A Prospective Study of Optimal Cord Selection for Haplo-Cord Transplantation: Targeting the Inherited Paternal Antigen (IPA) and Matching for the Non-Inherited Maternal Antigen (NIMA)
Phase: PHASE2
Conditions: Hematologic Malignancies
Sponsor: Weill Medical College of Cornell University

Title: A Prospective Study of Optimal Cord Selection for Haplo-Cord Transplantation: targeting the 
Inherited Paternal Antigen (IPA) and Matching for the Non-Inherited Maternal Antigen (NIMA) 
NCT01810588 
Initial IRB Approval Date: 8/13/2012 
 
Amendment History 
• 
Amendment #1 16DEC2013 
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Amendment #2 26APR2013 
• 
Amendment #3 01AUG2013 
• 
Amendment #4 09JUN2014 
• 
Amendment #5 23SEP2014 
• 
Amendment #6 30JUN2015 
• 
Amendment #7 24APR2017 
• 
Amendment #8 14JUN2017 
• 
Amendment #9 07MAY2018 
• 
Amendment #10 18OCT2018 
• 
Amendment #11 10SEP2020 
• 
Amendment #12 08JUL2022 

IRB Protocol Number: 1205012383 
 
Version: 08JUL2022 
 
 
 
 
 
 
 
TITLE:  A Prospective Study of Optimal Cord Selection for Haplo-Cord Transplantation: 
targeting the Inherited Paternal Antigen (IPA) and Matching for the Non-Inherited 
Maternal Antigen (NIMA)  
 
 
Principal Investigator: 
Alexandra Gomez Arteaga, MD 
                                                525 East 68th Street 
                                                Telephone: (646) 962-7950 
                                                Fax: (212) 746-6678 
                                               alg9117@med.cornell.edu 
 
U Chicago PI:  
 
Hongtao Liu, MD, PhD 
 
 
 
 
Section of Hematology/Oncology 
 
 
 
 
University of Chicago Medical Center 
 
 
 
 
5901 S. Maryland Ave 
 
 
 
 
Chicago, Il, 60637 
 
 
 
 
hliu2@medicine.bsd.uchicago.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IRB Protocol Number: 1205012383 
 
Version: 08JUL2022 
 
 
 
STUDY SCHEMA 
 
1. 
INCLUSION/EXCLUSION: See Section 3 
 
2. 
ENROLLMENT: All potential participants will have complete human leukocyte antigen 
(HLA) typing and determination of HLA antibodies.   
 
3. 
TREATMENT PLAN: 
 
Conditioning Regimen: 
 
 
Day -7 
Day -6  
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0 
 Day 1 
or day 0 
Fludarabine 
 
30 mg/m2 
30 mg/m2 
30 mg/m2 
30 mg/m2 
30mg/m2 
 
 
Haplo 
Stemcell 
UCB stem 
cell 
Melphalan 
 
 
 
 
 
 
140 mg/m2 
 
 
 
rATG 
 
1.5 mg/kg 
 
1.5 mg/kg 
 
1.5 mg/kg 
 
 
 
TBI* 
 
2Gray 
2Gray 
 
 
 
 
Fludarabine: 30 mg/m2 /day IV x 5 days total dose 150 mg/m2. Fludarabine will be dosed 
according to actual body weight.  
 
Melphalan: 140mg/m2/day IV x 1 day. Melphalan will be dosed according to actual body weight. 
Cryotherapy with ice chips will be administered to prevent mucositis.  
 
Rabbit ATG (rATG): 1.5 mg/kg/day IV x x3 days total 4.5 mg/kg for all patients. ATG will be 
dosed according to actual body weight. The first dose will be infused over at least six hours, and 
subsequent doses over at least 4 hours.  Pre-medications include acetaminophen 650 mg PO, 
diphenhydramine 25-50 mg PO/IV, and methylprednisolone 2 mg/kg (1 mg/ kg at the initiation 
and 1 mg/kg half-way through anti-thymocyte globulin administration). 
Circumstances may require minor changes in scheduling of chemotherapy. Variations of up to 24 
hours in scheduling will be acceptable. 
 
Rituximab for prevention of PTLD: All patients not previously exposed to rituximab or who 
have not received rituximab in the six months prior to transplant, will receive one dose of rituximab 
375 mg/m2 prior to or upon admission.  
 
TBI*: Because of occasional cases of graft failure, condition has been intensified for certain 
groups of patients. Patients at high risk for CNS relapse (e.g ALL or Burkitt’s), or patients at high 
risk for graft rejection (i.e., donor-specific HLA antibodies, patients with severe aplastic anemia 
or hemoglobinopathies) may receive 2 doses of TBI as part of the conditioning 
 
GVHD Prophylaxis: 
Tacrolimus: 0.03 mg/kg/day IV continuous infusion (CI) over 24 hr from 4 PM Day -2 until 
engraftment or when subject is able to take PO, then tacrolimus approximately 0.09 mg/kg PO in 

IRB Protocol Number: 1205012383 
 
Version: 08JUL2022 
 
 
 
2 divided doses.   Tacrolimus should be given at full dose to maintain levels of 5-15 ng/mL through 
day 180, tapered by 20% every week thereafter. Infection, toxicity or other clinical circumstances 
may prompt earlier discontinuation or adjustment of doses. In the presence of GVHD, a clinical 
decision by the attending physician will determine if tacrolimus can be tapered or should be 
continued. PO tacrolimus can be used when IV access for CI tacrolimus is unavailable.  
 
Mycophenolate Mofetil (MMF): will be started on day -2 and given at a dose of 1000 mg q 8 
hours until day 28. MMF can be given PO or IV. Infection, toxicity, very low patient weight 
(<50kg) may prompt earlier discontinuation or adjustment of doses. 
 
Note: Patient specific circumstances may mandate minor variations in conditioning regimen and/or 
GVHD prophylaxis, such as reduction of some of the doses of medications, changes in schedule 
or-rarely- substitution of a particular drug. These changes will be noted and justified, but will not 
require IRB approval. Refer to Section 2.9.4 for further details. 
 
Stem Cell infusion:  
The infusion of UCB and the haplo-identical units will be separated by at least 2 hours and 
preferably they will occur on successive days (Day 0 and Day 1).  The order of infusion is not 
specified.  
 
Supportive care: 
 
In case of cytomegalovirus (CMV) sero-positivity of donor and/or recipient, CMV prophylaxis 
will use high dose ganciclovir and (val) acyclovir as outlined below. Adjustment for renal 
dysfunction should follow institutional guidelines.  
 
Supportive Care Schedule 
 
Admission to Day -2 
Day -1 until 
engraftment 
Engraftment until 
Day 210 
Day 210 
Ganciclovir 
5mg/kg IV q 12hrs 
Acyclovir 
500mg/m2 IV q 8hrs 
(or equivalent PO) 
Valacyclovir 
2gm PO QID 
Acyclovir 
400 mg po TID (or 
equivalent IV) 
 
CMV seronegative donor and recipients: Acylovir 400 mg po TID or IV equivalent. 
 
• A prophylactic broad-spectrum antifungal with anti-mold activity is strongly recommended.  
• Other infection prophylaxis and supportive care will be as per institutional unit policy. 
In some cases, a drug called filgrastim (G-CSF) may be administered to hasten the recovery of 
blood counts. Generic formulations of filgrastim may be utilized as required by insurance or 
pharmacy.  
• Blood transfusion policy should follow institutional policy.  
• Cytomegalovirus (CMV)  monitoring  at least weekly until Day 100 and at least monthly until 
Day 210, regardless of donor/recipient CMV status. Pre-emptive CMV treatment should be 
strongly considered for any positive result on by DNA testing (i.e, viral load) within the first 
100 days of transplant. 

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• Epstein-Barr virus (EBV)  monitoring: 
o EBV viral load monitoring by PCR at least weekly until Day 100 and at least monthly until 
Day 365 is strongly recommended. 
o Rising 
EBV 
titers 
should 
warrant 
investigation 
for 
EBV 
post-transplant 
lymphoproliferative disorder (PTLD) including CT imaging and PET scanning for positive 
CT findings. A bone marrow evaluation is recommended if any evidence of PTLD by 
imaging or on peripheral blood findings  
o Evidence of PTLD or consecutive increases in EBV PCR should lead to treatment with 
rituximab at a dose and schedule per institutional policy.   

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TABLE OF CONTENTS 
 
 
Page 
SCHEMA ........................................................................................................................................ i 
 
1.0  OBJECTIVES .........................................................................................................................1 
1.1 
Primary Objectives ......................................................................................................1 
1.2 
Secondary Objectives ..................................................................................................1 
 
2.0  BACKGROUND .....................................................................................................................1 
2.1  
Umbilical-cord Blood Transplantation in Hematologic Malignancies ...................1 
2.2 
Haplo-cord Transplantation .......................................................................................2 
2.3 
Umbilical Cord Blood Transplant and GVL Effect .................................................2 
2.4 
NIMA (Non-inherited maternal antigens) and Tolerance Induction .....................3 
2.5 
Novel Determinants of Graft Failure after UCB SCT: HLA Antibodies and 
 
Graft Viability ..............................................................................................................3 
2.6 
Rationale for the current study ..................................................................................4 
2.7 
Conflict with Other Studies ........................................................................................5 
2.8    
Adjustment of dose of ATG for older patients and use of Low Dose TBI for 
patients at high risk of CNS recurrence………………......………………………..5 
2.9 
Protocol Amendments……………………………………………………………….5 
2.9.1 Adjustment of Dose of ATG for All Patients and Inclusion of Mismatched 
Unrelated Donors as Alternative to Haplo-Related Donors………………………5 
2.9.2 Extension of indications for use of TBI; Establishment of minimal acceptable 
CBU dose and increasing cohort size……………………………………………….6 
2.9.3 Changes in Primary Objective……………………………………………………...6 
2.9.4 Various Changes…………………………………………………………………..…8 
 
