Clinical trial NCT02519712
Conditions: Acute Myeloid Leukemia (AML)
Keywords: Induction Chemotherapy G-CSF-Mobilized Stem Cells Haploidentical Related Donors 15-141
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2015-07-28; Completion date: 2017-09-01
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to test a method of bone marrow transplantation that results in only temporary donor immune function. In other words, the donor immune cells are given in a way that will allow them to attack leukemia briefly before being destroyed by their own immune system, or "rejected." The investigators want to test whether temporary donor immune function is enough to improve the odds of achieving a remission without exposing the patient to the toxicities of a full bone marrow transplant. To do this, the investigators will use standard chemotherapy for AML followed by an infusion of donor stem cells. The donor will be a family member who is haploidentically, or half matched, to the patient such as a child or sibling. Chemotherapy designed to treat AML should not be strong enough to prevent them from rejecting the donor stem cells. The investigators will then follow the patient to see how long the donor stem cells stay in them. The study will test whether this process is feasible and can result in improved chances of obtaining a remission.

Detailed description:

Arms: arm 1: This is a single center trial to assess the feasibility of standard induction chemotherapy followed by a single dose of unmanipulated G-PBSC for the treatment of elderly patients with newly diagnosed AML.
Interventions: intervention 1: Induction Chemotherapy intervention 2: G-PBSC Infusion
Intervention descriptions: intervention 1: Patients with newly diagnosed AML will receive standard induction chemotherapy with daunorubicin and cytarabine (7+3 scheme). Patients who achieve CR may undergo consolidation chemotherapy at the discretion of the treating leukemia physician. intervention 2: G-CSF-mobilized peripheral blood cells will be collected from the donors in the Donor Room according to standard MSKCC BMT guidelines. Patients will be infused by infusion of unmanipulated G-PBSC from a haploidentical related donor.

Protocol documents:
Prot_SAP_000.pdf: 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Treatment of Elderly AML Patients with Induction Chemotherapy followed by G- 
CSF-Mobilized Stem Cells from Haploidentical Related Donors 
 
PROTOCOL FACE 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Brian Shaffer, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Katharine Hsu, MD, PhD 
Virginia Klimek, MD 
Medicine 
Medicine 
Investigator(s)/Department: 
Martin S. Tallman, MD 
Faye Feller, MD 
Jae Park, MD 
Stephen S. Chung, MD 
Dan Douer, MD 
Michael Mauro, MD 
Eytan M. Stein, MD 
Alan Shih, MD, PhD 
David Scheinberg, MD, PhD 
Peter Maslak, MD 
Omar Abdel-Wahab, MD 
Ellin Berman, MD 
Renier J. Brentjens, MD, PhD 
Ross L. Levine, MD 
Raajit K. Rampal, MD, PhD 
Juliet N. Barker MBBS (Hons) 
Hugo R. Castro-Malaspina, MD 
David Chung, MD, PhD 
Parastoo Dahi, MD 
Sergio Giralt, MD 
Boglarka Gyurkocza, MD 
Ann A. Jakubowski, MD, PhD 
Robert Jenq, MD 
Guenther Koehne, MD, PhD 
Heather Landau, MD 
Matthew Matasar, MD 
Craig Moskowitz, MD 
Esperanza B. Papadopoulos, MD 
Miguel-Angel Perales, MD 
Doris Ponce, MD 
Craig Sauter, MD 
Roni Tamari, MD 
James W. Young, MD 
Marcel van den Brink, MD, PhD 
Richard C. Meagher, PhD 
Medicine 
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MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Scott T. Avecilla, MD, PhD 
Lilian M. Reich, MD 
Glenn Heller, PhD 
Medicine 
Medicine 
Epidemiology & Biostatistics 
Consenting Professional(s)/Department: Katharine Hsu, MD, PhD 
Virginia Klimek, MD 
Brian Shaffer, MD 
Martin S. Tallman, MD 
Faye Feller, MD 
Jae Park, MD 
Stephen S. Chung, MD 
Dan Douer, MD 
Michael Mauro, MD 
Eytan M. Stein, MD 
Alan Shih, MD, PhD 
Raajit K. Rampal, MD, PhD 
David Scheinberg, MD, PhD 
Peter Maslak, MD 
Omar Abdel-Wahab, MD 
Ellin Berman, MD 
Renier J. Brentjens, MD, PhD 
Ross L. Levine, MD 
Juliet N. Barker MBBS (Hons) 
Hugo R. Castro-Malaspina, MD 
David Chung, MD, PhD 
Parastoo Dahi, MD 
Sergio Giralt, MD 
Boglarka Gyurkocza, MD 
Ann A. Jakubowski, MD, PhD 
Robert Jenq, MD 
Guenther Koehne, MD, PhD 
Heather Landau, MD 
Matthew Matasar, MD 
Craig Moskowitz, MD 
Esperanza B. Papadopoulos, MD 
Miguel-Angel Perales, MD 
Doris Ponce, MD 
Craig Sauter, MD 
Roni Tamari, MD 
James W. Young, MD 
Marcel van den Brink, MD, PhD 
Medicine 
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Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 5 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 5 
 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 5 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION............................................................ 8 
 
4.1 
Design............................................................................................................................. 8 
 
4.2 
Intervention ..................................................................................................................... 9 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 10 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 12 
 
6.1 
Subject Inclusion Criteria............................................................................................... 12 
 
6.2 
Subject Exclusion Criteria ............................................................................................. 12 
 
7.0 
RECRUITMENT PLAN ..................................................................................................... 13 
 
8.0 
PRETREATMENT EVALUATION .................................................................................... 13 
 
9.0 
TREATMENT/INTERVENTION PLAN.............................................................................. 14 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................. 16 
 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 18 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 20 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 22 
 
14.0 BIOSTATISTICS .............................................................................................................. 22 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES23 
 
15.1 Research Participant Registration ................................................................................. 23 
 
15.2 Randomization .............................................................................................................. 23 
 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 23 
 
16.1 Quality Assurance ......................................................................................................... 23 
 
16.2 Data and Safety Monitoring ........................................................................................... 24 
 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 24 
 
17.1 Privacy .......................................................................................................................... 25 
 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 25 
 
17.2.1 ................................................................................................................................... 26 
 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 26 
 
19.0 REFERENCES ................................................................................................................. 27 
 
20.0 APPENDICES .................................................................................................................. 30 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a single center trial of induction chemotherapy followed by a single dose of 
unmanipulated donor-derived GCSF-mobilized peripheral blood stem cells (G-PBSC) for the 
treatment of elderly patients with acute myeloid leukemia (AML).  Patients older than 60 
years of age with newly diagnosed disease will be eligible.  Selection of haploidentical 
related donors will be based on KIR/HLA genotypes to maximize missing self-MHC, anti- 
tumor, and anti-GVHD NK activity.  No drug prophylaxis against GVHD will be administered 
following G-PBSC infusion.  The primary objective will be to assess the feasibility of 
delivering this treatment in terms of timely HLA/KIR typing, donor selection, pheresis 
procedure, and infusion of stem cell product. The target accrual is 15 patients in 18 months. 
Secondary objectives will be to determine the anti-leukemic effects (in terms of CR rate), 
reduction of cytopenia-related toxicity (infection, bleeding, duration of hospital stay), and 
toxicity of treatment (GVHD) of this therapy in elderly AML patients and to correlate response 
to KIR and HLA genotyping and NK function.  Correlative studies will assess NK activity 
against standard target cells in vitro, donor NK activity against AML blasts, donor-host 
chimerism, and immune reconstitution. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 
Primary objective: 
 
• 
To assess the feasibility of rapid donor selection, pheresis, and stem cell infusion for AML 
patients undergoing induction chemotherapy. The first objective is to enroll and to treat 15 
patients in 18 months. 
 
