A Multicenter Phase II Trial of Hematopoietic Stem Cell Transplantation for the Treatment of Patients With Fanconi Anemia Lacking a Genotypically Identical Donor, Using a Chemotherapy Only Cytoreduction With Busulfan, Cyclophosphamide and Fludarabine
Phase: PHASE2
Conditions: Aplastic Anemia, Leukemia, Myelodysplastic Syndrome
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 08-031 A(10) 
Amended:  06/18/14 
 
 
 
 
 
A Multicenter Phase II Trial of Hematopoietic Stem Cell Transplantation for the 
Treatment of Patients with Fanconi Anemia Lacking a Genotypically Identical Donor, 
Using a Chemotherapy Only Cytoreduction with Busulfan, Cyclophosphamide and 
Fludarabine 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: Farid Boulad, MD 
Pediatrics, BMT 
 
 
Co-Principal 
Investigator(s)/Department: 
Susan Prockop, MD 
Pediatrics, BMT 
 
Investigator(s)/Department: 
Kevin Curran, MD 
Aisha Hasan, MD 
Nancy Kernan, MD 
Rachel Kobos, MD 
Andromachi Scaradavou, MD 
Richard O’Reilly, MD 
 
Glenn Heller, PhD 
 
Heidi Abendroth, R.N., P.N.P. 
Catherine Copeland, R.N., P.N.P. 
Anne Casson, R.N., P.N.P. 
Maura Murphy, R.N., P.N.P. 
Joanne Torok-Castanza, R.N., P.N.P. 
Nicole Zakak, R.N., P.N.P. 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
 
Epidemiology and Biostatistics 
 
Nursing, Pediatrics 
Nursing, Pediatrics 
Nursing, Pediatrics 
Nursing, Pediatrics 
Nursing, Pediatrics 
Nursing, Pediatrics 
 
Consenting 
Professional(s)/Department: 
Kevin Curran, MD 
Aisha Hasan, MD 
Farid Boulad, MD 
Susan Prockop, MD 
Nancy Kernan, MD 
Rachel Kobos, MD 
Andromachi Scaradavou, MD 
Richard O’Reilly, MD 
 
 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. New 
York, NY 10021 

Amended:  06/18/14 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 08-031 A(10) 
 
 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Collaborating 
Institution(s): 
 
 
 
Boston Children's Hospital,Data Collection 
Cincinnati Children’s Hospital ,Data Collection 
Children’s Hospital of Wisconsin,Data Collection 
Rockefeller University, Data analysis and/or specimen analysis 
Fred Hutchinson Cancer Research Center, Data Collection 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 08-031 A(10) 
Amended:  06/18/14 
- 3 - 
 
 
 
 
Table of Contents 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL..................................................... 1 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................... 4 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................ 5 
3.0 
BACKGROUND AND RATIONALE ...................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................. 8 
4.1 
DESIGN ..................................................................................................... 8 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................. 9 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................ 15 
6.1 
SUBJECT INCLUSION CRITERIA .......................................................... 15 
6.2 
SUBJECT EXCLUSION CRITERIA ......................................................... 16 
7.0 
RECRUITMENT PLAN ....................................................................................... 17 
8.0 
PRETREATMENT EVALUATION....................................................................... 17 
9.0 
TREATMENT/INTERVENTION PLAN................................................................ 18 
9.1. PREPARATIVE CYTOREDUCTION ................................................................... 18 
9.2 
IMMUNOSUPPRESSIVE THERAPIES ............................................................... 20 
9.3 
STEM CELL COLLECTION................................................................................ 22 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................... 25 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................. 26 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...... 30 
13.0 CRITERIA FOR REMOVAL FROM STUDY ....................................................... 31 
14.0 BIOSTATISTICS................................................................................................. 32 
15.1 RESEARCH PARTICIPANT REGISTRATION -  MSKCC ........................ 33 
CONFIRM ELIGIBILITY AS DEFINED IN THE SECTION ENTITLED CRITERIA 
FOR PATIENT/SUBJECT ELIGIBILITY. ............................................................ 33 
15.2 RESEARCH PARTICIPANT REGISTRATION -  OTHER CENTERS ........ 34 
16.0 DATA MANAGEMENT ISSUES ........................................................................ 34 
16.2 QUALITY ASSURANCE .......................................................................... 35 
16.3 DATA AND SAFETY MONITORING........................................................ 36 
17.0 PROTECTION OF HUMAN SUBJECTS ............................................................ 36 
17.1 PRIVACY ................................................................................................. 37 
FOR IND/IDE PROTOCOLS: ........................................................................................ 38 
17.2.1 SERIOUS ADVERSE EVENT (SAE) REPORTING FOR PARTICIPATING 
INSTITUTIONS................................................................................................... 38 
18.0 INFORMED CONSENT PROCEDURES............................................................ 40 
19.0 REFERENCE(S)................................................................................................. 40 
20.0 APPENDICES .................................................................................................... 44 
APPENDIX 1 ................................................................................................................. 45 
APPENDIX 2 ................................................................................................................. 46 
APPENDIX 3 ................................................................................................................................... 48 
APPENDIX 4 ................................................................................................................. 50 
APPENDIX 5 ................................................................................................................. 52 

Amended:  06/18/14 
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Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 08-031 A(10) 
 
 
 
 
 
1.0       PROTOCOL SUMMARY AND/OR SCHEMA 
 
The  trial  proposed  is  a  single  arm  phase  II  multicenter  treatment  protocol  designed  to  examine 
engraftment, toxicity, graft-versus-host disease, and ultimate disease-free survival following a novel 
cytoreductive regimen including busulfan, cyclophosphamide and fludarabine and ATG for the treatment 
of patients with Fanconi anemia who have severe aplastic anemia (SAA), severe isolated single lineage 
cytopenia (SISLC),  myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), lacking 
HLA-genotypically identical donors using stem cell transplants derived from HLA-compatible unrelated 
donors or  HLA haplotype-mismatched related donors. 
 
Candidates for this trial will include patients with Fanconi anemia who have severe aplastic anemia 
(transfusion dependent), severe isolated single lineage cytopenia or myelodysplastic syndrome, or acute 
myelogenous leukemia for whom an allogeneic stem cell transplant is indicated. 
 
All patients will be conditioned for transplantation with intravenous busulfan (busulfex®) (0.6-.8 
mg/Kg/dose Q 12 hours x 4 doses), cyclophosphamide (10 mg/Kg/dose x 4 doses) and fludarabine (35 
mg/m2/day x 4 doses). All patients will also receive rabbit ATG (thymoglobulin®) (2.5 mg/Kg/dose x 4 
doses) prior to transplant to promote engraftment. Cyclosporine will be used for prophylaxis against 
GvHD. All patients will also receive G-CSF post-transplant to foster engraftment. 
 
Busulfan doses were adjusted based on Busulfan pharmacokinetics. 
 
As of April 2012, patient accrual is nearly complete. As a result, after the completion of the planned 25 
patient study, we have amended the protocol to accrue at most an additional 20 patients in order to gain 
clinical experience using alternative levels of Busulfan. 
 
Previously, 25 patients were treated with 0.8-1.0 mg/kg of Busulfan. In this continuation study, 10 
patients will be treated at 0.6-0.8 mg/kg of Busulfan. If no primary graft failures are observed in these 10 
patients, then a further cohort of 10 patients will be treated at 0.4-0.6 mg/kg. If however, at any time 
during this accrual a graft failure is observed, then the Busulfan dose will be modified and a final cohort 
will be treated at the initial dose of 0.8-1.0 mg/kg. 
 
Although no graft failure has been seen with the dose of .6-.8 mg/kg of Busulfan, it was decided to enroll 
the remainder of the patients at this cohort, as a precautionary measure and in order to maintain the safety 
and effectiveness of the condition regimen. Some patients have had some evidence of mixed chimerism, 
and we therefore do not see any benefit in reducing the Busulfan dose any further. 
 
The preferred source of stem cells will be peripheral blood stem cells (PBSC) induced and mobilized by 
treatment of the donor with G-CSF for 4-6 days. T-cell depletion will be uniformly performed in all 
centers by positive CD34 selection with the use of the Miltenyi system (CliniMACS device). The CD34+ 
peripheral blood progenitors will then be administered to the patients after they have completed 
cytoreduction. 
 
Patients will be carefully monitored for engraftment, chimerism, incidence and severity of acute and 
chronic GvHD, regimen-related toxicity, characteristics of hematopoietic and immune reconstitution and 
survival and disease-free survival. 
 
This  phase  II  trial  is  designed  to  investigate  the  safety  and  efficacy  of  a  chemotherapy-based 
cytoreductive regimen plus a CD34+ selected T-cell depleted peripheral blood stem cell (PBSC) stem cell 

Amended:  06/18/14 
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Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 08-031 A(10) 
 
 
FLU 
FLU 
FLU 
FLU 
CY 
CY 
CY 
CY 
 
 
 
transplant for the treatment of patients with Fanconi anemia and severe hematologic disease. The majority 
of patients will receive grafts derived from PBSC and will be the focus of the trial. 
 
The  study  population  will  consist  of  one  patient  population  with  two  types  of  donors:  (1)  HLA- 
compatible unrelated donors, and (2) HLA–mismatched related donors.   Donor preference will be 
determined by each center. All patients eligible for this protocol by virtue of being seen at a participating 
center and having (1) hematologic disease AND (2) lack of genotypically matched related donor will be 
captured on the database of this protocol. 
 
It is anticipated that the accrual will last 6 years and a total of approximately 45 PBSC patients will enter 
the study. 
 
In order to reduce patient risk, the study design includes early termination in the event of excessive graft 
failure, grade 3-4 acute graft-versus-host disease or severe chronic graft-versus host disease, or early 
transplant related mortality during the accrual period. Stopping rules will be utilized. See below for 
approximate schema of cytoreduction and preparation for allogeneic PBSCT: 
 
 
 
 
 
 
 
 
BU 
BU 
CD34+ 
PBSCT 
 
 
 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
+1 
 
ATG 
ATG 
ATG 
ATG 
 
START CSA  
 
 
START G-CSF  
 
 
BU 
Busulfan 
0.6-0.8 mg/Kg/dose IV Q 12H 
X 4 doses 
FLU 
Fludarabine 
35 mg/m2/dose IV once daily 
X 4 doses 
CY 
Cyclophosphamide 
10 mg/Kg/dose IV once daily 
X 4 doses 
ATG 
Anti-thymocyte globulin - Thymoglobulin 
2.5 mg/Kg/dose IV daily 
X 4 doses 
CSA 
Cyclosporine 
2.5 mg/Kg/dose IV Q 8-12 H 
G-CSF Filgrastim 
as per institutional guidelines 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
A prospective phase II trial is proposed. Patients with FA who lack an HLA-genotypically matched 
related donor and have severe hematologic disorders will be eligible to receive CD34+ selected, T cell 

Amended:  06/18/14 
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IRB Protocol 
IRB#: 08-031 A(10) 
 
 
 
 
 
depleted allogeneic hematopoietic stem cell transplants after chemotherapy-based cytoreduction using 
intravenous busulfan, cyclophosphamide, fludarabine and rabbit ATG. Stem cells will be collected from 
(1) HLA-compatible unrelated donors, or (2) HLA-mismatched related donors. 
The primary objectives of this trial are to establish: 
1. the incidence and quality of engraftment and hematopoietic reconstitution. 
2. the incidence of early transplant related mortality 
3. the incidence and severity of acute GvHD and chronic GVHD. 
 
Secondary objectives of this study are to establish initial estimates of: 
4. the incidence of overall survival and disease-free survival over time 
 
3.0       BACKGROUND AND RATIONALE 
 
3.1. 
BACKGROUND 
Fanconi anemia (FA) is a genetic disease characterized by chromosome fragility, multiple birth defects, 
and an increased risk for hematopoietic disorders and solid tumors (1-2). Progressive bone marrow failure 
results in aplasia, myelodysplasia and/or leukemia (3). When an HLA-matched sibling is identified, stem 
cell  transplantation  using  cytoreduction  with  low  doses  of  radiation  and  chemotherapy  has  been 
successful in curing the hematologic manifestations of FA (4-24). The chromosome fragility of FA and its 
hypersensitivity to DNA cross-linking agents and radiation has for some time limited the ability to 
perform marrow transplantation using donors other than HLA-matched siblings (25-27). In the context of 
alternative donors such as unrelated marrow donors or cord blood, the use of a similar cytoreduction has 
been associated with high rates of rejection/graft failure and GvHD, resulting in poor overall survival (28- 
37). 
 
 
Since the first report of marrow transplantation for FA in 1977 (4), approximately 200+ recipients of 
marrow transplants from HLA-matched siblings have been reported; the risk of rejection has been less 
than 10%, the risk of developing acute and/or chronic GvHD has been approximately 45%, and 69% of 
patients are alive disease-free (4-24). More recent studies however have shown improved results (80%) 
when transplants have been performed in younger patients, with fewer prior transfusions (13). 
 
Approximately 110 patients with FA were initially reported who received stem cell transplants from 
closely matched unrelated donors; 69 reported recently to the European Group for Blood and Marrow 
Transplantation and approximately 40 in the US (28-36). A proportion of these transplants were T-cell 
depleted for the prevention of GvHD. Overall, there was an increased risk of rejection of 17-37%, risks of 
grade II-IV GvHD and of chronic GvHD were as high as 50%, and only one third of the patients were 
alive at the time of the reports. The cytoreduction used in the majority of these transplants consisted of 
low dose TBI (450-600 cGy) (TBI), and cyclophosphamide (Cy) (10 mg/Kg x 4) with the addition of 
ATG,  steroids,  and  cyclosporin  A.  In  an  analysis  of  49  patients  with  FA  who  received  stem  cell 
transplants from unrelated donors reported by 12 centers, the incidence of acute GvHD grades II-IV was 
52% in conventional grafts and 29% in T-cell-depleted grafts (30). Using elutriation to deplete T-cells the 
Minnesota group observed a 32% incidence of grade II-IV acute GvHD in 20 transplanted patients (35). 
 
Guardiola et al. (33) using CD34+ selection (ISOLEX) to T-cell deplete FA unrelated bone marrow, 
observed an incidence of only 15% II-IV grade acute GvHD. However, two of the 16 patients died of 
acute GvHD. Graft rejection has also been a major problem for unrelated donor transplants for FA. In 
those patients receiving T-cell-depleted transplants, the incidence of graft failure was 20-37% (29, 30, 

Amended:  06/18/14 
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Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 08-031 A(10) 
 
 
 
 
 
35). The presence of lymphocyte mosaicism (i.e. presence of DEB insensitive cells) was associated with a 
significant increased risk of graft failure (35). Escalation of TBI from 450 cGy (standard FA dose) to 600 
cGy did not decrease the risk of graft rejection in the most recent Minnesota trial (35). In all of the 
unrelated donor trials for patients with FA, infectious mortality has been significant. In a Minnesota trial 
of 29 FA MUD transplants, eight patients succumbed to invasive Aspergillus infection despite aggressive 
antifungal therapy (35). 
 
Based on the results cited above, the problems associated with stem cell transplants for FA were: immune 
complications, including graft-versus-host disease (GvHD), graft rejection, infections, and organ toxicity. 
The challenges to the optimization of stem cell transplants for Fanconi anemia using alternative donors 
were thus based on the need for (1) a regimen immunosuppressive enough to allow engraftment, with a 
low risk of rejection, (2) a regimen for marrow processing (T-cell depletion) that can decrease the risk of 
GvHD, and (3) a regimen that does not give rise to excessive toxicity in children with FA. 
 
