Clinical trial NCT03615105
Conditions: Acute Lymphoid Leukemia (ALL) Acute Myeloid Leukemia (AML) Chronic Myeloid Leukemia (CML) Hodgkin Lymphoma Non-Hodgkin Lymphoma Chronic Lymphocytic Leukemia
Keywords: Allogeneic Hematopoietic Cell Transplantation α/β+ T-lymphocyte 18-224
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2018-07-25; Completion date: 2024-03-06
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being done to learn whether a new method to prevent rejection between the donor immune system and the patient's body is effective.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Hyperfractionated total body irradiation intervention 2: Thiotepa intervention 3: Cyclophosphamide intervention 4: Busulfan intervention 5: Fludarabine intervention 6: Melphalan intervention 7: Clofarabine intervention 8: HPC(A) stem cell allograft intervention 9: Rituximab intervention 10: Rabbit antithymocyte globulin
Intervention descriptions: intervention 1: Hyperfractionated TBI is administered by a linear accelerator at a dose rate of \<20 cGy/minute. Doses of 125 cGy/fraction are administered at a minimum interval of 4 hours between fractions, three times/day for a total of 11 or 12 doses (1,375 or 1,500 cGy) over 4 days (days -9 through -6). intervention 2: Thiotepa 5 mg/kg IV intervention 3: Cyclophosphamide 60 mg/kg IV intervention 4: Busulfan (adult/ped dose) intervention 5: Fludarabine 25 mg/m2 IV intervention 6: Melphalan 70 mg/m2 IV intervention 7: Clofarabine 20-30 mg/m2 IV intervention 8: All patients will receive anti-thymocyte globulin based conditioning followed by a G-CSF mobilized, peripheral blood hematopoietic progenitor cell HPC(A) product depleted of TCR-α/β+ Tlymphocytes using the CliniMACS system. intervention 9: Rituximab 200 mg IV flat dose intervention 10: Rabbit antithymocyte globulin dosing per nomogram. This dynamic nomogram is based on absolute lymphocyte count at the start of conditioning and can result in either 2 or 3 day ATG administration. If a patient requires 2 day administration the subjequent chemotherapies may be moved forward by one day at the treating physician's discretion.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 1 of 47
 
I 
I 
I
 
 
Allogeneic Hematopoietic Cell Transplantation Using a/J3+ T-lymphocyte Depleted 
Grafts from HLA Mismatched Donors 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
Principal Investigator/Department: 
Brian Shaffer, MD 
Medicine/BMT 
Co-Principal
lnvestigator(s)/Department: 
Miguel-Angel Perales, MD
Scott Avecilla, MD, PhD 
Maria Cancio, MD 
Medicine/BMT
Laboratory Medicine 
Pediatrics 
lnvestigator(s)/Department:
Juliet Barker, MD, MBBS
Medicine/BMT
 
David Chung, MD, PhD
Medicine/BMT
 
Sergio Giralt, MD
Medicine/BMT
 
Heather Landau, MD
Medicine/BMT
 
Boglarka Gyurkocza, MD
Medicine/BMT
 
Parastoo Dahi, MD
Medicine/BMT
 
Esperanza Papadopoulos, MD
Medicine/BMT
 
Doris Ponce, MD
Medicine/BMT
 
Craig Sauter, MD
Medicine/BMT
 
Jonathon Peled, MD, PhD
Medicine/BMT
 
Melody Smith, MD
Medicine/BMT
 
Christina Cho, MD
Medicine/BMT
 
Alan Hanash, MD, PhD
Medicine/BMT
 
Scott James, MD, PhD
Medicine/BMT
 
Michael Scordo, MD
Medicine/BMT
 
Gunjan Shah, MD
Medicine/BMT
 
Roni Tamari, MD
Medicine/BMT
 
loannis Politikos, MD
Medicine/BMT
 
Arnab Ghosh, MD
Medicine/Genitourinary One
 
Richard Lin, MD
Medicine/BMT
 
Kate Markey, MD, PhD
Medicine/BMT
 
Katharine C. Hsu, MD, PhD
Medicine/BMT
 
Oscar Lahoud, MD
Medicine/ Leukemia
 
Cheryl Goss, MD
Laboratory Medicine
 
Sean Devlin, PhD
Epidemiology/Biostatistics
 
Farid Boulad, MD
Pediatrics
 
Kevin Curran, MD
Pediatrics
 
Nancy Kernan, MD
Pediatrics
 
Andrew Kung, MDm PhD
Pediatrics
 
Richard O'Reilly, MD
Pediatrics
 
Susan Prockop, MD
Pediatrics
 
Andromachi Scaradavou, MD
Pediatrics
 
Barbara Spitzer, MD
Pediatrics
 
Jaap Jan Boelens, MD PhD
Pediatrics
 
Ann Jakubowski, MD
Medicine/BMT
 
Shani Irby, NP
Nursing
 
Sheila Kenny, NP
Nursing
 
Chelsea Mintz, NP
Nursing
 
Courtney McElrath, NP
Nursing


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 2 of 47
 
 
 
 
 
Jason Batalha, NP
Nursing
Marci Andrejko, NP
Nursing
Stefanie Kelly, NP
Nursing
Kathleen Kilroy, NP
Nursing
Melissa Cortes, NP
Nursing
Dayna Palumbo, NP
Nursing
Victoria Szenes, NP
Nursing
Melissa Varda, NP
Nursing
Theresa Elko, PA
Medicine
Natasia Rodriguez, RN
Nursing
Caroline Carino, RN
Nursing
Jennifer Bieler, RN
Nursing
Linh Nguyen, RN
Nursing
Naomi Cazeau, NP
Nursing
Christina Kiss, NP
Nursing
Kathryn Mazzarella, NP
Nursing
Christianne Supan, NP
Nursing
Kathleen Cavalier, NP
Nursing
Consenting Professional(s)/Department:
Brian Shaffer, MD
Medicine/BMT
 
Miguel-Angel Perales, MD
Medicine/BMT
 
Juliet Barker, MD, MBBS
Medicine/BMT
 
David Chung, MD, PhD
Medicine/BMT
 
Sergio Giralt, MD
Medicine/BMT
 
Heather Landau, MD
Medicine/BMT
 
Boglarka Gyurkocza, MD
Medicine/BMT
 
Parastoo Dahi, MD
Medicine/BMT
 
Esperanza Papadopoulos, MD
Medicine/BMT
 
Doris Ponce, MD
Medicine/BMT
 
Craig Sauter, MD
Medicine/BMT
 
Jonathon Peled, MD, PhD
Medicine/BMT
 
Melody Smith, MD
Medicine/BMT
 
Christina Cho, MD
Medicine/BMT
 
Alan Hanash, MD, PhD
Medicine/BMT
 
Scott James, MD, PhD
Medicine/BMT
 
Michael Scordo, MD
Medicine/BMT
 
Gunjan Shah, MD
Medicine/BMT
 
Roni Tamari, MD
Medicine/BMT
 
loannis Politikos, MD
Medicine/BMT
 
Arnab Ghosh, MD
Medicine/ Genitourinary One
 
Richard Lin, MD
Medicine/BMT
 
Kate Markey, MD, PhD
Medicine/BMT
 
Katharine C. Hsu, MD, PhD
Medicine/BMT
 
Oscar Lahoud, MD
Medicine/Leukemia
 
Cheryl Goss, MD
Laboratory Medicine
 
Maria Cancio, MD
Pediatrics
 
Farid Boulad, MD
Pediatrics
 
Kevin Curran, MD
Pediatrics
 
Nancy Kernan, MD 
Pediatrics 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 3 of 47
 
 
 
 
 
Andrew Kung, MD, PhD
Pediatrics
Richard O'Reilly, MD
Pediatrics
Susan Prockop, MD
Pediatrics
Andromachi Scaradavou, MD
Pediatrics
Barbara Spitzer, MD
Pediatrics
Jaap Jan Boelens, MD PhD
Pediatrics
Ann Jakubowski, MD
Medicine/BMT
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
OneMSK Sites
Manhattan
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 4 of 47
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .......................................................................... 5 
Protocol Schema: Cytoreductive Regimens ................................................................................... 6 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................... 7 
3.0 
BACKGROUND AND RATIONALE ......................................................................................... 7 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................... 11 
4.1 
Design ................................................................................................................................ 11 
4.2 
Intervention ......................................................................................................................... 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................... 13 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................... 18 
6.1 
Subject Inclusion Criteria .................................................................................................... 18 
6.2 
Subject Exclusion Criteria ................................................................................................... 21 
7.0 
RECRUITMENT PLAN .......................................................................................................... 22 
8.0 
PRETREATMENT EVALUATION .......................................................................................... 22 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................... 23 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ....................................................... 29 
11.0 
TOXICITIES/SIDE EFFECTS ................................................................................................. 31 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................... 37 
• 
13.0 CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 38 
14.0 BIOSTATISTICS .................................................................................................................... 39 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ..... 40 
15.1 Research Participant Registration ....................................................................................... 40 
16.0 DATA MANAGEMENT ISSUES ............................................................................................ 40 
16.1 
Quality Assurance .............................................................................................................. 40 
16.2 Data and Safety Monitoring ................................................................................................ 41 
17.0 PROTECTION OF HUMAN SUBJECTS ................................................................................ 41 
17.1 Privacy ............................................................................................................................... 42 
17.2 
Serious Adverse Event (SAE) Reporting............................................................................. 42 
18.0 INFORMED CONSENT PROCEDURES ................................................................................ 43 
19.0 REFERENCES ...................................................................................................................... 44 
20.0 
APPENDICES ....................................................................................................................... 46 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 5 of 47
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a Phase II study evaluating human leukocyte antigen (HLA) mismatched unrelated 
donor (URD) or related haploidentical donor allogeneic hematopoietic cell transplantation (allo 
HCT) using TCR-a/W lymphocyte depletion based graft versus host disease (GVHD) 
prophylaxis. 
The major barrier to successful outcomes in HLA mismatched allograft recipients is the 
propensity of recipients to develop severe acute GVHD. This protocol will evaluate the use of 
unrelated donor hematopoietic progenitor cells depleted of TCR-a/W lymphocytes using 
immunomagnetic (CliniMACS™) methodology. The primary objective of the study is to 
estimate the incidence of severe acute GVHD in recipients of this allograft type. Secondary 
endpoints are to estimate core clinical outcomes in recipients including cumulative incidence 
of non-relapse mortality, relapse, and death at one year post transplant. Additionally, this study 
will explore immune reconstitution in all recipients. 
Subjects with high risk hematologic malignancies who lack a HLA matched sibling or matched 
unrelated donor and who otherwise meet the eligibility outlined in section 6.0 may be offered 
enrollment. Three regimens for cytoreduction will be employed (figure): Regimen A will consist 
of hyperfractionated total body irradiation, cyclophosphamide, and thiotepa, Regimen B will 
consist of busulfan, melphalan, and fludarabine, and Regimen C will consist of clofarabine, 
melphalan, and thiotepa. All regimens are myeloablative in intensity and have demonstrated 
safety and efficacy in facilitating engraftment of CD34+ selected allografts in MSKCC protocol 
10-050. All recipients will additionally receive rabbit antithymocyte globulin and short course 
tacrolimus after transplantation. Finally, all recipients will receive a single infusion of rituximab 
shortly after transplantation to prevent development of lymphoproliferative disorders that may 
result from infusion of CD19+ donor cells. The use of similar cytoreductive regimens to 10-050 
participants will facilitate comparison in terms of core clinical outcomes and immune 
reconstitution to those patients receiving CD34+ selected allografts. Patients will receive 
standard supportive care as per adult and pediatric BMT service guidelines. 
Donors for study participants will include unrelated donors matched at 6 or 7 loci among HLA- 
A, -B, -C, and -DRB1 or haploidentical related donors. Donor selection will be based first on 
donor availability and second on treating physician preference. All donors will undergo a 
standard GCSF mobilization to obtain a peripheral blood derived graft. The cell product will 
subsequently undergo TCR-a/W lymphocyte depletion using the Miltenyi CliniMACS device. 
The target CD34+ cell dose will be >5.0 x 106 CD34+ cells per recipient kg body weight. 
Patients will receive pharmacologic immune suppression with tacrolimus from two days before 
the allograft infusion until 100 days post allograft infusion. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 7 of 47 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary objectives: 
• 
To estimate the incidence of grade 3-4 acute graft versus host disease in persons 
undergoing HLA-mismatched allogeneic hematopoietic cell transplantation with grafts 
depleted of TCR-a/W cells. 
Secondary objectives: 
• 
To estimate overall survival at one year. 
• 
To estimate the cumulative incidence of non-relapse mortality at one year. 
• 
To estimate the cumulative incidence of relapse at one year. 
• 
To determine reconstitution of CD4+, COB+ T-lymphocytes, CD19+ B-lymphocytes. 
Translational objectives: 
• 
To determine reconstitution of TCR-a/W T-lymphocytes after TCR-a/W lymphocyte 
depleted allografts at 30, 100, 180, and 365 days post transplantation. 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
Use of HLA-Mismatched Unrelated Donor Sources in Allogeneic Hematopoietic Cell 
Transplantation 
Allogeneic hematopoietic cell transplantation (allo HCT) is a curative therapy for persons with 
advanced hematologic malignancies. Successful application of allo HCT depends upon 
managing the toxicities of conditioning and graft versus host disease as well as obtaining a 
histocompatible donor. Outcomes after allo HCT are influenced by the degree of human 
leukocyte antigen (HLA) matching between donor and recipient. The most obvious and 
preferred HLA-matched stem cell donors are siblings that share both HLA haplotypes with the 
recipient, however; this occurs in only 25-30% of potential candidates. Among those who do 
not have a matched sibling, the use of a volunteer unrelated donor (URD) matched at the HLA- 
A, -B, -C, and DRB1 loci confers a similar outcome to transplantation with a HLA-matched 
sibling donor.[1] Unfortunately, not all recipients will have a suitable HLA-matched donor 
available. Due to allotypic diversity in various ethnic populations, the likelihood of obtaining a 
suitable HLA-matched URD varies by the ethnic background of the recipient. For example, 
among persons who identify primarily as of European descent the likelihood of finding a HLA 
matched URD is 75%, whereas the probabilities in African Americans, persons from Latin 
America, and Asia are approximately 16%, 30-40%, and 25-45%, respectively.[2] Therefore, 
access to a HLA matched donor remains a significant barrier to patients seeking allo HCT, 
particularly those from racial and ethnic minority backgrounds. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 8 of 47 
 
