Unrelated Umbilical Cord Blood (UCB) Transplantation
Phase: NA
Conditions: Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), Myelodysplastic Syndrome, Multiple Myeloma, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Severe Aplastic Anemia
Sponsor: West Virginia University

WVU1909 
UNRELATED UMBILICAL CORD BLOOD (UCB) TRANSPLANTATION 
 
NCT01768845 
 
September 17, 2018 

 
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WVU1909 
 
UNRELATED UMBILICAL CORD BLOOD (UCB) TRANSPLANTATION  
 
 
TABLE OF CONTENTS 
 
 
 
 
SECTION 
 
 
 
 
 
     PAGE NUMBER 
 
1.0  
OBJECTIVES  
 
 
 
 
            2 
2.0 
BACKGROUND AND RATIONALE 
 
 
2 
3.0 
STUDY DESIGN  
 
 
 
 
 
4 
4.0 
ELIGIBILITY  
 
 
 
 
            5 
5.0 
PATIENT CLINICAL EVALUATION 
 
 
6 
 
 
6.0 
PATIENT TREATMENT PLAN 
 
 
 
7 
7.0 
MANAGEMENT OF COMPLICATIONS  
 
8 
8.0 
HAZARDS AND DISCOMFORTS  
 
 
8 
9.0 
WITHDRAWAL FROM THE STUDY 
 
 
9 
10.0 
RESPONSE CRITERIA 
 
 
 
 
9 
11.0 
STASTICAL CONSDIERATIONS  
 
 
9 
12.0 
FINANCIAL CONSIDERATIONS  
 
 
10 
13.0 
REFERENCES 
 
 
 
 
            10 
 
 
APPENDICES  
 
I. 
DISEASE STAGING AND RESPONSE DEFINITIONS  
II.  
GVHD GRADING SCALE  
 
 
PRINCIPAL INVESTIGATOR: 
 
 
 
 
 
Michael Craig 
 
 
 
CO-INVESTIGATOR(S): 
Aaron Cumpston 
Abraham Kanate 
Nilay Shah 
Kelly Ross 
Lauren Veltri 
 
 
 
 
 
 

 
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1.0 
OBJECTIVES 
1.1 
To assess the outcome including disease-free survival, overall survival, and treatment-
related mortality in patients with hematologic malignancies treated with umbilical cord 
blood (UCB) transplantation 
1.2 
To evaluate engraftment and the rate of hematopoietic recovery 
1.3 
Evaluate donor-recipient chimerisms 
1.4 
To determine the incidence and severity of acute and chronic graft-versus-host disease 
(GVHD) 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
Allogeneic hematopoietic cell transplantation (allo- HCT) is a curative therapy for the treatment of 
hematological and non-hematological malignancies and certain non-malignant conditions. Bone marrow 
or peripheral blood from an HLA matched sibling donor is the most commonly used source of allogeneic 
stem cells. However, HLA matched siblings are available for less than one third of the patients who 
require allo- SCT. In the absence of an HLA matched sibling, volunteer unrelated donors or partially 
mismatched related donors (PMRD), stored cord blood may be used as a source of allogeneic stem cells. 
Stored cord blood has been used as a source of allogeneic stem cells in infants and children, but had early 
skepticism in adults because of concerns about the engraftment potential of the relatively limited number 
of stem cells. The number of stem cells in a unit of cord blood is generally one log less than the number of 
stem cells on an average collection of bone marrow from an adult for transplantation. 
 
2.1  Advantages and disadvantages of using cord blood as a source of stem cells. 
 
There are many potential advantages of using cord blood as a source of allogeneic stem cells. It is a 
readily available source and umbilical cord units can be harvested at no risk to the mother or child since it 
is post-delivery.  Collection of marrow from unrelated donors is commonly a lengthy process.  Cord 
blood is available on demand and avoids delays in treatment for patients with unstable disease.  Cord 
blood is less likely to be exposed to infectious agents, especially viruses such as CMV that result in an 
inferior outcome after allogeneic stem cell transplantation. The risk of severe acute graft versus host 
disease (GVHD) may be less after cord blood transplantation in comparison to volunteer unrelated donor 
transplantation. Up to a two antigen mismatch may be tolerated without a significant effect on the overall 
transplant outcome, expanding the patient population who may undergo allogeneic transplant.  For 
patients who lack an HLA matched bone marrow donor, cord blood from an unrelated donor is an 
alternative source of hemopoietic progenitor cells. 
 