Three groups in the US including the University of Minnesota, Cincinnati Children’s Hospital and 
Memorial Sloan-Kettering Cancer Center have pioneered new regimens that included low dose total body 
irradiation, cyclophosphamide, ATG and the addition of fludarabine followed by T-cell depleted marrow 
or peripheral blood stem cell transplants (37-39). All three centers have had promising results with 
minimal risks of graft rejection, low rates of graft-versus-host disease and overall promising disease-free 
survival.  However, with the small numbers of patients with FA who undergo allogeneic stem cell 
transplants, results of single center trials are difficult to interpret in terms of optimal cytoreductive 
regimens and dosing. In addition, T-cell depletion methods were also different in all three centers. 
 
Moreover, the use of TBI in these studies also poses additional concerns with respect to widespread 
adoption of one of these approaches. It is possible (based on risks of secondary malignancies in non-FA 
patients) that irradiation plays some role in the increased risk of secondary malignancies in FA patients. 
To date, a significant number of FA survivors of stem cell transplantation have developed solid tumors 
post transplant (40-43). These solid tumors are mostly squamous cell carcinomas. The relative 
contributions of TBI and chronic GvHD to the development of such tumors are unknown. However, the 
elimination of TBI coupled with T-cell depletion are aimed at decreasing these risks. 
 
Based on these data, we propose to use a non-TBI based cytoreductive regimen of busulfan (instead of 
TBI), cyclophosphamide and fludarabine with ATG and cyclosporine followed by peripheral blood stem 
cell grafts, aggressively T-cell depleted. 
 
3.2        RATIONALE 
 
The purpose of the use of busulfan is to avoid the use of TBI and possibly decrease the risk of secondary 
malignancies. 
 
The use of the cyclophosphamide / fludarabine and ATG / CSA combination is because it has been 
successful in most recent trials with limited toxicity and decreased risks of rejection. 
 
The purpose of peripheral blood stem cells is to achieve high doses of stem cells in order to prevent graft 
rejection. In addition, it could potentially decrease mucositis and possible related infectious morbidity by 
improving time to engraftment.  The use of CD34selected stem cells (which are highly T cell depleted) is 
intended to minimize the risks of GVHD. 

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IRB Protocol 
IRB#: 08-031 A(10) 
Amended:  06/18/14 
- 8 - 
 
 
FL 
FL 
FL 
FL 
CY 
CY 
CY 
CY 
 
 
 
4.0       OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
The  trial  proposed  is  a  single  arm  phase  II  multicenter  treatment  protocol  designed  to  examine 
engraftment, toxicity, graft-versus-host disease, and ultimate disease-free survival following a novel 
cytoreductive regimen including busulfan, cyclophosphamide and fludarabine and ATG for the treatment 
of patients with Fanconi anemia lacking HLA-genotypically identical donors using stem cell transplants 
derived  from  HLA-compatible  unrelated  donors  or  HLA  haplotype-mismatched  related  donors. 
Candidates for this trial will include patients with Fanconi anemia and severe aplastic anemia (transfusion 
dependent), severe isolated single lineage cytopenia, myelodysplastic syndrome, or acute myelogenous 
leukemia for whom an allogeneic stem cell transplant is indicated. 
 
This  phase  II  trial  is  designed  to  investigate  the  safety  and  efficacy  of  a  chemotherapy-based 
cytoreductive regimen plus a CD34+ selected T-cell depleted peripheral blood stem cell (PBSC) stem cell 
transplant for the treatment of patients with Fanconi anemia and severe hematologic disease. The majority 
of patients will receive grafts derived from PBSC from HLA-compatible unrelated donors, and (2) HLA– 
mismatched related donors and will be the focus of the trial. 
 
The primary objectives of this trial are to establish (1) the incidence and quality of engraftment and 
hematopoietic reconstitution, (2) the incidence of early transplant related mortality, (3) the incidence and 
severity of acute GvHD and chronic GVHD, and (4) the probability of overall survival and disease-free 
survival over time. 
 
4.2 
Intervention 
 
Patients will receive cytoreduction with busulfan, fludarabine, and cyclophosphamide with the 
addition of immunosuppression with ATG and cyclosporine. They will receive a CD34+ T-cell 
depleted peripheral blood stem cell transplant. See below for approximate schema of 
cytoreduction and preparation for allogeneic PBSCT: 
 
 
BU 
BU 
 
CD34+ 
PBSCT 
 
 
 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
+1 
 
ATG 
ATG 
ATG 
ATG 
 
START CSA  
 
START G-CSF  
 
 
BU 
Busulfan 
0.6-0.8 mg/Kg/dose IV Q 12H 
X 4 doses 
FLU 
Fludarabine 
35 mg/m2/dose IV once daily 
X 4 doses 
CY 
Cyclophosphamide 
10 mg/Kg/dose IV once daily 
X 4 doses 
ATG 
Anti-thymocyte globulin - Thymoglobulin 
2.5 mg/Kg/dose IV daily 
X 4 doses 
CSA 
Cyclosporine 
2.5 mg/Kg/dose IV Q 8-12 H 
G-CSF Filgrastim 
as per institutional guidelines 

Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 08-031 A(10) 
Amended:  06/18/14 
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5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1. Busulfan (busulfex®) 
 
a.   Source and Pharmacology: Supplier: Orphan Medical Company; Busulfan is a bifunctional alkylating 
agent known chemically as 1,4-butanediol, dimethanesulfonate. BUSULFEX® (busulfan). This is an 
agent in which two labile methanesulfonate groups are attached to opposite ends of a four carbon alkyl 
chain. In aqueous media, busulfan hydrolyzes to release the methanesulfonate groups. This produces 
reactive carbonium ions that can alkylate DNA. DNA damage is thought to be responsible for much of the 
cytotoxicity of busulfan. 
 
b.   Formulation and Stability:  It is supplied as a clear, colorless, sterile, solution in 10 mL single use 
ampoules. Each ampoule of BUSULFEX contains 60 mg (6 mg/mL) of busulfan, the active ingredient, a 
white crystalline powder with a molecular formula of CH3SO2O(CH2)4OSO2CH3 and a molecular weight 
of 246 g/mole. Busulfan is dissolved in N,N-dimethylacetamide (DMA) 33% wt/wt and polyethylene 
glycol 400, 67% wt/wt. Busulfan’s solubility in water is 0.1 g/L and the pH of a >0.5% solution in 0.9% 
Sodium Chloride Injection, USP or 5% Dextrose Injection, USP as recommended for infusion reflects the 
pH of the diluent used and ranges from 3.4 to 3.9. 
c.   Solution Preparation: BUSULFEX is supplied as a sterile solution in 10 mL single-use clear glass 
ampoules  each  containing  60  mg  of  busulfan  at  a  concentration  of  6  mg/mL  for  intravenous  use. 
BUSULFEX must be diluted prior to use with either 0.9% Sodium Chloride Injection, USP (normal 
saline) or 5% Dextrose Injection, USP (D5W). The diluent quantity should be 10 times the volume of 
BUSULFEX, ensuring that the final concentration of busulfan is approximately 0.5 mg/mL. 
 
d.   Storage  and  Stability:    Unopened  ampules  of  BUSULFEX  must  be  stored  under  refrigerated 
conditions between 2° -8° C (36° -46° F). 
 
e.   Administration:  Intravenous, over 2 hours. 
 
5.2        Fludarabine (FLUDARA®) 
 
a.   Source  and  Pharmacology:  Supplier:  Berlex  Laboratories,  Inc.  FLUDARA  FOR  INJECTION 
contains fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-ß-D- 
arabinofuranosyladenine (ara-A) that is relatively resistant to deamination by adenosine deaminase. The 
chemical name for fludarabine phosphate is 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-ß-D- 
arabinofuranosyl). Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-ara-A and then 
phosphorylated intracellularly by deoxycytidine kinase to the active triphosphate, 2-fluoro-ara-ATP. This 
metabolite appears to act by inhibiting DNA polymerase alpha, ribonucleotide reductase and DNA 
primase, thus inhibiting DNA synthesis. The mechanism of action of this antimetabolite is not completely 
characterized and may be multi-faceted. 
 
b.   Formulation and Stability: Each vial of sterile lyophilized solid cake contains 50 mg of the active 
ingredient fludarabine phosphate, 50 mg of mannitol, and sodium hydroxide to adjust pH to 7.7. The pH 
range for the final product is 7.2-8.2. Reconstitution with 2 mL of Sterile Water for Injection USP results 
in a solution containing 25 mg/mL of fludarabine phosphate intended for intravenous administration. 

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FLUDARA FOR INJECTION is supplied in a clear glass single dose vial (6 mL capacity) and packaged 
in a single dose vial carton in a shelf pack of five. 
 
c.   Solution Preparation: FLUDARA should be prepared for parenteral use by aseptically adding Sterile 
Water for Injection USP. When reconstituted with 2 mL of Sterile Water for Injection, USP, the solid 
cake should fully dissolve in 15 seconds or less; 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 7.7. The pH range 
for the final product is 7.2-8.2. In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% 
Dextrose Injection USP or 0.9% Sodium Chloride USP. 
 
d.   Storage and Stability: FLUDARA is supplied as a white, lyophilized solid cake. Each vial contains 50 
mg of fludarabine phosphate, 50 mg of mannitol and sodium hydroxide to adjust pH to 7.7. The pH range 
for the final product is 7.2-8.2. Store under refrigeration, between 2°-8° C (36°-46° F). 
 
e.   Administration: Intravenous, over thirty minutes. 
 
5.3.       Cyclophosphamide (Cytoxan®) 
 
a.   Source and Pharmacology: Supplier: Bristol-Meyers. Cytoxan®,. Cyclophosphamide is an alkylating 
agent that is initially inactive but then is activated by metabolism in the liver by the mixed-function 
oxidase system of the smooth endoplasmic reticulum. The hepatic cytochrome P-450 mixed-function 
converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in a steady state with the acyclic 
tautomer, aldophosphamide. 
 
b.   Formulation and Stability: Injections: Each lyophilized vial contains: cyclophosphamide USP 500, 
1000 or 2000 mg with mannitol. Cartons of 6 (1 000 and 2 000 mg) and 12 (500 mg). 
c.   Solution Preparation: Prepare Cytoxan for Injection for parenteral use by adding Sterile Water for 
Injection USP or Bacteriostatic Water for Injection USP (paraben preserved only) to the vial and shaking 
to dissolve to produce a clear colorless solution. Heating should not be used to facilitate dissolution. 
Solutions of Cytoxan for Injection may be infused i.v. in Dextrose Injection USP (5% Dextrose, 5% 
Dextrose and 0.9% Sodium Chloride) Dextrose 5% and Ringers Injection, Lactated Ringers Injection 
USP, Sodium Chloride Injection USP (0.45% sodium chloride) and Sodium Lactate Injection USP (1/6 
molar sodium lactate). 
 
d.   Storage and Stability: Reconstituted Cytoxan for Injection is chemically and physically stable at room 
temperature for 24 hours and for 6 days in the refrigerator. For solutions further diluted for i.v. infusion, it 
is recommended that the solutions be used within 24 hours at room temperature or 72 hours under 
refrigeration. Solutions prepared with Sterile Water for Injection should be used for single dose 
administration and any unused solution discarded. 
 
e.   Administration: Intravenous, over thirty-sixty minutes. 
 
5.4.       Anti-Thymocyte Globulin (Rabbit) (Thymoglobulin®) 
 
a.   Source and Pharmacology: Supplier: Sangstat, The Transplant Company®. Thymoglobulin®  [Anti- 
thymocyte Globulin (Rabbit)] is a purified, pasteurized, gamma immune globulin, obtained by 
immunization of rabbits with human thymocytes. This immunosuppressive product contains cytotoxic 
antibodies directed against antigens expressed on human T-lymphocytes. 

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IRB Protocol 
IRB#: 08-031 A(10) 
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b. Formulation and Stability: Thymoglobulin is a sterile, freeze-dried product for intravenous 
administration after reconstitution with sterile Water for Injection, USP (WFI).  Each package contains 
two 7 mL vials: Vial 1: Freeze-Dried Thymoglobulin Formulation Active ingredient: Anti-thymocyte 
Globulin (Rabbit) 25 mg - Inactive ingredients: Glycine (50 mg), mannitol (50 mg), sodium chloride (10 
mg); Vial 2: Diluent Sterile Water for Injection, USP 5 mL. The reconstituted preparation contains 
approximately 5 mg/mL of Thymoglobulin, of which >90% is rabbit gamma immune globulin (IgG). The 
reconstituted solution has a pH of 7.0± 0.4. Human red blood cells are used in the manufacturing process 
to deplete cross-reactive antibodies to non-T-cell antigens. The manufacturing process is validated to 
remove or inactivate potential exogenous viruses. All human red blood cells are from US registered or 
FDA  licensed  blood  banks.  A  viral  inactivation  step  (pasteurization,  i.e.,  heat  treatment  of  active 
ingredient at 60°C/10 hr) is performed for each lot. Each Thymoglobulin lot is released following potency 
testing (lymphocytotoxicity and E-rosette inhibition assays), and cross-reactive antibody testing 
(hemagglutination, platelet agglutination, anti-human serum protein antibody, antiglomerular basement 
membrane antibody, and fibroblast toxicity assays on every 5th lot). 
c. Solution Preparation: Each reconstituted vial contains 25 mg or 5 mg/mL of Thymoglobulin. Transfer 
the contents of the calculated number of Thymoglobulin vials into the bag of infusion solution (saline or 
dextrose). Recommended volume: per one vial of Thymoglobulin use 50 mL of infusion solution (total 
volume usually between 50 to 500 mL). Mix the solution by inverting the bag gently only once or twice. 
 
d.   Storage and Stability: Store in refrigerator between +2° C to +8° C (36° F to 46° F). Protect from 
light. Do not freeze. Do not use after the expiration date indicated on the label. Reconstituted vials of 
Thymoglobulin should be used within 4 hours. Infusion solutions of Thymoglobulin must be used 
immediately. Any unused drug remaining after infusion must be discarded. 
 
e. Administration: Infuse through a 0.22-micron filter into a high-flow vein. Set the flow rate to deliver 
the dose over a minimum of 6 hours for the first dose and over at least 4 hours for subsequent doses. 
 
5.5  
Cyclosporine (Sandimmune) 
 
a. Source and Pharmacology: Supplier:  Novartis. Cyclosporine 
 
b.   Formulation and Stability: 
SUPPLIED AS: 50 mg/ml; 5 ml ampule (Protect from light) 
 
c. Solution Preparation: 
1.   Dilute cyclosporine concentrate for injection in 20 -100 ml of NS or D5W injection.  Prepare 
injections in glass containers to avoid possible leaching of diethylhexylphthalate (DEHP) from 
polyvinyl chloride (PVC) containers into injections of cyclosporine. 
2.   Diluted solutions are stable for 24 hours in D5W injection and 12 hours in NS in glass containers. 
3.   Visually inspect parenteral products for particulate matter and discoloration prior to 
administration whenever solution and container permit. 
 
d.   Storage and Stability: 
72 hours under refrigeration or at room temperature. 
 
e. Administration: 
- 
I.V. PUSH contraindicated 

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Amended:  06/18/14 
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- 
I.V. PIGGYBACK: Dilute in D5W or NS to make a 2.5 mg/ml solution. Infuse slowly over 
approximately 2 hours (intermittent infusion) or 24 hours for continuous infusion. Prepare in a glass 
bottle only. The bottle should be spiked with vented tubing and primed with either D5W or NS. 
- 
Do not administer rapidly; rapid administration may cause acute nephrotoxicity, flushing, and nausea. 
 