 
 
Lack of a HLA matched donor necessitates the use of a HLA mismatched donor for such 
recipients. If unrelated adult donors that are mismatched at a single HLA loci are included as 
suitable donors, the likelihood of finding a donor increases to 97%, 76%, 80-90%, and 75-90% 
for recipients who identify as from European, African, Latin-American, or Asian descent, 
respectively. Haploidentical related family donors are also feasible allo HCT donors and are 
available in approximately 80% of patients presenting to Memorial Sloan Kettering Cancer 
Center for transplantation evaluation (unpublished data). 
T-Lymphocyte Depletion to Prevent Graft Versus Host Disease after Allogeneic 
Hematopoietic Cell Transplantation 
The primary barrier to successful outcomes after HLA mismatched transplantation is GVHD.[3] 
Several studies support that the incidence of clinically significant acute GVHDusing HLA 
mismatched adult unrelated donors is 30-40%. [1, 4] A larger study sponsored by the NMDP 
and CIBMTR conducted by Lee and colleagues demonstrate more significant findings, where 
a mismatch at a single HLA class 1 antigen or allele or DRB1 results in an approximately 60% 
increase in the likelihood of severe acute GVHD and similar increase in the likelihood of 
treatment related mortality (TRM).[3] The incidence of disease relapse in the HLA mismatch 
group was less than that of the HLA matched group, indicating that TRM due to GVHD remains 
the most significant problem in HLA mismatched allograft recipients. 
GVHD results from infusion of alloreactive CD3+ T-lymphocytes and other cells within the 
hematopoietic progenitor cell product.[5] Despite pharmacologic immune suppression, these 
lymphocyte populations may engraft and cause GVHD. We and others investigated broadly 
the concept of purifying CD34+ hematopoietic progenitor cells from the donor allograft prior to 
infusion. This effort has led to several prospective clinical trials at this institution. More recently, 
CD34+ cell enrichment has been performed via magnetic cell separation techniques using the 
CliniMACS device (Miltenyi Biotec, Auburn, CA). In this system, the G-CSF mobilized HPC(A) 
product is introduced into a closed device where the cells are incubated with anti-CD34+ 
murine monoclonal antibody coated magnetic beads. The cell product is then passed through 
an electromagnetic field, retaining the CD34+ cells bound to the magnetic beads and allowing 
other cell populations to wash through the device in the eluent. The enriched CD34+ cell 
fraction is then infused into the patient. Using this approach we found acceptable CD34+ cell 
doses (range 0.6-28.8 CD34+ cells/recipient kg) and neutrophil engraftment in 102 patients 
recently reported.[6] The incidence of acute GVHD in HLA matched transplant recipients was 
approximately 10%. These findings are similar to those reported in a national study examining 
this method.[?] Based on the strength of these and other's findings the CliniMACS CD34 
Reagent System has been approved by the FDA as a Humanitarian Use Device for the 
prevention of GVHD in patients with AML in first complete remission undergoing matched 
sibling donor allo HCT. 
In order to address the problem of acute GVHD in HLA-mismatched allo HCT we performed 
CD34+ selection using the CliniMACS device in 87 individuals undergoing HLA mismatched 
URD allo HCT (any HLA class 1 or DRB1). Results from these individuals were compared to 
169 recipients of HLA matched, CD34+ selected URD allografts. The 2 year survival was 52% 
(41-63%) in the HLA mismatched group compared to 60% (51-67%) in the HLA matched group 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 9 of 47 
 
 
 
(P = 0.17). The incidence of grade 2-4 and grade 3-4 acute GVHD was 15.6% and 4.7%, 
respectively in 64 subjects undergoing 7/8 HLA mismatched allografts with complete data. 
These outcomes are comparable to the incidence of acute GVHD in HLA matched transplant 
recipients using CliniMACS based CD34+ selection, indicating that the increased death in HLA 
mismatched transplant recipients results from poor immune reconstitution. Among 64 
recipients of HLA mismatched CD34+ selected allografts with complete data, poor graft 
function contributed to 5 deaths and infection resulted in 6 deaths. Thus, improving immune 
reconstitution in these individuals is the most likely mechanism to improve outcomes in HLA 
mismatched, CD34+ selected transplant recipients. 
 
 
TCR-yl>+ T-Lymphocyte Subsets are Beneficial after Hematopoietic Cell Transplantation 
 
Blood and tissue T-lymphocytes may be subdivided by the T-cell receptor (TCR) isotype. The 
canonical TCR-a/W lymphocyte population represent approximately 95% of circulating cells, 
are responsible for the majority of antigen specific T-cell responses, and are implicated in the 
formation of GVHD after hematopoietic cell transplantation.[8, 9] In contrast, TCR-yiY T-cells 
are capable of antigen recognition but are more akin to innate immune effector cells such as 
natural killer cells in that they are activated against conserved peptide epitopes. [10, 11] Similar 
to other elements of innate immunity, TCR-yo+ cells are activated by immunoglobulin-like, 
lectin-like, and other natural cytotoxicity receptors.[12] Importantly, this allows for activation of 
TCR-yo+ lymphocytes outside of the canonical HLA pathway, thereby opening the possibility 
of anti-tumor potential in the context of an HLA disparate transplant. 
 
In the context of human transplantation, TCR-yo+ T-lymphocytes play an important role in 
pathogen control early after transplantation. TCR-yo+ T-cells proliferate in response to CMV 
reactivation and demonstrate similar activity as TCR-a/W cells against CMV in murine 
models.[13, 14] TCR-yo+ T-cells may also confer protection from adenoviral mediated end 
organ injury.[15] Perko and colleagues demonstrate that improved reconstitution of TCR-yo+ 
T-cells after allo HCT was associated with lower incidence of peri-transplant infections and 
better event-free survival in 102 pediatric transplant recipients.[16] These results would 
suggest that removal of alloreactive TCR-a/W cells while preserving other beneficial 
lymphocyte subpopulations may be advantageous in terms of improving post transplant 
immune function without increasing the incidence of GVHD. 
CD34+ selection results in a broad depletion of both TCR-a/W and TCR-yo+ T-lymphocytes 
as well as B-lymphocytes and NK cells. While this is effective at reducing alloreactive T- 
lymphocytes, beneficial populations such as NK cells and TCR-yo+ cells are removed as well. 
More recently, Miltenyi Biotec has made available the TCRa/13 Selection Reagent for selection 
depletion of TCR-a/W T-cells from hematopoietic progenitor cell products. In a series of 102 
depletions, Schumm and colleagues were able to achieve a median log 4.1 (range 3.0-4.7) 
reduction in TCR-a/W cells using the CliniMACS device and TCRa/13 Selection Reagent 
protocol.[17] The median absolute number of TCR-a/W cells was 2.8 x 10
5 
 (range 0.4-12.8 x 
 
 
 
 
 
5 
 
 
). The median number of mononuclear cells was 5.8 x 10
10 
 (range 1.2-10.4 x 10
10
 
and the 
median number of CD34+ cells was 358 x 106 (range 92-1432 x 106). The recovery of 
10
)


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 10 of 47
 
 
 
mononuclear cells was 55% (33-77%) and the recovery of CD34+ cells was 73% (43-98%). 
Viability of the cell product was not affected by TCRa/f3 selection. 
 
