Combined Haploidentical-Cord Blood Transplantation for Adults and Children
Phase: NA
Conditions: Leukemia, Myelodysplastic Syndrome, Multiple Myeloma, Lymphoma
Sponsor: University of Chicago

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THE UNIVERSITY OF CHICAGO 
 
DIVISION OF MEDICINE 
 
 
 
 
Combined Haploidentical-Cord Blood Transplantation  
 
 
 
 
 
 
for Adults and Children 
 
 
1.0  
OBJECTIVES 
 
 2.0 
BACKGROUND 
 
3.0 
PATIENT ELIGIBILITY 
 
4.0 
PATIENT SELECTION AND STEM CELL SOURCE 
 
5.0 
TREATMENT PLAN 
 
 6.0  
PRE-TREATMENT EVALUATION 
 
 7.0  
EVALUATION DURING STUDY 
 
 8.0  
CRITERIA FOR STUDY EVALUATION  
 
 9.0  
STATISTICAL CONSIDERATIONS 
 
10.0 
DATA AND PROTOCOL MANAGEMENT 
 
11.0 
CRITERIA FOR REMOVAL FROM PROTOCOL 
 
12.0 
REPORTING REQUIREMENTS 
 
13.0 
RETROSPECTIVE REVIEW  
 
14.0 
REFERENCES 
 
 
APPENDIX A: 
TREATMENT PLAN:  FLUDARABINE - MELPHALAN 
APPENDIX B: 
TREATMENT PLAN:  THIOTEPA - FLUDARABINE - TBI 
APPENDIX C: 
TREATMENT PLAN:  FLUDARABINE - BUSULFAN 
APPENDIX D: 
BACKGROUND DRUG INFORMATION 
APPENDIX E: 
ZUBROD PERFORMANCE STATUS 
APPENDIX F: 
PRZEPIORKA CRITERIA FOR ACUTE GVHD 
 APPENDIX G:           HAPLO-CORD SAMPLES 
APPENDIX H:            INFUSION OF CRYOPRESERVED HEMATOPOIETIC PROGENITOR 
                                       CELLS  BY NURSES  

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APPENDIX I:  
ALLO DONOR SELECTION CRITERIA  
APPENDIX J:               APHERESIS EVALUATION AND MANAGEMENT 
 
STUDY CHAIRMEN: 
 
 
___________________________ 
 
 
__________________________  
Andrew Artz, M.D. 
 
 
 
            Amittha Wickrema, Ph.D. 
 
 
 
CO-INVESTIGATORS: 
 
 
___________________________ 
 
 
__________________________ 
 Wendy Stock, M.D.  
 
 
 
 
Hongtao Liu, M.D., Ph.D 
 
___________________________ 
 
 
__________________________ 
 Richard Larson, M.D.  
 
 
 
 
Toyosi Odenike, M.D. 
 
 
___________________________ 
 
 
__________________________ 
 John Cunningham, M.D. 
 
 
 
 
Lucy Godley, M.D., Ph.D. 
 
 
 ___________________________ 
 
 
 Justin Kline, M.D. 
 
 
 
 
STATISTICIAN: 
 
 
 
 
 
 
Theodore Karrison, Ph.D. 
 
RESEARCH NURSE: 
 
 
 
 
 
Paula Del Cerro, R.N., O.C.N. 
 
DATA MANAGEMENT: 
 
 
 
 
Scott Allen, CRA 
                                                                                     
 
 
 
 
 
 
 
 
 
Patricia Popa, CRA 
 
 
 
 
 
 
 
 
 
 
REGULATORY AFFAIRS MANAGER:   
Inga Krueger, MA, CCRP 
 
 
 
 
 
 
PROTOCOL VERSION: 04/05/2010, 09/13/2011, 03/23/2012, 10/14/2012, 11/19/2012, 12/05/2013 
 
 

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1.0    OBJECTIVES: 
 
     1.1     Primary Objective 
 
               To assess the rate of engraftment with combined haploidentical-cord blood transplantation. 
      
     1.2     Secondary Objective 
 
               To evaluate the incidence and severity of acute and chronic GVHD. 
 
 
2.0    BACKGROUND 
 
     2.1     Umbilical cord blood transplantation in hematologic malignancies 
 
Transplantation of hematopoietic stem cells derived from bone marrow and       
peripheral blood of sibling and unrelated donors has been used successfully to treat 
patients with high-risk or recurrent hematological malignancies.  However, bone 
marrow transplants (BMT) are limited by the lack of human leukocyte antigen (HLA) 
matched donors and the high risk of graft-versus-host disease (GVHD) after 
transplantation.  Although there are more than 10 million registered donors worldwide, 
more than 30% of patients requiring transplants are unable to find a matched donor.1  
This proportion is higher for patients of minority descent.  Patients who receive 
unmatched transplants have decreased survival secondary to severe GVHD (80%) and 
opportunistic infections.2  
 
