Clinical trial NCT02046122
Conditions: Acute Myeloid Leukemia Myelodysplastic Syndrome
Sponsor: Duke University
Start date: 2014-07-01; Completion date: 2019-07-31
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary hypothesis is that chemotherapy followed by donor lymphocyte infusion (DLI) from HLA-haploidentical donors is a safe procedure that will not cause Graft versus Host Disease (GVHD) or increased treatment-related mortality. The Investigator further believes that this will improve outcomes of elderly patients with high-risk AML or MDS compared to chemotherapy alone, and that that this benefit will be even greater in donor-recipient pairs that share maternal-fetal microchimerism or non-inherited maternal antigen (NIMA) mismatch. A large part of this trial will include immune function assays as well as assessments of efficacy, toxicity, and GVHD. Because this therapy may be a tolerable alternative to allogeneic hematopoietic stem cell transplantation (alloHSCT) for elderly patients, the Investigator will validate functional measurements (e.g. Comprehensive Geriatric Assessment (CGA)) with biologic correlates (cytokine and genomic profiles) and clinical outcomes.

Detailed description:

Arms: arm 1: Chemotherapy combined with adoptive transfer of HLA-haploidentical donor lymphocyte infusion (DLI)
Interventions: intervention 1: Idarubicin intervention 2: Cytarabine intervention 3: DLI
Intervention descriptions: intervention 1: Eligible subjects will receive induction chemotherapy with idarubicin (12 mg/m2 intravenously for 3 days) and cytarabine (100 mg/m2 intravenously for 7 days) starting Day 1 and ending Day 7. Patients 80 years or older will only receive 2 and 5 days of idarubicin and cytarabine respectively starting Day 1 and ending Day 5.

Subjects who experience no remission or partial remission will receive a second course of the identical induction chemotherapy. intervention 2: Cytarabine (100 mg/m2 intravenously for 7 days) starting Day 1 and ending Day 7. Patients 80 years or older will only receive 2 and 5 days of idarubicin and cytarabine respectively starting Day 1 and ending Day 5.

Subjects who achieve a complete remission (CR) will receive 2 further courses of cytarabine postremission chemotherapy (consolidation) at 1.0 g/m2 for 6 dosages followed by HLA-mismatched DLI after the second consolidation. intervention 3: HLA-mismatched DLI will be administered Day 9, approximately 24-48 hours following completion of chemotherapy at a dose of 1x10\^8 cluster of differentiation 3 (CD3+) cells; however, due to logistics of planning infusions with staffing, donor availability, weekends/holidays, etc., it may be necessary to postpone cell infusion up to 96 hours.

Given the time constraints presented by the need to start induction chemotherapy as soon as possible, in some cases, it may not be logistically possible to administer cells with induction. In these cases, patients would just receive standard induction chemotherapy and cells would be administered after consolidation 1 in addition to consolidation 2

Subjects who achieve a CR will receive 2 further courses of cytarabine postremission chemotherapy (consolidation) at 1.0 g/m2 for 6 dosages followed by HLA-mismatched DLI after the second consolidation.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 7/10/2017 
Page 1  of 42 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Study title: 
Adoptive Transfer of Haplo-identical DLI for AML 
and MDS 
 
 Principle Investigator: 
Anthony Sung, MD 
 
 Clinical Trials.Gov #: 
NCT02046122 
 
 Document reference date: 10Jul2017 
 
 IRB approval date: 
13Jul2017 
 
 
 
 
 


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A Phase 1/2 Study of the Safety and Efficacy of Chemotherapy Combined with 
Adoptive Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in Older 
Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
 
 
Principal Investigator: 
Anthony Sung, M.D. 
Duke University Medical Center 
Division of Hematological Malignancies & Cellular Therapy 
DUMC Box 3961 
Durham, NC 27710 
Tel: 919-668-5710 
Fax: 919-668-1091 
Pager: 919-684-8111 
email: anthony.sung@duke.edu 
 
 
 
Sub-investigators: 
David A. Rizzieri, M.D. 
Nelson J Chao, M.D. 
Mitchell Horwitz, M.D. 
Cristina Gasparetto, M.D. 
Gwynn Long, M.D. 
Keith Sullivan, M.D. 
Joseph O. Moore, M.D. 
Carlos de Castro, M.D. 
Louis F. Diehl, M.D. 
Anne Beaven, M.D. 
Danielle Brander, M.D. 
Matthew McKinney, M.D. 
 
 
Laboratory collaborators: 
Dongfeng Chen, Ph.D. 
Michael Datto, M.D., Ph.D. 
Virginia Kraus, M.D., Ph.D. 
 
 
Statistician: 
Zhiguo Li, Ph.D. 
Duke University Medical Center 
Department of Biostatistics and Bioinformatics 
DUMC 2721 
Durham, NC 27710 


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TABLE OF CONTENTS 
1.0 
INTRODUCTION ................................................................................................. 4 
2.0 
STUDY OBJECTIVES ......................................................................................... 4 
2.1 Primary Objective .......................................................................................... 4 
2.2 Secondary Objectives ................................................................................... 5 
3.0 
BACKGROUND .................................................................................................. 5 
3.1 High-Risk AML and MDS in the Elderly ......................................................... 5 
3.2 Stem Cell Transplant for Elderly High-Risk AML and MDS ........................... 5 
3.3 Graft versus Leukemia (GVL) Effect ............................................................. 6 
3.4 
Donor Leukocyte Infusions as a way to Induce GVL Effect ...................... 6 
3.5 
NK Alloreactivity ....................................................................................... 6 
3.6 
NIMA and Maternal-Fetal Microchimerism ............................................... 7 
3.7 
Infusion of HLA-mismatched peripheral blood stem cells in 
elderly AML .............................................................................................. 7 
3.8 
Geriatric assessment ................................................................................ 7 
4.0 
RATIONALE ........................................................................................................ 8 
5.0 
ELIGIBILITY CRITERIA ...................................................................................... 8 
5.1 
Patient Eligibility ....................................................................................... 8 
5.2 
Exclusion criteria ...................................................................................... 9 
5.3 
Donor selection......................................................................................... 9 
6.0 
TREATMENT PLAN .......................................................................................... 10 
6.1 
Prior to starting therapy .......................................................................... 10 
6.2 Donor priming and apheresis ...................................................................... 10 
6.3 Treatment Plan ............................................................................................ 11 
6.4 
Subject Evaluation .................................................................................. 15 
7.0 
EVALUATION CRITERIA AND DEFINITIONS .................................................. 19 
8.0 
SUBJECT REGISTRATION .............................................................................. 20 
9.0 TOXICITY MONITORING AND ADR REPORTING ............................................... 20 
10.0 DATA MANAGEMENT AND DATA SAFETY MONITORING ............................... 21 
10.1 Data Management ..................................................................................... 21 
10.2 Data Safety Monitoring .............................................................................. 22 
11.0 STUDY DESIGN AND ANALYSIS ....................................................................... 23 
11.1 Primary Objectives .................................................................................... 23 
11.2 Secondary Objectives ............................................................................... 25 
11.3 Subgroup analysis ..................................................................................... 27 
12.0 ANTICIPATED TOXICITY OF DLI PROCEDURE ............................................... 27 
12.1 GVHD ........................................................................................................ 27 
12.2 Infections ................................................................................................... 27 
12.3 Infusion Reaction/Engraftment Syndrome ................................................. 28 
12.4 Risk of sensitization .................................................................................. 28 


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13.0 DRUG INFORMATION ........................................................................................ 28 
13.1 Cytarabine (ara-C) ..................................................................................... 28 
13.2 Idarubicin ................................................................................................ 29 
14.0 REFERENCES ................................................................................................... 32 
14.0 APPENDIX ........................................................................................................... 36 
I. RECIPIENT SCHEDULE OF EVENTS TABLE* ............................................. 36 
II. DONOR SCHEDULE OF EVENTS TABLE ................................................... 37 
III. GVHD Grading Criteria ................................................................................. 38 
IV  Toxicity Summary Form ............................................................................... 39 
V. Comprehensive Geriatric Assessment .......................................................... 42 


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1.0 
INTRODUCTION 
 
The outcome of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in 
patients ≥55 years still remains unsatisfactory, with a low complete remission (CR) rate 
and poor overall survival (OS) due to a variety of reasons including increased incidence 
of poor-risk cytogenetics, increased activation of RAS, Src, and TNF pathways and 
intrinsic resistance of leukemic blasts to therapeutic agents. The 30-day induction 
mortality is also high and ranges from 10-50% and this is due to prolonged 
pancytopenia, febrile neutropenia and other systemic side effects that burden the 
already aging patient with comorbidities. [1-3]. Allogeneic stem cell transplantation 
(alloSCT) has curative potential; however, it is associated with severe graft-versus-host 
disease (GVHD), infections, and other treatment related morbidities or mortality for a 
high proportion of elderly patients [4, 5]. Thus, recent work has centered on less toxic 
ways to manipulate donor cells to achieve antitumor benefits. 
 
A pilot study performed in China in elderly patients with AML treated with conventional 
chemotherapy followed by infusion of human leukocyte antigen (HLA) mismatched G- 
CSF mobilized peripheral blood stem cell infusion (G-PBSC) reported higher CR and 
disease-free-survival (DFS) rates, faster neutrophil and platelet recovery, and no GVHD 
or increase in treatment-related mortality [6]. Interestingly, although no patients 
exhibited full or mixed chimerism, donor microchimerism was monitored and observed in 
all four women who had male donors (sons or brothers). This may be due to long-term 
maternal-fetal microchimerism, and studies of HLA-haploidentical allo-SCT have shown 
improved outcomes after transplantation from noninherited maternal antigen (NIMA) 
mismatched donors [7]. Improved responses after HLA-mismatched G-PBSC infusion 
may also be due to natural killer (NK) cells: infusion of haploidentical NK cells from killer 
immunoglobulin-like receptor (KIR) ligand mismatched donors have shown alloreactivity 
against leukemia [8, 9]. Because induction and consolidation chemotherapy followed by 
infusion of HLA-haploidentical cells, or donor lymphocyte infusion (DLI), is a new 
procedure, our first priority is to replicate the above study as a Phase I trial to assess 
safety. 
 
Our primary hypothesis is that chemotherapy followed by infusion of HLA-haploidentical 
DLI from KIR-ligand mismatched donors is a safe procedure that will not cause GVHD or 
increased treatment-related mortality. We further believe that this will improve outcomes 
of elderly patients with high-risk AML or MDS compared to chemotherapy alone, and  
that that this benefit will be even greater in donor-recipient pairs that share maternal-fetal 
microchimerism or NIMA-mismatch. A large part of this trial will include immune function 
assays as well as assessments of efficacy, toxicity, and GVHD. Because this therapy 
may be a tolerable alternative to alloHSCT for elderly patients, we will validate functional 
measurements (e.g. Comprehensive Geriatric Assessment (CGA)) with biologic 
correlates (cytokine and genomic profiles) and clinical outcomes. 
 
2.0 STUDY OBJECTIVES 
 
2.1 Primary Objective 
2.1.1 Evaluate the safety of HLA-haploidentical DLI combined with 
conventional induction and consolidation chemotherapy in terms of 
unacceptable toxicity as defined in section 7.0. 


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2.1.2 Evaluate the efficacy of HLA-haploidentical DLI combined with 
conventional induction and consolidation chemotherapy in terms of one-year 
DFS. 
 
2.1.3 Validate the use of the CGA in elderly AML and MDS patients 
undergoing cellular therapy 
 
2.2 Secondary Objectives 
2.2.1 : Evaluate incidence and severity of acute GVHD. 
 
2.2.2 : Evaluate incidence and severity of other adverse events. 
 
2.2.3 : Evaluate efficacy with respect to CR and OS. 
 
2.2.4 : Evaluate immune recovery. 
 
2.2.5 : Evaluate hematopoietic recovery. 
 
3.0 BACKGROUND 
 
3.1 High-Risk AML and MDS in the Elderly 
Elderly AML and MDS patients have long been known to have much worse 
rates of CR, DFS, and OS compared to their younger counterparts [1, 3]. The 
CR rates in elderly AML patients treated with standard induction 
chemotherapy (7+3, i.e. 7 days of cytarabine and 3 days of anthracycline) is 
~30-65%, with more than half of these patients relapsing within six months [1, 
10], and survival in high-risk MDS is only 26 months vs. 141 months for very 
low risk[11]. In part, this is because elderly patients are less likely to have 
favorable cytogenetics: an analysis of 1065 elderly patients with AML found 
7% to have favorable cytogenetics, 73% intermediate, and 20% poor, with 
complete remission rates of 72%, 53-63%, and 26% respectively, and five- 
year overall survival rates of 34%, 10-15%, and 2% respectively [12]. 
However, even with favorable cytogenetics, patients older than 65 have poor 
outcomes with <10% two-year overall survival [1]. 
 
3.2 Stem Cell Transplant for Elderly High-Risk AML and MDS 
Nonmyeloablative or reduced intensity conditioning (RIC) allogeneic stem cell 
transplantation (alloSCT) does have curative potential for elderly patients with 
AML and MDS; however, it is associated with severe graft-versus-host 
disease (GVHD), infections, and organ toxicity that may lead to unacceptably 
high rates of morbidity and mortality [4, 5, 13]. Further, the lack of an 
available human leukocyte antigen (HLA)–matched donor remains a major 
obstacle for many patients. Haploidentical transplantation may provide a 
larger pool of available donors, but it is limited by significant morbidity and 
mortality (e.g., GVHD and infections) [14]. DLI can also mediate strong graft- 
versus-leukemia (GVL) effects but may be associated with severe GVHD and 
delayed neutrophil recovery after alloSCT [15, 16]. 


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3.3 Graft versus Leukemia (GVL) Effect 
Most patients with hematologic malignancies are not cured with standard 
chemotherapy. Outcomes are improved by alloSCT, which can induce an 
immunologic effect against the cancer. In patients with leukemia, this has 
been termed a graft versus leukemia effect. Evidence for this includes: 
 
1. temporal relationship between graft versus host disease and hematologic 
remission [17] 
2. reduced incidence of leukemic relapse after alloSCT compared to 
syngeneic SCT [18] 
3. reduced incidence in leukemic relapse in alloSCT recipients who do 
develop GVHD compared to those who do not [19] 
 
Multiple laboratory studies have been published in support of this clinical data 
as well. Tumor specific antigens, histocompatibility antigens, and killer 
immunoglobulin receptors (KIR) may play a role through direct cell contact, 
activating NK cells, or indirect production of cytotoxic cytokines (interferon, 
TNF-alpha, IL-2, IL12). 
 