 
Outcomes of TCR-a/W Lymphocyte Depletion in Human Transplantation 
TCR-a/W cell depletion is effective at preventing GVHD in the context of HLA mismatched 
related donor transplantation. Bertaina and colleagues evaluated the use of TCR-a/W cell 
depletion using the CliniMACS system as the sole GVHD prophylaxis in 23 children undergoing 
haploidentical related donor transplantation for non-malignant conditions.[18] All patients 
received pre-transplant anti-thymocyte globulin and rituximab to prevent graft rejection and 
post-transplant lymphoproliferative disorder (PTLD), respectively. The median number of 
CD34+ cells/recipient kg infused was 15.8 x 106 (range 10.2-40.0 x 106) and the median 
number of TCR-a/WCD3+ cells infused was 4 x 104 (range 1.0-9.5 x 104). The median time to 
neutrophil engraftment was 13 days (10-20 days) and platelet engraftment was 10 days (7-40 
days). Four patients failed to engraft but responded to second allograft. Three patients 
developed grade 1-2 acute GVHD of the skin, there was no incidence of severe or visceral 
acute GVHD or chronic GVHD. The two year survival probability was 91%. Lang and 
colleagues have additionally treated 24 pediatric patients with malignant diagnoses with a 
similar protocol of fludarabine, melphalan, and thiotepa based conditioning with anti-thymocyte 
globulin and TCR-a/W cell depleted G-CSF mobilized haploidentical related donor allograft. 
(Unpublished results) The outcomes in this series are similar, with the median time to 
neutrophil engraftment being 10 days. Four patients (16%) developed grade 3+ acute GVHD 
and 70% of patients are alive albeit with a relatively short median follow up period of 0.5 years. 
Bertaina and colleagues expanded the use of TCR-a/W cell depletion based GVHD 
prophylaxis pediatric patients undergoing matched sibling donor (n = 41) or matched URD (n 
= 51) allo HCT for acute leukemia.[19] The majority of recipients were treated with total body 
irradiation based myeloablative conditioning. All treated patients achieved sustained donor cell 
engraftment. The cumulative incidence of acute GVHD was 41% and 42% for recipients of 
matched sibling and matched URD, respectively. Visceral involvement was 17% and 16.3%, 
respectively. The cumulative incidence of extensive chronic GVHD was 8 and 14%, 
respectively. Seven children died of non-relapse mortality (8%). The three year event-free 
survival was 66.1% and 65.4% in sibling and unrelated donor recipients, respectively. 
Results in recipients of HLA mismatched and HLA matched donor allo HCT using TCR-a/W 
cell depletion based GVHD prophylaxis are thus favorable when compared to unmodified 
allografts. The greater degree of acute GVHD noted in the latter Bertaina study suggests that 
short course pharmacologic immune suppression may be beneficial in preventing acute GVHD 
in recipients. Tacrolimus levels within the first 4 weeks post allo HCT correlate strongly with 
the incidence of acute GVHD, suggesting that early pharmacologic immune suppression is the 
most critical in reducing the incidence of GVHD.[20, 21] In the context of this study we will 
propose to include a short course (30 days) of tacrolimus based pharmacologic GVHD 
prophylaxis in order to maximize GVHD prevention without instituting long term pharmacologic 
immune suppression in study participants. 


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IRB Number: 18-224 A(7) 
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Use of post-transplantation Rituximab to deplete CD19+ donor B-lymphocytes 
 
The majority of published studies using TCR-a/W cell depletion based GVHD prophylaxis 
include an additional ex vivo depletion of CD19+ B-lymphocytes prior to allograft infusion. The 
purpose of this additional step is to minimize the propensity for donor derived EBV driven PTLD 
by reducing the reservoir for EBV from the donor allograft. This additional step may reduce the 
quantity of infused CD34+ hematopoietic progenitor cells and increases the cost and 
complexity of the allograft manipulation. More recently, infusion of low-dose, peri-transplant 
rituximab has demonstrated efficacy to reduce EBV viremia and PTLD without impacting long- 
term immune reconstitution.[22] Dominietto and colleagues demonstrate that 200 mg/m2 of 
rituximab on day +5 post transplant reduced the incidence of EBV viremia from 85% to 56% 
compared to untreated control patients. These results suggest that peri-transplant rituximab 
may be administered safely and will reduce the incidence of EBV related disorders. This 
practice is in use in the ongoing studies of TCR-a/W cell depletion based GVHD prophylaxis 
for haploidentical related donors conducted by the Italian group. 
 
 
Summary of Rationale for the Proposed Study 
 
In the current study we propose to conduct HLA mismatched allotransplant using TCR-a/W 
cell depletion based GVHD prophylaxis. The TCR-a/W cell depletion platform has validated 
results in HLA matched donors and in related HLA-haploidentical donors with an acceptable 
rate of acute GVHD and excellent engraftment and long term disease control. This platform 
represents a logical extension of the CD34+ selection based GVHD prophylaxis for 
mismatched donors in that it allows for innate effector cells such as NK and TCR-yiY T-cells 
to participate in pathogen control early after allo HCT. The proposed study addresses a 
shortcoming in the use of CD34+ selection for HLA mismatched donors in that diminished 
immune reconstitution is a major contributor to early transplant related mortality. 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a phase 2 study evaluating the rate of acute grade 3-4 GVHD following allo-HCT using 
a/WT-lymphocyte depleted grafts from HLA haploidentical or mismatched unrelated donors. 
Eligible candidates will include persons with advanced hematologic malignancies who do not 
have a suitable HLA-matched sibling or unrelated donor available and who meet criteria for 
myeloablative conditioning. The target accrual will be 38 individuals over 24 months. Three 
myeloablative conditioning programs are included and are outlined below. All participants will 
receive rabbit antithymocyte globulin and short course tacrolimus based GVHD prophylaxis. 
All recipients will receive a TCR-a/W lymphocyte depleted allograft from a HLA mismatched 
URD. The conditioning regimens are similar to those employed in the MSKCC 10-050 study. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 12 of 47
 
 
 
The primary objective of the study will be to determine the incidence of grade 3-4 acute GVHD 
by day +100 after transplantation. The intervention will be considered unpromising if the rate 
of GVHD is greater than 40% and promising if the rate is 20% or less. A Simon two-stage 
optimal design will accrue 11 patients in the first stage. If 5 or more develop grade 3-4 acute 
GVHD, the study will close due to a lack of efficacy; otherwise an additional 27 will accrue. If 
at the end of study, at least 27 out of the 38 patients are free of grade 3-4 GVHD, the study 
will be considered promising. The study also includes sequential safety stopping rules to 
monitor for non-relapse mortality. Secondary objectives will evaluate other clinical outcomes. 
Translational endpoints will define immune reconstitution in study participants which will be 
benchmarked against the estimates from MSKCC 10-050. 
 
 
4.2 
Intervention 
Patients will be identified appropriate for this therapy in the weekly Adult or Pediatric BMT 
Service meeting. Eligible patients will be registered and enrolled prior to the start of 
conditioning therapy. All patients will receive conditioning treatment with either Regimen A, B, 
or C outlined below. Selection of the conditioning regimen is outlined in section 9.1. All patients 
will receive anti-thymocyte globulin based conditioning followed by a G-CSF mobilized, 
peripheral blood hematopoietic progenitor cell HPC(A) product depleted of TCR-a/ + T- 
lymphocytes using the CliniMACS system. Participants will receive pharmacologic immune 
suppression to prevent graft versus host disease using tacrolimus for 30 days followed by a 
taper post transplantation. Standard supportive care will be administered per Adult and 
Pediatric BMT Service guidelines. 
Donors will be evaluated according to standard criteria for unrelated and haploidentical donors. 
Donors are considered eligible if they are matched at 6 or 7 alleles among HLA-A, -B, -C, and 
-DRB1 (unrelated donors) or if they are related haploidentical donors. Donors will donate a 
standard, G-CSF mobilized peripheral blood hematopoietic progenitor cell (HPC(A)) product 
that will subsequently be transferred to the MSKCC Cell Therapy Laboratory for processing. 
HPC(A) products will then undergo TCR-aW depletion using the CliniMACS reagents 
according to the manufacturer's guidelines. The cell dose will be capped to prevent infusion of 
>1 x 105 TCR-aW cells/kg. 
Patients will be assessed daily until after hematopoietic recovery and hospital discharge post 
transplantation. After hospital discharge patients will be assessed for acute GVHD weekly until 
day +100. Thereafter patients will be assessed for overlap or chronic type GVHD at 3 month 
intervals or more frequently if clinically indicated. Disease response and GVHD assessments 
will be performed at +100, +180, +270, and +360 days after transplant. 
Translational Endpoints 
Immune reconstitution of major lymphocyte subsets will be performed according to service 
guidelines. 


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IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 13 of 47
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
TCR-a/rl+ lymphocyte depleted stem cells from donor (related or unrelated) 
peripheral blood stem cells (PBSC) 
The investigational product in this study is TCR-a/!3+ lymphocyte depleted stem cells from 
donor (related or unrelated) peripheral blood stem cells (PBSC), administered intravenously. 
In this study, donor apheresis will be divided in two portions: one for the manufacture TCR- 
a/!3+ lymphocyte depleted stem cells and the other, for the manufacture of CD34+ enriched 
stem cells (section 5.2). Both products will be manufactured in the Cell Therapy Processing 
Facility at MSK using the CliniMACS Miltenyi Device. TCR-a/!3+ lymphocyte depleted stem 
cells will be separated using the investigational reagent kit from Miltenyi and following 
institutional SOPs. Reference is made to Miltenyi BB-MF 15, 678 for the CliMACS TCR 
depletion reagent. All testing is performed in a CUA-certified laboratory. Pre-release testing 
includes identity, viability, purity, sterility (gram stain) endotoxin, potency, and cell 
count/volume. The final product will contain no more than 1x105 TCR-a/!3+/kg (matched 
related) and 1x104 TCR-a/!3+/kg (mismatched). Post-release testing consists of sterility (14 
day culture, 21CFR610.12). 
In the event that the 14-day sterility culture and/or endotoxin assay yield a positive result, the 
the physician and patient will be notified immediately as well as the Co-Principal Investigators 
and Data Coordinating Center. The cell processing laboratory will be notified and will perform 
a thorough review of all processes and procedures during the manufacturing to determine if 
any deviations may have occurred leading to the positive culture or endotoxin assay. Further 
actions will be dependent on this review and will be left to the discretion of the Pl and the 
laboratory personnel. If the sterility culture is positive, the organism will undergo speciation and 
drug sensitivity testing and the results will be reported to the Pl and/or treating physician, 
patient, study chairpersons, and Data Coordinating Center. The IRB and the FDA will be 
notified of these results within 15 days. 
The final product is stored between 2-6°C until ready for infusion. 
 
 
5.2 
Allogeneic CD34+ selected stem cells 
CD34+ enriched stem cells will be obtained using the FDA approved reagents from Miltenyi, 
according to the instruction manual. The Miltenyi CD34+ Reagent System is an FDA 
approved Humanitarian Use Device. MSK has extensive experience using the Miltenyi 
CliniMACS® system under institutional INDs. 
CD34+ enriched stem cells are manufactured in the Cell Therapy Processing Facility at MSK, 
an FDA-registered, NY State Licensed Tissue Bank lab. Operations and quality assurance 
(QA) activities of the facility are overseen by the MSK Bone Marrow Transplant 
service QA Committee, by the MSK Blood Bank Transfusion Committee, and by the MSK 
Clinical Research Compliance Office. All testing is performed in a CUA-certified laboratory. 
Pre-release testing includes identity, viability, purity, sterility (gram stain) endotoxin, potency, 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 14 of 47
 
 
 
and cell counUvolume. The final product will contain no more than 1x105 CD3/kg (matched 
related) and 1x104 CD3/kg (mismatched). Post-release testing consists of sterility (14 day 
culture, 21CFR610.12). 
In the event that the 14-day sterility culture and/or endotoxin assay yield a positive result, the 
the physician and patient will be notified immediately as well as the Co-Principal 
Investigators and Data Coordinating Center. The cell processing laboratory will be notified 
and will perform a thorough review of all processes and procedures during the manufacturing 
to determine if any deviations may have occurred leading to the positive culture or endotoxin 
assay. Further actions will be dependent on this review and will be left to the discretion of the 
Pl and the laboratory personnel. If the sterility culture is positive, the organism will undergo 
speciation and drug sensitivity testing and the results will be reported to the Pl and/or treating 
physician, patient, study chairpersons, and Data Coordinating Center. The IRB and the FDA 
will be notified of these results within 15 days. 
The final product is stored between 2-6°C until ready for infusion. 
 