The major disadvantage of cord blood transplantation is the slow rate of hematopoietic recovery and 
relatively higher incidence of failure to engraft. This delay of recovery may result in a higher incidence of 
infectious complications in the early post transplant period. Lack of donor lymphocytes for future use is 
another major disadvantage with cord blood transplantation.1,2 
 
2.2   Results of cord blood transplantation in children and adults 
 
In a retrospective analysis from the Eurocord and International Bone Marrow Transplantation Registry, 
the long-term survival after transplantation from cord blood was similar or superior to survival after 
transplantation of marrow when the donor is a sibling.3 Also, Eurocord analysis revealed that children 

 
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with acute leukemia who received bone marrow, marrow depleted of T cells, or HLA mismatched cord 
blood transplantation from unrelated donors had similar survival.4 The cause of death was different in 
different groups. There were early deaths from delayed engraftment in the groups that received cord 
blood, more relapses in the group that received T cell depleted bone marrow, and more cases of GVHD in 
the group that received unmanipulated marrow. In a matched pair analysis from the University of 
Minnesota, the survival after transplantation of unrelated donor cord blood was found to be comparable to 
HLA matched unrelated donor marrow transplantation in children. Despite increased HLA disparity in the 
cord blood group, GVHD was similar in both groups. Donor derived engraftment of 88% at day 45 was 
not statistically significant in difference compared to engraftment rate in the marrow group (96%).5 
 
Rocha et al.6 compared cord blood versus bone marrow transplant for patients with acute leukemia.  There 
were 98 patients who received cord blood and 584 patients who received bone marrow.  Cord blood 
recipients were younger, weighed less, and had more advanced disease at the time of transplant.  Bone 
marrow recipients were all 6/6 HLA matches, whereas 94% of cord blood recipients had an HLA-
incompatible graft [5/6 (51%), 4/6 (39%), and 3/6 (4%)].  Cord blood recipients were shown to have 
lower risks of grade II, III, or IV acute GVHD (relative risk, 0.57; P=0.01), but delayed neutrophil 
recovery (relative risk, 0.49; P<0.001).  There was no significant difference in chronic GVHD, transplant-
related mortality, relapse rate, and disease-free survival. 
 
Laughlin et al.7 also compared cord blood versus bone marrow transplant in patients with leukemia.  The 
cord bloods were mismatched at one HLA antigen (34pts) or two HLA antigens (116pts).  The bone 
marrow patients were HLA matched (367pts) or had one HLA mismatch (83pts).  The cord blood 
recipients were younger and had more advanced disease.  As expected, cord blood recipients had a slower 
hematopoietic recovery.  Acute GVHD was higher in patients receiving bone marrow and chronic GVHD 
was higher in patients receiving cord blood.  Mismatched bone marrow transplant and mismatched cord 
blood showed similar rates of treatment-related mortality, treatment failure, relapse rate, and overall 
mortality. 
 
Reduced-intensity BMT has become more appealing as an attempt to minimize the toxicity and mortality 
of the preparative regimen while maintaining the anti-leukemic activity of the transplanted immune 
system.  This approach may also offer some benefit in cord blood transplant, considering a major barrier 
is the delay in neutrophil recovery.  Using a lower intensity regimen should allow some recipient 
neutrophils to persist during the engraftment phase.  One example of this approach was published by 
Barker et al8 who utilized two regimens: fludarabine, busulfan, total body irradiation (Flu/Bu/TBI) and 
fludarabine, cytoxan, and total body irradiation (Flu/Cy/TBI).  Sustained donor engraftment was 76% 
with Flu/Bu/TBI and 94% with Flu/Cy/TBI.  The median day of neutrophil recovery was 26 and 9.5 days, 
respectively between the two regimens.  Incidence of grades III-IV GVHD was 9% and 1 year survival 
was 39%.  Numerous other centers have successfully utilized a reduced intensity approach in cord blood 
transplantation.9-14  Despite the possible advantages of reduced-intensity conditioning, a recent 
publication by the Minnesota group has shown higher relapse risk in the patients treated with a reduced-
intensity regimen as compared to a more standard myeloablative regimen.17  We have amended our 
protocol to allow an ablative preparative regimen for patients who can tolerate them, due to this data. 
 
