin, hives, headache, fatigue, anxiety, 
depression, and sleep disorders. Less common side effects include sweating, thinning of hair, 
back pain, muscle and joint pains, runny noses, and cough. 
  
Diphenhydramine may cause tiredness, dizziness, upset stomach, disturbed coordination, dry 
mouth, flushing, or difficulty urinating. 
  
Valacyclovir can cause nausea, vomiting, headache, dizziness, abdominal pain, bone pain, 
allergic reactions, mild liver inflammation, kidney injury, and abnormal nervous system 
function. 
  
Fluconazole can cause nausea, vomiting, headache, skin rash, abdominal pain, and diarrhea.  
Rare but sometimes serious liver toxicity has also been reported.  Fluconazole can increase the 
blood levels of other drugs, which can increase their effectiveness and/or their side effects. 
  
Trimethoprim/sulfamethoxazole (Bactrim) may cause nausea, vomiting, loss of appetite, allergic 
skin rashes, and suppression of bone marrow function.  Rare but severe reactions may affect the 
skin and bone marrow; these have sometimes been fatal. 
  
Reproductive Risks:  This treatment is likely to result in sterility (the inability to produce 
children).  However, we cannot predict for certain that you will become sterile during this 
treatment.  It is unknown what effects the chemotherapy and other drugs included in this 
treatment may have on an unborn child, but they would most likely be harmful.  For this reason, 


 
  
CONTINUATION SHEET for either: 
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NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
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STUDY NUMBER: 
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CONTINUATION:  page  17  of  23  pages 
 
 
PATIENT IDENTIFICATION 
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NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
File in Section 4:  Protocol Consent 
 
if you have not been placed on a contraceptive (birth control) as part of this study, you will need 
to use an effective form of contraception while on this study, and for one year after transplant 
(examples include: intrauterine device (IUD), hormonal (birth control pills, injections, or 
implants), tubal ligation/hysterectomy (self or partner), partner’s vasectomy, barrier methods 
(condom, diaphragm, or cervical cap), or abstinence.   
 
Potential Benefits of Participation 
This study has the potential to: 1) cure your cancer; 2) improve your immune system function 
after transplantation, diminishing the risks of transplant including GVHD and life-threatening 
infections; 3) improve the ways that we evaluate the success of bone marrow transplantation 
through imaging.   
 
The chemotherapy you receive may cause improvement in your cancer, although it is not likely 
to result in a cure by itself.  The allogeneic SCT may improve the chance that your disease will 
enter into a long remission and possibly be cured.  However, you should understand that this 
cannot be guaranteed.  In addition, your participation in this study may contribute to 
understanding and developing new ways of using allogeneic SCT for the treatment of cancer. 
 Alternative Treatment 
To be eligible for this study, you must have already received the standard treatment for your 
disease and be recommended for BMT because the data suggests that this is a beneficial 
treatment option, but there are other options other than participating on this trial: 
x You may consider other treatments such as other forms of chemotherapy, radiation, 
surgery, or immune therapies.  
x Taking part in another research study 
x Instead of participating in a research study such as this, you may also be eligible to 
receive a standard allogeneic stem cell transplant without the experimental elements of 
this transplant (lupron and FLT imaging). 
x Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by cancer. It does not treat the 
cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you 
as active and comfortable as possible. 
x Another option is not to receive any further treatment at all.  
 
You should discuss with your referring doctor and your doctors at the NCI whether or not any of 
these other treatments might be a reasonable choice for your disease. 
 


 
  
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STUDY NUMBER: 
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CONTINUATION:  page  18  of  23  pages 
 
 
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P.A.: 09-25-0099 
 
 
File in Section 4:  Protocol Consent 
 
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
x If your doctor believes that it is in your best interest 
x If you request to be withdrawn from active therapy  
x Completion of 1year protocol therapy 
x If new information shows that another treatment would be better for you 
  
In this case, you will be informed of the reason therapy is being stopped. 
 
Participation in this research study is voluntary.  You may stop your participation in the study at 
any time.  There are no penalties for withdrawing from the study.  However, if you decide to stop 
taking part in the study, we would like you to talk to the study doctor and your regular doctor 
first. If you withdraw after the transplant chemotherapy (“conditioning regimen”) without 
receiving the infusion of donor stem cells, you would be at high risk for serious complications, 
including death.   
 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the Sponsor or designated 
representatives. If you withdraw your consent and leave the trial, any samples of yours that have 
been obtained for the study and stored at the NCI can be destroyed upon request. However, any 
samples and data generated from the samples that have already been distributed to other 
researchers or placed in the research databases cannot be recalled and destroyed. 
 
 Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
x 
You will receive study treatment at no charge to you. This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, National 
Institutes of Health (NIH), or arranged for you by the research team to be done 
outside the Clinical Center, NIH if the study related treatment is not available at the 
NIH.  
x 
There are limited funds available to cover the cost of some tests and procedures 
performed outside the Clinical Center, NIH.  You may have to pay for these costs if 
they are not covered by your insurance company. 
x 
Medicines that are not part of the study treatment will not be provided or paid for by 
the Clinical Center, NIH. 


 
  
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x 
Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH. 
 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
 
x The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
x National Cancer Institute Institutional Review Board 
x The study Sponsor, Dr. Karen Kurdziel, or her agent(s) 
x We may share data from this study with a blood and bone marrow registry called:  The 
Center for International Blood and Marrow Transplant Research (CIBMTR). The 
CIBMTR (www.cibmtr.org) is committed to respecting your privacy and the data we 
share with is sent without revealing any personal information. The information that is 
sent to the CIBMTR is combined with information from other transplant centers to better 
understand how transplants work and to improve patient care. 
 
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. 
 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
 
x will be used for auditing or program evaluation internally by the NIH; or  
x must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
x is necessary for your medical treatment and you have consented to this disclosure;  


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  20  of  23  pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
File in Section 4:  Protocol Consent 
 
x is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
Use of Specimens and Data for Future Research  
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that it may be used for future research on any topic and shared broadly for 
research purposes. Your specimens and data will be used for research purposes only and will not 
benefit you.  It is also possible that the stored specimens and data may never be used.  Results of 
research done on your specimens and data will not be available to you or your doctor.  It might 
help people who have cancer and other diseases in the future.   


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  21  of  23  pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
File in Section 4:  Protocol Consent 
 
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  22  of  23  pages 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
OTHER PERTINENT INFORMATION 
 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Christopher Kanakry, M.D., Telephone: 240-760-6171. You may also call 
the Clinical Center Patient Representative at (301) 496-2626. If you have any questions about the 
use of your specimens and data for future research studies, you may also contact the Office of the 
Clinical Director, Telephone:  240-760-6070.  
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
11-C-0136 
CONTINUATION:  page  23  of  23  pages 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 05, 2020 THROUGH JUNE 04, 2021. 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name