 
 
5.3 
Melphalan (Evomela®) 
Formulation and stability: A lyophilized powder of 50 mg melphalan. 
Solution preparation: 
1. Vial/50 mg: Reconstitute with 8.6ml NS to yield a final concentration of 5 mg/ml. 
2. Shake vigorously until the solution is clear. 
3. Dilute the dose to be administered in 0.9% Sodium Chloride, USP, to a 
concentration of 0.45 - 5 mg/ml 
Storage and stability: Should be stored at room temperature (15-30°C) protected from light. 
Infusions with concentration of 0.45mg/ml have a 4 hour stability at room 
temperature 
Administration: Intravenous, over 30 minutes. 
 
 
5.4 
Fludarabine (FLUDARA®) 
Supplied as: 50mg vial 
Reconstitution directions: add 2ml of sterile water for injection to a 50mg vial; yields a final 
concentration of 25 mg/ml. 
Storage and stability: 
1. Store vials under refrigeration. 
2. Refrigerated: prepare infusion in D5W; stable for 16 days. 
3. Room temperature: prepare infusion in D5W; stable for 16 days. 
Solution Preparation: 
1. Standard iv fluid: D5W. 
2. Final infusion concentration range: 1 mg/ml. 
3. IV piggyback volume: 50 ml. 


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IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 15 of 47
 
 
 
Clinical considerations: 
1. Hydration: None. 
2. Emetic potential: low. 
3. Supportive medications: none. 
Incompatibilities: acyclovir, amphotericin B, chlorpromazine, daunorubicin, ganciclovir, 
hydroxyzine, miconazole, prochlorperazine. 
 
5.5 
Antithymocyte globulin (Rabbit) 
 
Supplied as: Each package contains two 7 ml vials: Vial 1 contains freeze-dried thymoblobulin 
formulation active ingredient: Anti-thymocyte globulin 25 mg plus inactive ingredients 
including glycine 50 mg, sodium chloride 10 mg, and mannitol 50 mg. Vial 2 contains 
Diluent sterile water for injection, USP 5 ml. 
Reconstitution directions and solution preparation: Vial 1 and 2 are combined to form a solution 
of 5 mg/ml antithymocyte globulin. Transfer the contents of the calculated number of 
thymoglobulin vials into the bag of infusion solution (saline or 5% dextrose). The 
recommended volume for the infusion solution is 50 ml of solution per vial 1 of 
thymoglobulin. Mix the solution by inverting the bag 1-2 times. 
Storage and stability: Store un reconstituted vials in refrigerator between 2-8 degrees C. 
Protect from light. Do not freeze. Do not use after the expiration date indicated on the 
label. Reconstituted vials should be used within 4 hours. Infusion solutions should be 
used immediately. Any unused drug after infusion will be discarded. 
Clinical considerations: Patients will receive pre-hydration and anaphylaxis prophylaxis to 
include diphenhydramine and acetaminophen according to institutional guidelines. The 
infusion solution will be administered through a 0.22-micron filter with flow rate set to 
deliver the dose over 12 hours. Methylprednisolone 1 mg/kg may be administered 
concurrently with ATG. 
 
 
5.6 
Busulfan (Busulfex®) 
 
Supplied as: Busulfex is supplied as a clear solution in 10 ml single use vials. Each ampoule 
of Busulfex contains 60 mg of busulfan dissolved in N,N-dimethyl acetamide 33% wt/wt 
and polyethylene glycol 400 67% wt/wt. 
Reconstitution directions: Busulfex is diluted prior to use with 0.9% sodium chloride. The 
diluent should be 1OX the volume of Busulfex and the final concentration of busulfan is 
approximately 0.5 mg/ml 
Storage and Stability: Unopened ampules of Busulfex must be stored at 2-8 degrees C. 
Reconstituted busulfan is administered immediately. 
Clinical considerations: Busulfan is emetogenic. Busulfan is administered intravenously over 2 
hours. Seizure prophylaxis is co-adminstered according to institutional guidelines. 
Acetaminophen and metronidazole should not be given 24 hours pre or post busulfan 
administration. 


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IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
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5.7 
Filgrastim (Neupogen®) 
 
Supplied as: 300 mcg/ml; 1 ml vial (300 mcg) and 1.6 ml vial (480 mcg); 300 mcg/0.5 ml pre 
filled syringe; 480 mcg/0.8 ml pre-filled syringe. 
Storage and Stability: Store in a refrigerator (2-8°C). Do not freeze. If inadvertently the 
filgrastim is exposed to freezing temperatures for up to 24 hours, it may be thawed 
and refrigerated for use. Avoid shaking. Filgrastim may be allowed to reach room 
temperature for 24 hours prior to use. 
Solution Preparation: 
1. For IV infusion, dilute filgrastim in 25-50 ml O5W. 
2. The minimum concentration must not be less than 5 mcg/ml. 
3. If the final concentration of filgrastim in solution is between 5-15 mcg/ml, albumin 2 
mg/ml must be added to the solution prior to addition of the drug. 
4. Stability (IV) once diluted in 25-50 ml of O5W, filgrastim is stable for 7 days. 
5. Stability (plastic syringe) filgrastim is stable for two weeks in BO 1 ml plastic TB syringes 
at 2-8°C. 
 
5.8 
Tacrolimus (Prograf®) 
Supplied as: Capsules (1 and 5 mg) for parenteral administration or as a sterile solution in 1 
ml vials containing 5 mg anhydrous tacrolimus per ml, in boxes of 10 vials, for 
intravenous administration. Tacrolimus compounded suspension can be used. 
Storage and Stability: Tacrolimus injection ampules are stored between 5°-25°C. Prograf 
capsules are stored at room temperature (15°-30°C). 
Solution Preparation: Tacrolimus injection must be diluted with 0.9% sodium chloride injection 
or 5% dextrose injection to a concentration between 0.004 and 0.02 mg/ml prior to 
use. Diluted infusion solution should be stored in glass or polyethylene containers and 
should be discarded after 24 hours. The diluted infusion solution should not be stored 
in a PVC container due to decreased stability and the potential for extraction of 
phthalates. Parenteral preparations should be inspected visually for particulate matter 
and discoloration prior to administration. 
Clinical Considerations: Due to chemical instability of tacrolimus in alkaline media, injection 
should not be mixed or co-infused with solutions of pH 9 or greater (e.g. ganciclovir or 
acyclovir). Prograf capsules should be taken regularly at 12 hour intervals. 
 
 
5.9 
Thiotepa (Thioplex®) 
Formulation: 15 mg vial lyophilized powder; must be diluted prior to infusion. 


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IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 17 of 47
 
 
 
Reconstitution: Add 1.5 ml of sterile water for injection (SWFI) to 15mg vial to yield 
10mg/ml. Solutions which are grossly opaque or contain a precipitate, should not be 
used. In order to eliminate haze, solutions should be filtered through a 0.22-mcron filter 
prior to administration. 
Storage and Stability: 
1. Store vials in refrigerator and protect from light. 
2. Reconstituted solutions are stable for 24 hours under refrigeration and room 
temperature. 
3. Reconstituted solutions further diluted in NS (0.9% sodium chloride) at 
concentrations of 1mg/ml, 2mg/ml and 5 mg/ml are stable for up to 24 hours at 
room temperature and 48 hours under refrigeration. 
4. Diluted solutions of 0.5 mg/ml in NS should be used immediately after preparation. 
Preparation: 
1. Standard IV fluid: NS 
2. Final concentration range up to: 5mg/ml. 
Clinical Considerations: Emetogenic potential high. 
Hydration: NA 
Incompatibilities: Cisplatin, filgrastim (G-CSF), vinorelbine. 
 
 
5.10 
Clofarabine (CLOLAR®) 
Supplied as: 20 mg vial (1 mg/ml). The pH range of the solution is 4.0 to 7.0. The solution in 
clear to yellow in color and should be free from particulate matter. 
Storage and Stability: Undiluted vials are stored at room temperature. 
Solution Preparation: Clofarabine for injection should be filtered through a sterile 0.22 µm 
syringe filter and then further diluted with 5% dextrose or 0.9% sodium chloride 
injection. The resulting mixture may be stored at room temperature but must be used 
within 24 hours of dilution. 
Clinical Considerations: Clofarabine should be administered over 2 hours through a centralized 
venous catheter. No other medications should be administered through the same line 
concurrently. 
 
 
5.11 
Rituximab (Rituxan ®) 
Supplied as: 100 mg and 500 mg vials (10 mg/ml) 
Storage and Stability: Store vials under refrigeration once diluted, protect from sunlight. 
Diluted rituximab is stable for 24 hours at room temperature. 
Solution Preparation: Rituximab for injection should be diluted in normal saline to a 
concentration of 1-4 mg/ml. 
Clinical Considerations: Anticipate infusion reactions, particularly in individuals who have not 
previously received rituximab infusion. Infusion schedule will be adjusted according to 
standard  guidelines.  Emetogenic  potential  is  low.  Patients  should  receive 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 18 of 47
 
 
 
acetaminophen and diphenhydramine according to service guidelines 30-60 minutes 
prior to infusion. 
 
5.12 
Cyclophosphamide 
Supplied as: 200 mg, 500 mg, 2000 mg vials 
Reconstitution directions: add sterile water for injection to yield a final concentration of 20 
mg/ml. 
Storage and stability: 
1. Store vials at room temperature. 
2. Refrigerated: prepare infusion in D5W, stable for 28 days. 
3. Room temperature: prepare infusion in D5W: stable for 48 hours 
Solution Preparation: 
1. Standard iv fluid: D5W. 
2. Final concentration range up to: 20mg/ml. 
3. IV piggyback volume: for doses < 1200mg/m2, infuse in 25cc D5W; for doses> 
1200mg, infuse as straight drug. 
Clinical considerations: 
1. Hydration: as per MSKCC guidelines for BMT patients receiving> 3000 mg/m2. 
2. Emetic potential: high and delayed. 
3. Supportive medications: anti-emetics and mesna. 
Incompatibilities: do not administer with other drugs. 
 