2.3   Cord blood banking  
After the success of the first allogeneic umbilical cord blood transplantation in 1988, programs for 
banking screened unrelated donor CBSC have been initiated both in the United States and Europe.  Dr 
Pablo Rubenstein started the first such bank at the New York Blood Center (NYBC) in 1993. Since its 
inception, the NYBC has provided unrelated donor cord blood stem cells for over 1000 transplants. 
Analysis of outcomes for the initial 562 transplant recipients from the NYBC revealed a cumulative rate 

 
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of engraftment of 81% by day 42 for PMNs. and 85% by day 180 for platelets.15 Currently approximately 
more than 100,000 cord blood units are available in cord blood banks worldwide and more than 2000 
patients have received cord blood transplants from these banks. Netcord, an international cooperative 
group of cord blood banks, has developed a detailed set of standards for cord blood banking to facilitate 
international exchanges and to guarantee the quality of these products. 
 
 
3.0 STUDY DESIGN  
Cord Blood Unit Selection 
UCB units will be required to be a 4/6 to a 6/ 6 HLA  A, B , DRB1 antigen match with the patient as 
allowed per NMDP guidlines.  A minimum total nucleated cell (TNC) dose of >2.0 x 107/kg at the time of 
freezing will be utilized when possible.  When using double units, each unit should contain a minimum 
pre-cryopreserved TNC dose of 1.5 x 107/kg. 
 
UCB Transplant Procedure 
There will be a myeloablative and reduced-intensity preparative regimen that can be given prior to 
infusion of cord product.  The myeloablative approach will be selected in younger patients (<50yo) with a 
HCT-CI score <3.  The reduced-intensity regimen will be selected for all older patients (>50) or younger 
patients with a HCT-CI score >3.  The reduced-intensity regimen will also be chosen for any patients 
being transplanted for indolent/follicular lymphomas, CLL, myeloma, or Hodgkin lymphoma; irrelevant 
of age or HCT-CI score.  On a case by case basis, patients may  receive a preparative regimen outside of 
their designated category as noted above with the approval of the PI, if deemed in the patient’s best 
interest.  Example:  A patient that is 55yo with high-risk AML and a HCT-CI score 1, may be approved 
for the myeloablative preparative regimen.. 
 
Myeloablative Preparative Regimen: 
• Fludarabine 40 mg/m2 IV on Days -6, -5, -4, and -3 
• Busulfan 130mg/m2 IV on Days -6, -5, -4, and -3 
• TBI 200cGy on Day -1 
• Thymoglobulin (rabbit ATG) 1.5mg/kg IV Days -4, -3, -2 (may be given at the discretion of 
treating physician) 
 
 
Reduced-intensity Preparative Regimen: 
• Cyclophosphamide 50mg/kg IV Day -6 
• Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 
• TBI 200cGy on Day -1 
• Thymoglobulin (rabbit ATG) 1.5mg/kg IV Days -4, -3, -2 (may be given at the discretion of 
treating physician) 
 
 
The preparative regimen will be followed by infusion of one or two UCB unit(s).  UCB unit(s) will be 
thawed according to methods of Rubinstein et al.16  If two products are used, they will be administered 
sequentially on the same day 1-6 hours apart.  Tacrolimus and mycophenolate mofetil (MMF) will be 
used for GVHD prophylaxis.  On day  +30, +60, +100, +180, and +365 the chimeric status of patients will 
be interpreted by VNTR analysis.  Immune reconstitution (Digeorge Panel) will also be checked at these 
time points. 

