Phase II Trial of T-cell Depleted Hematopoietic Stem Cell Boosts Without Conditioning for Poor Marrow Graft Function Following Allogeneic Hematopoietic Stem Cell Transplantation
Phase: PHASE2
Conditions: Hematopoietic Stem Cell Transplant, Poor Marrow Graft Function
Sponsor: Memorial Sloan Kettering Cancer Center

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Phase II trial of T-cell depleted hematopoietic stem cell boosts without conditioning for 
poor marrow graft function following allogeneic hematopoietic stem cell transplantation 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
 
 
Principal Investigator/Department: 
Roni Tamari, M.D. 
Medicine, BMT 
Co-Principal 
Investigator(s)/Department: 
Hugo Castro-Malaspina, MD 
Nancy Kernan, M.D. 
Medicine, BMT 
Pediatrics, BMT 
Investigator(s)/Department: 
Juliet Barker, M.B.B.S 
David Chung, M.D., Ph.D. 
Parastoo Dahi. M.D. 
Sergio Giralt, M.D. 
Boglarka Gyurkocza, M.D. 
Alan Hanash, M.D. 
Katherine Hsu, M.D., Ph.D. 
Ann Jakubowski, M.D., Ph.D. 
Robert Jenq, M.D. 
Guenther Koehne, M.D., Ph.D. 
Heather Landau, M.D. 
Esperanza Papadopoulos, M.D. 
Miguel-Angel Perales, M.D. 
Doris Ponce, M.D. 
Craig Sauter, M.D. 
Brian Shaffer, M.D. 
Melody Smith, M.D. 
Marcel van den Brink, M.D., Ph.D. 
James Young, M.D. 
Farid Boulad, M.D. 
Kevin Curran, M.D 
Aisha Hasan, M.D 
Rachel Kobos, M.D 
Richard O’Reilly, M.D. 
Susan Prockop, M.D. 
Andromachi Scaradavou, M.D 
Scott Avecilla, M.D., Ph.D. 
Richard Meagher, PhD 
Malcolm AS Moore, PhD 
Sean Devlin, Ph.D. 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Laboratory Medicine 
Laboratory Medicine 
Sloan Kettering Institute/Cell 
biology program 
Epidemiology and 
Biostatistics 

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Consenting 
Professional(s)/Department: 
Juliet Barker, M.B.B.S 
Hugo Castro-Malaspina, M.D. 
David Chung, M.D., Ph.D. 
Parastoo Dahi, M.D. 
Sergio Giralt, M.D. 
Boglarka Gyurkocza, M.D. 
Alan Hanash, M.D. 
Katherine Hsu, M.D., Ph.D. 
Ann Jakubowski, M.D., Ph.D. 
Robert Jenq, M.D. 
Guenther Koehne, M.D., Ph.D. 
Heather Landau, M.D. 
Esperanza Papadopoulos, M.D. 
Miguel-Angel Perales, M.D. 
Doris Ponce, M.D. 
Craig Sauter, M.D. 
Brian Shaffer, M.D. 
Melody Smith, M. D. 
Roni Tamari, M.D. 
Marcel van den Brink, M.D., Ph.D. 
James Young, M.D. 
Farid Boulad, M.D. 
Kevin Curran, M.D 
Aisha Hasan, M.D 
Nancy Kernan, M.D. 
Rachel Kobos, M.D 
Richard O’Reilly, M.D. 
Susan Prockop, M.D. 
Andromachi Scaradavou, M.D 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
Pediatrics, BMT 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Amended:  02-DEC-2015 
Page  3 of 24 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 4 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 4 
 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 5 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION............................................................ 7 
 
4.1 
Design............................................................................................................................. 7 
 
4.2 
Intervention ..................................................................................................................... 8 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 8 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 11 
 
6.1 
Subject Inclusion Criteria............................................................................................... 11 
 
6.2 
Subject Exclusion Criteria ............................................................................................. 12 
 
7.0 
RECRUITMENT PLAN ..................................................................................................... 12 
 
8.0 
PRETREATMENT EVALUATION .................................................................................... 13 
 
9.0 
TREATMENT/INTERVENTION PLAN.............................................................................. 13 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 
 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 15 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 15 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 16 
 
14.0 BIOSTATISTICS .............................................................................................................. 16 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES19 
 
15.1 Research Participant Registration ................................................................................. 19 
 
15.2 Randomization .............................................................................................................. 19 
 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 19 
 
16.1 Quality Assurance ......................................................................................................... 19 
 
16.2 Data and Safety Monitoring ........................................................................................... 19 
 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 20 
 
17.1 Privacy .......................................................................................................................... 21 
 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 21 
 
17.2.1 ................................................................................................................................... 22 
 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 22 
 
19.0 REFERENCES ................................................................................................................. 23 

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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This protocol includes two parallel single arm phase II trials to assess the efficacy and confirm the 
safety of T cell depleted (TCD) hematopoietic progenitor cell, apheresis (HPC(A) boost or bone 
marrow (BM) HPC (M) boost from original donor for patients who have poor graft function (PGF) 
after allogeneic hematopoietic stem cell transplantation. 
 