 
5.13 
Total body irradiation 
Hyperfractionated TBI is administered by a linear accelerator at a dose rate of <20 cGy/minute. 
Doses of 125 cGy/fraction are administered at a minimum interval of 4 hours between fractions, 
three times/day for a total of 11 or 12 doses (1,375 or 1,500 cGy) over 4 days (days -9 through 
-6). If general anesthesia is required, 150 cGy q12h x 8 doses to a total dose of 1,375 cGy 
may be given. Sequential doses are administered in an anterior/posterior or lateral orientation. 
Compensators and lung blocks are used to shield the lung so that the lung receives 800 cGy. 
The blocked areas of the chest will be boosted with high-energy electrons so that the 
cumulative chest wall dose is approximately 1,500 cGy. This insures that marrow sites int eh 
ribs are adequately treated. 
 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
Describe the characteristics of the patient/subject population. 
6.1 
Subject Inclusion Criteria 


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IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
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• 
Patients with any of the following hematologic malignancies who are considered to be 
eligible for allogeneic transplantation: 
 
o 
Acute lymphoid leukemia (ALL) in first complete remission (CR1) with high risk 
for relapse including: 
o 
Detectable minimal residual disease by either multicolor flow 
cytometry or by genomic assay after initial induction therapy 
o 
t(9;22) or detected BCR-ABL 1 translocation by genomic 
methodologies 
o 
BCR-ABL 1-Like B-ALL [23] including mutations of IKZF1 or CRLF2 
o Translocations or mutations involving 11q23 (MLL) gene. 
o 
Hypodiploid karyotype 
o 
Deletion of 9p 
o 
Loss of 17p or TP53 mutation 
o 
T-lymphocyte lineage antigen expression (T-ALL) 
o 
Prior CNS or other extramedullary involvement 
o 
WBC count 
100,000 cells/µL at diagnosis 
 
o 
Acute biphenotypic or bilineal leukemia in CR1 
 
o 
Acute myeloid leukemia (AML) in CR1 with 
o 
Detectable minimal residual disease (MRD) by either multicolor 
flow cytometry or by genomic assay after initial induction therapy. 
o 
In the absence of MRD any intermediate or high risk features 
according to the European LeukemiaNet 2017 guidelines[24], 
including: 
• 
Mutated FLT3-ITD or FLT3-TKO 
• 
Cytogenetic abnormalities not classified as favorable 
• 
Cytogenetic abnormalities associated with myelodysplastic 
syndrome including abnormalities of chromosome 5, 7, or 
17p 
• 
Complex karyotype or monosomal karyotype 
• 
t(9;11)(p21.1;q23.3); MLL-KMT2A or other rearrangements 
of KMT2A 
• 
t(9;22); BCR-ABL1 
• 
Inversions or translocations of chromosome 3 
• 
T(6;9)(p23;q34.1); DEK-NUP214 
• 
Somatic mutation of RUNX1, ASXL1 or TP53 
o 
Extramedullary involvement 
o 
WBC count 100,000 cells/µL at diagnosis 
 
o 
Relapsed acute leukemia with :5 5% blasts in the bone marrow prior to 
transplantation (i.e. CR2 or greater). 


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IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
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o 
Myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/MPN overlap 
syndrome with s; 10% blasts and at least one of the following: 
■ 
Revised International Prognostic Scoring System risk score of INT, HIGH, 
or VERY HIGH at the time of transplant evaluation. 
■ 
Life-threatening cytopenias. 
■ 
Karyotype or genomic changes that indicate high risk for progression to 
acute myelogenous leukemia, including abnormalities of chromosome 7 or 
3, mutations of TP53, or complex or monosomal karyotype. 
■ 
Therapy related disease or disease evolving from other malignant 
processes. 
 
o 
Chronic myelomonocytic leukemia (CMML) with s; 10% blasts prior to 
transplantation. 
 
o Chronic myeloid leukemia (CML) meeting one of the following criteria: 
■ 
Failed or are intolerant to BCR-ABL tyrosine kinase inhibitors. 
■ 
CML with BCR-ABL mutation consistent with poor response to tyrosine 
kinase inhibition (e.g. T351I mutation). 
■ 
CML with accelerated or blast phase with <10% blasts after therapy. 
 
o Chronic lymphocytic leukemia (CLL) with high risk disease as defined by the 
EBMT consensus criteria. 
 
o Hodgkin lymphoma meeting both of the following criteria: 
■ 
Responding to therapy prior to enrollment 
■ 
Relapse after autologous bone marrow transplant or are ineligible for 
autologous bone marrow transplant. 
 
o 
Non-Hodgkin lymphoma meeting both of the following criteria: 
■ 
Responding to therapy prior to enrollment. 
■ 
Relapse after prior autologous bone marrow transplant or are ineligible for 
autologous bone marrow transplant. 
 
• 
Patients aged from birth through 65 years old are eligible. 
 
• 
Patients must have Karnofsky/Lanksy performance status70%. 
 
• 
Cardiac left ventricular ejection fraction 50% at rest. 
 
• 
Serum bilirubin s; 2 mg/dl. Patients with Gilbert's disease or ongoing hemolytic 
anemia are acceptable if the direct bilirubin is s; 2 mg/dl. 
 
• 
AST and ALT s; 2.5 x ULN unless thought to be disease related. 


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IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 21 of 47
 
 
 
• 
Estimated or measured creatinine clearance > 50 ml/min/1.73 m2 body surface area. 
 
• 
Adult patients and pediatric patients capable of performing pulmonary function 
studies must have hemoglobin adjusted pulmonary DLCO 50% of predicted. 
 
 
6.2 
Subject Exclusion Criteria 
 
• 
Persons with a HLA matched sibling donor or a 8/8 allele level HLA-matched unrelated 
donor. 
 
• 
Female patients who are pregnant or breast-feeding. 
 
• 
Persons with an infection that is not responding to antimicrobial therapy. 
 
• 
Persons who are seropositive for HIV. 
 
• 
Persons with active/detectable central nervous system malignancy. 
 
• 
Persons who do not meet the age and organ function criteria specified above. 
 
• 
Presence of psychiatric or neurologic disease, or lack of social support that limits the 
patient's ability to comply with the treatment protocol including supportive care, follow- 
up, and research tests. 
 
• 
Prior allogeneic hematopoietic cell transplantation are ineligible. 
 
• 
Patients with history of other malignancy within 5 years of study therapy are ineligible 
with the following exceptions: Low grade prostate cancer (Gleason's ::;;6) treated with 
curative intent, breast ductal carcinoma in situ treated with curative intent, or non- 
melanomatous skin carcinomas. 
 
• 
Patients with previous checkpoint inhibitor therapy such as PD-1/PDL-1 inhibitors 
cannot undergo transplantation less than 6 weeks from the last checkpoint inhibitor 
therapy. 
 
 
6.3 Donor Inclusion and Exclusion Criteria 
 
• 
Partially HLA-matched unrelated volunteers (allele level matched at 6-7 of 8 HLA loci: 
-A, -B, -C, and -DRB1) are eligible. 
 
• 
Related, haploidentical donors are eligible. 


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IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
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• 
Able to provide informed consent to the donation process 
 
• 
Meet standard criteria for donor collection as defined by the National Marrow Donor 
Program Guidelines. 
 
 
7.0 
RECRUITMENT PLAN 
Eligible patients are identified via the weekly Adult or Pediatric BMT/Leukemia Patient Review 
Conference. Patients that do not have a matched sibling or unrelated adult donor option and 
who do have either an unrelated donor that is matched at least 6/8 loci (HLA-A, -8, -C, ORB1) 
or a haploidentical related donor and meet the other eligibility criteria will be offered 
participation in this study. 
This protocol will take due notice of NIH/ADAMHA policies concerning inclusion of women and 
minorities in clinical research populations. We anticipate that this study will preferentially 
benefit persons of racial or ethnic minority populations as these individuals are less likely to 
have a HLA matched allo HCT donor. Otherwise, we expect that the study population will be 
fully representative of the range of patients referred for transplant without exclusion as to age 
or gender with the exception that pregnant women are excluded from participation in this study. 
 
8.0 
PRETREATMENT EVALUATION 
The patient will receive an extensive medical evaluation within 45 days of starting treatment. 
Tests outside of the 45 day window need only be repeated if clinically indicated. The evaluation 
includes: 
• 
Complete history and physical exam 
• 
Dental evaluation 
• 
Complete blood count, PT/PTT, serum chemistries and hepatic panel, and ABO 
type and screen 
• 
Serum will be tested for CMV serostatus, Hepatitis B (core antibody, surface 
antigen), Hepatitis C antibodies, EBVantibodies, toxoplasmosis antibodies, HIV 
antibodies, and HTLV-1/2 antibodies 
• 
Pregnancy test for females of childbearing potential 
• 
Bone marrow aspirate (biopsy if clinically indicated) 
• 
Urinalysis 
• 
Electrocardiogram and echocardiogram 
• 
Spirometry (adults and pediatric patients) and pulmonary diffusion capacity 
(adults only) 
• 
Donor-specific anti-HLA antibody titers 
• 
Recipient short-tandem repeat (STR) profile for chimerism analysis 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 23 of 47
 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 
Regimen for Cytoreduction 
Three cytoreduction regimens are outlined below. Patients with myeloid malignancies such as 
MOS or AML will be treated with either regimen A or regimen B based on investigator 
preference. Patients with lymphoid malignancies including ALL will be treated with regimen A 
or regimen C based on investigator preference. Patients with biphenotypic or mixed phenotypic 
acute leukemia may be treated with any regimen based on investigator preference. All drugs 
are administered relative to the date of stem cell infusion (day 0). 
9.1.1 Conditioning Regimen A: TBI/CY/THIO 
 
Day
Treatment
-12
Rabbit ATG dosing per nomogram
-11
Rabbit ATG dosing per nomogram
-108 
Rabbit ATG dosing per nomogram
-9
TBI
-8
TBI
-7
TBI
-6
TBI
-5
Thiotepa 5 mg/kg IV#
-4
Thiotepa 5 mg/kg IV#
-3
Cyclophosphamide 60 mg/kg/day IV
-2
Cyclophosphamide 60 mg/kg/day IV
-1
0
Cell infusion
+5
Rituximab 200 mg/m2 IV
hiotepa may be given as 10 mg/kg/d x 1 on day -5 only. 
a) If day 3 ATG is not required the conditioning program can begin, moving all 
subsequent treatments to the prior day, at the investigators discretion. 


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IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
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9.1.2 Conditioning Regimen B: BU/MEL/FLU 
 
Day
Treatment
-12
Rabbit ATG dosing per nomogram
-11
Rabbit ATG dosing per nomogram
-108 
Rabbit ATG dosing per nomogram
-9
Busulfan 3.2 mg/kg/day IV#
-8
Busulfan IV*
-7
Busulfan IV*
-6
Melphalan 70 mg/m2 IV
Fludarabine 25 mg/m2 IV 
-5
Melphalan 70 mg/m2 IV
Fludarabine 25 mg/m2 IV 
-4
Fludarabine 25 mg/m2 IV
-3
Fludarabine 25 mg/m2 IV
-2
Fludarabine 25 mg/m2 IV
-1
Rest
0
Cell infusion
+5
Rituximab 200 mg/m2 IV
#Busulfan dosing modifications for children :54 are outlined below. 
*Busulfan will be dosed with pharmacokinetic modifications to target an AUC of 4800 
min*mmol/L ± 10%/dose according to institutional guidelines. 
a) If day 3 ATG is not required the conditioning program can begin, moving all subsequent 
treatments to the prior day, at the investigators discretion. 


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IRB Number: 18-224 A(7) 
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9.1.3 Conditioning Regimen C: CLO/MEL/THIO 
 
Day
Treatment
-12
Rabbit ATG dosing per nomogram
-11
Rabbit ATG dosing per nomogram
-1oa
Rabbit ATG dosing per nomogram
-9
Clofarabine 20* mg/m2 IV
-8
Clofarabine 20* mg/m2 IV
-7
Clofarabine 20* mg/m2 IV
-6
Clofarabine 20* mg/m2 IV
-5
Clofarabine 20* mg/m2 IV
-4
Thiotepa 10 mg/kg IV
-3
Melphalan 70 mg/m2
-2
Melphalan 70 mg/m2
-1
Rest
0
Cell infusion
+5
Rituximab 200 mg/m2 IV
*In patients <18 years old clofarabine 30 mg/m2 may be used at the discretion of the principle 
investigator. 
a) If day 3 ATG is not required the conditioning program can begin, moving all subsequent 
treatments to the prior day, at the investigators discretion. 
 
