Clinical trial NCT02880293
Conditions: Hematologic Malignancy
Keywords: transplant conditioning KIR/HLA based haploidentical donor selection allogeneic hematopoietic cell transplantation
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2016-08-23; Completion date: 2023-11-20
Enrollment: 44 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will test whether half matched donors with favorable KIR genes will reduce the risk of cancer recurring after transplant.

Detailed description:

Arms: arm 1: All patients will undergo haploidentical, allogeneic hematopoietic cell transplantation. Conditioning will consist of fludarabine, melphalan, and thiotepa. Graft versus host disease prophylaxis will be with post-transplant cyclophosphamide in addition to standard tacrolimus and mycophenolate mofetil. Donors will undergo HLA and KIR geno- and allotyping to determine the best donor.
Interventions: intervention 1: melphalan intervention 2: fludarabine intervention 3: thiotepa intervention 4: Cyclophosphamide intervention 5: Mesna intervention 6: Mycophenolate Mofetil intervention 7: Filgrastim intervention 8: Tacrolimus
Intervention descriptions: intervention 1: melphalan (140 mg/m2 IV on day -7) intervention 2: fludarabine (40 mg/m2/d on days -5 through -2) intervention 3: thiotepa (5 mg/kg IV on day -67) intervention 4: cyclophosphamide (50 mg/kg IV on day +3 and +4) intervention 5: None intervention 6: (15 mg/kg PO/IV TID) intervention 7: None intervention 8: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1237 A(10) 
Approval date: 21-Jan-2020 
Page 1 of 37
 
Partially HLA-Mismatched Related Donor Hematopoietic Stem Cell Transplantation 
Using Killer Immunoglobulin Receptor and Human Leukocyte Antigen Based Donor 
Selection 
PROTOCOL FACE PAGE FOR 
 
Principal Investigator/Department:
Brian Shaffer, MD
Adult BMT
 
Sergio Giralt, MD 
Katharine C. Hsu, MD, PhD 
Adult BMT 
Adult BMT 
 
Juliet Barker, MD, MBBS
Adult BMT
Christina Cho, MD
Adult BMT
David Chung, MD, PhD
Adult BMT
Parastoo Dahi, MD
Adult BMT
Arnab Ghosh, MD
Adult BMT
Sergio Giralt, MD
Adult BMT
Boglarka Gyurkocza, MD
Adult BMT
Ann Jakubowski, MD, PhD
Adult BMT
Scott James, MD, PhD
Adult BMT
Oscar Lahoud, MD
Adult BMT
Richard Lin, MD
Adult BMT
Kate Markey, MBBS, PhD
Adult BMT
Esperanza Papadopoulos, MD
Adult BMT
Jonathan Peled, MD
Adult BMT
Miguel-Angel Perales, MD
Adult BMT
Ioannis Politikos, MD
Adult BMT
Doris Ponce, MD
Adult BMT
Craig Sauter, MD
Adult BMT
Michael Scordo, MD
Adult BMT
Gunjan Shah, MD
Adult BMT
Melody Smith, MD
Adult BMT
Roni Tamari, MD
Adult BMT
Marcel van den Brink, MD, PhD
Adult BMT
James Young, MD
Adult BMT
Sean Devlin, PhD
Epidemiology/Biostatistics
Scott Avecilla, MD, PhD
Laboratory Medicine
Marci Andrejko, NP
Nursing
Jason Batalha, NP
Nursing
Kathleen Cavalier, NP
Nursing
Naomi Cazeau, NP
Nursing
Abigail Cohen, NP
Nursing
Melissa Cortes, NP
Nursing
Theresa Elko, NP
Nursing
Shani Irby, NP
Nursing
Rebecca Goldberg, NP
Nursing
Carter Hibbs, NP
Nursing
Stefanie Kelly, NP
Nursing
Sheila Kenny, NP
Nursing
Christina Kiss, NP
Nursing


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1237 A(10) 
Approval date: 21-Jan-2020 
Page 2 of 37
 
 
 
Nicole Lestrange, NP
Nursing
Kathryn Mazzarrella, NP
Nursing
Courtney McElrath, NP
Nursing
Chelsea Mintz, NP
Nursing
Dayna Palumbo, NP
Nursing
Emily Patterson, NP
Nursing
Natasia Rodriguez, RN
Nursing
Megan Scott, NP
Nursing
Allison Tucker, NP
Nursing
Tara Wolff, NP
Nursing
Consenting Professional(s)/Department: 
Juliet Barker, MD, MBBS 
Christina Cho, MD 
Adult BMT 
Adult BMT 
 
David Chung, MD, PhD
Adult BMT
 
Parastoo Dahi, MD
Adult BMT
 
Sergio Giralt, MD
Adult BMT
 
Arnab Ghosh, MD
Adult BMT
 
Boglarka Gyurkocza, MD
Adult BMT
 
Ann Jakubowski, MD, PhD
Adult BMT
 
Scott James, MD, PhD
Adult BMT
 
Oscar Lahoud, MD
Adult BMT
 
Richard Lin, MD
Adult BMT
 
Kate Markey, MBBS, PhD
Adult BMT
 
Esperanza Papadopoulos, MD
Adult BMT
 
Jonathan Peled, MD
Adult BMT
 
Miguel-Angel Perales, MD
Adult BMT
 
Ioannis Politikos, MD
Adult BMT
 
Doris Ponce, MD
Adult BMT
 
Craig Sauter, MD
Adult BMT
 
Michael Scordo, MD
Adult BMT
 
Gunjan Shah, MD
Adult BMT
 
Melody Smith, MD
Adult BMT
 
Roni Tamari, MD
Adult BMT
 
Marcel van den Brink, MD, PhD
Adult BMT
 
James Young, MD
Adult 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: 16-1237 A(10) 
Approval date: 21-Jan-2020 
Page 3 of 37 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ........................................................................ 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................. 5 
3.0 
BACKGROUND AND RATIONALE ...................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................. 12 
4.1 
Design ............................................................................................................................. 12 
4.2 
Intervention ...................................................................................................................... 12 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................ 13 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................ 16 
6.1 
Subject Inclusion Criteria .................................................................................................. 16 
6.2 
Subject Exclusion Criteria ................................................................................................ 18 
7.0 
RECRUITMENT PLAN ........................................................................................................ 19 
8.0 
PRETREATMENT EVALUATION ....................................................................................... 20 
9.0 
TREATMENT/INTERVENTION PLAN................................................................................. 20 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 23 
11.0 
TOXICITIES/SIDE EFFECTS .............................................................................................. 24 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 28 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................ 30 
14.0 
BIOSTATISTICS ................................................................................................................. 30 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES. 31 
15.1 
Research Participant Registration .................................................................................... 31 
15.2 
Randomization ................................................................................................................. 31 
16.0 
DAT A M ANAGEMENT ISSUES.......................................................................................... 31 
16.1 
Quality Assurance ............................................................................................................ 31 
16.2 
Data and Safety Monitoring .............................................................................................. 32 
17.0 
PROTECTION OF HUMAN SUBJECTS .............................................................................. 32 
17.1 
Privacy ............................................................................................................................. 32 
17.2 
Serious Adverse Event (SAE) Reporting .......................................................................... 33 
18.0 
INFORMED CONSENT PROCEDURES ............................................................................. 34 
19.0 
REFERENCES .................................................................................................................... 34 
20.0 
APPENDICES ..................................................................................................................... 37 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1237 A(10) 
Approval date: 21-Jan-2020 
Page 4 of 37 
 