LARGE VOLUME INFUSION: PRECAUTIONS AND COMMENTS: 
1.   Patients should be under close observation for possible allergic manifestations including facial 
flushing, respiratory distress, with dyspnea and wheezing, blood pressure changes and 
tachycardia. 
2.   Prior to infusion solution should be inspected visually for particulate matter and discoloration. 
3.   Concomitant use of immunosuppressive agents (steroids, ATG) require aggressive monitoring for 
infection. 
4.   Nephrotoxic agents will increase the risk of nephrotoxicity (amphotericin B, aminoglycosides, 
and acyclovir) high doses. 
5.   Plasma concentration of cyclosporine may be affected by the following drugs: 
a. Increased cyclosporin levels: ketoconazole, erythromycin, cimetidine, calcium channel 
blockers, 
fluconazole, itraconazole, norfloxacin, imipenem/cisplatin 
b. Decreased cyclosporin levels: rifampin, phenytoin, phenobarbital, imipenem/cilastin. 
6. 
The IV to oral dose conversion is 1:3. 
7.   The target serum level of 200 - 400 is desirable; 800 is considered toxic. 
8.   Renal and hepatic parameters should be monitored routinely with dosage adjustments in the case 
of serum creatinine or LFT elevations. 
 
5.6  
The CliniMACS device 
 
Drug Formulation and Procurement 
 
5.6.1.The CliniMACs device (Miltenyi Biotec, Auburn, CA) will be employed for the CD34 selection 
procedure. It consists of tubing, bags, and a pair of columns, placed at appropriate locations in the Tubing 
Set to facilitate the cell selection process. The CliniMACS System intended for selection of CD34+ cells 
is comprised of four primary components listed here. A brief description of each component is provided 
below. 
 
5.6.1.1. A software controlled instrument that processes the blood sample, CliniMACS 
Instrument 
5.6.1.2. A  single-use,  sterile  disposable  tubing  set  with  two  proprietary  cell  selection  columns, 
CliniMACS Tubing Set 
5.6.1.3. A monoclonal antibody reagent specific for CD34+ cells, CliniMACS CD34 Reagent 
5.6.1.4. A sterile, isotonic phosphate buffered, 1 mM EDTA, saline solution, used as external wash and 
transport fluid for the in vitro preparation of blood cells, CliniMACS PBS/EDTA Buffer. 
 
5.6.2.        CliniMACS Instrument 
 
The CliniMACS Instrument is a bench-top instrument consisting of a supporting structure to hold the 
column/tubing assembly and various bags, a series of valves through which the tubing set is fitted, a 
magnet between the poles of which the separation column is placed, a peristaltic pump through which a 
section of tubing is placed, software to control the instrument and user interface and a computer touchpad 

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with a display window. The instrument is operated at ambient temperature and it is intended to be multi- 
use item. 
 
The software for the CliniMACS Instrument controls the function of the electromechanical components 
of the instrument and the user interface.  Two separate computers, one a micro-controller located on a 
control board of the CliniMACS Instrument and the second a PC compatible computer which operates the 
user interface are incorporated with the instrument. Software Version 2.31, the current version of software 
is directly traceable to the version of software utilized in pre-clinical testing and European Safety trials, 
and has been inspected and approved by TÜV product services with the CE Mark. 
 
5.6.3.        CliniMACS Tubing Set 
 
5.6.3.1.  The CliniMACS Tubing Set consists of a tubing element combined with a pair of proprietary 
cell selection columns.   These form a closed, sterile system for processing the cells. The separation 
column is a proprietary component of the CliniMACS System consisting of a plastic column housing with 
polypropylene frits in each end.  The interior of the column housing is filled with a matrix of sub- 
millimeter  iron  beads  coated  with  a  heat-cured  biocompatible  resin.    The  columns  are  placed  at 
appropriate locations in the CliniMACS Tubing Set to facilitate the cell selection process.   The first 
column serves as a device to remove components that bind non-specifically to the column.  The second 
column performs the actual cell selection.  The columns are incorporated sterile as part of the tubing set 
and are intended for single use only. 
 
5.6.3.2. The tubing element consists of a series of tubes, connectors, spikes, Luer locks, and collection 
bags.  The tubing of the tubing element is comprised of materials that have been qualified for use in this 
application  by testing to ISO 10993.    The  principal  constituents  are  polyvinyl  chloride (PVC)  and 
silicone.  The connectors are made of various polymers (e.g., ABS and PVC) suitable for use in a blood 
contact environment. They are solvent bonded to the PVC tubing.  The silicone pump tubing is softened 
with petroleum ether for manufacturing and mechanically fixed to connectors. The cell wash bags are 
composed of PVC. 
 
5.6.3.3. The CliniMACS Tubing Set is packaged in a thermoformed tray and heat sealed with a Tyvek® 
lid. The CliniMACS Tubing Set is sterilized by ethylene oxide gas in a validated sterilization cycle and 
supplied as a single-use component for the CliniMACS Instrument. 
 
5.6.4.        CliniMACS CD34 Reagent 
 
The CliniMACS CD34 Reagent is a dark amber, nonviscous, colloidal solution containing the antibody 
conjugate in buffer.   The conjugate consists of a monoclonal antibody towards the human CD34 antigen. 
The murine monoclonal IgG1 antibody is covalently linked to dextran beads having an iron 
oxide/hydroxide core. The concentration of the conjugate is equivalent to 20 micrograms (µg) per mL of 
antibody protein, 800 µg/mL of dextran and 800 µg/mL of iron.   The colloid is buffered in a phosphate- 
buffered saline (PBS) containing ethylenediaminetetraacetic acid (EDTA) and Poloxamer 188. The 
nominal concentrations of its components are 0.0095 M phosphate, 0.004 M potassium, 0.163 M sodium, 
0.139 M chloride, 0.005 M EDTA and 0.03 % (w/v) Poloxamer 188.  The pH is 7.4 - 7.7. Poloxamer 188 
is added to the CliniMACS CD34 Reagent to stabilize it during shipping, handling and storage.    The 
CliniMACS CD34 Reagent is supplied sterile and pyrogen-free in glass vials containing 7.5 mL and is 
intended for single use and in vitro use only. 

Memorial Sloan-Kettering Cancer Center 
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IRB#: 08-031 A(10) 
Amended:  06/18/14 
- 14 - 
 
 
Ingredient 
Compendial 
Amount 
NaCl 
Ph. Eur. 
8.0 
g/L 
KCl 
Ph. Eur. 
0.19 
g/L 
Na2HPO4 anhy. 
Ph. Eur. 
1.15 
g/L 
KH2PO4 
Ph. Eur. 
0.19 
g/L 
Na2EDTA 
Ph. Eur. 
0.37 
g/L 
Water for Injection 
Ph. Eur. 
ad 1L 
 
 
 
 
5.6.5. 
The CliniMACS PBS/EDTA Buffer 
 
The CliniMACS PBS/EDTA Buffer is an isotonic and isohydric buffer solution with a pH-value of 7.2 
and osmolarity of 290 mosmol/L.   Its formulation is shown in the following table. 
 
Table 1.  Formulations of the CliniMACS PBS/EDTA Buffer 
 
 
 
 
 
 
 
 
 
 
The  CliniMACS  PBS/EDTA  Buffer  is  used  as  external  wash  and  transport  fluid  for  the  in  vitro 
preparation of human heterogeneous cell populations intended to be separated with the CliniMACS Cell 
Selection System.  This is achieved by the following procedure: 
 
Mononuclear cells for separation are collected. After incubating the cells with CD34 Reagent in 
PBS/EDTA Buffer the excess of unbound reagent is removed by washing with the PBS/EDTA Buffer. 
Prior to and during incubation of the antiCD34 beads with the mobilized PBSC, intravenous 
gammaglobulin is added to the incubation fluid at a concentration of 1.5 mg IVIG/ml. 
 
During the following automated selection, using PBS/EDTA Buffer supplemented with 0.5 % human 
serum albumin (HSA), the unwanted cells are removed and, in the final step, the selected cells are eluted 
from the column by the means of the PBS/EDTA Buffer. The HSA is not a component of the buffer and 
should be supplied by the clinical site. 
 
5.6.6.        Principles of Operation 
5.6.6.1.1.           The function of the CliniMACS System with the CliniMACS CD34 reagent is to select 
CD34+ cells from heterogeneous cell populations.   The detailed procedures are provided in the 
CliniMACS User Manual that accompanies the CliniMACS Instrument.  The selection process involves 
two phases; cell labeling prior to selection (phase 1) and the automated cell selection process (phase 2). 
Provided below is a brief summary of the procedure. 
 
5.6.6.1.2.           Phase 1 – Labeling. This phase is referred to as the cell-labeling step.  This step involves 
combining the antibody reagent with the cellular harvest from the donor or patient.  The antibody reagent 
is incubated for 30 minutes at room temperature with the heterogeneous cell population during which the 
antibody selectively binds to cells expressing the CD34 antigen.  The mixture is then washed twice in 
PBS/EDTA separation buffer.  Following centrifugation, the resulting cell pellet is resuspended in the 
separation buffer and the labeled product is ready for cell selection. 
 
 
 
5.6.6.1.3.    Phase 2 – Cell Selection. The labeled cell product is attached to the sterile tubing set of the 
CliniMACS system.  Following a series of automated priming steps‚ the cell product is passed through a 
blood filter to remove any cell aggregates that may be present. The cell suspension is then passed through 

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the  first  column,  which  serves  as  a  pre-column  separation  step  to  eliminate  cells  that  bind  non- 
specifically.  The labeled product then passes through the second column positioned within the magnetic 
field.  The CD34+ cells‚ to which the antibody reagent has been bound‚ are selected and retained in the 
column matrix.  All other cells flow through the column and are collected in the negative fraction bag. 
After automated buffer washes of the column containing the isolated CD34+ cells‚ the column is removed 
from the magnetic field‚ and the CD34+ cells are eluted into a positive fraction bag.  The selected cells 
can be used immediately after analysis or cryopreserved for later infusion into the patient.  The device is 
non-invasive in all aspects that involve processing of the cellular harvest and is not connected to the 
patient at any time. 
 
6.0       CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
6.1.1. Diagnosis 
Patients must have a diagnosis of Fanconi anemia (confirmed by mitomycin C or diepoxybutane 
[DEB] chromosomal breakage testing at an approved laboratory). 
 
6.1.2. Hematologic Diagnosis and Status 
Patients must have one of the following hematologic diagnoses: 
 
1. Severe Aplastic Anemia (SAA), with bone marrow cellularity of <25%    or 
Severe Isolated Single lineage Cytopenia 
AND at least one of the following features: 
1. Platelet count <20 x 109/L or platelet transfusion dependence* 
2. ANC <1000 x 109/L 
3. Hgb <8 gm/dl or red cell transfusion dependence* 
 
2. Myelodysplastic Syndrome (MDS) (Appendix 1: MDS Classification) 
MDS at any stage, based on either one of the following classifications: 
-  WHO Classification 
- Refractory anemia and transfusion dependence* 
- Any of other stages 
- IPSS Classification 
- Low risk (score 0) and transfusion dependence* 
- Any other risk groups Score > 0.5 
 
3. Acute Myelogenous Leukemia 
Patients with acute leukemia are included in this trial in remission, refractory or 
relapsed disease. 
 
* Transfusion dependence will be defined as greater than ONE transfusion of platelets or red blood cells 
in the last year prior to evaluation on protocol. 
 
6.1.3.    Donor 
Donor choices will be determined by the investigators at each of the centers according to their own 
institutional criteria. All patients evaluated at trial sites and eligible for this trial by virtue of disease and 

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lack of an HLA-genotypically matched related donor will be captured in the database of this trial. Patients 
who will be enrolled on this protocol must have one of the following donor choices: 
 
 
 
HLA-compatible Unrelated volunteer donors 
Patients who do not have a related HLA-matched donor but have an unrelated donor who is either 
matched at all A, B, C and DRB1 (8/8) loci or who is mismatched at 1/8 loci (A, B, C or DRB1) (7/8) as 
tested by DNA analysis (high resolution), will be eligible for entry on this protocol. 
 
HLA-mismatched Related donors 
Patients who do not have a related or unrelated HLA-compatible donor must have a healthy family 
member who is at least HLA-haplotype identical to the recipient. First degree related donors must have a 
normal DEB test. 
 
The donor must be healthy and willing and able to receive a 4-6 day course of G-CSF and undergo 1-3 
daily leukaphereses. 
 
Related and Unrelated donors must be medically evaluated and fulfill the criteria for collection of PBSCs 
as per institutional guidelines. 
 
6.1.4. Patients and donors may be of either gender or any ethnic background. 
 
6.1.5. Patients must have a Karnofsky adult, or Lansky pediatric performance scale status > 70%. 
 
6.1.6. At the time of referral for transplantation, patients must have no co-existing medical problems 
that would significantly increase the risk of the transplant procedure. 
 
6.1.7. Patients must have adequate physical function measured by : 
 
a) 
Cardiac: 
asymptomatic or if symptomatic then 1) LVEF at rest must be > 50% and must 
improve with exercise or 2) Shortening Fraction > 29% 
b) 
Hepatic: 
< 5 x ULN SGOT and < 2.0 mg/dl total serum bilirubin. 
c) 
Renal: 
serum creatinine <1.5 mg/dl or if serum creatinine is outside the normal range, 
then CrCl > 60-ml/min/1.73 m2 
d) 
Pulmonary: 
asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected for 
hemoglobin) 
 
6.1.8. Each patient must be willing to participate as a research subject and must sign an informed 
consent form.  Parent or legal guardians of patients who are minors will sign the informed consent form. 
Assents will be obtained as age appropriate. 
 
6.1.9. Female patients and donors must not be pregnant or breastfeeding at the time of signing consent. 
Women must be willing to undergo a pregnancy test prior to transplant and avoid becoming pregnant 
while on study. 
6.2 
Subject Exclusion Criteria 
 
1. Active CNS leukemic involvement 

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2. Female patients who are pregnant (positive serum or urine HCG) or breast-feeding. Women 
of childbearing age must avoid becoming pregnant while on study. 
3. Active uncontrolled viral, bacterial or fungal infection 
4. Patient seropositive for HIV-I/II; HTLV -I/II 
 
7.0 
RECRUITMENT PLAN 
 
One of the BMT attendings will see the patient in consultation; typically, this is the outpatient BMT 
attending.  As part of the consultation, the BMT attending will present the patient with the risks and 
benefits of different types of cytoreduction and transplants. The BMT attending will then recruit 
patients who fulfill the eligibility criteria as listed in Section 6.0 for this study.  After confirmation of 
patient eligibility by the medical or Protocol Participant Registration office, one of the participating 
investigators authorized to obtain consent will obtain informed consent. A copy of the signed informed 
consent will be placed in the chart, as well as in the research file. 
 
8.0 
PRETREATMENT EVALUATION 
 
8.1. 
Pretreatment Evaluation of the patient 
 
Prior to instituting preparatory cytoreduction, the patient will receive an extensive medical evaluation: 
 
This evaluation should ideally include the following: 
 
Complete physical examination 
 
Detailed history with special attention to prior medical history, allergies, previous therapies, and 
response to treatment 
 
Dental evaluation. 
 
Laboratory studies performed may include: 
 
Complete Blood Count with differential count and reticulocyte count. 
 
Bone marrow aspiration and biopsy will be performed within approximately 1 month from starting 
cytoreduction.   Marrow aspiration will be studied by morphology. It will also be studied by cytogenetic 
analysis by karyotype and FISH studies  as per the discretion of the each institution’s treating physician.* 
Bone marrow biopsy should be performed for the determination of cellularity. 
 
Coagulation profile 
 
Serum  chemistries  including  BUN,  creatinine,  electrolytes,  Calcium,  magnesium,  phosphorus, 
glucose, total protein, albumin, liver function tests (AST, ALT, bilirubin, alkaline phosphatase) and 
LDH. Patients with advanced MDS or AML may also have uric acid determination if indicated. 
 