9.1.4 Clofarabine administration 
Clofarabine will be administered via approximately a 2 hour intravenous infusion. Adult 
patients may receive hydrocortisone 50 mg/m2 IV (maximum 100 mg) 30-60 minutes prior to 
clofarabine infusion. 
9.1.5 Melphalan administration 
Melphalan will be infused once daily intravenously. Adjusted body weight will be used if the 
patient's actual weight is > 125% of adjusted body surface area. Dosing melphalan in young 
children is difficult and may require case by case adjustment. Therefore, investigators are 
permitted to modify the dosing of melphalan in children :s; 3 years based on the discretion of 
the principal/co-principal investigators. 
 
9.1.6 Fludarabine administration 
 
Fludarabine is administered intravenously over 30 minutes. 
9.1.7 Busulfan administration 
Intravenous busulfan is administered at a total dose of 3.2 mg/kg/day of adjusted recipient 
body weight for adults and children 4 years old (only if the child is >125% of ideal body 
weight). The dose may be administered either as a single dose or divided over four doses 
administered every six hours. For children <4 years old busulfan will be administered at a total 
dose of 1.0 mg/kg/dose q6 hours x 12 doses/3 days of actual body weight. Target dosing 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 26 of 47
 
 
 
through pharmacokinetic assays will be performed as per institutional guidelines. The target 
AUC = 4800 min*mmol/L ± 10%. 
9.1.8 Rituximab administration 
Rituximab will be administered according to institutional protocols to minimize infusion 
reaction. 
9.1.9 Thiotepa administration 
Thiotepa dosing will be based on adjusted body weight if a patient is >125% of ideal body 
weight. 
9.1.11 Cyclophosphamide administration 
Cyclophosphamide dosing will be based on adjusted body weight if a patient is >125% of ideal 
body weight. Hydration and mesna administration will be according to institutional guidelines. 
9.1.12 Rabbit anti-thymocyte globulin dosing 
Rabbit ATG dosing will be based on a dynamic nomogram as defined in the PARACHUTE 
study (Admiraal, Rick et al; BBMT 26;3,S33-34, Appendix A). This dynamic nomogram is 
based on absolute lymphocyte count at the start of conditioning and can result in either 2 or 3 
day ATG administration. If a patient requires 2 day administration the subjequent 
chemotherapies may be moved forward by one day at the treating physician's discretion. 
9.1.13 Adjustment of chemotherapy based on adjusted body weight 
Adult patients who are >125% of ideal body weight that require adjustment of agents listed 
above will receive therapy based on the following formulas: 
Ideal body weight (IBW) formula: 
Male IBW = 50 kg+ 2.3 kg/inch over 60 inches 
Female IBW = 45.5 kg+ 2.3 kg/inch over 60 inches 
 
Adjusted body weight (ABW) formula: 
ABW = IBW + 0.4 x (actual weight - IBW) 
 
Patients <18 years old IBW is calculated as follows (IBW in kg): 
Less than 152.4 cm: 
IBW = (Height in cm2 x 1.65)/1000 where ht= cm, IBW = kg 
 
More than 152.4 cm: 
IBW (male) = 39.0 + (2.27 x (ht - 60)) where ht= inches 
IBW (female) = 42.2 + [2.27 x (ht - 60)] 
 
9.2 Donor mobilization and TCR-a(J+ T-cell Depletion 


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9.2.1 Mobilization of Donor 
Donors will undergo filgrastim based mobilization according to institutional standards. Donor 
stem cell apheresis, HPC(A) will be performed per institutional standards. The donor shall not 
undergo more than 2 days of collection unless extenuating circumstances permit for an 
additional day (total 3 days). 
9.2.2 TCRaJ3+ T-Cell Reduction using the Miltenyi CliniMACS® 
 
 
Reduction of TCRaJ3 T-cells from the donor HPC(A) product will be performed according to 
procedures given in the CliniMACS® Users Operating Manual and institutional Standard 
Operating Procedures (SOP) implemented in the Cell Therapy Laboratory (see Appendix for 
SOP). 
A single TCRaJ3+ T-cell reduction procedure will be performed for adult donors. The target 
CD34+ cells/kg cell dose for the final product is 5 x 106. An additional CD34+ cell selection 
(CD34 enrichment) may be performed to achieve the target CD34+ cell dose, if required. If 
there are less than a total of 2.0 x 106 CD34+ cells/kg recipient body weight in the combined 
allografts, the laboratory will contact the investigator. If required, CD34+ cell selection on 
additional HPC(A) will be performed according to procedures given in the CliniMACS® Users 
Operating Manual and approved institutional SOP. Testing of the product will be conducted in 
a CUA certified laboratory as described in the CMC section. 
The TCR a-b graft is depleted of potentially allo-reactive T cells (TCR a-b positive cells). 
Because all other cells are retained (CD34, TCR gamma-delta, NK cells etc) the size of the 
graft is similar to an unmodified PBPC graft, and therefore it is usually dispensed in a bag. 
The CD34 selected graft only retains the CD34 cell fraction, which is relatively rare and 
therefore the volume of the product is much smaller and as such the product is dispensed in a 
syringe. 


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If both products are available simultaneously to infuse, the recommendation is to first infuse 
the CD34 selected graft due to its small volume and nearly absent reaction rate. Once the 
CD34 selected graft has been infused, then the bag of the TCR a-b depleted graft may be 
administered as per SOP for HPCs in the bag format. There is no necessity for a delay 
between infusions. 
Pre-medications and fluids should be administer per standard BMT practice guidelines for 
CD34 selected products. 
 
9.3 
Pharmacologic graft versus host disease prophylaxis 
Tacrolimus will be administered as follows: 
• 
Patients will receive tacrolimus beginning on day -3 and continuing through day +30. 
• 
Tacrolimus will be administered by continuous IV infusion to achieve a level of 5-12 
ng/ml plasma concentration. 
• 
When a patient is able to tolerate oral medications tacrolimus may be transitioned to 
twice (three times daily dosing may be used in pediatric patients <40 kg) to achieve a 
similar trough level. Tacrolimus will be tapered linearly to off by day +100 after 
transplantation. 
• 
The tacrolimus taper may be altered or suspended if suspected/confirmed symptoms 
of GVHD arise. Tacrolimus may be discontinued if patients become intolerant to 
tacrolimus. 
9.3 
Supportive Therapy 
The following standard therapies will be provided for all patients: 
9.3.1 Infection prophylaxis 
 
• 
Infection prophylaxis will be administered according to institutional guidelines. 
• 
Specific infection prophylaxis will be administered for Pneumocystis cannu, 
Herpesviridae, and fungal infections to all recipients and for Toxoplasmosis gondii to 
seropositive recipients. Seronegative recipients may elect to receive Toxoplasmosis 
gondii prophylaxis if the donor is seropositive at the discretion of the treating physician. 
9.3.2 Growth factor support 
Patients will receive G-CSF beginning on day +7 at a dose of 5 mcg/kg/dose subcutaneously 
or intravenously every 12 hours (rounding to nearest vial dose is allowed) until the absolute 
neutrophil count is 1,000/µL on three consecutive days. Intravenous administration of G-CSF 
is allowed at the discretion of the treating physician. 
9.3.4 
Sinusoidal obstructive syndrome prophylaxis 
Patients will receive ursodiol according to pediatric or adult service guidelines. 


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10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
10.1 
Post transplantation evaluation 
Post transplantation evaluations are summarized the table below: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
 
 
 
I 
I 
I 
I 
I 
• 
 
 
 
 
 
I Research Blood1 
I 
I 
I 
I 
X 
I 
I 
I 
X 
I 
X 
I 
I 
X 
 
I GVHD Evaluation 
I 
X 
I 
X 
I 
X 
I 
X 
I 
X 
I 
X 
I 
X 
I 
X 
I 
I 
X 
I 
X 
 
1. For all patients weighing to 10kg, research samples will consist of three 10 ml sodium heparin tubes of blood on the days 
described above. If a patient is at risk for exceeding maximum allowable blood draw limits (per  Seattle Children's Hospital Guideline 
for Maximum Blood Volumes), clinical laboratory assessments will be prioritized and research samples will be discontinued. 
 
 
 
 
 
 
 
 
 
 
Page 30 of 47 
I Toxicity Assessment
 
 
 
 
 
 
 
 
 
 
Day? 
Day 14 
Day 21 
Day28 
Day42 
Day60 
Day 100 
Day 180 
Day 270 
Day 365 
Early 
Term 
Window 
±3 
±3 
±3 
±7 
±3 
±3 
±7 
±14 
±14 
± 30 
± 30 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T-Cell and myeloid
X 
chimerism (ARC) 
X 
X 
X 
X 
Bone marrow aspirate 
X 
and/or biopsy 
X 
X 
X 
Restaging Imaging
studies (if clinically 
indicated) 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
Immune recovery,
clinical (Phenotyping, 
short panel) 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
X 
 


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• 
Fever 
• 
Headache 
• 
Restlessness 
• 
Hypertension 
• 
Nausea, vomiting, or loss of appetite 
• 
Diarrhea 
• 
Dry or irritated mouth 
• 
Electrolyte abnormalities 
• 
Low blood white cell, platelet, and red cell counts 
• 
Alopecia 
 
 
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 
consultations discussing the risks and potential benefits of an allogeneic stem cell 
transplantation and the different procedures which will be a normal part of the transplant 
course. The risks and potential benefits of the transplant procedure are also discussed. 
In addition to tracking patients for survival and graft failure, all participants will also be 
monitored for post-transplant toxicities. Toxicities will be graded according to NCI CTCAE 
version 5.0 at the time points outlined in Section 10.1. All grade 3-4 adverse events will be 
captured and assessed for attribution to protocol treatment. Additional toxicities will be 
reviewed and graded/attributed at the discretion of the Pl. Toxicities which are attributable to 
underlying disease and/or grade 1-2 expected toxicities from the transplant will not be tracked. 
 