This is a pilot study evaluating a novel killer immunoglobulin-like receptor (KIR) and human leukocyte 
antigen (HLA) based donor selection algorithm in the context of a standard HLA-mismatched related 
donor allogeneic hematopoietic cell transplantation (allo HCT). Donor derived NK cells are known to 
play an important role in controlling malignancy after transplant. Engagement of inhibitory and 
activating KIR on the surface of the NK cell with their cognate ligand class 1 HLA on malignant cells 
governs effector function of the NK cell. We have previously demonstrated that donor KIR 
genotyping, when taken in the context of donor and recipient HLA allotype may be used to select 
“KIR advantageous” donors that yield lower rates of recipient relapse of AML after allo HCT. 
Importantly, NK cells are not associated with graft versus host disease (GVHD). Based on this, we 
hypothesize that KIR/HLA based selection may be used to increase NK mediated graft versus 
malignancy phenomenon without increasing GVHD. The purpose of this study is to estimate the 
proportion of patients who have a “KIR favorable” donor. Eligible candidates include persons aged 
18-75 with a hematologic malignancy requiring allo HCT and who do not have a HLA-matched 
related or unrelated donor. Potential haploidentical HLA matched related persons, will be typed for 
HLA and KIR. Persons with at least one related donor matched for 4 to 7 of 8 HLA alleles (HLA-A, 
HLA-B, HLA-C, and HLA-DRB1) and who meet the eligibility criteria may be enrolled. If multiple 
donors are identified a KIR/HLA based donor selection algorithm, detailed below, will direct selection 
of the donor with greatest NK alloreactivity. Recipients will undergo a standard melphalan, 
fludarabine, and thiotepa based conditioning regimen. The hematopoietic stem cells will be derived 
from donor bone marrow and are infused in an unmodified fashion. Following stem cell infusion, 
post-transplant cyclophosphamide (PT-Cy), tacrolimus, and mycophenolate mofetil based graft 
versus host disease (GVHD) prophylaxis will be used. Patients will be monitored carefully after 
transplant for GVHD, infections, and other medical complications of the procedure. The targeted 
enrollment will be 50 ealuable patients over 2.5 years. 
The primary objective of this protocol will be to estimate the proportion of patients undergoing 
partially HLA matched allo HCT who do and do not have a “KIR favorable” donor as defined by 
KIR/HLA donor selection algorithm. The secondary endpoint of the study will be to explore overall 
survival, relapse incidence, non-relapse mortality, engraftment failure, and GHVD for patients who 
do and do not have a KIR favorable donor. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1237 A(10) 
Approval date: 21-Jan-2020 
Page 5 of 37 
 
M
C
C
Recipient meets eligibility 
criteria 
 
BM Stem Cells 
 
Tacrolimus 0.02 mg/kg/d IV/PO 
 
M = Melphalan 140 or 100 mg/m2 IV 
T = Thiotepa 5 mg/kg IV 
F = Fludarabine 40 mg/m2 
C = Cyclophosphamide 50 mg/kg IV 
MMF = Mycophenolate mofetil, continues to day +100 
Tacrolimus continues to day +100 then taper to off on day +180 
1.1 
Protocol Schema 
 
 
 
 
T
F
F
F
F
-7 
-6  -5  -4  -3 
-2 
-1 
0 
+1 
+2 
+3 
+4 
+5 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
2.1 
Primary Objectives 
 
To estimate of the proportion of patients who have a KIR favorable donor while 
undergoing an allogeneic transplant with a partially HLA-matched related donor. 
2.2 
Secondary Objectives 
 
To explore the incidence of relapse, non-relapse mortality, and overall survival for 
patients who were and were not transplanted with a KIR favorable donor. 
 
To determine the incidence of acute and chronic graft versus host disease in 
patients treated with PT-Cy. 
 
To determine the cumulative incidence of engraftment failure at 100 days post 
transplantation. 
 
No 
KIR/HLA type available donor 
Transplantation therapy: 
Select KIR favorable donor if 
available 
Yes 
Donor Selection Algorithm 
Multiple partially HLA- 
matched related donors 
available? 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1237 A(10) 
Approval date: 21-Jan-2020 
Page 6 of 37 
 
2.3 
Translational Objectives 
 
To describe NK cell surface activating and inhibitory receptor phenotype using 
multicolor flow cytometry on blood NK populations after haploidentical alloHCT 
using post transplant cyclophosphamide based GVHD prophylaxis in study 
participants. 
 
To determine NK cell cytotoxicity against HLA mismatched leukemia cell lines in 
vitro using post transplant blood cells obtained from study participants. 
3.0 
BACKGROUND AND RATIONALE 
Allogeneic hematopoietic cell transplantation using partially HLA-matched related 
donors 
Allogeneic hematopoietic cell transplantation (allo HCT) is a potentially curative therapy for 
persons with advanced hematologic malignancies. While matched sibling and unrelated 
donors remain the preferred stem cell sources for allo HCT, only 25-30% of eligible recipients 
will have a matched sibling donor. The probability of procuring a suitably matched unrelated 
donor (URD) for allo HCT varies widely. Among persons of Euro-Caucasian descent, the 
probability of having an available 8/8 HLA-matched unrelated donor (URD) is approximately 
70%; however, persons from racial or ethnic minority groups have a <25-40% probability of 
finding such a donor. Therefore, development of an alternative stem cell source other than 
matched related or unrelated donors will expand access to allo HCT, particularly for persons 
in racial or ethnic minority groups. 
Partially HLA-matched related donors have emerged as a viable alternative for persons who 
lack fully matched sibling or unrelated donor options.[1-4] Partially HLA-matched related 
donors, who are typically haploidentical matched, offer at least two advantages over 
unrelated donor sources: First, because parents and children share one HLA haplotype, and 
other family sources such as siblings or cousins may be haploidentical matched, there is a 
high likelihood that a suitable donor will be available. Second, collection of stem cells is more 
likely to proceed rapidly when obtained from a related donor as compared to an URD, where 
the average time to procurement is approximately 7 weeks.[5] This facilitates rapid allo HCT 
in persons who are not candidates for umbilical cord blood transplantation. 
Post-allograft high dose cyclophosphamide for graft versus host disease prevention 
The major historical barrier to haploidentical allo HCT has been a high rate of both acute and 
chronic GVHD secondary to recipient/donor HLA disparity. Historical series confirm a rate of 
moderate to severe acute graft versus host disease (GVHD) >50% and chronic GVHD >80% 
in recipients of <5-6/6 HLA-matched related donor allografts.[6] Infusion of high dose 
cyclophosphamide (CY) shortly after allo HCT has emerged as a viable mechanism to 
prevent GVHD in recipients of haploidentical allo HCT.[1, 7, 8] The rationale behind this 
approach is that donor lymphocytes activated by recipient major and minor histocompatibility 
antigens will enter cell division and become susceptible to Cy toxicity, while tolerant 
lymphocytes and hematopoietic stem cells remain at rest and are resistant to Cy.[7, 9] In an 


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IRB Number: 16-1237 A(10) 
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Page 7 of 37 
 
initial report, O’Donnell and colleagues demonstrated that haploidentical allo HCT using 
fludarabine, Cy, and total body irradiation (TBI) based non-myeloablative (NMA) conditioning 
followed by infusion of 50 mg/kg of Cy on day +3 and +4 post allo HCT with cyclosporine and 
mycophenolate mofetil resulted in acceptable engraftment, toxicity, and GVHD.[1] In a follow- 
up study, Luznik et al reported the outcomes of 68 persons with hematologic malignancies 
treated in phase II study with haploidentical bone marrow allografts using fludarabine, Cy, 
and TBI based NMA conditioning followed by 50 mg/kg Cy on day +3 and +4 post allo HCT.[2] 
Traditional cyclosporine and mycophenolate mofetil GVHD prophylaxis was also used. The 
median time to neutrophil and platelet recovery was 15 and 24 days, respectively. Graft 
failure occurred in 9/66 persons. The incidence of grade III-IV acute GVHD was 6% and the 
incidence non-relapse mortality (NRM) was 15% at one year. The rate of relapse was 51% 
at one year, resulting in a two year survival of 36%. 
In order to improve on these results, several groups tested the use of post allo HCT Cy (PT- 
Cy) with myeloablative or reduced intensity (RIC) preparative regimens. Raiola and 
colleagues reported their findings in 55 patients who underwent haploidentical allo HCT using 
myeloablative conditioning with busulfan, thiotepa, and fludarabine or fludarabine and TBI 
followed by PT-Cy, cyclosporine, and mycophenolate mofetil.[10] The incidence of grade II- 
IV acute GVHD was 12% and chronic GVHD was 10%. The rate of NRM was 18% and 
relapse rate was 26%, resulting in a 22 month disease-free survival rate of 68% for persons 
in remission and 37% for persons with active disease at the time of allo HCT. Ciurea and 
colleagues reported similar results using fludarabine, melphalan, and thiotepa based RIC 
followed by haploidentical allo HCT and PT-Cy in 28 persons with hematologic 
malignancies.[4] Here, 6/28 persons developed primary graft failure. In a follow-up, Ciurea 
and colleagues reported improved results with ablative dose fludarabine, melphalan, and 
thiotepa or TBI in 94 patients with hematologic malignancies treated with haploidentical allo 
HCT and post transplantation CY, tacrolimus, and mycophenolate mofetil. The median time 
to neutrophil engraftment was 18 days and 95% of persons achieved full donor 
hematopoiesis. The rate of grade II-IV acute GVHD was 45% and chronic GVHD was 15%. 
The NRM, relapse rate, and overall survival were 24%, 38%, and 45%, respectively. 
In aggregate, these results suggest that HLA-mismatched related donor transplantation with 
PT-Cy confers acceptable rates of donor cell engraftment, acute and chronic GVHD, and 
overall survival. The most frequent cause of adverse outcomes after allo HCT remains 
relapse; therefore, methods to improve donor alloreactivity that do not result in greater 
incidence of GVHD have the greatest likelihood of improving outcomes. 
 