 
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The parameters to be monitored are:  
1) TNC dose 
2) CD34+ cell dose 
3) Degrees of donor-recipient chimerism by VNTR analysis (to be collected approximately on day  +30, 
+60, +100, +180 and +365) using peripheral blood. 
4) Neutrophil recovery (first day of ANC >0.5 x 109/l for 3 consecutive days). 
5) Platelet recovery (days to platelet count of 20 x 109/l and 50 x 109/l, without platelet transfusion 
within 7 days). 
6) Incidence and severity of acute GVHD. 
7) Incidence and severity of chronic GVHD. 
8) Disease-free survival and overall survival. 
9) Transplant related mortality before and after day 100. 
10)  Cause of death 
11) Immune reconstitution (to be collected approximately on day  +30, +60, +100, +180 and +365) 
 
 
4.0 ELIGIBILITY 
 
4.1    Inclusion criteria 
4.1.1  Age: 16-70 years 
4.1.2  Available 4/6, 5/6, or 6/6 HLA antigen match (using A,B, and DRB1) cord blood unit 
4.1.3  ECOG performance status of 0-2 (Karnofsky ≥ 70%) 
4.1.4  Serum bilirubin <2 x upper limit of normal 
4.1.5  Serum creatinine < 2 mg/dl 
4.1.6  DLCO  or  FEV1 ≥50% predicted 
4.1.7  Left ventricular ejection fraction ≥ 35% 
4.1.8  No uncontrolled infection 
4.1.9  If female, not pregnant 
4.1.10   Informed consent given 
4.1.11   No major organ dysfunction precluding transplantation. 
  
 
4.1.12   One of the following malignancies or bone marrow failure syndromes: 
a) Chronic myelogenous leukemia (CML) 
b) Acute myelogenous leukemia (AML) 
c) Myelodysplastic syndrome 
Intermediate or high risk disease by prognostic scoring system 
d) Multiple myeloma 
e) Hodgkin lymphoma 
f) Non-Hodgkin lymphoma 
g) Chronic lymphocytic leukemia (CLL) 
h) Acute lymphocytic leukemai (ALL) 
i) Severe Aplastic Anemia 
 
 
4.2    Exclusion criteria 
4.2.1    Patient pregnant 
4.2.2 Age <16, >70 

 
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4.2.3 ECOG performance status of >2 (Karnofsky < 70%) 
4.2.4 Psychiatric disorder or mental deficiency of the patient sufficiently severe as to make 
compliance with the BMT treatment unlikely, or making informed consent impossible 
4.2.5 Serum bilirubin ≥ 2 x upper limit of normal, transaminases >3x upper limit of normal 
4.2.6 Serum creatinine ≥ 2mg/dl 
4.2.7 DLCO <50% predicted 
4.2.8 Left ventricular ejection fraction <35% 
4.2.9 Major anticipated illness or organ failure incompatible with survival from BMT 
 
 
5.0 
PATIENT CLINICAL EVALUATION 
 
5.1 
Pre-transplant patient evaluation per BMT SOPs, including the following: 
5.1.1 HLA typing 
5.1.2 Chimerism assay (VNTR analysis) 
5.1.3 Blood typing (ABO, Rh) 
5.1.4 Bone marrow biopsy, chromosome analysis, molecular analysis and flow cytometry 
5.1.5 Disease staging (see Appendix I). 
5.1.6 Antibody screen for HBV, HCV, HIV, HTLV I/II, CMV, EBV, syphilis (VDRL or 
RPR) 
5.1.7 CBC with differential, coagulation screen, chemistry profile 
5.1.8 Serum pregnancy test, if female with child-bearing potential 
5.1.9 Pulmonary function tests and DLCO 
5.1.10  Cardiac function: EKG and MUGA scan or Echocardiogram 
5.1.11  Nutritional assessment 
5.1.12  Dental assessment 
5.1.13  Ophthalmology assessment 
5.1.14  Informed consent signed 
 
5.2 
Follow Up to Day 180 
 
Disease staging on day +100, or earlier if clinical suspician of relapse.  Disease assessment 
testing varies with disease, see Appendix I for appropriate testing. 
 
Peripheral blood will be drawn and/or bone marrow aspirate will be taken approximately 
on day +30, +60, +100 +180 and +365 to assess for degrees of donor-host chimerism using 
VNTR.  Peripheral blood is the preferred sample, but if WBC is not adequate, bone 
marrow aspirate sample may be used.  Immune reconstitution will also be monitored at 
these time points. 
 