 
11.1 
Busulfan 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving busulfan more than 20 and up to 100 may have: 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving busulfan from 4 to 20 may have: 
 
• 
Mouth ulcers 
• 
Abnormal liver function studies 
• 
Rash 


Memorial Sloan Kettering Cancer Center 
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Page 32 of 47
 
• 
Decreased blood counts including anemia, low white blood cell count, and low platelet 
count 
• 
Irritation to the bowel, causing nausea, vomiting, loss of appetite, or diarrhea 
• 
Abnormal liver function studies (increased ALT or AST) 
• 
Fluid retention/edema 
• 
Rash 
• Neurotoxicity (agitation or confusion, visual disturbances, blindness, loss of hearing, 
peripheral neuropathy) 
• Severe hepatic injury causing hepatic failure 
• Hemolytic anemia 
• Phlebitis 
• Deep venous thrombosis 
• 
Fever 
• 
Chills 
• 
Low white blood cell count 
• 
Low platelet count 
• 
Headache 
• 
Hypertension 
 
 
 
 
RARE, AND SERIOUS 
In 100 people receiving busulfan 3 or fewer may have: 
 
 
11.2 
Fludarabine 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving fludarabine more than 20 and up to 100 may have: 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving fludarabine from 4 to 20 may have: 
 
 
RARE, AND SERIOUS 
In 100 people receiving fludarabine 3 or fewer may have: 
 
11.3 
Anti-thymocyte globulin 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving antithymocyte globulin more than 20 and up to 100 may have: 
• Seizures 
• Hepatic sinusoidal obstructive syndrome 
• Pericarditis 
• Alveolar hemorrhage 
• Encephalopathy 
• Hemorrhagic cystitis 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
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Page 33 of 47
 
 
RARE, AND SERIOUS
 
• 
Decreased blood counts including anemia, low white blood cell count, and low platelet 
count 
• 
Irritation to the bowel, causing nausea, vomiting, loss of appetite, or diarrhea 
• 
Alopecia (loss of hair) 
• 
Fatigue 
• 
Insomnia 
• 
Abnormal liver function studies (increased ALT, AST, or alkaline phosphatase) 
• 
Hyponatremia (low sodium) 
• 
Allergic reaction to infusion (fever, hives, itching) 
• 
Anaphylactic infusion reaction (hypotension, allergic symptoms) 
• 
Interstitial pneumonitis 
• 
Severe hepatic injury or hepatic failure 
• 
Diarrhea 
• 
Nausea or loss of appetite 
• 
Fever or chills 
• 
Fatigue 
• 
Anxiety or restlessness 
• 
Itching 
• 
Rash 
• 
Low blood counts 
 
 
 
 
 
11.4 
Melphalan 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving melphalan more than 20 and up to 100 may have: 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving melphalan from 4 to 20 may have: 
 
 
RARE, AND SERIOUS 
In 100 people receiving melphalan 3 or fewer may have: 
11.5 
Clofarabine 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Clofarabine more than 20 and up to 100 may have: 
OCCASIONAL, SOME MAY BE SERIOUS 
 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
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Page 34 of 47
 
• 
Increased blood creatinine 
• 
Increased liver function studies (AST, ALT, alkaline phosphatase, bilirubin) 
• 
Infusion reaction 
• 
Liver failure due to sinusoidal obstructive syndrome 
• 
Kidney failure 
• 
Pulmonary edema 
• 
Stevens-Johnson syndrome 
• 
Infections 
• 
Nausea 
• 
Headache 
• 
Restlessness 
• 
Body aches 
• 
Loose stool 
• 
Low blood counts 
• 
Rash 
• 
Bladder irritation 
• 
Elevation of the liver functions studies (AST, ALT, alkaline phosphatase, bilirubin) 
• 
Minor infusion reaction such as itching or rash 
• 
Fluid retention 
• 
Exfoliative skin reaction 
• 
Delirium 
• 
Myocarditis 
• 
Hepatic failure due to sinusoidal obstructive syndrome 
• 
Anaphylactic infusion reactions 
• 
Acute kidney injury 
 
 
 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Clofarabine from 4 to 20 may have: 
 
RARE, AND SERIOUS 
In 100 people receiving Clofarabine 3 or fewer may have: 
11.6 
Thiotepa 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Thiotepa more than 20 and up to 100 may have: 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Thiotepa from 4 to 20 may have: 
 
RARE, AND SERIOUS 
In 100 people receiving Thiotepa 3 or fewer may have: 
 
11.7 
Rituximab 


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•
High blood pressure
• 
Moderate infusion reaction such as fever, chills, shaking, cough, or wheezing 
• 
Low phosphorous level 
•
Anaphylactic infusion reaction (hypotension, allergic symptoms)
• 
Myocardial infarction (heart attack) 
• 
Stroke 
• 
Delayed neutropenia 
• 
Decreased blood counts including anemia, low white blood cell count, and low platelet 
count 
• 
Irritation to the bowel, causing nausea, vomiting, loss of appetite, or diarrhea 
• 
Loss of hair, or alopecia 
• 
Irritation to the bladder, which may cause discomfort. Rarely, bleeding may occur in the 
bladder 
• 
Abnormal electrolyte concentration in the blood 
 
 
 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Rituximab more than 20 and up to 100 may have: 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Rituximab from 4 to 20 may have: 
 
RARE, AND SERIOUS 
In 100 people receiving Rituximab 3 or fewer may have: 
11.8 
Cyclophosphamide 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving cyclophosphamide more than 20 and up to 100 may have: 
 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving cyclophosphamide from 4 to 20 may have: 
•
Minor infusion reaction such as itching or rash
• 
Infections 
• 
Low immunoglobulin level 
• 
Nausea 
• 
Headache 
• 
Restlessness 
• 
Body aches 
• 
Loose stool 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
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Page 36 of 47
 
• Irritation to the heart or heart lining, called the pericardium
• Abnormal heart rhythms 
• Irritation to the lungs 
• Veno-occlusive disease of the liver 
• Injury to the kidneys, causing kidney failure 
• Allergic reaction to the infusion of cyclophosphamide 
 
 
 
 
RARE, AND SERIOUS 
In 100 people receiving cyclophosphamide 3 or fewer may have: 
 
 
11.8 
Transplant Related Risks 
 
11.8.1 Blood transfusions 
Transfusions 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. Fluid overload can be managed with 
diuretics. Allergic reactions of variable severity can be prevented or mitigated by premedication 
with antipyretics, antihistamines, and opiates. 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 per AABB and FACT 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. 
 
 
11.8.2 Hematopoietic progenitor cell infusion 
 
Possible side effects include: 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. Reactions will be treated as per standard MSKCC guidelines. 
 
11.8.3 Graft-versus-host-disease (GVHD) 
 
GVHD occurs when the donor immune system attempts to reject normal tissues and is 
described below. Approximately 20-40% of persons may develop acute GVHD and 5-20% may 
develop chronic GVHD. A biopsy may be necessary to make the diagnosis of GVHD. 
 
Acute GVHD usually occurs in the first 3 months or as immune suppressive medications are 
tapered and may cause: skin rashes, nausea, vomiting, diarrhea, hepatitis, increased risk of 
infection, ulceration of the surfaces of the oral cavity, esophagus, and intestines, and 
suppressed or delayed recovery of the hematopoietic and immune system. 
Chronic GVHD can occur any time after the first 3 months and is 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. 


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Severe GVHD: Rarely, GVHD can be severe or deadly. Severe acute GVHD could involve a 
severe skin rash like a burn, severe vomiting and/or diarrhea, liver failure and infections or 
bleeding. Severe acute GVHD will be treated with intense immunosuppressive therapy 
according to standard clinical practice or other experimental protocol. Severe chronic GVHD 
could involve similar symptoms but may produce other symptoms such as severe skin 
changes, severe dry eyes and weight loss. 
 
Steroids, as treatment for GVHD: inability to sleep, high blood sugar, puffiness of the face, 
changes in the skin, high blood pressure, increased risk of infection, weight gain, reduced 
growth in children, thinning of the bones 
11.8.4 Serious bleeding 
 
Serious bleeding may result from low platelet counts and/or injury to tissues from treatment. 
This can happen in spite of platelet transfusions. Bleeding is rarely lethal. 
 
11.8.5 Infections 
 
Patients will be at increased risk of infections due to pancytopenia induced by the transplant. 
Low T-cell count for an additional 9-12 months after transplantation increases the risk for 
certain opportunistic infections such as pneumocystis jiroveci pneumonia, cytomegalovirus, 
and others. Medications are given to reduce the chance of infections. Patients will receive 
treatment if they do get an infection and most infections can be treated successfully with 
antibiotics. Patients will stay in the hospital longer or be readmitted iffound to have an infection. 
Patients are watched closely for bleeding and given platelet transfusions to prevent serious 
bleeding, but minor bleeding may occur. 
 
11.8.6 Risk of a secondary cancer 
Secondary cancers may occur after chemotherapy. The risk of developing a secondary cancer 
of the skin, cervix, etc., which has been seen in other transplant studies is less than 5%. 
 
11.8.7 Graft Failure/rejection 
Stem cell grafts may fail to grow or may start to grow and then be rejected by the patient's 
immune system. 
 
11.8.8 Impaired fertility 
 
Conditioning chemotherapy has a high probability of resulting in impaired fertility of the 
recipient. Fertility counseling will be offered to appropriate patients pre-transplantation. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 
Graft versus Host Disease 
 
• 
Acute and chronic GVHD are defined by standard criteria.[25, 26] 
12.2 
Disease response criteria 


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• 
Disease will be staged using standard response criteria. 
12.3 
Engraftment 
• 
Engraftment of neutrophils is defined as sustained 500 neutrophils/µL blood after 
conditioning chemotherapy. 
• 
Primary engraftment failure is defined as failure to achieve neutrophil engraftment by 
day 30 after transplantation. The patient may pursue alternative transplantation 
options in such instances. 
• 
Secondary engraftment failure is defined as <500/µL circulating neutrophils at any 
time after primary engraftment that is not attributed to disease recurrence or drug 
therapy. 
• 
Engraftment of platelets is defined as sustained 50,000/µL after conditioning 
chemotherapy. 
12.4 
Donor chimerism 
• 
The percentage of donor contribution to CD3+ lymphopoiesis and myeloid 
hematopoiesis (chimerism) will be determined using short tandem repeat (STR) 
based analysis of the blood at the time points outlined in section 10.1. 
• 
12.5 
Survival 
• 
Relapse incidence: The duration of time between transplantation and progression of 
primary malignancy or relapse of primary malignancy. Death in the absence of 
relapse or progression is considered a competing risk. 
• 
Overall survival: The duration of time between transplantation and death due to any 
cause. 
• 
Non-relapse mortality: The duration of time between transplantation death from any 
cause in the absence of disease progression or relapse. Relapse and progression are 
considered competing risks. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
The patient may be withdrawn from the study for the following reasons: 
• 
If at any time the patient is found to be ineligible for the protocol as designated in the 
section on patient/subject eligibility. 
• 
Subjects with relapsed or progressive disease may pursue other therapies and thus 
will be monitored for survival but not further toxicity. 
• 
Patients may remove themselves from the study. 
• 
The Pl may remove patients from the study 
o 
Patinet noncompliance that makes continued study therapy dangerous for the 
patient. 


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IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 39 of 47
 
 
 
o 
New information with respect to the patients health status that makes it unsafe 
for the patient to continue with study therapy. 
o 
Adverse events that make ongoing study therapy unsafe for the patient. 
In all instances of study removal, supportive care will continue as is appropriate for the patient. 
14.0 
BIOSTATISTICS 
Primary objectives: 
This is a phase II study to evaluate the rate of acute grade 3-4 GVHD following allo-HCT using 
a/WT-lymphocyte depleted grafts from haploidentical or mismatched unrelated donors. The 
intervention will be considered unpromising if the rate of GVHD is greater than 40% and 
promising if the rate is 20% or less. The unpromising rate of 40% or higher is established 
based on the rate of anticipated GVHD in patients receiving HLA mismatched allografts.[1, 3] 
Based on these rates, a Simon two-stage optimal design will accrue 11 patients in the first 
stage. If six or fewer are free of grade 3-4 GVHD, the study will close due to a lack of efficacy; 
otherwise an additional 27 will accrue. If at the end of study, at least 27 out of the 38 patients 
are free of grade 3-4 GVHD, the study will be considered promising. The type I and type II 
errors are both set at 0.10. Accrual for this study will not be held at the interim analysis if it is 
uncertain whether seven or more patients are free of GVHD. The study will potentially close 
after the 11th patient completes the GVHD evaluation window. 
Patients who die or relapse without developing acute GVHD will be included in the analysis. 
They will be considered as not developing acute GVHD for the primary endpoint in order for 
the primary endpoint to align with published cumulative incidence estimates of acute GVHD. 
Estimates of patient survival and relapse are separately estimated in the secondary objectives. 
The study also includes sequential safety stopping rules to monitor for non-relapse mortality. 
In the event one of the stopping rules is crossed, accrual on the study will be suspended and 
all safety data will be reviewed by the Pl. These rules are provided in the table below. 
 