Candidates for this trial will include patients who have undergone allogeneic hematopoietic stem cell 
transplantation and whose post transplant course has been complicated by poor graft function. 
Patients who underwent transplant at another facility and suffer from PGF will be eligible as well. 
Patients will be treated on one of two arms based on their condition at time of TCD boost 
administration. The two arms are: (A) patients with no active infection or end organ compromise or 
GVHD and (B) patients with active infection, active or controlled GVHD and/or organ compromise. 
 
 
Poor graft function is defined as follows: cytopenia in the presence of hypocellular BM (<25%), and 
full donor chimerism. The severity of PGF is adapted from severity levels of aplastic anemia and 
include Severe PGF: requires 2 of the following – absolute neutrophil count (ANC)< 0.5x109/L, 
platelets <20x109/L, reticulocyte count< 20x109/L. Very severe PGF is defined by the above criteria 
with ANC< 0.2x109/L 
 
 
 
Donors of the TCD boost will be the original donors. The boost will be given without any pre-infusion 
conditioning therapy. 
 
The primary endpoint of the study is recovery of neutrophil, red cell and platelet counts. Secondary 
endpoints include overall survival, incidence and severity of acute and chronic graft versus host 
disease (GvHD) post TCD boost, incidence of infections, effect on donor T cell chimerism and pace 
of immune reconstitution. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
To study the efficacy and confirm the safety of the administration of HPC(A) or HPC (M) TCD stem 
cell boost in patients with poor graft function after hematopoietic stem cell transplant (HSCT) from 
histocompatible matched or mismatched related or unrelated donors for various hematologic or 
immunologic disorders. 
 
Primary objective: 
 
To evaluate peripheral blood counts recovery at three months following the administration of TCD 
HPC(A) or HPC (M) boost, without further conditioning. 
 
Secondary objectives: 
 
1.  To explore count recovery by the severity of PGF at the time of the TCD boost 
2.  To evaluate overall survival after administration of the TCD boost. 
3.  To assess the incidence of acute and chronic GvHD after administration of the TCD boost. 
4.  To assess the frequency of infections after administration of the TCD boost 
5.  To assess the effect of the TCD boost on donor T cell chimerism. 

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6.  To characterize the trend of immune reconstitution after administration of the TCD boosts. 
 
Correlative studies: 
 
To explore the interaction between the donor stem cells and the BM stroma in patients with poor 
graft function 
 
 
 
3.0 BACKGROUND AND RATIONALE 
 
3.1 
Graft failure 
 
Bone marrow failure following allogeneic hematopoietic stem cell transplantation (graft failure) is a 
complex syndrome characterized by pancytopenia and hypocellular or acellular bone marrow. 
Several pathophysiological mechanisms are possible.  The best characterized form of graft failure is 
immune rejection (graft rejection- GR).  Preexisting anti-HLA antibodies1, 2 or residual host T 
lymphocytes can eliminate the donor stem cells and typically these patients have only host cells3,4. 
 
Another form of graft failure following allogeneic HSCT is due to qualitative or quantitative 
deficiencies of hematopoietic stem cells (poor graft function – PGF). A distinctive feature of PGF is 
persistence of donor cells in the recipient.  PGF occurs in 5-27% of patients undergoing allogeneic 
HCST 5 and the severe form is associated with high morbidity and mortality due to infectious and 
hemorrhagic complications6.  A number of factors are associated with PGF and this includes: (1) 
inadequate stem cell dose due to poor harvest/collection; (2) stem cell damage during ex-vivo 
manipulation or storage; (3) mismatched donor, (4) graft-versus-host disease (GvHD)7; (5) infection 
or medications used to treat an infection; or non-infectious medications (6) use of a T-cell depleted 
graft 8. 
 
PGF can be primary with suboptimal recovery of blood counts after the initial HSCT, or secondary, 
with decreasing blood counts after successful and prompt hematopoietic engraftment. We have 
defined the severity categories of PGF according to the criteria used to define the severity of 
acquired aplastic anemia; severe PGF is defined as BM cellularity of <25% with 2 of the following – 
absolute neutrophil count (ANC)< 0.5x109/L, platelets <20x109/L and reticulocyte count< 20x109/L. 
Very severe PGF is defined by the above criteria with ANC< 0.2x109/L. PGF can be a transient 
event secondary to a reversible insult, such as an acute infection/sepsis or drugs and  blood counts 
can recover after removal of the insult. However, persistence of low blood counts require further 
intervention, either in the form of a second transplant or infusion of more stem cells without further 
pre-infusion conditioning therapy. 
 
In a recent analysis of 182 patients who underwent HPC(A) TCD transplant at MSKCC between 
9/2009-7/2012 (presented as a poster in ASH meeting 2012) the cumulative incidence of PGF was 
close to 20% at 1 year post transplant. Infections and anti-viral therapies were the most common 
etiologies for PGF (87%) followed by GVHD, medications related and unknown etiology in one case. 
It is important to note that while infections and anti viral therapies were the most common etiologies 
for PGF treating the infection did not always result in improvement in graft function. At time of 
analysis 36% of patients who were diagnosed with PGF died from either infectious complications or 
GVHD, 33% patients had recovery of blood counts either after treatment of an identified offending 

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PGF Cumulative In cidence  
0.0 
0.1 
0.2 
0.3 
0.4 
agent (mostly viral infection) or discontinuation of  medications, 15% had counts recovery after 
HPC(A) TCD stem cell boost, 10%  had persistent PGF and in 6% there was evidence of relapsed 
disease. 
 