 
5.3 
Beyond Day 180 
After 6 months, patients will be off the clinical protocol and will be monitored per standard 
BMT SOP's.  Physical exam, CBC and complete blood chemistry testing will be done to 
monitor patient’s condition.  Additional testing not already mentioned in the protocol such 
as chest x-ray, CT and PET scans, disease staging studies, pulmonary function testing will 
be performed as necessary based on individual patient conditions and will be at the 
discretion of the investigator. 
 
 

 
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6.0 
PATIENT TREATMENT PLAN 
6.1 
Pre-transplant treatment 
Eligible patients may receive appropriate chemotherapy according to standard indications 
to control malignancy prior to the preparative regimen. 
 
6.2 
Central Venous Catheter Placement 
Appropriate central venous access will be obtained pre-transplant.  A triple-lumen 
Hickman catheter is preferred. 
 
 
6.3 
Infection Prophylaxis/Empiric Anti-infective Therapy  
WVU BMT SOP for infection prophylaxis and empiric anti-infective therapy in allogeneic 
HSCT recipients will be followed.  Patients will receive prophylaxis as follows: 
• Antiviral: Acyclovir 400mg PO (or IV) q12hrs starting at beginning of preparative 
regimen, continuing until Day +365 or longer if still receiving 
immunosuppressants.  CMV and EBV will be monitored weekly (every Monday) 
for reactivation by PCR analysis. 
• Antifungal: Fluconazole 400mg PO Daily starting Day -2 until Day +100 
• Antibacterial: Levofloxacin 500mg PO Daily starting Day -2 until ANC>500 post-
nadir 
• PCP prophylaxis will start at the time of engraftment (ANC >500 post-nadir) with 
Bactrim DS qMWF until Day +180 or longer if still receiving immunosuppressants. 
• Growth Factors: Filgrastim 5mcg/kg subcutaneously daily starting Day +5 until 
ANC>1,500 post-nadir. 
 
6.4 
Preparative regimen 
Myeloablative Preparative Regimen: 
• Fludarabine 40 mg/m2 IV on Days -6, -5, -4, and -3 
• Busulfan 130mg/m2 IV on Days -6, -5, -4, and -3 
• TBI 200cGy on Day -1 
• Thymoglobulin (rabbit ATG) 1.5mg/kg IV Days -4, -3, -2 (may be given at the 
discretion of treating physician) 
 
OR 
 
Reduced-intensity Preparative Regimen 
• Cyclophosphamide 50mg/kg IV Day -6 
• Fludarabine 40 mg/m2 IV Days -6, -5, -4, -3, -2 
• TBI 200cGy on Day -1 
• Thymoglobulin (rabbit ATG) 1.5mg/kg IV Days -4, -3, -2 (may be given at the 
discretion of treating physician) 
 
6.5 
UCB Infusion 
UCB unit(s) will be thawed according to methods of Rubinstein et al.16 If two products are 
used, they will be administered sequentially on the same day 1-6 hours apart.   
 
 
6.6 
GVHD Prophylaxis  
• Tacrolimus 0.03 mg/kg/day PO or 0.015mg/kg/day IV starting Day -3 to Day +180, 
with dosage adjustments to maintain appropriate levels. 

 
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• MMF 15 mg/kg PO BID, with dose rounded to the nearest 250mg beginning day -3 
to Day +30, then tapered until Day +60. 
 
6.7 
Transfusion support  
Leukocyte reduced and irradiated blood products. CMV negative recipients to receive 
CMV safe blood products. 
 
 
6.8 
Hospital Discharge 
Patient will be admitted to the hospital for approximately 6 weeks and will be discharged 
when he/she fulfills criteria per BMT SOPs. 
 
7.0 
MANAGEMENT OF POST TRANSPLANT COMPLICATIONS 
 
The major complications of allogeneic transplantation are CMV reactivation, acute and chronic 
GVHD, disease progression, graft failure and opportunistic infection (bacterial/ fungal). Patients 
with these complications will be treated following WVU BMT SOPs. 
 