Chest and other X rays as clinically indicated 
 
Electrocardiogram 
 
Gated pool scan or echocardiogram 
 
Urinalysis 
 
Infectious Disease Markers will be tested as per each institutional guidelines as well as the discretion 
of the treating physician 
 
In addition, all patients will undergo pre-transplant complete immunologic evaluation as per each 
Center’s standard testing and at the discretion of each institution’s treating physician. 
 
Blood  or  marrow  will  be  sent  for  diagnostic  molecular  pathology  for  DNA  extraction  for  the 
definition of donor host differences. 

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*Cytogenetic studies will be obtained from marrow and/or peripheral blood cells. In cases of "same sex" 
donor recipient combinations, restriction fragment length polymorphisms (RFLP) or other institutional 
standard CLIA approved analyses will be carried out in an attempt to define donor/host differences. 
 
8.2.      Pretransplant Evaluation of the Donor 
 
Family Donor 
 
Any consenting healthy family donor who is HLA compatible with the recipient will be given highest 
priority as a potential donor for PBSC or marrow transplant as a standard of care or per other study. A 
prospective HLA-non-identical related donor must be at least genotypically HLA-A, B, C, DRB1 
haploidentical to the patient, but can differ for 1-4 HLA alleles on the unshared haplotype. Selection of 
the histocompatible donor will be based on high resolution typings of HLA A, B, C and DRB1 loci to be 
carried out on the recipient, and his/her siblings, parents or other family members. 
 
The donor must also provide signed informed consent to receive a 4-6 day course of G-CSF, and to 
undergo 1-3 leukaphereses. 
 
In preparation for the stem cell donation, the donor will provide informed consent and then undergo a 
detailed medical history and physical examination. Clinical studies may include: 
-     DEB testing (for first degree related donors) to be performed. 
-     Full hemogram 
-     Coagulation profile 
-     Complete screening biochemical profile. 
- 
Cytogenetic studies (RFLP) will be performed on peripheral blood if the donor is of matched sex and 
may, per institutional practice, be obtained regardless of sex match. 
-     Type and cross match 
- 
Infectious disease markers will be tested  per each institutional guidelines or at the discretion of the 
treating physician 
-     Urinalysis 
- 
A chest x-ray and/or EKG or other additional medical evaluation will be obtained as  clinically 
indicated by the evaluating physician. 
-     Blood  or  marrow  will  be  sent  for  diagnostic  molecular  pathology  for  DNA  extraction  for  the 
definition of donor host differences. 
-     Pregnancy testing will be performed for postpubertal and premenopausal female donors 
 
Unrelated donor 
Unrelated donors will undergo preparation for peripheral blood harvest as per the standards of the 
National Marrow Donor Program (NMDP). The donor will undergo pretransplant work-up and will sign a 
consent for G-CSF administration and leukapheresis at the donor center, also according to standard 
procedure as dictated by the NMDP. 
 
9.0       TREATMENT/INTERVENTION PLAN 
 
9.1. PREPARATIVE CYTOREDUCTION 

Memorial Sloan-Kettering Cancer Center 
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IRB#: 08-031 A(10) 
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The below outlines the approximate schema of cytoreduction for allogeneic PBSCT: 
 
Day 
Treatment - Doses - Infusion guidelines 
 
-7  
Busulfan  
 
0.6-0.8 mg/Kg IV 
Q 12H 
over 2 hours 
 
-6  
Busulfan  
Dose adjusted per PK studies  
Q 1 2 H  
over 2 hours  
 
-5 
Cyclophosphamide 
10 mg/kg IV, 
Once daily 
over 1 hour 
Fludarabine 
35 mg/m2 IV 
Once daily 
over 30 minutes 
  
Rabbit Antithymocyte globulin  
2.5 mg/kg IV.  
On ce d aily  
over 6-9 hours  
 
-4 
Cyclophosphamide 
10 mg/kg IV, 
Once daily 
over 1 hour 
Fludarabine 
35 mg/m2 IV 
Once daily 
over 30 minutes 
  
Rabbit Antithymocyte globulin  
2.5 mg/kg IV.  
On ce d aily  
over 6-9 hours  
 
-3 
Cyclophosphamide 
10 mg/kg IV, 
Once daily 
over 1 hour 
Fludarabine 
Rabbit Antithymocyte globulin 
35 mg/m2 IV 
2.5 mg/kg IV. 
Once daily 
Once daily 
over 30 minutes 
over 6-9 hours 
  
Start Cyclosporine  
 
-2 
Cyclophosphamide 
10 mg/kg IV, 
Once daily 
over 1 hour 
Fludarabine 
35 mg/m2 IV 
Once daily 
over 30 minutes 
  
Rabbit Antithymocyte globulin  
2.5 mg/kg IV.  
On ce d aily  
over 6-9 hours  
 
-1  
Rest day  
 
0** 
CD34+ PBSCT 
+1 
Start G-CSF 
 
** Day 0 could extend to two days 
 
Busulfan 
As of April 2012, patient accrual is nearly complete. As a result, after the completion of the planned 25 
patient study, we have amended the protocol to accrue at most an additional 20 patients in order to 
gain clinical experience using alternative levels of Busulfan. Previously, patients were treated with 
0.8-1.0 mg/kg of Busulfan. 
 
Of the 25 patients previously treated on this protocol, at doses of 0.8-1.0 mg/Kg of busulfan, 
12  patients  had  adequate  busulfan  levels,  and  TEN  patients  had  HIGH  busulfan  levels 
requiring a dose reduction, with no patients with low levels requiring an increase in the dose. 
 
Toxicity included: oral mucositis – grade 3 for 10 patients and grade 4 for one patient.  Five 
patients had hyperbilirubinemia; seven patients had transaminitis and one patient veno- 
occlusive disease. One patient developed renal failure. Two patients developed pulmonary 
hemorrhage and one patient developed a gastrointestinal hemorrhage. 
Based on this data, in this continuation study, the first 10 additional patients will be treated at 0.6-0.8 
mg/kg of Busulfan. If no primary graft failures are observed in these 10 patients, then a second cohort 
of 10 patients will be treated at 0.4-0.6 mg/kg. 
 
If however, at any time during this accrual a graft failure is observed, then the Busulfan dose will be 
modified and a final cohort of patients will be treated at the initial dose of 0.8-1.0 mg/kg. 

Memorial Sloan-Kettering Cancer Center 
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Amended:  06/18/14 
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Although no graft failure has been seen with the dose of .6-.8 mg/kg of Busulfan, it was decided to 
enroll the remainder of the patients at this cohort, as a precautionary measure and in order to maintain 
the safety and effectiveness of the condition regimen. Some patients have had some evidence of mixed 
chimerism, and we therefore do not see any benefit in reducing the Busulfan dose any further. 
 
- 
Busulfan pharmacokinetics will be done and dose adjustments will be made according 
to “institutional” standard clinical practice as indicated.  The optimal desired steady 
state CSS target should be 300-350. 
 
Research participants will have busulfan levels drawn whenever possible after the first dose 
on day 1, with adjustments in dosing based on the pharmacokinetics of the first dose 
according to institutional standard practice as indicated. The doses administered on days -7 
and -6 should be adjusted if patient is > 125% ideal body weight and should be calculated on 
adjusted ideal body weight per MSKCC standard of care guidelines. Once pharmacokinetics 
are available, subsequent dosing will be adjusted as per pharmacokinetics. 
 
-      Levetiracetam or other antiseizure medications may be administered for seizure prophylaxis with 
Busulfan from day –8 until day -4 
 
 
 
-     Patients should not receive any acetaminophen or azoles during busulfan administration. 
 
Cyclophosphamide 
Cyclophosphamide 10 mg/kg is to be given as an approximately 1-2 hour infusion for 4 days for a total 
dose of 40 mg/kg.  Strict attention should be made to vigorous hydration, fluid balance and maintenance 
of good urine output. Mesna may be given per institutional practice. The dose will be adjusted according 
to patients ideal body weight for obese patients. 
 
Fludarabine 
Fludarabine 35 mg/m2 will be given IV over approximately 30 minutes daily for 4 days for a total dose of 
140 mg/m2. The dose will be adjusted according to renal function according to Institutional guidelines. 
 
9.2 
IMMUNOSUPPRESSIVE THERAPIES 
 
Graft Failure Prophylaxis 
 
Methylprednisolone 1 mg/kg/day intravenously approximately every 12 hours will be given on days -5, - 
4,  -3,  and  -2  immediately  prior  to  the  infusion  of  antithymocyte  globulin.  It  will  be  discontinued 
thereafter. Methylprednisolone will be given with the infusion of ATG as per institutional guidelines, and 
will be discontinued after the completion of the ATG infusion. 
 
Rabbit antithymocyte globulin (Thymoglobulin) 2.5 mg/kg will be given once daily on days -5, -4, -3 and 
-2. Premedication will include the use of methylprednisolone (as defined above). In the event of a severe 
reaction to antithymocyte globulin, further doses of the agent will not be administered.   In this event, 
Equine antithymocyte globulin (ATGAM, Upjohn) 15 mg/kg IV once daily can be substituted for each 
remaining day of ATG on the schema. In the event of reaction to ATGAM, Alemtuzumab (Campath 1H) 

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FLU 
FLU 
FLU 
FLU 
CY 
CY 
CY 
CY 
ATG 
ATG 
ATG 
ATG 
 
 
 
at 10 mg/m2 IV once daily may be administered for each remaining day of ATG on the schema. 
 
GVHD Prophylaxis 
 
 Cyclosporine- Patients will receive cyclosporin A (CSA) as GVHD prophylaxis. CSA therapy will begin 
on day -3 with a taper commencing on day +100, to be completed by day +180 unless the patient 
develops  graft-versus-host  disease.    For  adults  with  normal  baseline  renal  function (creatinine <1.2 
mg/dL), the initial CSA dose is recommended to be 2.5 mg/kg IV approximately over 2 hours every 12 
hours; for children <40 kg, the initial dose  is recommended to be 2.5 mg/kg IV  approximately over 2 
hours every 8 hours. Initial and subsequent doses of CSA may be adjusted and administered as per 
institutional guidelines. Trough levels will be obtained, and doses will be adjusted according to each 
Center’s standard of care guidelines. 
 
Additional GVHD Prophylaxis will be administered to patients as per guidelines outlined in Table 
9.3.2.2, Guidelines for achieving target allograft cell doses. 
 
Other 
G-CSF  will  be  administered  to  all  patients  post  transplant  starting  day  +1  as  per  institutional 
guidelines. G-CSF doses will be rounded according to institutional guidelines. 
 
 
 
APPROXIMATE SCHEMA OF CYTOREDUCTION AND PREPARATION FOR ALLOGENEIC PBSCT 
 : 
 
DONOR 
-6 
-5 
-4 
-3 
-2 
-1 
0 
 
G-CS F 
 
 
 
Miltenyi 
CYTOPHERESIS 
CD34 Column 
 
 
 
PATIENT 
 
 
 
BU 
BU 
CD34+ 
PBSCT 
 
 
 
 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
+1 
 
Start G-CSF 
 
START CSA  
 

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9.3       STEM CELL COLLECTION 
 
9.3.1 Mobilization of Donor 
Related Donors 
Following screening and enrollment, the donor will receive mobilization therapy with G-CSF as per each 
institution’s guidelines. 
 
Unrelated Donors 
For Unrelated donors, G-CSF will be administered and the leukaphereses obtained according to the 
National Marrow Donor Program protocol and IND. Mononuclear cell fractions collected on the fifth and 
sixth days will be pooled. CD34+ progenitor cells in the mononuclear cell rich leukapheresis cell fraction 
will be positively selected. 
 
9.3.2. Progenitor Cell Collection and Processing 
 
9.3.2.1 Leukapheresis – for Related Donors 
Leukapheresis will be performed on a continuous flow cell separator according to Institutional standards 
and will commence on the morning of the 5th  day of G-CSF treatment. The anti-coagulant used for the 
procedure will be acid citrate dextrose (ACD). No additional anti-coagulants or additives (heparin etc.) 
should be added beyond those normally used during leukapheresis. The volume of blood processed per 
leukapheresis session should be approximately 3-4 times the total blood volume as tolerated by the donor. 
A  unique  identification  and  labeling  system  shall  be  used  to  track  the  leukapheresis  product  from 
collection to infusion  as per each institution’s guidelines. 
 
The target allograft cell doses following processing on the CliniMACS device are a CD34+ cell dose of > 
5.0 x 106 cells/Kg recipient weight with a maximum CD3+ cell dose of < 5.0 x 104 cells/Kg of recipient 
weight. A minimum CD34+ cell dose of 2.5 x 106  cells/Kg will be targeted. If this minimum target 
CD34+ cell dose is not achieved after 2 leukaphereses, a third leukapheresis may be planned after 
discussion with the principal investigator of the Institution. 
 
This protocol requires an absolute minimum CD34+ cell dose of 2.0 x 106  cells/Kg in order to be 
evaluable for all study endpoints. If the post CD34+ selection allograft content is < 2.0 x 106 CD34+ 
cells/Kg after 2 leukapheresis procedures, the Transplant Center should perform a third leukapheresis 
collection without CD34+ selection in order to ensure that an adequate CD34+ cell dose is transplanted. 
Since this graft will contain a high number of CD3+ cells, such patients must also receive the addition of 
pharmacologic GvHD prophylaxis per Institutional standards. 
 
During mobilization and leukapheresis, Institutional Standards for donor supportive care should be 
maintained. 
 
9.3.2.2. CD34+Selection with the CliniMACS Device – Related or Unrelated Donors 
 
CD34+ cell selection will be performed according to procedures given in the CliniMACS Users Operating 
Manual and institutional Standard Operating Procedures (SOPs) in place and validated at the study sites. 
 
Products will be received into the cell processing laboratories and will be either processed that day, or 
stored overnight.  Products stored overnight must be processed the following day. At receipt the  product 

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will be accessioned and assigned a unique product identifier if not already assigned during collection. 
The product will be inspected at the time of receipt and the label information regarding donor name, 
medical record number (or other identifier) and ABO and Rh group will be compared for consistency to 
the information in the laboratory chart record and physicians order form. 
 
The product will be sampled for total nucleated cell count (TNC), and if processing is to be performed on 
the day of receipt, additional sample will be obtained for starting CD34+ cell and starting T cell content 
and product sterility.  Products may be stored overnight for one of two reasons, 1) late arrival preventing 
selection and infusion the same day, or 2) low TNC content that would permit pooling of two collections 
for a single column selection.  If the product is to be stored overnight, the cells will be diluted to < 2.0 x 
108   cells/mL  using  either  autologous  plasma  or  the  CliniMACS  PBS/EDTA-1.0%  Human  Serum 
Albumin  (HSA) (CliniMACS  buffer)  and  stored in a  monitored refrigerator at  either 6oC or 2-8oC 
depending upon the institutional policy.  Products that are stored overnight will be sampled the following 
day, prior to processing, for TNC, starting CD34+ cell and starting T cell content, and for sterility. 
 
Cell processing personnel will receive training by Miltenyi on the CliniMACS system prior to initiation 
of clinical product selection. The site will provide documentation to Miltenyi on competency in the 
processing procedures including the results of validation runs on the CliniMACS System. 
 