3.4 Donor Leukocyte Infusions as a way to Induce GVL Effect 
Recent work with patients who have relapsed or have persistent disease 
post-alloSCT has centered on using donor leukocyte infusions to stimulate 
more graft versus tumor effect and re-attain remission [20, 21]. Reports are 
growing of clinically significant results in various types of malignant and non- 
malignant processes, and it is now the standard of care to proceed with donor 
leukocyte infusions in patients who have relapsed disease post allogeneic 
transplantation [22]. 
 
For non-selected DLIs, donors are asked to provide peripheral blood 
progenitor cells in the same manner as for transplantation; these are then 
transfused through a peripheral intravenous line into the recipient. Typically, 
somewhere between 105 to 106 CD3+ T cells/kg recipient weight are infused 
over 1 to 2 days every 4-12 weeks, though there is no set standard. Although 
higher doses are associated with increased anti-tumor immunity, they are 
also associated with increased GVHD. The time between infusions allows for 
observation and management of pancytopenia, the anticipated side effect if 
significant graft versus tumor effects is encountered along with suppressive 
effects on the patient’s innate hematopoiesis. Immunosuppressive agents are 
continued during leukocyte infusions; however, if clinically significant graft 
versus host disease does occur, treatment may be initiated to control the 
degree of response at that time. 
 
3.5 NK Alloreactivity 
Donor-versus-recipient NK alloreactivity has emerged as a crucial factor for 
the outcome of haploidentical SCT [8]. Alloreactivity is mediated by KIR- 
ligand mismatch between donor and recipient [23]. Ruggeri et al showed a 
low relapse risk for patients with acute myeloid leukemia transplanted from 
NK-alloreactive donors [9]. Further, adoptive transfer of alloreactive 
haploidentical NK cells has been shown to be safe and effective in treatment 


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of AML [24, 25]. NK-enriched DLI may also improve outcomes and immune 
recovery [26]. 
 
3.6 NIMA and Maternal-Fetal Microchimerism 
Outcomes after HLA-haploidentical allo-SCT are better when using the 
patient’s mother as the donor compared to the father [7, 27, 28]. This is 
thought to be secondary to in-utero exposure of NIMA, leading to the 
establishment of long-term maternal-fetal microchimerism, which can be 
found in 40% of adults [29] and lead to both tolerogenic as well as sensitizing 
effects [30, 31]. One study by Stern et al found the five-year event-free 
survival rate was 50% in patients who had transplants from their mother 
versus 11% for those who had transplants from their father, in large part due 
to reduced incidence of relapse, thought secondary to improved graft-versus- 
leukemia[27]. Maternal-fetal microchimerism may also mediate a graft- 
versus-leukemia effect in cord blood transplantation [32]. Thus, adoptive 
transfer of cells from mother to child or child to mother may improve 
outcomes. 
 
3.7 Infusion of HLA-mismatched peripheral blood stem cells in elderly AML 
A recent Chinese study reported that mice infused with a high dose of G- 
CSF–mobilized allogeneic spleen cells (3-12 x107) after cytarabine 
chemotherapy exhibited rapid hematopoietic recovery and persistent 
microchimerism without GVHD despite absence of GVHD prophylaxis and 
immunosuppressive treatment [6]. On the basis of these observations, they 
designed a clinical control study to investigate the effects of G-PBSC 
combined with conventional induction and intensive postremission 
chemotherapy on outcomes of AML in elderly patients. Fifty-eight AML 
patients aged 60-88 years were randomly assigned to receive induction 
chemotherapy with cytarabine and mitoxantrone (control group; n=28) or 
same chemotherapy plus HLA-mismatched G-PBSCs (G-PBSC group; n=30) 
(median CD3+ cell dose: 0.9 x 10E8 CD3+ cells/kg recipient body weight). 
Patients who achieved CR received another 2 cycles of postremission 
therapy with intermediate-dose cytarabine plus G-PBSCs. The complete 
remission rate was significantly higher in the G-PBSC group than in the 
control group (80.0% vs. 42.8%; P= .006). The median recovery times of 
neutrophils and platelets in the G-PBSC group were 11 days and 14.5 days, 
respectively, and 16 days and 20 days in the control group. The 2 year 
probability of disease-free survival was significantly higher in the G-PBSC 
group than in the control group (38.9% vs. 10.0%; P =.01). No graft-versus- 
host disease was observed in any patient. 
 
Given that none of these patients experience engraftment, yet there was a 
significant improvement in disease free survival, we hypothesize that these 
results were due to infused donor lymphocytes rather than CD34+ stem cells. 
As a result, G-PBSC may not be necessary and HLA-haploidentical DLI 
would suffice. 
 
3.8 Geriatric assessment 
To better understand the mechanisms that contribute to the poor prognosis of 


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elderly AML patients, our laboratory has demonstrated that differences in the 
underlying biology (higher probability of Src, TNF, and RAS pathway 
activation in elderly AML patients as compared to their younger counterparts) 
contribute to poor survival[33]. We will build on this knowledge by using the 
CGA to improve our clinical assessment of functional status in elderly AML 
and MDS patients to predict responses to and toxicity from induction therapy 
as well as mortality and correlate these results with biologic markers of frailty 
using cytokine and genomic profiles. 
 
4.0 
RATIONALE 
 
Elderly patients with high-risk AML and MDS respond very poorly to conventional 
induction regimens and have high relapse rates. AlloSCT is one way of 
decreasing relapse but at the cost of toxicity and GVHD. Infusion of HLA- 
haploidentical stem cells may provide an alternate means of inducing a graft- 
versus-leukemia effect with less toxicity. This may be mediated by NK- 
alloreactivity and potentiated by maternal-fetal microchimerism. Our trial will 
attempt to confirm the safety and efficacy of the Chinese study in an attempt to 
improve 2-year survival in elderly high-risk AML and MDS patients, with minimal 
toxicity and GVHD, with a focus on immunological correlates and function in an 
attempt to further understand the mechanism of this phenomenon. 
 
We have selected the dose of 1 x 10E8 CD3+ cells/kg recipient body weight 
based on the success of this dose in the study by Guo et. al.[6] and the use of 1 
x 10E8 – 2 x 10E8 CD3+ cells/kg recipient body weight by Colvin et. al. in a 
similar study[34]. In both the Guo and Colvin studies, GVHD was not seen at this 
dose. 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Laboratory, bone marrow biopsy, and radiographic evaluation to determine eligibility 
should be done within 4 weeks of registration. Baseline staging studies not needed for 
eligibility but used to assess disease prior to transplantation may be performed up to 8 
weeks before registration. 
 
5.1 Patient Eligibility 
 
1. Subjects must have their diagnosis of high-risk AML or high-risk MDS 
confirmed by pathologic review of bone marrow biopsy according to WHO 
guidelines [35] (see below for definitions of high-risk) 
• 
We will define patients as high risk AML and thus eligible if they meet 
one or more of the following criteria: 
a. 
Secondary AML (from underlying MDS or therapy related) 
b. 
Presence of complex cytogenetic abnormalities (≥ 3 
cytogenetic abnormalities), all monosomies, del 5q, del 7q, 
inv3, t(3;3), t(6;9), t(9;22), abn 11q23 (excluding t(9;11))[36] 
c. 
FLT3-ITD mutation positive 
d. 
Age >65 years given poor outcomes even with favorable 


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cytogenetics[1] 
• 
We will define subjects as high risk MDS and thus eligible if they have 
a MD Anderson Comprehensive Cancer MDS Risk Score ≥9[3] 
2. Subjects must have ECOG Performance status of 0,1,or 2; if ECOG 2, they 
must also have a Charlson comorbidity index of ≤5.[37] 
3. Subjects must be ≥ 55 years of age 
4. Subjects should have a potential 3-5/6 HLA-matched related haploidentical 
donor that will be evaluated for eligibility to provide DLI. 
5. Patient should be able to provide informed consent 
6. Subjects must have a MUGA and /or ECHO or cardiac MR. The required 
minimum standards include MUGA or ECHO or cardiac MR showing an EF of 
40%. Those with an EF 40-49% must also have a cardiologist consult and 
assist with management. 
7. PFTs with DLCO are conditional for subjects at the discretion of the 
physician. The required minimum standards for those who have PFTs 
include DLCO of 40%. Those with DLCO of 40-49% must have a 
pulmonologist consult and assist with management. 
8. Subjects of all genders and races are eligible 
 
5.2 Exclusion criteria 
 
1. Pregnant or lactating women. 
2. Patients with other major medical or psychiatric illnesses which the treating 
physician feels could seriously compromise tolerance to this protocol 
3. Patients with known active CNS disease 
4. Patients with acute promyelocytic leukemia (FAB M3) 
 
5.3 Donor selection 
 
1. Adult donors must be must be a HLA 3-5/6 related haploidentical match with 
the patient and must be capable of providing informed consent 
2. Donors must not have any medical condition which would make apheresis 
more than a minimal risk, and should have the following: 
a. Family members will be considered for donation if they do not have a 
history of known cardiac problem and do not have abnormal cardiac 
findings by physical examination. Those with a history of cardiac 
problems or abnormal cardiac findings by physical examination should 
undergo a stress evaluation or be evaluated by a cardiologist and 
deemed eligible to donate 
b. Bilirubin and hepatic transaminases < 2.5 x ULN, 
c. Adequate hematologic parameters including a hematocrit > 35% for 
males and 33% for females, white blood cell count of ≥ 3,000, and 
platelets ≥80,000. 
d. FACT labs must be drawn within 7 days of collection and final test results 
available prior to infusion into the patient (copy of labs included in 
appendices). In the case of multiple donations from the donor, the FACT 
labs must be redrawn within 7 days of each initiation of apheresis 
(positive serologies are not repeated as they remain positive for lifetime 
but all other donor labs are performed as per the donor appendix sheet). 


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3. Females of childbearing potential should have a negative serum beta-HCG 
test within 1 week of beginning growth factor of choice 
 
5.3.1 Donor selection algorithm 
Preference is first given to: 
a. the best matched family member who meets other donor criteria, followed 
by 
b. age (younger donor preferred) 
c. KIR reactivity according to the following rules: 
i. 
If a recipient is missing HLA-C group2 ligand, a preferable donor has an 
inhibitory KIR to HLA-C group2 ligand (KIR2DL1) 
ii. If a recipient is missing HLA-A3/A11 ligand, a preferable donor has an 
inhibitory KIR to HLA-A3/A11 ligand (KIR3DL2) 
iii. If a recipient is missing HLA-Bw4 ligand, a preferable donor has an 
inhibitory KIR to HLA-Bw4 ligand (KIR3DL1) 
iv. A preferable donor has more than one inhibitory KIR (2DL1/2/3, 3DL1/2) 
without corresponding ligand in a recipient, followed by 
d. CMV negativity 
e. NIMA mismatch over NIPA mismatch 
 
 
6.0 
TREATMENT PLAN 
 
6.1 Prior to starting therapy 
Prior to enrollment, potential subjects will have a complete history and 
physical examination performed as well as the following required lab tests: 
CBC with differential (auto or manual), creatinine, AST, ALT, total 
bilirubin,and bone marrow biopsy with cytogenetics and molecular mutation 
studies. These should all be completed within four weeks prior to enrollment. 
Cardiopulmonary testing as per section 5.1 must be completed within eight 
weeks. Other recommended tests (not required but helpful for final analysis) 
include: CMV immune screen, LDH, uric acid, alkaline phosphatase, sodium, 
potassium, chloride, bicarbonate, glucose, total protein, albumin, calcium, 
magnesium, phosphorous. 
 
If a potential subject is awaiting the above required lab tests to assess 
suitability for enrollment (e.g. normal cytogenetics and FLT-3 mutation 
testing), and if WBC is elevated and/or rising, hydrea or leukapheresis may 
be initiated at the discretion of the treating physician. 
 
6.2 Donor priming and apheresis 
Exam and laboratory analyses will follow current Foundation for the 
Accreditation of Cellular Therapy (FACT) standard of care accreditation 
requirements for cellular therapy practices. 
 
6.2.1 Mobilization 
Recommended mobilization includes G-CSF 8 mcg/kg subcutaneously twice 
daily for 4 days prior to stem cell collection and continuing until pheresis is 


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completed.  Dose  should  be  rounded  to  nearest  vial  size. 
Alternative 
mobilization strategies may be employed at the investigator’s discretion. 
 
6.2.2 Collection of cells 
General guidelines (though may be altered for program standards and 
evolving stand of care without being a violation): The goal is to collect 3 x 
108 CD3+ cells/kg recipient body weight. If, after a maximum of 2 
leukaphereses, the target collection is not reached, the treating physician 
may decide to proceed with a third collection after re-discussion with the 
patient and donor. If the goal dose is not reached, infusion will still take 
place if a minimum of 2x x 108 CD3+ cells are collected, and recovery will 
be monitored as the patient will normally have autologous recovery.. The 
infusion schedule will be modified as below (6.3.4). Leukapheresed cells 
will be processed and frozen in the cryopreservation lab according to 
standard procedures, unless they are to be immediately infused into the 
patient after processing (e.g. freshly collected cells to be given following 
induction). 
 
The donor lymphocyte infusion meets criteria to be regulated solely as 
HCT/P instead of a drug/biologic. There is no manipulation of donor cells 
and the donor is a first or second degree relative. 
 
6.2.3 Storage and processing 
The stem cells are processed in the Duke University Medical Center Stem 
Cell Laboratory and infused to the donor following the standard laboratory 
procedures for allogeneic stem cell infusions. Freshly collected cells will 
be used in the first course of treatment and donor cells will be divided into 
aliquots and cryopreserved in liquid nitrogen for subsequent infusions. 
Each infusion of the cells will be performed 1 day following each 
chemotherapy regimen and that day will be counted as ’day 0’. The target 
dose of CD3+ cells is 1x10^8 cells/kg (the collection goal of 3x10^8 CD3+ 
cells/kg is to obtain 1 aliquot of 1x10^8 CD3+ cell/kg for each of induction 
and consolidation2, with 1x10^8 CD3+ cell/kg saved in case of need for 
re-induction). If only 2-3x10^8 CD3+ cell/kg is collected, then cells will 
only be given with IND1 and CON2 (IND2 may still be done, but cells will 
not be given). We will also monitor the total number of mononuclear, 
CD34+, CD3-CD16+CD56+ (NK) cells, CD3+CD16+CD56+ (NKT) cells, 
and gamma-delta T-cells infused, but the infusion dose will be calculated 
around CD3+ population. 
 