 
 
 
 
 
N=182 
 
 
 
 
 
 
 
 
 
 
 
 
0  
6  
12  
18  
24  
 
Mo nt hs p ost  trans pla nt  
 
 
3.2  Therapeutic Interventions for Poor graft function 
 
The best course of treatment for PGF is not well defined.  Hematopoietic growth factors, namely 
granulocyte colony-stimulator factor (G-CSF), granulocyte-macrophage colony-stimulating factor 
(GM-CSF) or erythropoietin have been used but often with less than optimal response9.  The 
administration of additional hematopoietic stem cells following prior conditioning (second 
transplants) has had limited success secondary to toxicity of the conditioning regimen and high rates 
of grade III-IV GVHD10. An alternative approach is to administer additional donor- derived stem 
cells, un-manipulated or TCD (i.e. CD34+ selected), without additional conditioning (stem cell boost). 
The use of un-manipulated donor stem cell boost, however, is associated with a high incidence of 
acute and chronic GVHD and poor survival rates11. A boost of HPC(A) TCD stem cells following 
conventional or T-cell depleted allogeneic HSCT has been more successful mainly related to the low 
incidence of GVHD12, 13, however reported in a very small cohort of patients. An important study that 
demonstrated the benefit of a TCD boost for PGF directly compared patients treated with either a 
HPC(A) TCD  boost, an un-manipulated stem cell boost or supportive care alone. Trilineage 
recovery was more common and non-relapse mortality was lower in those receiving donor stem cells 
following TCD boost (CD34+ selection) compared to the other two groups. In addition, the incidence 
of GVHD was significantly lower in the TCD group compared to the conventional boost arm6. 
 
3.3 TCD stem cell boost for Poor graft function 
 
A retrospective analysis of patients who were treated for severe PGF at MSKCC identified 35 
patients who underwent allogeneic TCD boost of either peripheral blood (N=14) or bone marrow 
(N=21) stem cells; all boost grafts were from the original donors, without any further pre- boost 
conditioning therapy. The etiologies for PGF in this group of patients included infections (N=17), 
GVHD (N=12), low cell dose (N=2) and idiopathic (N=5). The median time between the first 
transplant and the TCD boost was 4.5 months (0.7-90.7 months). 7 patients died early post TCD 
boost (within the first 28 days post boost) and were not evaluable for blood count recovery. 

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Objective improvement in counts (ANC>0.5x109/L without G-CSF support and Plt>50x109/L) 
occurred in 20 patients with a median of 3.4 months (range 0.36-22.2 months) post TCD boost. In 17 
out of the 20 patients there was further improvement of peripheral blood counts (ANC>1.0x109/L and 
Plt>100x109/L) with median of 8.8 months. For the 20 patients who had objective improvement in 
counts, the median cell dose was 1.8x107 SBA-E- cells/kg when bone marrow, HPC(M) was used as 
source of stem cells and 6.7x106 CD34+ cells/kg for patients who received HPC(A) TCD  boost. 
Among the other 8 patients who were alive post day 28 after the TCD boost and had persistent poor 
graft function without objective improvement in blood counts, 2 had ongoing GVHD and in the other 
6 patients the lack of response was of unknown reason. The stem cell boost infusion was well 
tolerated in all patients and no grade 2 or higher adverse events were reported. New onset GVHD, 
acute or chronic, was not documented in any of the patients, however, GVHD flare was documented 
in 2 patients with preexisting GVHD. The 2 and 5 years survival post TCD boost were 48.6% and 
37.1%, respectively. The median survival for patients who achieved minimal objective count recovery 
was 77.58 months and for those who achieved optimal count recovery 80.34 months as compared to 
6.61 months for patients who had no peripheral blood counts recovery. The 2 years OS for patients 
with peripheral blood counts recovery was 90% as compared to 18% for patients without counts 
recovery. Patient’s medical condition at time of TCD boost administration had significant impact on 
response to treatment and survival. The best outcomes were seen in patients with no evidence of 
end-organ dysfunction (defined as creatinine>2, total bilirubin>2, need for mechanical ventilation and 
active infection) and who were still outpatients. In this group of patients 56% were alive and with 
stable peripheral blood counts on day 100 post administration of TCD boost as 
oppose to the other group of patients where only 10% were alive and with stable counts. 
 
3.4   Study rationale 
 
PGF is characterized by full donor chimerism and therefore we hypothesize that further stem cell 
infusion without further immunosuppression/conditioning will improve the overall graft function. This 
will be the first prospective study to assess an intervention to treat PGF in the form of TCD boost 
from the original donor. Based on the retrospective data of the 35 patients who received TCD boost 
for PGF at MSKCC, the goal will be to administer the boost as early as possible after the diagnosis 
of PGF is made. The large differences (while not significant due to low number of patients) noted 
between patients who received the TCD boost when they had active infection and/or GVHD and /or 
organ dysfunction and patients who received a boost without any of the above at time of TCD boost 
administration is the rationale for having the two cohorts of patients. This study will also provide the 
opportunity to study, in a prospective manner, the natural history of PGF. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This protocol includes two single-arm phase II trials to assess the efficacy and confirm the safety of 
administration of TCD stem cell boost from the original donor for patients with poor graft function 
after allogeneic hematopoietic stem cell transplantation. 