Analysis of allograft 
Samples will be taken from each leukapheresis product pre- and post-CD34+ selection and 
characterized as follows: 
• Graft Evaluation (all of these tests are standard of care) 
 
Gram stain (done locally) post-selection on each leukapheresis product 
 
Total nucleated cell count (done locally) pre- and post-selection on each leukapheresis 
product 
 
Endotoxin testing post-selection on each leukapheresis product, done locally or sent to an 
authorized lab 
 
Flow cytometric analysis for CD34+  cells pre- and post-selection done locally using 
validated SOPs 
 
Flow cytometric analysis for CD3+ cells pre- and post-selection and log depletion on each 
leukapheresis product done locally using validated SOPs 
 
Viability testing (trypan blue dye exclusion assay) post-selection 
 
14 day sterility cultures post-selection on each leukapheresis product 
 
• Criteria for release of product 
 
Viability 70% after selection 
 
Negative gram stain 
 
CD34+ cell count of product 
 
As noted above, the target optimal allograft cell doses following processing on the CliniMACS 
device  include both a CD34+ cell count of  > 5.0 x 106/kg recipient weight and a CD3+ cell dose 
of < 5.0 x 104/kg recipient weight.   The targeted minimum CD34+  cell dose following CD34+ 
selection is 2.5 x 106/kg. If after two leukapheresis collections followed by CD34+  selection the 
total allograft contains 2.5-5.0 x106 CD34+ cells/kg and < 5.0 x104 CD3+ cells/kg, a total of three 
leukapheresis collections followed by CD34+ selection are allowed as long as the total CD3+ cell 
dose transplanted does not exceed 5.0 x 104/kg.  That is, a graft containing 2.5-5.0x106  CD34+ 

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Leuka- 
Pheresis 
Attempt 
Total CD34+ dose 
after Leu k aph eresis1 
(X 106/Kg ) 
Total CD3+ dose 
after Leu k aph eresis1 
(x 104/Kg ) 
ACT ION  
< 1.0 
1.0-2.0 
2.0-4.9 
> 5.0 
< 5.0 
> 5.0 
Administer 
Allograft 
Pro ceed 
To nex t 
L eu k a- 
Ph eresis  
L eu k a- 
Pheresis 
Co m pleted 
Reduce CD3 
dose to < .5. 
Maintain CD 
34 dose > 2.0 
B eg in 
Gv HD 
Pro p hy la xis  
1 
X 
X 
X 
X2 
1 
X 
X 
X 
X3 
1 
X4 
X4 
X4 
X 
X 
X 
1 
X4 
X4 
X4 
X 
X 
X3 
2 
X 
X 
X 
X 
2 
X 
X 
X5 
2 
X4 
X4 
X 
X 
X 
2 
X4 
X4 
X 
X6 
2 
X 
X7 
X7 
X 
X8 
X9 
3 
X 
X 
X 
X 
3 
X 
X 
X 
X 
3 
X 
X 
X10 
3 
X 
X 
X10 
3 
X 
X 
X 
X 
3 
X 
X 
X11 
3 
X12 
X7 
X7 
 
 
cells/kg and < 5.0 x104  CD3+  cells/kg is acceptable whereas a graft containing 5.0x106  CD34+ 
cells/kg but > 5.0 x104 CD3+ cells/kg is not.  A major goal is to administer a CD34+ cell dose > 
5.0x106/kg while limiting the CD3+  cell dose to < 5.0 x104  but as long as a minimum of 2.0 
x106/kg CD34+ cells are infused, the CD3+ cell dose should be kept to < 5.0 x104 /kg.  It may be 
possible to give only a proportion of the CD34+ selected product in order to maintain an adequate 
CD34+ cell dose while limiting the CD3+ cell dose to < 5.0 x104 /kg. 
 
It is also possible that doses of CD34+ cells far exceeding 5.0 x 106/kg can be given without 
exceeding the maximum T cell dose of 5.0 x104  CD3+  cells/kg.  High doses of CD34+  cells in 
extensively T cell depleted transplants are postulated to hasten immune reconstitution, without 
altering the low risk of  GVHD. Consequently, there is no upper limit for the dose of CD34+ 
cells/kg as long as the dose of CD3+ cells does not exceed 5.0 x104 /kg. Furthermore, a minimum 
of 2 leukaphereses should be obtained from each donor even if the first leukapheresis provides 
5.0 x 106  CD34+  cells/kg, if the anticipated cumulative CD3+  cell dose is expected to be < 5.0 
x104 /kg of recipient weight. 
 
Decisions concerning the release of samples from the CD34+ selected product will be based on  
CD34+ 
and CD3+ cell analysis done by the flow cytometry laboratory at the site.  The attached table outlines the 
various scenarios that may be encountered after each CD34+ cell selection and 
indicates 
appropriate 
steps for achieving target allograft cell doses. 
 
Table 9.3.2.2 – Guidelines for achieving target allograft cell doses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 
This number refers to CD34+ (x 106/Kg) or CD3+ (x 104/Kg) doses after CD34+ selection. If after leukapheresis   #2 or #3, 
this number refers to total pooled CD34+ and CD3+ cell doses following all CD34+ selections 
2. 
If unsuccessful in reducing CD3+ cell dose to < 5.0 x 104  cells/Kg at any CD34+ cell dose, hold allograft overnight 
and proceed to leukapheresis #2. If leukapheresis #2 results in a post selection CD34+ cell count of > 2.0 x 10 6 cells/Kg with 
CD3+ cell dose of < 5.0 x104 cells/Kg, give that allograft, proceed to leukapheresis #3 and discard or cryopreserved graft from 
leukapheresis #1. The primary goal is to reduce the total CD3+ cell dose to < 5.0 x 10 4  cells/Kg while maintaining the total 
CD34+ cell dose to > 2.0 x 106 cells/Kg. 

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3.    Refers to any one of these three possible CD34+ cell doses (<1.0 – 4.9) 
4. 
If unsuccessful in reducing   CD3+ cell dose to < 5.0 x104  cells/Kg at any CD34+ cell dose, begin GvHD prophylaxis 
and administer allograft within 24 hours 
5.    If able to reduce CD3+ cell dose to < 5.0 x 104 cells/Kg while maintaining CD34+ cell dose > 2.0 x 106 cells/Kg,   proceed 
to leukapheresis #3. If unsuccessful in reducing CD3+ cell dose to < 5.0 x 10 4/Kg at any CD34+ cell dose,     begin       additional 
GvHD prophylaxis with steroids at 2.0 mg/Kg/day or Mycophenolate mofetil (Cellcept®)* and then administer allograft. 
6.    Refers to either one of the two possible CD3+ cell doses. 
7.    Proceed to leukapheresis #3, but do not perform CD34+ selection on product from leukapheresis #3 
8.    If  the  CD3+  cell  dose  is  >  5.0  x  104   /Kg,  begin  additional  GvHD  prophylaxis  with  steroids  at  2.0  mg/Kg/day  or 
Mycophenolate mofetil (Cellcept®)* and then    administer product from leukapheresis #2. 
9.    If the patient has already received total allograft containing > 2.0 x 106/kg CD34+ cell dose and < 5.0 x 104/kg  CD3+ cell 
dose, hold allograft of leukapheresis #3. If the patient has received total allograft containing < 2.0 x 10 6/kg CD34+ dose, 
administer product from leukapheresis #3 and begin additional GVHD prophylaxis with steroids at 2.0 mg/kg/day or 
Mycophenolate mofetil (Cellcept®)*. 
10.  Begin additional GvHD prophylaxis with steroids at 2.0 mg/Kg/day or Mycophenolate mofetil (Cellcept®)* and then 
administer product from leukapheresis  #3. 
11.  Contact one of the Protocol Chairs to discuss options. 
 
* Mycophenolate mofetil (Cellcept®) will be administered as per institutional guidelines and if needed, Mycophenolate 
sodium (Myfortic®) may be substituted for Mycophenolate mofetil (Cellcept®) after appropriate dose conversion. 
 
9.4. 
Stem Cell Transplantation  
 
The final CD34+ T-cell depleted product will be infused into the patient intravenously according to 
Institutional standards. The day of the transplant will be designated as day 0 of transplant. 
 
9.5. 
Supportive Care 
 
Institutional standard of care guidelines will be followed for transplant related supportive care, including 
monitoring for CMV reactivation and provision of PCP prophylaxis. CMV safe blood products will be 
administered and prophylaxis against peritransplant infections by mold must be used in all centers 
according to Institutional guidelines. 
 
10.0  EVALUATION DURING TREATMENT/INTERVENTION 
 
Post-transplant Evaluation 
 
 
a. 
Clinical Assessments 
 
Patients will undergo physical examinations daily until discharge with particular attention to assessments 
of potential toxicities induced by preparatory cytoreductive therapy, including mucositis, cystitis, sepsis, 
pneumonia,  veno-occlusive  disease  (VOD)  and  transplant-associated  complications  including  graft 
failure, acute and chronic GvHD, and transplant associated infections.  Patients are closely monitored for 
alterations in vital signs, weight, oral and intravenous intake, and intestinal and urinary output. Cardiac 
assessments are obtained prior to admission to assess cardiac function and thereafter when clinically 
indicated. Pulmonary status is closely monitored when clinically indicated by radiographic and functional 
analysis. Baseline physical examinations and any subsequent abnormal new findings will be recorded. 
Following discharge, physical examination, will be performed at least every 2-4 weeks or as clinically 
indicated. 

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All timelines are dose approximations and adhere to good clinical practice. Certain tests may be 
held at the discretion of the treating physician and/or if deemed in the best clinical interest 
of the patient. 
 
 
 
b.          Laboratory Evaluations 
Baseline laboratory evaluations and any subsequent abnormal new findings will be recorded. 
 
-    Complete hemograms: 
- daily until successful discontinuation of GCSF - then three times/week until discharge; 
- and at least every two weeks post-discharge to day 100. 
 
-    Comprehensive metabolic panel with liver function tests 
- twice weekly for the first 30 days 
- then weekly to discharge 
- more frequently if clinically indicated. 
 
- 
Bone marrow aspirates or peripheral blood will be obtained to monitor engraftment by FISH for sex- 
mismatched donor and host or by RFLP or VNTR for sex matched donor or sex- mismatched donor 
and host, at approximately 1,3,6,12 months. Further engraftment studies after the 1-year mark will be 
done as clinically indicated. 
 
-     Bone Marrow aspirates for morphology, and cytogenetics will be done at the Investigator’s discretion. 
Proposed  time  points  are  at  approximately  1,3,6,12  months  for  patients  with  MDS  or  AML. 
Additional analyses will be done as clinically indicated. 
 
- 
Immunologic reconstitution will be monitored by in vitro assays, possibly including but not limited to 
phenotypic analysis of circulating lymphocytes, lymphocyte transformation responses to T-cell 
mitogens, and to viruses, and immunoglobulin levels and antibody responses. 
 
11.0     TOXICITIES/SIDE EFFECTS 
Patients recruited to this transplantation trial are individuals who are either referred by physicians or self- 
referred for marrow transplantation as a potentially curative treatment for their malignancy. Prior to 
consideration for transplant, all patients undergo a series of 1-3 hour consultations discussing the risks 
and potential benefits of an allogeneic marrow transplant and the different procedures which will be a 
normal part of the transplant course. The risks and potential benefits of the transplant procedure, as well 
as the participation in any given research, experimental, or therapeutic protocol are also discussed. All 
patients entered into our studies provide written informed consent. In the case of minors, consent of the 
parent or guardian and assent of the child are obtained. All protocols and consent forms are reviewed and 
approved by the Institutional Review Board. 
 
The potential risks of an allogeneic transplant from an HLA-compatible unrelated donor or HLA- 
mismatched related donor  are significant. These risks along with approaches to circumvent or mini mize 
their effects on the health and well being of the patient can be summarized as follows. 
 
11.1.      General Description of Risks to Recipients 

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Infections and hemorrhage constitute major and continuing risks throughout the period of marrow aplasia. 
These are, however, also the major risks associated with the primary disease. Certain opportunistic 
infections remain a risk in bone marrow transplant recipients beyond recovery of circulating leukocytes, 
for at least 9-12 months post-transplant, e.g. Pneumocystis carinii and cytomegalovirus. 
 
The above risks are carefully considered both by the physicians and by the patients prior to admission to a 
study protocol. The patients who are being considered for allogeneic peripheral blood stem cell 
transplantation are afflicted with Fanconi anemia and aplastic anemia, myelodysplastic syndrome or 
leukemias which are lethal diseases for whom a hematopoietic stem cell transplant from a an HLA- 
compatible unrelated donor or HLA-mismatched related donor currently constitutes the only curative 
option in the treatment of this disease. In the protocol proposed, use is made of an experimental device 
produced by Miltenyi Biotec, Auburn, CA. This device is approved for experimental applications under 
an IDE from the Food and Drug Administration. 
 
All patients undergoing cytoreduction in the protocol will be treated with busulfan, cyclophosphamide 
and fludarabine.  They will also receive anti-human thymocyte globulin to prevent graft rejection. All of 
the treatments as well as other drugs used before and during the transplant may produce side effects. 
These risks are listed below. 
 
a.          Busulfan 
- Myelosuppression, complete ablation is expected. 
- Gastrointestinal: nausea and vomiting, anorexia, diarrhea 
- Alopecia 
- Mucositis 
- Seizures: generally preventable by phenytoin therapy or other antiseizure medications such as Keppra, 
started 24 hours prior to administration and continued for 24 hours post busulfan 
- Abnormal liver function 
- Pulmonary fibrosis 
- Gonadal dysfunction 
- Hyperpigmentation 
 
 
 
 
b.          Cyclophosphamide 
- Bone marrow suppression, complete bone marrow ablation is expected. 
- Gastrointestinal: Nausea, vomiting, anorexia, diarrhea, stomatitis, esophagitis, colitis 
- Alopecia 
- Fever 
- Serious hypersensitivity reactions: Edema, rash, anaphylaxis 
- Water retention: inappropriate secretion of ADH, usually manifested 4-8 hours after IV administration 
- Cardiomyopathy:  Cyclophosphamide may cause a severe, sometimes lethal cardiomyopathy. 
- Hemorrhagic cystitis:  serious complication related to the interaction of cyclophosphamide metabolites 
- Skin rash: This may develop 1-3 days post infusion and subsides thereafter. 
- Hemolytic anemia 
- Sterility: This is a likely complication after puberty. Risk may be reduced in young children. 
- Late effects:   Late effects may occur with varying degree following cyclophosphamide and include 

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growth failure, gonadal failure and sterility, hypothyroidism, and secondary malignancies. 
 
c.          Fludarabine 
- Nausea, vomiting 
- Mouth sores, stomach cramps and diarrhea, 
- Jaundice, and elevations of liver enzymes. 
- Scaling and redness of the skin, which is usually of short duration. 
- Effects on the nervous system are not usually seen at the fludarabine dose used in this protocol, but, 
when they occur, can include cerebellar dysfunction with loss of balance and trouble walking. 
 
d.           Methylprednisolone 
- Increased risk of infection 
- Increased blood pressure 
- Stomach upset including ulcers. Prophylaxis (such as antacids) will be administered as protection. 
- Hyperlipidemia 
- Hypergylcemia 
 
e.          Anti-Thymocyte Globulin 
- ATG is a rabbit protein which may induce an immune response in humans. Prior exposure to rabbit 
proteins  may  predispose  to  serious  allergic  reactions  such  as  anaphylaxis,  generalized  urticaria,  or 
bronchospasm. This risk remains significant. Such reactions will be treated with epinephrine and anti- 
histamines. In the event of a severe systemic allergic reaction, a trial of an alternative equine ATG will be 
administered. If a similar reaction occurs with the equine ATG, no further ATG will be administered. 
 
- Serum sickness - approximately 10-30% of patients treated with rabbit ATG will develop a late immune 
reaction to the globulin resulting in serum sickness 3-10 days after administration. This is manifested by 
fever, rash, and arthralgias. Renal toxicity is rare. Prednisone for one week at 1 mg/kg has been shown to 
be effective therapy. 
 