 
8.0  
HAZARDS AND DISCOMFORTS 
 
 
Allogeneic HSCT is a complex procedure associated with a significant bone marrow failure, 
morbidity, and mortality. Patients eligible for this protocol will all have a life threatening 
hematologic malignancy for which allogeneic HSCT has shown to be the only treatment with 
curative potential. The exact incidence of hazards and discomforts is highly variable, and depends 
on factors like age, disease status, degree of HLA matching, CMV serostatus, etc. The following is 
an incomplete list of hazards and discomforts: 
Occurring uniformly in all patients: 
1. Alopecia (reversible) 
2. Nausea and vomiting, ranging in severity from grade 1 to grade 4 
3. Grade 4 anemia, neutropenia and thrombocytopenia 
4. Mucositis, ranging in severity from grade 1 to grade 4 
5. Ovarian/testicular ablation resulting in long-term (irreversible) sterility 
 
Occurring in > 25% of all patients: 
1. Acute GVHD ranging in severity from grade I to grade IV 
2. Infection, ranging in severity from grade 1 to grade 4 
3. CMV reactivation 
4. Chronic GVHD, ranging in severity from limited to extensive 
5. Cataract formation  
 
Rare (<10%), but potentially lethal complications: 
1. Veno Occlusive Disease of the liver 
2. Cardiac arrhythmias and congestive heart failure 

 
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3. Pulmonary hemorrhage  
4. TTP/HUS 
  
 
9.0  
WITHDRAWAL FROM THE PROTOCOL 
 
 
 
Withdrawal from the transplant procedure 
Patients will be given ample time to withdraw from the protocol prior to admission for transplant. 
Thereafter, the nature of the procedure does not permit safe withdrawal from the protocol. 
 
10.0 
RESPONSE CRITERIA AND EVALUATION OF RESULTS 
10.1 
End Points 
Tumor regression, acute and chronic GVHD, transplant-related mortality (TRM), disease-
free survival, overal survival, degrees of marrow chimerism and graft failure. 
 
10.2 
Tumor response criteria 
Varies by disease (See Appendix I) 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design 
The study is a Phase II, non-randomized, single-center trial. 
11.2 
Accrual 
It is estimated that we will accrue 1 to 5 patients per year on this protocol. 
11.3 
Randomization 
There is no randomization aspect to this trial. 
11.4 
Analysis of Outcomes 
Engraftment: defined as neutrophil recovery associated with donor engraftment within the 
first 60 days after transplant. 
 
Overall Survival: Overall survival at day 180 after transplant. 
11.5 
Interim Analysis and Stopping Guideline 
Interim analyses for safety will be conducted after every fifth patient in each regimen, 
reaches the 180 day post-transplant time point, for the first 15 patients in each regimen.  A 
goal engraftment rate will be >70% and a goal overall survival rate will be >40%.  The 
study will be evaluated for termination if: 
• After 5 patients, if none survive or <1 have engrafted 
• After 10 patients, if <2 survive or <4 have engrafted   
• After 15 patients, if <4 survive or <8 have engrafted 
 
12.0 
FINANCIAL CONSIDERATIONS 
 
Coverage for the procedure will be by patient insurance approval. 
 