6.3 Treatment Plan 
 
6.3.1 Induction therapy 
Eligible subjects will receive induction chemotherapy with idarubicin (12 
mg/m2 intravenously for 3 days) and cytarabine (100 mg/m2 intravenously 
for 7 days) starting Day 1 and ending Day 7 as described in Figure 1. 
Patients 80 years or older may receive 2 and 5 days of idarubicin and 
cytarabine respectively starting Day 1 and ending Day 5 (optional, at 
physician discretion). HLA-mismatched DLI will be administered Day 9 


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Chemo with Adoptive Haplo DLI 
 
 
 
 
(DLI will occur on Day 7 for 5+2 regimen), approximately 24-48 hours 
following completion of chemotherapy at a dose of 1x10^8 CD3+ cells; 
however, due to logistics of planning infusions with staffing, donor 
availability, weekends/holidays, etc., it may be necessary to postpone cell 
infusion up to 96 hours, which will be allowed without being considered a 
protocol violation. 
Subjects who experience no remission or partial remission will receive a 
second course of the identical induction chemotherapy (IND2). IND2 
should include 7+3+DLI as per IND1, but if cells are not available as per 
6.2.3, chemotherapy alone can be given without being considered a 
protocol violation. 
Given the time constraints presented by the need to start induction 
chemotherapy as soon as possible, in some cases, it may not be 
logistically possible to administer cells with induction (e.g., obtaining 
insurance approval for clinical trial/DLI may take a while, and approval 
may not be back in time for a patient to receive cells). In these cases, 
patients would just receive standard induction chemotherapy and cells 
would be administered after CON1 in addition to CON2 (see below). 
Timing of correlative laboratory studies will be adjusted to match cell 
infusion. Guo et al. have reported improved outcomes with high cell 
doses (1x 10^8 CD3+ cells/kg) administered after consolidation, even in 
patients who receive standard induction chemotherapy without cells.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Guo M, Hu KX, Liu GX, Yu CL, Qiao JH, Sun QY, Qiao JX, Dong Z, Sun WJ, Sun XD, Zuo HL, 
Man QH, Liu ZQ, Liu TQ, Zhao HX, Huang YJ, Wei L, Liu B, Wang J, Shen XL, Ai HS. HLA- 
mismatched stem-cell microtransplantation as postremission therapy for acute myeloid leukemia: 
long-term follow-up. J Clin Oncol. 2012 Nov 20;30(33):4084-90. doi: 10.1200/JCO.2012.42.0281. 
Epub 2012 Oct 8. 


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6.3.2 Postremission treatment 
Subjects who achieve a CR will receive 2 further courses of 
cytarabine postremission chemotherapy (consolidation) at 1.0 g/m2 for 
6 dosages followed by HLA-mismatched DLI after the second 
consolidation. Cytarabine will be given twice daily at 12 hour intervals 
on days 1, 3, and 5; HLA-mismatched DLI will be administered the 
day following the completion of the second consolidation (day 7) at a 
dose of 1x10^8 CD3+ cells, although as above, a 24-96 hour interval 
between completion of chemotherapy and infusion of cells will be 
allowed for logistical reasons without being considered a protocol 
violation. 
 
No cells will be given after the first consolidation, as chemotherapy 
given with the second consolidation will likely kill any cells infused 
after the first consolidation (i.e. infusion of cells after the first 
consolidation would be costly and low-yield) (Note that while this 
argument could also be applied to cells infused after induction, Guo et 
al. showed an improvement in the CR rate from 40% to 80% with the 
use of cells with induction, which is why we plan to use cells after 
induction in this trial). 
 
The timing of consolidation typically takes place after count recovery, 
around 6-12 weeks after induction, following standard protocols and 
timing for cytarabine consolidation. 


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6.3.3 Dose Adjustments 
Patients with Hepatic Impairment Dosing: Dosage will be modified 
depending on clinical response and degree of hepatic impairment, but 
no quantitative recommendations are available. 
 
Subjects with Renal Impairment Dosing: 
Our program follows the following guidelines: Estimate a creatinine 
clearance using the formula for the estimated CrCl in ml/min: 
 
(140- age)/serum Cr x (ideal body wt/72). 
In addition, for females this value is multiplied by .85 
 
For subjects with a CrCl > 60 ml/min: No dosage adjustment. 
CrCl <= 60 ml/min: There is an increased risk of cerebellar and 
cerebral toxicity with high dose regimens. The recommended dosage 
adjustment will be as follows: For a serum creatinine of 1.5—1.9 mg/dl 
or increase of serum creatinine from baseline of 0.5—1.2 mg/dl during 
treatment, the dose of cytarabine will remain 100 mg/m2 during 
induction and be reduced to  500 mg/m2  during postremission 
therapy. For a serum creatinine ≥ 2 mg/dl or if the change in baseline 
serum creatinine was > 1.2 mg/dl, we will reduce the dose of 
cytarabine to 50 mg/m2 during induction and to 250 mg/m2 during 
postremission therapy. 
 
 
6.3.4 DLI 
Allogeneic DLI will be collected from the donor as described in section 
6.2.2. The allogeneic DLI will be infused as per current practice. 
Subjects will be given premedications including Benadryl 25 mg IV, 
and Acetaminophen 650 mg po prior to infusion. Hydrocortisone is 
used at the physician’s discretion. 
 
If needed, modifications to the infusion rate may be made as per 
standard practice. 
 
6.3.5 Supportive Care 
GVHD prophylaxis: GVHD prophylaxis will not be administered. 
 
Growth factor use: A growth factor of choice may be initiated at the 
treating physician’s discretion. 
 
Antibiotic prophylaxis (may be altered to follow the treating 
physicians standard practice without affecting overall study): 
a. Voriconazole 200 mg PO BID or Posaconazole 200 mg PO 
TID beginning at day 9 (or Day 7 for subjects receiving 5+2 
regimen) until CD4+ >200/uL or 1 year following therapy, 
whichever occurs first. Alternatives may be substituted at the 
physician’s discretion. 


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b. Acyclovir 400 mg PO BID beginning day 9 (or Day 7 for 
subjects receiving 5+2 regimen) until ANC > 1000/uL or day 
+30 if a donor or recipient is only HSV seropositive; acyclovir 
800mg PO BID will continue from day +30 through 1 year or 
until CD4 count is >200/uL if a donor or recipient is VZV 
seropositive. 
c. Ciprofloxacin 500mg po BID should be initiated beginning on 
day 9 (or Day 7 for subjects receiving 5+2 regimen) and 
continue until CD4 count >200/uL or 1 year following therapy if 
tolerated orally. Alternative prophylactic antibiotics may be 
used at the physician’s discretion. 
d. CMV monitoring will occur at baseline. The treating physicians 
may use their own test of choice for this surveillance, though a 
PCR based assay is recommended. A positive test 
necessitates initiating therapy per local standards (low positive 
typically requires a repeat confirmation and a high positive 
immediate initiation of anti-CMV therapy with ganciclovir or 
foscarnet). 
 
Blood products: All blood products (except DLI) will be irradiated 
following local standards to prevent possible GVHD. Hematocrit 
should be maintained at > 25%, and platelets at > 10,000/mm3 
(subject to treating physician discretion). All blood products should be 
filtered prior to infusion 
 
Other care: Agents designed to minimize other side effects of 
transplantation such as decreasing mucositis are allowed at the 
physician’s discretion. 
 
6.4 
Subject Evaluation 
6.4.1 Clinical Evaluation 
Subjects will be evaluated daily during induction and recovery from 
therapy while admitted to the hospital. Evaluation will include history 
and physical exam and toxicity monitoring, including acute GVHD 
monitoring. They will return for post-remission therapy and typically be 
re-admitted to our service for further treatment. In selected cases, 
subjects may remain outpatient with very close care and follow up per 
the treating team’s discretion. Upon completion of therapy, they will be 
seen at least every other week until 8 weeks, after which they will be 
seen at least every 3 months for 2 years. 
 
6.4.2 Laboratory and other testing 
(Correlative Studies for 00043247 v. 15.06.19 Lab Manual) 
Evaluation for supportive care during therapy/recovery and after 
therapy will be as follows (Recommended but may change based on 
clinical status per treating physician): 
(a) CBC will be obtained daily during induction until transfusions of 
platelets and red blood cells are not regularly required, then as 
clinically indicated. When the white count reaches greater than 


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500/uL, then add differential and follow to document when ANC > 
1,500/uL. After consolidation, CBC and differential will be checked 
every 2 weeks or as clinically indicated. 
(b) Serum chemistries and liver functioning tests at least weekly and 
as clinically indicated while during therapy/recovery; chemistries 
and liver function tests will also be checked at 8 weeks and then 
every 3 months for 2 years. 
(c) Serum quantitative beta-HCG will be checked one week prior to 
induction in females. 
(d) Biopsies of organs suspected to be involved with GVHD as 
clinically indicated (e.g., skin, liver, GI tract). 
(e) Chest X-ray as clinically indicated. 
(f) Bone marrow biopsy at Day 14 (per investigator discretion) as well 
as after count recovery (mandatory) 
(g) HLA Antibodies at count recovery and 8 weeks after CON2. 
(h) For patients who relapse or have refractory disease going off 
study, collect the following labs: peripheral blood for minimal 
residual disease testing, NK lysis assay, microchimerism, TCR 
sequencing, PD1/PDL1/PDL2 expression. 
 
6.4.3 Detection of donor chimerism and microchimerism: 
Hematopoietic donor chimerism will be assessed in all subjects 
with the use of standard cytogenetic and semiquantitative PCR- 
based analysis of short tandem repeats with 1% sensitivity. 
Microchimerism will be analyzed using real time PCR (qPCR) at a 
sensitivity of 1/100,000. 
These assays will be performed at count recovery prior to each 
new cycle of therapy, at 8 weeks after the last round of 
consolidation, and if still positive, every 3 months after completing 
therapy for up to two years. Additionally, in the case of mother- 
child pairs or sibling pairs that are mismatched in NIMA, this will 
be conducted before first infusion to assess for persistent 
maternal-fetal microchimerism. 
 
6.4.4 Evaluation of immune function 
We will evaluation immune function based peripheral blood and bone 
marrow analysis using the following assays: 
1. Cytokines will be measured, particularly levels of IL1, IL1beta, 
CRP, IL2, IL6, IL8, IL15, IL21, IFN-gamma, TNF-alpha, TGF-beta 
2. Lymphocyte subsets will be analyzed using flow cytometric 
lymphocyte immunotyping with fluorochrome conjugated 
monoclonal antibodies to CD3, CD4, CD8, CD11c, CD16, CD19, 
CD25, CD28, CD45RA/RO, CD56, CD57, CD62L, CD107, 
CD123, TCR gamma-delta, FOXP3, HLA, and KIR 
3. Quantification of recent thymic immigrants will be determined by 
the presence of TCR rearrangement excision circles (TREC), 
retrospectively performed by real-time quantitative-PCR of DNA 
collected from an isolated fraction of CD31 T cells and next 


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generation sequencing to analyze diversity in the TCR repertoires 
produced by the rearrangements of the variable region genes. 
4. NK activity will be assessed by FACS (CD56+CD107+). 
These assays will be done at count recovery prior to each new 
cycle of therapy, at 8 weeks after the last round of consolidation, 
and every 3 months after completing therapy for up to two years. 
Additional blood will not be drawn for this testing. 
 
6.4.5 T cell receptor sequencing 
T-cell recovery and repertoire diversity will also be analyzed using 
next-generation DNA sequencing of the complementarity 
determining region 3 (CDR3) of T-cell receptor (TCR) beta chains 
using the Illumina platform. The effectiveness of deep sequencing 
has been reported by van Heijst et al., who successfully used 5’ 
RACE and deep sequencing to analyze TCR diversity after 
alloHSCT, demonstrating that this is strategy is feasible and that 
results are reproducible[38]. Intriguingly, in their study, van Heijst 
et al. were able to identify a clonal population of T cells associated 
with EBV relapse, suggesting that TCR deep sequencing may 
provide insight into ongoing anti-infectious and anti-tumor 
immunity. We have conducted our own pilot studies of TCR 
sequencing through our Immune Core, lead by our collaborator, H. 
Kim Lyerly, M.D., using frozen tumor biopsies from the Duke 
Breast SPORE tissue bank, demonstrating our ability to apply this 
technology as well evidence of oligoclonality and antigen-specific 
immune responses in cancer. 
 
Working with Dr. Lyerly and other collaborators, we will use deep 
sequencing of TCR genes to analyze T cell recovery and TCR 
repertoire after chemotherapy and infusion of HLA-haploidentical 
donor lymphocytes. Starting with 5’ RACE, which allows for the 
linear, unbiased and comprehensive amplification of all TCRs 
irrespective of the TCR beta variable (TRBV) or joining (TRBV) 
gene usage, or other primer-based methods (e.g. Adaptive), we 
will then use real-time PCR to add sequences that incorporate 
barcodes and Illumina flow cell-binding sequences while 
restricting amplification to the linear phase. After cluster 
generation by bridge PCR, 200bp paired-end sequencing 
reactions are then performed using MiSeq and HiSeq2000 
sequencers. TRBV, TRBJ and TRBV-TRBJ usage frequencies are 
initially determined as well as repertoire diversity using Shannon 
entropy and Simpson's diversity index as well as non-parametric 
methods, such as abundance-coverage and incidence-coverage. 
Comparisons of individual sequences and their frequencies may 
be made within and between T cell populations and depicted 
graphically as pie charts or overlapping sets, with statistical 
calculations of repertoire relationships made using JMP Software, 
SAS Institute, Inc., Cary, NC. As each sequence is defined 
individually, any subtle differences in repertoire may be reported. 


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Importantly, CDR3 motifs may be revealed not only at the level of 
amino acid sequence but also in terms of the biochemical and 
biophysical properties of the amino acids therein. Taken together, 
these attributes will be used to examine the clonotypic 
composition of the naïve and memory CD4 and CD8 T cell pools 
to determine particular TCR signatures. 
 