- Fever and chills - are managed by antipyretics and meperidine but are usually only severe after first 
dose. 
 
- Leukopenia/thrombocytopenia - ATG may also cause further decrease in leukocyte and platelet counts 
which will be managed by transfusion therapy. 
 
f.    Cyclosporine 
• Renal dysfunction 
• Increased blood pressure 
• Hirsutism 
• Neurological side effects: Tremor (common), seizures (rare), ataxia, cortical blindness (rare), and 
peripheral neuropathies. 
• Liver toxicity 
• Hyperkalemia or hypokalemia 
• Low serum magnesium 
• Gastrointestinal complaints including anorexia, nausea, and ileus 
• Gingival hyperplasia 
• Skin pigmentation changes 
• Depression 

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• Capillary leak syndrome (rare) 
• Lymphoproliferative disorders (malignant lymphoma) (rare) 
• Hemolytic anemia (rare) 
• Thrombotic thrombocytopenic purpura (rare) 
 
g 
G-CSF 
-- 
Fever 
-- 
Fatigue 
-- 
Bone pain 
-- 
Allergic reaction, mild to severe 
-- 
Splenomegaly 
 
h. 
 Pneumocystis carinii prophylaxis 
The risk of trimethoprim and sulfamethoxazole in the doses given are primarily hypersensitivity reactions 
and signs of folate deficiency. Any patient with known hypersensitivity to these compounds will not 
receive these drugs. The risks of parenteral pentamidine are primarily hypotension and hypoglycemia 
both of which will be monitored during and following administration of the drug. Hypokalemia or 
hypomagnesemia  associated  with  prolonged  QT  syndrome  or  Torsade  de  pointe  necessitates  strict 
electrolyte monitoring. The risks of aerosolized pentamidine are mild bronchospasm primarily observed 
in (prior) tobacco abusers and easily managed with bronchodilator therapy. 
 
i. 
Malignancies 
a. Patients transplanted for leukemia are at significant risk of recurrence of their original disease. 
 
b. Patients receiving T-cell depleted marrow grafts with ATG are at significant risk of developing an EBV 
lymphoproliferative disease. For patients treated with horse ATG, this risk is approximately 10-15%. 
However, for those treated with rabbit ATG, it is less than 4%. This complication might be prevented 
with Acyclovir prophylaxis and may be treatable by infusions of peripheral blood leukocytes from the 
marrow donor. 
 
c. Secondary malignancies - there is a possibility that secondary malignancies may develop. The age- 
adjusted incidence of secondary cancers in transplant patients after radiation and chemotherapy has 
recently been estimated to be 6.7 times higher than that of first cancers in the general population. Most of 
these were non-Hodgkin's lymphomas. 
 
j. 
Graft Failures 
The risk of rejection of a T-cell depleted related, HLA-disparate marrow and peripheral blood progenitor 
graft may be 20% or greater. Patients rejecting their grafts may receive a secondary transplant from the 
same or an alternative donor, or may receive a reinfusion of autologous cryopreserved marrow whenever 
available. 
 
k. 
Graft Versus Host Disease 
Acute GvHD is manifested by skin rash; hepatitis; ulceration of the surfaces of the oral cavity, esophagus, 
and intestines; and suppressed or delayed recovery of the hematopoietic and immune system. In patients 
transplanted and engrafted with SBA-E- T-cell depleted marrow from HLA 1-3 allele disparate related 
donors, this complication has been observed in fewer than 20% of patients and has rarely been severe. It 
may be fatal in at least 20-50% of cases and may also predispose to lethal infections which contribute to 

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an additional mortality of 10-25%. Severe acute GvHD will be treated with intense immunosuppressive 
therapy according to standard clinical practice or other experimental protocol. 
 
Approximately 50% of patients with acute GvHD may also develop chronic GvHD, manifested to varying 
degrees by scleroderma-like changes of the skin, cirrhosis of the liver, sclerosis of lacrimal and salivary 
ducts, chronic inflammation and scarring of the gastrointestinal tract with consequent malabsorption and 
diarrhea, chronic bronchitis, and suppression of the immune system. This can be treated with standard or 
protocol-based experimental immunosuppression, but may be refractory. 
 
l. 
Blood product infusions 
The volume of the T-cell depleted peripheral blood stem cells infused is approximately 30-50 cc. They 
may induce allergic reactions. Small, subclinical pulmonary emboli may occur, but these rarely if ever 
require any intervention. Standard pre-medications for blood products may be used before administration 
of the marrow graft. 
 
Infusions of fractionated blood products may produce volume overload, which can be managed with 
diuretics. They may also induce allergic reactions of variable severity, many of which can be prevented or 
mitigated by premedication with antipyretics, antihistamines, and narcotics. These products may also 
serve as vectors of serious infection (e.g., CMV, hepatitis, AIDS). To circumvent this, prospective blood 
and marrow donors will be screened  as per each institution’s guidelines. CMV antibody (-) blood 
products will be used in CMV (-) individuals, whenever possible, regardless of the antibody status of the 
marrow donor. ALL blood products are irradiated (3000r, 137Cs) to circumvent the risk of GvHD caused 
by contaminating lymphocytes in the transfused fractions. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Definition of events in the post-transplant course important for analysis and treatment 
 
 
12.1.     Graft Failure or Rejection 
Graft failure or rejection will be the primary endpoint of this study. 
Primary non-engraftment is diagnosed when the patient fails to achieve an ANC 500/l at any time in 
the first 28 days post-transplant. If (1) after achievement of an ANC 500/mm3, the ANC declines to 
<500/mm3  for more than 3 consecutive days in the absence of relapse, or, (2) there is absence of donor 
cells in the marrow and/or blood as demonstrated by chimerism assay in the absence of relapse, a 
diagnosis  of  secondary  graft  failure  is  made.  If,  however,  recurrence  of  host  MDS  is  detected 
concurrently, the patient is not evaluable for graft failure or rejection. Patients with evidence of graft 
failure without evidence of recurrence of host MDS will have additional studies drawn to ascertain cause 
and define relevant histoincompatibilities. 
 
These analyses may include (1) Evaluation  of  bone  marrow  aspirates  and  biopsies  for  residual  or 
recurrent MDS/AML, when indicated, and (2) Culture and/or molecular analyses of marrow and/or blood 
for viral pathogens potentially causing graft failure including CMV, HHV6 and parvovirus B 19. 
 
Patients who suffer graft failure will be considered for a secondary transplant. The need for additional 
immunosuppression or treatment for viral infection prior to the secondary transplant will be determined 
by the results obtained from chimerism and viral studies. We have performed secondary transplants for 

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patients with graft failure and have published our experience on rescuing patients with graft failure with 
fludarabine based regimens – including one patient with Fanconi anemia (Chewning JH, et al. 
Fludarabine-based conditioning secures engraftment of second hematopoietic stem cell allografts 
in the treatment of initial graft failure.  Biol Blood Marrow Transplant. 13(11):1313-23; 2007) 
 
 
12.2.     Early post-transplant severe morbidity and mortality 
The occurrence of severe post transplant regimen-related severe morbidity (grade IV toxicity) and/or 
mortality will be the second endpoint of this study. In the context of the agents or agent-combination used 
for cytoreduction used, particular attention will be given to toxicity involving (1) the liver, (2) the lungs, 
(3) the  oral  mucosa and gastrointestinal tract,  and (4) the  central  nervous system.  The  grading for 
monitoring the morbidity and mortality will be based on the NCI/CTEP common toxicity criteria version 
3.0. 
 
 
 
12.3.     Graft Versus Host Disease 
 
Patients will be observed for acute and/or chronic GvHD. Standard clinical criteria for the grading of 
acute and chronic GvHD will be done according to IBMTR guidelines See Appendices 3 and 4. 
 
To determine the severity of acute GvHD, data  may be collected approximately weekly to characterize 
the severity of symptoms and signs caused by GvHD and to evaluate possible confounding factors. Real 
time data collection of GvHD will include grades for each organ involved and overall grade. 
 
Patients with moderate to severe acute GvHD (grade II-IV)  will be treated with immunosuppressive 
therapy according to standard clinical practice or other experimental protocol. 
 
Treatment of chronic GvHD will consist of corticosteroids, and other agents or modalities, according to 
Institutional standard of care guidelines and protocols. 
 
12.4.     Leukemic Relapse 
 
For patients with MDS or AML, relapse will be analyzed as to type and genetic origin of the 
MDS/leukemic cells. These will be defined by an increasing number of blasts in the marrow over 5%, by 
the presence of circulating peripheral blasts, or by the presence of blasts in any extramedullary site. 
Cytogenetic analysis of the marrow and/or peripheral blood will also be obtained for the diagnosis of 
relapse. 
 
12.5.     Secondary malignancies 
Patients will be followed indefinitely through annual contact with their treatment center in order to 
track the risk of developing a secondary malignancy. 
 
 
 
13.0      CRITERIA FOR REMOVAL FROM STUDY 
 
Patients may be removed from the study at any point deemed appropriate by the principle investigator. 
However, once the busulfan is given, patients will continue on study until after administration of the stem 

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cells.  Failure to rescue the patient with stem cells at this point in the cytoreduction would most likely be 
fatal. 
 
 
 
14.0     BIOSTATISTICS 
 
This phase II trial is designed to investigate the safety and efficacy of hematopoietic stem cell 
transplantation for the treatment of patients with Fanconi Anemia lacking a genetically identical donor. A 
maximum of 25 patients will be accrued onto the study. It is anticipated that the accrual will last 3 years, 
and will include patients from 6 different centers. 
 
The primary objectives of this study are to assess the incidence of engraftment, graft versus host disease, 
and treatment related morbidity and mortality (treatment related morbidity will be assessed through the 
incidence of grade 1 to 3 toxicity). At the conclusion of the study, the probability of each these events will 
be computed along with their attendant 95% confidence interval. In addition, Kaplan-Meier estimates of 
overall and disease free survival will be computed over time for the entire cohort and by disease (AA and 
early MDS / advanced MDS and AML). 
 
In order to reduce patient risk, the study design includes early termination in the event of excessive graft 
failure, graft versus host disease, or early treatment related mortality during the accrual period.  The 
stopping rules are provided in the table below and consider only the marginal failure probabilities. 
 
 
 
Failure type 
# of failures needed 
to stop the study 
Projected probability 
of failure in 
population  
Probability of 
study completion (based 
on projection) 
Graft failure 
2 within the first 11 patients 
3 within the first 24 patients 
4 in 25 patients 
0.20 
0.10 
0.04 
0.89 
Acute 
Graft 
Versus 
Host 
Disease 
Grades 2-4 
2 within the first 8 patients 
3 within the first 19 patients 
4 in 25 patients 
0.25 
0.06 
0.05 
0.90 
Treatment 
Related 
Mortality 
4 within the first 10 patients 
5 within the first 14 patients 
6 within the first 19 patients 
7 within the first 23 patients 
8 in 25 patients 
0.40 
0.08 
0.15 
0.90 
 
As of April 2012, patient accrual is nearly complete in the HSCT Fanconi Anemia study. As a result, after 
the completion of the planned 25 patient study, we have amended the protocol to accrue at most an 
additional 20 patients in order to gain clinical experience using alternative levels of Busulfan. Previously, 
patients were treated with 0.8-1.0 mg/kg of Busulfan. In this continuation study, 10 patients will be 
treated at 0.6-0.8 mg/kg of Busulfan. If no primary graft failures are observed in these 10 patients, then a 
further cohort of 10 patients will be treated at 0.4-0.6 mg/kg. If however, at any time during this accrual a 

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graft failure is observed, then the Busulfan dose will be modified and a final cohort of patients will be 
treated at the initial dose of 0.8-1.0 mg/kg. If no graft failures are observed in 10 patients at a given dose 
level, then we are confident that the probability of graft failure in this population is less than 0.20. 
In addition to monitoring for graft failure, the stopping rules below will be used to monitor the additional 
20 patients for acute GvHD and treatment related mortality. 
 
 
 
 
Failure endpoint 
# of failures needed 
  Failure rate 
Probability boundary 
to stop the study 
in the population 
 
is crossed 
 
Acute graft versus host 
disease 
2 in the first 13 patients 
3 within 20 patients 
0.04 
0.10 
0.25 
0.94 
Treatment related 
mortality 
3 in the first 9 patients 
4 in the first 14 patients 
5 within 20 patients 
0.10 
0.09 
0.40 
0.96 
 
 
Although no graft failure has been seen with the dose of .6-.8 mg/kg of Busulfan, it was decided to enroll 
the remainder of the patients at this cohort, as a precautionary measure and in order to maintain the safety 
and effectiveness of the condition regimen. These patients have had some evidence of mixed chimerism, 
and we therefore do not see any benefit in reducing the Busulfan dose any further. 
 
15.0 
Research Participant registration and randomization procedures 
 
15.1   Research Participant Registration -  MSKCC 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 

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15.2 Research Participant Registration -  Other Centers 
 
Study coordinators at other institutions will contact the Research Study Assistant (RSA) at 
Memorial Sloan Kettering Cancer Center within 48 hours of patients signing the informed consent to 
notify him/her of the patient registration and send registration/eligibility documents to the Department 
of Pediatrics Clinical Trials Office at MSKCC. 
 
All patients must be registered at the site where they are being treated. 
Each participating institution must have an independent patient registration process  and 
the procedures by which patients are registered onto the protocol should be followed in 
parallel. 
 
 
 
Once eligibility has been established the patient will be assigned a unique ID number. This 
number is unique to the patient and must be written on all data and correspondence for the 
patient. This protocol patient number will be relayed to the sites via e-mail and will serve as the 
enrollment confirmation. 
 
 
16.0 
DATA  MANAGEMENT ISSUES 
 
 
16.1. Data Management at Participating Centers 
The PI at each site will be responsible for the conduct of the study and the 
monitoring of the progress and will review all case report forms. 
 
Research staff  will be assigned at Boston Children’s Hospital, Cincinnati Children’s Hospital, 
Children’s Hospital of Wisconsin, Rockefeller University, and Fred Hutchinson Cancer Research 
Center. 
 
Their responsibilities will include maintaining file documentation of data for the clinical trial on 
each patient enrolled on study and all regulatory documents. A designated data manager at each 
institution will be responsible for submitting the data on a weekly basis to the RSA at MSKCC. 
Contact Information: 
 
Pediatric Clinical Trials Office 
Memorial Sloan-Kettering Cancer Center 
405 Lexington Avenue 
3rd Floor 
New York, New York 10174 
Telephone:  ( 646 ) 888-5721 
Fax: (646) 888-5727 
 
The research staff at each site is responsible for upholding their institutional data management 
guidelines. 
 
All sites are using the same protocol, therefore all amendments will originate from Memorial Sloan 
Kettering Cancer Center and will be communicated to the other   sites. 

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16.1.1 Data Management at MSKCC 
 
A Research Study Assistant (RSA) at Memorial Sloan-Kettering Cancer Center, will be assigned 
to the study. The responsibilities of the RSA include project compliance, data collection, 
abstraction and entry, data reporting regulatory monitoring, problems and prioritization. 
 
MSKCC will be the data collection site for all 5 sites. 
Data collection forms will be drafted in a standard format and will be provided to each 
participating institution by MSKCC.   Case Report Forms (paper) will be submitted with the 
protocol.    Completed  data  collection  forms  will  be  submitted  to  Memorial  Sloan-Kettering 
Cancer Center on a weekly basis. 
 
The data collected for this study will be entered into a secure database by the MSKCC RSA. Data 
will be collected, stored, and monitored at an institutional level via the Clinical Record Database 
(CRDB version 3.3) system. 
 