 
Incidence of primary engraftment failure after post transplantation cyclophosphamide 
Early reports of haploidentical allo HCT using PT-Cy describe an incidence of primary 
engraftment failure (PEF) of approximately 20-40%.[1, 2] Early preparative regimens were 
insufficiently lymphoablative to allow for donor engraftment in the setting of PT-Cy. More 
modern regimens including those based on fludarabine, melphalan, and thiotepa (FMT) 
conditioning as is proposed here are sufficiently lymphoablative to prevent host versus graft 
mediated rejection. The rate of PEF with FMT conditioning is approximately 5%.[11] An 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1237 A(10) 
Approval date: 21-Jan-2020 
Page 8 of 37 
 
important factor determining the likelihood of PEF is the presence of antibodies directed at 
donor specific HLA in the recipient. The majority of patients in early studies who developed 
PEF were found to have donor specific HLA antibodies at moderate or high titers. [12] For 
the purposes of this study all participants will undergo screening for donor specific HLA 
antibodies. If the recipient has antibodies against a specific donor HLA, this donor will be de- 
prioritized irregardless of their KIR status. 
 
Role of NK alloreactivity in haploidentical allogeneic hematopoietic cell 
transplantation 
Allo HCT confers an immune-mediated graft versus tumor effect, whereby donor lymphocytes 
eradicate malignant cells, protect the recipient from relapse, and allow for long-term disease 
free survival.[13, 14] Natural killer (NK) cells have emerged as key mediators of this 
phenomenon. NK cells control innate immunity, are typically the first cells to recover after allo 
HCT, and have potent anti-neoplastic and anti-viral properties NK.[15-19] Importantly, there 
is no evidence that allogeneic NK cells mediate or contribute to GVHD, even in a highly HLA- 
mismatched environment.[20-23] Capturing and maximizing donor NK alloreactivity in allo 
HCT, therefore, is an attractive strategy to reduce the risk of malignancy relapse without 
increasing the risk of GVHD. 
 
NK effector function is controlled by an array of cell surface receptors, among which the killer 
Ig-like receptors (KIR) stand out as key regulatory elements. NK cells are tolerized to 
autologous cells via engagement of inhibitory KIR with specific class I human leukocyte 
antigen (HLA) epitopes[24]: KIR2DL1 recognizes HLA-C alleles characterized by Asn77 and 
Lys80 (HLA-C2 group); KIR2DL2/3 recognizes HLA-C alleles characterized by Ser77 and 
Asn80 (HLA-C1 group); and KIR3DL1 recognizes HLA-A and -B alleles with the Bw4 
epitope.[25] In addition to their inhibitory interaction, engagement of the same inhibitory KIR 
with self-HLA educates, or “licenses,” NK cells for higher effector function against neighboring 
cells lacking “self” HLA.[26, 27] Target cells lacking the self-class I HLA ligand to the NK KIR 
are sensitive to cytotoxicity unleashed by licensed NK cells, whose recognition of “missing 
self” in the target cell results in reactivity. In individuals who lack cognate class I ligands for 
their inhibitory KIR, NK cells expressing inhibitory KIR for non-self HLA are termed 
“unlicensed.” Although these cells exhibit decreased effector capacity in vitro, we have 
demonstrated that unlicensed NK cells can achieve significant levels of effector function when 
stimulated by cytokines or by CD16 engagement and can play an important role in tumor 
eradication.[28-31] 
 
Ruggeri and colleagues described the relevance of inhibitory KIR signaling in the context of 
HLA mismatched AHST.[32] Expression of a KIR ligand (HLA-C1, HLA-C2, or HLA-Bw4) in 
the allo HCT donor that was absent in the recipient, so called “missing-self,” was associated 
with increased NK alloreactivity. Importantly, missing-self was not associated with increased 
graft rejection or GVHD. In a follow-up study of 112 patients with AML undergoing HLA- 
haploidentical ASHT, Ruggeri and colleagues demonstrated that transplantation from a 
donor/recipient pair with missing self (N = 51) results in a significant reduction in the risk of 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1237 A(10) 
Approval date: 21-Jan-2020 
Page 9 of 37 
 
relapse or death (relative risk 0.48; 95% confidence interval 0.29-0.78, P<0.001).[33] Single 
center and registry data further support that lack of expression of KIR ligand (missing ligand) 
in the context of HLA-matched ASHT is associated with decreased relapse incidence.[34, 35] 
These data would suggest that haploidentical transplantation may be optimized by 
preferential selection of donors to promote missing self. An important limitation to this strategy 
is that expression of KIR ligands in the recipient is fixed; therefore recipients who express all 
KIR ligands, or who lack a donor that does express the missing ligand, will not benefit from 
this strategy. In the context of the Ruggeri study, donor/recipient pairs with missing self were 
identified in approximately 45% of transplants. Therefore, strategies to promote NK 
alloreactivity in the absence of missing self are necessary. 
 
Promotion of unlicensed NK cells in KIR-ligand matched allogeneic hematopoietic cell 
transplantation 
 
Despite being HLA-mismatched, the majority of haploidentical donors are likely to be KIR- 
ligand matched with the transplant recipient. For example, because different HLA-C alleles 
may contain the C1 epitope, HLA-C mismatched donors may both express C1. This results 
in a scenario analogous to HLA-matched allo HCT, where NK alloreactivity may be inhibited 
by expression of cognate class I HLA KIR ligands on recipient neoplastic cells. In this 
scenario, KIR genes and KIR alleles may be used to minimize the degree of inhibitory signals 
and maximize the degree of activating signals delivered to donor NK cells via KIR. 
 
Selection of donors with increased KIR mediated activating signals results in greater NK 
alloreactivity, such as those found in individuals homozygous for the partial centromeric KIR- 
haplotype B (cenBB), are more protective for AML relapse.[36, 37] We found that the most 
protective activating KIR for relapse is KIR2DS1, whose in vitro activity we originally reported 
to be diminished by high levels of its ligand HLA-C2.[38] In line with our in vitro studies, we 
subsequently demonstrated in a allo HCT cohort of 1277 transplants for AML that protection 
from relapse was restricted to donors with HLA-C1, and HLA-C2C2 minimizes any KIR2DS1 
effect (Figure 1).[39] These findings have subsequently been confirmed in a recent 
publication by a separate group of investigators.[40] In this cohort, we found that the degree 
of relapse in donor/recipients who were mismatched at HLA-C was significantly reduced in 
the presence of donor KIR2DS1 expression (17.1 versus 35.6%, HR 0.40 [0.20-0.78], P = 
0.007), Figure 1. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 16-1237 A(10) 
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Figure 1: (A) Cumulative incidence of AML relapse in persons transplanted from a KIR2DS1 
positive versus negative donor. (B) The benefit in relapse prevention was enhanced in 
patients transplanted from HLA-C mismatched donors. 
 
 
Supporting these data, Oevermann and colleagues recently demonstrated that use of donors 
with the activating KIR rich haplotype B were associated a reduction in relapsed pediatric 
acute lymphoblastic leukemia (50.6% versus 29.5%, P = 0.033). [41] Mancusi and colleagues 
also note an association between donor KIR2DS1 expression and reduction in transplant 
related mortality after haploidentical allo HCT. [42] Approximately 30-40% of persons express 
KIR2DS1. Therefore, it is likely that a KIR2DS1 donor will be available among 2-3 
haploidentical family members. 
 