 
# of failures needed 
Failure rate 
Probability boundary
Failure Type 
to stop the study 
in the population 
is crossed 
 
 
 
I 
 
 
Secondary objectives: 
• 
Overall survival will be estimated at one year following transplantation using Kaplan- 
Meier methodology. 
Non-relapse 
Mortality 
4 in the first 14 patients 
5 in the first 21 patients 
0.1 
0.1 
6 in the first 28 patients 
1 7 in the first 34 patients 
 
0.35 
 
0.99 
 
8 at any point 


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• 
Cumulative incidence functions will be used to estimate non-relapse mortality at one 
year following transplantation. Relapse is considered a competing risk for this 
analysis. 
• 
Cumulative incidence functions will be used to estimate relapse incidence at one year 
following transplantation. Death in the absence of relapse is considered a competing 
risk for this analysis. 
• 
Summary statistics will be used to describe the reconstitution of CD4+, CD8+ T- 
lymphocytes, CD19+ B-lymphocytes at 30, 100, 180, and 365 days post 
transplantation. 
Translational objectives: 
• 
Summary statistics will be used to describe the reconstitution of TCR-a/W T- 
lymphocytes after TCR-a/W lymphocyte depleted allografts at 30, 100, 180, and 365 
days post transplantation. 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. 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. The individual signing the Eligibility Checklist 
is confirming whether or not the participant is eligible to enroll in the study. Study staff are 
responsible for ensuring that all institutional requirements necessary to enroll a participant to 
the study have been completed. See related Clinical Research Policy and Procedure #401 
(Protocol Participant Registration). 
 
16.0 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA 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 Database (CRDB). 
Source documentation will be available to support the computerized patient record. 
 
 
 
 
16.1 
Quality Assurance 
Monthly 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 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 41 of 47
 
 
 
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. 
 
 
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: 
https://one.mskcc.org/sites/pub/clinresearch/Documents/MSKCC Data and Safety Monitoring 
Plans.pdf 
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 Ill 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: From the studies that have been done so far it appears that adding G-PBSC to standard 
induction chemotherapy can safely be performed in elderly patients with AML and that these 
patients may benefit from the treatment. However, given this is a new treatment approach, it 
is possible that there are side effects that have not yet been seen. 
Benefits: This protocol may benefit patients by shortening the duration of chemotherapy- 
induced aplasia, reducing the related severe complications rate (infections, hemorrhagic 
events etc). This protocol may result in higher anti-leukemic activity compared to standard 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 42 of 47
 
 
 
chemotherapy, achieving higher CR rate and translating in higher OS. The information from 
this study will help future leukemia patients. 
Possible toxicities/side effects: Toxicities and side effects of the agents used 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 getting treatment with standard 
chemotherapy; taking part in another study; or getting no treatment. 
Costs/Incentives: No incentives will be offered to patients/subjects for participation in the 
study. Participation is voluntary. The patient/subject will be responsible for the costs of 
standard medical care, including the conventional agents cytarabine and filgrastim, antibiotics, 
blood and platelet transfusions, radiographic studies, laboratory tests, and all hospitalizations, 
even for complications of treatment. 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). 
The consent indicates that individualized de identified information collected for the purposes 
of this study may be shared with other qualified researchers. Only researchers who have 
received approval from MSK will be allowed to access this information which will not include 
protected health information, such as the participant's name, except for dates. It is also 
stated in the Research Authorization that their research data may be shared with other 
qualified researchers. 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 43 of 47
 
 
 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant starts investigational 
treatment/intervention. SAE reporting is required for 30-days after the participant's last 
investigational treatment/intervention. Any event that occur after the 30-day period that is 
unexpected and at least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention 
and is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per 
IRB SOP RR-408 'Reporting of Serious Adverse Events', the SAE report must be submitted 
within 5 calendar days of the event. All other SAEs must be submitted within 30 calendar 
days of the event. 
 
The report should contain the following information: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment(s) 
• 
If the AE was expected 
• 
Detailed text that includes the following 
o 
An explanation of how the AE was handled 
o 
A description of the participant's condition 
o 
Indication if the participant remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
 
For IND/IDE protocols: The SAE report should be completed as per above instructions. If 
appropriate, the report will be forwarded to the FDA by the IND Office 
 
 
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 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 44 of 47
 
 
 
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 
REFERENCES 
 
1. 
Saber, W., et al., Outcomes after matched unrelated donor versus identical sibling 
hematopoietic cell transplantation in adults with acute myelogenous leukemia. Blood, 2012. 
119(17): p. 3908-3916. 
2. 
Gragert, L., et al., HLA Match Likelihoods for Hematopoietic Stem-Cell Grafts in the U.S. 
Registry. New England Journal of Medicine, 2014. 371(4): p. 339-348. 
3. 
Lee, S.J., et al., High-resolution donor-recipient HLA matching contributes to the success of 
unrelated donor marrow transplantation. Blood, 2007. 110(13): p. 4576-4583. 
4. 
Kroger, N., et al., HLA-mismatched unrelated donors as an alternative graft source for 
al/ogeneic stem cell transplantation after antithymocyte globulin-containing conditioning 
regimen. Biol Blood Marrow Transplant, 2009. 15(4): p. 454-62. 
5. 
Ball, L.M. and R.M. Egeler, Acute GvHD: pathogenesis and classification. Bone Marrow 
Transplant, 2008. 41(S2): p. S58-S64. 
6. 
Tamari, R., et al., CD34-Selected Hematopoietic Stem Cell Transplants Conditioned with 
Myeloablative Regimens and Antithymocyte Globulin for Advanced Myelodysplastic 
Syndrome: Limited Graft-versus-Host Disease without Increased Relapse. Biol Blood Marrow 
Transplant, 2015. 21(12): p. 2106-14. 
7. 
Pasquini, M.C., et al., Comparative outcomes of donor graft CD34+ selection and immune 
suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid 
leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic 
cell transplantation. J Clin Oncol, 2012. 30(26): p. 3194-201. 
8. 
Brooks, E.G., et al., Human T-ce/1 receptor (TCR) alpha/beta+ CD4-CD8- T cells express 
oligoclonal TCRs, share junctional motifs across TCR V beta-gene families, and 
phenotypically resemble memory T cells. Proceedings of the National Academy of Sciences 
of the United States of America, 1993. 90(24): p. 11787-11791. 
9. 
Felix, N.J. and P.M. Allen, Specificity of T-ce/1 alloreactivity. Nat Rev lmmunol, 2007. 7(12): 
p. 942-953. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(7) 
Approval date: 08-Aug-2022 
Page 45 of 47
 
 
 
10. 
Silva-Santos, B., K. Serre, and H. Norell, [gamma][delta] T cells in cancer. Nat Rev lmmunol, 
2015. 15(11): p. 683-691. 
11. 
Jensen, K.D., et al., Thymic selection determines gammadelta T cell effector fate: antigen- 
naive cells make interleukin-17 and antigen-experienced cells make interferon gamma. 
Immunity, 2008. 29(1): p. 90-100. 
12. 
Vantourout, P. and A. Hayday, Six-of-the-best: unique contributions of [gamma][delta] T cells 
to immunology. Nat Rev lmmunol, 2013. 13(2): p. 88-100. 
13. 
Khairallah, C., et al., ?? T Cells Confer Protection against Murine Cytomegalovirus (MCMV). 
PLoS Pathog, 2015. 11(3): p. e1004702. 
14. 
Dechanet, J., et al., Major expansion of gammadelta T lymphocytes following 
cytomegalovirus infection in kidney allograft recipients. J Infect Dis, 1999. 179(1): p. 1-8. 
15. 
Hammerich, L. and F. Tacke, Role of gamma-delta T cells in liver inflammation and fibrosis. 
World Journal of Gastrointestinal Pathophysiology, 2014. 5(2): p. 107-113. 
16. 
Perko, R., et al., Gamma delta T cell reconstitution is associated with fewer infections and 
improved event-free survival after hematopoietic stem cell transplantation for pediatric 
leukemia. Biol Blood Marrow Transplant, 2015. 21(1): p.130-6. 
17. 
Schumm, M., et al., Depletion of T-cell receptor alpha/beta and CD19 positive cells from 
apheresis products with the CliniMACS device. Cytotherapy, 2013. 15(10): p. 1253-1258. 
18. 
Bertaina, A., et al., HLA-haploidentical stem cell transplantation after removal of a/3+ T and B 
cells in children with nonmalignant disorders. Blood, 2014. 124(5): p. 822-826. 
19. 
Bertaina, A., et al., Children with Acute Leukemia Given Hematopoietic Stem Cell 
Transplantation (HSCT) from an HLA-Compatible Sibling, or an Unrelated Donor (UD) or an 
HLA-Haploidentical Relative after Alpha/Beta T-Cell Depletion Have a Comparable Outcome. 
Blood, 2015. 126(23): p. 195-195. 
20. 
Offer, K., et al., Efficacy of tacrolimus/mycophenolate mofetil as acute graft-versus-host 
disease prophylaxis and the impact of subtherapeutic tacrolimus levels in children after 
matched sibling donor allogeneic hematopoietic cell transplantation. Biol Blood Marrow 
Transplant, 2015. 21(3): p. 496-502. 
21. 
Mori, T., et al., Effect of early posttransplantation tacrolimus concentration on the 
development of acute graft-versus-host disease after allogeneic hematopoietic stem cell 
transplantation from unrelated donors. Biol Blood Marrow Transplant, 2012. 18(2): p. 229-34. 
22. 
Dominietto, A., et al., In vivo 8-cell depletion with rituximab for alternative donor hemopoietic 
SGT. Bone Marrow Transplant, 2012. 47(1): p. 101-106. 
23. 
Roberts, K.G., et al., Targetable kinase-activating lesions in Ph-like acute lymphoblastic 
leukemia. N Engl J Med, 2014. 371(11): p. 1005-15. 
24. 
Dohner, H., et al., Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood, 2017. 129(4): p. 424-447. 
25. 
Filipovich, A.H., 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): p. 945-56. 
26. 
Rowlings, P.A., et al., IBMTR Severity Index for grading acute graft-versus-host disease: 
retrospective comparison with Glucksberg grade. Br J Haematol, 1997. 97(4): p. 855-64. 


 
 
 
 
 
 
 
 
 
 
 
 


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Memorial Sloan Kettering Cancer Center 
IRB Number: 18-224 A(?) 
Approval date: 08-Aug-2022 
 
 
70
 
8
-12
2.7
70
 
10 
-12
3.3
70 
4 
10 
-12 
3.3 
80
0.1
4.5
-12
2.3
80
0.5
 
-12
1.7
80
 
 
-12
2.0
80
 
8
-12
2.7
80
 
10
-12
3.3
 
 
 
 
 
For patient above 80Kg (peds and adults) according to ALC only: starting day -12 
ALC before ATG dosing: 
0.1 
360mg in 2 days (180mg per day) 
 
0.5 
400mg in 2 days (200mg per day) 
 
1 
480mg in 3 days (160mg per day) 
 
2 
::::e640mg in 3 days (215mg per day) 
 
3 
::::e800mg in 3days (270mg per day) 
 
4 
::::e800mg in 3 days (270mg per day)