2.2 
Secondary objectives: 
 
2.2.1 Clinical Outcomes 
 
• 
Rate of achievement of CR 
• 
Duration of neutropenia and thrombocytopenia 
• 
Treatment Related Mortality (TRM) 
• 
Graft versus Host Disease (GVHD) 
• 
Severe (CTCAE v4.0 grade 4-5) infection 
• 
Donor chimerism >5% at 100 days 
• 
Likelihood of patients to be enrolled and to receive treatment 
• 
Duration of hospital stay 
 
 
 
2.2.2 Correlative studies 
 
 
 
• 
To assess lymphocyte reconstitution: NK, T, and B 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
Acute myeloid leukemia (AML) is a malignancy that results in an accumulation of leukemic 
blasts  and  ineffective  hematopoiesis  producing  varying  degrees  of  thrombocytopenia, 


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anemia, and neutropenia.  The incidence of AML increases with age, with a median age at 
diagnosis of 67 years.[1]  Of the almost 13,000 patients diagnosed annually, there will be an 
estimated 9000 deaths attributable to AML.[2] A 60-80% complete remission rate (CR) is 
reported for younger adults whereas only 40% of older adults enter CR, and <10% are long- 
term survivors.[3] 
 
AML in older adults is often preceded by myelodysplastic syndrome (MDS) or 
myeloproliferative disorders, has an increased incidence of poor-risk cytogenetics, more 
frequently expresses multidrug resistence and has a lower response rate to chemotherapy. 
There is a significant difference in biology of AML in older adults along with an increase in 
co-morbid diseases and impaired bone marrow stem cell reserves, resulting in an extremely 
poor overall prognosis.[3, 4] 
 
There is a significant  need for more effective therapy in elderly patients with AML,  as 
standard chemotherapy results in poor outcomes that have not changed for the past 30 
years. Allogeneic stem cell transplantation (allo SCT) after nonmyeloablative or reduced 
intensity conditioning (RIC) has been shown to offer an improvement in outcome of elderly 
patients with AML. However, there are several major obstacles to the more widespread use 
of allogeneic transplant in this population: First, the number of persons who achieve an 
adequate remission for allo SCT is rare; second many persons lack a human leukocyte 
antigen (HLA)–matched donor, finally, increased treatment-related mortality (TRM) in elderly 
persons from prolonged marrow aplasia and graft-versus-host disease (GVHD) means that 
only the fittest patients are referred for allo SCT. This limits the utility of allo SCT in elderly 
patients because of their often poor performance status and increased comorbidities. [5-7] 
 
Clinical and pre-clinical studies demonstrate that G-CSF–mobilized donor peripheral blood 
stem  cell  (G-PBSC)  infusion  results  in  a  graft-versus-leukemia  effect  and  hastens 
hematologic recovery.[5, 8, 9] Mice infused with a high dose of G-CSF–mobilized allogeneic 
spleen cells (3-12 x 107) after cytarabine chemotherapy and without immunosuppressive 
pretreatment 
exhibited 
rapid 
autologous 
hematopoietic 
recovery 
and 
persistent 
microchimerism without GVHD.  This led to a recent clinical control study to investigate the 
effects of conventional chemotherapy combined with G-PBSC infusion on outcomes of AML 
in elderly patients.[10] In this study, patients received conventional chemotherapy (cytarabine 
and mitoxantrone) followed 36 hours later by G-CSF mobilized PBSC from an HLA- 
haploidentical related donor.  The median numbers of CD34+, CD3+, CD3-CD16+CD56+ and 
CD3+CD16+CD56+ cells infused per course were 1.7 (1.1-4.6) x 106/kg, 0.9 (0.5-2.6) x 108/kg, 
0.19 (0.075-0.25) x 108/kg and 0.13 (0.05-0.45) x 108/kg, respectively.   Patients receiving 
combination chemotherapy (induction and consolidation chemotherapies) and G-PBSC 
achieved a higher CR rate (80%) and 2-year probability of disease-free survival (39.2%) 
compared with patients receiving conventional chemotherapy alone (42.8% and 10%). The 
median  recovery  time  of  neutrophils  and  platelets  was  shorter  in  the  G-PBSC  group 
compared with the control group with first cycle of induction chemotherapy (11 and 14.5 days 
versus 16 and 20 days from donor cell infusion). All pts received GCSF upon neutropenia. 
The severe infection rate with first induction was lower in the G-PBSC group (26.7% vs. 
57.1%).   These findings demonstrate the potential of G-PBSCs in combination with 
conventional chemotherapy in improving the outcome of AML in elderly patients. In an 
expansion  paper,  Guo  et  al  treated  an  additional  101  patients  with  G-PBSC  following 
induction therapy for AML.[11] Both in this cohort and the original case-control series there 


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were  no  reported  incidences  of  acute  or  chronic  GVHD.  Chimerism  studies  here 
demonstrated persistent microchimerism (<10-5  to 10-4) for 0.5-34 months in most persons 
tested. A third study further demonstrated the safety of infusing allogeneic stem cells with as 
many  as  1x108    CD3/kg  into  13  minimally  pre-treated  patients  without  evidence  of 
engraftment of development of GVHD.[12]  Chimerism and/or GVHD with donor lymphocyte 
infusions containing up to 6.85x108  mononuclear cells/kg and 1.9x108  CD3/kg, even with 
fairly minimal conditioning, has occurred, but only in patients who were heavily pre-treated, 
including those with a prior autologous stem cell transplantation.[13, 14] Taken together, 
these studies suggest that haploidentical G-PBSC retains a graft versus leukemia effect 
despite non-engraftment. Furthermore, patients who are minimally pretreated can receive a 
stem cell infusion containing T-cells of 1 x108/kg without significant risk of GVHD. 
 
 
In the Guo study, the decreased time to hematopoietic recovery in patients who received G- 
PBSC after chemotherapy was associated with a profound decrease in infectious 
complications, thereby reducing the high morbidity and mortality rates associated with 
induction chemotherapy in the elderly. It is known that PBSC therapy can significantly speed 
hematopoietic recovery after chemotherapy, thereby reducing treatment-related morbidity 
and mortality. In 1958, a radiation accident at a nuclear power plant in Vinca, Yugoslavia 
resulted in radiation poisoning to 6 workers, one of whom died from prolonged aplasia.[15, 
16] Unrelated individuals donated bone marrow to the remaining 5 stricken workers, all of 
whom recovered autologous hematopoiesis after brief allo-engraftment without GvHD. It was 
universally accepted that without the aid of stem cell infusion, these individuals would also 
have died due to prolonged aplasia. At least two other modern applications of “cell-assisted” 
marrow recovery currently exist in transplant medicine, where the infusion of two umbilical 
cord allografts allows faster engraftment of one, and where infusion of haploidentical stem 
cells assists in the rapid engraftment of a single cord allograft.[17-19] Hastened engraftment 
leads to lower infectious and bleeding complications, without engraftment or GvHD from the 
“enabling” stem cell graft.  Furthermore, the reduced neutropenic period leads to shorter 
hospitalization. 
 