In addition to the activating KIR2DS1, we have also examined the role of inhibitory KIR in 
determining transplant outcomes. Among the inhibitory KIR, KIR3DL1 and HLA-Bw4 are the 
most polymorphic of the KIR/KIR ligand pairs, and different pairings of each have been 
described to result in substantial differences in strength of inhibition, suggesting an important 
role in NK biology.[43-46] Highly expressed KIR3DL1 alleles (KIR3DL1hi) interact strongly 
with HLA-Bw4 alleles containing an isoleucine at position 80 (Bw4-I80) to produce a strong 
licensing/inhibition signal, while the poorly expressed KIR3DL1 alleles (KIR3DL1lo) have 
similar interactions with HLA-Bw4 containing threonine at position 80 (Bw4-T80).[43-47] In 
persons infected with HIV, these 3DL1/HLA combinations predictive of higher licensing [48] 
result in a reduced incidence of progression to AIDS.[49] The strong interactions that produce 
higher licensing, however, also predict for easier inhibition. In collaboration with the National 
Marrow Donor Program (NMDP) and Center for International Blood & Marrow Transplant 
Research (CIBMTR), which provided sequencing -based donor KIR allele typing, we 
completed a pilot study of donor KIR3DL1-Bw4 allele combinations for 299 AML patients 
undergoing HCT from largely HLA-matched unrelated donors.[50, 51] We found that donors 
with poorly inhibitory KIR3DL1-Bw4 allele combinations were associated with significantly 
lower relapse and higher survival following HCT, and the highly licensed, but highly 
“inhibitable” combinations were associated with higher relapse (Figure 2). Importantly, there 
was no association with relapse protection when considering donor KIR3DL1 allele 
independent of HLA. These data are consistent with our model that HLA expression on tumor 


MSK IRB#: 16-1237 A(10), Approval Date: 21-Jan-2020
Page 11 of 37
 
cells leads to inhibition of licensed NK cells, an outcome avoided by unlicensed NK cells 
(Bw6/Bw6) and NK cells with poor or no KIR3DL1-Bw4 interaction.[28, 31, 52] 
 
 
 
 
 
 
 
 
HR&0.62 
P=&.03& 
HR&0.24 
P<&.001 
 
 
 
 
Figure 2: Relapse and survival in AML recipients of 9/10 or 10/10 URD allo HCT, stratified by with donors with 
high inhibitory KIR3DL1/Bw4 combinations (3DL1 hi+Bw4-I80 or 3DL1lo+Bw4-T80), low inhibitory combinations 
(3DL1hi+Bw4-T80 or 3DL1lo+Bw4-I80), or lack of inhibition altogether (Bw6/Bw6). 
 
 
Based on the strength of these univariate results, we devised and validated (99.5% 
concordance with allele typing by sequencing) a novel high through-put PCR-SSP method 
for “intermediate-resolution” identification of the most frequent and functionally defined 
KIR3DL1 allele groups.[53] Collectively, the allele groups represent 97.5% alleles found in a 
sequenced population of 426 individuals. Applying this method to an expanded cohort of 1328 
AML patients undergoing HCT from 9/10 and 10/10 HLA-matched unrelated donors, we have 
confirmed the beneficial effect of no/low-inhibitory KIR3DL1-Bw4 allele combinations on 
relapse in a multivariate analysis [HR 0.72 (95%CI 0.57-0.90), p=0.0035), even after 
adjustment for KIR2DS1/HLA-C1 (HR 0.74 (95%CI 0.58-0.95), p=0.018) and cenBB (HR 0.72 
(95%CI 0.57-0.92), p=0.009), (Preliminary Results). 
 
 
Rationale for the proposed study 
Taken together, these results indicate that NK alloreactivity plays an important role in disease 
control after allotransplantation, particularly in patients with myeloid malignancies. The role 
of NK mediated alloreactivity against lymphoid malignancies appears to be enhanced in the 
HLA mismatched environment. Whether the KIR advantageous donors are favorable for 
these individuals is unclear but they do not appear to result in any significant harm to these 
patients, therefore, it is reasonable to include persons with lymphoid malignancies in this pilot 
study. 
 
Because of the relatively low rate of treatment related mortality seen with PT-Cy based GVHD 
prophylaxis, reduction in relapse is now the most important determinant of post transplant 
outcomes. Therefore mechanisms to increase donor alloreactivity that are specifically 
targeted to malignant cells are key to improve this transplant platform. The proposed study 
will use a novel KIR donor selection algorithm developed at MSKCC to select haploidentical 
High&inhibiEon&3DL1/Bw4&pairs&(n=57)&
Bw6/Bw6&(n=81)&
Low&inhibiE on&3DL1/Bw4&pairs&(n=59)&
 
 
 
 
 
 
 
 
Low&inhibiE on&3DL1/Bw4&pairs&(n=59)&
 
High&inhibiE on&3DL1/Bw4&pairs&(n=58)&


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donors for allo HCT. This study will estimate the probability of finding a KIR advantageous 
donor in this setting. The secondary endpoints will address other primary transplant 
outcomes. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a pilot study evaluating a KIR/HLA based haploidentical donor selection for persons 
requiring allogeneic hematopoietic cell transplantation for hematologic malignancy. The goal 
of the study is to estimate the proportion of patients with a KIR-favorable donor. Eligible 
patients will be identified at the weekly service rounds of the adult BMT service. Recipients 
who are identified as suitable for transplantation but who lack a matched sibling or unrelated 
donor option will undergo a search for a suitable haploidentical matched related donor. If at 
least one eligible related donor matched at 4-7/8 HLA alleles (HLA-A, -B, -C, -DRB1) is 
identified and the patient provides informed consent this person may be enrolled onto the 
study. If multiple potential donors are identified, a donor selection algorithm will be used to 
select the donor predictive to result in the greatest NK alloreactivity versus the recipient 
malignancy. This selection process is outlined above and in section 9. Briefly, donors are 
prioritized to maximize the missing ligand phenomenon, whereby donor KIR fail to interact 
with their cognate ligand on recipient cells, inducing alloreactivity. Donors/recipient pairs with 
missing self (donor expresses KIR ligand absent in the recipient) are prioritized. If none are 
available, KIR/HLA gene and allele based selection will be used to select donors with a high 
degree of licensing via the KIR associated with the missing recipient ligand. In recipients who 
express all KIR ligands, KIR/HLA gene and allele based selection may be used to minimize 
inhibitory signaling through KIR2DL1 and KIR3DL1 and to select donors who express the 
stimulatory KIR2DS1. An exception to this algorithm is allowed for recipients with high titers 
of donor-specific anti-HLA antibodies. Donors will undergo eligibility evaluation and 
subsequent bone marrow stem cell harvest per FACT and MSKCC instructional guidelines. 
The trial is anticipated to enroll 50 evaluable patients over 2.5 years. The study will assess 
whether KIR/HLA based donor selection is feasible and practical in the context of 
haploidentical related donor allo HCT. Outcomes will be assessed in persons transplanted 
with and without a KIR-favorable donor. The study will employ a stopping rule considering 
treatment related mortality ≥30% before 100 days as an unacceptable risk. 
4.2 
Intervention 
All study participants will receive similar therapy. Transplant conditioning will consist of: 
melphalan (140 mg/m2 IV on day -7), fludarabine (40 mg/m2/d on days -5 through -2), and 
thiotepa (5 mg/kg IV on day -6). Melphalan must be reduced to 100 mg/m2 for recipients ≥55 
years old or for persons with significant cardiac comorbidities precluding full dose 
conditioning. The donor stem cell product will be derived from the bone marrow with a target 
cell infusion of 400 million total nucleated cells per recipient kg. GVHD prophylaxis will consist 