 
3.0  SUBJECT SELECTION ........................................................................................................8 
3.1 
Inclusion Criteria  ........................................................................................................8 
3.2 
Exclusion Criteria ........................................................................................................9 
 
4.0  ENROLLMENT AND REGISTRATION PROCEDURES ...............................................9 
4.1  
Central Patient Registration .....................................................................................10 
 
5.0  STEM CELL SOURCE AND CELL DOSE ......................................................................10 
5.1 
UCB Unit ....................................................................................................................10 
5.2 
Third Party Donor .....................................................................................................11 
5.3 
Infusion of Cells .........................................................................................................11 
 
6.0  TREATMENT PLAN ...........................................................................................................12 
6.1  
Conditioning Regimen ...............................................................................................12 
6.2 
Post-Transplant Course (GVHD Prophylaxis) .......................................................12 
6.3 
Supportive Care .........................................................................................................13 
 

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7.0  PRE-TRANSPLANT EVALUATION ................................................................................14 
 
8.0  POST-TRANSPLANT EVALUATION ..............................................................................15 
 
9.0  ADVERSE EVENT REPORTING REQUIREMENTS ....................................................17 
9.1  
Investigational Risks ..................................................................................................17 
9.2  
Adverse Event Characteristics..................................................................................17 
9.3  
Recording and Reporting of Adverse Events ..........................................................18 
9.4  
Reporting of Adverse Events to FDA .......................................................................18 
 
 
10.0 CRITERIA FOR STUDY EVALUATION .......................................................................19 
 
11.0 STATISTICAL CONSIDERATIONS ...............................................................................20 
 
 
12.0   CRITERIA FOR REMOVAL OF SUBJECTS FROM PROTOCOL THERAPY .....22 
12.1 
Disease progression or Disease Persistence .............................................................22 
12.2 
Extraordinary Medical Circumstances ...................................................................22 
 
13.0   DATA, SAMPLE AND PROTOCOL MANAGEMENT ...............................................22 
 
14.0 
DATA SAFETY MONITORING BOARD ...................................................................23 
 
15. REGULATORY CONSIDERATIONS ...............................................................................23 
15.1 
Institutional Review Board/Ethics Committee Approval ......................................23 
15.2 
Informed Consent Procedures ..................................................................................24 
15.3  
Protecting privacy and confidentiality ....................................................................24 
15.4 
Study Records Requirements ...................................................................................24 
15.5 
Protection of Human Rights .....................................................................................25 
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ...............................................................................................26 
 
APPENDIX B 
WCMC SAE Reporting Forms ..........................................................................................27 
 
 
APPENDIX C 
Background Drug Information ...........................................................................................28 
 
REFERENCES .............................................................................................................................33 
 

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1.0 OBJECTIVES 
 
     1.1     Primary Objective 
 
• To provide access to haplo-cord transplants for patients in need of alternative donor 
transplant and to determine long-term outcomes. 
 
     1.2     Secondary Objectives 
• To evaluate  outcomes of subjects undergoing haplo cord transplants using an 
optimally matched umbilical cord blood (UCB) graft including overall survival, 
profession-free survival (PFS), relapse, transplant-related mortality (TRM), toxicities, 
infections and GVHD) 
• To determine the proportion of units selected for optimal Inherited Paternal Antigen  
(IPA) targeted and Non-Inherited Maternal Antigen (NIMA) matched transplant. 
• To conduct preliminary studies of the impact of IPA targeting and NIMA matching 
on transplant outcome 
• To evaluate outcomes in specific disease subgroups. 
 
2.0 BACKGROUND 
 
2.1     Umbilical-Cord Blood Transplantation in Hematologic Malignancies 
 
Transplantation of hematopoietic stem cells derived from bone marrow and peripheral blood of 
siblings and unrelated donors have been successfully used to treat patients with high-risk or 
recurrent hematological malignancies.  However, allogeneic hematopoietic cell transplants 
(HCT) are limited by the lack of human leukocyte antigen (HLA) matched donors and the high 
risk of graft-versus-host disease (GVHD) after transplantation.  Although there are more than 18 
million registered donors worldwide, more than 30% of patients requiring transplants are unable 
to find a matched donor.1  This proportion is higher for patients of minority descent.  Patients 
who receive unmatched transplants have decreased survival secondary to severe GVHD (80%) 
and opportunistic infections.2  
 
In order to increase the donor pool, umbilical cord blood (UCB) UCB is now being used for 
transplants.  UCB matching is less stringent than for adult donors as matches at class I loci of 
HLA-A and HLA-B are determined by intermediate resolution techniques, essentially ignoring 
allele level mismatches. Moreover, HLA-C has generally been ignored until recently. HLA-
DRB1 however, is matched at high resolution.  Therefore, UCB matching is limited to matching 
at 6 loci, HLA-A, B, and DRB1 on each haplotype whereas matching for adult unrelated donors 
considers at least HLA-A, B, C and DRB-1 loci and sometimes additional loci. Unrelated UCB 
transplants have a low risk of acute GVHD even in the 1-2 HLA mismatched setting in children3-
5 and adults.6  However, delayed engraftment and associated treatment-related toxicity and 
opportunistic infections result in high treatment-related mortality from slow engraftment. Most 
studies show a median time to neutrophil recovery of 16 to 24 days, with a considerable 
proportion of patients having very delayed neutrophil and platelet recovery. For those whose 

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neutrophil recovery is delayed beyond approximately 16 days after transplant, the risk for 
treatment related mortality rapidly increases with further delays.7;8 
 
Laughlin et al emphasized the importance of nucleated cell dose as a predictor of hematopoietic 
recovery. 6    Subsequently Eapen et al showed that HLA matching also affects survival, with 6/6 
matches faring better than 5/6 or 4/6 matches.9 Cell dose was important only with less well 
matched grafts. In other words, a 6/6 graft with low cell dose (<2.5 x 107 total nucleated cells per 
kilogram) resulted in equivalent outcomes to a 4/6 graft with higher cell doses.  
 
The standard decision algorithm emphasizes cell dose and utilizes >2.5 x107 nucleated cells/kg 
as a minimum threshold. Using this threshold, 5/6 cords can be identified for approximately 60% 
of whites, but only approximately 20% of blacks or other minorities.10  
 
2.2   Haplo-Cord Transplantation  
 
Disappointed with the delayed engraftment after cord blood transplantation, several groups have 
tried to enhance recovery by (1) in vitro expansion of cords;8 (2) infusion of multiple cords;9 or 
(3) combination of cord blood transplant with cells from other origins.11 We recently completed 
a study of haplo-cord transplantation.12 For a detailed explanation of the procedure we refer to 
our recent publication. In brief, we transplant after reduced intensity conditioning two very 
different stem cell products: a related haplo-identical graft that is in-vitro CD34 enriched (in 
effect removing haplo T cells) and an UCB graft. 
 
We conducted a 45 subject prospective study of this procedure. Median age was 50; weight 80 
kg and 58% had active disease. Neutrophil engraftment occurred at 11 days (Interquartile range 
(IQR), 9 -15) and platelet engraftment at 19 days (IQR, 15-33). In the majority of subjects, early 
haplo-identical engraftment was replaced by durable engraftment of umbilical cord blood by 100 
days, with regular persistence of minor cell populations of host and/or haplo-hematopoiesis. 
Higher haplo chimerism at Day 100 correlated with greater haplo CD34 dose (p=0.003). The 
cumulative incidence of acute GVHD was 25% and chronic GVHD was 5%.  Actuarial survival 
at one year was 55%, profession-free survival was 42%, non-relapse mortality was 28% and 
relapse was 30%.  We concluded that reduced intensity conditioning and haplo-cord transplant 
result in fast engraftment of neutrophils and platelets, low incidences of acute and chronic 
GVHD, low frequency of delayed opportunistic infections and promising long term outcomes. 
Compared to double UCB transplant, transfusion requirements are reduced and length of hospital 
stay is shortened. UCB cell dose no longer had an impact on time to hematopoietic recovery as 
opposed to studies of UCB studies not augmented by a haplo graft. A group at the National 
Institute of Health has reported similar encouraging data.13 
 
2.3 Umbilical Cord Blood Transplant and Graft versus Leukemia (GVL) Effect 
 
In our series, haplo cord stem cell transplant was associated with a quantitative reduction in rate 
of recurrence compared to adult unrelated or related donor transplant (unpublished data), though 
the difference has not reached statistical significance in this small study. More compelling data 
on the effects of UCB transplant on rates of recurrence have been reported by others.14 The 
reasons for the reduced rate of disease recurrence after UCB transplant has until recently 

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remained elusive, but may be explained by the presence in the umbilical cord graft of a 
substantial number of lymphocytes of maternal origin that are primed against the paternal HLA-
haplotype of the fetus (the inherited paternal antigen or  IPA). 
 
It has long been known that cord blood contains between 0.1% and 0.5% lymphocytes of 
maternal origin.15 These lymphocytes are protected from immune mediated destruction by the 
presence of a very high number of fetal T-regulatory cells.  At the same time, the maternal cells 
residing and surviving within the umbilical cord are exposed to the IPA antigens expressed on 
the child’s cells. In the large majority of cases, the IPA HLA haplotype is not present in these 
maternal cells; they are foreign antigens and the maternal cells experience them as foreign and 
are primed to them.  Van Rood et al speculated that the IPA-primed maternal cells were 
responsible for the graft versus leukemia (GVL) activity of the cord and that a similar 
mechanism explained why haplo-identical transplant from a mother to her child is associated 
with less relapse than that from a father.  In an elegant study, they analyzed for a large number of 
UCB transplants, the HLA type of both mother and UCB and deduced the IPA of the UCB.16  By 
comparing those to the HLA antigens of the recipient patients, they identified transplant cases 
with IPA-targeting UCB (i.e. cases in which the maternal lymphocytes would be primed against 
the IPA of the UCB and also against the recipient.) They compared their outcome with that of the 
rare cases where there was no IPA reactivity. (These are cases where father and mother have a 
common HLA-haplotype, and the IPA is not foreign to the maternal cells). They found a much 
increased rate of disease recurrence in the latter. This phenomenon was mostly observed in 
recipients of well-matched transplants (5/6 matched). Importantly the decreased recurrence rate 
after IPA targeted UCB SCT was not associated with increased GVHD.  
 