 
Another factor contributing to the positive findings is an enhanced antileukemic effect 
mediated by the G-PBSC, leading to a higher rate of CR. While anti-leukemic alloactivities in 
DLI have been well demonstrated, these are primarily mediated by long-lived T-cells with 
specificity for host leukemic antigens.[13, 20-22] A more intriguing prospect is that the higher 
anti-leukemic effect is mediated by donor alloreactive NK cells.  Several features of NK cells 
support this possibility: 1) NK cells have inherent anti-tumor effects and therefore “naïve” NK 
cells can mediate tumor eradication immediately upon infusion or development from stem 
cells;  2) NK cells are the first lymphocyte to develop from the stem cell and to populate the 
periphery following allogeneic stem cell transplantation; therefore, given the lack of sustained 
allo-engraftment seen in the recipients, the only donor-derived cell that could mediate short- 
term anti-leukemic effects is the donor NK cell; 3) HLA-mismatched NK cells have a high 
likelihood of becoming alloreactive due to missing self-HLA ligands in the recipient.[23] 
 
On the basis of the two Guo trials and prior observation of the safety of infusion HLA- 
mismatched stem cells into non-heavily pre-treated patients our trial will assess the feasibility 
and efficacy of combining a standard induction chemotherapy regimen of daunorubicin and 


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cytarabine (7+3 scheme) with the infusion of unmanipulated G-PBSC from a haploidentical 
related donor, for elderly patients (>60 years old) with newly-diagnosed AML. The majority of 
patients  are  expected  to  have  an  eligible  haploidentical  donor,  but  in  contrast  to  the 
previously reported study, donor selection will be based on KIR/HLA genotypes.  This will be 
done to maximize the likelihood of NK alloreactivity due to missing self-MHC, to enhance NK 
activity due to activating KIR, and, subsequently, to maximize anti-leukemic potential. 
 
Previous studies have shown the feasibility and safety of NK infusion in patients affected by 
hematological (AML) and non-hematological diseases. In all of these previous experiences 
no GVHD has been documented.[24, 25] To maximize in vivo donor NK survival and 
alloreactivity, related but HLA-disparate donors are screened and prioritized based on 
KIR/HLA genotypes. To maximize NK activation due to “missing self,” selection will be 
prioritized for donors exhibiting KIR ligands that are lacking in the patient. Cognate inhibitory 
KIR in the donor is confirmed by KIR genotyping. To capture KIR2DS1-mediated NK 
activation, donors with activating KIR2DS1 are then prioritized if the donor exhibits an HLA- 
C1 allele. Donors who are KIR-ligand matched to the recipient are acceptable if KIR typing 
indicates that the recipient lacks class I ligand for the donor inhibitory KIR, leading to 
activation of unlicensed NK cells.  Donors lacking class I ligands present in the recipient are 
less desirable, as this may result in rapid clearance of the infused product by residual host 
NK cells. Based on HLA and KIR genotype frequencies in the Caucasian population: 1) 40% 
of patients will have all KIR ligands present and will not benefit from missing self or missing 
ligand NK alloreactivity; 2) 60% will benefit from missing ligand; and in overlapping groups, 3) 
approximately 24% will benefit from “missing self” donor alloreactivity; and 4) 32% of patients 
will benefit from KIR2DS1-mediated NK activity.[26-29] 
 
It is recognized that some of the patients who receive this therapy and achieve CR will be 
eligible for a standard allogeneic hematopoietic cell transplant (HCT) and that a fraction of 
these patients may have a fully HLA-matched sibling donor.  Allosensitization from prior 
exposure to blood products from family members can predispose to stem cell allograft 
rejection. The goal of this trial, however, is to successfully achieve higher rates of sustained 
CR.  Assuming that this is accomplished to the same degree as published, twice as many 
patients will achieve CR and will therefore be eligible for allogeneic HCT.  Of these, however, 
only a portion will undergo HCT, and of this portion, only 25% will have an HLA-identical 
sibling.   Therefore, it is the determination of both the Leukemia and the Adult Allogeneic 
Bone Marrow Transplantation Services that the risk of HCT graft rejection due to 
allosensitization should not preclude pursuing the proposed treatment plan. Furthermore, at 
present most of these patients will receive a T-replete, unmodified cell allograft.  The risk of 
graft rejection with this type of allograft is <5%. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1     Design 
 
This is a pilot study designed to assess the feasibility and to estimate the efficacy of standard 
induction chemotherapy followed by a single dose of unmanipulated G-CSF mobilized 
haploidentical peripheral blood stem cells for the treatment of newly diagnosed elderly AML 
patients. 


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The study will use a two-step enrollment process. First, patients eligible for this study will be 
enrolled. Second, the donors are HLA and KIR genotyped to determine if they are 
appropriately mismatched and are willing to participate in the study. The feasibility objective 
will examine whether a sufficient percentage of prospective patients that are enrolled in this 
protocol undergo the stem cell infusion. Patients declared eligible will be enrolled. Feasibility 
will be determined by the number of patients who receive treatment. Treatment will consist of 
one cycle of  standard induction chemotherapy followed by infusion of haploidentical G- 
PBSC. An additional cycle of consolidation with haploidentical G-PBSC infusion is allowed at 
the investigator’s discretion. It is anticipated that 15 patients will be treated within 18 months. 
Patients enrolled who do not proceed to stem cell infusion due to donor unavailability or 
ineligibility will be removed from the protocol and treated with standard chemotherapy. The 
efficacy objective will provide pilot data for the response rate, as defined by achievement of 
CR. 
 
Secondary outcomes evaluated will be: Rate of achievement of CR, duration of neutropenia 
and  thrombocytopenia,  incidence  of  TRM,  GVHD,  and  severe  infections;  donor  cell 
chimerism at 100 days <5%; NK immunogenetics and CR; duration of hospital stay during 
induction therapy. Correlative studies will assess NK activity against standard target cells in 
vitro, immune reconstitution (NK, T, B) and, if AML blasts available, donor NK activity against 
tumor targets. 
 
 
4.2     Intervention 
 
Donor intervention: 
 
G-CSF mobilized PBSC will be collected according to standard protocol. Donors will receive 
filgrastim 10 µg/kg/day subcutaneously x 5 days and then undergo 1day of apheresis using 
standard protocol on days 5±6. 
 
Patient intervention: 
 
Elderly patients (>60 y) with a new diagnosis of AML will receive a standard induction 
chemotherapy with daunorubicin and cytarabine (7+3 scheme) followed by infusion of 
unmanipulated G-PBSC from a haploidentical related donor. 
 
The treatment plan for the patients receiving 7+3 chemotherapy is outlined below: 
 
DAY 
1 
2 
3 
4 
5 
6 
7 
8 
9-11 
Cytarabine 
(100 mg/m2 IVCI) 
X 
X 
X 
X 
X 
X 
X 
rest 
G-PBSC 
infusion 
Daunorubicin 
(60 mg/m2 IVP) 
X 
X 
X 
 
 
Due to variability in donor availability and/or pheresis scheduling, patients may receive the G- 
PBSC up to 84 hrs after completion of chemotherapy. The dose of the GCSF-mobilized 
PBSC allograft will be capped so as not to exceed a CD34 count of 2x10e6/kg or a CD3+ 


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count   of   1x10e8/kg.   Remaining   donor   G-PBSC   after   the   initial   infusion   may   be 
cryopreserved. 
 
Some patients will require additional consolidation chemotherapy. This study allows G-PBSC 
to be infused after the first cycle of consolidation. To minimize the potential for persistent 
donor cell macro-engraftment G-PBSC will only be used after the first cycle of consolidation. 
Additional cycles of consolidation may be used at the investigator’s discretion without G- 
PBSC. Patients requiring treatment for relapse will not receive G-PBSC. The treatment plan 
for consolidation is below: 
 
DAY 
1 
2 
3 
4 
5 
6 
7-9 
Cytarabine 
1.5-3 g/m2/BID 
X 
X 
X 
G-PBSC 
infusion 
 
 
 
 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1  DAUNOrubicin (Daunomycin, Cerubidine®) 
 
Daunorubicin hydrochloride is the hydrochloride salt of an anthracycline cytotoxic antibiotic 
produced by a strain of Streptomyces coeruleorubidus.  Daunorubicin has antimitotic and 
cytotoxic activity through a number of proposed mechanisms of action. Daunorubicin forms 
complexes with DNA by intercalation between base pairs. It inhibits topoisomerase II activity 
by stabilizing the DNA topoisomerase II complex, preventing the religation portion of the 
ligation-religation reaction that topoisomerase II catalyzes. Single strand and double strand 
DNA breaks result.  Daunorubicin hydrochloride may also inhibit polymerase activity, affect 
regulation of gene expression and produce free radical damage to DNA.  In the treatment of 
adult acute nonlymphocytic leukemia, daunorubicin hydrochloride, used as a single agent, 
has produced complete remission rates of 40 to 50%, and in combination with cytarabine, 
has produced complete remission rates of 53 to 70%. 
 
The contents of the 50 mg vial should be reconstituted with 10 mL of Sterile Water for 
Injection, USP, and agitated gently until the material has completely dissolved. The sterile 
vial contents provide 50 mg of daunorubicin, with 5 mg of daunorubicin per mL.  The desired 
dose is withdrawn into a syringe containing 10 mL to 15 mL of 0.9% Sodium Chloride 
Injection, USP and then injected into the tubing or sidearm in a rapidly flowing IV infusion of 
5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP.   Daunorubicin 
hydrochloride should not be administered mixed with other drugs or heparin. Unopened vials 
of daunorubicin must be stored per package label refrigerated at 2° to 8°C (36° to 46°F). 
Store prepared solution for infusion at 15° to 30°C (59° to 86°F) for up to 24 hours. Solution 
contains no preservative and must be protected from light. 
 
Daunorubicin will be administered intravenously at a dose of 60mg/m2 daily for 3 days.  It will 
be administered as an IVP. 


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5.2 Cytarabine (Ara-C®) 
 
Cytarabine is a pyrimidine nucleoside analogue that is one of the most widely employed and 
effective drugs for the treatment of AML.  It acts by inhibiting DNA polymerase and promoting 
DNA chain termination through the ability of its phosphorylated metabolite, ara-CTP, to 
incorporate into DNA.  The most important catabolic step in the metabolism of cytarabine is 
its conversion to an inactive intermediate, ara-U, by a deaminase.  Resistance to the drug 
appears to occur through a variety of mechanisms including poor cellular uptake, deletion of 
the activating enzyme, altered DNA affinity, and high levels of dCTP, a normal competitive 
inhibitor. 
 
Cytarabine is supplied as a sterile powder in 100 mg and 500 mg vials.  The drug is 
reconstituted with bacteriostatic water (without benzyl alcohol) for injection.  The resulting 
solution contains 50 mg/mL of cytarabine.   It may be stored at room temperature for 48 
hours.  The drug may be administered intravenously, subcutaneously, or intrathecally.  When 
given   intravenously   at   standard   doses   of   100-200   mg/m2,   cytarabine   is   generally 
administered by continuous infusion over 24 hours.  At higher doses (1-3 gm/m2), it is 
administered intravenously over 1-3 hours. 
Cytarabine will be administered at a dose of 100 mg/m2/day by continuous IV infusion (Days 
1-7). 
 
 
 
 
5.3     Filgrastim (G-CSF, Neupogen®), for donor 
 
Granulocyte colony stimulating factor (G-CSF) is one member of a family of glycoproteins 
that  are  important  in  regulating  growth,  differentiation  and  survival  of  hematopoietic 
progenitor cells.  The gene for G-CSF is located on chromosome 17 and encodes a protein 
whose molecular weight varies from 18-22 kd.  The primary target of G-CSF is the colony- 
forming unit-granulocyte (CFU-G), and it exerts its primary effects in vivo on late progenitors. 
In addition to stimulating the differentiation of granulocyte precursors, G-CSF has also been 
shown to enhance the function of mature effector cells.  Human G-CSF has been purified, 
and the gene cloned.  The subsequent expression of the gene in E. coli has made large 
quantities of purified homogeneous G-CSF available for clinical use. Recombinant G-CSF is 
a human protein grown in an E. coli vector.  Cells expressing G-CSF are grown in culture 
under sterile conditions.  The cells are harvested, and the G-CSF is extracted and purified. 
Filgrastim is supplied by Amgen as a clear, colorless solution in single-use vials at a 
concentration of 0.3 mg/ml.  Vials contain either 1 ml or 1.6 ml.  The drug is generally 
administered as a subcutaneous injection but may be diluted in 5% dextrose solution for 
intravenous infusion. It is administered at a dose of 10 mcg/kg/d for 5 days. 


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6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
 
 
 
6.1 
Subject Inclusion Criteria 
 
• 
Age ≥ 60. 
• 
Patients with a new diagnosis of histologically confirmed (according to WHO 
classification 2008) acute myeloid leukemia (either primary or secondary AML) are 
included. 
• 
Patients must have a healthy blood-related donor (parent, child, sibling) willing to 
undergo apheresis after G-CSF administration. 
• 
Karnofsky performance status > 70%. 
• 
Hepatic function - total bilirubin <  2 and, AST < 2.5 x upper limit of normal, unless 
liver is involved with disease or a history of Gilbert’s disease. 
• 
Renal function – adequate renal function as demonstrated by a serum creatinine <2 
mg/dl. 
• 
LVEF ≥ 50% as determined by echocardiogram or MUGA. 
• 
Ability to give informed consent. 
 
6.1.2 
Donor Eligibility 
 
• 
Donor is blood-related and HLA-haploidentical to the recipient. 
• 
Donor ≥18 years old. 
• 
Donor  has  undergone  serologic  testing  for  transmissible  diseases  as  per  blood 
banking guidelines for organ and tissue donors. Tests include but are not limited to: 
HepBsAg, HepBsAb, HepBcAb, HepC antibody, HIV, HTLV I and II, VZV, CMV and 
VDRL, and West Nile Virus . Donor must have normal negative test results for HIV, 
HTLV I and II, and West Nile Virus. 
• 
Donor has a CXR and EKG performed. 
• 
Donor is not allergic to G-CSF. 
• 
Donor must be able to undergo leukapheresis. 
• 
Donor is not pregnant. 
• 
Donor does not have concurrent malignancy or autoimmune disease. 
• 
Ability to give informed consent. 
 
 
 
 
6.2 
Subject Exclusion Criteria 
 
• 
Patients  with  a  diagnosis  of  acute  promyelocytic  leukemia  (according  to  WHO 
classification 2008). 
• 
Major surgery or irradiation within two weeks. 
• 
Previous therapy with cytotoxic agents for AML. Persons with previous treatments for 
myelodysplasia/myeloproliferation such as hydroxyurea, interferon, hypomethylating 
agents (5-azacitidine or decitabine), lenalidomide, or JAK/STAT inhibitors may 
participate but must have >1 week off therapy prior to enrollment. 
• 
Active CNS disease. 


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• 
Uncontrolled infection. 
• 
Pregnant or lactating women – they are excluded, given the potential teratogenic 
effects of chemotherapy and agents used in the therapy. 
• 
Male and female patients of child-bearing potential unwilling to use effective means of 
contraception. 
• 
HIV or HTLV I/II seropositivity. 
• 
Concurrent active malignancy other than AML requiring therapy. 
• 
Clinically  significant  cardiac  disease  (NY  Heart  Association  Class  III  or  IV)  or 
pulmonary disease. 
• 
Inability or unwillingness to comply with the treatment protocol, follow-up, or research 
tests 
 
 
6.2.2 Donor Exclusion 
 
• 
Donor has cardiac risk factors precluding ability to undergo leukapheresis. 
• 
Donor has evidence of concurrent malignancy or autoimmune disease. 
• 
Donor is pregnant. 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients who fulfill the eligibility criteria as listed in Section 6.0 will be recruited for this study 
by an Attending Physician of the Leukemia Service.  Informed consent will be obtained by 
one of the participating investigators authorized to obtain consent. A copy of the signed 
informed consent will be placed in the medical record, as well as in the research file. 
 
This protocol will take due notice of NIH/ADAMHA policies concerning inclusion of women 
and minorities in clinical research populations. We expect that the study population will be 
fully representative of the range of elderly patients referred for leukemia without exclusion as 
to gender, or ethnic background within the limits of being able to identify a suitable PBSC 
donor. Pregnant women are excluded from participation in this study. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
8.1           Pretreatment evaluation of the patient 
 
The following tests must be performed prior to enrollment. Blood counts, chemistry, and disease 
assessment must have been performed within 28 days prior to starting chemotherapy regimen or 
less as clinically indicated: 
 
• Complete history, review of  systems, physical exam  (including performance status) and 
informed consent 
• Bone marrow biopsy (aspirate and trephine core, if clinically indicated) for morphology with 
surface markers, for documentation of disease status 
• CBC with differential, comprehensive metabolic panel (CMP), LDH, and serum uric acid 
basic coagulation profile.  ABO type and screen 
•   Urinalysis 


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• EKG and either echocardiogram or MUGA scan with measurement of left ventricular ejection 
fraction 
•   Chest radiograph 
• Serum testing for cytomegalovirus (IgG and IgM), toxoplasmosis, herpes zoster, Epstein-Barr 
virus (EBV) 
•   Peripheral blood to the Diagnostic Molecular Pathology laboratory for chimerism studies 
•   HLA genotyping 
 
8.2           Pretreatment evaluation of the donor 
 
Any consenting healthy family donor who is HLA haploidentical with the recipient will be given 
priority as a potential donor for G-PBSC. The donor (or the donor’s parent for minors) must also 
provide signed informed consent to receive a 5-day course of G-CSF followed by leukapheresis. 
 
In preparation for the stem cell donation, the donor will provide informed consent and then 
undergo the following evaluation. In general, the following tests must be performed within 7 days 
of initiating cytoreduction: 
 
•   Complete history, review of systems, and physical exam 
•   Complete blood count and differential 
•   Comprehensive panel 
•   Coagulation profile 
•   Type and Screen 
•   EKG and chest x-ray (if clinically indicated) 
• 
Serum will be tested for antibodies for CMV (IgG and IgM), HIV-1,2, HTLV1, 2, 
toxoplasmosis, Hep B, Hepatitis C, Hepatitis B surface antigen, Herpes Simplex, Herpes 
Zoster, Epstein-Barr virus, VDRL 
•   West Nile Virus PCR, Hepatitis C PCR and HIV PCR 
•   Pregnancy test for females of childbearing age 
•   HLA and KIR genotyping 
•   Short tandem repeat polymerase chain reaction profiling (for chimerism evaluation) 
 
 
 
 
 
9.0      TREATMENT/INTERVENTION PLAN 
 
9.1      General:  This  is  a  single  center  trial  to  assess  the  feasibility  of  standard  induction 
chemotherapy followed by a single dose of unmanipulated G-PBSC for the treatment of elderly 
patients with newly diagnosed AML. 
 
9.2      Pre-treatment:  Patients will be treated as inpatients at MSKCC. Supportive care including 
fluid hydration and prevention of tumor lysis syndrome are provided as clinically indicated by the 
inpatient Leukemia Service attending. 


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9.3 
Induction Chemotherapy 
 
Induction: 
 
Patients with newly diagnosed AML will receive standard induction chemotherapy with daunorubicin 
and cytarabine (7+3 scheme) as outlined below: 
 
DAY 
1 
2 
3 
4 
5 
6 
7 
8 
9-11 
Cytarabine 
(100 mg/m2 IVCI) 
Daunorubicin 
(60 mg/m2 IVP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
rest 
G-PBSC 
infusion 
 
Consolidation: 
 
Patients who achieve CR may undergo consolidation chemotherapy at the discretion of the treating 
leukemia physician. If there are remaining cryopreserved G-PBSC after the first infusion these may 
be infused after one additional consolidation chemotherapy cycle as below. Any further cycles of 
chemotherapy will be performed without G-PBSC support. 
 
DAY 
1 
2 
3 
4 
5 
6 
7-9 
Cytarabine 
1.5-3 g/m2/BID 
X 
X 
X 
G-PBSC 
infusion 
 
 
9.4      G-PBSC Infusion 
 
G-CSF-mobilized peripheral blood cells will be collected from the donors in the Donor Room 
according to standard MSKCC BMT guidelines.  The stem cell product is delivered to the Cell 
Therapy Laboratory, cell counts will be performed, and the stem cell product processed per 
institutional guidelines.  Up to 84 hours after the completion of chemotherapy, patients will receive 
an infusion of unmanipulated PBSC. 
 
To reduce the risk of full donor chimerism and GVHD, the PBSC cell dose will be restricted for: 
 
– CD34+ cells (not to exceed 2x10e6/kg) 
 
– CD3+ cells (not to exceed 1x10e8/kg) 
 
Donor treatment: G-CSF administration for PBSC mobilization in donors is outlined below: 
 
DAY 
1 
2 
3 
4 
5 
6 
7 
8 
9 
G-CSF 
(10 μg/kg SQ) 
X 
X 
X 
X 
X 
Pheresis 


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Donor cell cryopreservation: Donor cells not used in the initial G-PBSC infusion will be stored in 
the MKSCC Cell Therapy Lab for use after a subsequent consolidation. 
 
9.4      Supportive Treatment:  Patients will receive antibiotics, packed red blood cell transfusions, 
and platelet transfusions according to MSKCC standard care guidelines. Patients with an absolute 
neutrophil count < 500 cells/µL will receive G-CSF 5 µg/kg/day starting day +1. If there is evidence 
of ongoing leukemia (circulating blasts, >5% bone marrow blasts) the patient may stop G-CSF at the 
discretion of the investigator. 
 
9.5 
Selection of an immunogenetically optimal donor: Donors will be selected on the basis of 
KIR/HLA interactions that favor the reduction of relapse whenever possible. In the event that a 
favorable donor is identified this donor will be selected provided they are eligible. If a favorable 
donor does not exist an unfavorable donor may be used. Donor favorability is defined as follows: 
 
 
1.  If the patient lacks expression of any KIR ligand (HLA-C1, -C2, or –Bw4) a donor that 
expresses this ligand (“missing self”) is considered favorable. 
2.  In the absence of missing self pehenomenon, donor selection is based on minimizing 
inhibitory KIR signaling and maximizing activating KIR siganaling in the following order: 
a.  Donors with KIR3DL1 allotypes that generate weak inhibitory signaling 
b.  Donor who express KIR2DS1 and HLA-C1 
c.   Donors who are homozygous for centromeric haplotype B 
3.  In the absence of #1 or #2 any available donor may be used for donation. Donors are 
considered to be eligible based on availability, therefore these selection criteria should 
not delay treatment if another donor is available to donate on schedule. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1   Post-Treatment evaluation 
 
Treatment evaluations are summarized in the following table. Scheduled evaluations are 
performed daily during inpatient treatment. Long term follow-up evaluation days may be 
performed ±7 days to accommodate for patient schedules. Evaluations may be withheld if the 
treating physician feels that there is a strong contraindication to performing the study (e.g. 
patient has relapsed and is terminally ill). Also, additional tests will be performed as clinically 
indicated. 
 
 
 
 
ACTIVITY 
START OF 
THERAPY TO 
DISCHARGE 
DISCHARGE TO DAYS 
100 
Karnofsky score 
+100±7 
History and 
physical 
Daily until discharge 
from hospital 
As per out-patient 
schedule 
Chemistry 
Daily basic electrolyte 
panel with biweekly 
comprehensive 
metabolic panel 
As per out-patient 
schedule 


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(CMP) 
 
Counts/differential 
Daily, with differential 
when WBC ≥ 0.5 
 
 
As per out-patient 
schedule 
 
 
Disease evaluation, 
Bone marrow 
aspirate and 
chimerism 
 
 
Peripheral Blood 
Chimerism, T-Cell 
and NK-cell 
 
 
 
 
 
 
 
Day 21 - 25 
After hematologic 
recovery, approximately 
day 28-40. 
 
GVHD evaluation 
Daily after 
engraftment until 
discharge from 
hospital 
 
Weekly for the first 
month, then biweekly for 
the following 8 weeks, 
then as per out-patient 
schedule 
 
 
During the first 100 days patients will be closely monitored as per standard of care. Acute 
GVHD will be assessed and graded according to current MSKCC guidelines.  Follow up 
assessment for disease status by physician should also be completed approximately 1 year 
(± 2 weeks) post transplant. 
 
10.2    Research Samples 
 
Research blood samples will be obtained from patients at time points indicated (See table) to 
determine  KIR  genotyping,  NK  phenotype  (CD94/NKG2A,  ILT-2,  KIR  expression),  NK 
function (intracellular INF-γ, cytotoxicity), and chimerism. 
 
ACTIVITY 
PRE-TREATMENT 
START OF 
THERAPY TO 
DISCHARGE 
DISCHARGE TO DAYS 
100 
Leukemia sample 
When available: 
BM sample (2 EDTA 
tubes) and PB (3 
EDTA tubes) 
Peripheral blood 
for NK phenotype 
by flow cytometry 
(CD94/NKG2A, ILT- 
2, KIR expression) 
At the enrollment of 
donor and patient 
(before treatment) 
Day +28-35 
Day +100±7 
Peripheral blood 
for NK function by 
intracellular IFN- γ 
or cytotoxicity 
At the enrollment of 
donor and patient 
(before treatment) 
Day +28-35 
Day +100±7 
* If donor T-lymphocyte chimerism is >5% a repeat study will be performed at 2 week 
intervals until chimerism is ≤5% 


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11.0   TOXICITIES/SIDE EFFECTS 
 
Toxicity Grading:   Toxicity will be graded according to the NCI Common Toxicity Criteria, version 
4.0. 
 
11.1   Risks to Related Peripheral Blood Stem Cell Donors 
 
The risks of short-term treatment with G-CSF are likely negligible. However, administration of GCSF 
is frequently associated with low grade fever and low back pain which usually resolves within one 
day following cessation of GCSF treatment. Furthermore, there has now been one recorded patient 
who developed acute splenomegaly and splenic rupture in response to high dose GCSF. Bone pain 
may require treatment with analgesics. The risks of leukapheresis include temporary paresthesia in 
the perioral, circumoral, and acral areas as well as muscle stiffness and spasm secondary to 
hypocalcemia, pain and bruising at the needle insertion sites, vasovagal response to venipuncture, 
and the minimal hemodynamic alterations associated with single unit phlebotomies. To protect 
against these risks, leukaphereses are conducted in the Blood Bank Donor Room with full medical 
and nursing supervision and support systems to address adverse events. 
 
 
 
11.2 Risks to Patients 
 
11.2.1 Risks related to cytarabine: 
 
Likely, some may be serious: 
 
• 
Blood clots 
• 
Rash 
• 
Swelling or pain of the rectum 
• 
Diarrhea, loss of appetite, nausea, vomiting 
• 
Soreness in the mouth 
• 
Low blood cell counts that may require transfusion 
• 
Fever 
 
Occasional, some may be serious: 
 
• 
Infection, especially during periods of low white blood cell counts 
• 
Bruising or bleeding 
• 
Allergic reaction that may cause rash, low blood pressure, wheezing , shortness of 
breath, or swelling of the face or throat 
• 
Numbness and tingling in the arms and legs 
• 
Kidney damage that may require dialysis 
• 
Headache 
• 
Chest pain 
• 
Hair loss 


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• 
Liver damage 
• 
Swelling or irritation to the outside of the eye 
 
Rare but serious: 
 
Injury  to  the  cerebellum,  causing  difficulty  with  movement11.2.2  Risks  related  to 
daunorubicin: 
 
Likely, some may be serious: 
 
• 
Hair loss 
• 
Nausea, vomiting 
• 
Pink discoloration of urine, sweat, or saliva 
• 
Low blood counts (neutrophils, red-blood cells, platelets) 
Occasional, some may be serious: 
• 
Damage to the heart that may lead to fatigue or shortness of breath 
• 
Infections, especially during periods of low white blood cell count 
• 
Anemia that requires transfusion 
• 
Bruising or bleeding 
• 
Dark discoloration of the nails or skin 
• 
Loss of nails 
• 
Redness and pain at a site of previous radiation 
• 
Swelling or redness at the site of injection 
• 
Diarrhea or mouth pain 
 
Rare but serious: 
 
• 
Other cancers of the bone marrow 
• 
Allergic reactions that may cause rash, low blood pressure, wheezing, shortness of 
breath, or swelling of the face or throat 
 
11.2.3 Risks related to donor G-PBSC infusion: 
 
Likely: 
 
• 
None 
 
Less likely: 
 
• 
Infusion reactions. Patients may experience temporary allergic reactions to the donor 
cell product including hives, flushing, rapid heart rate, itching, or rash. These may be 
treated with anti-histamines and/or acetaminophen when appropriate. 
 
Rare but serious: 
 
• 
Graft versus host disease (GVHD). GVHD is a syndrome where donor cells target 
and attempt to reject normal tissues in the patient. The syndrome may include rash, 
diarrhea, nausea, vomiting, poor bone marrow function (resulting in low blood cell 


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counts), and abnormalities in liver function studies. GVHD is treated with steroids to
 
 
reduce inflammation from donor cells. Rarely GVHD can be fatal. 
• 
Infection. As with any blood product from another human being there is a risk of 
acquiring a viral or bacterial infection from the cell product. The donors will be tested 
for infections including hepatitis, HIV, and others according to standard protocol in 
order to minimize the risk of transmitting any infection. 
• 
Anaphylaxis: Rarely allergic reactions to the donor cell product may cause wheezing, 
swelling of the face or throat, or low blood pressure. 
 
 
11.2.4 General risks for patients undergoing chemotherapy: 
 
 
Infection:  Patients with low blood counts may be at risk of bacterial, fungal, and viral 
infections. Infusion of the donor cell product is not anticipated to increase the patient’s 
risk of infections during the treatment course. 
 
 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1    Complete Remission (CR) requires that all of the following criteria are met for at 
least 4 weeks: 
 
Peripheral Blood Counts:   The peripheral blood neutrophil count should be ≥1,500/µl 
(sustained without growth factor support), and the platelets count should be ≥100,000/µl 
(without transfusion).  No circulating blasts (in the absence of growth factor) should be 
detected. 
 
Bone Marrow Aspirate:   The cellularity of the bone marrow should approximate normal. 
There must be evidence of maturation of all cell lines.   The bone marrow aspirate should 
contain < 5% blasts.  Auer rods should not be detected. 
 
Extramedullary   Leukemia:      Extramedullary   leukemia,   such   as   CNS   or   soft   tissue 
involvement, must not be present. 
 
12.2    CRp (Complete Remission with Incomplete Platelet Recovery) is defined as CR, 
except that a platelet count is not specified although platelet transfusion-independence must 
be maintained for at least one week. 
 
12.3    Partial Remission (PR) requires that all criteria for CR be met except that the bone 
marrow may contain > 5% but < 25% blasts.  A value of ≤ 5% blasts in the presence of Auer 
rods or abnormal morphology is also considered a PR. 
 
12.4    Treatment  Failures  include  patients  who  do  not  achieve  a  CR  or  PR  due  to 
persistent disease or complications of cytopenias. 
 
12.5    Relapse is defined as reappearance of blasts in the blood or the finding of > 5% 
blasts in the bone marrow not attributable to another cause. 


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the chemotherapy, toxicity from prophylactic measures and treatment procedures for side 
effects and complications, pancytopenic complications such as infections, and immunological 
complications such as GVHD. 
 