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of cyclophosphamide (50 mg/kg IV on day +3 and +4), mycophenolate mofetil (15 mg/kg 
PO/IV TID), and dose adjusted tacrolimus. 
Supportive care will include standard antimicrobial prophylaxis programs as outlined by the 
adult BMT service handbook. These will include prophylaxis for Pneumocystis jiroveci, 
Herpesviridae spp., fungal infections, and Toxoplasmosis gondii when appropriate. Other 
supportive care measures will include treatment of emergent infections, blood product 
support, prophylaxis for tumor lysis syndrome and sinusoidal obstructive syndrome, and 
management of acute medical complications during transplantation therapies. 
Patients will undergo donor/recipient bone marrow chimerism at 30 and 100 days post allo 
HCT and thereafter at the discretion of the treating clinician. Disease restaging will be 
performed at 3, 6, 9, 12, 18, and 24 months and as otherwise clinically indicated by the 
treating physician. 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
Melphalan (Alkeran®) 
Source and pharmacology: Supplier: Glaxo Wellcome. A derivative of nitrogen mustard, an 
analog of mustard gas. It is a poly functional alkylating agent that causes miscoding, 
cross-linkage of DNA, and single-strand breakage of DNA. It inhibits cellular 
glycolysis, respiration, and protein synthesis. It is cell cycle-phase non-specific. 
Formulation and stability: A lyophilized powder of 50 mg melphalan and 20 mg povidone per 
vial. Also provided is 10 ml of sterile diluent for use in reconstituting the product and 
a 0.45 micron filter.  The special diluent has the following composition: Sodium citrate 
0.2 g, Propylene glycol 6.0 ml, Ethanol (95%) 0.5 ml, and sterile water 10 ml. 
Solution preparation: 
1. Vial/50 mg: Reconstitute by rapidly injecting 10 ml of the supplied diluent into the 
vial to yield a final concentration of 5 mg/ml. 
2. Shake vigorously until the solution is clear. 
3. Immediately dilute the dose to be administered in 0.9% Sodium Chloride, USP, 
to a concentration no greater than 0.45 mg/ml 
Storage and stability: The intact packages should be stored at room temperature (15-30°C) 
protected from light. Shelf-life surveillance of the intact dosage form is ongoing. 
Constitution with the special diluent as directed results in a solution that retains at 
least 90% potency for about three hours at 30°C. Storage at 5°C results in 
precipitation. 
Administration: Intravenous, over 30 minutes. Complete infusion within 60 minutes of 
preparation. 
5.2 
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. 


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3. Room temperature: prepare infusion in D5W; stable for 16 days. 
Solution Preparation: 
1. Standard iv fluid: D5W. 
2. Final infusion concentration range: up to 10mg/ml. 
3. IV piggyback volume: 50 cc. 
Clinical considerations: 
1. Hydration: during 500 cc saline. 
2. Emetic potential: low. 
3. Supportive medications: none. 
Incompatibilities: acyclovir, amphotericin B, chlorpromazine, daunorubicin, ganciclovir, 
hydroxyzine, miconazole, prochlorperazine. 
5.3 
Cyclophosphamide (Cytoxan®) 
 
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. 
5.4 
Mesna (Mesnex®) 
 
Supplied as: 200 mg/2 ml ampule, 1 gram/10 ml multi-dose vials 
Reconstitution: not applicable. 
Storage and stability: 
1. Store vials at room temperature. 
2. Multi-dose vials may be stored and used for up to 8 days after initial entry. 
3. Infusions prepared in D5W are stable for 48 hours when stored under refrigeration 
or at room temperature. 
Solution Preparation: 
1. Must be diluted prior to infusion 
2. Standard IV fluid: D5W. 
3. IV piggyback volume: 50ml D5W 
Usual Dosage and administration: 100% of the total cyclophosphamide dose divided into 
3 doses, and administered at 30 minutes prior to and 4 and 8 hours after the start of 
the chemotherapy. Given as IVPB over 15 minutes. 
Clinical Considerations: mesna functions solely for uroprotection to prevent hemorrhagic 
cystitis and has no cytotoxic activity. 
Toxicities: none. 


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Incompatibilities: Carboplatin, Cisplatin, and Epirubicin. 
5.5 
Mycophenolate Mofetil (CellCept®) 
Supplied as: 500 mg vial of powder for reconstitution. 
Reconstitution: reconstitute each 500 mg vial with 14 ml of D5W only. Gently shake the vial 
to dissolve the drug. The vial will contain 500 mg of mycophenolate in approximately 
15 ml. 
Storage and Stability: Store at 15 -30C. Drug compatible with D5W only. A final 
concentration of 6mg/ ml must be achieved prior to administration. Reconstituted 
vials and IV preparations are stable for up to 4 hours after preparation. 
Solution Preparation: 
1. Reconstitute each 500 mg vial with 14 ml of D5W. 
2. Gently shake the vial to dissolve the drug. 
3. Drug must be further diluted to a final concentration of 6 mg/ml. A 1000 mg dose 
should be placed in 140 ml of D5W. 
4. MMF vials are stable for 4 hours at room temperature after reconstitution. 
5. Doses of MMF may begin infusion into the patient up to 4 hours after initial 
reconstitution of the vials. 
Clinical Considerations: administer only with D5W, over at least 2 hours. Mycophenolate is 
mutagenic, carcinogenic, and teratogenic. Precautions must be taken when handling 
this product. If medication comes in contact with skin, wash thoroughly with soap and 
water. 
Incompatibilities: Only compatible with D5W. 
 
5.6 
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 D5W. 
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 D5W, filgrastim is stable for 7 days. 
5. Stability (plastic syringe) filgrastim is stable for two weeks in BD 1 ml plastic TB 
syringes at 2-8°C. 
5.7 
Tacrolimus (Prograf®) 
 
Supplied as: Capsules (1 and 5 mg) for parenteral administration or as a sterile solution in 1 
mL ampules containing 5 mg anhydrous tacrolimus per mL, in boxes of 10 ampules, 
for intravenous administration. 
Storage and Stability: Tacrolimus injection ampules are stored between 5º-25ºC. Prograf 
capsules are stored at room temperature (15º-30ºC). 
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 


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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. 
5.8 
Thiotepa 
 
Supplied as: 15 mg vial lyophilized powder that must be diluted prior to infusion. 
Storage and Stability: Thiotepa vials are stored in a refrigerator protected from light. Once 
reconstituted in saline, thiotepa solution is stable for 14 days in refrigeration or 7 
days at room temperature. 
Solution Preparation: Thiotepa powder is dissolved in normal saline to achieve a final 
concentration up to 5 mg/mL and delivered in a final volume of 500 mL. 
Clinical Considerations: Thiotepa infusion should be through IMED 2200 tubing. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
 
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 
riskfor relapse including: 
o t(9;22) or detected BCR-ABL1 translocation by genomic 
methodologies 
o BCR-ABL1-Like B-ALL [54] 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 CNS or other extramedullary involvement 
o WBC count ≥ 100,000 cells/µL at diagnosis 
 
o Relapsed ALL, biphenotypic/bilineal leukemia, or AML with ≤ 10% blasts in the 
bone marrow prior to transplantation. 
 
o Acute biphenotypic or bilineal leukemia in first or greater complete remission. 


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o Acute myeloid leukemia (AML) in CR1 with intermediate or high risk features 
including: 
o Cytogeneic abnormalities associated with myelodysplastic 
syndrome including abnormalities of chromosome 5 or 7 
o History of anti-neoplastic therapy (radiation or chemotherapy) 
o Extramedullary involvement 
o WBC count ≥100,000 cells/µL at diagnosis 
o Rearrangements or mutations of 11q23 (MLL) 
o Abnormalities of chromosome 3 
o TP53 mutation or loss of 17p 
o Complex or monosomal karyotype 
o Normal karyotype with mutations of FLT3, RUNX1, or ASXL1 
 
 
o Myelodysplastic syndrome, myeloproliferative neoplasms, or MDS/MPN 
overlap syndrome with: 
 
International prognostic scoring system risk score of INT-2 or high risk at 
the time of transplant evaluation. 
 
Any risk category if life-threatening cytopenia exists. 
 
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, 
 
o Myelofibrosis with DIPSS scores of INT-2 or high risk or any risk category if life 
threatening cytopenias are present. 
 
o Chronic myelomonocytic leukemia (CMML) 
 
o Chronic myeloid leukemia (CML) who have failed or are intolerant to BCR-ABL 
tyrosine kinase inhibitors. 
 
o CML with BCR-ABL mutation consistent with poor response to tyrosine kinase 
inhibition (e.g. T351I mutation). 
 
o CML with accelerated or blast phase with <20% blasts after therapy. 
 
 
o Hodgkin lymphoma: 
 
Relapsed disease with progression after autologous bone marrow 
transplant or are ineligible for this procedure.. 
 
Responding to therapy prior to enrollment 
 
o Non-Hodgkin lymphoma: 
 
Responding to therapy prior to enrollment. 


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 
Progression after autologous bone marrow transplant or are ineligible for 
this procedure 
o Chronic lymphocytic leukemia with high risk disease as defined by the EBMT 
consensus criteria. 
 
 
Patients aged 18 through 69 years old are eligible. 
 
 
Patients aged 70-75 with HCT-CI of 0-1 are eligible. 
 
 
Patients must have Karnofsky performance status ≥70%. 
 
 
Cardiac left ventricular ejection fraction ≥50% at rest. 
 
 
Total bilirubin ≤ 2 mg/dL, except for patient’s with Gilbert’s syndrome 
 
 
AST and ALT ≤ 5x ULN unless thought to be disease related. 
 
 
Estimated or measured creatinine clearance > 50 mL/min. 
 
 
Hemoglobin adjusted pulmonary DLCO ≥50% of predicted, if Hgb is within normal 
range, unadjusted DLCO must be ≥ 50%.. 
 
 
 
6.2 
Subject Exclusion Criteria 
6.2.1 
Persons with a HLA matched sibling donor. 
6.2.2 
Female patients who are pregnant or breast-feeding. 
6.2.3 
Persons with an infection that is not responding to antimicrobial therapy. 
6.2.4 
Persons who are seropositive for HIV. 
6.2.5 
Persons with uncontrolled central nervous system malignancy. 
6.2.6 
Persons who do not meet the age and organ function criteria specified above. 
6.2.7 
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. 
6.2.8 
Prior diagnosis of non-hematologic malignancy within 5 years of planned protocol 
therapy EXCEPT: 
 
Diagnosis of breast ductal carcinoma in situ treated with curative intent 


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 
Diagnosis of prostate adenocarcinoma with Gleasons score ≤ 6 treated with 
curative intent 
 
Non-melanomatous skin cancer 
 
 
6.3 
Donor Inclusion Criteria 
6.3.1 
Partially HLA-mismatched relative (allele level matched at 4 to 7 of 8 HLA loci: -A, - 
B, -C, and -DRB1). 
6.3.2 
Meets criteria outlined in the FACT-approved SOP for “DONOR EVALUATION AND 
SELECTION FOR ALLOGENEIC TRANSPLANTATION” in the Blood and Marrow 
Transplant Program Manual, document E-1. (Link to URL: 
https://one.mskcc.org/sites/pub/corp/bmt/Documents/D2_SOP_Donor%20Selection 
%20and%20Evaluation_04_2015.pdf) 
6.3.3 
Donor must be willing to undergo general anesthesia and bone marrow stem cell 
harvest. 
6.3.4 
Donor must be ≥14 years old. 
6.4 
Donor Exclusion Criteria 
6.4.1 
Evidence of infection not responding to antibiotic therapy. 
6.4.2 
Chronic viral infection including active hepatitis B, hepatitis C, HIV, or HTLV-1/2. 
6.4.3 
Factors that place the donor at increased risk of general anesthesia and bone 
marrow harvest, such as congenital or acquired bleeding disorders, intolerance or 
allergy to anesthesia, prior serious surgical complications, or uncontrolled cardiac or 
pulmonary disorders. 
6.4.4 
Pregnant or breast-feeding. 
6.4.5 
Unwilling or unable to provide informed consent. 
6.4.6 
Unable to provide a bone marrow allograft product. 
7.0 
RECRUITMENT PLAN 
Eligible patients are identified via the weekly BMT/Leukemia Patient Review Conference. Patients 
that do not have a matched sibling or unrelated adult donor option and who do have a haploidentical 
matched related donor and meet the other eligibility criteria will be offered participation in this study. 
Both the patient and potential donor must meet the eligibility criteria before enrollment in the study. 
This protocol will take due notice of NIH/ADAMHA policies concerning inclusion of women and 
minorities in clinical research populations. We expect that the study population will be fully 


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representative of the range of patients referred for transplant without exclusion as to age, gender, or 
ethnic background. 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 antibodies against CMV, , Hepatitis B (core antibody, surface 
antibody), Hepatitis C, EBV, and Toxoplasmosis, HIV, and HTLV-1/2 
 
Pregnancy test for women of childbearing potential 
 
Bone marrow aspirate (biopsy if clinically indicated) 
 
Urinalysis 
 
Electrocardiogram and echocardiogram 
 
Spirometry and pulmonary diffusion capacity 
 
Donor-specific anti-HLA antibody titers 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Regimen for Cytoreduction 
All drugs are administered relative to the date of stem cell infusion (day 0). 
9.1.1 
Conditioning program 
 
Melphalan 100-140 mg/m2 (adjusted as per section 9.1.2) on day -7. 
 
Fludarabine 40 mg/m2 on day -5, -4, -3, -2. 
 
Thiotepa 5 mg/kg on day -6. 
9.1.2 
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 weight. 
Persons ≥55 years old or those with any cardiac comorbidies (including known cardiovascular 
disease, history of recurrent or chronic arrythmia, or history of chemotherapy induced 
cardiomyopathy) receive melphalan 100 mg/m2. Patients who are not felt to be fit for higher 
dose therapy or who have a hematopoietic cell comorbidity index >3 receive melphalan 100 
mg/m2. 
9.1.3 
Fludarabine administration 


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Fludarabine is administered intravenously over 30 minutes. Persons with creatinine 
clearance < 50 mL/min/1.73 m2 BSA will receive a 25% reduction in dose (30 mg/m2). 
9.1.4 
Adjustment of chemotherapy based on adjusted body weight 
Patients who are >125% of ideal body weight will receive melphalan based on adjusted body 
weight. Fludarabine will be dosed based on actual body weight. Ideal and adjusted body 
weights are calculated as below: 
Ideal body weight (IBW) formula: 
Male IBW = 50 kg + 2.3 kg/inch over 60 inches 
Female IBW = 45.5 kg + 2.3 kg/inches over 60 inches 
 
Adjusted body weight (ABW) formula: 
ABW = IBW + (0.4 x (actual weight – IBW)) 
 
 
9.2 
Selection of Haploidentical Donors 
9.2.1 
Up to 5 potentially haploidentical donors will be typed for HLA alleles, KIR genes, and 
KIR 3DL1 alleles. 
9.2.2 
If the recipient produces high titers of anti-HLA antibodies to a HLA antigen 
expressed in any donor, this donor will automatically be prioritized last in the donor 
selection process. 
9.2.3 
Otherwise eligible donors are prioritized as follows: 
IF the recipient is lacking a KIR ligand that is expressed in a potential donor (missing 
self) this donor will be prioritized. 
 
IF the recipient expresses all KIR ligands or the available donors are also missing the 
absent KIR, donors will be prioritized in the following fashion: 
a. Donors with KIR3DL1 non-engaging (combination of KIR3DL1-null and/or 
KIR3DS1). 
b. Donors with predicted low inhibitory KIR3DL1 interactions. 
c. Donors that express KIR2DS1 AND HLA-C1. 
d. Donor who is centromeric B haplotype homozygous (cenBB). 
Donors may be de-prioritized at the discretion of the treating physician if extenuating 
circumstances make them unlikely to be suitable stem cell donors. Examples include 
advanced donor age, donor comorbidities, or social/supportive care factors that may 
limit a donor’s ability to participate in the protocol. The protocol will capture 
prospectively whether the preferred KIR donor was used. 
Potential donors who decline participation will be deprioritized. 


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Reason for the selection of the donor used for transplantation will be gathered 
prospectively. The donor selected and reason for selection will be documented in 
Appendix A – KIR Donor Selection form. 
9.3 
Bone Marrow Harvest and Stem Cell Infusion 
9.3.1 
Bone marrow progenitor cells are harvested according to the MSKCC Blood and 
Marrow Transplant Program Manual Document F-1. 
9.3.2 
G-CSF mobilized peripheral blood progenitor cells may be used for patients at risk 
of engraftment failure who are receiving melphalan 100 mg/m2. 
9.3.3 
Appropriate reduction in red cell content will be performed according to MSKCC 
Cytotherapy Laboratory guidelines for persons with a donor-recipient major ABO 
incompatibility. 
9.3.4 
The target cell dose will be 4 x 108 nucleated cells per kg recipient body weight. 
9.4 
Post-transplant GVHD Prophylaxis 
9.4.1 
Post-transplant cyclophosphamide 
All recipients will receive post-transplant cyclophosphamide as follows: 
 
Cyclophosphamide will be administered at a dose of 50 mg/kg recipient IBW IV on 
days +3 and +4 according to institutional infusion guidelines. 
 
Mesna will be administered at 100% of the dose of cyclophosphamide intravenously 
in three divided doses per day on days +3 and +4. 
 
All recipients will peri-cyclophosphamide hydration as per adult BMT service 
guidelines.. 
 
Corticosteroid administration is forbidden prior to infusion of the second dose of 
cyclophosphamide except for the treatment of life-threatening emergencies. 
9.4.2 
Tacrolimus 
 
Tacrolimus will be administered at a dose of 0.02 mg/kg/day continuous IV infusion 
beginning on day +5. Patients ≥70 years old may start at 0.015 mg/kg/day based on 
institutional guidelines. 
 