2.4 NIMA (Non-inherited Maternal Antigens) and Tolerance Induction 
 
A similar reasoning underpins the observations of reduced GVHD when umbilical cords are 
selected that match the recipient for NIMA (the non-inherited maternal antigen). Umbilical cord 
blood cells, in utero have been exposed to NIMA antigens, which are, in the majority of cases 
foreign to them. This prolonged exposure leads to tolerance to these NIMA antigens. 
Most umbilical cord blood transplants are conducted using HLA mismatched cords. Under usual 
circumstances, when the UCB cells are infused in the host, they recognize the host HLA as 
foreign and can cause GVHD (though at a lower frequency and intensity than adult grafts).  
But if the host HLA mismatch happens to be an antigen that was also present in the UCB’s 
mother (i.e. NIMA antigen), then the UCB cells have been rendered tolerant to that antigen, will 
not recognize it as foreign and they will not cause GVHD. This is called a NIMA matched 
transplant (but HLA mismatched).   This principle again was investigated by van Rood et al in a 
study comparing the outcomes of NIMA matched UCB transplant with that of NIMA 
mismatches.17 In principle, it is possible to find NIMA matched UCB grafts in a substantial 
fraction of donor recipient combinations.  
 
2.5 Novel Determinants of Graft Failure after UCB SCT: HLA Antibodies and Graft 
Viability 
 
Graft failure has frequently been observed after cord blood transplant and until recently the 
mechanism was not understood.  An increasing percentage of graft failures can however be 

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attributed to the presence of donor specific anti- HLA antibodies present in a substantial minority 
of patients. Avoidance of UCB units that are targeted by anti-HLA antibodies should decrease 
the risk for graft failure.18;19 
 
Viability of the umbilical cord graft as determined upon thawing is also emerging as a potentially 
important predictor of engraftment.  Cords with <75% viability tend to engraft poorly and 
account for up to 20% of grafts in some studies. 20 
 
2.6 Rationale for the Current Study 
 
Our pilot study of haplo-cord SCT established that early hematopoietic recovery is extremely 
rapid and appears independent of the UCB cell dose. We also observed encouraging long term 
outcomes. Van Rood et al, provided preliminary evidence that  this GVL effect is mediated by 
IPA targeting of the graft, which is particularly operative in patients with at least 5/6 grafts. We 
speculate that identification of a graft that is at least 5/6 matched and IPA targeted (i.e., CB 
grafts share one or more IPA antigens with the prospective recipient) is more important to the 
outcome of haplo cord transplant than the nucleated cell dose. The identification of such a graft 
for a large proportion of the patients may necessitate accepting a lower UCB graft dose. 
 
Data provided to us by the National Marrow Donor Program (Courtesy Martin Maiers) clearly 
indicate the increased likelihood for identification of a 5/6 match with decreasing cord blood cell 
dose. 
 
 
Figure 1: Shows the likelihood of identifying a 5/6 matched donor in various ethnic groups. A 
cell dose of 2.5 TNC x 107 per kg (the current standard) allows the identification of a 5/6 
matched UCB in only 20% of African Americans and about 60% of Caucasians. A dose of 

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0.5x10^7 TNC allows finding a unit for 70% of African Americans and 90% of Caucasians. 
Similar findings apply to other ethnic groups. The purpose of this study is to establish in a 
prospective fashion the minimally acceptable UCB graft dose for successful haplo cord 
transplant and to obtain preliminary data on outcome of haplo cord SCT with optimally selected 
UCB units.  
 
In addition to establishing the minimal UCB cell dose, we will take into account the avoidance of 
donor specific HLA antibodies (DSA) and insist on a high UCB post-thaw viability.  
 
 
2.7 Conflict with Other Studies 
 
In parallel to this study, WCMC is conducting a randomized study of haplo-cord transplant vs. 
double umbilical cord blood transplant. The latter study takes precedent. There are many subjects 
who are not eligible for the randomized study due to disease or subject characteristics, lack of an 
adequate cord blood dose, or because some subjects refuse participation in randomized studies. 
Such subjects will be offered enrollment in this study. 
 
Addendum: This study was closed in 2016 and no longer presents a conflict. A BMT CTN 
randomized study comparing haplo-transplant with cord blood transplant opened to enrollment at 
WCMC in 2016, but has since closed to accrual and no longer presents a conflict. 
 
 
2.8 Adjustment of dose of ATG for older patients and use of Low Dose TBI for patients at 
high risk of CNS recurrence: 
Post-transplant lymphoproliferative disorder (PTLD) is a life threatening complication of 
allogeneic transplantation. It is often caused by EBV reactivation.  Three risk factors have been 
well defined: (1) T-cell depletion with narrow spectrum antibodies such as thymoglobulin. (2) 
recipient age >50 and (3) mismatched transplant including umbilical cord blood transplant. Some 
data suggest that the risk increases with increasing levels (~dose) of thymoglobulin. We have 
observed several cases of PTLD in our ongoing protocol, all occurring in patients over age 50. I 
order to reduce the risk for PTLD in this subgroup, we are decreasing the dose of ATG by 25%. 
For patient at high risk of CNS recurrence, particularly those with acute lymphoblastic leukemia 
(ALL), we will add low dose TBI (200 cGy x2) to the conditioning regimen. 
 
2.9 Protocol Amendments: 
 
2.9.1 Adjustment of Dose of ATG for All Patients and Inclusion of Mismatched Unrelated 
Donors as Alternative to Haplo-Related Donors 
 
Reduction in the dose of ATG (three instead of four doses) for older patients has been associated 
with a decrease in the incidence of PTLD. We now will implement this reduced dose for all 
patients regardless of age. 
 
We continue to regularly face patients who lack haplo-identical related donors or who have high 
levels of HLA antibodies directed against all haplo-identical related donors. For such patients we 

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now propose to utilize HLA mismatched unrelated donors, so chosen as not to be targeted by 
Donor specific antibodies. 
 
2.9.2 Extension of indications for use of TBI; Establishment of minimal acceptable CBU 
dose and increasing cohort size: 
 
We have used low dose TBI (200 cGy x 2) in patients at high risk for CNS recurrence. This has 
been generally well-tolerated. We now plan to also use this in patients at high risk for graft 
rejection - for example: those with benign hematologic disorders such as aplastic anemia and 
hemoglobinophathies and those with Donor Specific Antibodies.   
 
As we have systematically studied the use of ever lower CBU doses we have identified a lower 
CBU threshold dose. When analyzed by CBU cell dose, the incidence of UCB failure increased 
with decreasing UCB cell dose (P<0.001 U test). For example, there were 2 (6%) UCB failures 
for 30 evaluable pts with UCB cell dose >1.5 vs 5 (35%) UCB failures for 14 evaluable pts with 
UCB cell dose <1.5. Though the formal threshold for closing any cohort was not reached, the 
investigators concluded that a UCB cell dose of 1.2 x10^6 NC/kg was the minimum acceptable. 
We will continue accrual to this protocol to increase the number of patients and have robust 
estimates of secondary endpoints for all hematologic malignancies included. 
 
2.9.3 Changes in Primary Objective 
 
We have over the past years continued to accrue experience with the haplo-cord procedure and 
have identified short term outcomes and its predictors. Many aspects of our experience have 
been reported including determinants of engraftment and outcome (21-23), effects of variations 
in conditioning regimens(24), outcomes in specific disease entities(25),  comparisons with other 
approaches(26) and aspects of supportive care(27). As shown in Figure 2, long-term outcomes 
parallel those of matched unrelated or HLA-identical sibling transplantation. 

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But allogeneic transplantation is a procedure with long-term consequences and side-effects. Late 
complications and even late mortality can adversely affect outcomes beyond the initial years, 
particularly in patients with chronic GVHD.(28, 29) Furthermore, allogeneic transplantation is 
used across hematological malignancies and even for hemoglobinopathies and autoimmune 
disorders, some of which are quite rare. It is also used across age groups and -particularly in 
older patients- individual of various levels of frailty, with potentially major impacts on long-term 
outcome. Much therefore remains to be learned of this procedure; ongoing data collection of 
additional patients as well as long-term follow up is warranted. 
 
Additional concerns are the semi-investigational nature of both CD34 collection device and 
many umbilical cord blood products that are utilized under IND.  
 
Weill Cornell and University of Chicago are the leading centers for haplo-cord transplantation 
and our experience can be extremely useful to the transplant community.  
 
For all these reasons, we have modified the protocol to allow ongoing accrual of additional 
patients for the following three years at a rate of approximately 70 patients per year 
 
 
 
 

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2.9.4 Various changes 
Acceptable Deviations: To avoid frequent request for exemptions or waivers, the eligibility 
criteria are relaxed. Minor variations in conditioning regimens, GVHD prophylaxis, donor 
management and supportive care are allowed. This addresses the complexities of transplant care.  
 
Examples include: 
a) Adjustments in doses of melphalan and fludarabine may be necessitated by age or renal 
function. (30-32) 
b) Sirolmus may substitute for tacrolimus when serious tacrolimus toxicity occurs or is 
likely. (33) 
c) Mycophenolate dose may be reduced or discontinued for early toxicity. 
d) Pre-emptive Rituximab will be administered to patients not previously exposed. This 
should reduce risks of EBV reactivation and PTLD. (34) 
e) We have also eliminated several redundancies in post-transplant monitoring, including 
frequent thyroid function checks. 
 
3.0 SUBJECT SELECTION 
 
3.1     Inclusion Criteria 
 
Subjects will be eligible for this study if they have any one of the diseases that are known to be 
cured after allogeneic stem cell transplantation.   
 
 
All subjects have to fulfill the criteria listed below: 
 
1. Subject must have a confirmed diagnosis of one of the following:  
a. Relapsed or refractory acute leukemia (myeloid or lymphoid)   
b. Acute leukemia in first remission at high-risk for recurrence 
c. Chronic myelogenous leukemia in chronic, accelerated phase or blast-crisis 
d. Recurrent, refractory or high risk malignant lymphoma or Hodgkin’s lymphoma 
e. Chronic lymphocytic leukemia, relapsed or with poor prognostic features 
f. Multiple myeloma 
g. Myelodysplastic syndromes 
h. Chronic myeloproliferative disease 
i. Hemoglobinopathies 
j. Aplastic anemia 
k. Other hematological disorder in need of allogeneic transplant (e.g. blastoid 
dendritic cell neoplasm) 
2. Age ≥ 18 years  
3. Likely to benefit from allogeneic transplant in the opinion of the transplant physician 
4. An HLA-identical related or unrelated donor cannot be identified within an appropriate 
time frame 
5. Karnofsky (KPS) Performance status of  > 70% 

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6. Acceptable organ function as defined below: 
• Serum bilirubin: < 2.0 mg/dL 
• ALT(SGPT): < 3 X upper limit of normal 
• Creatinine Clearance: > 50 mL/min/1.73m2 (eGFR as estimated by the modified 
MDRD equation)  
• Patients whose organ function or KPS do not fulfill these criteria, may still be 
enrolled if considered appropriate transplant candidates and after discussion in 
transplant conference.  
7. Ability to understand and the willingness to sign a written informed consent document 
 
3.2     Exclusion Criteria 
 
 
1. Life expectancy is severely limited by concomitant illness or uncontrolled infection 
2. Severely decreased Left Ventricular Ejection Fraction (LVEF) or severely impaired 
pulmonary function tests (PFT’s) 
3. Evidence of chronic active hepatitis or cirrhosis 
4. Uncontrolled HIV disease 
5. Pregnant or lactating 
 
 
4.0 ENROLLMENT AND REGISTRATION PROCEDURES 
 
Subjects at Weill Cornell Medical College and at the University of Chicago will be enrolled 
simultaneously to reach the end goal of 300 total subjects across both sites.   
 
At University of Chicago, subjects will be screened for eligibility utilizing identical guidelines. 
A baseline eligibility form will be faxed to the transplant office at WCMC (212-746-6678) and 
the PI will be contacted (by WCMC).  Subjects will then be assigned to the cohort in sequential 
order by the WCMC team and the treatment assignment emailed and by telephone to Dr. Liu or 
her delegate. Researchers at Chicago shall not proceed with study procedures until they receive a 
confirmation of registration from WCMC, which will include the cohort assignment.  
 
 
Principal Investigator at University of Chicago: 
Hongtao Liu 
5841 S. Maryland Ave, MC 2115 
Room I210 
Chicago, IL 60637 
(773) 702-4400 
hliu2@medicine.bsd.uchicago.edu 
 
All potential recipients will have complete human leukocyte antigen (HLA) typing at HLA A, B, 
C, DR, DP and DQ and determination of HLA class I and II antibodies An appropriate donor 
source for haplo-cord transplant will have been identified. (See section 5.1 for definitions of 
donor source.) 

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4.1  Central Patient Registration 
 
Subjects will be centrally registered with the Weill Cornell Medical College (WCMC), Division 
of Hematology and Medical Oncology Clinical Research Office.  To register a subject, fax the 
following documents to the Clinical Research Office at (646) 962-1610: 
 
• WCMC Patient registration form 
• First and last page of the fully executed informed consent form, plus additional pages if 
checkboxes for correlative studies are required. 
• Fully executed HIPAA research authorization form 
• Eligibility checklist signed and dated by investigator and research nurse 
• Documentation of any eligibility waivers granted  
• For inpatients at WCMC, signed consent documentation template  
 
Central registration information is reviewed and entered into the HemOnc centralized research 
database.   
 
 
5.0 STEM CELL SOURCE AND CELL DOSE 
 
5.1 UCB UNIT 
 
The UCB unit must supply a minimum number of nucleated cells – this number depends on the 
study cohort to which the subject is assigned.  Three cohorts are anticipated.   
 
Cohort # 
 
 Minimal Cell Dose 
Number of Evaluable Subjects 
1 
2 x 10^7 TNC/kg 
10 
2 
1 x 10^7 TNC/kg 
10 
3 
0.5 x 10^7 TNC/kg 
10 
 
In cohort 1, the minimum required cell dose is 2.0x10^7 TNC/kg.  In cohort 2, the minimum 
required cell dose is 1.0x10^7 TNC/kg. In cohort 3, the minimum required cell dose is 0.5 x10^7 
TNC/kg. The unit must match at a minimum of 4 of 6 at HLA-A, -B, -DRB1 loci with the recipient. 
This may include 0-2 antigen mismatches at each A or B (at the antigen level) or DRB1 (at the 
allele level) loci. The best matched unit fulfilling the cell dose requirements should be utilized.  
 
All typing will be done using molecular typing. Though molecular level typing will be available, 
a match is defined at intermediate resolution for HLA-A and –B and at high resolution for –DRB1. 
All recipients should have been tested for class I and class II HLA antibodies. If antibodies are 
present UCB should be chosen that are not targeted. This may require DQ and DP testing of the 
umbilical cord blood.19;21;22 The testing for HLA antibodies should be done within 100 days from 
the planned transplant.  
 
When available, the cord blood and maternal HLA typings will be reviewed by WCMC or the 

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Cord Blood Bank to identify units with IPA shared targets with the recipient, or HLA-mismatched 
but NIMA matched units. These cord blood units will be preferred as grafts for the present study 
assuming a similar HLA match. 
 
HLA-C matching at the antigen level will also be considered after the above selection criteria. 
Thus, for units equal on all other accounts, an HLA-C match will be considered. 
 
One back-up unit will also be identified per subject following similar selection criteria. 
 
5.2 Third Party Donor     
 
The preferred 3rd party donor will be a young HLA haplo-identical relative. After appropriate 
evaluation as per transplant program criteria, the donor will receive G-CSF (filgrastim) 5 mcg/kg 
SQ BID or 10 mcg/kg SQ daily for four consecutive days (doses rounded to the nearest vial size). 
Apheresis will start on the morning of the fifth day and proceed until sufficient cells have been 
collected. If a second day of collection is required, G-CSF will be administered day 5 after 
collection. 
 
The apheresis procedure will be conducted as per transplant program policy. Typically four total 
blood volumes (TBV) will be collected or less if a high CD34 yield is expected based on high 
number of circulated CD34+ cells in the blood sample drawn immediately prior to apheresis. The 
use of pediatric donors is restricted to donors who are over the age of 14 and weigh more than 50 
kg. After collection and prior to cryopreservation, cells will be T-cell depleted using the Miltenyi 
Clinimax® depletion device. The target will be to obtain a product containing less than 
1x104CD3+ cells per kg of recipient body weight and approximately 3x106/kg CD34 positive cells. 
The CD34 selection procedure will be performed if possible in the stem cell laboratory of the 
transplant center. We also have obtained FDA approval to use contract services provided by 
progenitor cell tech. (Hackensack, NJ) 
 
If donor specific HLA-antibodies are present in the recipient an effort should be made to choose a 
third party donor who is not targeted. This may require DQ and DP testing of the third party donor.  
Occasionally the use of a mismatched unrelated CD34 selected PBSC graft will be 
permissible, for cases where no haplo-identical relative can be identified, or when the 
recipient has donor specific antibodies directed against all haplo-identical relatives. 
 
5.3 Infusion of Cells 
 
The infusion of UCB and the haplo-identical units will be separated by at least 2 hours and 
preferably they will occur on successive days (Day 0 and Day 1).  The order of infusion is not 
specified.  
 
Several lines of evidence indicate that post-thaw cord viability affects engraftment. If an umbilical 
cord blood product turns out to have less than 70% CD34 cell viability upon thawing, a second 
UCB product will be rapidly ordered and infused as soon as possible. 
6.0 TREATMENT PLAN 
 

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6.1 Conditioning Regimen: 
 
 
Day 
-7 
Day -6  
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0 
 Day 1 
or day 0 
Fludarabine 
 
30 
mg/
m2 
30 
mg/m2 
30 
mg/m2 
30 
mg/m2 
30mg/m
2 
 
 
Haplo 
Stem 
Cell 
UCB 
stem 
cell 
Melphalan 
 
 
 
 
 
 
140 
mg/m2 
 
 
 
rATG 
 
 
1.5 
mg/kg 
 
1.5 
mg/kg 
 
1.5 
mg/kg 
 
 
TBI* 
 
 
 
2 Gray 
2 Gray 
 
 
 
 
 
Fludarabine: Administer 30 mg/m2 /day intravenously x 5 days (Day -7 to Day -3) of a total dose 
of 150 mg/m2. Fludarabine will be dosed according to actual body weight.  
 
Melphalan: Administer 140mg/m2/day intravenously on day -2. Melphalan will be dosed 
according to actual body weight. Cryotherapy with ice chips will be administered to prevent 
mucositis.23  
 
Rabbit ATG (rATG)-thymoglobulin: 1.5 mg/kg/day IV x3 days total for all patients. ATG will 
be dosed according to actual body weight. The first dose will be infused over at least six hours, 
and subsequent doses over at least 4 hours.  Pre-medications include acetaminophen 650 mg by 
mouth, diphenhydramine 25-50 mg by mouth or intravenously, and methylprednisolone 2 mg/kg 
(1 mg/ kg at the initiation and 1 mg/kg half-way through anti-thymocyte globulin administration). 
Circumstances may require minor changes in scheduling of chemotherapy. Variations of up to 24 
hours in scheduling will be acceptable.  
 
Rituximab for prevention of PTLD: All patients not previously exposed to rituximab or who 
have not received rituximab in the six months prior to transplant, will receive one dose of rituximab 
375 mg/m2 prior to or upon admission.  
 
 
TBI*: Because of occasional cases of graft failure, conditioning has been intensified for certain 
groups of patients. Patients at high risk for CNS relapse (e.g ALL or Burkitt’s) or patients at high 
risk for graft rejection (i.e., donor-specific HLA antibodies, patients with severe aplastic anemia, 
or hemoglobinopathies) may receive 2 doses of TBI as part of the conditioning 
 
6.2 Post-Transplant Course (GVHD Prophylaxis) 
 
Subjects will receive the drug tacrolimus (Prograf ®) and another immunosuppressant, 
mycophenolate mofetil (Cellcept ®), starting before transplant also to reduce the risks of graft 
versus host disease and to promote the growth of the graft.   
 
Tacrolimus: 0.03 mg/kg/day using continuous intravenous infusion over 24 hour time period from 
Day -2 until engraftment or when subject is able to take by mouth, then tacrolimus approximately 

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0.09 mg/kg by mouth in 2 divided doses.  Tacrolimus should be given at full dose to maintain 
levels of 5-15 ng/mL through approximately Day 180, tapered by 20% every week thereafter. 
Infection ,toxicity or other clinical circumstances may prompt earlier discontinuation. In the 
presence of GVHD, a clinical decision by the attending physician will determine if tacrolimus can 
be tapered or should be continued.  PO tacrolimus can be used in the pre-engraftment period when 
IV access for tacrolimus is not available. 
 
Mycophenolate mofetil (MMF): will be started on Day -2 and given at a dose of 1000 mg every 
8 hours until Day 28. Earlier discontinuation, dose adjustments or more prolonged administration 
may be required for clinical reasons. MMF may be given PO or IV. . Infection, toxicity, very low 
patient weight (<50kg) may prompt earlier discontinuation or adjustment of doses 
 
Note: Patient-specific circumstances may mandate minor variations in conditioning regimen 
and/or GVHD prophylaxis, such as reduction of some of the doses of medications, changes in 
schedule or-rarely- substitution of a particular drug. These changes will be noted and justified, but 
will not require IRB approval. Refer to section 2.9.4 for further details. 
 
6.3 Supportive care 
 
 
If successful, transplantations will result in production of normal blood and cure of the underlying 
disorder. In some cases, a drug called filgrastim (G-CSF) may be administered to hasten the 
recovery of counts. Filgrastim administration will follow institutional guidelines. Generic 
formulations of filgrastim may be utilized as required by insurance or pharmacy.  
 
In case of cytomegalovirus (CMV) seropositivity of donor and/or recipient, CMV 
prophylaxis will use high dose ganciclovir and (val) Acyclovir as outlined below. All doses 
should be adjusted for renal function. 24;25 Adjustment for renal dysfunction should follow 
institutional guidelines.   
 
Supportive Care Schedule 
 
Admission to Day -2 
Day -1 until 
engraftment 
Engraftment until 
Day 210 
Day 210 
Ganciclovir 5mg/kg IV 
every 1hr 
Acyclovir  500mg/m2 
IV every 8hrs (or 
equivalent PO) 
Valcyclovir 2gm by 
mouth four times per 
day 
Acyclovir 400 mg by 
mouth three times per 
day(or equivalent IV) 
Changes and incorporation of alternative medications, unless dictated by clinical circumstances 
(side-effect, intolerance, failure, contra-indication), require discussion with the Principal 
Investigator. 
 
CMV seronegative donor and recipients: Acyclovir 400 mg po TID or IV equivalent. 
 
• A prophylactic broad-spectrum antifungal with anti-mold activity is strongly recommended.  
• Other infection prophylaxis and supportive care will be as per institutional unit policy. 

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• In some cases, a drug called filgrastim (G-CSF) may be administered to hasten the recovery of 
blood counts. Filgrastim administration will follow institutional guidelines. Generic 
formulations of filgrastim may be utilized as required by insurance or pharmacy. 
• Blood transfusion policy should follow institutional policy.  
• Cytomegalovirus (CMV)  monitoring at least weekly until Day 100 and at least monthly until 
Day 210, regardless of donor/recipient CMV status. 
• Epstein-Barr virus (EBV) monitoring: 
o EBV viral load monitoring at least weekly until Day 100 and at least monthly until Day 
365 is strongly recommended. 
o Rising EBV titers should warrant investigation for an EBV post-transplant 
lymphoproliferative disorder (PTLD) including CT imaging and PET scanning for 
positive CT findings. A bone marrow evaluation is recommended if any evidence of 
PTLD by imaging or on peripheral blood findings.  
o Evidence of PTLD or consecutive increases in EBV polymerase chain reaction should 
lead to treatment with rituximab at a dose and schedule per institutional policy. 
 
7.0     PRE-TRANSPLANT EVALUATION (See also TABLE 2) 
 
Subjects will be admitted to the hospital for a period of four to six weeks, sometimes more. In 
the first six days, subjects will receive the conditioning regimen.  
 
The following observations are considered standard evaluations for transplant eligibility and 
should be determined as close to conditioning as possible and at a reasonable interval from 
transplant usually < 12 weeks before initiation of conditioning therapy. More remote tests may be 
utilized upon approval of the patient’s physician.  
These tests may be adjusted as warranted by clinical circumstances and evolving transplant 
policy. Please also refer to institutional transplant work up guidelines.  
 
1. Medical history, physical examination, vital signs, height and weight. 
2. KPS (Karnofsky Performance Score)  
3. Complete blood count (CBC) with differential and platelet count, serum creatinine, 
bilirubin, alkaline phosphatase, ALT, and AST. 
4. Infectious disease titers, as per institutional guidelines. 
5. Immunoglobulin levels 
6. High resolution HLA typing, if not already performed. 
7. Left ventricular ejection fraction or shortening fraction.,  
8. Diffusing capacity the lung for carbon monoxide (DLCO), Forced Expiratory Volume in 
One Second (FEVI) and Forced Vital Capacity (FVC) or O2 saturation.  
9. Bone marrow evaluation with aspirate and/or biopsy. Cytogenetic analysis as clinically 
indicated. 
10. Beta -HCG serum pregnancy test for females of childbearing potential within 4 weeks of 
conditioning. 
11. Chest CT as clinically indicated. 
12. Pre-transplant chimerism testing.  
13. Diagnostic Lumbar Puncture as clinically indicated (particularly ALL and High grade 
lymphoma) 

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8.0   POST-TRANSPLANT EVALUATION  
 
The follow-up schedule for scheduled study visits is outlined in Table 1 below.  
 
Study Visit 
Target Day Post-Transplant 
1 week 
7 + 2 days 
2 week 
14 + 5 days 
3 week 
21 + 5 days 
4 week 
28 + 5 days 
7 weeks 
49 + 7 days 
10 weeks 
70 + 7 days 
100 day 
100 + 7 days 
6 month 
180 + 28 days 
12 month 
365 + 28 days 
 
Table 1: The follow-up schedule for scheduled study visits is outlined in Table2. These tests 
may be adjusted as warranted by clinical circumstances and evolving transplant policy. Please 
also refer to institutional transplant work up guidelines.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Baseline** 
7 
14 
21 
28 
49 
70 
100 
180 
365 
Physical exam, height, weight, and KPS 
performance status 
X 
 
 
 
X 
 
 
X 
X 
X 
GVHD and other morbidity assessments5 
 
 
 
X 
 
 
X 
X 
X 
Toxicity assessments 
X 
 
 
 
X 
 
 
X 
X 
X 
Infectious disease titers3 
X 
 
 
 
 
 
 
 
 
 
Chest CT or x-ray 
X 
 
 
 
 
 
 
 
 
 
LVEF, or shortening fraction 
X 
 
 
 
 
 
 
 
 
 
DLCO, FEV I and FVC and 02-saturation 
X 
 
 
 
 
 
 
 
 
 
HLA typing7 
X 
 
 
 
 
 
 
 
 
 
B-HCG serum pregnancy test (pre-menopausal  
females only) within 4 week of conditioning 
X 
 
 
 
 
 
 
 
 
 
CBC1 , differential, platelet count, and blood 
chemistries2 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Disease restaging  
X 
 
 
 
 
 
 
X 
X 
X 
Bone marrow biopsy and aspirate for pathology 
X 
 
 
 
X6 
 
 
X6 
X6 
X6 
Chimerism 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Lymphocyte Subsets and Ig Levels 
X 
 
 
 
X 
 
 
X 
X 
X 
Pneumococcal antibody levels5 
X 
 
 
 
 
 
 
 
X 
X 
HLA Antibodies 
X 
 
 
 
X5 
 
 
X5 
 
X5 
Sample for correlative assays5 
X 
 
 
 
X 
X 
X 
X 
 
X 
Table 2: Table of study visit time points and assessments. 
 
Note: 
*The exact day of the tests is approximate. Tests can be scheduled several days before or after. 
The window is up to five days before and after in the first three weeks. Up to seven days before 
and after in the first 100 days and up to one month before and after at subsequent time points. 
**Baseline tests: see also section 7.0 

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1. CBC performed at least three times a week from Day 0 until ANC >500 mcL for three days 
after nadir. CBC performed twice weekly until Day 28.CBC performed approximately 
weekly after Day 28 until 12 weeks post-transplant. 
2. Blood chemistries include: serum creatinine, bilirubin, alkaline phosphatase, AST, and 
ALT, LDH, sodium, magnesium, potassium, chloride, and thyroid function tests (where 
standard of care should be according to institutional guidelines). Blood chemistries 
performed twice weekly if possible until Day 28. Blood chemistries performed weekly if 
possible after Day 28 until day 100 post-transplant. 
3. Infectious disease titers to be done as per institutional guidelines. 
4. Correlative Assays may include lymphocyte subset enumeration, spectratyping and TREC 
assays. 
5. Recommended, not required.  
6. Bone Marrow Biopsy and Aspirate for Pathology post-transplant will be performed as per 
the treating physician’s medical-related recommendation.  
7. If not already performed. 
 
 
9.0 ADVERSE EVENT REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug under investigation.  Safety will be monitored by evaluation of adverse events 
reported by subjects or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, x-rays, and electrocardiographs. 
 
9.1  Investigational Risks 
 
See consent form. There are no known side-effects related to the use of the Miltenyi CliniMacs 
device to select cells. 
 
9.2 Adverse Event Characteristics  
 
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 

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9.3 
Recording and reporting  of Adverse Events and SAE 
 
• Stem Cell transplant is a complex procedure with prolonged initial admission and 
numerous immediate and delayed complications as well as frequent readmissions. 
 
• Expected adverse events are those listed in the consent form and include regimen-related 
toxicities, myelosuppression, opportunistic infections and GVHD.   Most expected 
adverse events of grade III and higher CTC severity will be captured in the transplant 
database and reported to the IRB upon request.  
 
 
• Adverse events that are judged to be unexpected and possibly related to the 
investigational procedure, will be reported to the study chairman within 48 hours. 
Such events will be reported to the local IRB within the institution’s prescribed 
time period. 
 
• All fatal Adverse Events will also be reported to the study chairman within 48 
hours and reported to the local IRB within the institution’s prescribed time period. 
 
 
 
 
Immediate Reporting 
Report quarterly 
Hematopoietic Toxicity 
Graft failure and death 
Time to Hematopoietic 
recovery 
Extramedullary Toxicity 
Fatal toxicity.  
Grade III-IV Toxicity 
deemed unexpected and 
possibly related to the 
investigational procedure 
Grade III-IV toxicities not 
deemed 
expected/unrelated 
Infections 
Fatal  
Grade II-IV 
Acute GVHD 
Fatal or Grade IV 
Grade II-III 
Chronic GVHD 
Fatal  
Limited and extensive 
 
 
9.4 Reporting of Adverse Events  to FDA   
 
If a reportable AE occurs on this study, the event will be filed on a MedWatch form with the 
FDA. Adverse drug reactions that are Serious, Unlisted/Unexpected, and at least possibly 
associated, and that have not previously been reported in the Investigators brochure, or reference 
safety information document should be reported promptly to the Food and Drug Administration 
(FDA) in writing by the PI (the principal sponsor-investigator).  A clear description of the 
suspected reaction should be provided along with an assessment as to whether the event is drug 
or disease related.   
 
The principal sponsor-investigator shall notify the FDA by telephone or by fax of any 
unexpected fatal or life threatening experience associated with the use of the drug or device as 

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soon as possible but no later than 7 calendar days after the sponsors initial receipt of the 
information.   Each phone call or fax shall be transmitted to the FDA new drug review division 
in the Center for Drug Evaluation and Research or the product review division in the Center for 
Biologics Evaluation and Research that has responsibility for review of the IND. 
 
The principal investigator must also call the FDA as soon as an unexpected and possibly related 
adverse reaction occurs.  The phone number is (301) 796-8240.  A recorder is available after 
hours.  Report these reactions to the FDA within ten (10) working days both verbal and written. 
 
The address for Center for Biologics Evaluation & Research (CBER) FDA is: 
 
 
U.S. Food and Drug Administration 
Center for Biologics Evaluation and Research 
10903 New Hampshire Avenue 
Silver Spring, MD 20993-0002 
 
The phone number of the CBER is: 800-835-4709 
 
10.0 CRITERIA FOR STUDY EVALUATION 
 
• Event Free Survival 
• Relapse will be recorded by the day of initial detection of malignant cells if these cells 
were on subsequent testing confirmed to be increasing in number or by unequivocal 
radiological progression. The molecular detection of matched related donor will not be 
taken into account for the definition of clinical recurrence. The diagnosis of disease 
recurrence will be based on clinical and pathological criteria. 
• Treatment Related Mortality 
Treatment related mortality is considered any death that cannot be explained by 
persistence, relapse or progression of the underlying malignancy once the preparative 
regimen starts.  
 
• Acute GVHD 
Acute GVHD will be scored according to the criteria proposed by Przepiorka et al. 23 
 
• Chronic GVHD 
Chronic GVHD will be scored according to the NIH Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease:  I. Diagnosis and Staging 
Working Report.24 
 
• Neutrophil engraftment 
Neutrophil engraftment will be defined as the first day in which the ANC is > 500/mm3 for 
three consecutive days.   
 
• Platelet engraftment 
Platelet engraftment will be defined as the first day the platelet count is > 20,000/mm3 
without transfusion support for seven consecutive days. Chimerism studies will be used to 

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determine the percentage cord vs. haplo-identical donor engraftment. 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
Statistical Design and Analysis Plan: 
 
The primary end point of the study is percentage of cord engraftment defined as the presence of 
at least 40% cord chimerism in peripheral blood of unfractionated cells by Day 100 or earlier.  
Cord blood cells are required to invoke cord versus leukemia effects and therefore an essential 
ingredient to success is to establish a minimum degree of cord blood cells at day 100. In our 
initial experience, cord blood levels often increased over time once a minimum proportion of 
cord blood cells are present  
 
We will define the lowest tolerated dose of UCB as the lowest dose which assures cord blood 
engraftment (as defined above) in at least 80% of subjects. 
 
 
Cohort # 
Minimal Cell Dose 
Number of Evaluable Subjects 
1 
2 x 10^7 TNC/kg 
10 
2 
1 x 10^7 TNC/kg 
10 
3 
0.5 x 10^7 TNC/kg 
10 
 
We will enroll 10 evaluable subjects in each cohort consecutively. However, accrual will 
continue at the same cell dose level until at least 10 subjects are evaluable.  Because of the day 
100 endpoint of chimerism, cohorts may enroll more than 10 subjects.  With 10 subjects per dose 
cohort (the first 10  subjects evaluable), a two-sided 95% confidence interval for the proportion 
of subjects with successful engraftment in any dose group can be constructed to be within +/- 
24.8% of the observed proportion of subjects with successful engraftment. This calculation 
assumes an expected engraftment proportion of 80%.   
 
We will then calculate the rate of engraftment for each cohort using all the subjects accrued at 
each dose level. If the confidence interval of rate of engraftment includes 80% within the 95% 
confidence interval in all groups, then further accrual will continue using the minimum cell dose 
limits set in the lowest cohort for a total of 30 subjects (thus around 20 more subjects or slightly 
less if the cohort overaccrued).   
 
With 30 subjects treated at lowest cell dose cohort, a two-sided 95% confidence interval for the 
proportion of subjects with successful engraftment can be constructed to be within +/- 14.3% of 
the observed proportion of subjects with successful engraftment (binomial distribution). This 
calculation assumes an expected engraftment proportion of 80%. 
 
Subjects who die or relapse before chimerism can be assessed, will be considered not evaluable, 
and will be replaced. We predict that up to 16 subjects will fall into this category. Some cohorts 
that are not expanded will have more than 10 evaluable subjects as above. We estimate this will 
be four subjects. Thus, we are stating our accrual number as 150 total subjects. 
 

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Increase in Sample Size and New Primary Endpoints – September 2018 
 
Accrual to this protocol has occurred more rapidly than initially anticipated and primary 
objective has been revised to provide access to haplo-cord transplants for patients in need of 
alternative donor transplant and to determine long-term outcomes. We currently accrue 
approximately 40 patients per year at Weill Cornell and another 30 at the University of Chicago. 
Close to 300 patients have been accrued over the past six years and we now propose to increase 
this number to an overall number of 500 patients and utilize this study to provide access to this 
procedure, report results and collect correlative samples. 
 
This will also allow us to obtain data on long-term outcomes including late complications and 
cure rates on patients in various disease and age categories. We will continue to monitor 
secondary endpoints as described below. 
 
Secondary endpoints 
 
The proportion of subjects where desirable IPA or NIMA targeting from the cord blood unit 
occurred will be determined.  We expect that by using lower cord blood doses and having more 
units available, we can perform IPA or NIMA targeting in 33% of units.  
 
At the conclusion of the study, 95% confidence intervals will be generated for PFS, the incidence 
of graft failure, and the cumulative incidence of acute and chronicGVHD.  Kaplan-Meier estimates 
of progression-free and overall survival rates will be calculated, and the median progression-free 
and overall survival times and their associated 95% confidence intervals derived. Cumulative 
incidence of neutrophil recovery, platelet recovery, and acute and chronic GVHD, will be 
calculated using relapse or death as a competing outcome. The cumulative incidence of 1) relapse 
using transplant-related mortality (TRM) as a competing outcome and 2) TRM using relapse as a 
competing outcome, will also be calculated using the cumulative incidence method.   
 
We will conduct preliminary analysis to assess the impact of IPA targeting and NIMA matching 
on outcome of transplant, though we realize that subject numbers in this pilot trial may not allow 
definitive conclusions.  
 
Guidelines for Early Stopping of the Trial 
 
The study could be stopped early for subject safety, particularly if in one of the cohorts  time to 
hematopoietic recovery is delayed in an excessive fraction of subjects (i.e. >40% of subjects in a 
cohort require more than 18 days to recovery ANC> 100/uL).  We do not expect other unusual 
toxicities. In particular we do not expect an excess GVHD, given our previous encouraging 
experience at the University of Chicago with low GVHD and the fact that better HLA- matching 
as we expect to occur in this study should further minimize GVHD.   
 
Addendum September 2018: At no point during the trial has there been an incidence of adverse 
outcomes that would have warranted early closing of the trial. Therefore, the protocol’s stopping 
rules will be abandoned. Instead, we will continue to monitor long-term outcomes on a six month 

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basis and provide updates to the IRB. If at any moment one year survival drops below 50%, the 
protocol will be suspended for evaluation. 
 
 
 
12.0 
 CRITERIA FOR REMOVAL OF SUBJECTS FROM PROTOCOL THERAPY 
 
Because this is a one-time treatment, there is no indication for subjects to be taken off protocol 
for any reason except the ones mentioned below. Even if the subject had near fatal toxicity, it 
would not harm him/her to stay active on the study. 
 
 
12.1 Disease Progression or Disease Persistence 
 
Relapsing subjects (i.e. those with pathologically proven disease progression) will be removed 
from protocol therapy and followed for survival and secondary malignancy. 
 
12.2 Extraordinary Medical Circumstances 
 
If, at any time, the constraints of this protocol are detrimental to the subject’s health and/or the 
subject no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event: 
• Notify the Study Chair. 
• Document the reason(s) for discontinuation of therapy in subject records. 
• Follow the subject for survival, progression, relapse, and secondary malignancies 
 
13.0 
DATA, SAMPLE AND PROTOCOL MANAGEMENT 
 
• Protocol Compliance:  Subjects will be reviewed weekly during admission by the study 
investigators who will score the subject for standard endpoints. After discharge they will 
be reviewed at least once a month. 
• Data Entry: REDCap (Research Electronic Data Capture) is a free data management 
software system that is fully supported by the Weill-Cornell Medical Center CTSC.  It is 
a tool for the creation of customized, secure data management systems that include Web-
based data-entry forms, reporting tools, and a full array of security features including user 
and group based privileges, authentication using institution LDAP system, with a full audit 
trail of data manipulation and export procedures.  REDCap is maintained on CTSC-owned 
servers that are backed up nightly and support encrypted (SSL-based) connections.  
Nationally, the software is developed, enhanced and supported through a multi-
institutional consortium led by the Vanderbilt University CTSA. The data entry will 
follow formats proposed by CIBMTR.  
Data Collection: Many endpoints of allogeneic transplant such as acute and chronic 
GVHD, certain infections and/or viral reactivations can occur at any moment after 
transplant and can go through many different phases. (evolution to different stage, 
improvement, recurrence, resolution, in case of infections: viremia to disease etc). The 

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assignment of stage and extent often requires the input of various investigators and 
clinicians. All outcomes of allogeneic transplant patients including GVHD status, 
infections, graft function, disease outcomes etc are discussed at a biweekly conference 
and the data collected and discussed there will serve for data entry purposes for this study. 
This will also include discussion of data from patients enrolled at University of Chicago 
who will be discussed at biweekly conference for the first one hundred days. Thereafter 
they will be discussed when there is a change in their status. 
• Accuracy of Data Collection: The Study Chairman will be the final arbiter of toxicity or 
assignment of disease related outcome should a difference of opinion exist 
 
• Management of Research Samples: Research samples will be cryopreserved after 
ficolling and isolation of viable cells. The serum will be stored separately. Part of the 
product may be stored after DNA extraction. The samples will be stored securely. They 
will coded with the key to identification of the samples kept in a secure location and 
available only to the PI or his delegate. Samples and appropriate clinical information may 
be shared with other investigators at WCMC and elsewhere, but will be de-identified. 
Samples will be kept indefinitely.  
 
 
14.0 DATA SAFETY MONITORING BOARD 
The Weill Cornell Medical College Data Safety Monitoring Board (DSMB) is being requested to 
review safety data and to make recommendations regarding continuation, termination, or 
modification to the study.  
The research team will report all adverse events to the DSMB after half the patients have been 
enrolled. The report to the DSMB will include the choice of cell dose for the continuation of the 
study and the justification for the choice. 
 
15.0 
REGULATORY CONSIDERATIONS 
 
15.1 
Institutional Review Board/Ethics Committee Approval 
 
The protocol for this study has been designed in accordance with the general ethical principles 
outlined in the Declaration of Helsinki.  The review of this protocol by the IRB/EC and the 
performance of all aspects of the study, including the methods used for obtaining informed 
consent, must also be in accordance with principles enunciated in the declaration, as well as ICH 
Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 Protection of Human 
Subjects and Part 56 Institutional Review Boards. 
 
The Investigator will be responsible for preparing documents for submission to the relevant 
IRB/EC and obtaining written approval for this study.  The approval will be obtained prior to the 
initiation of the study. 
 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. 
 

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Any amendments to the protocol after receipt of IRB/EC approval must be submitted for 
approval by the Investigator to the IRB/EC.  The Investigator is also responsible for notifying the 
IRB/EC of any serious deviations from the protocol, or anything else that may involve added risk 
to subjects. 
 
Any advertisements used to recruit subjects for the study must be reviewed and approved by the 
IRB/EC prior to use. 
 
15.2 
Informed Consent Procedures 
The Investigator must obtain informed consent of a subject or his/her designee prior to any study 
related procedure as per GCP’s as set forth in the CFR and ICH guidelines. 
 
Documentation that informed consent occurred prior to the subject’s entry into the study and the 
informed consent process should be recorded in the subject’s source documents.  The original 
consent form signed and dated by the subject and by the person consenting the subject prior to 
the subject’s entry into the study, must be maintained in the Investigator’s study files.   At the 
pre-admission consultation, subjects will be fully informed as to the purposes and potential risks 
and benefits involved in this study. Subjects will have ample opportunity to ask questions before 
consenting. Legal guardians will sign informed consent for legally incompetent patients in 
accordance with hospital policy. 
 
15.3 
Protecting Privacy and Confidentiality 
Confidentiality will be maintained within the limits of the law. Subject names or any other 
identifying information will not be used in reports or publications resulting from this study. Only 
qualified staff from New York Presbyterian Hospital, Weill Medical College of Cornell 
University, the Food and Drug Administration, or other study support such as the National 
Cancer Institute will be able to review subject medical records. 
 
Should direct access to medical records require a waiver or authorization separate from the 
subject’s statement of informed consent, it is the responsibility of the Investigator to obtain such 
permission in writing from the appropriate individual. 
 
15.4 
Study Records Requirements 
The Investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the study drug, that is copies of CRFs and source documents 
(original documents, data, and records [e.g., hospital records; clinical and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; pharmacy dispensing 
records; recorded data from automated instruments; copies or transcriptions certified after 
verification as being accurate copies; microfiches; photographic negatives, microfilm, or 
magnetic media; x-rays; subject files; and records kept at the pharmacy, at the laboratories, and 
at medico-technical departments involved in the clinical study; documents regarding subject 
treatment and study drug accountability; original signed informed consents, etc.]) be retained by 
the Investigator for as long as needed to comply with national and international regulations 
(generally 2 years after discontinuing clinical development or after the last marketing approval).  
The Investigator agrees to adhere to the document/records retention procedures by signing the 
protocol. 

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15.5 
Protection of Human Rights 
Participation in this trial is voluntary. All subjects will be required to sign a statement of 
informed consent, which must conform to Weill Cornell Medical College IRB guidelines.  
 
Subjects will be eligible for this trial regardless of gender or racial/ethnic background.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX A 
 
 
Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 

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APPENDIX B 
 
WCMC IRB SAE Reporting Forms 
 
http://researchintegrity.weill.cornell.edu/institutional_review_board/irb_adv.html 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX C 
 
BACKGROUND DRUG INFORMATION 
 
 
FILGRASTIM  (G-CSF:  Granulocyte Colony Stimulating Factor, Neupogen)   
 
AVAILABILITY 
G-CSF is commercially available in 1.0 and 1.6 mL vials containing 300 mcg and 480 mcg G-CSF, and in 
prefilled syringes containing 300 mcg/0.5 mL and 480 mcg/0.8 mL. 
 
 
STORAGE & STABILITY 
Intact vials and prefilled syringes should be stored under refrigeration.  Do not allow the drug to freeze.  
 
ADMINISTRATION 
The daily dose of G-CSF should be injected subcutaneously in one or two sites.  The dose following 
peripheral blood stem cell infusion is 5 mcg/kg/day.  The dose of G-CSF may be rounded up to the 
nearest vial size. 
 
TOXICITY 
The most common side effect associated with G-CSF is bone pain.  Bone pain is usually reported as mild 
or moderate and, if necessary, may be treated with non-opiod or opiod analgesics. 
 
 
FLUDARABINE(Fludara) 
 
AVAILABILITY 
Fludarabine is commercially available as a white, lyophilized powder.  Each vial contains 50 mg of 
fludarabine, 50 mg of mannitol and sodium hydroxide to adjust pH. 
 
STORAGE & STABILITY 
Intact vials should be stored under refrigeration.  Reconstituted vials are stable for 16 days at room 
temperature or under refrigeration.  Solutions diluted in D5W or NS are stable for 48 hours at room 
temperature or under refrigeration. 
 
PREPARATION 
Fludarabine should be reconstituted with Sterile Water for Injection, USP or normal saline per 
institutional pharmacy guidelines.   
 
ADMINISTRATION 
Fludarabine will be administered as an IV infusion over 30 minutes. 
 
TOXICITY 
Myelosuppression, (dose-limiting toxicity), fever, mild nausea and/or vomiting, diarrhea, stomatitis, skin 
rashes, myalgia, headache, agitation, hearing loss, transient episodes of somnolence and fatigue, 
autoimmune hemolytic anemia (may be life-threatening), peripheral neuropathy, and pulmonary toxicity.  
(Both pneumonia and hypersensitivity reactions have been reported.  Fatal pulmonary toxicity has been 
described, especially when fludarabine was used in combination with pentostatin.  Severe, fatal CNS 
toxicity presenting with loss of vision and progressive deterioration of mental status was encountered 

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almost exclusively after very high doses of fludarabine.  Such toxicity has only been rarely demonstrated 
at the 25-30 mg /m2 dosage of fludarabine.  Very rarely described complications include transfusion-
associated graft versus host disease.  Tumorlysis syndrome has been observed, especially in patients with 
advanced bulky disease.  Opportunistic infections (protozoan, viral, fungal, and bacterial) have been 
observed.     
 
 
MELPHALAN(Alkeran) 
 
AVAILABILITY 
Melphalan for IV use is commercially available in sterile 50 mg vials.  The product is a lyophilized 
powder with 20 mg povidone per vial.  Also provided is 10 mL of special diluent for use in reconstituting 
the product.  The special diluent has 0.20 g sodium citrate, 6 mL propylene glycol, 0.5 mL 95% ethanol, 
and sterile water. 
 
 
STORAGE & STABILITY 
Intact vials should be stored at room temperature (15oC-30oC) and protected from light.  Reconstituted 
solutions are chemically and physically stable for at least 90 minutes at room temperature.  Solutions 
further diluted in 0.9% sodium chloride to a concentration of 0.1 mg/mL to 0.45 mg/mL are stable for at 
least 60 minutes.  Solutions diluted to 1 mg/mL are reported to be physically stable for at least 4 hours at 
room temperature-chemical stability of this dilution is not known.  Because of the relative instability of 
melphalan solutions, it is recommended that administration of the diluted solution be completed within 60 
minutes of reconstitution.  Reconstituted solutions should not be refrigerated. 
 
PREPARATION 
Melphalan should be prepared immediately before intended use.  Each vial is reconstituted with 10 mL of 
the special diluent to yield a concentration of 5 mg/mL.  The reconstituted solution may be diluted with 
0.9% sodium chloride to a concentration of 0.1 mg/mL to 0.45 mg/mL. 
 
ADMINISTRATION 
The total dose of melphalan will be administered by short IV infusion over 30-60 minutes, as per 
institutional pharmacy guidelines. 
 
TOXICITY 
The major toxicity of melphalan is bone marrow suppression, usually lasting four to eight weeks.  Other 
toxicities include nausea, vomiting, diarrhea, and mucositis.  Less common toxicities include pulmonary 
fibrosis, interstitial pneumonitis, vasculitis, alopecia, hemolytic anemia, and allergic reactions.  Transient 
rises in BUN and creatinine have occurred with high dose melphalan and also acute renal failure. Tissue 
necrosis may result if infiltration occurs.    
 
 
MYCOPHENOLATE MOFETIL (Cellcept; Myfortic; MMF) 
 
AVAILABILITY 
Mycophenolatemofetil is available as a Capsule, as mofetil:  CellCept®: 250 mg;  
as Injection, powder for reconstitution, as mofetil hydrochloride:  CellCept®: 500 mg [contains 
polysorbate 80]; as Powder for oral suspension, as mofetil: CellCept®: 200 mg/mL (225 mL) [provides 
175 mL suspension following reconstitution; contains phenylalanine 0.56 mg/mL; mixed fruit flavor]; as 
a Tablet, as mofetil: CellCept®: 500 mg [may contain ethyl alcohol]; and as a Tablet, delayed release, 
as mycophenolic acid: Myfortic®: 180 mg, 360 mg [formulated as a sodium salt]. 

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STORAGE & STABILITY 
Intact vials should be stored at room temperature 15ºC to 30ºC (59ºF to 86ºF).  Store solutions at 15ºC to 
30ºC (59ºF to 86ºF) and begin infusion within 4 hours of reconstitution.  Store capsules at room 
temperature of 15ºC to 39ºC (59ºF to 86ºF).  Tablets should be stored at room temperature of 15ºC to 
39ºC (59ºF to 86ºF) and protected from light.  Store powder for oral suspension at room temperature of 
15ºC to 39ºC (59ºF to 86ºF).  Once reconstituted, the oral solution may be stored at room temperature or 
under refrigeration. Do not freeze. The mixed suspension is stable for 60 days. 
 
PREPARATION 
Mycophenolatemofetil is stable in D5W should be reconstituted per institutional pharmacy guidelines.  
 
ADMINISTRATION 
Intravenous solutions of mycophenolatemofetil should be administered over at least 2 hours (either 
peripheral or central vein); do not administer intravenous solution by rapid or bolus injection.  Oral 
dosage formulations (tablet, capsule, suspension) should be administered on an empty stomach to avoid 
variability in MPA absorption. The oral solution may be administered via a nasogastric tube (minimum 8 
French, 1.7 mm interior diameter); oral suspension should not be mixed with other medications. Delayed 
release tablets should not be crushed, cut, or chewed. 
 
TOXICITY 
Pain, abdominal pain, fever, headache, infection, sepsis, asthenia, chest pain, back pain, hypertension, 
tremor, insomnia, dizziness, acne, rash, diarrhea, constipation, mild N/V, oral monoliasis, anemia, 
leukopenia, thrombocytopenia, hypochromic anemia, leukocytosis, peripheral edema, 
hypercholesterolemia, hypophosphatemia, edema, hypo or hyperkalemia, hyperglycemia, infection, 
dyspnea, cough increase, pharyngitis, bronchitis, pneumonia, UTI, hematuria, kidney tubular necrosis, 
urinary tract disorder. 
 
RABBIT ANTITHYMOCYTE GLOBULIN(Thymoglobulin, rATG) 
 
AVAILABILITY 
Antithymocyte globulin is commercially available.  Each package contains two vials:  the first vial 
contains 25 mg antithymocyte globulin, and the second vial contains > 5 mL SWFI diluent. 
 
 
STORAGE & STABILITY 
Ampuls must be refrigerated (2oC-8oC/ 36oF-46oF),).  Do not freeze.   
 
 
PREPARATION 
Reconstitute 25 mg vial with diluent provided by manufacturer (SWFI > 5 mL).  Roll vial gently to 
dissolve powder.  Use contents of vial within 4 hours of reconstitution.  Dilute dosage to a final 
concentration of 0.5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection.  Gently invert 
admixture 1-2 times to mix solution.  Use admixture solution immediately.  Final concentration must be 
0.5 mg/mL. 
 
ADMINISTRATION 
Infuse the first dose over at least six hours, and subsequent doses over at least 4 hours.  Infuse through a 
0.22 micron in-line filter into a high-flow vein.  Premedications include acetaminophen 650 mg PO, 
diphenhydramine 25-50 mg PO/IV, and methylprednisolone 1 mg/kg (at the initiation and half-way 

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through antithymocyte globulin administration). 
 
TOXICITY 
Infusion-related toxicities, including fevers, chills, rash, dyspnea, cardiovascular (hypo- or 
hypertension, tachycardia, edema, chest pain).  In rare cases, anaphylaxis has been reported in 
which case the infusion should be terminated immediately, and emergency treatment with 
epinephrine and other resuscitative measures should be instituted.  rATG should not be 
administered again to this patient.  Immunosuppression is a common feature of rATG and can 
result in severe infections including sepsis, CMV, and urinary tract infections.  Serum sickness, 
neutropenia (57%), thrombocytopenia (37%), leucopenia (57%), pain (46%), headache (40%), 
nausea and diarrhea (37%), peripheral edema (34%), systemic infection, malaise, pain, stomatitis, 
GI bleed, swelling or redness at injection site, myalgia, back pain, development of human anti-
rabbit antibodies (HARA).  
 
TACROLIMUS (Prograf, FK506) 
 
AVAILABILITY 
Tacrolimus is commercially available as an injection (5 mg/mL; 1 mL ampuls) and as oral capsules (0.5 
mg, 1 mg, and 5 mg). 
 
 
STORAGE & STABILITY 
Store tacrolimus capsules and injection at controlled room temperature, 15oC-30oC (59oF-86oF). 
 
PREPARATION – FOR IV USE 
Tacrolimus injection must be diluted prior to IV infusion with 0.9% sodium chloride or 5% dextrose 
injection to a concentration of 4-20 mcg/mL.  Solutions should be prepared in non-PVC plastic or glass.  
Tacrolimus injection and diluted solutions of the drug should be inspected visually for particulate matter 
and discoloration prior to administration whenever solution and container permit. 
 
ADMINISTRATION 
Oral therapy should be started as soon as possible as per protocol and 8 to 12 hours after stopping 
intravenous therapy.  Oral doses will be administered twice a day.  The conversion from IV to oral 
therapy should take into account concomitant medications (such as voriconazole). 
 
TOXICITY 
In patients receiving tacrolimus, 5% to 47% experienced anemia, 8% to 32% experienced leukocytosis, 
and 14% to 24% experienced thrombocytopenia.  Rare cases of microangiopathic hemolytic anemia have 
been reported.  Chest pain was reported in 19%.  Mild to moderate hypertension is a common adverse 
effect associated with tacrolimus therapy.  Antihypertensive therapy may be required.  The most common 
adverse effects of tacrolimus have involved the central nervous system, and include headache (37% to 
64%), tremors (48% to 56%), insomnia (32% to 64%), paresthesia (17% to 40%), and dizziness (19%).  
Tremor and headache may respond to dosage reduction.  Visual changes, agitation, anxiety, confusion, 
seizures, depression, hallucinations, myoclonus, neuropathy, psychosis, incoordination, and abnormal 
dreams have been reported in 3% to 15%.  Hyperkalemia (13% to 45%), hypokalemia (13% to 29%) 
hypophosphatemia (49%) and hypomagnesemia (16% to 48%) have been associated with tacrolimus 
therapy.  Hyperuricemia has been reported in >3%.  Gastrointestinal adverse effects included nausea 
(32% to 46%), vomiting (14% to 29%), anorexia (7% to 34%), constipation (23% to 35%), and diarrhea 
(37% to 72%).  Nephrotoxicity was reported in 38% to 52% of liver and kidney transplant patients, 
respectively.  Hematuria has been reported in greater than 3%.  Abnormal liver function tests have been 
reported in 6% to 36% of patients; ascites in 7% to 27%.   

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Other effects reported in clinical trials include pain, fever, asthenia, back pain, and peripheral edema.  The 
incidence of hyperglycemia was 17% and may require therapy with insulin.  Other less frequently 
occurring effects include abscess, chills, peritonitis, and photosensitivity reactions.  Anaphylaxis has been 
reported in a few patients receiving intravenous tacrolimus.  Tacrolimus injection contains cremophor 
which in other drugs has been associated with anaphylaxis.  Because tacrolimus is an 
immunosuppressant, the risk of opportunistic infections is increased. 
 
DRUG INTERACTIONS   
Tacrolimus is metabolized by cytochrome P450 3A4.  Drugs that are inhibitors (e.g. itraconazole) of 
inducers (e.g. phenytoin) of 3A4 might be expected to increase or decrease tacrolimus concentrations, 
respectively, possibly resulting in increased or decreased effects.  
 
 

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