Source documentation will be available to support the computerized patient record. Variables that 
will be recorded include the patient's birth date, date of diagnosis, date of study entry and 
histologic diagnosis. The results of the pretreatment and end of therapy evaluations, including the 
extent of disease evaluation (history, physical examination and imaging studies), baseline 
laboratory values, renal and hepatic function, will be recorded. The presence of toxicity during 
and after administration of the transplant will be monitored and recorded by each institution. On 
this study, we will be capturing and tracking Grade 3-4 toxicities which occur within 30 days 
following  a  transplant  and  are  potentially  attributable  to  treatment  on  study.  Hematologic 
toxicities which are attributable to underlying hematologic disease will not be tracked. The results 
of the extent of disease evaluation (history, physical examination and imaging studies) following 
each course of treatment will be collected by the participating institutions and recorded. The 
patient's disease status and last follow-up will be collected by the participating institutions and 
recorded. If disease progresses or recurs, the results of the repeat extent of disease evaluation will 
be collected by the participating institutions and recorded. Any secondary malignancy arising in 
any organ will also need to be captured in database. Data collected for secondary malignancies at 
annual visits will include: (1) site, (2) pathology, (3) grade, (4) treatment and (5) outcome. 
 
Standard baseline information will also be collected for donors. 
 
The protocol will be conducted as a single research study effort and data from each participating 
institution will be included in the analysis of results. 
 
16.2     Quality Assurance 
 
Registration reports will be generated to monitor patient accruals and completeness of registration data. 
Routine data quality reports will be generated to assess missing data and inconsistencies.  Accrual rates 
and extent and accuracy of evaluations and follow-up will be monitored periodically throughout the study 
period and potential problems will be brought to the attention of the study team for discussion and action 

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Random-sample data quality and protocol compliance audits will be conducted by the study team, at a 
minimum of  once a  year, more frequently if indicated. 
 
In Case of an FDA audit, the FDA will audit each participating site individually as each site will 
hold their own IDE. Thus each center will be responsible for having all source documents, research 
records, all IRB approval documents, Drug Accountability Record forms, patient registration lists, 
response assessments scans, x-rays, etc. available for the audit 
 
Response Review 
 
Patients participating on trials at MSKCC where therapeutic efficacy is a stated primary objective, 
typically phase II and III trials, are subject to review by MSKCC’s Therapeutic Response Review 
Committee (TRRC).  In these cases, radiology, additional lab reports and possibly bone marrow 
biopsies and/or aspirates may need to be obtained from the outside sites for MSKCC TRRC review 
and confirmation of response assessment. These materials must be obtained within sixty days of 
request to the site. 
 
16.3 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were approved 
by the National Cancer Institute in September 2001. The plans address the new policies set forth by the 
NCI in the document entitled “Policy of the National Cancer Institute for Data and Safety Monitoring of 
Clinical Trials” which can be found at:   http://cancertrials.nci.nih.gov/researchers/dsm/index.html.   The 
DSM Plans at MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and quality. 
There are institutional processes in place for quality assurance (e.g., protocol monitoring, compliance and 
data verification audits, therapeutic response, and staff education on clinical research QA) and 
departmental procedures for quality control, plus there are two institutional committees that are 
responsible for monitoring the activities of our clinical trials programs.  The committees: Data and Safety 
Monitoring Committee (DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring 
Board (DSMB) for Phase III clinical trials, report to the Center’s Research Council and Institutional 
Review Board. 
 
During the protocol development and review process, each protocol will be assessed for it’s level of risk 
and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, in-house sponsored, 
industrial sponsored, NCI cooperative group, etc.) Will be addressed and the monitoring procedures will 
be established at the time of protocol activation. 
 
Data from all participating sites will be monitored by the MSK DSMC on a quarterly basis. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Risks: From the studies that have been done so far there appears to be no increase in risk to the patients. 
However, given this is a new treatment, it is possible that there are side effects that have not yet been 

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seen. 
 
Benefits: The information from this study will help future patients. 
 
Possible toxicities/side effects: Toxicities and side effects of the agents used are listed in section 11 and 
reporting of serious adverse events are found in section 17.2. 
 
Consent Process: Participation in this study is voluntary. All patients will be required to sign a statement 
of informed consent which must conform to MSKCC IRB guidelines. 
 
Alternatives:   Alternative treatment options will be presented to the patient prior to taking part in this 
study. Alternative treatment options may include getting a transplant from a volunteer unrelated donor, if 
one is available; getting treatment for your cancer with either chemotherapy or a transplant without being 
on a study; taking part in another study; or getting no treatment. 
 
 
 
Costs: The patient’s health plan/insurance company will need to pay for all of the costs of treatment in 
this study. The patient will be responsible for the costs of standard medical care, all hospitalizations and 
any transplant complications. Pre-authorization for the transplant will be cleared with the health 
plan/insurance company prior  to  admission.  Patients  will  not  be  paid for taking part  in  this study. 
Research tests will be done at no cost to the patient. 
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and hospital 
records are confidential. 
 
17.1 
Privacy 
 
All institutional, FDA, and NCI requirements for human subjects must be met.  This study will be 
carried  out  in  compliance  with  the  regulations  of  the  Health  Insurance  Portability  and 
Accountability Act (HIPAA).  Each participating institution will have an appropriate assurance on 
file with the Office for Human Research Protection (OHRP), NIH. 
The risks and benefits of participation in this study will be reviewed with the patient and/or 
parent/legal guardian. 
 
Enrollment on this study is on a voluntary basis and every effort will be made to maintain privacy 
and confidentiality.  The patient's records will be confidential. Only authorized individuals or 
agencies  may  inspect  the  records.    No  identifying  information  will  be  used  in  reports  or 
publications resulting from this study. 
 
The following section is a Mandatory Section that pertains to MSKCC only: 
 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form.  The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form.  A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 

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17.2 Serious Adverse Event (SAE) Reporting Guidelines for MSKCC 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. The 
IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted electronically to the 
SAE Office at  sae@mskcc.org containing the following information: 
 
Fields populated from the CRDB: 
 
Subject’s name 
 
Medical record number 
 
Disease/histology (if applicable) 
 
Protocol number 
Data needing to be entered: 
 
The date the adverse event occurred 
 
The adverse event 
 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
 
If the AE was expected 
 
The severity of the AE 
 
The intervention 
 
Detailed text that includes the following information: 
o An explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
For IND/IDE protocols: 
 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number written at 
the top of the report. If appropriate, the report will be forwarded to the FDA by the SAE staff through the 
IND Office. 
Each participating center will follow their institutional guidelines in regards to SAE submission to the 
FDA. 
 
The MSKCC PI is responsible for reporting all grade 3-5 unexpected, definite, probable, possible 
related SAEs on protocol to all participating sites within 5 calendar days of receipt. 
 
All SAEs must be entered into the CRDB SAE form page. 
 
17.2.1 Serious Adverse Event (SAE) Reporting for Participating Institutions 
 
Participating sites are responsible for reporting all SAEs to their IRB, the FDA and the MSKCC PI via 
fax or e-mail within 5 calendar days.   Each participating center will follow their institutional guidelines 
in regards to SAE submission to their IRB. 
 
17.2.2 Definition of SAE 

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An SAE is an undesirable experience that meets one of the following criteria: 
 
 
Is fatal or life-threatening 
 
Is disabling 
 
Results in hospitalization or prolongation of hospitalization 
 
Results in a congenital anomaly or occurrence of malignancy 
 
Important medical event that jeopardizes the participant AND requires medical or surgical 
intervention to prevent one of the outcomes above Note: Hospital admission for a planned 
procedure/disease treatment is not considered an SAE. 
 
Attribution: 
 
 
Unrelated: The AE is clearly NOT related to the intervention 
 
Unlikely: The AE is doubtfully related to the intervention 
 
Possible: The AE may be related to the intervention 
 
Probable: The AE is likely related to the intervention 
 
Definite: The AE is clearly related to the intervention 
 
Expected and Unexpected Event: 
 
 
Expected: Any experience previously reported (in nature, severity, or incidence) in the 
current Investigator’s Brochure or general investigational plan 
 
Unexpected: Any experience not previously reported (in nature, severity, or incidence) in the 
current Investigator’s Brochure or general investigational plan 
 
UNEXPECTED EVENT: 
 
 
Grades 1-2: Adverse Event Reporting NOT required. 
 
 
Grades 3: Possible, Probable or Definite attribution to the drug and/or device. 
 
 
Grades 4 and 5: Regardless of Attribution. This includes all deaths within 30 days of the last dose 
of treatment with an investigational agent regardless of attribution. 
 
EXPECTED EVENT 
 
 
Grades 1 – 3: Adverse Event Reporting NOT required. 
 
 
Grades 4 and 5: Regardless of Attribution. This includes all deaths within 30 days of the last dose 
of treatment with an investigational agent regardless of attribution. 
 
*Reportable events are those which occur within 30 days of the last dose of treatment on protocol. Events 
beyond 30 days will be reported at the discretion of the PI. 
 
17.2.4  SAE Reporting Requirements to Miltenyi 
 
A courtesy copy of the SAE report will be provided to Miltenyi: 

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ATTN: Normand Pilon 
Clinical Application Manager 
North East USA, Canada 
Miltenyi Biotec Inc. 
26 Des Bolets 
Blainville, Quebec, Canada, 
J7C 5T8 
Cell: 514-451-7275 
Email:  Normand@miltenyibiotec.com 
Fax: 450-419-9628. 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
1.   The nature and objectives, potential risks and benefits of the intended study. 
2.   The length of study and the likely follow-up required. 
3.   Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4.   The name of the investigator(s) responsible for the protocol. 
5.   The right of the participant to accept or refuse study interventions/interactions and 
to withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
19.0 
REFERENCE(S) 
 
1.   Young, N.S., Alter B.P. Clinical features of Fanconi’s Anemia. In: Young NS, Alter BP, eds. (1994). 
Aplastic Anemia acquired and inherited. Philadelphia, PA: Saunders; pp275-309, 1994.2. Gluckman 
E. Auerbach. 
 
2.   Auerbach AD, Woman SR. Susceptibility of Fanconi Anemia fibroblasts to chromosome damage by 

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carcinogens. Nature 261: 494-496, 1976. 
 
3.  Butturini A, Gale RP, Verlander PC, Adler-Brecher B, Gillio AP, Auerbach AD. Hematologic 
abnormalities in Fanconi Anemia: an International Fanconi Anemia Registry study. Blood 84:1650- 
1655, 1994. 
 
4.   Barrett AJ, Brigden WD, Hobbs JR, Hugh-Jones K, Humble JG, James DC, Retsas S, Rogers TR, 
Selwyn S, Sneath P, Watson JG. Successful bone marrow transplant for Fanconi's anaemia. British 
Medical Journal. 1(6058):420-2, 1977 
 
5.   Gluckman E., Devergie A., Schaison G., Bussel A., Berger R., Sohier J., Bernard J.  Bone marrow 
transplantation for Fanconi Anemia.  Brit J. Haematol. 45:557-564, 1980. 
 
6.   Deeg HJ. Storb R. Thomas ED. Appelbaum F. Buckner CD. Clift RA. Doney K. Johnson L. Sanders 
JE. Stewart P. Sullivan KM. Witherspoon RP. Fanconi's anemia treated by allogeneic marrow 
transplantation. Blood. 61(5):954-9, 1983 
 
7.   Gluckman E. Auerbach AD. Horowitz MM. Sobocinski KA. Ash RC. Bortin MM. Butturini A. 
Camitta BM. Champlin RE. Friedrich W. et al. Bone marrow transplantation for Fanconi anemia. 
Blood. 86(7):2856-62, 1995 
 
 
 
8.   Gluckman E. Auerbach A. Ash RC. Biggs JC. Bortin MM. Camitta BM. Champlin RE. Friedrich W. 
Gale RP. Good RA. et al. Allogeneic bone marrow transplants for Fanconi anemia. A preliminary 
report from the International Bone Marrow Transplant Registry. Bone Marrow Transplantation. 10 
Suppl 1:53-7, 1992 
 
9.  Socie G. Gluckman E. Raynal B. Petit T. Landman J. Devergie A. Brison O. Bone marrow 
transplantation for Fanconi anemia using low-dose cyclophosphamide/thoracoabdominal irradiation 
as conditioning regimen: chimerism study by the polymerase chain reaction. Blood. 82(7):2249-56, 
1993 
10. Flowers MED., Doney KC., Storb R., Sanders JE., Sullivan KM., Bryant E., Witherspoon RP., 
Appelbaum F., Buckner CD., Hansen JA., Thomas ED., Marrow transplantation for Fanconi Anemia 
with or without leukemic transformation: an update of the Seattle experience.  Bone Marrow Transpl. 
9:167-173, 1992. 
 
11. Di Bartolomeo P. Di Girolamo G. Olioso P. Angrilli F. Dragani A. Palka G. Guanciali-Franchi P. 
Ciancarelli M. Papalinetti G. Fioritoni G. et al. Allogeneic bone marrow transplantation for Fanconi 
anemia. Bone Marrow Transplantation. 10(1):53-6, 1992 
 
12. Yabe  M.,  Yabe  H.,  Matsuda  M.,  Hinohara  T.,  Oh  Y.,  Hattori  K.,  Ishikawa  K.,  Ohshima  T., 
Yamamoto H., Kato S.  Bone marrow transplantation for Fanconi Anemia. Adjustment of the dose of 
cycloposphamide for preconditioning.  Amer. J. Pediatr. Hematol. Oncol. 15:377-382, 1993. 
 
13. Kohli-Kumar M., Morris C., DeLaat C., Sambrano J., Masterson M., Mueller R., Shahidi N., Yanik 
G., Desantes K., Friedman DJ., Auerbach AD., Harris RE.  Bone marrow transplantation in Fanconi 
Anemia using matched sibling donors. Blood 84:2050-2054, 1994. 

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15. Flowers MED., Zanis J., Pasquini R., Deeg JH., Ribeiro R., Longton G., Medeiros CR., Doney K., 
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abdominal irradiation for conditioning.   British Journal of Haematology. 103(1):249-55, 1998 
 
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Timonova LA. Bogatcheva NY. Samochatova EV. Roumjantzev AG. Intermediate-dose busulfan and 
cyclophosphamide as a conditioning regimen for bone marrow transplantation in a case of Fanconi 
anemia in myelodysplastic transformation. Bone Marrow Transplantation. 19(4):385-7, 1997 

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24. Hows JM. Chapple M. Marsh JC. Durrant S. Yin JL. Swirsky D. Gordon-Smith EC. Bone marrow 
transplantation for Fanconi's anaemia: the Hammersmith experience 1977-89. Bone Marrow 
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25. Auerbach AD. Adler B. O'Reilly RJ. Kirkpatrick D. Chaganti RS. Effect of procarbazine and 
cyclophosphamide on  chromosome breakage in Fanconi anemia cells: relevance to bone marrow 
transplantation. Cancer Genetics & Cytogenetics. 9(1):25-36, 1983 
 
26. Gluckman E., Devergie A., Dutreix J.   Radiosensitivity in Fanconi Anaemia: application to the 
conditioning regimen for bone marrow transplantation.  Brit. J. Haematol. 54:431-440, 1983. 
 
27. Yule SM., Price L., Cole M., Pearson AD., Boddy AV.  Cyclophosphamide metabolism in children 
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28. Hows JM. Unrelated donor bone marrow transplantation for severe aplastic anaemia and Fanconi's 
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30. Davies SM, Harris RE, van Weel-Sipman, Dokal J, Skinner R, Casper JT, Kurtzberg J, Smith F, 
Karanes C, Chen A, Cairo A, Yeaker AM, Defor T, Wagner JE: Unrelated donor stem cell transplant 
for Fanconi anemia: Multicenter report of 49 cases. Blood 90:108a, 1997. 
 