12.7    Graft versus Host Disease (GVHD) 
 
Acute GVHD is manifested by skin rash, nausea, vomiting, diarrhea and ulceration of the 
intestines, hyperbilirubinemia and hepatitis, and suppressed or delayed recovery of the 
hematopoietic and immune system. Standard BMT-CTN and IBMTR systems clinical criteria 
will be used to establish and grade acute GVHD (See appendix A).[30] In the first 100 days 
after  stem cell infusion patients will be assessed for the development  of  acute GVHD. 
Patients with acute GVHD will be treated with immunosuppression as per standard Adult 
Allogeneic Bone Marrow Transplantation service guidelines. 
 
Chronic GVHD is characterized to varying degrees by sclerosis of lacrimal and salivary 
ducts, scleroderma-like changes of the skin, chronic inflammation and scarring of the 
gastrointestinal tract with consequent malabsorption and diarrhea, inflammation of the liver, 
suppression of the immune system and occasionally other auto-immune phenomena (e.g. 
auto-immune hemolysis) or involvement of other organs (e.g. pulmonary involvement). 
Chronic GVHD will be diagnosed and graded according to NIH consensus criteria.[31] 
Patients will be assessed for chronic GVHD at day 100, 6 months and annually after stem 
cell infusion, and more frequently if clinically indicated. Chronic GVHD will be treated with 
standard immunosuppressive therapy as per standard Adult Allogeneic Bone Marrow 
Transplantation service guidelines. 
 
12.8    Poor Hematopoietic Recovery 
 
 
Hematopoietic failure is diagnosed when (1) the patient fails to achieve an ANC ≥ 500/µl for 3 
consecutive days within the first 42 days post-stem cell infusion in a patient who had a 
sustained ANC ≥ 500/μL prior to therapy or (2) in the absence of relapse, there is absence of 
patient cells in the blood and/or marrow as demonstrated by chimerism assay. If the clinical 
criteria for bone marrow failure are fulfilled, infusion of donor stem cells will occur within 2 
months of G-PBSC infusion. 
 
 
12.9    Early Deaths 
 
Early  deaths  are  defined  those  patients  who  die  within  4  weeks  of  beginning  therapy. 
Patients  who  die  of  treatment  associated  complications  before  this  timeline  will  be 
considered early deaths and inevaluable for leukemia response, but evaluable for toxicity 
and overall survival (OS). 
 
12.10  Lost to Follow Up 
 
Those patients, in whom there is inadequate information to determine response to therapy or 
toxicity due to loss of contact with the patient, will be considered lost to follow-up and will be 
deemed inevaluable. 


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12.11  Major Protocol Violation 
 
Deviations from the treatment program by either adding a therapeutic agent, or receiving 
concomitant radio- or other chemotherapy will be considered a major protocol violation. 
Patients who receive care that is considered to be a major protocol violation will be deemed 
inevaluable. 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
If at any time the patient is found to be ineligible for the protocol as designated in the section 
on Criteria for patient/subject eligibility (e.g. a change in diagnosis), the patient will be 
removed from the study.   Participants may be removed from the study if at any time it is 
determined to be in the participant’s best interest to do so.  Also patients may be removed 
from the study if requested by the patient. Management will depend on where they are in 
their treatment course. Such patients will receive appropriate supportive care. 
 
 
 
14.0 
BIOSTATISTICS 
 
This is a pilot study designed to assess the feasibility and an initial study of the efficacy of 
chemotherapy followed by G-CSF mobilized stem cells from haplo-identical related donors of AML 
patients above the age of 60. The study will use a two-step enrollment process. First, patients 
eligible for this study with potential haplo-identical donors will be registered. Second, potential 
donors are screened by HLA/KIR genotype, and the immunogenetically optimal donor selected. The 
feasibility objective will examine whether a sufficient percentage of prospective patients that are 
eligible for this protocol are enrolled and undergo the stem cell infusion. The efficacy objective will 
provide pilot data for the response rate among patients that receive the stem cell infusion. 
 
To assess feasibility, we will determine the number of patients screened in order to treat 15 patients 
with the stem cell infusion. For this endpoint, a success indicates that a screened patient undergoes 
the infusion. A design that differentiates between success rates of 0.10 and 0.20 will be used to 
determine feasibility. If less than 90 patients are screened in order to attain the 15 patients that are 
treated with the stem cell infusion, then we will declare this approach feasible. The probability of 
declaring the screening process feasible is ≤ 0.10 when the success rate in the population is 0.10 
and increases to ≥ 0.90 when the success rate in the population is 0.20. The probability calculations 
are based on the negative binomial distribution. 
 
The study will be terminated in the event of a single observation of a grade III or IV graft versus host 
disease, a death due to the stem cell infusion, or a recorded aplasia within 42 days of the infusion. 
 
At the conclusion of the study, the following descriptive statistics will be generated: 
 
• 
The probability of receiving treatment among patients enrolled on the study 
• 
The probability of a complete response 
• 
The median duration of neutropenia and thrombocytopenia 
• 
The median duration of hospital stay 


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In addition, the cumulative incidence function will be used to generate over time the probability of 
treatment related mortality, graft versus host disease, grade 3-4 infection, and greater than 5% 
donor chimerism. Immunologic recovery of NK, T and B cell populations over time will be estimated 
using nonparametric curve smoothing methods. It is anticipated that the study will be completed 
within 18 months. If the study requires longer than 18 months for completion, then we will consider a 
modification to the study design in order to increase the accrual rate. 
 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/). The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.2 
Randomization 
 
There is no randomization. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study.  The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
 
The data collected for this study will be entered into the Clinical Research Database (CRDB). 
Source documentation will be available to support the computerized patient record. 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data.  Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to 
the attention of the study team for discussion and action 


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Page  24 of 30 
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Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
 
16.2    Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001.  The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html.   The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research.  The MSKCC Data and 
Safety     Monitoring     Plans     can     be     found     on     the     MSKCC     Intranet     at: 
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality.  There are institutional processes in place for quality assurance (e.g., protocol 
monitoring,  compliance  and  data  verification  audits,  therapeutic  response,  and  staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs.  The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required.  Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Risks: From the studies that have been done so far it appears that adding G-PBSC to 
standard induction chemotherapy can safely be performed in elderly patients with AML and 
that these patients may benefit from the treatment.  However, given this is a new treatment 
approach, it is possible that there are side effects that have not yet been seen. 
 
Benefits: This protocol may benefit patients by shortening the duration of chemotherapy- 
induced aplasia, reducing the related severe complications rate (infections, hemorrhagic 
events etc). This protocol may result in higher anti-leukemic activity compared to standard 
chemotherapy, achieving higher CR rate and translating in higher OS. The information from 
this study will help future leukemia patients. 
 
Possible toxicities/side effects: Toxicities and side effects of the agents used are listed in 
section 11 and reporting of serious adverse events is found in section 17.2. 
 
Consent Process: Participation in this study is voluntary. All patients will be required to sign 
a statement of informed consent which must conform to MSKCC IRB guidelines. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
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o A description of the subject’s condition 
Amended: 13-OCT-2015 
Page 25 of 30 
 
 
Alternatives:   Alternative treatment options will be presented to the patient prior to taking 
part in this study. Alternative treatment options may include getting treatment with standard 
chemotherapy; taking part in another study; or getting no treatment. 
 
Costs/Incentives: No incentives will be offered to patients/subjects for participation in the 
study.  Participation is voluntary.  The patient/subject will be responsible for the costs of 
standard  medical  care,  including  the  conventional  agents  cytarabine  and  filgrastim, 
antibiotics, blood and platelet transfusions, radiographic studies, laboratory tests, and all 
hospitalizations, even for complications of treatment. Research tests will be done at no cost 
to the patient. 
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential. 
 
 
 
17.1 
Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at  sae@mskcc.org. The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 


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o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FDA by the 
SAE staff through the IND Office. 
 
All patients will be followed for safety and toxicity related to the study. Potentially serious 
toxicities are an expected part of this therapy. The reportable serious adverse events (SAEs) 
will be defined according to current MSKCC BMT Service SAE Guide (Appendix B). 
 
 
 
17.2.1 
 
If this protocol is an Industry or Cooperative group protocol, the SAE reporting information 
should also be included in this section. If the protocol has an IND, this section should include 
that the SAE will also be reported to the FDA through the IND Office and that the report must 
include the FDA assigned BB-IDE, BB-IND or IND number and name. 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Patients recruited to this study are elderly individuals with newly diagnosed or relapsed AML 
who are suitable for intensive chemotherapy. 
 
Prior to consideration for this study, all patients undergo a series of consultations discussing 
the risks and potential benefits of induction chemotherapy and the different procedures which 
are  a  normal  part  of  the  leukemia  treatment.  The  risks  and  potential  benefits  of  the 
procedure, as well as the participation in a research protocol are also discussed. 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
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Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. Related donors will also sign a consent 
form, which reviews the risks and alternatives to G-CSF-elicited PBSC mobilization, and 
collection of PBSC via leukapheresis. 
 
 
 
 
 
19.0 
REFERENCES 
 
1. 
Altekruse, S., C. Kosary, and M. Krapcho, SEER Cancer Statistics Review, 1975- 
 
2007, National Cancer Institute. Bethesda, MD, 
http://seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data 
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2. 
Jemal, A., et al., Cancer statistics, 2009. CA Cancer J Clin, 2009. 59(4): p. 225-49. 
 
3. 
Tallman, M.S., New strategies for the treatment of acute myeloid leukemia including 
antibodies and other novel agents. Hematology Am Soc Hematol Educ Program, 
2005: p. 143-50. 
 
4. 
Appelbaum, F.R., et al., Age and acute myeloid leukemia. Blood, 2006. 107(9): p. 
 
3481-5. 
 
5. 
Ai, H.S., et al., [Multicenter report of nonmyeloablative allogeneic stem cell 
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6. 
Estey, E., et al., Prospective feasibility analysis of reduced-intensity conditioning 
(RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients 
with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). 
Blood, 2007. 109(4): p. 1395-400. 
7. 
Slavin, S., et al., Nonmyeloablative stem cell transplantation and cell therapy as an 
alternative to conventional bone marrow transplantation with lethal cytoreduction for 
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8. 
Slavin, S., et al., Allogeneic cell therapy with donor peripheral blood cells and 
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9. 
Morris, E.S., K.P. MacDonald, and G.R. Hill, Stem cell mobilization with G-CSF 
 
analogs: a rational approach to separate GVHD and GVL? Blood, 2006. 107(9): p. 
 
3430-5. 
 
10. 
Guo, M., et al., Infusion of HLA-mismatched peripheral blood stem cells improves the 
outcome of chemotherapy for acute myeloid leukemia in elderly patients. Blood, 
2011. 117(3): p. 936-41. 
 
11. 
Guo, M., et al., HLA-mismatched stem-cell microtransplantation as postremission 
therapy for acute myeloid leukemia: long-term follow-up. J Clin Oncol, 2012. 30(33): 
p. 4084-90. 
12. 
Ballen, K.K., et al., Low-dose total body irradiation followed by allogeneic lymphocyte 
infusion may induce remission in patients with refractory hematologic malignancy. 
Blood, 2002. 100(2): p. 442-50. 
13. 
Porter, D.L., et al., Graft-versus-tumor induction with donor leukocyte infusions as 
primary therapy for patients with malignancies. J Clin Oncol, 1999. 17(4): p. 1234. 
14. 
Porter, D.L., et al., Allogeneic cell therapy for patients who relapse after autologous 
stem cell transplantation. Biol Blood Marrow Transplant, 2001. 7(4): p. 230-8. 
15. 
Andrews, G.A., Criticality accidents in Vinca, Yugoslavia, and Oak Ridge, Tennessee. 
 
Comparison of radiation injuries and results of therapy. Jama, 1962. 179: p. 191-7. 
 
16. 
Mathe, G., Application of hematopoietic cell grafts to the treatment of leukemias and 
allied diseases. A critical review. Blood, 1960. 16: p. 1073-88. 
17. 
Ponce, D.M., et al., Reduced late mortality risk contributes to similar survival after 
double-unit cord blood transplantation compared with related and unrelated donor 
hematopoietic stem cell transplantation. Biol Blood Marrow Transplant, 2011. 17(9): 
p. 1316-26. 
18. 
Fernandez, M.N., Improving the outcome of cord blood transplantation: use of 
mobilized HSC and other cells from third party donors. Br J Haematol, 2009. 147(2): 
p. 161-76. 
19. 
Fernandez, M.N., et al., Unrelated umbilical cord blood transplants in adults: Early 
recovery of neutrophils by supportive co-transplantation of a low number of highly 
purified peripheral blood CD34+ cells from an HLA-haploidentical donor. Exp 
Hematol, 2003. 31(6): p. 535-44. 
20. 
Medina, D.J., et al., A pilot study of allogeneic cellular therapy for patients with 
advanced hematologic malignancies. Leuk Res, 2008. 32(12): p. 1842-8. 
21. 
Strair, R.K., et al., Antineoplastic effects of partially HLA-matched irradiated blood 
mononuclear cells in patients with renal cell carcinoma. J Clin Oncol, 2003. 21(20): p. 
3785-91. 


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22. 
Rezvani, K., et al., Leukemia-associated antigen-specific T-cell responses following 
combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies. 
Blood, 2008. 111(1): p. 236-42. 
23. 
Ruggeri, L., et al., Effectiveness of donor natural killer cell alloreactivity in 
mismatched hematopoietic transplants. Science, 2002. 295(5562): p. 2097-100. 
24. 
Miller, J.S., et al., Successful adoptive transfer and in vivo expansion of human 
haploidentical NK cells in patients with cancer. Blood, 2005. 105(8): p. 3051-7. 
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Rubnitz, J.E., et al., NKAML: a pilot study to determine the safety and feasibility of 
haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J 
Clin Oncol, 2010. 28(6): p. 955-9. 
26. 
Hsu, K.C., et al., Improved outcome in HLA-identical sibling hematopoietic stem-cell 
transplantation for acute myelogenous leukemia predicted by KIR and HLA 
genotypes. Blood, 2005. 105(12): p. 4878-84. 
27. 
Guinan, K.J., et al., Receptor systems controlling natural killer cell function are 
genetically stratified in Europe. Genes Immun, 2010. 11(1): p. 67-78. 
28. 
Chewning, J.H., et al., KIR2DS1-positive NK cells mediate alloresponse against the 
 
C2 HLA-KIR ligand group in vitro. J Immunol, 2007. 179(2): p. 854-68. 
 
29. 
Fauriat, C., et al., Education of human natural killer cells by activating killer cell 
immunoglobulin-like receptors. Blood, 2010. 115(6): p. 1166-74. 
30. 
Rowlings, P.A., et al., IBMTR Severity Index for grading acute graft-versus-host 
disease: retrospective comparison with Glucksberg grade. Br J Haematol, 1997. 
97(4): p. 855-64. 
 
31. 
Filipovich, A.H., et al., National Institutes of Health consensus development project on 
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20.0 
APPENDICES 
 
Appendix A: Acute GVHD Grading Scale (IBMTR) [30] 
 
Skin Involvement 
Liver Involvement 
Bowel Involvement 
 
Index* 
Stage 
Extent of rash 
Stage 
Total bilirubin 
(µmol/L) 
Stage 
Volume of 
diarrhea (mL/day) 
A 
1 
< 25% 
1 
< 34 
1 
< 500 
B 
2 
25-50% 
2 
34-102 
2 
500-1500 
C 
3 
>50% 
3 
103-255 
3 
>1500 
D 
4 
Bullae 
or 
4 
> 255 
or 
4 
Severe pain or 
ileus 
*Assigned based on maximum involvement in an individual organ system. 
 
 
 
 
Appendix B:  MSKCC BMT Service SAE Guide