Dosing will be adjusted to obtain a serum concentration between 5-15 ng/mL 
 
Patients may be converted to twice daily oral therapy when oral intake resumes 
after transplantation. 
 
Tacrolimus taper will begin on day 100. The dose may be reduced by 5-10% per 
week to off at day +180-270. The investigator may increase or suspend the 
tacrolimus taper if clinical symptoms of GVHD are present. 
9.4.3 
Mycophenolate mofetil (Cellcept™) 


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 
Mycophenolate mofetil will be administered at a dose of 15 mg/kg three times daily 
(max 1 gram per dose) starting day +5 and continuing through day +100 post- 
transplantation. There will be no taper. The clinician may adjust the dose of 
mycophenolate mofetil if clinically significant adverse side effects to this medication 
occur. 
9.5 
Supportive Therapy 
 
9.5.1 
Tumor lysis prophylaxis 
Patients may receive tumor lysis syndrome prophylaxis at the discretion of the treating 
physician. Tumor lysis syndrome prophylaxis includes allopurinol 300 mg PO/IV on day -5 
then 300 mg/day until day 0 with or without normal saline 100 mL/hour continuous IV infusion 
from day -5 until day -1. 
9.5.2 
Infection prophylaxis 
 
Infection prophylaxis will be administered according to institutional guidelines. 
 
Specific infection prophylaxis will be administered for Pneumocystis carinii, 
Herpesviridae, and fungal infections to all recipients and for Toxoplasmosis gondii to 
seropositive persons/recipients. 
9.5.3 
Growth factor support 
Patients will receive G-CSF beginning on day +7 at a dose of 5 mcg/kg/day subcutaneously 
(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. 
9.5.4 
Sinusoidal obstructive syndrome prophylaxis 
Patients will receive ursodiol 300-600 mg PO BID beginning on day -8 and continuing at least 
until discharge from the inpatient unit. If a patient is unable to take oral medications ursodiol 
may be discontinued at that time. 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
10.1 
Post transplantation evaluation 
Post transplantation evaluations are summarized in the following table. Additional testing may 
be performed as is clinically indicated. Scheduled evaluations on day +30 and +100 may 
occur ±7 days from the schedule time point. Long term follow up at 9 months and 12 months 
may be done ±14 days from the scheduled time point. Follow up at 12 months, 18 months 
and 24 months may be done ±30 days from the scheduled time point. 


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Page 24 of 37
 
 
 
7 
14 
21 
30 
42 
49 
56 
70 
84 
100 
6 
mo. 
9 
mo. 
12 
mo. 
18 
mo. 
24 
mo. 
Window 
± 3 
± 3 
± 3 
± 7 
± 3 
± 3 
± 3 
± 7 
± 7 
± 7 
± 14 
± 14 
± 30 
± 30 
± 30 
History and Physical 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with diff, 
CMP, Mg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Disease Specific 
Monitoring Studies1 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Total Bone Marrow 
Chimerism 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Research Blood2 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
Research BMA2 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Lymphocyte Subsets3  
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
GvHD Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
1. 
May include but is not limited to the following studies: bone marrow aspirate and/or biopsy for patients with 
MDS, acute or chronic leukemia, and CLL. Patients with lymphoma or extramedullary leukemia will undergo 
CT scans. 
2. 
Research collection for translational objectives will consist of three 10 mL heparinized green top tubes of 
blood on the dates described above and one bone marrow aspiration (2 -3 mL, heparinized green top tube) 
on day +30. Bone marrow aspirate collected in lavender EDTA tubes are acceptable. 
3. 
Flow cytometry-7 Markers Short BMT Panel (Lymphocyte Subsets) should be ordered during 6 month and 
9 month windows per institutional guidelines. 
 
 
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. 
Toxicities and adverse events will be graded using the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03. All event reporting will be done per the MSKCC 
Adult Bone Marrow Transplant SAE SWP. 
 
 
11.1 
Cyclophosphamide 


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COMMON, SOME MAY BE SERIOUS
In 100 people receiving cyclophosphamide more than 20 and up to 100 may have: 
 
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 
 
 
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving cyclophosphamide from 4 to 20 may have: 
 
Irritation to the bladder, which may cause discomfort. Rarely, bleeding may occur in the 
bladder 
 
Abnormal electrolyte concentration in the blood 
 
 
RARE, AND SERIOUS
In 100 people receiving cyclophosphamide 3 or fewer may have: 
 Irritation to the heart or heart lining, called the pericardium 
 Abnormal heart rhythms 
 Irritation to the lungs 
 Second malignancies such as myelodysplastic syndrome or acute myelogenous leukemia 
 Veno-occlusive disease of the liver 
 Injury to the kidneys, causing kidney failure 
 Allergic reaction to the infusion of cyclophosphamide 
 
11.2 
Fludarabine 
 
COMMON, SOME MAY BE SERIOUS
In 100 people receiving fludarabine more than 20 and up to 100 may have: 
 
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 
 
 
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving fludarabine from 4 to 20 may have: 
 
Abnormal liver function studies (increased ALT or AST) 
 
Fluid retention/edema 
 
Rash 


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RARE, AND SERIOUS
In 100 people receiving fludarabine 3 or fewer may have: 
 Neurotoxicity (agitation or confusion, blurred vision, loss of hearing, peripheral neuropathy) 
 Severe hepatic injury causing hepatic failure 
 Hemolytic anemia 
 Phlebitis 
 Deep venous thrombosis 
 
11.3 
Thiotepa 
 
COMMON, SOME MAY BE SERIOUS
In 100 people receiving thiotepa more than 20 and up to 100 may have: 
 
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) 
 
 
OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving thiotepa from 4 to 20 may have: 
 
Redness or irritation of the skin 
 
Headache 
 
Allergic reaction to infusion (fever, hives, itching) 
 
Abnormal liver function studies (increased ALT, AST, or alkaline phosphatase) 
 
 
RARE, AND SERIOUS
In 100 people receiving cyclophosphamide 3 or fewer may have: 
 
Anaphylaxis infusion reaction (hypotension, allergic symptoms) 
 
Interstitial pneumonitis 
 
Severe hepatic injury or hepatic failure 
 
11.4 
Melphalan 
 
COMMON, SOME MAY BE SERIOUS
In 100 people receiving melphalan more than 20 and up to 100 may have: 
 
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 


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OCCASIONAL, SOME MAY BE SERIOUS
In 100 people receiving melphalan from 4 to 20 may have: 
 
Abnormal liver function studies (increased ALT, AST, or alkaline phosphatase) 
 
Hyponatremia (low sodium) 
 
Allergic reaction to infusion (fever, hives, itching) 
 
 
RARE, AND SERIOUS
In 100 people receiving melphalan 3 or fewer may have: 
 
Anaphylactic infusion reaction (hypotension, allergic symptoms) 
 
Interstitial pneumonitis 
 
Severe hepatic injury or hepatic failure 
 
 
11.7 
Transplant Related Risks 
11.7.1 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 narcotics. These products may also 
serve as vectors of serious infection (e.g., CMV, hepatitis, AIDS). To circumvent this, 
prospective blood and marrow donors will be screened per AABB and FAHCT 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. 
11.7.2 Bone marrow stem 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. 
11.7.3 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. 


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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. 
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 
 
11.7.4 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. 
11.7.5 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 if found to have an 
infection. Patients are watched closely for bleeding and given platelet transfusions to prevent 
serious bleeding, but minor bleeding may occur. 
11.7.6 Risk of a secondary cancer 
 
Secondary cancers may occur after chemotherapy. The risk of developing a secondary 
cancer of the skin, cervix, etc is less than 5%. 
11.7.7 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. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
12.1 
Disease response criteria 
 
 
Disease will be staged to standard response criteria. 


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12.2 
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 35 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. 
12.3 
Donor chimerism 
 
The percentage of donor contribution to hematopoiesis (chimerism) will be 
determined using short tandem repeat (STR) based analysis of the blood at monthly 
intervals after transplantation until full donor chimerism is obtained for two 
consecutive measurements. Full donor chimerism is defined as ≥95% donor. 
 