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peripheral blood stem cell transplantation for Fanconi Anemia. Bone Marrow Transpl. 19:299-300, 
1997. 
 
32. Zwaan CM. Van Weel-Sipman MH. Fibbe WE. Oudshoorn M. Vossen JM. Unrelated donor bone 
marrow transplantation in Fanconi anaemia: the Leiden experience. Bone Marrow Transplantation. 
21(5):447-53, 1998 
 
33. Guardiola P, Locatelli F, Pasquini R, Socie G, Devergie A, Riband P, Esperou H, Gardenet L, 
Bittencourt M, Marollease J, Gluckman E. Results of a phase I/II multicenter prospective study using 
CD34+ selection for HLA matched unrelated transplants in Fanconi anemia. Blood 92:290a, 1998. 
 
34. Guardiola P, Pasquini R, Dokal I, Ortega JJ, van Weel-Sipman M, Warsh JC, Ball S, Locatelli F, 
Vermylen C, Skinner R, Ljungman P, Miniero R, Shaw PJ, Souillet G, Michalet M, Bekassy AN, Di 
Bartolomeo P, Heilmann C, Zanesco L, Cahn JY, Arcese W, Bacigalupo A, Gluckman E.  Outcome 
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A study on behalf of the European Group for Blood and Marro Transplantation. Blood 95: 422-429, 
2000. 
 
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in patients with Fanconi anemia using non-genotypically identical donors: Results of a TBI dose 
escalation trial. Br J Haematol. 2000 Apr;109(1):121-9. 

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36. Fischer A. Friedrich W. Fasth A. Blanche S. Le Deist F. Girault D. Veber F. Vossen J. Lopez M. 
Griscelli C. et al. Reduction of graft failure by a monoclonal antibody (anti-LFA-1 CD11a) after HLA 
nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis, and 
Fanconi's anemia: a European Group for Immunodeficiency/European Group for Bone Marrow 
Transplantation report. Blood. 77(2):249-56, 1991 
 
37. Tan PL, Wagner JE, Auerbach AD, Defor TE, Slungaard A, Macmillan ML.  Successful engraftment 
without   radiation   after   fludarabine-based   regimen   in   Fanconi   anemia   patients   undergoing 
genotypically identical donor hematopoietic cell transplantation.   Pediatr Blood Cancer. 2006 May 
1;46(5):630-6. 
 
38. Boyer MW, Gross TG, Loechelt B, Leemhuis T, Filipovich A, Harris RE.  Low risk of graft-versus- 
host disease with transplantation of CD34 selected peripheral blood progenitor cells from alternative 
donors for Fanconi anemia.  J Pediatr Hematol Oncol. 2003 Nov;25(11):890-5. 
 
39. Boulad F, Auerbach AD, Kernan NA, Small TN, Prockop SE, Chaudhury S, Castanza J, Casson A, 
Copeland C, Abendroth H, Collins N, O’Reilly RJ. Fludarabine (Flu) based cytoreductive regimen 
and T-cell depleted grafts from unrelated or mismatched related donors for the treatment of high risk 
patients with Fanconi anemia (FA). Blood 2004; 2152;592a. 
 
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Pediatr Pathol Lab Med. 15(4):597-607, 1995 
 
 
 
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99(2):410-4, 1997 
 
42. Socie G. Scieux C. Gluckman E. Soussi T. Clavel C. Saulnier P. Birembault P. Bosq J. Morinet F. 
Janin A. Squamous cell carcinomas after allogeneic bone marrow transplantation for aplastic anemia: 
further evidence of a multistep process. Transplantation. 66(5):667-70, 1998 
 
43. Witherspoon, R.P., Fisher, L.D., Schoch, G., Martin, P., Sullivan, K.M., Sanders, J., Deeg, H.J., 
Doney, J., Thomas, D. & Storb, R. Secondary cancers after bone marrow transplantation for leukemia 
or aplastic anemia. New England Journal of Medicine, 321, 784-789, 1989 
 
 
20.0 
APPENDICES 
 
Appendix 1 – WHO Classification 
Appendix 2 – Performance Scores 
Appendix 3 – Acute GVHD 
Appendix 4 – Chronic GVHD 
Appendix 5 – Toxicity 

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APPENDIX 1 
 
MDS Classification 
 
WHO Classification 
BLOOD 
BONE MARROW 
Refractory Anemia 
RA 
- 
0 or rare blasts 
- 
Anemia 
- 
< 1 x 109/L monocytes 
- 
<5% blasts 
- 
Dysplasia only Erythroid 
- 
Myeloid-MegaK dysplasia 
< 10% of cells 
Refractory cytopenia with 
multilineage dysplasia 
RCMD 
- 
0 or rare blasts 
- 
Cytopenias (2-3 lineages) 
- 
No Auer rods 
- 
< 1 x 109/L monocytes 
- 
<5% blasts 
- 
Dysplasia in 2-3 lineages 
- 
Dysplasia in 
10% of cells 
- 
No Auer rods 
Refractory anemia with excess 
blasts – 1 
RAEB-1 
- 
<5% blasts 
- 
Cytopenias (2-3 lineages) 
- 
No Auer rods 
- 
< 1 x 109/L monocytes 
- 
5-9% blasts 
- 
Dysplasia in 1-3 lineages 
- 
No Auer rods 
Refractory anemia with excess 
blasts – 2 
- 
5-19% blasts 
- 
Cytopenias (2-3 lineages) 
- 
10-19% blasts 
- 
Dysplasia in 1-3 lineages 

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RAEB-2 
- 
Auer rods +/- 
- 
< 1 x 109/L monocytes 
- 
Auer rods +/– 
Myelodysplastic syndrome, 
unclassified 
MDS-U 
- 
0 or rare blasts 
- 
Cytopenias (2-3 lineages) 
- 
No Auer rods 
- 
<5% blasts 
- 
Myeloid-MegaK dysplasia 
- 
No Auer rods 
 
IPSS Classification* 
1. Single Lineage Score 
 
BM Blasts 
Cytogenetics** 
Cytopenia 
0 
<5% 
Good 
0-1 
0.5 
5-10% 
Intermediate 
2-3 
1 
- 
Poor 
- 
1.5 
11-20% 
- 
- 
2 
21-30 
- 
- 
**Good: 
normal, -Y, del(5q), del (20q); 
Poor: 
complex ( 3 abnormalities) or chromosome 7 anomalies; 
Intermediate: 
other abnormalities. 
 
 
2. Overall IPSS Risk Group 
 
Risk Group 
Combined IPSS Score 
Low 
0 
Intermediate 1 
0.5-1.0 
Intermediate 2 
1.5-2.0 
High 
> 2.0 
APPENDIX 2 
 
Performance Scores 
 
LANSKY SCALE (<16 y.o.) 
 
The score is defined by the phrase which best describes the activity status of the recipient. 
 
. Able to carry on normal activity; no special care is needed. 
100 
Fully active 
90 
Minor restriction in physically strenuous play 
80 
Restricted in strenuous play, tires more easily, otherwise active 
 
. Mild to moderate restriction 
70 
Both greater restrictions of, and less time spent in, active play 
60 
Ambulatory up to 50% of time, limited active play with assistance/supervision 
50 
Considerable assistance required for any active play; fully able to engage in quiet play 
 
. Moderate to severe restriction 
40 
Able to initiate quiet activities. 
30 
Needs considerable assistance for quiet activity 
20 
Limited to very passive activity initiated by others (e.g. TV) 

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10 
Completely disabled; not even passive play 
 
KARNOFSKY SCALE (>16 y.o.) 
 
The score is defined by the phrase which best describes the activity status of the recipient. 
 
. Able to carry on normal activity; no special care is needed. 
100 
Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity 
80 
Normal activity with effort 
 
. Unable to work; able to live at home, care for most personal needs; a varying amount of 
assistance is needed. 
70 
Cares for self; unable to carry on normal activity or to do active work 
60 
Requires occasional assistance but is able to care for most needs 
50 
Requires considerable assistance and frequent medical care 
 
. Unable to care for self; requires equivalent of institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization indicated, although death not imminent 
20 
Very sick; hospitalization necessary 
10 
Moribund; fatal process progressing rapidly. 

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Appendix 3 
Acute GvHD 
CLINICAL STAGING AND GRADING OF ACUTE GRAFT VERSUS HOST DISEASE 
ORGAN INVOLVEMENT 
STAGE 
Skin 
Liver 
Gut 
 
1 
maculopapular rash 
<25% body surface 
 
 
 
2 
maculopapular rash 
25-50 % of body surface 
 
 
3 
maculopapular rash 
>50 % of body surface 
 
 
 
4 
 generalized 
erythroderma 
with bullous formation 
Bili 2.0 – 3.0 mg/dl 
Diarrhea 
500-1000 ml/d 
(children: 280-555 ml/m2/d) 
OR persistent nausea 
 
Bili 3.1 – 6.0 mg/dl 
Diarrhea 
>1000 but < 1500 ml/d 
(children: 556-833 ml/m2/d) 
 
Bili 6.1 - 15 mg/dl 
Diarrhea 
>1500 ml/d 
(children: >834 ml/m2/d) 
Bili > 15 mg/dl 
Severe abdominal pain + Ileus 
 
 
GRADING 
 
GRADE 
Skin 
Liver 
Gut 
0 
I 
NONE 
Stage 1-2 AND 
None AND 
None AND 
NONE 
NONE 
II 
Stage 3 AND/OR 
Stage 1 AND/OR 
Stage 1 
III 
IV 
None OR Stage 3 AND 
Stage 4 OR 
Stage 2-3 OR 
Stage 4 
Stage 2-4 
NA 
STAGING 
- For skin GvHD: - Use “Rule of Nines or burn chart to determine extent of rash 
- For liver GvHD: - Range of bilirubin given as total bilirubin. 
- Downgrade one stage if an additional cause of hyperbilirubinemia is documented 
- For gut GvHD:   - Downgrade one stage if an additional cause of diarrhea is documented 
- St 1: 
Persistent nausea, vomiting and anorexia in the absence of other known cause 
Unless histology is negative 
 
GRADING- Criteria for grading given as minimum degree of organ involvement required to confer that grade 
REF: Przepiorka et al. 1994 Consensus Conference on Acute GVHD Grading (“Keystone 
Criteria”). Bone Marrow Transplant 1995; 15:825-8. 

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4.5% 
front of head 
4.5% 
back of head 
4.5% 
front of arm x 2 arms, max 9% 
4.5% 
back of arm x 2 arms, max 9% 
18% 
chest/trunk 
18% 
back/trunk 
9% 
front of leg x 2 legs, max 18% 
9% 
back of leg x 2 legs, max 18% 
1% 
Perineum 
 
 
 
 
 
ADULT Rule of Nines (for GvHD scoring) 
(see diagram for children – varies with age) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 

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APPENDIX 4 
 
 
 
Chronic GvHD Scoring 
Chronic GvHD 
Limited 
Either or both: 
1.   localized skin involvement 
2.   hepatic dysfunction due to chronic GvHD 
Extensive 
Either 
1.   generalized skin involvement, OR 
2.   localized skin involvement AND/OR hepatic dysfunction due to chronic GvHD 
PLUS 
3a. liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis, 
OR 
3b. involvement of eye (Schirmer’s <5mm wetting) 
3c. involvement of minor salivary glands or oral mucosa demonstrated on labial bx 
3d. involvement of any other target organ. 
REF: Forman et al. Bone Marrow Transplantation (text) 1994, page 350. 
 
Clinical Manifestations of Chronic GvHD 
 
 
Organ 
Clinical Manifestation 
Evaluation 
Intervention 
 
 
Skin 
 
Erythematous papular rash (lichenoid) or 
thickened, tight, fragile skin (sclerodermatous). 
Clinical and biopsy to 
confirm the diagnosis of 
GVHD. 
Moisturize (petroleum jelly), treat 
local infections, protect from 
further trauma. Topical steroid 
ointment may be used if it gives 
symptomatic relief to localized 
areas. 
 
 
Nails 
Vertical ridging, fragile. damage. 
Clinical. 
Nail polish may help to decrease 
further 
 
 
Sweat glands 
Destruction leading to risk of hyperthermia. 
Avoid excessive heat. 
 
 
Hair 
Scalp and body hair is thin and fragile, can be 
partially or completely lost. 
Clinical. 
 
 
Eyes 
Dryness, photophobia, and burning. 
Progression to corneal abrasion. 
Regular ophthalmologic 
evaluation including 
Schirmer’s test. 
Preservative free tears during the 
day and preservative free 
ointment at night. 
 
 
Mouth 
Dry; sensitivity to mint, spicy food, tomato. 
Whitish lace-like plaques Avoid foods which 
are not tolerated. Regular in the cheeks and 
tongue identical to lichen planus. Erythema 
and dental care preceded by appropriate 
endocardi-painful ulcerations, mucosal 
Regular dental evaluation (with 
appropriate endocarditis 
prophylaxis). Viral and fungal 
cultures at diagnosis and at any 
worsening. tis prophylaxis. 
Topical steroid rinses followed by 

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scleroderma with decreased sensitivity to 
temperature can also happen. 
an antifungal agent for 
symptomatic relief. 
 
 
Respiratory tract 
 
Bronchiolitis Obliterans can manifest as 
dyspnea, wheezing, cough with normal CT scan 
and marked obstruction at pulmonary function 
tests. Chronic sinopulmonary symptoms and/or 
infections are also common.With abnormal 
chest CT, must rule out infections. Lung biopsy 
if clinically indicated. 
Pulmonary function tests 
including FEV1, FVC, 
DLCO, helium lung 
volumes. CT scan in 
symptomatic patients. 
Investigational therapy. 
 
 
Gastrointestinal 
Abnormal motility and strictures. Weight loss. 
 Swallowing studies, 
endoscopy if clinically 
indicated. Nutritional 
evaluation. intervention. 
Systemic treatment of GVHD; 
endoscopical/ surgical treatment 
of strictures. Nutritional 
 
 
Liver 
 
Cholestasis (increased bilirubin, alkaline 
phosphatase). Isolated liver involvement needs 
histologic confirmation. 
Liver function tests. Liver 
biopsy if clinically 
indicated. 
No specific therapy is proven 
superior. FK506 may concentrate 
in the liver. 
 
 
Musculoskeletal 
Fasciitis. Myositis is rare. Osteoporosis may 
occur secondary to hormonal deficits, use of 
steroids, decreased activity. 
Periodical physical 
therapy evaluation to 
document the range of 
motion. Bone density 
evaluation especially in 
patients using steroids. 
Aggressive physical therapy 
program. 
 
 
Immune system 
Variable IgG 
levels. 
Profound immunodeficiency. Functional 
asplenia. High risk of pneumococcal sepsis, 
PCP, and invasive fungal infections. GVHD has 
resolved. 
Assume all patients as 
severely immuno- 
compromised and 
asplenic to 6 months after 
vaccinations. 
PCP prophylaxis (until 6 months 
after no GVHD) and 
Pneumococcal prophylaxis 
(lifetime). Delay 
 
 
Hematopoietic 
system 
Cytopenias. Occasional eosinophilia. 
 Counts. Bone marrow 
aspirate and biopsy, anti- 
neutrophil and anti- 
platelet antibodies when 
indicated. 
Systemic treatment of GVHD. 
 
 
Others 
 Virtually all autoimmune disease 
manifestations have been described in 
association with chronic GVHD. 
As clinically indicated. 

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APPENDIX 5 
 
 
 
 
 
Website: 
Toxicity 
 
Refer to NCI Common Toxicity Criteria 3.0 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf