Myeloablative Unrelated Donor Cord Blood Transplantation With T-Cell Depleted Haplo-identical Peripheral Blood Stem Cells for Patients With High Risk Hematological Malignancies
Phase: PHASE2
Conditions: Leukemia, Myelodysplastic Syndrome, Lymphoma
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Page 1 of 43 
 
 
Approval date: 29-Jan-2018 
Myeloablative Unrelated Donor Cord Blood Transplantation with T 
identical Peripheral Blood Stem Cells for Patients with High Ri 
Malignancies 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOC 
Principal Investigator/Department: 
Juliet N. Barker, M.B.B.S. (Hons) 
-Cell Depleted Haplo- 
sk Hematological 
OL 
Medicine 
Co-Principal 
Katharine C. H
Investigator(s)/Department: 
Nancy A. Kern 
su, M.D., Ph.D. 
an, M.D. 
Medicine 
Pediatrics 
 
 
Investigator(s)/Department: 
Sean Devlin, Ph.D. 
Biostatistics/ Epidemiology 
Richard Meagher, Ph.D 
Laboratory Medicine 
Scott T. Avecilla, M.D., Ph.D 
Laboratory Medicine 
Genovefa Papanicolaou, M.D. 
Infectious Disease 
Hugo R. Castro-Malaspina, M.D. 
Medicine 
Sergio Giralt, M.D. 
Medicine 
Ann A. Jakubowski, M.D., Ph.D. 
Medicine 
Esperanza B. Papadopoulos, M.D. 
Medicine 
Miguel-Angel Perales, M.D. 
Medicine 
Doris Ponce, M.D. 
Medicine 
Craig Sauter, M.D.Marcel R.M. 
Medicine 
VandenBrink, M.D., Ph.D. 
Medicine 
James W. Young, M.D. 
Medicine 
Parastoo Dahi, M.D. 
Medicine 
Roni Tamari, M.D. 
Medicine 
Boglarka Gyurkocza, M.D. 
Medicine 
Brian Shaffer, M.D. 
Medicine 
Melody Smith, M.D. 
Medicine 
Jonathan Peled, M.D. 
Medicine 
Gunjan Shah, M.D. 
Medicine 
Michael Scordo, M.D. 
Medicine 
Christina Cho, M.D. 
Medicine 
Oscar Lahoud, M.D. 
Medicine 
Ioannis Politikos, M.D. 
Medicine 
Scott James, M.D. Ph.D. 
Medicine 
Farid Boulad, M.D. 
Pediatrics 
. 
Kevin Curran, M.D. 
Pediatrics 
Richard J. O‟Reilly, M.D. 
Pediatrics 
Andromachi Scaradavou, M.D. 
Pediatrics 
Susan E. Prockop, M.D. 
Pediatrics 
Maria Cancio, M.D. 
Pediatrics 
Carolyn Jackson, M.D. 
Pediatrics 
Pediatrics 

Page 2 of 43 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
 
 
Barbara Spitzer, M.D. 
Suzanne Wolden, M.D. 
Joachim Yahalom, M.D. 
Shani Irby, NP 
Megan Scott, NP 
Abigail Cohen, NP 
Nicole Lestrange, NP 
Allison Tucker, NP 
Tara Wolff, NP 
Chelsea Mintz, NP 
Sheila Kenny, NP 
Carter Hibbs, NP 
Emily Patterson, NP 
Elaina Preston, PA 
Radiation Oncology 
Radiation Oncology 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Consenting 
Juliet N. Barker, M.B.B.S. (Hons) 
Medicine 
Professional(s)/Department: 
Hugo R. Castro-Malaspina, M.D. 
Medicine 
Sergio Giralt, M.D. 
Medicine 
Ann A. Jakubowski, M.D., Ph.D. 
Medicine 
Esperanza B. Papadopoulos, M.D. 
Medicine 
Miguel-Angel Perales, M.D. 
Medicine 
Doris Ponce, M.D. 
Medicine 
Craig Sauter, M.D. 
Medicine 
James W. Young, M.D. 
Medicine 
Parastoo Dahi, M.D. 
Medicine 
Roni Tamari, M.D. 
Medicine 
Boglarka Gyurkocza, M.D. 
Medicine 
Brian Shaffer, M.D. 
Medicine 
Melody Smith, M.D. 
Medicine 
Jonathan Peled, M.D. 
Medicine 
Gunjan Shah, M.D. 
Medicine 
Michael Scordo, M.D. 
Medicine 
Christina Cho, M.D. 
Medicine 
Oscar Lahoud, M.D. 
Medicine 
Ioannis Politikos, M.D. 
Medicine 
Scott James, M.D. Ph.D. 
Medicine 
Farid Boulad, M.D. 
Pediatrics 
Nancy A. Kernan, M.D. 
Pediatrics 
Richard J. O‟Reilly, M.D. 
Pediatrics 
Andromachi Scaradavou, M.D. 
Pediatrics 
Susan E. Prockop, M.D. 
Pediatrics 
Kevin Curran, M.D. 
Pediatrics 
Maria Cancio, M.D. 
Pediatrics 
Carolyn Jackson, M.D. 
Pediatrics 
Barbara Spitzer, M.D. 
Pediatrics 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 

Page 3 of 43 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Page 4 of 43 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................... 7 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 8 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................. 15 
4.1 
Design .............................................................................................................................. 15 
4.2 
Intervention ........................................................................................................................... 16 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ........................................................................... 16 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................. 19 
6.1 
Subject Inclusion Criteria .................................................................................................. 19 
6.2 
Subject Exclusion Criteria ................................................................................................ 21 
7.0 
RECRUITMENT PLAN ................................................................................................................... 22 
8.0 
PRETREATMENT EVALUATION ...................................................................................... 23 
9.0 
TREATMENT/INTERVENTION PLAN ............................................................................... 24 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................... 29 
11.0 
TOXICITIES/SIDE EFFECTS .................................................................................................... 32 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ........................ 34 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ....................................................................... 35 
14.0 
BIOSTATISTICS ............................................................................................................... 37 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES38 
15.1 Research Participant Registration ......................................................................................... 39 
15.2 
Randomization ................................................................................................................... 40 
16.0 
DAT A M ANAGEMENT ISSUES ........................................................................................ 40 
16.1 
Quality Assurance ............................................................................................................ 40 
16.2 
Data and Safety Monitoring .................................................................................................. 40 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 41 
17.1 
Privacy ............................................................................................................................. 41 
17.2 
Serious Adverse Event (SAE) Reporting ............................................................................. 41 
17.2.1 Costs ......................................................................................................................... 42 
18.0 
INFORMED CONSENT PROCEDURES .................................................................................. 42 
19.0 
REFERENCES ...................................................................................................................... 43 

Page 5 of 43 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
1.0 PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a phase 2 study to obtain an estimate of the speed of neutrophil recovery after 
myeloablative double-unit cord blood (CB) transplantation (CBT) with abrogation of prolonged 
cytopenia by the infusion of T-cell depleted peripheral blood stem cells  (PBSC)  from  a  haplo- 
identical family member. The CB graft will consist of one or two (or double) units from unrelated 
newborn donors to be administered on day +0 (or +1 if needed for scheduling) and haplo-identical 
related donors will be used to obtain PBSC for infusion on day 0 or +1. Candidates for this trial will 
include patients aged 2-70 years with high-risk or advanced forms of hematologic malignancies 
including acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), myelodysplastic 
syndrome (MDS), chronic myeloid leukemia (CML), or lymphoma for whom an allogeneic 
hematopoietic stem cell transplant is indicated and for whom no suitably human leukocyte antigen 
(HLA)-matched and readily available unrelated donor exists. For the purposes of analysis and 
monitoring of stopping rules, patients will be enrolled on 2 arms according to their risk for early 
transplant-related mortality (TRM) or relapse-related death. Arm A will include patients who are at 
standard risk of early post-transplant death from TRM or relapse, and Arm B will include patients 
who are at high risk of early post-transplant death. 
 
Patients must be suitable for myeloablative conditioning but this can be at high dose 
(cyclophosphamide 120 mg/kg, fludarabine 75 mg/m2, and total body irradiation 1375  cGy),  or 
reduced intensity using either 10 mg/kg or 5 mg/kg of thiotepa (cyclophosphamide 50 mg/kg, 
fludarabine 150 mg/m2, thiotepa 10 mg/kg, total body irradiation 400 cGy or cyclophosphamide 50 
mg/kg, fludarabine 150 mg/m
2, thiotepa 5 mg/kg, total body irradiation 400 cGy) as appropriate 
according to disease status, patient age, extent of prior therapy, organ function, and presence of co- 
morbidities. Cyclosporine-A (CSA) and mycophenolate mofetil (MMF) will be used for graft-versus- 
host disease (GVHD) prophylaxis. CB grafts will consist of one or two CB units 4-6/6 HLA-matched 
to the patient to augment graft cell dose and additional T-cell depleted PBSC from a haplo-identical 
donor will be infused on day 0 or +1. The aim of the haplo-identical PBSC graft is to facilitate 
transient engraftment and consequent abrogation of the prolonged cytopenia normally associated 
with CBT by providing a neutrophil and platelet bridge until CB engraftment occurs. The haplo- 
identical natural killer (NK) cells could also mediate additional anti-leukemia activity, especially in 
myeloid malignancies. 
 
Patients will be carefully monitored for donor engraftment and count recovery, donor chimerism, 
incidence and severity of acute and chronic GVHD, serious infections, immune recovery, TRM, 
length of hospital stay, relapse as well as overall and disease-free survival. A total of 26 patients will 
be accrued to the standard risk arm A and 75 to the high risk arm B. Stopping rules will guard 
against excess toxicity according to the study arm. It is anticipated that the accrual period will last 
approximately 3-4 years. The primary endpoint of the study is the day to neutrophil recovery. This 
will be analyzed in each arm separately.  Historically, the median time to neutrophil recovery for 
myeloablative double unit CBT patients is 25 days. A design that differentiates between population 
median recovery times of 25 days and 15 days will be used to assess the neutrophil recovery rate in 
this trial. The design has power equal to 0.90 if the population median neutrophil recovery time for 
patients treated under the proposed approach is 15 days; the one-sided test size is 0.10 when the 
median recovery time is  25 days. At the conclusion of the study a definitive assessment as to 
whether this approach speeds neutrophil recovery will be possible. In addition, a preliminary 
assessment of platelet engraftment and the efficacy of CBT plus haplo-identical PBSC will be made, 
and results can also be compared to historical MSKCC double-unit CBT controls. 

Page 6 of 43 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
TREATMENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 7 of 43 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
 
 
 
Cyclosporine and Mycophenolate Mofetil will be the GvHD prophylaxis for all 3 Regimens. 
 
2.1 OBJECTIVES AND SCIENTIFIC AIMS 
 
Data from MSKCC have shown that double-unit CBT is efficacious with 2-year progression-free 
survival comparable to unrelated and related donor hematopoietic stem cell (HSC) sources
1. 
However, CBT is associated with delayed engraftment as compared with the transplantation of adult 
donor PBSC, even when using CB grafts
1. This can contribute to increased toxicity, extended 
hospitalization, and increased transplantation costs. This protocol will investigate a novel treatment 
strategy that supplements the double-unit graft with additional haplo-identical PBSC that have been 
T-cell depleted with the aim that the haplo-identical cells will mediate transient engraftment and thus 
form a neutrophil and platelet bridge until sustained CB engraftment can be achieved. NK cells from 
the PBSC graft could also provide additional anti-leukemia activity. 
 
The primary aim of this study is to obtain an estimate of the speed of neutrophil recovery after 
double-unit CBT with a T-cell depleted haplo-identical allograft. 
 
Secondary objectives include: 
• 
the incidence of sustained cord blood-derived neutrophil engraftment; 
• 
the speed of platelet recovery and incidence of platelet engraftment by day 180; 
• 
the contribution of the haplo-identical PBSC to initial and sustained engraftment by assessment 
of chimerism in blood and bone marrow; 
• 
the contribution of each CB unit to initial and sustained engraftment by assessment of 
chimerism in blood and bone marrow; 
• 
the incidence and severity of acute GVHD at 100 days; 
• 
the incidence and severity of chronic GVHD at 1 year; 

Page 8 of 43 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
• 
the incidence of day 100 and 180 TRM; 
• 
the length of initial hospitalization post-CBT; 
• 
the number of days hospitalized from day 0 to day 100 post-CBT; 
• 
immune recovery after transplant; 
• 
the incidence of malignant relapse at 1 and 2 years; 
• 
the probabilities of overall and disease-free survival at one and 2 years after CBT. 
• 
graft characteristics potentially associated with engraftment. 
 
At study completion an estimate of the efficacy of CBT with a T-cell depleted haplo-identical PBSC 
transplant in augmenting the speed of neutrophil engraftment will be possible. 
 
3.0 BACKGROUND AND RATIONALE 
 
Clinical Results with Unrelated Donor Double-Unit CBT 
 
HSC transplantation is now recognized as an effective form of therapy for an increasing number 
of malignant and non-malignant disorders. To reconstitute hematopoiesis after myeloablative 
therapy, the transplantation of pluripotent HSCs is required. In the allogeneic setting such HSCs are 
traditionally obtained from the bone marrow or peripheral blood of related or unrelated adult donors. 
Unfortunately suitably HLA-matched allogeneic donors are not available for many patients, 
especially those from racial and ethnic minorities. A recent MSKCC study has shown that unrelated 
donor availability is limited in many patients of southern and mixed European ancestry, as well as 
the majority of patients of Asian, Hispanic, African, Middle Eastern backgrounds and partial non- 
European origins2. 
 
Human CB is an alternative source of HSCs that is capable of reconstituting hematopoiesis after 
myeloablative therapy. Known benefits of publically banked CB include: 1) rapid  availability,  2) 
absence of donor risk, 3) absence of donor attrition, and 4) very low risk of transmissible infectious 
diseases such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Furthermore, this HSC source 
permits the expansion of the available donor pool in targeted racial and ethnic minorities. All published 
studies to date have indicated that the level of HLA-match required for a successful unrelated donor 
CBT is less than that required for a successful unrelated donor transplant
1. Moreover, a MSKCC study 
has proven that CB extends transplant access to racial and ethnic minorities due to reduced 
stringency of the required HLA-match (Figure 1)
2. 
 
Figure  1. Stem  Cell Source  According to 
Patient Ancestry (n = 385). 

Page 9 of 43 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
Single unit CBT, however, has been associated with a significant incidence of graft failure3,4. 
Double-unit CBT has been adopted, therefore, to augment graft cell dose and has been associated 
with improved sustained donor engraftment as compared with historical single unit controls despite 
nearly all patients exhibiting sustained donor engraftment with only one of the two units of the graft 
(known as the dominant unit)5-7. Double-unit transplantation has also been associated  with  a 
reduced incidence of malignant relapse as compared with single unit CBT or adult donor 
transplantation8 -11. A study from MSKCC has shown that double-unit CBT is efficacious with 2-year 
progression-free survival comparable to related and unrelated donor transplantation (Figure 2)1. In a 
recent series of 75 patients transplanted with double-unit CB grafts for the treatment of high-risk 
acute leukemia in remission or myelodysplasia with < 5% blasts, the 2 year relapse incidence has 
been very low at 6% in adults and 9% in children 12. This has translated to relatively high rates of 
disease-free survival at 2 years post-transplant (Figure 3). Importantly, there was no difference in 
the disease-free survival after high-dose and reduced intensity regimens supporting the adoption of 
reduced intensity CBT in patients unsuitable for high dose conditioning (Figure 4). Thus, double-unit 
CBT can extend transplant access to racial and ethnic minorities and achieve very promising 
disease-free survival in children and adults. 
 
 
 
 
 
 
 
 
 
Figure  2.  Post-Transplant  PFS  by  HSC 
Source (n = 367). 
Figure  3. 2  Year  DFS  after  Double-Unit 
CBT for Acute Leukemia/ MDS (n = 75). 

Page 10 of 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
 
 
 
Figure 4. 2 Year DFS by Conditioning after 
Double-Unit 
CBT: High 
Dose vs 
Reduced 
Intensity (n = 75). 
 
 
These findings support double-unit CBT as an important alternative treatment approach for high 
risk hematological malignancies. However, a limitation of double-unit CBT is that neutrophil recovery 
remains delayed even with the use of double-unit grafts. A recent review of the engraftment after 
myeloablative double-unit CBT (n = 80) at MSKCC demonstrated a sustained donor engraftment 
incidence of 94% (95% CI: 88-100) but at a delayed median of 25 days (range 13-43) (J.Barker, 
unpublished data, 2011). Platelet recovery was also prolonged with a cumulative incidence of 84% 
(95% CI: 75-92) occurring at a median of 48 days (range 30-162). As patients do not recover from 
the toxicity of the preparative regimen until neutrophil engraftment occurs, slow count recovery 
contributes to increased cost of transplantation from additional days of hospitalization, antibiotic use, 
narcotic use, total parenteral nutrition requirements, and transfusion dependence for red blood cells 
and platelets. This delayed engraftment also increases infectious complications and exacerbates 
pulmonary and gastro-intestinal toxicity. Most importantly, MSKCC data suggests there may be an 
adverse effect on survival from slow engraftment with TRM occurring in 6/32 (19%) of fast engrafters 
and 9/29 (31%) of slow engrafters (J.Barker, unpublished data, 2011, Figure 5). 
 
 
 
 
Figure 5. 2-year DFS After Myeloablative Double- 
Unit CBT in Adults (n = 65). 

Page 11 of 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
Other investigators have reported an increased TRM in engrafting patients with delayed 
neutrophil recovery
10. This protocol seeks to improve the safety and tolerability of CBT by testing 
whether additional infusion of T-cell depleted haplo-identical PBSC can abrogate prolonged 
neutropenia and thrombocytopenia. These cells are capable of rapid engraftment, but are not likely 
to mediate sustained engraftment given they are T-cell depleted and will compete against the T-cell 
replete double-unit CB graft. Thus, it is hoped that the T-cell depleted haplo-identical PBSC will 
provide a neutrophil and platelet bridge prior to the engraftment of the double-unit CB graft at 3-4 
weeks post-transplant. Optimizing the success of CBT by such an approach is important as this will 
significantly broaden the availability of allogeneic transplantation as a treatment modality. 
 
Methods of Improving Neutrophil Recovery Post-transplant 
 
Ex vivo expansion of CB has been investigated as a potential solution to the prolonged 
neutropenia observed after unmodified single or double-unit CBT13,14. However, this strategy has 
proven to be extremely challenging from a logistical standpoint as expansion of a portion of a single- 
unit graft, or one of the two units of a double-unit graft, must commence prior to the patient‟s 
transplant admission date. Expansion is also very expensive due to the cost of supplemental GMP 
grade cytokines and other reagents. To date, no expansion strategy has yet proven to reliably 
mediate early neutrophil recovery or can easily be applied in a multi-center setting. 
 
Fernandez et al have investigated the alternative approach of infusing a T-cell depleted haplo- 
identical or third party donor graft to supplement single-unit CBT15. Fifty-five patients with high-risk 
hematologic malignancies (median age 34 years and median weight 70 kg) received a single-unit 
CBT with a median infused total nucleated cell (TNC) dose of 2.39 x 107/kg with mobilized PBSC 
cells from a G-CSF mobilized haplo-identical (n = 38) or third-party donor that did not  share 
haplotypes (n = 17). This graft was T-cell depleted using CD34+ cell selection. Initial predominance 
of the haplo or third-party donor was seen with a median time to neutrophil recovery of 10 days post- 
transplant and a median time to a platelet count of > 20 x 109/l of 32 days. Subsequently, 50/55 
patients switched to CB mediated hematopoiesis as would be predicted given the CB graft was T- 
replete. The 5 year overall and disease-free survival were 56% and 47%, respectively. 
 
More recently, van Besien and colleagues have investigated this approach in 45 patients with 
advanced hematologic malignancies16. The median age was 50 years and patients received reduced 
intensity conditioning with melphalan, fludarabine, and anti-thymocyte globulin with tacrolimus and 
mycophenolate mofetil immunosuppression. The median haplo-identical CD34+ cell dose was 3.5 x 
106/kg with 0.7 x 104/kg CD3+ T-cells whereas the median infused TNC dose of the single-unit CB 
graft was 1.5 x 107/kg. The cumulative incidence of neutrophil engraftment was 95% (95%CI: 87- 
100) at day 50 with a median time to neutrophil recovery of 11 days. The cumulative incidence of 
platelet engraftment was 83% (95%CI: 69-97) with a median time to recovery of 19 days. In the 
majority of patients, early haplo-identical engraftment was subsequently replaced by durable CB 
mediated hematopoiesis by 100 days post-transplant, although in 6 patients there was only 
engraftment of the haplo-identical donor, 4 patients had engraftment with only the CB unit and 4 
patients had secondary graft failure. The percentage of haplo-donor chimerism on day 100 
corresponded with the infused CD34+ cell dose of the haplo-identical graft. No grade IV acute 
GVHD was seen. The estimated 1 year overall survival was 55% (95%CI: 39-71) and the 
progression-free survival was 42% (95%CI: 25-79). These results represent promising preliminary 
data but could be further improved upon. As no reports exist of double-unit CBT with a T-cell 
depleted haplo-identical graft we will pursue this strategy in an attempt to further improve upon post- 
transplantation engraftment and survival. 
 
T-Cell Depletion (TCD) Using Clinimacs 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
MSKCC has a long history of using TCD to facilitate allogeneic transplantation with a much 
reduced risk of GVHD. Graft manipulation with TCD is a routine procedure for our Bone Marrow 
Transplant Program. In this protocol, allogeneic haplo-identical G-CSF-mobilized PBSC will be T-cell 
depleted by positive selection of CD34+ progenitor cells using the CliniMACS system. The 
CliniMACS Fractionation system requires an IND; it positively selects CD34+ progenitor cells from 
PBSC by immunoadsorption of cells binding an anti-CD34+ monoclonal antibody to para-magnetic 
beads which can then be isolated by  passage through a magnetized column and released by 
removing the magnetic field and agitation of beads. This approach has been successfully used at 
MSKCC, and has provided CD34+ cell enrichment with a median CD3+ T-cell dose of only 5 x 
103/kg in 74 recipients of adult donor allografts  (G.  Koehne,  personal  communication,  October 
2011). 
 
Potential Anti-leukemic Activity of Natural Killer Cells in Haplo-identical Grafts 
 
Haplo-identical grafts have the potential to mediate anti-malignancy effects, even if not 
associated with sustained engraftment of the haplo-identical donor. This is highly relevant for this 
protocol as patients in morphologic relapse will be included. Such patients are not usually 
considered for transplantation due to their high risk of relapse. The anti-leukemic effects of haplo- 
identical grafts are primarily mediated by NK cells. NK cells are tolerant to cells expressing self-MHC 
class I molecules and cytotoxic to cells lacking self-MHC class I molecules. Recognition of HLA 
class I ligands on potential target cells occurs through surface inhibitory receptors: KIR2DL2/3 
recognize HLA-C alleles (HLA-C1 group); KIR2DL1 recognizes HLA-C alleles (HLA-C2 group); and 
KIR3DL1 recognizes HLA-A and HLA-B alleles with the Bw4 epitope. With expression of inhibitory 
KIR receptors for self-class I molecules, NK cells are “licensed” for effector function (cytokine 
production and cytotoxicity), and become activated against target cells lacking self-HLA class I 
ligands (“missing self”)17,18. In HLA-mismatched HSC transplants, allo-reactivity of donor NK cells 
due to missing self recognition in the patient is the basis for a marked reduction in AML relapse and 
improved survival19. The activating KIR2DS1, which recognizes HLA-C2 molecules, also educates 
NK cells for effector function, where NK cells from HLA-C2/C2 individuals who are 2DS1-positive 
exhibit reduced functional capacity20. Therefore, both inhibitory and activating KIR receptors 
contribute to NK education. Because the receptors are constitutively expressed in the NK repertoire, 
licensed NK activity and allo-reactivity can be predicted based upon KIR and HLA genotypes with a 
high degree of accuracy. In this proposal, to maximize NK allo-reactivity, potential haplo-identical 
donors will be prioritized based on KIR/HLA where possible. 
 
We have evaluated the impact of donor-recipient KIR-HLA genotypes for 1277 AML patients 
transplanted between 1989-2008 from 9-10/10 HLA-matched unrelated donors (K. Hsu, unpublished 
data, manuscript submitted 2012). Two activating KIR genes exhibited significant impact on relapse. 
Patients receiving allografts from donors positive for KIR2DS1 (n = 412) had lower relapse (HR 0.76, 
p = 0.02, Figure 6). Consistent with recent in vitro findings identifying its role in education of NK cells 
with an HLA-C1 background, HLA-C1 donors positive for KIR2DS1 had significantly better impact on 
relapse compared with HLA-C2/C2 donors positive for KIR2DS1 (HR 0.45, p = 0.002, Figure 7). 
Notably, the most potent KIR2DS1 effect was evident in an HLA-C mismatched transplant (HR 0.44, 
p = 0.01, Figure 8). These data suggest that KIR2DS1 provides a potent protection from relapse, 
and have significant implications for donor selection algorithms in that allografts from KIR2DS1 
positive HLA-C1 donors have the highest anti-AML potency and that 2DS1 positive HLA-C2/C2 
donors should be avoided. A clear algorithm will be used for donor selection based on KIR/HLA 
genotyping, applying the most current findings in NK biology to clinical practice. To maximize NK 
alloreactivity, potential haplo-identical donors will be prioritized based on KIR/HLA genotypes (see 
section 6.4). 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 7. Benefit of Donor KIR2 DS1 is Most 
Significant in Donors with an HLA-C1 
Background. 
 
 
 
 
 
 
 
 
 
 
Figure 6. Donor KIR2DS1 is Associated with 
Lower Relapse After Unrelated Donor HSC 
Transplantation for AML. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 8. Potent Donor KIR2 DS1-Mediated 
Graft-versus-Leukemia Effect in HLA-C 
Mismatched Unrelated Donor HSC 
Transplantation for AML. 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
Reasons to Pursue Double-Unit CBT with Haplo-identical Transplant Versus Other Transplant 
Strategies 
 
An alternative treatment approach for patients with high risk hematologic malignancies would be 
to receive a T-cell depleted haplo-identical transplantation without CBT. However, haplo-identical 
transplantation in adults has been associated with a high incidence of TRM and relapse with only 
relatively small series being published to date with most series showing no clear plateau on the 
survival curve
21. By contrast, unrelated donor double-unit CBT has become a standard alternative 
treatment approach at MSKCC and other centers in the United States, and a comparable disease- 
free survival after double-unit CBT and related and unrelated donor transplantation has been 
demonstrated in 2 series1,10. 
 
Another possibility would be to perform a single-unit CBT with haplo-identical PBSC. However, 
we have demonstrated variable CD34+ cell viability in CB units from public CB banks as shown in 
Figure 9 with poor viability units unlikely to engraft22. In a series of 44 double-unit CBT recipients 
engrafting with one unit, using a threshold of 75% (mean-2SD), all but one (43/44) engrafting units 
had CD34+ viability >75% and only 1/16 poor viability units engrafted (p=0.0006). Poor viability 
correlated with lower colony-forming-unit content (p = 0.02). This raises the possibility that one of the 
reasons why double-unit CBT is effective is that it increases the chance of infusing at least one unit 
of high quality and thus with engraftment potential. 
 
An additional reason why double-unit CBT has been associated with augmented engraftment is 
due to the increased dose of total nucleated cells. The MSKCC study of Avery et al has shown that 
the speed and success of engraftment is associated with the total TNC and CD3+ T-cell doses of 
both units combined (Figure 10) as well as the CD34+ cell dose of the dominant unit7. This suggests 
that the non-engrafting unit is facilitating the engraftment of the dominant unit despite the fact that it 
does not contribute to engraftment itself, and that this effect is dose dependent. Single-unit CBT plus 
TCD haplo-identical transplantation has been associated with a risk of graft failure of the CB, and 
patients with sustained engraftment of the haplo-identical cells or failure of both stem cell sources 
have a poor prognosis16. 
 
 
 
 
Figure 9. Variable CD34+ Cell Viability Reflecting 
Variable Quality of CB Units from Public Banks. 

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Figure 10. Total Graft Cell Dose & Neutrophil Engraftment After Myeloablative Double-Unit CBT (n = 61). 
 
Finally, the most compelling reason to use double-unit CBT is that multiple analyses have 
suggested that double-unit CBT protects against malignant relapse8-11. This is especially important in 
adults who receive reduced intensity conditioning. It is unknown whether such benefits would be 
derived from single-unit CB with haplo-identical PBSC transplantation. As survival after double-unit 
CBT has been comparable to that of HSC transplantation from adult donors, this protocol will use of 
double-unit grafts for the vast majority of patients and investigate the addition of haplo-identical 
PBSC to abrogate the prolonged cytopenia and potentially facilitate an additional NK-mediated anti- 
leukemia effect. Most importantly, our approach will also facilitate comparison of the results with 
those of MSKCC double-unit CBT historical controls. However, single unit CBT plus haplo-identical 
PBSC infusion will be considered in the occasional pediatric patient with a large well matched single 
unit from a good quality bank or the rare patient with only one unit of suitable match and dose 
characteristics. 
 
4.1 OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.2 Design 
 
This is a 2 arm phase 2 study to obtain an estimate of the speed of neutrophil recovery after 
myeloablative CBT with abrogation of prolonged cytopenia by infusion of haplo-identical family 
member T-cell depleted PBSC in patients with high-risk or advanced hematologic malignancies. 101 
patients will be recruited over 4 years and transplant outcomes will be assessed as per Section 2.0. 
Arm A (n = 26) will include eligible patients who are at standard risk of early post-transplant death 
from TRM or relapse, whereas Arm B (n = 75) will include eligible patients who are at high risk for 
early death. Stopping rules will guard against excess toxicity as evidenced by graft failure, severe 
GVHD, and high day 100 death rates from TRM or relapse according to risk group (i.e. if in Arm A or 
B, see Section 14). Problems with engraftment, severe GVHD, TRM, early death due to relapse and 
other adverse experiences will be carefully monitored by the MSKCC BMT research data managers 
and reported to the Principal Investigator. Outcomes will be analyzed in each study arm separately 
and at the conclusion of the study the results of study patients can also be compared to MSKCC 
double-unit CBT historical controls. 

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4.3 Intervention 
 
This is a two arm phase 2 study. In the majority of patients the CB graft will consist of double 
units from two unrelated newborn donors. However, rare patients may be able to proceed with a 
single CB unit. The CB graft (administered day 0 or day 0 and +1) will be combined with a PBSC 
graft obtained from a haplo-identical related donor and this will be administered on day 0 or +1. 
Candidates will include patients aged 2-70 years with high-risk or advanced hematologic 
malignancies for whom an allogeneic HSC transplant is indicated and for whom no suitably HLA- 
matched and readily available donor exists. Patients must be suitable for myeloablative conditioning 
but this can be at high dose or reduced intensity as appropriate. GVHD prophylaxis will include CSA 
and MMF. CB grafts will consist of partially HLA-matched CB unit(s) and additional T-cell depleted 
haplo-identical PBSC will be infused on day 0 or +1. The aim of the haplo-PBSC graft is to achieve 
transient engraftment that will abrogate the prolonged cytopenia usually associated with CBT until 
sustained CB engraftment can occur. The haplo-identical NK cells could also mediate additional 
anti-leukemia activity. 
 
 
5.1 THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.2 Cyclophosphamide (Cytoxan®, Neosar®) 
 
Supplied as: 200 mg, 500 mg, 2000 mg vials 
Reconstitution directions: add sterile water for injection to yield a final concentration of 20 mg/ml. 
Storage and stability: 
1. Store vials at room temperature. 
2. Refrigerated: prepare infusion in D5W, stable for 28 days. 
3. Room temperature: prepare infusion in D5W: stable for 48 hours. 
Preparation: 
1. Standard iv fluid: D5W. 
2. Final concentration range up to: 20mg/ml. 
3. IV piggyback volume: for doses < 1200mg/m
2, infuse in 25cc D5W; for doses> 1200mg, infuse as 
straight drug. 
Clinical considerations: 
1. Hydration: as per MSKCC guidelines for BMT patients receiving > 3000 mg/m2. 
2. Emetic potential: high and delayed. 
3. Supportive medications: anti-emetics and mesna. 
Toxicities: see Section 11.0. 
Incompatibilities: do not administer with other drugs. 
 
5.3 Mesna (Mesnex®) 
 
Supplied as: 200 mg/2 ml ampule, 1 gram/10 ml multi-dose vials 
Reconstitution: not applicable. 
Storage and stability: Store vials at room temperature. Multi-dose vials may be stored and used for 
up to 8 days after initial entry. Infusions prepared in D5W are stable for 48 hours when stored under 
refrigeration or at room temperature. 
Preparation: 
1. Must be diluted prior to infusion 
2. Standard IV fluid: D5W. 
3. IV piggyback volume: 50ml D5W 
Dosage and administration: 100% of total cyclophosphamide dose divided into 3 doses administered 
at 30 minutes prior to and 4 and 8 hours after the start of the chemotherapy. Given as IVPB over 15 
minutes. 

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Clinical Considerations: functions as an uroprotectant to prevent hemorrhagic cystitis. 
Toxicities: none. 
 
5.4 Fludarabine phosphate (Fludara®) 
 
Supplied as:50mg vial 
Reconstitution directions: add 2ml of sterile water for injection to a 50mg vial; yields a final 
concentration of 25 mg/ml. 
Storage and stability: 
1. Store vials under refrigeration. 
2. Refrigerated: prepare infusion in D5W; stable for 16 days. 
3. Room temperature: prepare infusion in D5W; stable for 16 days. 
Preparation: 
1. Standard iv fluid: D5W. 
2. Final infusion concentration range: up to 10mg/ml. 
3.IV piggyback volume: 50 cc. 
Clinical considerations: 
1. Hydration: during 500 cc saline. 
2. Emetic potential: low. 
Supportive medications: none. 
Toxicities: see Section 11.0. 
Incompatibilities: acyclovir, amphotericin B, chlorpromazine, daunorubicin, ganciclovir, hydroxyzine, 
miconazole, prochlorperazine. 
 
5.5 Thiotepa (Thioplex®) 
 
Supplied as:15 mg, 30 mg, powder for reconstitution 
Reconstitution directions: Reconstitute each vial to 10 mg/mL. Solutions for  infusion  should  be 
diluted to a concentration ≥5 mg/mL in 5% dextrose or 1, 3, or 5 mg/mL in 0.9% sodium chloride 
injection. Filter through a 0.22 micron filter prior to administration. 
Storage and stability: 
1. Store intact vials under refrigeration (2°C to 8°C). Protect from light. 
2. Reconstituted solutions (10 mg/mL) are stable for up to 28 days under refrigeration (4°C to 8°C) 
or 7 days at room temperature (25°C). 
3. Solutions for infusion in D5W (≥5 mg/mL) are stable for 14 days under refrigeration (4°C) or 3 days 
at room temperature (23°C). 
4. Solutions for infusion in NS (1, 3, or 5 mg/mL) are stable for 48 hours under refrigeration (4°C to 
8°C) or 24 hours at room temperature (25°C). Solutions in NS at a concentration ≤0.5 mg/mL are 
stable for <1 hour. 
Clinical considerations: 
Hydration: NA 
Emetic potential: low. 
Supportive medications: none. 
Toxicities: see Section 11.0. 
 
5.6 Total Body Irradiation (TBI) 
 
The  intensity  of  the  TBI  will  be  determined  by  the  treating  BMT  physician  who  will  select  a 
conditioning regimen of either high dose or reduced intensity conditioning as described in Section 
9.1. Treatment planning begins with a simulation. Patients will receive high-dose treatment (a total of 
1375 cGy over 4 days in 11 fractions, or a total of 1200 cGy over 4 days in 8 fractions if unable to 
tolerate 11 fractions) or reduced intensity (a total of 400 cGy over 2 days in 2 fractions). Lung 

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shielding will be done in recipients of high dose radiation (> 1200 cGy) as per MSKCC standard 
practice. Pre-transplant radiation boosts to the testis or other areas are permitted as appropriate for 
the underlying diagnosis and will be decided in consultation with Radiation Oncology clinicians. 
Patients are treated in a standing position and the treatment takes 20-30 minutes. Toxicities are 
outlined in Section 11.0. 
 
5.7 Cyclosporine 
 
Supplied as: 50 mg/ml; 5 ml ampule (protect from light) 
Reconstitution: N/A 
Indications: Immunosuppressant used in the allogeneic transplantation. 
Storage and Stability: Prepare in a glass bottle only. Stability is 72 hours under refrigeration or at 
room temperature. 
Preparation: 
1. Dilute in D5W or NS to make a 2.5 mg/ ml solution. 
2. Infuse slowly over approximately 1-4 hours. 
Clinical Considerations: 
1. Patients should be under close observation for possible allergic manifestations including flushing, 
dyspnea and wheezing, blood pressure changes and tachycardia. 
2. Prior to infusion solution should be inspected for particulate matter and discoloration. 
3. Other nephrotoxic agents will increase the risk of nephrotoxicity. 
4. Plasma concentrations of cyclosporine may be affected by the following drugs: 
Increased cyclosporine levels:  ketoconazole,  erythromycin,  cimetidine,  calcium  channel blockers, 
fluconazole, itraconazole, norfloxacin, imipenem/ cisplatin. 
Decreased cyclosporine levels: rifampin, phenytoin, phenobarbital, imipenem/ cisplatin. 
5. The target serum level of 200- 400 is desirable; 600 is considered toxic. 
6. 
Renal and hepatic function should be monitored closely. 
Toxicities: see section 11.0 
Incompatibilities: Do not co-administer with any drug. 
 
5. 7  Mycophenolate Mofetil (CellCept®) 
 
Supplied as: 500 mg vial of powder for reconstitution. 
Reconstitution: reconstitute each 500 mg vial with 14 ml of D5W only. Gently shake to dissolve. 
Storage and Stability: Store at 15 -30C. Drug compatible with D5W only. A final concentration of 
6mg/ ml must be achieved prior to administration. Reconstituted vials and IV preparations are stable 
for up to 4 hours after preparation. 
Preparation: 
1. Reconstitute each 500 mg vial with 14 ml of D5W. 
2. Gently shake the vial to dissolve the drug. 
3. Drug must be further diluted to a final concentration of 6 mg/ml. A 1000 mg dose should be placed 
in 140 ml of D5W. 
4. Mycophenolate Mofetil vials are stable for 4 hours at room temperature after reconstitution. 
5. Doses of mycophenolate may begin infusion up to 4 hours after initial reconstitution. 
Clinical Considerations: administer only with D5W over at least 2 hours. Mycophenolate is 
mutagenic, carcinogenic, and teratogenic. Precautions must be taken when handling this product. If 
medication comes in contact with skin, wash thoroughly with soap and water. 
Toxicities: see section 11.0 
Incompatibilities: Only compatible with D5W. 
 
5.8 Filgrastim/ Granulocyte-Colony Stimulating Factor (Neupogen®) 

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Supplied as 1 ml vial (300 mcg) and 1.6 ml vial (480 mcg); 300 mcg/0.5 ml pre-filled syringe; 480 
mcg/0.8 ml pre-filled syringe. 
Store at 2-8C. Do not freeze. Avoid shaking. May reach room temperature for 24 hours prior to use. 
Preparation: 
1. For IV infusion, dilute filgrastim in 25-50 ml D5W. 
2. The minimum concentration must not be less than 5 mcg/ml. 
3. If the final concentration is between 5-15 mcg/ml, albumin 2 mg/ml must be added prior to 
addition of the drug. 
4. Stability (IV) once diluted in 25-50 ml of D5W, filgrastim is stable for 7 days. 
5. Stability (plastic syringe): filgrastim is stable for two weeks in BD 1 ml plastic TB syringes at 2- 
8C. 
Dose: ≤ 60 kg = 300 mcg daily subcutaneously; > 60 kg = 480 mcg subcutaneously daily. 
Clinical Considerations: If administered as an intermittent IV infusion, give via an infusion control 
device over a 15- 30 minute period. 
Incompatibilities: The drug may precipitate in Normal Saline. Do not mix with any other drugs. 
 
5.9 Cord Blood (CB) and Haplo-identical PBSC 
 
CB units are processed to remove excess plasma; most banks also deplete red blood cells. They 
are tested for sterility, HLA-typed, cryopreserved and stored. The CB units will be thawed in the 
Cytotherapy Laboratory as per standard operating procedures. CB units should be infused 
intravenously via a central venous catheter according to standard MSKCC Nursing guidelines. 
Haplo-identical PBSC will be collected from a family member after G-CSF mobilization. TCD will be 
done by positive selection of CD34+ cells using CliniMACS. The CliniMACS Fractionation system 
requires an IND; it positively selects CD34+ progenitors by immunoadsorption of cells to 
paramagnetic beads. Cells are isolated by passage through a magnetized column and released by 
agitation of the beads. 
 
 
6.1 CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 Subject Inclusion Criteria 
 
The criteria below determine eligibility for the protocol. 
 
Note: protocol eligible patients according to the criteria outlined below will then be divided according 
to age, diagnosis, performance status, organ function, prior transplantation, hematopoietic cell 
transplant comorbidity index (HCT-CI)23, and CB TNC dose into those who are at standard risk (Arm 
A) or high risk (Arm B) for early post-transplant death for the purposes of applying stopping rules 
and outcome analysis. 
 
Protocol eligibility criteria are: 
 
• 
Age: 
o 2 - 70 years. 
• 
Diagnosis of severe aplastic anemia: eligibility to be discussed with PI and Service Chief. 
Such patients will be assessed in Arm B. 
• 
Diagnosis of high risk hematological malignancy: 
o Any acute leukemia in first complete remission (CR) considered at high risk for relapse, 
or second or third CR, or relapse/refractory less than 10% blasts in bone marrow, or 
aplasia post-therapy. This includes de novo acute leukemia or acute leukemia that is 
therapy   related   or   arising   from   an   antecedent   hematologic   disorder   including 

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myelodysplasia  (MDS), chronic myeloid  leukemia  (CML)  or  other myeloproliferative 
disorder. 
o Juvenile myelomonocytic leukemia (JMML) in CR, or relapse with less than 10% bone 
marrow blasts. 
o CML with tyrosine kinase inhibitor failure in chronic or accelerated phase or evolved to 
acute leukemia (blast crisis, see above). 
o MDS or other myeloproliferative disorder with life-threatening cytopenia(s), and/or red 
blood cell or platelet transfusion dependence, or patients with aplasia, or patients with 
excess blasts less than 10% blasts in the bone marrow at work-up. 
o Aggressive lymphoma: patients in CR1 with disease at high risk of relapse or CR2-3.. 
o Indolent lymphoma or chronic lymphocytic leukemia (CLL): any disease status 
provided any transformed component is in CR. 
o Hodgkins lymphoma that is primary refractory or relapsed not suitable for other 
therapy and in PR or CR or small volume stable disease. 
• 
Performance status: 
o Karnofsky score  >70 or Lansky score >70. 
• 
Organ function: 
o Resting left ventricular ejection fraction (LVEF) > 50%. 
o Spirometry (FEV1  and FVC) & corrected DLCO > 50% predicted. In small children use 
history and physical and CT scan to determine pulmonary status. 
o Total bilirubin < 1.5 mg/dL (unless benign congenital elevated bilirubin); ALT < 3 x 
upper limit of normal (ULN). 
o Calculated creatinine (calc. creat.) clearance > 60 ml/min. 
o Albumin > 3.0. 
 
• 
Graft: 
o Cryopreserved dose will be > 1.5 x 10
7 TNC/kilogram in each unit for double unit CB 
grafts. This will be the CB graft for the majority of patients. 
o In select patients with access to CB units that have high TNC (> 5.0 x 10
7/kg), and 
are from good quality CB banks a single unit could be considered with a back-up CB 
unit on standby. 
o In select patients who have a very poor search and only have one suitable CB 
unit available, this unit could be given as a si ngle unit. This unit must have a 
TNC > 2.0 x 107 TNC/kilogram and a CD34+ cell dose ≥1.5 x 105 
CD34+/kilogram. 
o Haplo-identical donors who are 5/10 or better but not HLA-identical will be used as 
outlined in section 6.4. 
 
Assignment of conditioning intensity (high dose vs reduced intensity) will be  based  on 
patient disease status, age, extent of prior therapy, organ function and presence of 
significant co-morbidities as outlined in Section 9.2. 
 
For the purposes of analysis (not assignment of preparative regimen), patients will be 
assigned to Arms A and B as summarized below according to their risk of early post- 
transplant death. 
 
Eligible patients who fulfill all of the following criteria will be assigned to risk Ar m A: 
 
Arm A: Standard Risk for Early Post-Transplant Death 
Age 
2-49 years 
Diagnosis 
Any acute leukemia in CR1 - CR2 (includes therapy-related and 
arising from MDS or myeloproliferative disease). 

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JMML in CR. 
CML with TKI failure & < 5% blasts. 
MDS with < 5% blasts at work-up. 
Lymphoma (including CLL) CR1-2. 
Performance Status 
Karnofsky >80; Lansky >80. 
Organ Function 
Resting LVEF > 60%. 
Spirometry (FEV1 and FVC) & corrected DLCO > 80% 
predicted. 
Total bilirubin normal; ALT normal-1.4 x ULN. 
Calc. creat. clearance > 70 ml/min. 
Prior HSC Transplant 
No 
HCT-CI score
23
 
0-2 
Pre-thaw TNC Dose 
Each unit > 2.0 x 107/kg. 
 
Eligible patients who meet any of the following criteria will be assigned to risk Ar m B: 
 
Arm B: High Risk for Early Post-Transplant Death 
Age 
50-70 years 
Diagnosis 
Any acute leukemia in relapse/ refractory disease in BM or circulating 
blasts or CR3 or aplasia. 
JMML not in CR. 
MDS with aplasia or > 5% blasts. 
Lymphoma (including CLL) with disease other than CR1-2. 
Severe myelofibrosis of the bone marrow 
Performance Status 
Karnofsky 70; Lansky 70 
Organ Function 
Resting LVEF 50-59%. 
Spirometry (FEV1  and FVC) & corrected DLCO 50-79% predicted. 
Total bilirubin 1.1-1.5 mg/dL; ALT 1.5-3 x ULN. 
Calc. creat. clearance 60-69 ml/min. 
Prior HSC Transplant 
Yes 
HCT-CI score23 
3 or higher 
Pre-thaw 
TNC Dose 
Either or both units 1.5-1.9 x 10
7/kg. 
 
6.3 Subject Exclusion Criteria 
 
• 
Active CNS leukemia. 
• 
Any acute leukemia (including prior myelodysplasia or CML blast crisis) with morphologic 
relapse or persistent disease > 10% blasts in the BM, or doubling of the blasts in the 
blood in the 2 weeks preceding admission, or need for hydroxyurea in the 2 weeks prior 
to admission, or uncontrolled extra-medullary disease. 
• 
Two prior stem cell transplants of any kind. 
• 
One prior autologous stem cell transplant within the preceding 12 months. 
• 
One prior allogeneic stem cell transplant within the preceding 24 months. 
• 
Prior radiation therapy with 400cGy or more of TBI. If 200 cGy of prior TBI then only 400 
cGy of TBI on this protocol is permitted.. 
• 
Uncontrolled viral, bacteria or fungal infection at time of study enrollment. 
• 
Sero-positive or NAT positive for HIV. 
• 
Females who are pregnant or breast feeding. 

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• 
Patient or guardian unable to give informed consent or unable to comply with the treatment 
protocol including appropriate supportive care, follow-up, and research tests. 
 
6.4 Cord Blood Grafts 
 
Units will be selected based on the HLA-match to the patient and individual cell doses of the 
units according to current MSKCC unit selection criteria. HLA-testing will be done using 
molecular techniques. The standard cord blood graft for this protocol will consist of 2 units as a 
double unit graft although single units are permitted. Each unit will be at least 4 of 6 HLA-A, -B 
antigen and -DRB1 allele matched with the recipient. Each unit of a double unit graft will have a 
cryopreserved dose of at least 1.5 x 107 TNC/recipient body weight (TNC/kg). In the occasional 
patient with a large well matched good quality single unit or the rare patient with only one unit of 
suitable match and dose characteristics the cord blood graft can consist of a single unit as 
described in section 6.1. 
 
6.5 Haplo-identical Donor Inclusion Criteria 
 
• 
A HLA-haplo-identical related donor will be selected as available as per standard MSKCC 
Adult BMT guidelines. Mismatched family members who are matched at more than 5 of 10 
HLA-loci are permitted. Factors to be taken into account when selecting a haplo-identical 
donor will include donor age, weight, health status and comorbidities, compliance, venous 
access, recipent donor specific HLA-antibody status, and NK cell alloreactivity. 
• 
The donor must meet criteria outlined in the FACT-approved SOP  for  “DONOR 
EVALUATION AND SELECTION FOR  ALLOGENEIC  TRANSPLANTATION”  in the  Blood 
and Marrow Transplant Program Manual, document E-1 (see attached, or link to URL: 
(https://one.mskcc.org/sites/pub/corp/bmt/Documents/D2_SOP_Donor%20Selection%20and 
%20Evaluation_04_2015.pdf). 
• 
The donor must have adequate peripheral venous catheter access for leukapheresis or must 
agree to placement of a central catheter. 
• 
The donor must be >25 kg in weight. 
 
6.6 Haplo-identical Donor Exclusion Criteria 
 
• 
Evidence of active infection (including active urinary tract infection, or upper respiratory tract 
infection) or evidence of viral hepatitis exposure on screening unless only HbsAb+ and HBV 
DNA negative. 
• 
Medical or physical reason which makes the donor unlikely to tolerate or cooperate with 
growth factor therapy and leukapheresis. 
• 
Factors which place the donor at increased risk for complications from leukapheresis or G- 
CSF therapy (e.g., active autoimmune disease, sickle cell trait, symptomatic coronary artery 
disease requiring therapy). 
• 
Pregnancy (positive serum or urine -HCG) or breastfeeding.   Women of childbearing age 
must avoid becoming pregnant while on the study. 
 
7.0  RECRUITMENT PLAN 
 
Adult and pediatric patients will be considered for this therapy and recruited as appropriate 
according to their diagnosis, availability of alternative therapies, and availability of appropriate cord 
blood grafts and related haplo-identical donors as described in the protocol eligibility. Patients who 
fulfill the eligibility criteria as listed in Section 6.0 will be recruited by a BMT attending. Informed 

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consent will be obtained by one of the participating investigators authorized to obtain consent. After 
consent is obtained, confirmation of patient eligibility will be done by the Clinical Trials Office. 
 
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 patients referred for transplant without exclusion as to age, gender, or 
ethnic background within the limits of transplant eligibility and of being able to identify a suitable CB 
graft and a suitable haplo-identical related donor. Pregnant women are excluded from participation 
in this study. 
 
8.1 PRETREATMENT EVALUATION 
 
8.2 Pretreatment evaluation of the patient 
 
 
1. Standard clinical pretreatment evaluations 
The following tests must be performed as per Adult BMT standard of care: 
 
a. Within 30 days prior to admission: 
i. Complete history, review of systems, physical exam (including performance 
status). 
ii. CBC with differential, comprehensive metabolic panel including albumin, LDH, 
PT/ PTT. 
 
b. Within 45 days prior to admission: 
i. Bone marrow aspirate (trephine core if clinically required) for morphology, and 
special studies (surface markers, cytogenetics, FISH and molecular studies) 
as warranted for documentation of disease status and bone marrow 
morphology. 
c. Prior to admission standard workup studies per Adult BMT Program including: 
i. Spinal or intra-Ommaya tap for evaluation of evidence of CNS leukemia as 
appropriate if patients with acute leukemia are at risk for CNS disease.Red 
blood cell type and screen (ABO blood type).. 
ii. EKG. 
iii. Echocardiogram or MUGA scan with measurement of left ventricular ejection 
fraction. 
iv. Radiographic studies if clinically indicated for diagnosis. 
v. Chest CT scan without contrast to exclude occult fungal infection prior to 
transplant (unless CT with contrast required for disease assessment eg NHL). 
vi. Pulmonary function testing including DLCO.   Clinical and radiological 
assessment can substituted in small children. 
vii. Testing for CMV (IgG and IgM), HIV-1/2, HTLV-1/2, toxoplasmosis, Hepatitis 
B (surface antigen, surface antibody), Hepatitis C antibody, Herpes Simplex, 
Herpes Zoster, Epstein Barr Virus, and syphilis. Pregnancy test for females of 
childbearing age (serum or urine HCG). 
viii. Peripheral blood from the patient should be submitted to the Diagnostic 
Molecular Pathology (DMP) Laboratory for future chimerism studies. 
ix. HLA antibodies to the American Red Cross. 
 
Note if prior serology testing has documented sero-positivity for an infection such as CMV or EBV it 
does not need to be repeated during the pre-transplant workup. 

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2. Pretreatment Protocol Research Tests 
a. Prior to conditioning: 
i. Research labs: approximately 30cc (green and red top tubes) should be sent 
to the research laboratories as part of correlative laboratory studies. 
 
 
 
9.1 TREATMENT/INTERVENTION PLAN 
 
9.1 General and Assignment of Conditioning Regimen 
 
Patients will be admitted to the Pediatric or Adult Bone Marrow Transplant Unit. Patients will be 
maintained in reverse isolation as per the BMT clinical care guidelines. Prior to the administration of 
the pre-transplant conditioning, a double or triple lumen central venous catheter will be inserted. 
The conditioning regimen will be selected based on the patient age as well as disease status, extent 
of prior therapy, organ function and presence of significant co-morbidities. Note that: 
• 
Patients < 30 years are potentially eligible for high dose or reduced intensity regimens i.e. 
Regimens A), B) or C) and decision should be made based on comorbidity status. 
• 
Patients 30-59 years are eligible for regimens B) or C) and choice will be made based on 
comorbidity status. 
• 
Patients aged 60 - 70 years and patients with HCT-CI score of 5 or higher are only eligible 
for regimen C). 
 
9.2 Treatment Schedule and Conditioning 
 
Regimen A) Cy 120/ Flu 75/ TBI 1375: Fit patients < 30 years 
 
 
Patients most suitable for high-dose conditioning will receive: 
 
Day 
Treatment 
-7 
Admission 
-6 
Fludarabine 25 mg/m2  IV 
Cyclophosphamide 60 mg/kg IV 
(+Mesna) 
-5 
Fludarabine 25 mg/m
2  IV 
Cyclophosphamide 60 mg/kg IV 
(+Mesna) 
-4 
Fludarabine 25 mg/m2  IV 
-3 
TBI (125 cGy) x 3* 
Start CSA and MMF 
-2 
TBI (125 cGy) x 3* 
-1 
TBI (125 cGy) x 3* 
0 
TBI (125 cGy) x 2* then CBT** 
Day 0 or +1 
Administer haplo-identical PBSC 
* Can be given as 150 cGy per fraction BID for 4 days for a total of 1200 cGy if not able to 
tolerate TID dosing. 
** If haplo-identical cells are given on day 0 and the CB units need to be split, CB can be 
given on day +1. 

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• 
Fludarabine: 25 mg/m2/day IV over approximately thirty minutes x 3 days (days -6, -5 and -4) 
for a total dose of 75 mg/m
2 . Dose should be adjusted if the patient is > 125% ideal body 
weight (IBW) and calculated on adjusted body weight per MSKCC guidelines. 
• 
Cyclophosphamide: 60 mg/kg/day  IV over 30-60 minutes x 2 days  (days -6 and -5) per 
MSKCC guidelines with high volume fluid flush and Mesna after the fludarabine is complete. 
Cyclophosphamide dose should be adjusted if the patient is > 125% ideal body weight (IBW) 
and calculated on adjusted body weight per MSKCC guidelines. High volume fluids should 
commence approximately 12 hours prior to drug and continue until 24 hours after the second 
dose. Rate should be per MSKCC standard of care (as documented on website under "for 
BMT patients receiving > 3000 mg/m2). Use intravenous diuretic (LasixTM) as required to 
maintain fluid balance. 
• 
Mesna: Dose is 100% of the total daily cyclophosphamide dose divided into 3 doses (20 
mg/kg/dose) and administered at 30 minutes prior to and 4 and 8 hours after the start of 
Cyclophosphamide on days -6 and -5. Give as IVPB over 15 minutes. Pediatric patients can 
receive the same dose as continuous infusion. 
• 
Total Body Irradiation: 125 cGy x 11 doses (TID on days -3, -2, -1 and BID on day 0) for a 
total TBI dose of 1375 cGy. Patients unable to tolerate a TID dosing schedule for TBI can 
receive 150 cGy BID x 8 doses for a total of 1200 cGy. 
 
Regimen B) Cy 50/ Flu 150/ Thio 10/ TBI 400: Fit patients 30-59 years or patients < 30 years 
not suitable for high dose conditioning. 
Patients most suitable for reduced intensity conditioning will receive: 
 
Day 
Treatment 
-7 
Admit and line placement 
-6 
Fludarabine 30 mg/m2  IV 
Cyclophosphamide 50 mg/kg IV 
-5 
Fludarabine 30 mg/m2  IV 
Thiotepa 5 mg/kg IV 
-4 
Fludarabine 30 mg/m2  IV 
Thiotepa 5mg/kg IV 
-3 
Fludarabine 30 mg/m2  IV 
Start MMF and CSA IV 
-2 
Fludarabine 30 mg/m2  IV, TBI 200 
cGy 
-1 
TBI 200 cGy 
0 
CBT* 
Day 0 or +1 
Infuse haplo-identical PBSC 
** If haplo-identical cells are given on day 0 and the CB units need to be split, CB can be 
given on day +1. 
 
• 
Fludarabine: 30 mg/m²/day should be administered as per MSKCC guidelines in the morning 
over approximately 30-60 minutes on days -6 to -2 (5 doses). Fludarabine dose should be 
calculated based upon adjusted body weight if the patient is > 125% ideal body weight. 
• 
Cyclophosphamide: 50 mg/kg IV will be given for one dose. It should be administered as per 
MSKCC guidelines on day -6 after the fludarabine is complete. Cyclophosphamide dose 
should be adjusted if patient is > 125% ideal body weight (IBW) and should be calculated on 
adjusted body weight per MSKCC standard of care guidelines. Fluids should be per MSKCC 
standard of care with diuretics as required to maintain fluid balance. 
• 
Thiotepa: 5 mg/kg/day IV given as a 4 hour infusion on days -5 and -4. Thiotepa dose will be 
calculated based upon adjusted body weight if the patient is > 125% ideal body weight. 

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• 
Total Body Irradiation: 200 cGy per dose on days -2 and -1 (2 doses). . 
 
Regimen C) Cy 50/ Flu 150/ Thio 5/ TBI 400: patients 60-70 years or patients < 60 years not 
suitable for conditioning of higher intensity including patients with HCT-CI score of 5 or 
higher. 
 
 
Patients most suitable for reduced intensity conditioning with thiotepa 5 mg/kg will receive: 
 
Day 
Treatment 
-7 or -6 
Admit and line placement 
-6 
Fludarabine 30 mg/m2  IV 
-5 
Fludarabine 30 mg/m2  IV 
Cyclophosphamide 50 mg/kg IV 
-4 
Fludarabine 30 mg/m2  IV 
Thiotepa 5mg/kg IV 
-3 
Fludarabine 30 mg/m2  IV 
Start MMF and CSA IV 
-2 
Fludarabine 30 mg/m2  IV, 
TBI 200 cGy 
-1 
TBI 200 cGy 
0 
CBT 
Day 0 or +1 
Infuse haplo-identical PBSC 
** If haplo-identical cells are given on day 0 and the CB units need to be split, CB can be 
given on day +1. 
 
• 
Fludarabine: 30 mg/m²/day should be administered as per MSKCC guidelines in the morning 
over approximately 30-60 minutes on days -6 to -2 (5 doses). Fludarabine dose should be 
calculated based upon adjusted body weight if the patient is > 125% ideal body weight. 
• 
Cyclophosphamide: 50 mg/kg IV will be given for one dose. It should be administered as per 
MSKCC guidelines on day -5 after the fludarabine is complete. Cyclophosphamide dose 
should be adjusted if patient is > 125% ideal body weight (IBW) and should be calculated on 
adjusted body weight per MSKCC standard of care guidelines. Fluids should be per MSKCC 
standard of care with diuretics as required to maintain fluid balance. 
• 
Thiotepa: 5 mg/kg/day IV given as a 4 hour infusion on day -4. Thiotepa dose will be 
calculated based upon adjusted body weight if the patient is > 125% ideal body weight. 
• 
Total Body Irradiation: 200 cGy per dose on days -2 and -1 (2 doses). 
 
9.3 GVHD Prophylaxis 
 
All patients will receive GVHD prophylaxis with 2 drugs as follows: 
 
Cyclosporine 
 
• 
Cyclosporine A (CSA) will be given per current MSKCC guidelines. 
• 
It will begin on day -3 intravenously in the AM to achieve therapeutic levels per MSKCC 
guidelines. 
• 
Initial dosing will be per the MSKCC guidelines of 3 mg/kg per dose (adjusted weight in 
the setting of marked obesity) starting day -3 and dose adjustments should be made on 
the basis of toxicity and sub- or supra-therapeutic CSA levels. 
• 
Once the patient can tolerate oral medications, CSA can be converted to an oral form. 

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• 
In case of major CSA toxicity (e.g. CNS neurotoxicity documented by MRI), CSA should 
be discontinued. Patients may be re-challenged when clinically  appropriate  and 
alternative immune suppression should be substituted per MSKCC guidelines. 
• 
Patients unable to tolerate CSA due to renal impairment should also be considered for an 
alternative immunosuppressant in addition to mycophenolate mofetil as per MSKCC 
guidelines. 
• 
Standard patients will receive CSA for approximately 5-6 months in the absence  of 
ongoing GVHD requiring systemic immune suppression. If no history or  evidence  of 
GVHD, CSA may be tapered with monitoring for GVHD with the aim to be off 
immunosuppression by approximately 8-9 months after transplant. 
• 
In patients intolerant of CSA due to renal impairment or other toxicity CSA can be tapered 
before MMF. This is a reverse taper (see guidelines). 
• 
For patients with GVHD, CSA may be continued for longer time periods according to 
standard of care guidelines 
• 
If disease progression or persistence occurs, or the patient is considered to be at very 
high risk of relapse, early taper or cessation of CSA can be considered with close 
observation for GVHD. 
 
Mycophenolate mofetil (MMF) 
 
• 
Mycophenolate mofetil (MMF) will be given per current MSKCC  MMF  guidelines.  It 
should begin on day -3 intravenously in the AM. Standard dose for adults is 15 mg per kg 
per dose IV q8 hours-see detailed dosing instructions in the 
• 
Obtain therapeutic trough levels as per MSKCC guidelines. 
• 
In preparation for discharge, switch to oral route (CellCept or generic mycophenolate 
mofetil). For oral conversion round to tablet size. If possible ensure both tablet strengths 
are given to patient to permit easy taper in clinic. On Pediatric Service can use liquid 
suspension. Avoid suspension on Adult Service. 
• 
No dose adjustments for renal or liver disease are needed routinely unless severe organ 
dysfunction. 
• 
If patient is > +28 days and without neutrophil engraftment, consideration can be made to 
dose reduce dosing after discussion with PI or co-PI. 
• 
If no evidence of GVHD, MMF can be tapered at approximately 60-100 days post- 
transplant. Taper at approximately 10-20% decrements. The aim to be off the drug by 
approximately 5-6 months. Earlier tapers can be considered if myelosuppression or high 
relapse risk with very close monitoring for GVHD. Abrupt reductions or cessation should 
be avoided due to GVHD risk. 
• 
Patients who are intolerant of MMF due to myelosuppression may require earlier taper at 
the treating physician‟s discretion. Do not abruptly stop the drug unless life-threatening 
toxicity is suspected. 
• 
If the patient is intolerant of CSA, MMF taper may be delayed i.e. do a reverse taper 
where CSA tapered first (see above). 
• 
If the patient has acute GVHD requiring systemic therapy, MMF should only be tapered if 
control of GVHD has been obtained 
 
9.4 CB Thaw and Administration 
 
• 
CB grafts will be received at the  MSKCC Cytotherapy Laboratory prior to the start of the 
preparative regimen. 
• 
Units will be thawed by and released from the Cytotherapy Laboratory according to curr ent 
standards of practice and release criteria. As per standard practice, ABO blood group, total 

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nucleated cells (TNC), CD34+ and CD3+ cell number and viability, and sterility  will be 
measured post-thaw. 
• 
A small number of cells (< 0.5% of the post-thaw TNC of each unit) may be used for 
laboratory research studies. 
• 
A sample of each unit should be sent to the American Red Cross for chimerism studies. 
• 
Units should be administered upon arrival to the patient care unit by IV infusion by the 
nursing staff under supervision of a BMT attending physician. CB infusion nursing guidelines 
should be followed. 
• 
Pre-medication as per current MSKCC guidelines should be given as appropriate for patient 
age. 
• 
IV hydration per standard of care. . 
• 
Sample from each CB unit must be submitted to the Diagnostic Molecular Pathology 
Laboratory. 
 
9.5 Haplo-identical PBSC Collection, Processing and Infusion 
 
• 
Beginning 5-6 days before the day of transplant, the haplo-identical donor will receive 10 
mcg/kg of G-CSF administered subcutaneously daily for at least 5 days as per MSKCC 
standards of care. 
• 
On the 5th (and 6th if needed) days of G-CSF, the donor will undergo leukapheresis. 
Leukapheresis will be performed on a continuous flow cell separator according to institutional 
standards. Mononuclear cell fractions will be pooled. Isolation of CD34+ cells will be 
performed with the CliniMACS TM System, Miltenyi Biotec. 
• 
Pheresis will aim for a collection target of at least 6 x 106 CD34+ cells/kg recipient body 
 
weight if possible following one or two leukapheresis procedures. The collection target of 6 
million will permit the target of 5 million CD34+ cells to be reached post-processing. There is 
no cap on CD34+ cell dose (see below). 
• 
Bone marrow harvest will not be performed. 
• 
The apheresis product will be first co-incubated with the CliniMacs CD34 reagent (antibody- 
coated paramagnetic particles). After magnetic labeling and washing, the cells are passed 
through a high-gradient magnetic separation column in the CliniMACS clinical cell selection 
device. Magnetically labeled CD34+ cells are retained in the magnetized column, and CD34- 
cells flow through as the effluent and are discarded. The CD34+ cells retained in the column 
are eluted by removing the magnetic field and washing the cells through the column. The 
final CD34+ cell enriched product is concentrated by centrifugation and tested before final 
release. 
• 
Before infusion, the CD34+ cells will be washed in normal saline for intravenous infusion 
containing 1% human serum albumin and suspended in a small but unrestricted volume per 
MSKCC standards. 
• 
QC testing is TNC count, flow cytometry phenotypic analyses of CD45, CD34, and CD3, and 
viability by 7-AAD, gram stain, and culture. 
• 
The haplo-identical CD34+ cell product can be collected in advance of day 0  if  this  is 
required for scheduling purposes and cryopreserved. The collection should occur after the 
patient has been admitted to guard against collection of haplo-identical cells for a patient 
whose transplant is subsequently cancelled. 
• 
On day 0 or +1, patients will receive an infusion of haplo-identical CD34+ cell-enriched, T-cell 
depleted G-CSF-mobilized PBSC. 

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• 
The target of CD34+ cells to be infused as the haplo-identical graft is approximately 5 
x 10
6/kg. Higher doses can be given only if the cap on CD3+ cells is met. 
• 
To guard against permanent engraftment of the haplo-identical graft, the CD3+ dose 
will be capped at a maximum of 8 x 103/kg. 
• 
Due to the stringent T-cell depletion, no significant GVHD from the haplo-identical cells is 
anticipated. 
• 
The CD34+ T-cell depleted PBSC will be infused intravenously over approximately 3-15 
minutes per standard of care with close monitoring of vital signs. The patient will be pre- 
medicated as for blood product transfusions. 
• 
The following details will be collected about the haplo-donor: age, relationship to patient, 
gender, weight, 10 allele HLA-match, ABO blood group, CMV serostatus, infused CD34+ 
dose, infused CD3+ dose, day/date of infusion, and whether the product was administered 
fresh or cryopreserved/ thawed. 
 
9.6 Growth Factor (Filgrastim or G-CSF) 
 
G-CSF 5 mcg/kg once-twice daily IV or once daily SQ (dose rounded to vial size to a maximum of 
480 mcg) will be given to all transplant recipients from day +7 until ANC recovery. 
10.1 
EVALUATION DURING TREATMENT/INTERVENTION 
 
10.2 
Prophylaxis Against Infection 
 
Patients will be treated according to the allogeneic BMT standard of care guidelines and will be 
given prophylaxis against 1) Pneumocystis, 2) Herpes simplex and Herpes Zoster, and 3) fungal 
infections. Sero-positive patients will be closely monitored for activation of  CMV and  CMV 
viremia will be treated according to the BMT guidelines. 
10.3 
Transfusions 
 
Following initiation of the pre-transplant cytoreduction, all blood products for transfusion (with 
the exception of the stem cell graft) will be irradiated as per MSKCC guidelines. 
 
10.4 
Prophylaxis Against Menstrual Bleeding 
 
Post-pubertal females will be considered for hormonal therapy to suppress menses unless a 
specific contra-indication to estrogen exists. 
 
10.5 
Nutritional Support 
 
Physicians will monitor nutritional status, and high-calorie supplementation and vitamin 
supplements will be administered as clinically indicated per standard practice. 
 
10.6 
Correlative Studies 
 
Laboratory studies will be performed on the CB graft using a maximum of 0.5% of each unit on 
the day of thaw investigating factors associated with unit dominance in patient engraftment. The 
correlative studies will include: 

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• 
Standard characterization of each unit by flow cytometry (Clinical Laboratory, Supervisor 
Katherine Smith) including analysis of CD34+ and T cells (standard of care and billable). This 
can be performed on < 5 million mononuclear cells. 
• 
Analysis of the Killer Ig-like receptor (K IR) genotype to assess if alloreactive NK cells are 
involved in unit predominance (Dr Katherine Hsu‟s laboratory). 
As a maximum of 0.5% of each unit will be used for research, these studies may be limited by 
the number of cells available. Studies will be prioritized by the Principle Investigator according to 
the cell number available. 
 
Laboratory research studies will be performed on the patient blood post-transplant. 
• 
To test if NK alloreactivity drives proliferation supporting haplo-PBSC engraftment we will 
specifically document NK expansion in vivo by following the phenotypic and functional NK 
repertoires at serial time-points post-transplant, and compare these to the phenotypic and 
functional repertoire of the donor and patient pre-transplant. Expansion of NK populations 
can be followed by 12-14 color flow cytometry. Activation markers include intracellular IFN-γ 
and CD107 (LMP-1, a marker of cytotoxic degranulation). 
 
• 
To test the recovery of the immune system. 
 
 
10.7 
Post-transplant Evaluation 
Post-transplant evaluations are summarized in the following table. Scheduled evaluations 
for day 21 should be performed +/-2 days, for day 28 should be performed +4/-2 days. For day 
60, evaluations should be performed +/-7 days. For day 100, evaluations should be performed 
+/- 10 days. For 6 and 9 months should be done +/-14 days, and 1 year, 18 months, 2 years 
should be performed +/-30 days of the targeted date. Immune studies will be done per MSKCC 
standard of care. Evaluations may be with-held at the treating physicians discretion (eg if the 
patient has  relapsed or is critically ill). Also, additional tests  will be performed as  clinically 
indicated. 
ACTIVITY 
DAY 0 TO CB 
ENGRAFTMENT 
ENGRAFTMENT 
TO DAY +100 
LONG TERM 
FOLLOW-UP 
History & physical 
1-2 weekly 
Month 6, 9, 12, 24 
Chemistry 
Per standard of care 
Month 6, 9, 12, 24 
Counts & 
differential 
Month 6, 9, 12, 24 
BM studies: 
morphology, 
cellularity, & 
chimerism 
Day 21 if 
indicated* 
(Aspirate & core) 
Day 100 
(Aspirate only 
unless core clinically 
indicated)* 
Month 6, 12 if needed 
for clinical management 
Chimerism: whole 
blood (DMP Lab) 
Day 14, (21 if no 
BM aspirate 
done) 
Day 60 & 100 
Month 6, 12, 24 
Chimerism: blood- 
(ARC Lab) 
Day 28 
Day 100 
Month 12 
GVHD evaluation 
- 
Once or bi-weekly 
Month 6, 12, 24 

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Immune 
recovery**(per MSKCC 
standard) 
Day 28 
Day 60 
Month 3-4, 6, 9, 12, 18, 
24 
Disease evaluation 
as appropriate 
- 
Day 100 
Month 6, 12 
Research Labs 
NK cell recovery 
Day 28 
Day 60 & 100 
Month 6, 12 
* If day 21 BM is not possible or the patient can be adequately assessed from the peripheral 
blood, peripheral blood chimerism should be performed as a substitute. Also, if BM studies are 
done prior to day 100 for clinical purposes and it is thought that a repeat is not clinically 
indicated then day 100 studies can be done on blood only. 
** Immune function and NK cell recovery testing can be withheld if the patient has very low 
circulating white blood cells making testing impossible. Also, if immune recovery studies are 
done for clinical care purposes and it is thought that a repeat is not clinically indicated they can 
be withheld. 
During the first 100 days patients will be closely monitored as  per standard of care. Acute 
GVHD will be assessed and graded according to MSKCC  guidelines.  To  determine  acute 
GVHD grading, clinical data will be collected weekly or bi-weekly for the first 100 days. 
Research blood (1-4 tablespoons/ week) will be obtained to assess the recovery of NK cells as 
indicated in the Table. 
 
10.8 
Evaluation > 100 Days Post-transplant 
 
These should include: history and physical examinations, blood counts and chemistries 
including liver function tests at a minimum of approximately every 6-8 weeks until 6 months, 
then at a minimum of approximately every three months for one year, and at approximately 3-6 
month intervals until 2 years post transplant and then at least annually as clinically indicated. 
The patient‟s referring physician, in consultation with the MSKCC transplant physician, may 
assist with follow-up. 
Chronic GVHD will be diagnosed and graded according to MSKCC criteria. Assessments 
will be obtained at approximately day 100, 6, 12 and 24 months after transplant and at 
additional time points as clinically indicated. Patients who develop chronic GVHD will be treated 
according to the current standards of care. 
Bone marrow aspirate with analysis for chimerism and disease status should be performed 
at 6 months and one year post transplant if clinically indicated. Blood chimerism should be done 
at 6, 12, and 24 months. Lymphoid immunophenotyping per MSKCC standards for immune 
recovery assessment will be evaluated as per MSKCC BMT standard of  care  guidelines. 
Patients will be vaccinated as per MSKCC guidelines. Also, research blood (approximately 20 
cc) will be obtained to assess the recovery of NK on days 180 and 1 year. 
11.1 
TOXICITIES/SIDE EFFECTS 
 
11.2 
Toxicity Grading 

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Toxicities will be graded according to Adult BMT Guidelines. 
 
11.3 
Total Body Irradiation (TBI) 
 
Nausea and vomiting: most patients will experience nausea and vomiting after irradiation 
which can be significantly diminished with anti-emetics. Parotitis: some patients may experience 
symptomatic parotitis within the first 24 hours post radiation. This resolves spontaneously over 
several days. Diarrhea: most patients develop some diarrhea in the first week post irradiation 
which is treated symptomatically. Fever: low grade fever may occur for 24 hr post irradiation. 
This is treated symptomatically. Skin changes: Erythema may occur in patients within 24 hours 
and resolves in 2-3 days. Most patients will get some degree of hyperpigmentation within 2-3 
weeks. Alopecia is always seen but is usually reversible. Myelosuppression and immune 
suppression is a major toxicity and is treated by donor stem cell infusion and supportive care. 
Mucositis: most patients will develop moderate to severe mucositis of the oral and GI tracts 
which will be managed with aggressive supportive care. High doses of radiation in combination 
with high dose chemotherapy may contribute to damage to vital organs such as the lung or the 
liver that is sometimes associated with myeloablative conditioning but is not attributable to one 
specific agent. Late effects include cataracts, sterility, growth retardation, second malignancies 
and hypothyroidism. Cataract formation is seen in < 30% of patients treated with 
hyperfractionated TBI. Sterility is extremely common following total body irradiation and 
administration of alkylating chemotherapy with the risk increasing with the number of years 
since puberty. Hypothyroidism will be routinely monitored post transplant and treated with 
hormonal replacement as indicated. 
 
11.4 
Cyclophosphamide 
 
Nausea and vomiting: virtually all patients will experience nausea and vomiting after high 
dose cyclophosphamide. This can be significantly diminished with anti-emetics. Diarrhea: most 
patients develop some diarrhea in the first week post cyclophosphamide. This is treated 
symptomatically. Myelosuppression and immune suppression is a major toxicity and is treated 
by donor stem cell infusion and supportive care. Mucositis: most patients will develop moderate 
to severe mucositis of the oral and GI tracts which will be managed with aggressive supportive 
care. Skin changes: Transient skin rashes have been described. Alopecia is always seen but is 
usually reversible. Hemorrhagic cystitis is a potential complication, can be variable in severity 
and occasionally can be severe. The risk of cystitis will be reduced by aggressive supportive 
care. Fluid weight gain and edema is associated with this fluid flush but is transient and can be 
treated with diuretics if necessary. A syndrome of inappropriate anti-diuretic hormone (SIADH) 
causing hyponatremia can be seen but is transient and will spontaneously resolve after drug 
administration. Cardiomyopathy has been described with cyclophosphamide but is very rare. 
High doses of cyclophosphamide in combination with high dose radiation may contribute to 
damage of vital organs such as the lung or the liver. This is sometimes associated with the 
myeloablative conditioning as used in this study but is not attributable to one specific agent. 
Late effects include sterility and the possibilities of second cancers. 
 
11.5 
Fludarabine 
Fludarabine may contribute to nausea, vomiting, mouth sores, and diarrhea which are 
primarily due to the high dose cyclophosphamide and TBI. Jaundice and elevations of liver 
enzymes 
have also been described. Transient skin rashes 
have 
been 
described. 
Myelosuppression and immune suppression is a major toxicity and is treated by donor stem cell 
infusion and supportive care. Effects on the nervous system are not expected at the doses used 
in this protocol, but if they occur could include confusion, coma, weakness or numbness, loss of 
balance, difficulty walking, or loss of vision and could be very serious or lethal. 

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11.6 
Thiotepa 
 
Side effects of thiotepa include: alopecia, nausea, vomiting, and diarrhea. Thiotepa can 
also cause myelosuppression, pancytopenia, sterility and fevers. Other less likely side effects 
include dizziness and transient hepatic transaminase elevation. Rare but serious side effects 
include CNS toxicity manifested by headache, mild cognitive dysfunction, disorientation, 
confusion, irritability, and bizarre behavior; as well as, interstitial pneumonitis and renal failure. 
 
11.7 
Mycophenolate Mofetil (MMF) 
 
The major toxicity of MMF is immune suppression which leads to increased risk  for 
infection. This is managed with aggressive supportive care with both prophylaxis and treatment 
of infectious complications. Other potential side-effects include myelosuppression, headache, 
insomnia, aches and pains, rash, nausea, anorexia and diarrhea. There is also a very rare side 
effect known as progressive multifocal leukoencephalopathy (PML), which is a progressive 
disease of the nervous system that can cause severe disability or death. A very small number of 
cases of PML have been reported in patients treated with MMF. PML can cause hemiparesis, 
confusion, cognitive deficiencies and ataxia. 
 
11.8 
Cyclosporine-A (CSA) 
 
The major toxicity of CSA is immune suppression which leads to increased risk for infection. 
This is managed with aggressive supportive care with both prophylaxis and treatment of 
infectious complications. Renal dysfunction is common and is treated with good hydration and 
reduction of the dose if necessary. Electrolyte abnormalities involving potassium and 
magnesium are also common and electrolytes must be closely monitored. Increased blood 
pressure is common and is treated with anti-hypertensive medication(s).  Neurological  side 
effects include tremor (common), seizures (rare), confusion, ataxia, cortical blindness (rare), 
and peripheral neuropathies and are usually reversible with cessation of the medication. While 
mild to moderate microangiopathic hemolysis is relatively common, serious thrombotic 
thrombocytopenic purpura (TTP) is rarely seen. Gastrointestinal side-effects include anorexia, 
nausea, swollen gums, and hyperbilirubinemia. Skin changes include hirsutism and gingival 
hyperplasia. 
 
11.9 
G-CSF (Neupogen) 
Side-effects of G-CSF are generally mild, include bone pain, headaches,  body  aches, 
fatigue, edema and nausea and are managed with supportive care. Pleuro- or pericarditis are 
seen rarely and are managed by cessation of the medication and corticosteroids if necessary. 
 
11.10 Mesna (Mesnex®) 
 
Mesna has little systemic side effects; side effects that are observed are usually due to the 
concomitant chemotherapy. Mesna is an uroprotectant and is used with the high dose 
cyclophosphamide. 
 
11.11 Blood Product, CB and PBSC Infusions 
Infusions of blood products may produce volume overload which can be managed with 
diuretics. They may also induce allergic reactions of variable severity, many of which can be 
prevented or mitigated by pre-medication with antipyretics, and antihistamines. Any donor or 
blood product may also transmit serious infections (e.g., CMV, hepatitis, HIV). To circumvent 
this, stem cell and blood donors are screened according to AABB and FACT guidelines. CMV 

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antibody negative blood products will be used in CMV seronegative individuals whenever 
possible. All blood products (other than the stem cell graft) are irradiated to circumvent the risk 
of GVHD caused by contaminating lymphocytes. 
Toxicities potentially associated with the infusion of the CB graft include DMSO toxicity and 
side effects from red cells and may include changes in heart rate or rhythm, changes in blood 
pressure, fever, chills, sweats, nausea/vomiting, diarrhea, abdominal cramping, headache, 
dyspnea, presence of DMSO taste and odor, hemoglobinuria, and acute renal failure. However 
due to the dilution, hydration, and pre-medication these toxicities are unlikely. The process of 
CB engraftment can also be associated with a pre-engraftment syndrome characterized by 
fever and manifestations of capillary leak syndrome. This process is highly responsive to 
corticosteroid therapy and this will be treated according to accepted clinical practice. 
The definitions and reporting of serious adverse events (SAEs) is defined in Section 17.2. 
 
12.0      CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Clinical Endpoints The primary aim of this study is to obtain an estimate of the speed of 
neutrophil recovery after double-unit CBT with a T-cell depleted haplo-identical allograft. Overall 
survival and disease free survival at one and two years will be monitored as secondary endpoints. 
 
12.1. 
Neutrophil and Platelet Engraftment and Graft Failure (GF) 
 
Patients will be monitored for donor cell engraftment as evidenced by neutrophil and platelet 
recovery and donor chimerism in the marrow and blood at serial time-points post-transplant. 
 
The day of neutrophil recovery is defined as the first of 3 consecutive days in which the absolute 
neutrophil count (ANC) is > 0.5. The cumulative incidence of neutrophil recovery will be reported at 
day 45 post-transplant. Sustained neutrophil engraftment is neutrophil engraftment without 
secondary graft failure. 
 
The day of platelet recovery is defined as the first of 3 consecutive days in which platelet counts 
are > 20,000 without requiring platelet transfusions in the previous 7 days. The cumulative incidence 
of platelet recovery will be reported at day 180. 
 
Engraftment of each CB unit and the haplo-identical donor will be defined tracked at serial time- 
points. 
 
Primary graft failure is diagnosed when the patient fails to achieve an ANC  0.5 within the 
first 45 days post-transplant. Infusion of another source of stem cells as a treatment of graft failure 
prior to day 45 will also be considered primary graft failure. Patients who die before day 45 without 
count recovery will be classed as graft failures after day 28 and as not evaluable if death occurs 
without count recovery between days 0-28. Should evaluation of primary graft failure indicate that 
the patient's leukemia has persisted or recurred the patient will be classified as having progressive 
disease or relapse and not as having primary graft failure. 
 
Secondary graft failure is defined as donor-derived neutrophil engraftment followed by severe 
neutropenia (ANC < 0.5 for more than 7 consecutive days unresponsive to growth factors in the 
absence of relapse), or an absence of donor cells in the marrow and/or blood without leukemic 
relapse. Patients with suspected graft failure will be evaluated with bone marrow biopsy to assess 
hematopoiesis and to test for residual or recurrent leukemia. Patients who suffer graft failure will be 
managed per MSKCC BMT guidelines. 

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12.2. 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 clinical criteria, and histological grading of skin, liver or 
gastrointestinal pathology where possible, will be used to establish and grade acute GVHD. In the 
first 100 days after transplant patients will be assessed by a transplant physician for the 
development of acute GVHD approximately weekly. Data will be collected as per standard practice 
of the Adult BMT service. Patients with moderate to severe acute GVHD (grade II-IV) will be treated 
as per standard of care. Patients failing to respond to steroids will be considered for treatment with 
standard or experimental immunosuppressive agents 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 (eg auto-immune hemolysis) or involvement of other organs  (eg  pulmonary 
involvement). Chronic GVHD will be diagnosed and graded according to  the  MSK  criteria  and 
treated with standard or experimental immunosuppressive therapy. Patients will be assessed for 
GVHD at day 100, 6 months, 1, and 2 years. 
 
12.3. Transplant-related Mortality (TRM) 
 
TRM is defined as death at any time from the commencement of pre-transplant conditioning due 
to any cause other than malignant relapse (with the exception of accidents such as automobile 
accidents). Stopping rules  are in place to consider cessation of the study if TRM at day 100 is 
excessive (see Section 14). 
 
12.4. Relapse 
 
Relapse of malignancy is a secondary endpoint of this study and will be defined by accepted 
clinical practice eg an increasing number of blasts/malignant cells of recipient origin in the marrow 
over 5%, by the presence of circulating peripheral blasts, or by the presence of malignant cells in 
any extramedullary site. Cytogenetic (eg if a diagnosis of CML) or flow cytometric analysis or 
molecular studies of the marrow and/or peripheral blood may also be obtained for the diagnosis of 
relapse. Isolated molecular persistence or reappearance of bcr-abl without cytogenetic positivity will 
not be considered relapse. 
 
 
12.5 
Immunologic Recovery 
 
Immunophenotyping of T, B, and NK cells, and T-cell proliferations in response to non-specific 
mitogens will be performed at serial time points after transplant to measure immune recovery as 
outlined in section 10.6. Patients may be re-immunized post-transplant according to the MSKCC 
guidelines. Immune recovery data will be analyzed at completion of study and interim analysis of 
immune recovery will be permitted. 
 
13.0CRITERIA FOR REMOVAL FROM STUDY 
 
Patients may be removed from the study at any point deemed appropriate by the Principal 
Investigator or if requested by the patient. However, once the pre-transplant conditioning regimen is 
given, patients will continue on study until after administration of their stem cells and will receive 
supportive care as appropriate. Failure to rescue the patient with stem cells after cytoreduction 
would most likely be fatal. 

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14.0BIOSTATISTICS 
 
Clinical Endpoints 
 
A phase 2 study design will be utilized to obtain preliminary estimates of clinical efficacy and 
safety of a myeloablative cord blood transplant combined with a T-cell depleted haplo-identical 
allograft. The population under study is pediatric and adult patients with high-risk or advanced 
hematologic malignancies. At the time of transplant patients will be classified into standard (Arm A) 
or high (Arm B) risk groups (see section 6). A maximum of 26 evaluable patients will be accrued into 
Arm A (standard risk for TRM) and 75 into Arm B (high risk for TRM). The accrual period will be 
approximately 3-4 years with an additional two years of follow up after accrual is completed. All 
endpoints in this study will be assessed separately in the two risk groups. 
 
The primary endpoint of the study is the number of days to neutrophil recovery. Historically, the 
median time to neutrophil recovery for myeloablative double unit cord transplant patients is 25 days 
with all engrafting patients recovering neutrophils by day 45. A design that differentiates between 
population median recovery times of 25 days and 15 days will be used to assess the neutrophil 
recovery rate in this trial. A truncated exponential maximum likelihood test will be used to test this 
hypothesis. For the purpose of the power calculation, it is assumed that the neutrophil recovery 
times are exponentially distributed and for the anticipated 5% of the patients that do not recover, the 
recorded time will be day 46. This design has power equal to 0.90 if the  population  median 
neutrophil recovery time for patients treated under the proposed approach is 15 days; the one-sided 
test size is 0.10 when the median recovery time is 25 days. 
 
In addition, the time to platelet recovery will also be tested relative to MSKCC historical controls. 
Based on prior data, the null hypothesis is that the median time to platelet recovery is 48 days. The 
26 patient study has power equal to 0.90 if the population median time to platelet recovery is 29 
days in the current study. Patients that do not have platelet recovery will be scored as day 180. A 
one-sided 0.10 size test will be used to determine if platelet recovery is improved relative to the 
historical data. 
 
After the initial 18 high risk (Arm B) patients were treated on the protocol with a haplo-identical 
peripheral blood stem cell graft of 1.0 - 3.0 x 106 CD34+ cells/kg, the haplo-identical CD34+ cell 
dose was increased to 5.0 x 106/kg due to promising results in the initial experience with 3 million 
CD34+ cells. The initial 26 patient high risk cohort was completed and the primary endpoint of ANC 
recovery was met. To further ascertain the clinical efficacy of the addition of a higher dose of haplo- 
identical CD34+ cells, the number of patients studied will be increased. An additional 49 patients will 
be added to Arm B as a high risk patient extension cohort for a total of 75 patients. The Arm B 
extension cohort will utilitize the same efficacy evaluations as the primary cohort. The stopping rules 
below for the high risk Arm B have been amended to include the primary and extension cohorts. 
 
The study design includes early termination in the event of excessive graft failure, severe acute 
GVHD, or early TRM/ death from relapse within the first 100 days post-transplant. The power 
calculations used to assess the adequacy of the treatments with respect to these endpoints are 
given as guidelines in the tables below. In the event that the stopping boundary is crossed in one 
risk group, the study will continue accrual in the other risk group. The stopping rules for the High 
Risk (Arm B) cohort includes the primary 26 patients cohort and the additional 49 patient extension 
cohort. 
 
 
Stopping Rule Guidelines for Arm A (Standard Risk) Group 

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Failure Type 
Failure Boundary 
to Stop Study 
Projected 
Probability of 
Failure 
Probability 
of Boundary 
Crossing 
Graft failure 
4 within first 11 patients 
0.13 
0.09 
5 within first 16 patients 
0.35 
0.90 
6 within first 22 patients 
7 within 26 patients 
Grade IV Acute 
GVHD 
3 in the first 14 patients 
4 in the first 23 patients 
5 within 26 patients 
0.07 
0.10 
0.25 
0.89 
TRM/ Death from 
3 in the first 10 patients 
0.09 
0.09 
Relapse Within 
4 in the first 16 patients 
0.30 
0.91 
100 Days 
5 in the first 23 patients 
6 within 26 patients 
 
 
Stopping Rule Guidelines for Arm B (High Risk) Group and Arm B Extension Cohort 
 
Failure Type 
Failure Boundary 
to Stop Study 
Projected 
Probability 
of Failure 
Probability 
of Boundary 
Crossing 
Graft failure 
5 in the first 11 
6 in the first 16 
7 in the first 26 
9 in the first 32 
10 in the first 38 
11 in the first 43 
12 in the first 54 
13 in the first 60 
14 in the first 66 
15 in the first 72 
16 at any point 
0.13 
0.1 
0.35 
0.99 
Grade IV Acute 
5 in the first 11 
0.17 
0.1 
GVHD 
6 in the first 14 
7 in the first 18 
8 in the first 22 
9 in the first 27 
10 in the first 31 
11 in the first 35 
12 in the first 39 
0.4 
0.99 
13 in the first 44 
14 in the first 48 
15 in the first 53 
16 in the first 58 
17 in the first 62 
18 in the first 67 
19 in the first 72 

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20 at any point 
TRM/ Death from 
7 in the first 13 
0.25 
0.07 
8 in the first 16 
9 in the first 19 
Relapse 
10 in the first 21 
Within 100 Days 
11 in the first 24 
12 in the first 27 
13 in the first 31 
14 in the first 34 
15 in the first 37 
16 in the first 40 
17 in the first 43 
18 in the first 46 
0.5 
0.98 
19 in the first 50 
20 in the first 53 
21 in the first 56 
22 in the first 59 
23 in the first 63 
24 in the first 66 
25 in the first 69 
26 in the first 73 
27 at any point 
 
 
Each patient will followed for at least two years and subsequently as clinically indicated. If the 
study is not terminated early due to graft failure, grade IV GVHD, or TRM/early death, the probability 
of remaining alive for one year will be assessed. Arm A includes patients with high risk hematologic 
malignancies but with standard TRM risk for CBT. Arm B includes high risk patients not usually 
offered transplant or those considered at very high risk for TRM. 
 
For the standard risk group (Arm A), a single stage design that differentiates between 
population 1 year overall survival rates of 0.60 and 0.85 will be used determine treatment activity. 
The treatment will be considered insufficiently active if the probability of remaining alive for 1 year in 
this patient population is less than or equal to 0.60. If at least 20 of the 26 patients remain alive for 
one year, the treatment will be considered successful. This design has power greater than 0.90 if the 
probability of overall survival at one year is 0.85, using a 0.10 one-sided size test. The high risk 
group (Arm B) has a larger sample size and survival will be analyzed according to disease risk and 
patient comorbidity scores., 
 
The use of a one-stage design is due to the one-year follow-up time for this endpoint. For each 
group, the Kaplan-Meier estimates of overall and disease-free survival will be computed over time. 
In addition to the survival analyses, the cumulative incidence of neutrophil and platelet engraftment, 
grade 2-4 acute GvHD, chronic GvHD, TRM, relapse, and length of hospitalization will be computed. 
Kernel smoothing will be used to assess the level of chimerism, neutrophil count, platelet count, NK, 
T cell and B cell populations over time. The outcomes of this study will also be compared to MSKCC 
double-unit CBT historical controls. 
 
15.1 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 Research Participant Registration 

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Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain 
informed consent, by following proc edures defined in section entitled Inform ed Consent 
Procedures. During the registration process registering individuals will be required to 
complete a protocol specific Eligibility Checklist. The individual signing the Eligibility 
Checklist is confirming whether or not the participant is eligible to enroll in the study. 
Study staff are responsible for ensuring that all institutional requirements necessary to 
enroll a participant to the study have been completed. See related Clinical Research 
Policy and Procedure #401 (Protocol Participant Registration). 
 
 
15.3 Randomization 
 
Not applicable. 
 
16.1 DAT A M ANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study at MSKCC. The 
responsibilities of the RSA include project compliance, data collection, abstraction and entry, 
data reporting, regulatory monitoring, problem resolution and prioritization, and coordination 
of the activities of the protocol study team. 
 
The data collected for this study will be entered into a secured database Clinical 
Research Database (CRDB) and a database in a secured Adult BMT drive. Source 
documentation will be available to support the computerized patient record. 
 
16.2 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. 
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. 
 
16.3 Data and Safety Monitoring 
 
The Data and Safety Monitoring Plans (DSM) at Memorial  Sloan-Kettering  cancer 
Center were approved by the National Cancer Institute in Se ptember 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/r esearchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Clinical Research Administration 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 

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Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
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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. 
 
17.1 PROTECTION OF HUMAN SUBJECTS 
 
17.2 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). 
17.3 Serious Adverse Event (SAE) Reporting 
 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
 
SAE reporting is required as soon as the participant signs consent. SAE reporting is required 
for 30-days after the participant‟s last investigational treatment or intervention. Any events 
that occur after the 30-day period and that are at least possibly related to protocol treatment 
must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 „Reporting of Serious 
Adverse Events‟, the SAE report must be sent to the IRB within 5 calendar days of the event. 
The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 

Page 41 of 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to  
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject‟s initials 
• 
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 
• 
The grade of the 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 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI‟s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office. 
NOTE: potentially serious toxicities are an expected part of  transplant therapy. The 
reportable serious adverse events (SAEs) will be based on the most recent version of the 
Adult and Pediatric BMT Adverse Event Reporting Standard Operating Procedures. 
 
 
 
 
17.2.1 
Costs 
 
The patient will be responsible for the costs of medical care, including the UCB and 
haplo-identical graft, all hospitalizations and any transplant complications. Research tests will be 
done at no cost to the patient. 

Page 42 of 
Memorial Sloan Kettering Cancer Center 
IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
18.1 INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to their 
inclusion in the study. Participants will also be informed that they are free to withdraw from the study 
at any time. All participants must sign an IRB/PB-approved consent form indicating their consent to 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to signing 
the IRB Informed Consent, all patients must agree to the Research Authorization component of the 
informed consent form. Each participant and consenting professional will sign the consent form . The 
participant must receive a copy of the signed informed consent form. 
 
 
19.0 
REFERENCES 
 
1. 
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survival after double-unit cord blood transplantation compared with related and unrelated donor 
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2. 
Barker  JN,  Byam  CE,  Kernan  NA,  et  al.  Availability  of  cord  blood  extends  allogeneic 
hematopoietic stem cell transplant access to racial and ethnic minorities. Biol Blood Marrow 
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3. 
Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated donor umbilical cord blood 
in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA 
disparity on treatment-related mortality and survival. Blood. 2002;100:1611-1618. 
4. 
Barker JN, Scaradavou A, Stevens CE. Combined effect of total nucleated cell dose and HLA- 
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5. 
Barker JN, Weisdorf DJ, DeFor TE, et al. Transplantation of two partially HLA-matched umbilical 
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6. 
Barker JN, Abboud M, Rice RD, et al. A "no-wash" albumin-dextran dilution strategy for cord 
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7. 
Avery S, Shi W, Lubin M, et al. Influence of infused cell dose and HLA-match on engraftment 
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Verneris MR, Brunstein CG, Barker J, et al. Relapse risk after umbilical cord blood 
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IRB Number: 12-153 A(14) 
Approval date: 29-Jan-2018 
 
 
 
 
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10. Brunstein CG, Gutman JA, Weisdorf DJ, et al. Allogeneic hematopoietic cell transplantation for 
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11. Kindwall-Keller TL, Hegerfeldt Y, Meyerson HJ, et al. Prospective study of one- vs two-unit 
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12. Barker JN, Ponce DM, Gonzales AM, al. e. Double-unit cord blod transplantation for acute 
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13. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch- 
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14. Shpall EJ, Bollard CM, Brunstein C. Novel cord blood transplant therapies. Biol Blood Marrow 
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15. Bautista G, Cabrera JR, Regidor C, et al. Cord blood transplants supported by co-infusion of 
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16. Liu H, Rich ES, Godley L, et al. Reduced-intensity conditioning with combined haploidentical 
and cord blood transplantation results in rapid engraftment, low GVHD, and durable remissions. 
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17. Anfossi N, Andre P, Guia S, et al. Human NK cell education by inhibitory receptors for MHC 
class I. Immunity. 2006;25:331-342. 
18. Yu J, Heller G, Chewning J, Kim S, Yokoyama WM, Hsu KC. Hierarchy of the human natural 
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19. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in 
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20. Chewning JH, Gudme CN, Hsu KC, Selvakumar A, Dupont B. KIR2DS1-positive  NK  cells 
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22. Scaradavou A, Smith KM, Hawke R, et al. Cord blood units with low CD34+ cell viability have a 
low probability of engraftment after double unit transplantation. Biol Blood Marrow Transplant. 
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23. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific 
comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912- 
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