Chimerism may be obtained in the blood or bone marrow at any time other than 
above if it is determined necessary by the treating investigator. 
12.4 
Graft versus Host Disease 
 
 
Acute and chronic GVHD are defined by standard criteria.[55, 56] 
12.4 
Survival 
 
Relapse: The duration of time between transplantation and progression of primary 
malignancy or relapse of primary malignancy. Death in the absence of 
relapse/progression is considered a competing risk. . 
 
Overall survival: The duration of time between transplantation and death due to any 
cause. 
Treatment related mortality: Death from any cause in the absence of disease progression or 
relapse. Persons who die for any reason after disease progression or relapse are 
considered to have experienced disease related mortality. 
12.5 
KIR-favorable donor 
 
A KIR favorable donor is defined as a donor who meet any of the following criteria: 
o Donor/recipient pair with missing self as defined by expression of one or 
more KIR ligand (HLA-C1, HLA-C2, HLA-Bw4) in the donor that is absent in 
the recipient. 
o Donor KIR3DL1 low or no inhibitory interaction with recipient Bw4. 
o Donor KIR2DS1 and HLA-C1+ in the absence of highly inhibitory KIR3DL1 
interactions. 


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13.0 
CRITERIA FOR REMOVAL FROM STUDY 
If at any time the patient is found to be ineligible for the protocol as designated in the section 
on patient/subject eligibility the patient will be removed from the study. Subjects with relapsed 
or progressive disease may pursue alternative transplantation outcomes and will be 
monitored for survival. Patients may remove themselves from the study. The PI may remove 
patients from the study for noncompliance. In all instances of study removal, supportive care 
will continue as is appropriate for the patient. 
Donors may be removed from consideration to donate if, during the workup, they are found 
to not meet standard NMDP criteria for allogeneic hematopoietic cell donors. 
 
 
14.0 
BIOSTATISTICS 
The primary aim of this pilot study is to estimate the proportion of patients undergoing an 
allo HCT transplant who have a KIR favorable donor. KIR favorable donor is defined in 
section 12.5. 
A total of 50 patients will accrue. After all patients have undergone allo HCT, the proportion 
along with the corresponding 95% exact confidence interval will be estimated. The table 
below provides the total width of the exact 95% confidence interval for different potential 
observed proportions. 
 
 
Observed Proportion with KIR Favorable 
Donor 
 
0.125 
0.25 
0.5 
0.75 
0.875 
Width of 
C.I. 
 
0.25 
 
0.32 
 
0.36 
 
0.32 
 
0.25 
 
 
 
In order to reduce patient risk, the study design includes early termination in event that 
patients have high rates of treatment-related mortality. The boundaries are based on the 
accrual of 50 evaluable patients. The stopping rules are provided in the table below. 
 
 
Failure Type 
# of failures needed 
Failure rate 
Probability boundary 
to stop the study 
in the population 
is crossed 
Treatment-Related 
3 in the first 8 patients 
 
 
Mortality (day+100) 
4 in the first 14 patients 
0.10 
0.10 
 
5 in the first 21 patients 
 
 
 
6 in the first 27 patients 
0.30 
0.93 
 
7 at any point 
 
 


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There are a number of secondary objectives included in this study. All endpoints will be 
descriptive and interpreted cautiously due to the small sample size. These include: 
 
To explore the incidence of relapse, non-relapse mortality, and overall survival for 
patients who were and were not transplanted with a KIR favorable donor. Relapse 
and non-relapse mortality will be estimated using cumulative incidence functions 
treating death in the absence of relapse and relapse as competing risks, 
respectively. Overall survival will be estimated using Kaplan-Meier methods. 
 
To determine the incidence acute and chronic graft versus host disease. 
Cumulative incidence functions will be used for the analysis, treating relapse and 
death without GVHD as competing events. This endpoint will be evaluated for all 
patients combined. 
 
To determine the cumulative incidence of engraftment failure at 100 days post 
transplantation. Disease progression and death without engraftment failure are 
considered competing events for this analysis. This endpoint will be evaluated for 
all patients combined. 
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 that 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). 
 
 
15.2 
Randomization 
There is no randomization in this study. 
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 


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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 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%20Data%20and%20Safe 
ty% 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus there 
are two institutional committees that are responsible for monitoring the activities of our clinical 
trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase 
I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical 
trials, report to the Center’s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
17.0 
PROTECTION OF HUMAN SUBJECTS 
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 


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IRB Number: 16-1237 A(10) 
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Page 33 of 37
 
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 
 
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 signs consent. SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are 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 


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IRB Number: 16-1237 A(10) 
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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 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this 
Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information. In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
 
1. 
O'Donnell, P.V., et al., Nonmyeloablative bone marrow transplantation from partially HLA- 
mismatched related donors using posttransplantation cyclophosphamide. Biol Blood 
Marrow Transplant, 2002. 8(7): p. 377-86. 
2. 
Luznik, L., et al., HLA-haploidentical bone marrow transplantation for hematologic 
malignancies using nonmyeloablative conditioning and high-dose, posttransplantation 
cyclophosphamide. Biol Blood Marrow Transplant, 2008. 14(6): p. 641-50. 
3. 
Burroughs, L.M., et al., Comparison of outcomes of HLA-matched related, unrelated, or 
HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative 
conditioning for relapsed or refractory Hodgkin lymphoma. Biol Blood Marrow Transplant, 
2008. 14(11): p. 1279-87. 


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IRB Number: 16-1237 A(10) 
Approval date: 21-Jan-2020 
Page 35 of 37
 
4. 
Ciurea, S.O., et al., Reduced-intensity conditioning using fludarabine, melphalan and 
thiotepa for adult patients undergoing haploidentical SCT. Bone Marrow Transplant, 2010. 
45(3): p. 429-36. 
5. 
Barker, J.N., et al., Searching for unrelated donor hematopoietic stem cells: availability and 
speed of umbilical cord blood versus bone marrow. Biol Blood Marrow Transplant, 2002. 
8(5): p. 257-60. 
6. 
Tomonari, A., et al., Using related donors other than genotypically HLA-matched siblings in 
allogeneic hematopoietic stem cell transplantation for hematologic disease: a single 
institution experience in Japan. Int J Hematol, 2002. 76(4): p. 354-9. 
7. 
Luznik, L., et al., Posttransplantation cyclophosphamide facilitates engraftment of major 
histocompatibility complex-identical allogeneic marrow in mice conditioned with low-dose 
total body irradiation. Biol Blood Marrow Transplant, 2002. 8(3): p. 131-8. 
8. 
Luznik, L., et al., Durable engraftment of major histocompatibility complex-incompatible 
cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, 
and posttransplantation cyclophosphamide. Blood, 2001. 98(12): p. 3456-64. 
9. 
Jones, R.J., et al., Assessment of aldehyde dehydrogenase in viable cells. Blood, 1995. 
85(10): p. 2742-6. 
10. 
Raiola, A.M., et al., Unmanipulated haploidentical bone marrow transplantation and 
posttransplantation cyclophosphamide for hematologic malignancies after myeloablative 
conditioning. Biol Blood Marrow Transplant, 2013. 19(1): p. 117-22. 
11. 
Ciurea, S.O., et al., Improved Early Outcomes Using a T Cell Replete Graft Compared with 
T Cell Depleted Haploidentical Hematopoietic Stem Cell Transplantation. Biology of Blood 
and Marrow Transplantation, 2012. 18(12): p. 1835-1844. 
12. 
Ciurea, S.O., et al., High Risk of Graft Failure in Patients with Anti-HLA Antibodies 
Undergoing Haploidentical Stem Cell Transplantation. Transplantation, 2009. 88(8): p. 
1019-1024. 
13. 
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. 
14. 
Schmid, C., et al., Donor Lymphocyte Infusion in the Treatment of First Hematological 
Relapse After Allogeneic Stem-Cell Transplantation in Adults With Acute Myeloid 
Leukemia: A Retrospective Risk Factors Analysis and Comparison With Other Strategies by 
the EBMT Acute Leukemia Working Party. Journal of Clinical Oncology, 2007. 25(31): p. 
4938-4945. 
15. 
Campbell, K.S. and J. Hasegawa, Natural killer cell biology: an update and future 
directions. J Allergy Clin Immunol, 2013. 132(3): p. 536-44. 
16. 
Velardi, A., et al., Clinical impact of natural killer cell reconstitution after allogeneic 
hematopoietic transplantation. Semin Immunopathol, 2008. 30(4): p. 489-503. 
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20.0 
APPENDICES 
 
Appendix A: KIR Donor Selection Assessment