TCR sequencing will be performed prior to starting treatment, at 
count recovery after induction and before consolidation, at 8 
weeks after the last round of consolidation, and at 1 year after 
therapy. Additional blood will not be drawn for this testing. 
 
6.4.6 Cytokine Release Syndrome 
We will measure cytokine release with DLI based on peripheral 
blood analysis. Blood will be taken on the day of cell infusion for 
both induction and consolidation 2, to be drawn before infusion 
and 2 days after infusion for both induction and consolidation 2 to 
evaluate for cytokine release syndrome with DLI, For subjects 
who do not receive their DLI during induction but rather following 
consolidation #1 and consolidation #2, blood will be drawn before 
infusion and 2 days after infusion to measure cytokine release. 
We will use about 4-8 teaspoons of blood drawn from a vein by a 
needle-stick or through a central line each time you have these 
blood tests. 
 
6.4.7 Geriatric evaluation 
Comprehensive geriatric assessment: Patients will be required to 
complete the CGA before induction and 8 weeks after the final 
round of cellular therapy. We have demonstrated previously that 
inpatient geriatric assessment and management has positively 
affected quality of life in the elderly cancer inpatient at no greater 
length of hospitalization or extra cost than usual care[39]. The 
CGA has been validated in CALGB studies in elderly patients with 
solid tumors (breast, colon, prostate cancers)[40]. The mean time 
to complete the assessment is 23 minutes. Most patients can 
complete the self-administered portion of the assessment without 
assistance, and there is no association between age or 
educational level and the ability to complete the assessment 
without assistance. Patients may require assistance from the 
research team for three items: 1) Blessed Orientation- Memory- 
Concentration (BOMC) test; 2) Timed Up and Go; and 3) 
Karnofsky performance status (KPS). The remainder of the CGA 
is either self-administered or administered by a research assistant 
if the patient requires assistance. The following domains of CGA 
will be measured: a) Functional Status: Activities of Daily Living, 
Instrumental Activities of Daily Living, Karnofsky Performance 
Rating Scale, Timed Up & Go, Number of Falls in Last 6 Months 
b) Comorbidity: Physical Health Section c) Cognition: Blessed 
Orientation-Memory-Concentration Test d) Psychological: Hospital 


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Anxiety and Depression Scale e) Social Functioning: MOS Social 
Activity Limitations Measure f) Social Support: MOS Social 
Support Survey: Emotional and Tangible Subscales, Seeman and 
Berkman Social Ties, and g) Nutrition: Body Mass Index, % 
Unintentional Weight Loss in the Last 6 Months. 
 
Biologic Markers: Serum concentrations of the candidate 
cytokines (IL-6, IL-1, IL-2, TNF-α, and CRP) will be determined 
using Luminex MAP, which facilitates the simultaneous evaluation 
of multiple immune mediators with advantages of higher 
throughput, smaller sample volume, and lower cost, when 
compared to ELISA. All testing will be done in triplicates using the 
human 29-plex LINCO assay. For RNA extraction, total cellular 
RNA will be extracted from the leukemic cells using a commercial 
RNA purification kit; RNA quality will be determined with an 
A260/A280 ratio and capillary electrophoresis on an Agilent 2100 
Bioanalyzer automated analysis system. For DNA microarray 
analysis, biotinylated cRNA synthesis will be generated with 10 
micrograms of total cellular RNA. RNA will be analyzed on the 
Agilent 2100 Bioanalyzer and then hybridized onto a U133A 
oligonucleotide array, and thus will be stained, and washed 
according to an Affymetrix protocol. DNA chips are scanned with 
the Affymetrix GeneChip scanner, and the signals are processed 
to evaluate the standard RNA measures of expression. Of note, 
each gene on this chip is represented by 10 to 20 
oligonucleotides, termed a “probe set.” The intensity of 
hybridization of labeled messenger RNA (mRNA) to these sets 
reflects the level of expression of a particular gene. Samples will 
be collected before induction, after induction and before 
consolidation, and at 8 weeks after completing final round of 
cellular therapy. 
 
Samples will be collected before start of induction and at count 
recovery prior to consolidation 1. 
 
 
7.0 
EVALUATION CRITERIA AND DEFINITIONS 
 
1. 
Standardized response criteria will be used following National Comprehensive 
Cancer Network (NCCN) recommendations found on the NCCN website: 
www.nccn.org. 
2. GVHD will be graded with standard criteria (see Appendix II). Other toxicity will 
be graded as per the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 (see Appendix III). Grade 3-4 will be reported. 
3. Unacceptable toxicity will be defined as either: 
a. Grade III or IV aGVHD of the gut or liver or Grade IV aGVHD of the skin 
lasting > 7 days; 


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b. Other grade IV CTCAE toxicity attributable to the DLI (e.g. infusion 
reaction, and distinct from grade IV toxicity attributable to chemotherapy) 
and lasting > 7 days 
c. Treatment-related mortality (TRM), keeping in mind that anticipated 
mortality from standard induction chemotherapy in the elderly ranges from 
11% for subjects 55-65 years-old with ECOG 0 to 50% for subjects older 
than 75 years with ECOG 2 [1]. 
4. Disease-free survival (DFS) is the time from CR to relapse or death. 
5. Overall survival (OS) is the time from start of therapy to either death or the last 
day of follow-up for that patient. 
6. Event Free Survival (EFS) is the time from start of therapy to progression of AML 
or relapse or death. 
7. Neutrophil recovery time is defined as the first of 3 consecutive days in which the 
ANC is >0.5 x 109/L 
8. Platelet recovery is defined as the first of 3 consecutive days in which the platelet 
count is >20 x 109/L 
9. PD1/PDL1/PDL2 expression (marker of T cell exhaustion) 
10. 
 
8.0 
SUBJECT REGISTRATION 
 
All subjects who meet eligibility criteria for this study and sign a consent form must be 
registered into Velos eResearch within 24 hours of consent by a member of the Division 
of Hematologic Malignancies and Cellular Therapy team. We also request an email to 
the study chair, Dr. Anthony Sung, atanthony.sung@duke.edu. The eligibility checklist 
must be completed and the IRB approved consent form signed before any protocol 
therapy may be started on the patient or donor. 
 
9.0 TOXICITY MONITORING AND ADR REPORTING 
 
The investigator is required by Federal Regulations to report adverse experiences 
(AEs) that occur through the duration of the study according to the appropriate 
procedures listed below. The investigator is required to notify, Duke University 
Health System (DUHS) Institutional Review Board (IRB) Office, and DUHS 
Comprehensive Cancer Center if an event is serious, unexpected, and related or 
possibly related to the study. All serious adverse events (SAEs) that occur up to 30 
days after the last Donor Lymphocyte Infusion (DLI) will be reported. After 30 days, 
SAEs will be reported if thought related to treatment for the duration of the study. 
 
Definitions: An adverse event is any new, undesirable medical experience or 
change of an existing condition that occurs during or after treatment, whether or not 
considered product-related. 
 
A serious adverse event is any untoward medical occurrence that suggests 
significant hazard or side effects that result in the following: 
• 
results in death 
• 
is life-threatening (places the patient at immediate risk of death) 
• 
requires or prolongs in patient hospitalization 
• 
is disabling or incapacitating 


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• 
is a congenital anomaly/birth defect 
Any SAE will be reported to the DUHS IRB within 24 hours. 
 
An unexpected adverse event is any adverse event, the specificity or severity of 
which is not consistent with the current investigator brochure or consent form. 
 
This study will utilize the NCI Common Toxicity Criteria for Adverse Events (CTCAE) 
version 4.0 to determine the severity of the reaction for adverse event reporting. Only 
adverse events meeting criteria Grade 3 or greater will be collected. Laboratory 
abnormalities will only be captured if considered clinically significant. Any reactions 
that is reportable (serious, unexpected and related/possibly related to the study) 
must be reported using the Duke University Health System (DUHS) Institutional 
Review Board (IRB) Office SAE form. All other side effects and toxicities will be 
recorded in the patient’s research chart or documented on the computer record for 
the patient. 
 
Specific plan in the event of microbial contamination of infused product: 
Product sterility testing will include a STAT gram stain which will have to be negative 
prior to release for infusion. A 14 day culture will be performed by our microbiology 
laboratory as per FDA requirements. In addition, per the SOP of sterility testing, 
cultures will be maintained for 5 days in our stem cell laboratory though typically the 
product is infused fresh the day of collection or the following day. In the event that a 
culture becomes positive, the lab notifies the treating physician immediately who in 
turn notifies the patient and the treating staff. Subjects will be evaluated within the 
same day of notification of a positive culture by the treating team for any infection 
related incidents and treated appropriately. The evaluation will include a minimum of 
physical examination, vital signs and blood culture. 
In the event of this occurrence, this will be considered an SAE and reported in an 
expedited manner as above for other serious adverse events if there is a change in 
the health status of the patient or requiring initiation of antimicrobials. 
 
Investigation plan in case of cellular microbial contamination: 
In the event that a product has a positive culture, all reasonable efforts will be 
undertaken to detect the possible source. For potential donor source, donor 
notification and return to clinic or primary care physician for examination if there are 
any signs or symptoms of infection will be recommended. Examination of the chain 
of custody log will occur to ensure proper transit of the product and review of the 
exact procedure with the laboratory technician who performed the cell selection to 
investigate any potential difficulties that arose (tubing malfunction, bag leakage, etc). 
10.0 DATA MANAGEMENT AND DATA SAFETY MONITORING 
 
10.1 Data Management 
10.1.1 Electronic Case Report Forms (eCRFs) 
The eCRF will be the primary data collection document for the study. The 
eCRFs will be updated in a timely manner following acquisition of new 
source data. Only data managers are permitted to make entries, 
changes, or corrections in the eCRF. 


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An audit trail will be maintained automatically by our in-house Microsoft 
Access database. All users of this system will complete user training, as 
required or appropriate per regulations. 
 
10.1.2 Data Management Procedures and Data Verification 
Users of the electronic CRF will have access based on their specific roles 
in the protocol. Data managers have full read/write access; all other key 
personnel have read only access. 
 
All data changes are tracked by an audit trail. Basic error checking is 
performed to ensure that legal values and dates are entered. Data 
managers do a full check of all data to maintain accuracy. The ability to 
make data modifications is based on the user’s role on the study. 
 
10.1.3 Study Closure 
Following completion of the studies, the PI will be responsible for 
ensuring the following activities: 
 
• 
Data clarification and/or resolution 
• 
Accounting, reconciliation, and destruction/return of used and 
unused study drugs 
• 
Review of site study records for completeness 
• 
Shipment of all remaining laboratory samples to the designated 
laboratories 
 
 
10.2 Data Safety Monitoring 
The DCI Monitoring Team will conduct monitoring visits to ensure subject safety 
and to ensure that the protocol is conducted, recorded, and reported in 
accordance with the protocol, standard operating procedures, good clinical 
practice, and applicable regulatory requirements. As specified in the DCI Data 
and Safety Monitoring Plan, the DCI Monitoring Team will conduct routine 
monitoring after the third subject is enrolled, followed by annual monitoring of 1- 
3 subjects until the study is closed to enrollment and subjects are no longer 
receiving study interventions that are more than minimal risk. 
 
The Safety Oversight Committee (SOC) will perform annual reviews on findings 
from the DCI Monitoring Team visit and additional safety and toxicity data 
submitted by the Principal Investigator. 
 
Additional monitoring may be prompted by findings from monitoring visits, 
unexpected frequency of serious and/or unexpected toxicities, or other concerns 
and may be initiated upon request of DUHS and DCI leadership, the CPC, the 
Safety Oversight Committee (SOC), , the Principal Investigator, the Duke Clinical 
Trials Quality Assurance (CTQA) office or the IRB. All study documents must be 
made available upon request to the DCI Monitoring Team and other authorized 
regulatory authorities, which may include but is not limited to the National 
Institute of Health, National Cancer Institute.. Every reasonable effort will be 
made to maintain confidentiality during study monitoring. 


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11.0 STUDY DESIGN AND ANALYSIS 
 
11.1 Primary Objectives: 
10.1.1 Safety: Evaluate the safety of HLA-haploidentical DLI combined 
with conventional induction and consolidation chemotherapy in terms of 
unacceptable toxicity as defined in section 7.0. 
 
A maximum of 30 subjects will be consented for a maximum of 21 
evaluable subjects accrued to this protocol over a period of 2 years. 
Safety will be evaluated by the number of subjects with unacceptable 
toxicity as defined by any of the following: 
 
i. Grade III or IV aGVHD of the gut or liver or Grade IV aGVHD of 
the skin lasting > 7 days; 
 
ii. Grade IV CTCAE toxicity attributable to DLI (e.g. infusion 
reaction, as opposed to Grade IV CTCAE toxicity from 
chemotherapy) and lasting >7 days 
 
iii. Treatment-related mortality (TRM), keeping in mind that 
anticipated mortality from standard induction chemotherapy in 
the elderly ranges from 11% for subjects 55-65 years-old with 
ECOG 0 to 50% for subjects older than 75 years with ECOG 2 
[1]. 
 
Simon’s optimal two stage design will be applied. These rules permit the 
study to be closed early if there is evidence that the true unacceptable 
toxicity rate is > 0.40. The stopping rules in the table below will also allow 
us to test the null hypothesis that the true toxicity rate is >0.40 against the 
alternative hypothesis that the true toxicity rate is < 0.20. The Type I and 
II error rates for this design are 0.15 and 0.2, respectively. Given that the 
true toxicity rate is 0.40 (0.20), the probability of stopping the trial at Stage 
1 to accept the null hypothesis is 0.7 (0.16). The significance level of this 
design is 0.15 and the power is 0.80. 
 
Stage 
Total 
Accrual 
Close study/therapy if number of subjects 
with unacceptable toxicity is > 
1 
11 
4 (45%) 
2 
21 
7 (33%) 
 
Rates of unacceptable toxicity will be calculated and monitored with the 
stopping rules in the table above. Toxicity in the other categories will be 
informally monitored and tabulated by Type and Grade, but they will not 
be used to determine tolerability of the procedure. 


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For purposes of toxicity monitoring, each patient will be followed for 
unacceptable toxicity until a toxic event occurs or until 8 weeks after last 
cell infusion, whichever comes first. Accrual will not be suspended while 
collecting data for the interim analyses. However, as soon as a boundary 
within a stage in the table above is crossed, the study will be closed to 
further accrual. This design and the above boundaries will constitute our 
stopping rules for safety. 
 