 
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13.0   REFERENCES 
 
1.  Gluckman E, Koegler G, Rocha V. Human leukocyte antigen matching in cord blood 
transplantation. Semin Hematol  2005;42(2):85-90. 
2.  Barker JN.  Umbilical Cord Blood Transplantation: An alternative to the use of unrelated 
volunteer donors?  Hematology 2007: 55-61. 
3. Gluckman E. Current status of umbilical cord blood hematopoietic stem cell transplantation. Exp 
Hematol 2000;28(11):1197-205. 
4. Rocha V, Cornish J, Sievers EL, Filipovich A et al. Comparison of outcomes of unrelated bone 
marrow and umbilical cord blood transplants in children with acute leukemia. Blood  
2001;97(10):2962-71. 
5. Barker JN, Davies SM, DeFor T et al. Survival after unrelated donor umbilical cord blood 
transplant is comparable to that of human leukocyte antigen-matched unrelated donor bone 
marrow: results of a matched-pair analysis. Blood 2001;97(10):2957-61. 
6. Rocha V, Labopin M, Sanz G, et al.  Transplants of umbilical-cord blood or bone marrow from 
unlrelated donors in adults with acute leukemia.  N Engl J Med  2004; 351:2276-85. 
7. Laughlin MJ, Eapen M, Rubinstein P, et al.  Outcomes after transplantation of cord blood or bone 
marrow from unrelated donors in adults with leukemia.  N Engl J Med  2004; 351:2265-75. 
8. Barker JN, Weisdorf DJ, DeFor TE, et al.  Rapid and complete donor chimerism in adult 
recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity 
conditioning.  Blood 2003; 102:1915-19. 
9. Del Toro G, Bradley MB, Satwani P, et al.  Reduced intensity allogeneic cord blood hematopoietic 
cell transplantation in pediatric patients with malignant and non-malignant diseases.  Blood 2005; 
106:479b. 
10. Koh LP, Chao NJ: Umbilical cord blood transplantation in adults using myeloablative and 
nonmyeloablative preparative regimens.  Biol Blood Marrow Transplant 2004; 10:1-22. 
11. McSweeney PA, Bearman SI, Jones RB, et al.  Monmyeloblative hematopoietic cell transplants 
using cord blood.  Blood 2001; 98:666a. 
12. Miyakoshi S, Yuji K, Kami M, et al.  Successful engraftment after reduced-intensity umbilical 
cord blood transplantation for adult patients with advanced hematological diseases.  Clin Cancer 
Res  2004; 10:3586-3592. 
13. Mori T, Amano I, Tanaka H, et al.  Reduced-intensity unrelated cord blood transplantation in adult 
patients with high-risk hematological malignancies.  Blood  2005; 106:444b. 
14. Rio B, Belhocine R, Renaud M, et al.  Reduced intensity conditioning regimen for unrelated cord 
blood transplantation in adults.  A multicentric phase I-II trial.  Blood  2005; 106:1018a. 
15. Rubinstein P, Carrier C, Scaradavou A et al.  Outcomes among 562 recipients of placental-blood 
transplants from unrelated donors.  N Engl J Med 1998;339(22):1565-77. 
16. Rubinstein P, Dobrila L, Rosenfield RE, et al.  Processing and cryopreservation of 
placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc Natl Acad Sci 
USA.  1995;92:10119-10122. 
17. Oran B, Wagner JE, DeFor TE, et al.  Effect of conditioning regimen intensity on acute myeloid 
leukemia outcomes after umbilical cord blood transplantation.  Biol Blood Marrow Transplant 
2011; (epub). 

 
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Appendix I: Disease Staging and Response Definitions  
Staging  
1. CML  
a. Bone marrow aspiration and biopsy  
b. Cytogenetics  
c. BCR/ABL gene rearrangement by PCR  
2. AML, MDS  
a. Bone marrow aspiration and biopsy  
b. Cytogenetics  
c. Disease-specific translocation by PCR (if available)  
3. Multiple myeloma  
a. Bone marrow aspiration and biopsy  
b. M-protein measurement (SPEP or 24 hour urinary light chain excretion light chain disease)  
c. SIEP, UIEP  
4. NHL, HD, CLL (only tests that were abnormal initially, unless otherwise indicated) 
a.  Physical exam  
b. CT scans  
c.  Bone marrow aspiration and biopsy  
d.  Cytogenetic analysis  
e. Disease-specific translocation by PCR (if available)  
 
 
Response Definitions 
 
1. CML  
 
a. Complete response (CR): Resolution of bone marrow and blood morphologic abnormalities and 
absence of Philadelphia chromosome by standard cytogenetic analysis.  
 

 
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b. Partial response: Reduction in percentage of Philadelphia chromosome positive metaphases by 
> 50% without disappearance of positive metaphases.  
 
c. Molecular complete remission: In addition to criteria above for complete remission, BCR/ABL 
rearrangement by RT-PCR is absent.  
 