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4.2 
Intervention 
 
Patients who are diagnosed with poor graft function will be given TCD boost without prior 
preparative therapy. Patients will be assigned to one of two groups based on their medical condition 
at time of boost administration: (A) patients who are free of active infection and GVHD and without 
end organ dysfunction and (B) patients with active infection, active or prior history of GVHD and/ or 
end organ damage. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
 
5.1. a  HPC(A) 
 
Donor peripheral blood progenitor cells: stimulation, harvesting, isolation and T-cell depletion. 
 
For related donors, beginning 5-6 days before the day of HPC(A) TCD boost infusion, the normal 
donor will receive GCSF per institutional guidelines. On the fifth and sixth days of this course of G- 
CSF, the donor will undergo daily leukapheresis designed to provide a minimum of 5x106 CD34+ 
cells/kg of the transplant recipient's weight. For unrelated donors, the G-CSF will be administered 
and the leukapheresis obtained according to the National Marrow Donor Program protocol IND, and 
institutional guidelines. Mononuclear cell fractions (i.e., CD34+ cells) collected on the fourth and fifth 
days will be pooled. 
 
5.1. b  HPC(M) 
 
 
Donor peripheral blood progenitor cells: harvesting, isolation and T-cell depletion. 
 
 
For related donors, beginning 1-2 days before the day of HPC(M) TCD boost infusion, the normal 
donor will undergo a bone marrow harvest per institutional guidelines. For unrelated donors, the 
bone marrow (HPC(M)) will be obtained according to the National Marrow Donor Program protocol 
IND, and institutional guidelines. The collected HPC(M) will be subsequently red blood cell reduced 
per MSKCC Cell Therapy Laboratory procedure to yield a cell product enriched for white blood cells 
which will undergo further  processing for CD34 enrichment  with the CliniMACS  Cell Selection 
System (see 5.2). 
 
 
 
 
5.2 CliniMACS Cell Selection System for Positive Selection of CD34+ Progenitor Cells and 
Reduction of CD3+ T-Cells 
 
 
The CliniMACS Cell Selection  System (Miltenyi Biotec, Auburn, CA) including the CliniMACSplus 
Instrument, a CliniMACS Tubing Set, the CliniMACS CD34 Reagent and the CliniMACS PBS/EDTA 
Buffer is intended for the selection and enrichment of human CD34 positive hematopoietic 
progenitor cells from a leukapheresis product. The CD34 antigen is a cell membrane glycoprotein 
expressed by early hematopoietic stem and progenitor cells. The CD34 positive cell separation 
process may be useful in several areas of clinical stem cell transplantation, including purging of 
tumor cells, T-cell depletion, ex vivo cell expansion and gene therapy. When re-infused after 
myeloablative chemotherapy, CD34 positive HPC(A) cells have been shown to reconstitute all 

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hematologic lineages and exhibit both short and long term repopulating capacities. The CliniMACS 
System uses selective CD34 monoclonal antibodies conjugated to superparamagnetic particles. The 
CD34 positive target cells are selected in an automated continuous flow separation system. The 
CD34 positive cells are specifically labeled by incubation with the CliniMACS CD34 Reagent. After 
unbound CD34 Reagent is washed from the suspension, the cells are ready for the automated cell 
separation process. The CliniMACS System passes the antibody-labeled suspension through a 
separation column in which strong magnetic gradients are generated. The Selection Column retains 
the magnetically labeled CD34 positive cells, while unwanted cells flow through the Selection 
Column and are collected in the Negative Fraction Bag. The system performs several washing 
steps, disposing most of the wash liquid into the Buffer Waste Bag. The Separated CD34 positive 
cells are then released from the column by removing the magnetic field and collecting the CD34+ 
cells into the Cell Collection Bag. While the CliniMACS System/CD34 Reagent has been FDA 
approved for HPC(A), the MSKCC Cell Therapy Laboratory has successfully validated performing 
the selection procedure on HPC(M). 
 
5.3  The components of the CliniMACS System include: 
 
 
5.3.1 The 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 check valves through which the tubing set is 
fitted, a high strength 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 with a display window. The instrument is operated at 
ambient temperature and it is intended to be a multi-use platform instrument. 
 
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 
microcontroller  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 which 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. 
 
5.3.2. CliniMACS Tubing Set 
 
 
The CliniMACS Tubing Set consists of a tubing element combined with a pair of proprietary cell 
selection columns. These form a functionally 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 which is placed within a magnetic field performs the actual cell selection. The 
columns are incorporated sterile as part of the tubing set and are intended for single use only. 

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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. 
 
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. 
 
5.3.3  CliniMACS CD34 Reagent 
 
 
The CliniMACS CD34 Reagent is a dark (amber), non-viscous colloidal solution containing the 
antibody conjugate in buffer solution. 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 for in vitro use 
only. 
 
5.3.4. 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 
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 
 
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 

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5.5 
Transplantation of the T-cell depleted stem cells 
 
The HPC(A) or HPC (M) TCD boost will be infused intravenously over 5-30 minutes with monitoring 
of vital signs. The patient is premedicated as for blood product transfusions. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Patients who underwent allogeneic stem cell transplantation and are diagnosed with either of the 
following are candidates for this trial. 
 
1.  Patients who are diagnosed with PGF are candidates for this trial. 
2.  Patients who underwent transplant at another facility and suffer from PGF will be eligible 
as well as long as a donor is available. PGF can be primary (no counts recovery after the 
preparative regimen) or secondary (cytopenia after engraftment has occurred). 
3.  Patients with auto-immune cytopenia with auto antibodies to neutrophils or platelets or 
positive Coombs test that did not respond to immunosuppressive agents within 3 months 
from initiation of therapy are eligible as well. 
 
6.1 
Subject Inclusion Criteria 
 
1.  Persistent cytopenia requiring growth factors and/or blood products AND evidence of 
hypocellular BM (<25%). Persistent cytopenia (at least 4 week period) is defined by presence 
of TWO of the following: 
1.  ANC <1.0x109/L without filgrastim support or any ANC value that requires recurrent 
support by filgrastim (administered at least once a week). 
2.  Plt<50x109/L 
3.  Hb<8 or PRBC transfusion dependent (once every 2 weeks or more) with reticulocyte 
count of < 40x109/L. 
This criteria for persistent cytopenia and hypocellular bone marrow does not apply to patients 
with auto-immune cytopenia (category #3 in Section 6.0), ONLY PGF patients. 
 
2.  Full donor myeloid chimerism. Patients after T cell depletion transplant can have a significant 
mixed T cell chimerism and this can affect the testing of marrow chimerism. In this case, the 
neutrophil chimerism will be used to determine eligibility for this trial. Patients will be 
excluded if neutrophils are less than 90% donor cells; a higher percentage of host cells could 
be due to relapse or impending relapse. 
 
3.  Age: pediatrics and adults patients. No age exclusion. 
 
 
4.  Each patient must be willing to participate as a research subject and must sign an informed 
consent form. 

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5.  For infections and end organs related criteria (at time of TCD boost administration) see table 
below: 
 
Criteria 
Arm A 
Arm B 
Infections 
Without active uncontrolled 
bacterial, fungal or viral infection. 
CMV- If CMV viremia is <137 IU/ml, 
but patients are on therapy for 
CMV. 
HHV-6 < 40,000 copies/ML and 
without active trend up. 
No limitation 
Karnofsky/Lansky performance 
scale 
>60% 
No limitation 
GVHD 
Without evidence of active or prior 
history of GVHD. 
Patients w ith active GV HD, or w ith 
GVHD controlled by steroids or other 
immunosuppressive medications 
Renal function 
Creatinine Clearance >60ml/min 
No limitation 
Hepatic function 
Liver enzymes (<x3 ULN), 
Bilirubin (<x2 ULN) 
and stable in the 30 days prior to 
TCD boost 
No limitation 
Cardiac function 
No evidence of uncontrolled heart 
failure or active angina 
No limitation 
Pulmonary function 
Spontaneous breathing, not requiring 
ventilatory support. 
No limitation 
 
 
6.2 
Subject Exclusion Criteria 
 
Patients will be excluded from the trial if at time of enrollment: 
 
1.  Evidence of relapsed disease by morphologic, cytogenetic or molecular diagnostic tools. 
2.  Hypersplenism documented by imaging study (US or CT) 
3.  Pregnant women 
4.  Patient who underwent TCD boost without counts recovery and are considered for another 
TCD boost will be treated off protocol. 
 
7.0 
RECRUITMENT PLAN 
 
Patients who fulfill the eligibility criteria as listed in section 6.0 will be recruited for this study 
by an attending physician of the Adult and Pediatric BMT service. This protocol will take due 
notice of NIH/ADAMHA policies concerning inclusion of women and minorities in clinical 
research population. 

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8.0 
PRETREATMENT EVALUATION 
 
The patient will undergo comprehensive medical evaluation which will include: 
 
1. 
Complete physical exam and medical history. 
2. 
GVHD assessment 
3. 
Infectious status assessment, including PCR studies for CMV, HHV6, EBV and adenovirus. 
Imaging studies if indicated. 
4. 
Complete medications review 
5. 
Complete blood counts (CBC) and reticulocyte count 
6. 
Complete metabolic panel 
7. 
Chimerism studies – bone marrow and peripheral blood lineage (T cells, B cells and 
Myeloid) 
8. 
Splenic size evaluation by US or CT scan only for patients for whom it is clinically relevant 
9. 
Anti-neutrophil antibodies, anti-platelet antibodies and Coombs test. 
10.  Bone marrow aspiration and biopsy including (1) complete disease evaluation for patients 
with hematologic malignancies and (2) cellularity evaluation for all patients 
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
1. 
CBC will be checked weekly for the first two months or until independent of G-CSF and 
transfusion support, then every two weeks (or more frequently if clinically indicated ) until 
day 100 post TCD stem cell boost. In patients who by day 100 have partial recovery, 
monitoring blood counts will continue every 2-4 weeks. 
2. 
Bone marrow aspirate and biopsy for assessment of engraftment will be done approximately 
on day 28 (+/- 7 days) and day 100 post TCD boost (+/- 10 days) and afterwards as 
required per BMT guidelines. 
3. 
Peripheral blood lymphocyte  phenotyping and in-vitro response to mitogen will be assessed 
on day 28 and day 100 post TCD boost  and afterwards as part of routine post transplant 
assessment until CD4 reaches 200 and PHA>100th percentile. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
All patients will be closely monitored and evaluated as per MSKCC BMT standard of care 
guidelines. Study specific assessment schedule listed in table below. 

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Procedures 
Pre- 
treat 
Days Post-Boost 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
100 
Window 
45 
(+/-) 
3 
(+/-) 
3 
(+/-) 
3 
(+/-) 
7 
(+/-) 
3 
(+/-) 
3 
(+/-) 
3 
(+/-) 
3 
(+/-) 
7 
(+/-) 
7 
(+/-) 
7 
(+/-) 
7 
(+/-) 
7 
Eligibility 
X 
Informed consent 
X 
History/Physical 
X 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte Count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry/CMP 
(1) 
X 
X 
X 
X 
X 
X 
X 
X 
Infection Testing (2) 
X 
ECG and/or ECHO (only 
for new cardiac 
symptoms) 
X 
US or CT (only if 
clinically indicated) 
X 
Pregnancy Test (3) 
X 
Creatinine Clearance 
X 
Anti-Neutrophil 
Antibodies 
X 
Coombs Test 
X 
Bone marrow aspirate 
and biopsy (standard of 
care and research 
samples) 
X 
X 
X 
Correlative Studies – PB 
Research Sample (4) 
X 
X 
Immune evaluation 
X 
X 
X 
Chimerism (Blood and 
BM) 
X 
X 
X 
GvHD evaluation (5) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
(1)    BUN, creatinine, electrolytes, glucose, total protein, albumin, AST, ALT, bilirubin, alkaline phosphatase 
(2)    CMV, EBV, HHV-6, adeno virus by PCR 
(3)    Required for FCBP only 
(4)    Peripheral blood samples will be collected for correlative research studies 
(5)    GvHD assessment to begin at engraftment 
 
10.1 Correlative Studies 
 
BM aspirate will be obtained prior to administration of the TCD boost as well as on day 30 and day 
100 post TCD boost. These studies will give an insight to the events at the level of the stem cells 
and its interaction with the bone marrow microenvironment. 
 
These correlative studies will be performed in Dr. Malcolm Moore’s lab, where the results will be 
analyzed as well. The studies  will include the following: 
 
1.  To study early hematopoietic progenitors colony forming cells assays will be used. These will 
include:  erythroid burst forming units (BFU-E), Megakaryocytes colony forming units (CFU- 
Meg) and granulocyte -macrophage colony forming unit (GM-CFU). 
 
2.  To study a more primitive hematopoietic progenitors the cobblestone area-forming cell 
(CAFC) assay will be used. 

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3.  To study the interaction between the patients BM stroma and the donor stem cells a 
cobblestone area-forming cell (CAFC) assay will be set from BM aspirate pre boost and an 
aliquot of donor stem cells will be added to the established culture. 
 
Peripheral blood sample will be obtained on days +28, +100 post TCD boost and will be sent to the 
clinical immunology laboratory to assess immune reconstitution with response to administration of 
the TCD boost. Peripheral blood samples will also be collected on those time-points and processed 
at HOTB for correlative studies. 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
Toxicities will be graded according to NCI CTAE version 4.0. 
 
Toxicities associated with stem cell infusion: The T-cell depleted peripheral blood 
stem cells are infused in a small volume (approximately 10-20 ml). Possible side 
effects include side effects associated with blood product infusions such as: changes 
in blood pressure, fever, headache, shortness of breath, chills, sweats, 
nausea/vomiting, bad taste in the mouth. Pre-medications are given to reduce these 
side effects. 
 
Graft-versus-host-disease (GvHD): ac ut e  an d  c hr on i c  GVHD may develop after 
allogeneic transplantation and can be disabling and fatal. CD34+ selection and CD3+ 
depletion reduces the number of T cells in the HPC(A)  or HPC(M)  graft but GVHD can 
occur after TCD transplant. Acute and/or chronic GVHD will be treated with 
immunosuppressive drugs as per transplant service guidelines. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Definitions of events in the study period that are important for analysis and treatment 
 
1.  Peripheral blood counts recovery 
Peripheral blood counts recovery will be documented by CBC checks every 2 weeks. 
Response will be defined by stable blood counts (ANC>1000, Hb>8 with absolute 
reticulocyte count>20x109/L ,and Plt>50,000) without support of blood product 
transfusions and/or growth factors. 
 
 
2. Chimerism 
Chimerism will be performed by analysis of bone marrow cells as well peripheral blood 
cells subpopulations (T cells, B cells, neutrophils)  by standard karyotype or FISH analysis 
for sex mismatched host-donor or short tandem repeat analysis at 1 month and at 100 
days post TCD boost and afterwards at regular time points as per routine BMT guidelines. 
 
3.  Immunologic reconstitution 
 
Our previous studies have identified time points at which the various immunologic functions 
can be expected to return. Immunophenotyping including CD4/CD8 will be performed on 
circulating lymphocytes of all patients as well as T cell proliferation in response to PHA at 1 
month and 100 days post-TCD boost. These markers will be used to 

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define immune reconstitution. 
 
 
 
4.  Graft versus Host Disease 
Standard BMT-CTN and IBMTR systems clinical criteria as defined by Rowlings, et al.14 
will be used to establish and grade acute GvHD. Data will be collected weekly a n d  u p t 
o  d a y  10 0  a f t er  t h e  T C D  b o o s t  to characterize the severity of symptoms and 
signs caused by acute GvHD and to evaluate possible confounding factors. 
 
Real time data collection will include descriptive characteristics of rash and estimated 
body surface area involved, extent of dermal/epidermal separation, identification of 
concomitant causes of increased bilirubin other than GvHD, presence or absence of 
nausea, vomiting or anorexia persistent after engraftment, peak diarrhea volume with 
annotations concerning the presence after engraftment, peak diarrhea volume with 
annotations concerning the presence or absence of urinary mixing and estimates of true 
diarrhea volume, presence or absence of abdominal cramps, presence or absence of 
frank stool blood or melena, concomitant causes of GI symptoms other than GvHD, 
biopsy results, identification of any agents used for treatment and autopsy results. 
 
Chronic GvHD will be diagnosed and graded according to the NIH consensus criteria15. 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient is found to be ineligible for the protocol as designated in the section on 
Criteria for patient/subject eligibility, the patient will be removed from the study. Also patients may be 
removed from the study if requested by the patient. Management will continue as per standard 
allogeneic HSCT guidelines. 
 
 
 
14.0 
BIOSTATISTICS 
 
This protocol investigates the efficacy of T-cell depleted boosts for poor graft function (PGF) in two 
cohorts of patients. The first cohort is patients who have PGF without any active infection, GVHD, 
and end organ compromise at the time of TCD boost administration (Cohort A). The second cohort 
is patients who have PGF with active infection, GVHD, or end organ compromise at the time of TCD 
administration (Cohort B). The protocol will have two single-arm phase II trials to investigate the 
efficacy separately in the two cohorts. The primary endpoint in both cohorts is the achievement of 
objective count recovery as defined in section 12.0 at 100 days following the intervention without the 
aid of growth factors.  Patients who die prior to 100 days or those who achieve count recovery but 
lose their counts prior to 100 days will be treated as treatment failures. 
 
Cohort A: 
 
A Simon’s 2-stage optimal design will be used to investigate the primary endpoint in patients without 
active infection or end organ disease. Based on historical MSKCC data, the boost treatment strategy 
will be considered promising for further investigation if 65% achieve objective recovery at 100 days. 
However, if 40% or fewer achieve sustained recovery, the strategy will not be considered 

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promising. Based on these rates, the trial will accrue a maximum of 28 patients. In the first stage of 
the trial, response will be evaluated in the first 13 patients. The trial will stop due to a lack of efficacy 
if 5 or fewer achieve objective recovery; otherwise, an additional 15 will accrue. At the end of the 
trial, if at least 15 out of the 28 patients achieve an objective recovery at 100 days, the boost 
intervention will be considered promising for further investigation. The type I and type II errors are 
both set at 0.10. 
 
The estimated accrual is 7-10 patients/year and the overall study duration is 3-4 years. 
 
The Cohort A trial includes early termination in the event that patients have high rates of grade III-IV 
acute GVHD. The stopping rules below are based on a maximum of 28 patients receiving the boost 
intervention. 
 
 
 
 
Failure Type 
# of failures needed 
to stop the study 
Failure rate 
in the 
population 
Probability 
boundary 
is crossed 
Acute GVHD 
(Grade III-IV) 
3 in the first 8 patients 
4 in the first 14 patients 
5 in the first 20 patients 
6 in the first 27 patients 
7 at any point 
0.10 
0.09 
0.35 
0.96 
 
 
Cohort B: 
 
A Simon’s 2-stage optimal design will be used to investigate the primary endpoint in patients with 
active infection and/or end organ disease. The boost treatment strategy will be considered promising 
for further investigation if 35% achieve objective recovery at 100 days. However, if 10% or fewer 
achieve sustained recovery, the strategy will not be considered promising. Based on these rates, the 
trial will accrue a maximum of 19 patients. In the first stage of the trial, response will be evaluated in 
the first 11 patients. The trial will stop due to a lack of efficacy if one or no patient achieves objective 
recovery; otherwise, an additional 8 will accrue. At the end of the trial, if at least 4 out of the 19 
patients achieve an objective recovery at 100 days, the boost intervention will be considered 
promising for further investigation. The type I and type II errors are both set at 0.10. 
 
The estimated accrual is 4-5 patients/year and the overall study duration is 4-5 years. 

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The Cohort B trial includes early termination in the event that patients have high rates of grade III-IV 
acute GVHD. The stopping rules below are based on a maximum of 19 patients receiving the boost 
intervention. 
 
 
 
 
Failure Type 
# of failures needed 
to stop the study 
Failure rate 
in the 
population 
Probability 
boundary 
is crossed 
Acute GVHD 
(Grade III-IV) 
2 in the first 4 patients 
3 in the first 8 patients 
4 in the first 14 patients 
5 at any point 
0.10 
0.10 
0.35 
0.89 
 
 
 
 
 
This trial includes a number of secondary objectives that will be explored separately for the two 
cohorts. 
 
1.  The objective count recovery will be tabulated by the severity of PGF at the time of the boost. 
 
 
2.  Overall survival following the TCD boost will be estimated using Kaplan-Meier methodology. 
 
 
3.  The incidence of grade II-IV and III-IV acute GVHD and chronic GVHD will be estimated using 
cumulative incidence functions. Competing risks for these events include relapse and non- 
relapse mortality. 
 
4.  The frequency of serious infections as defined by CIBMTR will be tabulated for the two patient 
cohorts. 
 
5.  The levels of T-cell chimerism will be compared for patients who do and who do not achieve the 
100-day objective count recovery endpoint. 
 
 
6.  Immune reconstitution will be explored using graphical and descriptive measures. 
 
As outline in section 10.1, this trial includes a number of correlative studies. These studies will be 
performed and analyzed in Dr. Malcolm Moore’s lab. 

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15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
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. 
 
15.2 
Randomization 
 
This is not a randomized trial. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study and will be responsible for 
both pediatric and adult accruals. The responsibilities of the RSA and principal investigator 
include project compliance, data collection, abstraction and entry, data reporting, regulatory 
monitoring, problem resolution and prioritization, and coordinate the activities of the protocol 
study team. The data collected for this study will be entered into The Clinical Research Data 
Base (CRDB), a secure database. Source documentation will be available to support the 
computerized patient record. 
 
16.1 
Quality Assurance 
 
Weekly 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. Random-sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
per year, more frequently if indicated. 

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16.2 
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 its 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. 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Risks: The TCD boost will be given to patients with PGF with evidence of full donor 
chimerism and the source of the TCD boost is the same as the original donor. In a 
retrospective analysis of 35 patients who received TCD for the same indication, there were 
no new cases of GVHD, however in 2 patients there was a flare of GVHD. While the risk of 
GVHD is small due to depletion of the T cells, it still exists since T cells are not completely 
eliminated from the product. 
 
Benefits: improvement of blood counts will lower the risk of bleeding and infectious 
complications. 
 
Possible toxicities/side effects: Toxicities and side effects of the TCD boost are listed in 
section 11 and reporting of serious adverse events is 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 not participating in this study and 
follow up as per regular standard of care post transplant with continuation of supportive 
therapy. 

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Costs: The patient’s health plan/insurance company will need to pay for all of the costs of 
standard medical care. 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 
 
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 (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
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. The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
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 
o A 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. 

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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. 
 
17.2.1 
 
This protocol is being conducted under an IDE and the safety reporting to the FDA will be 
IDE compliant as per 21 CRF 812.150, 21 CFR 812.3 and 21 CFR 312.32. 
 
17.2.2 Definition of SAE 
 
A Serious Adverse Event (SAE) is any undesirable experience that meets any of the 
following criteria: fatal, life-threatening, disabling, results in hospitalization or prolongation of 
hospitalization, results in a congenital anomaly or occurrence of malignancy. 
 
All SAEs will be reported according to the approved Adult and Pediatric BMT Adverse Event 
Reporting Guide, version 2.0 dated 29 December 2014. 
 
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. 

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19.0 
REFERENCES 
 
 
1   Spellman S, Bray R, Rosen-Bronson S, et al. The detection of donor-directed, HLA- 
specificalloantibodies inrecipients of unrelated hematopoietic cell transplantation is predictive of graft 
failure. Blood. 2010;115(13):2704-2708. 
 
2 Ciurea SO, Thall PF, Wang X, et al. Donor-specific anti-HLA Abs and graft failure in matched 
unrelated donor hematopoietic stem cell transplantation. Blood. 2011;118(22):5957-5964. 
 
3 Donohue J, Homge M, Kernan NA. Characterization of cells emerging at the time of graft failure 
after bone marrow transplantation from an unrelated marrow donor. Blood. 1993;82(3):1023-1029. 
 
4   Marijt WA, Kernan NA, Diaz-Barrientos T, et al. Multiple minor histocompatibility antigen-specific 
cytotoxic T lymphocyte clones can be generated during graft rejection after HLA-identical bone 
marrow transplantation. Bone Marrow Transplant. 1995;16(1):125-132. 
 
5   Dominietto A, Raiola AM, van Lint MT, et al. Factors influencing haematological recovery after 
allogeneic haemopoietic stem cell transplants: graft-versus-host disease, donor type, 
cytomegalovirus infections and cell dose. Br J Haematol. 2001;112(1):219-227. 
 
6 Larocca A, Piaggio G, Podesta M, et al. Boost of CD34+-selected peripheral blood cells without 
further conditioning in patients with poor graft function following allogeneic stem cell transplantation. 
Haematologica. 2006;91(7):935-940. 
 
7 Wolff SN. Second hematopoietic stem cell transplantation for the treatment of graft failure, graft 
rejection or relapse after allogeneic transplantation. Bone Marrow Transplant. 2002;29(7):545-552. 
 
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13   Milone G, Tornello A, Leotta S, et al. CD34+ selected haematopoietic stem cell (HSC) not 
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14 Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index for grading acute graft-versus- 
host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997; 97: 855-64. 

MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 14-228 A(4) 
Amended:  02-DEC-2015 
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15 Filipovich AH, Weisdorf D, Pavletic S et al National Institutes of Health consensus development 
project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging 
working group report. Biol Blood Marrow Transplant. 2005;11(12):945-56.