11.1.2 Efficacy: Evaluate the efficacy of HLA-haploidentical DLI infusion 
combined with conventional induction and consolidation chemotherapy in 
terms of donor-recipient chimerism and microchimerism. 
 
The assessment of efficacy will be conducted after collecting data for a 
maximum of 21 evaluable subjects. Our primary efficacy endpoint is the 
1-year DFS rate following adoptive transfer. Using the chi-square test, we 
will test the null hypothesis is the CR rate will be ≤0.20 against the true 
hypothesis that 1-year DFS rate is >0.45. With 21 patients, we can test 
this with approximately 84% power with one-sided alpha level of 0.05. 
Additional efficacy endpoints include the CR rate, overall response rate 
(CR + partial response), OS, and count recovery. CR and overall 
response rates will be calculated with one-sided 90% confidence interval. 
DFS and OS will be estimated using the method of Kaplan and Meier. All 
statistical analyses will be conducted in conjunction with our co- 
investigator, Zhiguo Li, Ph.D., Assistant Professor of Biostatistics and 
Bioinformatics. 
 
11.1.3 Geriatric assessment: Medians and frequencies will be used to 
describe the baseline characteristics of participants and performance on 
the CGA. Overall survival and associated 95% CI will be estimated as in 
Aim 1 and correlated with CGA measures. Cox proportional hazards 
models will be fit for each CGA measure as a predictor of OS, in 
unadjusted models and models controlling for age, gender, and ECOG 
score. We also will estimate the hazard ratios in adjusted Cox regression 
models for continuous variables. To assess the incremental impact of 
cognitive and physical function variables on predicting survival, we will 
use Integrated Discrimination Improvement as described for survival 
analysis by Chambless et al.[41] and implemented in the 
RiskPredictionParams SAS Macro (macro version 8, Chapel Hill, NC). 
The variables included in the model will be those associated with survival 
in our analysis and included in Kantarjian’s predictive model for early 
mortality[42]. Internal cross-validation of the model will be assessed using 
1000 bootstrap replicates implemented in the RiskPredictionParams SAS 
macro. Logistic regression analysis will be used to investigate 
relationships between baseline CGA and exploratory outcomes of 30-day 
mortality and CR. Competing risk modeling will be used to investigate a 
differential effect of impairment in CGA measures by cause of death[43]. 
 
For correlative studies, probe ID’s on Affymetrix U133A gene chip have 
been identified for the candidate cytokines and include: IL-6 (211000, 


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2055207, 204864, 204863, 205945, 212196), IL-1 (39402, 205067, 
10118, 208200, 201404, 216245), IL-2 (207849, 204116), TNF-α 
(211841, 211282, 210405, 211495, 211153, 207643, 207849), and CRP 
(207849, 204116). The mean value for each cytokine from the Luminex 
assay will allow us to identify patients with high or low levels of each 
cytokine, and relate them to genetic typologies. Correlations between the 
serum cytokine levels and mRNA gene expression level for the cytokines 
will be evaluated by Spearman correlation. Specifically, the range of 
genes will be related to the panel of cytokines. Statistical significance will 
be assessed controlling for Type-I error using Hochberg tests, which are 
less conservative relative to the more common Bonferroni corrections[44, 
45]. In order to reduce the dimensionality of the problem further, in follow- 
up tests, we will assess if factorization of the cytokines is feasible (using 
Principal Components Analysis (PCA)), and, if so, the resulting 
components will be related to the genetic typologies. We note that skew 
will likely be present in the cytokine panel which can impact the 
factorization above. We will assess skew, and, if necessary, transform the 
variables individually to bring about approximate normality All analyses 
will be conducted at a two-sided a-level of 0.05 using SAS statistical 
software, version 9.2 (SAS Institute Inc., Cary, NC). We will use 
Spearman’s correlation to assess the relationship between the biologic 
markers (serum cytokines and gene expression values) and clinical 
markers (each domain on the CGA and ECOG PS). While this work is 
exploratory and it could be argued that there is no need to adjust for 
multiple testing we will adjust p-values by the Hochberg method to control 
the Type-I error rate inherent in multiple testing[46]. All statistical 
analyses will be conducted in conjunction with our co-investigator, Zhiguo 
Li, Ph.D. 
 
11.2 Secondary Objectives: 
 
11.2.1 Evaluate incidence and severity of acute GVHD. 
 
In addition to monitoring the rate of grade III-IV aGVHD of the gut 
or liver and grade IV aGVHD of the skin as in 10.1.1, we will also 
monitor overall rates of GVHD. Rates will be calculated with one 
sided 85% confidence interval. 
 
11.2.2 Evaluate incidence and severity of other adverse events. 
 
We will monitor other adverse events as defined in sections 7.0 
and 9.0. Rates will be calculated with one sided 85% confidence 
interval. 
 
11.2.3 Evaluate efficacy with respect to disease response and survival. 
 
Additional efficacy endpoints include response rate, DFS, EFS, 
and OS. The response rate will be calculated with one sided 85% 


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confidence interval. DFS, EFS, and OS will be estimated using the 
method of Kaplan and Meier. 
 
11.2.4 Evaluate immune recovery. 
 
Immune reconstitution results will be tabulated and recorded. For 
the evaluation of recovery of immune function post-engraftment, we 
will use descriptive statistics of cytokine profiles, lymphocyte and 
NK enumeration and flow-based assays and make patient-specific 
plots of immune function parameters across time. These 
measurements will be performed prior to induction, prior to each 
round of consolidation, 8 weeks after the last cycle of consolidation, 
and every 3 months after treatment for up to 2 years. Specifically, 
we will: 
1. monitor leukocyte subsets using flow cytometry: 
· 
CD3+ 
· 
CD4+ 
· 
CD8+ 
· 
regulatory (CD4+, CD25+, CD62L+) 
· 
cytotoxic/late memory (CD8+, CD57+, CD28-) and activated 
(CD8+, HLADR+) T cells 
· 
naïve CD4+ T cells with L-selectin expression (CD4+, 
CD45RA+/CD45RO-, CD62L+) 
· 
gamma-delta T cells 
· 
B cells (CD19+, CD3-, CD16-, CD56-) 
· 
natural killer cells (NK) (CD3-, CD16+/CD56+, CD107+) 
· 
natural killer T cells (NKT) (CD3+, CD16+/CD56+, 
CD107+), 
· 
plasmacytoid dendritic cells (DCs) (CD123+, CD11c-) 
· 
myeloid DCs (CD123-, CD11c+) 
 
2. quantifiy recent thymic immigrants by the presence of TCR 
rearrangement excision circles (TREC) performed by real-time 
quantitative-PCR of DNA collected from an isolated fraction of 
CD31 T cells 
 
3. perform next generation sequencing of TCR gene 
rearrangements to analyze diversity in the TCR repertoires 
produced by the rearrangements of the variable region genes. 
 
4. in vitro assays of NK function (measure CD16 expression, 
intracellular CD107a degranulation and cytokine secretions of 
IFNy and TNFa after 4 hour co-culture with an effector:target ratio 
of 2:1) 
 
5. measure immunoglobulin levels as a function of B-cell activity 
and recovery 


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6. measure cytokine levels, particularly IL1, IL1-beta, IL2, IL6, IL8, 
IL15, IL21, IFN-gamma, TNF-alpha, TGF-beta, CRP 
 
7. microchimerism monitoring to determine the level of donor cells 
(as well as the presence of any pre-existing maternal-fetal 
microchimerism) 
 
8. KIR typing to determine the effect of KIR ligand mismatch 
 
9. PD1/PDL1/PDL2 expression (marker of T cell exhaustion) 
 
 
11.2.5 Evaluate hematopoietic recovery. 
 
Time to neutrophil and platelet recovery will be reported using 
descriptive statistics. Time to neutrophil recovery is defined 
according to the Center for International Blood and Marrow 
Transplant Research (CIBMTR) reporting guidelines. This is 
defined as the date of the first of three consecutive laboratory 
values where the ANC ≥ 500/μl. If daily laboratory values were 
not obtained, ANC recovery is defined as three consecutive 
laboratory values drawn more than a day apart as long as the 
ANC remains ≥ 500/μl. The CIBMTR defines the time to platelet 
recovery as the date of the first of three consecutive laboratory 
values obtained on different days where the platelet count was > 
20,000/μl without transfusion. 
 
11.3 Subgroup analysis: 
Subgroup analysis will be conducted based on age (55-70 vs >70), sex, WHO 
classification, relationship between donor and recipient, pre-existing maternal- 
fetal microchimerism in mother-child pairs, presence of post-infusion donor 
chimerism and microchimerism, HLA mismatch, and KIR-ligand mismatch. 
 
12.0 ANTICIPATED TOXICITY OF DLI PROCEDURE 
 
12.1 GVHD 
Although GVHD is a common complication of DLI, given the absence of GVHD in 
a similar study by Guo et al.[6], we do not anticipate any GVHD in our study. This 
is because unlike a traditional transplant in which that patient engrafts with donor 
cells, which then go on to cause GVHD, we do not expect long-term engraftment, 
and therefore donor cells should not persist long enough to cause GVHD. 
 
12.2 Infections 
Although infections are a common complication of hematopoietic stem cell 
transplantation and donor lymphocyte infusion, we do not expect any of the 
procedures specifically associated with DLI to increase the risk of infection 
beyond that associated with induction and consolidation chemotherapy. 


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12.3 Infusion Reaction/Engraftment Syndrome 
Patients may experience reactions to the infusion itself including fever, chills, skin 
rash, pulmonary infiltrates, diarrhea, hepatic dysfunction, renal dysfunction, or 
confusion. Any such reaction would be transient and we would respond by 
slowing the infusion as per 6.3.4. Steroids, tocilizumab, acetaminophen, and 
intravenous fluids may also be administered in the case of such a reaction. 
 
12.4 Risk of sensitization 
Infusion of haploidentical cells may result in alloimmunization of the donor; i.e., 
sensitization, which may make engraftment after allogeneic hematopoietic stem 
cell transplantation more difficult, if such a therapy were planned later. However, 
as an institution, we have considerable experience overcoming sensitization and 
alloimmunization in the allogeneic transplant situation, and we do not anticipate 
significant problems with engraftment should an allogeneic transplantation be 
needed in the future. 
13.0 DRUG INFORMATION 
13.1Cytarabine (ara-C) 
13.1.1 Source and Pharmacology: Cytarabine for Injection USP, commonly 
known as ara-C, an antineoplastic for intravenous, intrathecal, or 
subcutaneous administration, contains sterile lyophilized cytarabine (1- 
β-D-Arabinofuranosylcytosine). Cytarabine is an odorless, white to off- 
white, crystalline powder which is freely soluble in water and slightly 
soluble in alcohol and in chloroform. Cytarabine is a synthetic 
nucleoside which differs from the normal nucleosides cytidine and 
deoxycytidine in that the sugar moiety is arabinose rather than ribose or 
deoxyribose. 
 
13.1.2 Formulation and Stability: Cytarabine is rapidly metabolized and is 
not effective when taken orally; less than 20% of the orally administered 
dose is absorbed from the gastrointestinal tract. Following rapid 
intravenous injection of cytarabine labeled with tritium, the 
disappearance from plasma is biphasic. There is an initial distributive 
phase with a half-life of about 10 minutes, followed by a second 
elimination phase with a half-life of about 1 to 3 hours. After the 
distributive phase, more than 80% of plasma radioactivity can be 
accounted for by the inactive metabolite 1-β-D-Arabinofuranosyluracil 
(ara-U). Within 24 hours, about 80% of the administered radioactivity 
can be recovered in the urine, approximately 90% of which is excreted 
as ara-U. Relatively constant plasma levels can be achieved by 
continuous intravenous infusion. After subcutaneous or intramuscular 
administration of cytarabine labeled with tritium, peak plasma levels of 
radioactivity are achieved about 20 to 60 minutes after injection and are 
considerably lower than those after intravenous administration. 
 
13.1.3 Supplier: Commercial Supply. 


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13.1.4 Toxicity: Because cytarabine is a bone marrow suppressant, anemia, 
leukopenia, thrombocytopenia, megaloblastosis, and reduced 
reticulocytes can be expected as a result of administration of 
cytarabine. The severity of these reactions are dose and schedule 
dependent. Cellular changes in the morphology of bone marrow and 
peripheral smears can be expected. Following 5-day constant infusions 
or acute injections of 50 to 600 mg/m2, white cell depression follows a 
biphasic course. Regardless of initial count, dosage level, or schedule, 
there is an initial fall starting the first 24 hours with a nadir at days 7 to 
9. Viral, bacterial, fungal, parasitic, or saprophytic infections, in any 
location in the body may be associated with the use of cytarabine alone 
or in combination with other immunosuppressive agents following 
immunosuppressant doses that affect cellular or humoral immunity. 
These infections may be mild, but can be severe and at times fatal. 
 
13.1.5 Route of Administration: IV over 5 to 7 days. 
 
 
13.2 Idarubicin 
13.2.1 Source and Pharmacology: Idarubicin HCl Injection contains 
idarubicin hydrochloride and is a sterile, semi-synthetic, preservative- 
free solution antineoplasticanthracycline for intravenous use. 
 
Idarubicin HCl is a DNA-intercalating analog of daunorubicin which has 
an inhibitory effect on nucleic acid synthesis and interacts with the 
enzyme topoisomerase II. The absence of a methoxy group at position 
4 of the anthracycline structure gives the compound a high lipophilicity 
which results in an increased rate of cellular uptake compared with 
other anthracyclines. 
 
 
13.2.2 Formulation and Stability: Idarubicin HCl Injection is a sterile, red- 
orange, isotonic parenteral preservative-free solution, available in 5 mL 
(5 mg), 10 mL (10mg) and 20 mL (20 mg) single-use-only vials. Each 
mL contains idarubicin HCI 1 mg and the following inactive ingredients: 
glycerin 25 mg and water for injection q.s. Hydrochloric acid is used to 
adjust the pH to a target of 3.5. 
Pharmacokinetic studies have been performed in adult leukemia 
patients with normal renal and hepatic function following intravenous 
administration of 10 to 12 mg/m2 of idarubicin daily for 3 to 4 days as a 
single agent or combined with cytarabine. The plasma concentrations of 
idarubicin are best described by a two or three compartment open 
model. The elimination rate of idarubicin from plasma is slow with an 
estimated mean terminal half-life of 22 hours (range, 4 to 48 hours) 
when used as a single agent and 20 hours (range, 7 to 38 hours) when 
used in combination with cytarabine. The elimination of the primary 
active metabolite, idarubicinol, is considerably slower than that of the 
parent drug with an estimated mean terminal half-life that exceeds 45 


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Chemo with Adoptive Haplo DLI 
 
 
 
 
hours; hence, its plasma levels are sustained for a period greater than 8 
days. 
 