2. AML  
 
a. Complete response: Resolution of abnormal blood and bone marrow morphology with less than 
5% blasts and resolution of disease-specific chromosome abnormality (if present) by standard 
cytogenetic analysis.  
 
b. Partial response: Decrease in bone marrow and peripheral blood blast count by > 50%.  
 
c. Molecular complete remission: In addition to criteria above for a complete response, disease-
specific rearrangement is absent by PCR analysis.  
 
3. MDS 
  
a. Complete response: Resolution of abnormal blood and bone marrow morphology with less than 
5% blasts and resolution of disease-specific chromosome abnormality (if present) by standard 
cytogenetic analysis.  
 
b. Partial response: Decrease in bone marrow and peripheral blood blast count by > 50%.  
c. Molecular complete remission: In addition to criteria above for a complete response, disease-
specific rearrangement is absent by PCR analysis.  
 
 
4. Multiple myeloma  
 
a. Complete response: Bone marrow less than 5% plasma cells, polytypic by 
immunohistology, and absence of M-protein on electrophoresis and 
immunoelectrophoresis.  
 
b. Partial response: Reduction in M-protein by > 50%.  
 
5. NHL, HD, CLL  
 

 
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a. Complete response: Resolution of disease by physical findings and normalization of all 
previously abnormal clinical tests such as bone marrow examination and computed tomographic 
scans (CT). In addition, resolution of disease-specific chromosome abnormality (if present) by 
standard cytogenetics.  
 
 
b. Partial response: Reduction in disease volume in all measurable sites by > 50%, using product 
of diameters.  
 
c. Molecular complete remission: response above in addition rearrangement by PCR analysis.  

 
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APPENDIX II:  GVHD Grading Scale 
 
1.  Acute GVHD 
 
 
a. If patient develops acute GVHD at any time after BMT, acute GVHD is graded as outlined below. 
b. If patient dies before day 30 and has not developed acute GVHD, then the patient is considered 
not evaluable for GVHD. 
 
Clinical Stage of Acute GVHD according to Organ System 
Stage 
Skin 
Liver 
Intestine 
+ 
Maculopapular rash < 25% of 
body surface 
Bilirubin 2-3 mg/dl 
>500-1000 ml diarrhea /day or 
nausea, anorexia or vomiting 
with biopsy (EGD) confirmation 
of upper GI GVHD 
++ 
Maculopapular rash  25-50% if 
body surface 
Bilirubin 3-6 mg/dl 
>1000-1500 ml diarrhea/day 
+++ 
Maculopapular rash . 50% of 
body surface area or generalized 
erythroderma 
Bilirubin 6-15 mg/dl 
>1500 ml diarrhea/day 
++++ 
Generalized erythroderma with 
bullous formation and 
desquamation  
Bilirubin > 15mg/dl 
>1500 ml diarrhea/day plus 
severe abdominal pain with or 
without ileus 
 
 
 
Overall Clinical Grading of Severity of Acute GVHD 
Grade 
Skin 
Liver 
Gut 
I 
1-2 
0 
0 
II 
0 
0 
1-3 
1-3 
1-3 
3 
0-1 
1 
0-1 
1 
0 
X 
1 
0-1 
1 
0-1 
0 
X 
 
III 
0-3 
0-3 
0-3 
2-3 
0-3 
4 
0-2 
2-3 
0-3 
IV 
0-3 
4 
0-4 
0-4 
4 
0-4 
 
 
 
2. Chronic Graft-vs.-Host Disease  
a. If patient develops chronic GVHD at anytime after BMT, chronic GVHD is graded as outlined below.  
b. If the patient dies before day 100 and has not developed chronic GVHD, then the patient is considered 
not evaluable for chronic GVHD.  
• Limited chronic GVHD 
Either or both  
- Localized skin involvement  

 
Version Date 09/17/2018    Amendment 7 
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- 
Hepatic dysfunction due to chronic GVHD  
•   Extensive chronic GVHD  
Either  
- Generalized skin involvement, or  
- 
Localized skin involvement and/or hepatic dysfunction 
 Plus  
-  Liver histology showing chronic aggressive hepatitis, or  
-  Involvement of eye (Schirmers test with less than 5mm wetting), or  
-  Involvement of minor salivary glands or oral mucosa demonstrated on labial biopsy, or  
-  Involvement of any other target organ