13.2.3 Supplier: Commercial Supply. 
13.2.4 Toxicity: Idarubicin is intended for administration under the 
supervision of a physician who is experienced in leukemia 
chemotherapy. Idarubicin is a potent bone marrow suppressant. 
Idarubicin should not be given to patients with pre-existing bone 
marrow suppression induced by previous drug therapy or 
radiotherapy unless the benefit warrants the risk. 
 
Severe myelosuppression will occur in all patients given a 
therapeutic dose of this agent for induction, consolidation or 
maintenance. Careful hematologic monitoring is required. Deaths 
due to infection and/or bleeding have been reported during the 
period of severe myelosuppression. Facilities with laboratory and 
supportive resources adequate to monitor drug tolerability and 
protect and maintain a patient compromised by drug toxicity should 
be available. It must be possible to treat rapidly and completely a 
severe hemorrhagic condition and/or a severe infection. 
 
Pre-existing heart disease and previous therapy with anthracyclines 
at high cumulative doses or other potentially cardiotoxic agents are 
co-factors for increased risk of idarubicin-induced cardiac toxicity 
and the benefit to risk ratio of idarubicin therapy in such patients 
should be weighed before starting treatment with idarubicin. 
Myocardial toxicity as manifested by potentially fatal congestive 
heart failure, acute life-threatening arrhythmias or other 
cardiomyopathies may occur following therapy with idarubicin. 
Appropriate therapeutic measures for the management of 
congestive heart failure and/or arrhythmias are indicated. 
 
Cardiac function should be carefully monitored during treatment in 
order to minimize the risk of cardiac toxicity of the type described 
for other anthracycline compounds. The risk of such myocardial 
toxicity may be higher following concomitant or previous radiation to 
the mediastinal-pericardial area or in patients with anemia, bone 
marrow depression, infections, leukemic pericarditis and/or 
myocarditis. While there are no reliable means for predicting 
congestive heart failure, cardiomyopathy induced by anthracyclines 
is usually associated with a decrease of the left ventricular ejection 
fraction (LVEF) from pretreatment baseline values. Since hepatic 
and/or renal function impairment can affect the disposition of 
idarubicin, liver and kidney function should be evaluated with 


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conventional clinical laboratory tests (using serum bilirubin and 
serum creatinine as indicators) prior to and during treatment. In a 
number of Phase III clinical trials, treatment was not given if 
bilirubin and/or creatinine serum levels exceeded 2 mg%. However, 
in one Phase III trial, patients with bilirubin levels between 2.6 and 
5 mg% received the anthracycline with a 50% reduction in dose. 
Dose reduction of idarubicin should be considered if the bilirubin 
and/or creatinine levels are above the normal range. 


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tation. Proc Natl Acad Sci U S A, 2012. 109(7): p. 2509-14. 
Oncol, 2009. 
J Clin 
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A new method of classifying prognostic comorbidity in 
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Several methods to assess 
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f
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ly
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cer patient. J Gerontol A Biol Sci Med Sci, 2005. 60(6): p. 798- 
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Rao, A.V., et al., 
Nat Med, 2013. 
(3): p. 372-7. 
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patients (age 70 years or older) with acute myeloid leukemia. Blood, 2010. 
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Benjamini Y, H.Y., 
51(2): p. 524-32. 
1995. 
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Loubiere, L.S., et al., Maternal microchimerism in healthy adults in 
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. 
tensive chemotherapy does not benefit most older 
 
 
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lymphocytes, monocyte/macrophages and NK cells. Lab Invest, 2006. 86(11): 
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mans. Curr Opin Or
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i
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e
9
ri
.
ted 
(
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4
a
):
te
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3
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9
a
-
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4
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7
ig
. 
ens in 
 
 
 
33. 
microchimerism in cord blood mediates a graft-versus-leukemia effect in cord 
Age-specific differences in oncogenic pathway dysregulation 
and anthracycline sensitivity in patients with acute myeloid leukemia. 
34. 
Colvin, G.A., e
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(
l.
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8
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ft
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6.
ent haploidentical cellular immunotherapy for 
 
 
37. 
38. 
2
N
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:
io
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ematopoietic and Lymphoid Tissues. 
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inal studies: development and validation. J Chronic Dis, 1987. 40(5): p. 
Quantitative assessment of T cell repertoire recovery 
after hematopoietic stem cell transplantation. 
19 
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ia
.P
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6
e
0
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.
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G
C
.
li
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u
O
i,
ncol, 2011. 29(10): p. 1290-6. 
43. 
1
L
Bi
1
u
o
n
6
m
n
(2
,
e
M
2
tr
)
.
i
:
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eil, Applying Cox regression to competing risks. 
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powerful approach to multiple testing. 
Implementing a geriatric assessment in cooperative group


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Chemo with Adoptive Haplo DLI 
 
 
45. 
Benjamini Y, H.Y., On the adaptive control of the false discovery fate in multiple 
1(1): p. 43-6. 
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.
ependent statistics. Journal of Educational & Behavioral 
 
 
46. 
Rothman, K.J., 
25(1): p. 60-83. 


Protocol Version: 7/10/2017 
Page 36  of 42 
 
 
14.0 APPENDIX 
I. RECIPIENT SCHEDULE OF EVENTS TABLE* 
TEST1 
At entry 
During Therapy 
and Recovery2 
At Count Recovery after 
IND1 or IND2 
After Finishing All Therapies6 Relapse 
Weight (Epic) 
X 
Daily 
As clinically indicated 
At 8 weeks and q3months x 2 
years 
Height (Epic) 
X 
BSA Epic) 
X 
At the beginning of 
treatment 
As clinically indicated 
PS (Epic) 
X 
As clinically indicated 
At 8 weeks and q3months x 2 
years 
Comprehensive Geriatric Assessment 
(Research) 
X 
- 
- 
At 8 weeks 
ABC / DIFF (Epic) 
X 
ABC daily and ABC 
with diff daily when 
WBC reaches 
500/uL until ANC 
>1500/ul for 3 days 
As clinically indicated 
Every 2 weeks or as clinically 
indicated 
Serum 
BUN/Cr/CA/MG/PO/AST/ALT/Bili/TP/ 
ALB/K/NA/CL /CO3/Glu/CMV viral 
titre 
(Epic) 
X 
Weekly and as 
clinically indicated 
As clinically indicated 
At 8 weeks after last therapy 
and every 3 months for 2 years 
HLA antibody detection (serum 
preferred) 
X 
X 
At 8 weeks after last therapy 
Serum quantitative Beta-HCG testing 
for females 
(Epic) 
X 
- 
- 
- 
Bone marrow aspirate and biopsy 
with appropriate special studies (i.e. 
restaging/disease evaluation) (Epic) 
X 
Day 14 after 
induction5 
at hematologic recovery 
after induction (4-6 weeks) 
- 
Cardiopulmonary Testing3 
(Epic) 
X 
Immune Reconstitution Panel (Epic) 
X 
- 
X 
At 8 weeks after last therapy 
and every 3 months for 2 years 
Minimal Residual Disease 
(MDR)(Peripheral Blood) (Research) 
X 
X 
At 8 weeks after last therapy 
and every 3 months for 2 years 
X 
Minimal Residual Disease (MRD) 
(Bone Marrow aspirate4 (Research) 
X 
X (when BM bx is done to 
assess disease) 
X 


Protocol Version: 7/10/2017 
Page 37  of 42 
 
 
Chemo with Adoptive Haplo DLI 
 
KIR typing (Research) 
X 
NK lysis assay 
(Research8) 
X 
X 
At 8 weeks after last therapy 
X 
TEST1 
At entry 
During Therapy 
and Recovery2 
At Count Recovery after 
IND1 or IND26 
After Finishing All Therapies7 Relapse 
Microchimerism 
(Research) 
X 
X 
At 8 weeks after last therapy 
and every 3 months for 2 years 
X 
TCR sequencing 
(Research) 
X 
- 
X 
At 8 weeks after last therapy 
X 
Biomarkers of frailty 
(Research) 
X 
X 
At 8 weeks after last therapy 
PD1/PDL1/PDL2 expression 
(Research) 
X 
X 
At 8 weeks after last therapy 
X 
Cytokine Release Syndrome 
(Research) 
To be drawn before 
infusion and 2 days 
after infusion for 
IND1, IND2, and 
CON2 as applicable 
Toxicity monitoring 
(Grade 3-4) 
(Epic) 
Daily 
Qo wk 
Qo wk till 8 weeks after last 
therapy and then q 4 weeks for 
12 more weeks 
Acute GVHD monitoring 
(Epic) 
Daily 
Qo wk 
Qo wk till 8 weeks after last 
therapy and then q 4 weeks for 
12 more weeks 
1 Tests at entry are recommended to be done within 1 week before initiating therapy; however if there are no sig. change in patient’s status and tests are less than 
4 weeks old then they are acceptable; exceptions include bone marrow aspirate and biopsy and cardiopulmonary testing (acceptable if within 8 weeks) 
2 Therapy and recovery refer to the period while the patient is receiving induction (IND1 or IND2) or consolidation chemotherapy until count recovery and discharge 
3 For cardiopulmonary testing, refer to section 5.1. 
4If patient already had a bone marrow biopsy and this was not collected, ok to skip 
5 Per investigator discretion 
6 Count Recovery would be considered when the ANC count is >1000/ul 
7 If any subjects do not complete all the therapies (i.e. Induction 1/2, Consolidation 1 and 2), they will be followed for survival, but do not need to complete any 
listed assessments 
8Any leftover cells at q3months after completing therapy will be used to run NK Lysis, TCR sequencing, and PD1/PDL1/PDL2 expression research samples. 
Additional blood will not be drawn for this testing. 
*Other labs may be performed/followed per institutional policy 


Protocol Version: 7/10/2017 
Page 38  of 42 
 
 
II. DONOR SCHEDULE OF EVENTS TABLE 
Test 
At Entry 
History, physical (Epic) 
X 
ABC / DIFF, Serum BUN/Cr/CA/MG/PO/AST/ALT/Bili/TP/ALB/K/NA 
/CL/CO3/Glu/CMV viral titre (Epic) 
X 
Serum quantitative Beta-HCG for females (Epic) 
X 
CXR (AP/lateral), EKG (12 lead) (Epic) 
X 
FACT labs* (Epic) 
X 
KIR typing (Research) 
X 
Microchimerism (Research) 
TCR sequencing (Research) 
X 
*See appendix for standard FACT (Foundation for Accreditation of Cellular Therapy) labs. FACT labs must be 
drawn and final test results available within 7 days prior to infusion into the patient. 
 
III. GVHD Grading Criteria 
 
GvHD 
Grade value 
for overall 
scoring: 
+0 
+1 
+2 
+3 
+4 
Skin 
Maculo-papular 
eruption over <25% 
of body area 
Maculo-papular 
eruption over 25- 
50% of body area 
Generalized 
erythroderma 
Generalized 
erythroderma 
with bullous 
formation and 
often with 
desquamation 
Liver 
Bilirubin ≥2-<3 
mg/dl; SGOT 150- 
750 IU 
Bilirubin ≥3-<6 
mg/dl 
Bilirubin ≥6- 
<15 mg/dl 
Bilirubin ≥15 
mg/dl 
Gut 
Diarrhea >500- 
1000 ml/day 
Diarrhea >1000- 
1500 ml/day 
Diarrhea 
>1500-2000 
ml/day 
Diarrhea >2000 
ml/day; or 
severe 
abdominal pain 
with or without 
ileus 
Overall GvHD Grade 
Date 
Scored 
Grade value 
for overall 
scoring 
Skin 
Liver 
Gut 
ECOG 
Performance 
I 
+1 to +2 
0 
0 
0 
II 
+1 to +3 
+1 
And/or 
+1 
0 - 1 
III 
+2 to +3 
+2 to +3 
And/or 
+2 to +3 
2 - 3 
IV 
+2 to +4 
+2 to +4 
And/or 
+2 to +4 
3 - 4 


Protocol Version: 7/10/2017 
Page 39  of 42 
Chemo with Adoptive Haplo DLI 
 
 
IV Toxicity Summary Form 
 
Toxicity 
Grade 
3 
4 
5 
 
Allergy/Immunology 
Allergic 
Symptomatic bronchospasm, 
Anaphylaxis 
Death 
reaction/hypersen 
requiring parenteral 
sitivity (including 
medication(s), with or without 
drug fever) 
urticaria; allergy-related 
edema/angioedema 
Cardiovascular (Arrhythmia) 
Ventricular 
arrhythmia 
Symptomatic and requiring 
treatment 
Life-threatening 
(e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiovascular/Arr 
Symptomatic and requiring 
Life-threatening (e.g., 
Death 
ythmia – Other 
treatment of underlying cause 
arrhythmia associated 
Specify: 
with CHF, hypotension, 
syncope, shock) 
Cardiovascular (General) 
hypotension 
Requiring therapy and sustained 
medical attention, but resolves 
without sequelae 
Shock 
Death 
Coagulation 
Thrombotic 
Evidence of RBC destruction with 
Evidence of RBC 
Death 
microangiopathy 
creatinine (>3 x ULN) not 
destruction with renal 
(e.g., TTP or HUS) requiring dialysis 
failure requiring dialysis 
+/- encephalopathy 
Gastrointestinal 
Diarrhea 
(Autologous 
subjects) 
Increase of ≥ 7 stools/day, or 
incontinence, or need for 
parenteral support for 
dehydration 
Physiologic 
consequences requiring 
intensive care; or 
hemodynamic collapse 
Death 
Stomatitis/ 
Painful erythema, edema, or 
Severe ulceration 
Death 
mucositis 
ulcers preventing swallowing or 
requiring prophylactic 
requiring hydration or parenteral 
intubation or resulting in 
(or enteral) nutritional support 
documented aspiration 
pneumonia 
Vomiting 
≥6 episodes in 24 hours over 
pretreatment; or need for IV fluids 
Requiring parenteral 
nutrition; or physiologic 
consequences requiring 
Death 
intensive care; 
hemodynamic collapse 
Hemorrhage 
Hematuria 
Persistent gross bleeding or 
clots; may require catheterization 
or instrumentation, or transfusion 
Open surgery or necrosis 
or deep bladder 
ulceration 
Death 


Protocol Version: 7/10/2017 
Page 40  of 42 
Chemo with Adoptive Haplo DLI 
 
 
 
Other (specify site) Requiring transfusion 
Catastrophic bleeding, 
requiring major non- 
elective intervention 
Death 
Infection/Febrile Neutropenia [Enter type/species/site at bottom of this block] 
Infection 
(documented 
clinically or 
microbiologically) 
with grade 3 or 4 
neutropenia (ANC 
< 1.0 x 109/L) 
Present 
Life-threatening sepsis 
(e.g., septic shock) 
Death 
Febrile 
neutropenia (fever 
of unknown origin 
without clinically or 
microbiologically 
documented 
infection) 
Present 
Life-threatening sepsis 
(e.g., septic shock) 
Death 
Infection without 
febrile neutropenia 
Severe, systemic infection, 
requiring IV antibiotic or 
antifungal treatment, or 
hospitalization 
Life-threatening sepsis 
(e.g., septic shock) 
Death 
Infection Type: 
Species: 
Site: 
 
 
Event 
Date 
Toxicity 
Grade 
2 
3 
4 
5 
Neurology 
Neuropathy - Cranial 
Present, interfering 
with ADL 
Life-threatening, 
disabling 
Death 
Neuropathy – Motor 
Objective weakness 
interfering with ADL 
Paralysis 
Death 
Neuropathy – 
Sensory 
Sensory loss or 
paresthesia 
interfering with ADL 
Permanent sensory 
loss that interferes 
with function 
Death 
Seizure(s) 
Seizure(s) 
self-limited 
and 
consciousnes 
s is preserved 
Seizure(s) in which 
consciousness is 
altered 
Seizures of any 
type which are 
prolonged, 
repetitive, or 
difficult to control 
Death 
Pulmonary 
Carbon monoxide 
diffusion capacity 
(DLco) 
≥25% - < 50% of 
pretreatment or 
normal value 
<25% of 
pretreatment or 
normal value 
Death 
Dyspnea (shortness 
of breath) 
Dyspnea at normal 
level of activity 
Dyspnea at rest or 
requiring ventilator 
support 
Death 


Protocol Version: 7/10/2017 
Page 41  of 42 
Chemo with Adoptive Haplo DLI 
 
 
 
Hypoxia 
Decreased O2 
saturation at rest, 
requiring 
supplemental oxygen 
Decreased O2 
saturation, 
requiring pressure 
support (CPAP) or 
assisted ventilation 
Death 
Pneumonitis/pulmon 
Radiographic 
Radiographic 
Radiographic 
Death 
ary infiltrates 
changes and 
changes and 
changes and 
requiring 
requiring oxygen 
requiring assisted 
steroids or 
ventilation 
diuretics 
Renal/Genitourinary 
Creatinine 
>3 – 6 x ULN 
>6 x ULN 
Death 
Renal failure 
Requiring dialysis, 
but reversible 
Requiring dialysis 
and irreversible 
Death 
Secondary Malignancy 
Secondary 
Malignancy - Other 
Specify type: 
(excludes metastatic 
tumors) 
present 
Death 
VOD 
Weight gain 
≥10% or as ascities 
≥10% or fluid 
retention resulting 
in pulmonary failure 
Death 
Bilirubin 
>3 -10 x ULN 
>10 x ULN 
Death 
Hepatic pain 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
disabling 
Death 


Protocol Version: 7/10/2017 
Page 42  of 42 
Chemo with Adoptive Haplo DLI 
 
 
V. Comprehensive Geriatric Assessment 
 
The Comprehensive Geriatric Assessment is provided as a separate attachment. 
 
VI. FACT Donor Test Requirements 
 
Testing for the following infectious disease is performed within 30 days of donation for PBSC, Bone Marrow, 
and Directd Granulocyte donation, and within 7 days for DLI, NK Cell donation, on blood samples drawn on 
stem cell or other cellular therapy. Donors donating over a time period in excess of 30 days will have these 
tests repeated every 30 days (or 7 days if DLI or NK Cell). Unrelated cord blood donors are tested by the cord 
blood bank at the time of procurement of the cord blood donation. This information is provided to the 
transplant center through the NMDP data systems. 
 
The testing panel for autologous and allogeneic adult donors not on IVIG supplementation (within 6 months) of 
the donation is listed below. 
1. Hepatitis B Surface Antigen (HBsAg)1,2 
2. Hepatitis B Core Antibody (Anti-HBc)1 
3. Hepatitis C Virus Antibody (Anti-HCV)1 
4. HIV antibody (Anti-HIV 1/2/0)1,2 
5. HIV1/2 Nucleic Acid Testing (NAT)1,2 
6. Hepatitis C Virus NAT1,2 
7. Hepatitis B Virus NAT1,2 
8. HTLV I/II Antibodies Serum1,3 
9. CMV Immune Screen (Anti-CMV total antibodies)1,3 
10. CMV NAT-(if CMV positive Peds Only)2 
11. Syphilis-Treponemapallidum antibody for initial screen 
12. If Syphilis screen is reactive, a confirmatory test is performed using the RPR Card Test System 
13. West Nile Virus NAT1 
14. Trypanosoma Cruzi (Chagas Disease) 
15. ABO/Rh (Two separate sample collections i.e. NTL Panel and day 1 collection type and screen) 
16. Red blood cell antibody screen 
1FDA Required testing 
2FDA recommended. Obtain in all patients<6 months of age or on IVIG or unable to make endogenous 
antibody 
3FDA required for products containing high WBC content (i.e. granulocytes, DLI, and mobilized 
peripheral blood) 

ICF_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Study title: 
Adoptive Transfer of Haplo-identical DLI for AML 
and MDS 
Principle Investigator: 
Anthony Sung, MD 
Clinical Trials.Gov #: 
NCT02046122 
Document reference date: 04Jan2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol ID: Pro00043247 
Continuing Review Before: 1/30/2019 
Reference Date: 1/4/2018 
Page 1  of 12 
Subject Initials  
 
 
 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
You are being asked to take part in this research study because you have been diagnosed with high risk 
acute myeloid leukemia (AML), a cancer of the blood and bone marrow (the spongy tissue inside bones 
where blood cells are made) or myelodysplastic disease (MDS), also called pre-leukemia or smoldering 
leukemia, a group of diseases in which the bone marrow does not make enough healthy blood cells. 
 
Research studies are voluntary and include only people who choose to take part. Please read this 
consent form carefully and take your time making your decision. As your study doctor or study staff 
discusses this consent form with you, please ask him/her to explain any words or information that you 
do not clearly understand. We encourage you to talk with your family and friends before you decide to 
take part in this research study. The nature of the study, risks, inconveniences, discomforts, and other 
important information about the study are listed below. 
 
Please tell the study doctor or study staff if you are taking part in another research study. 
Anthony Sung, MD and his study team will conduct the study. 
WHO WILL BE MY DOCTOR ON THIS STUDY? 
If you decide to participate, Dr. Anthony Sung or one of his associates will be your doctor for the study 
and will be in contact with your regular health care provider throughout the time that you are in the 
study and afterwards, if needed. 
 
WHY IS THIS STUDY BEING DONE? 
The purpose of this study is to determine how safe, tolerable, and effective it is to combine donor 
lymphocyte infusions (DLIs) with the standard chemotherapy treatment for AML, which includes 
cytarabine and idarubicin. In DLI, blood cells (lymphocytes) from a donor (for example, parent, child) 
are infused into a patient, with the goal of helping the immune system attack and kill cancer cells. This 
has been suggested by some studies in the medical literature and is the reason we are doing this study. 
However, it has not been proven that outcomes are improved with DLI and the procedure is considered 
investigational. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 30 donors and 30 recipients, or up to 60 people total, will take part in this study at Duke. 
 
WHAT IS INVOLVED IN THE STUDY? 
Screening 
If you agree to be in this study, you will be asked to sign and date this consent form. 


Protocol ID: Pro00043247 
Continuing Review Before: 1/30/2019 
Reference Date: 1/4/2018 
Page 2  of 12 
Subject Initials  
 
 
 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
You will need to undergo the following exams, tests, or procedures to find out if you can be in the study. 
Some are part of regular leukemia-related care and may be performed even if you do not participate in 
the study. 
• 
Complete medical history, complete physical examination, vital signs, height, and weight 
• 
Comprehensive Geriatiric Assessment (CGA): An assessment of your ability to do daily tasks 
and mental processing. This questionnaire asks you about your daily activities, your health, 
your mood, your social activities and support. 
• 
Bone marrow sampling and analysis. 
• 
Blood Draw to perform the following tests: 
o Routine blood tests. 
o Serum pregnancy testing if you are a female of child bearing potential. 
• 
If the study doctor thinks it is necessary, you may have a pulmonary function test (PFT) to test 
how your lungs are functioning 
 
There may be reasons why you cannot be in the study. The study doctor or study staff will discuss these 
reasons with you. 
 
Study Drugs 
In this study, you will first receive standard chemotherapy for your AML or high risk MDS. The first 
cycle is called an “induction.” During induction, you will receive cytarabine + idarubicin: cytarabine is 
given for 7 days of continuous infusion in the vein and idarubicin is given in the vein as a short infusion 
on days 1, 2 and 3. This part is standard therapy. This will be followed by a DLI or donor lymphocyte 
infusion. The DLI procedure is the collection of white blood cells from a donor through a collection 
process known as leukapheresis. This part is new. Cells for DLI will be collected from a related donor 
and then infused into you either directly after being collected or frozen and then thawed to be infused 
into you at a later date. The purpose of our study is to see if adding a DLI will help improve responses as 
well as the safety and tolerability of adding DLI. 
 
If you are over 80 years of age, you will receive cytarabine for only 5 days of continuous infusion in the 
vein and idarubicin in the vein as a short infusion on days 1 and 2 followed by a DLI. 
 
If after 6 to 12 weeks after beginning induction your disease has been not been successfully treated, you 
will receive a second induction with the exact chemotherapy regimen given to you with your 1st 
induction followed by a DLI. There is a possibility that you may receive a second induction of the exact 
chemotherapy regimen without a DLI. Your study doctor will discuss this with you further at that time 


Protocol ID: Pro00043247 
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Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
If your disease still has not been successfully treated, you will come off study and be treated at the 
discretion of your physician. 
 
If after your first or second induction your doctors cannot find any evidence of disease, known as being 
“in remission,” you will move onto post-remission chemotherapy or “consolidation”. Consolidation is 
standard for the treatment of AML or high risk MDS and helps prevent the disease from returning 
(relapse). For consolidation, you will receive 2 courses of cytarabine, given twice daily at 12 hour 
intervals administered over about a week, followed by a DLI after the second course, assuming there are 
enough cells collected from your donor. Again, cytarabine is standard chemotherapy, while the DLI is 
new. 
 
The goal of giving DLI with induction is to help induce remission. However, in some cases, induction 
has to be given on an urgent basis to treat disease, and there may not be time to identify and evaluate a 
donor and collect cells for DLI before induction. In these cases, induction will be given as per clinical 
need, and DLI will be given with each course of consolidation. While giving DLI with consolidation 
would not carry the potential benefit of improving response rates and inducing remission, DLI with 
consolidations potentially may still improve disease-free and overall survival. There is no anticipated 
difference in the risks of giving DLI with induction + second consolidation vs. DLI with first and second 
consolidation. 
 
Study Procedures and tests 
The following procedures and tests will be performed: 
• 
Complete medical history, complete physical examination, vital signs, height, weight, and 
blood counts daily during therapy and recovery, 8 weeks after last therapy and every 3 months 
for 2 years (this is part of standard therapy). 
• 
Comprehensive Geriatiric Assessment (CGA): An assessment of your ability to do daily tasks 
and mental processing. A questionnaire about your daily activities, your health, your mood, 
your social activities and support (8 weeks after last therapy). 
• 
Bone marrow sampling and analysis approximately two weeks after the induction(s) and at 
hematologic recovery approximately 4 to 6 weeks after the induction(s) (this is part of standard 
therapy). 
 
• 
“Blood tests will be taken on selected days around the donor cell infusion to evaluate for 
cytokine release syndrome with DLI. We will use about 4-8 teaspoons of blood drawn from a 
vein by a needle-stick or through a central line each time you have these blood tests. 


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Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
• 
Special immune reconstitution blood tests, which evaluate how well your immune system is 
functioning at baseline and after chemotherapy (prior to beginning each next therapy, 8 weeks 
after last therapy and every 3 months for 2 years). We will use about 4-8 teaspoons of blood 
drawn from a vein by needle-stick or through a central line each time you have these blood 
tests. 
 
HOW LONG WILL I BE IN THIS STUDY? 
Your total time in the study will be approximately 3 years. 
 
WHAT ARE THE RISKS OF THE STUDY? 
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don't know all of the side effects that may happen. Side 
effects may be mild to very serious. Your health care team may give you medicines to help lessen side 
effects. Many side effects may go away soon after you stop taking cytarabine and idarubicin drug 
regimen. In some cases, side effects can be serious, long lasting, or may never go away. There is also a 
risk of death. 
 
You should talk to your study doctor right away about any side effects that you have while taking part in 
the study. It should not be administered to subjects who are pregnant or who have a history of increased 
sensitivity reaction to cytarabine or idarubicin. 
 
Drug-related risks 
Cytarabine can cause some or all of the following: 
Common 
• 
low white blood cell count with increased risk of infection 
• 
low platelet count with increased risk of bleeding 
• 
low red blood cell count (anemia) with symptoms like weakness, tiredness, shortness of breath 
• 
nausea 
• 
vomiting 
• 
stomach pain 
• 
tiredness (fatigue) 
• 
sores in mouth or on lips 
 
Less common 
• 
diarrhea 
• 
loss of appetite 
• 
rash 
• 
hair loss or thinning (may include face and body hair) 


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Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
• 
fever 
• 
muscle and bone aches 
• 
liver damage 
• 
blood clots and inflammation of the vein where the drug was given 
 
Rare 
• 
red or swollen eyes 
• 
sleepiness 
• 
muscle weakness 
• 
trouble walking 
• 
trouble writing 
• 
slurred speech 
• 
kidney damage 
• 
fetal changes that may lead to birth defects, prematurity, or serious illness in the newborn if you 
become pregnant while taking this drug 
• 
allergic reaction with itching, dizziness, trouble breathing, or swelling of the face, mouth, or 
throat 
• 
death due to infection, bleeding, or other causes 
 
At high doses, cytarabine can cause neurologic complications such as altered mental state, headaches, 
seizures, inflammation of the linings of the brain, dementia, weakness, numbness and tingling in 
extremities, nerve damage and uncoordinated muscle movement. Please tell your study doctor if you 
experience any of these symptoms. 
 
Idarubicin can cause some or all of the following: 
Common 
• 
decreased white blood cell count with increased risk of infection 
• 
decreased platelet count with increased risk of bleeding 
• 
nausea 
• 
vomiting 
• 
stomach pain 
• 
decreased appetite 
• 
sores in mouth or on lips 
• 
hair loss or thinning 
• 
skin rash 
 
Less common 
• 
darkening of nail beds 


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Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
• 
diarrhea 
• 
fever 
• 
abnormal blood tests which suggest that the drug is affecting the liver (Your doctor will discuss 
the importance of this finding, if any.) 
Rare 
• 
inflammation of the liver 
• 
heart damage with shortness of breath and swollen feet and ankles, which can happen months or 
years after treatment 
• 
irregular heartbeat 
• 
tumor lysis syndrome, kidney damage 
• 
pain, tingling, blistering, or peeling skin on palms and soles of feet 
 
Idarubicin may cause serious or life-threatening heart problems at any time during the study or months 
to years after the study has ended. Your doctor will order tests before and during the study to see if your 
heart is working well enough for you to safely receive idarubicin. These tests may include an 
electrocardiogram (ECG; test that records the electrical activity of the heart) and an echocardiogram 
(test that uses sound waves to measure your heart's ability to pump blood). Your doctor may tell you that 
you should not receive this medication if the tests show your heart's ability to pump blood has 
decreased. Tell your doctor if you have or have ever had any type of heart disease or radiation (x-ray) 
therapy to the chest area. Tell your doctor if you are taking or have ever received certain cancer 
chemotherapy medications such as daunorubicin (cerubidine), doxorubicin (Doxil), epirubicin (Ellence), 
mitoxantrone (Novantrone), cyclophosphamide (Cytoxan), or trastuzumab (Herceptin). If you 
experience any of the following symptoms, call your doctor immediately: shortness of breath; difficulty 
breathing; swelling of the hands, feet, ankles or lower legs; or fast, irregular, or pounding heartbeat.. 
 
Risks of Drug Infusions 
Cytarabine and idarubicin are to be given as an infusion through a vein. Common reactions to infusions 
include: flushing; shortness of breath; headache; chills; back pain; tightness in the chest; and low blood 
pressure. In most people, these reactions resolved over several hours to 1 day once the infusion was 
completed. In some people, the reaction stopped when the speed of the drug being given was slowed 
down. 
 
Risks of Donor Lymphocyte Infusions 
Graft-versus-host disease results from certain donor white blood cells (called lymphocytes) recognizing 
the host (patient) environment as being foreign, causing a reaction in which the donor cells may attack the 
recipient’s body. These lymphocytes may start an immunological reaction. This graft-versus-host 
reaction may affect the patient’s skin (in the form of a rash), the liver (by causing jaundice), and/or the 


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Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
gastrointestinal tract (gut) (by causing nausea, cramps and diarrhea). Most patients develop some degree 
of graft-versus-host disease but it is usually controllable with medications. 
 
However, some patients develop severe graft-versus-host reactions that can lead to death. Medications 
that suppress the immune system will be given to help prevent this complication. 
 
Transfusion of white blood cells can transmit infectious diseases to the recipient such as CMV 
(cytomegalovirus), hepatitis B and C and HIV (human immunodeficiency virus, which is the virus that 
causes acquired immunodeficiency syndrome [AIDS]). All donors are screened for these viruses, but 
there still remains a possibility that these infectious diseases could occur as a complication of receiving 
donor cells. There is a possibility of having a reaction to one of the solutions that is used to grow or 
process them. Signs of a transfusion reaction include a fever, rash, and difficulty with breathing, low 
blood pressure, or changes in your heart rate. You will be given medications prior to the infusion to help 
counteract these side effects and will be monitored closely during the infusion. 
 
The cells in an infusion (DLI) may cause the release of cytokines, chemicals in the body that produce a 
type of inflammatory response similar to that found in severe infection, including a significant decrease 
in blood pressure, fever and chills/shivering. You may feel unwell, as you do with a high fever. Deaths 
due to cytokine release syndrome have been reported. However, if treated appropriately, it is usually not 
dangerous. 
 
Risks of Drawing Blood 
Risks associated with drawing blood from your arm include momentary discomfort and/or bruising. 
Infection, excess bleeding, clotting, or fainting are also possible, although unlikely. 
 
Risks from Bone Aspiration 
A bone marrow aspiration is a procedure in which an area of the hip (either one hip or both hips) is 
numbed and a small sample of bone marrow is withdrawn. When the local anesthesia (numbing 
medication) is given, you may initially feel a burning sensation in your skin and bone surface for several 
seconds. During the procedure, you may temporarily feel pressure and/or pain of varying degrees. If 
necessary, you may ask your physician for additional local anesthesia or a medication to ease your 
stress. You also may experience bleeding, and/or bruising after the procedure is completed and you may 
experience soreness in the area for a few days afterwards. Rarely, infection can develop. 
 
Drug and Food Interactions 
For your safety, you must tell the study doctor or nurse about all the prescribed medical foods and drugs, 
herbal products, over-the-counter (OTC) drugs, vitamins, natural remedies, and alcohol that you are 


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Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
taking before you start the study and before starting to take any of these products while you are on the 
study. 
 
For Those of Reproductive Potential 
Female 
Being a part of this study while pregnant may expose the unborn child to significant risks, some of 
which may be currently unforeseeable. Therefore, pregnant women will be excluded from the study. If 
you are a woman of childbearing potential, a blood pregnancy test will be done (using 1 teaspoon of 
blood drawn from a vein by needle-stick), and it must be negative before you can continue in this study. 
If sexually active, you must agree to use two appropriate contraceptive measures for the duration of the 
study and for 1 month afterwards. Medically acceptable contraceptives include: (1) surgical sterilization 
(such as a tubal ligation or hysterectomy), (2) approved hormonal contraceptives (such as birth control 
pills, patches, implants or injections), (3) barrier methods (such as a condom or diaphragm) used with a 
spermicide, or (4) an intrauterine device (IUD). Contraceptive measures such as Plan B (TM), sold for 
emergency use after unprotected sex, are not acceptable methods for routine use. If you do become 
pregnant during this study or if you have unprotected sex, you must inform your study physician 
immediately. 
 
Male 
Your participation in this research may damage your sperm, which could cause harm to a child that you 
may father while on this study. Such harm may be currently unforeseeable. If you are sexually active, 
you must agree to use a medically acceptable form of birth control in order to be in this study and for 1 
month afterward. Medically acceptable contraceptives include: (1) surgical sterilization (such as a 
vasectomy), or (2) a condom used with a spermicide. Contraceptive measures such as Plan B (TM), sold 
for emergency use after unprotected sex, are not acceptable methods for routine use. You should inform 
your partner of the potential for harm to an unborn child.  She should know that if pregnancy occurs, 
you will need to report it to the study doctor, and she should promptly notify her doctor. 
 
There may be risks, discomforts, drug interactions or side effects that are not yet known. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
If you agree to take part in this study, there may be direct medical benefit to you such as disease 
remission, however, this cannot be guaranteed. We hope that in the future the information obtained 
from this study will benefit other people with leukemia and MDS. 
 
WHAT ALTERNATIVES ARE THERE TO PARTICIPATION IN THIS STUDY? 
Instead of being in this study, you have the following alternatives: 
• Receive cytarabine and idarubicin without participating in this study 


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Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
• Receive other chemotherapy combinations 
• Take part in another research study 
• You may choose to get comfort care only, also called palliative care. This type of care helps 
reduce pain, tiredness, appetite problems and other problems caused by the cancer. It does not 
treat the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and perhaps other options. 
 
WILL MY INFORMATION BE KEPT CONFIDENTIAL? 
Study records that identify you will be kept confidential as required by law. Federal Privacy Regulations 
provide safeguards for privacy, security, and authorized access. Except when required by law, you will 
not be identified by name, social security number, address, telephone number, or any other direct 
personal identifier (other than those mentioned above) in records disclosed outside of Duke University 
Health System (DUHS). For records disclosed outside of DUHS, your initials and a unique study 
number will be used. The information linking your name to the study number will be kept in the DUHS 
Division of Hematologic Malignancies and Cellular Therapies database on a secure server and in their 
locked research offices. 
 
Some of these tests and procedures would have been done as part of your regular care. The test results 
will be used both to treat you and to complete this research. These test results will be recorded in your 
medical record and will be reported to the sponsor or their representatives. Results of tests and studies 
done solely for this research study and not as part of your regular care will not be included in your 
medical record. 
 
The study results will be retained in your research record forever. Any research information in your 
medical record will also be kept indefinitely. 
 
Your records may be reviewed in order to meet federal or state regulations. Reviewers may include 
representatives of the Food and Drug Administration (FDA), the Duke University Health System 
Institutional Review Board (DUHS IRB), the Center for International Blood and Marrow Transplant 
Research (CIBMTR), the Foundation for Accreditation for Cell Therapy (FACT) and the Duke Cancer 
Institute. If any of these groups review your research record, they may also need to review your entire 
medical record. 
 
If this information is disclosed to outside reviewers for audit purposes, it may be further disclosed by 
them and may not be covered by the federal privacy regulations. 


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Page 10  of 
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Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
While the information and data resulting from this study may be presented at scientific meetings or 
published in a scientific journal, your identity will not be revealed. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
WHAT ARE THE COSTS? 
You or your insurance provider will be responsible for all costs related to your medical care, including 
the cost of cytarabine and idarubicin as well as collection and infusion of cells.  You may wish to 
contact your insurance representative to discuss this further before making your decision about 
participating in the study, as there may be extra uncovered costs. In order to make sure that tests and 
studies done solely for research purposes are charged correctly, we will carefully monitor your Duke 
Hospital and Clinic charges as long as you are participating in this study. These tests and studies are not 
a part of routine care, and people who are not part of the study do not usually have them performed. 
Please ask Dr. Sung if you would like to know more about which tests and studies are being done solely 
for research purposes. 
 
WHAT ABOUT COMPENSATION? 
You will not be paid for participating in this study. 
 
WHAT ABOUT RESEARCH RELATED INJURIES? 
Immediate necessary medical care is available at Duke University Medical Center in the event that you 
are injured as a result of your participation in this research study. However, there is no commitment by 
Duke University, Duke University Health System, Inc., or your Duke physicians to provide monetary 
compensation or free medical care to you in the event of a study-related injury. 
 
For questions about the study or research-related injury, contact Dr. Sung at 919- 668-5710 during 
regular business hours and at pager number 919- 684-8111 after hours and on weekends and holidays. 
 
WHAT ABOUT MY RIGHTS TO DECLINE PARTICIPATION OR WITHDRAW FROM THE 
STUDY? 
Your participation is voluntary. You may choose not to be in the study, or, if you agree to be in the 
study, you may withdraw from the study at any time. If you withdraw from the study, no new data about 
you will be collected for study purposes unless the data concern an adverse event (a bad effect) related 
to the study. If such an adverse event occurs, we may need to review your entire medical record. All 
data that have already been collected for study purposes, and any new information about an adverse 
event related to the study, will be collected by the study team. 


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Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
Your decision not to participate or to withdraw from the study will not involve any penalty or loss of 
benefits to which you are entitled, and will not affect your access to health care at Duke. If you do 
decide to withdraw, we ask that you contact Dr. Sung in writing and let him know that you are 
withdrawing from the study. His mailing address is Box 3961, 2400 Pratt Street, Durham, NC 27710. 
Your study doctor may ask you to complete the tests that would ordinarily occur when a person 
completes the study and discuss what follow-up care and testing could be most helpful for you. 
We will tell you about new information that may affect your health, welfare, or willingness to stay in 
this study. 
 
Your doctor may decide to take you off this study if your condition gets worse, if you have serious side 
effects, if you do not follow the study rules or if your study doctor determines that it is no longer in your 
best interest to continue. The sponsor or regulatory agencies may stop this study at anytime without 
your consent. If this occurs, you will be notified and your study doctor will discuss other options with 
you. 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about the study or a research-related injury, or if you have problems, concerns, questions 
or suggestions about the research, contact Dr.Sung at 919- 668-5710 during regular business hours and 
at pager number 919-684-8111 after hours and on weekends and holidays. 
For questions about your rights as a research participant, or to discuss problems, concerns or suggestions 
related to the research, or to obtain information or offer input about the research, contact the Duke 
University Health System Institutional Review Board (IRB) Office at (919) 668-5111. 


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Page 12  of 12 
 
 
 
 
Form 
M0345 
DUKE UNIVERSITY HEALTH SYSTEM 
 
Consent to Participate in a Research Study: 
A Phase 1/2 Study of the Safety and Efficacy of 
Chemotherapy Combined with Adoptive 
Transfer of HLA-Haploidentical Donor Lymphocyte Infusion in 
Older Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome 
Recipient Consent 
STATEMENT OF CONSENT 
"The purpose of this study, procedures to be followed, risks and benefits have been explained to me. I 
have been allowed to ask questions, and my questions have been answered to my satisfaction. I have 
been told whom to contact if I have questions, to discuss problems, concerns, or suggestions related to 
the research, or to obtain information or offer input about the research. I have read this consent form and 
agree to be in this study, with the understanding that I may withdraw at any time. I have been told that I 
will be given a signed and dated copy of this consent form." 
 
 
 
Signature of Subject 
Date 
Time 
 
 
 
Printed Name of Subject 
 
 
 
Signature of Person Obtaining Consent 
Date 
Time 
 
 
 
Printed Name of Person Obtaining Consent