In order to increase the donor pool, umbilical cord blood (UCB) is now being used for 
transplants.  Unrelated UCB transplants have a high rate of engraftment with a low risk 
of acute GVHD even in the 1-2 HLA mis-matched setting in children3-5 and adults.6  
However, delayed engraftment and associated treatment-related toxicity and 
opportunistic infections result in high treatment-related mortality in adults.  Laughlin et 
al emphasized the importance of nucleated cell dose in hematopoietic recovery while 
HLA compatibility played a less significant role.  Clearly demonstrated was an 
increased event-free survival rate in patients who received grafts containing more than 
1.2 x 105 CD34+ cells per kilogram.6  Recently the Institute of Medicine commissioned 
a study of UCB outcomes from pooled data of 755 cases of adults and children in the 
United States.  This study showed a clear effect of HLA matching on survival, with 6/6 
matches faring better than 5/6 or 4/6 matches.  The magnitude of this effect, however, 
was most apparent at lower cell doses (<2.5 x 107 total nucleated cells per kilogram), 
emphasizing the effect of cell dose relative to HLA match.7        
 
2.2   Double cord blood transplantation, Haploidentical transplantation, and Combined 
Haploidentical and Cord Blood transplantation 
 
Disappointed with the delayed engraftment after cord blood transplantation, several 
groups have tried to enhance recovery by (1) in vitro expansion of cords;8 (2) infusion 
of multiple cords;9 or (3) combination of cord blood transplant with cells from other 

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origins.  One way to increase the nucleated cell dose is to combine UCB units.  Initial 
animal studies have shown that combined grafts have a higher survival than single 
grafts.10 In a pilot series of patients with hematologic malignancies, Barker et al showed 
that combined transplantation of two partially matched UCB units resulted in a median 
time to neutrophil engraftment of 23 days (range 15-41).9  Interestingly, in each case, 
permanent hematopoiesis was derived from one of the two cords.  The other cord was 
eliminated.  While total nucleated nor CD34+ cell counts nor HLA match predicted 
which donor would predominate, the predominating unit had a significantly higher 
CD3+ dose (p<0.01).  Nucleated cell and CD34+ dose in the predominating unit were 
significantly associated with speed of neutrophil recovery.  With a median follow-up of 
10 months (range 3.5 months-2.5 years), disease-free survival (DFS) was 57% at one 
year, with 72% of patients alive at one year if transplanted in remission or chronic 
phase.11  Ballen et al reported results of a phase 1 study of double cord transplantation 
using a reduced intensity conditioning regimen of fludarabine, melphalan, and rabbit 
antithymocyte globulin (rATG, Thymoglobulin).10  The median time to neutrophil 
engraftment was 20 days (range 15-34).  The 100 day transplant-related mortality was 
14%.  Chimerism analysis showed predominance of one cord by Day +100 in 79% 
evaluable patients.  In 85% of these patients, the first cord infused predominated.  With 
a median follow-up of 7 months (range 2-16 months), the overall survival was 79%, 
and the DFS was 64%.  Two patients (both with MDS complicating aplastic anemia) 
experienced primary graft failure.11      
 
Haploidentical transplantation, the transplantation of stem cells from a partially 
matched related donor (typically a parent, child or sibling) has been explored starting in 
the early 1980’s.  Initial studies were characterized by a high incidence of graft failure, 
immunodeficiency, and GVHD.2  The administration of massive doses of CD34-
selected (thus T-cell depleted) stem cells can prevent  graft rejection, perhaps through a 
veto mechanism, and assure reliable engraftment without excessive GVHD.12  In 
clinical trials of pediatric and young adult patients, this has resulted in acceptable 
outcomes.13  We have previously tested this approach in adults with advanced 
hematologic malignancies with disappointing results.  Reliable and rapid engraftment 
occurred, and the incidence of GVHD was very low.  But patients had prolonged severe 
immunosuppression, and there was a high incidence of delayed fatal opportunistic 
infections.14 
 
In order to augment recovery of hematopoiesis following cord blood transplantation, a 
Spanish group has studied combined haploidentical and cord blood transplantation.  
Their observations indicated that initial rapid engraftment was obtained from the 
haploidentical T-cell depleted graft; subsequent hematopoiesis resulted from the cord 
blood which appeared to permanently replace the haploidentical hematopoiesis.15  
 
In an oral presentation at the 2004 American Society of Hematology Meetings16, 
Fernandez summarized results of this work, which has been updated at the 2005 Third 
Annual International Umbilical Cord Blood Transplantation Symposium17 and in a 
recent publication18.  His group has transplanted 28 patients with advanced hematologic 
malignancies.  The median age was 30 (16-63) and weight 67 (43-87) Kg.  The basic 

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conditioning regimen was fludarabine, cyclophosphamide, total body irradiation (TBI), 
and equine antithymocyte globulin (ATGAM), with modifications in 6 patients.  The 
UCB units had 2.37 (1.31-3.7) x107 TNC/Kg and 0.11 (0.035-0.37) x106 CD34+ 
cells/Kg and were 0-2 HLA mismatches to the recipient.  The 3rd party donor was an 
HLA haploidentical relative for 24 (mother for 4; also father, sibling, son, nephew), a 
higher HLA mismatched (mm) relative for 3, and a fully HLA mm unrelated donor for 
1.  All 3rd party cells were extensively T-cell depleted so that the infused cells 
contained a median of 2.31 (1.05-2.58) x106 CD34+/Kg and 0.25 (0.05-0.98) x104 
CD3+/Kg. 
 
Initially, post-transplant circulating granulocytes were predominantly from the 3rd party 
donor in all patients except the four receiving maternal CD34+ cells.  Analysis of DNA 
polymorphisms showed initial predominance of the 3rd party donor both in 
granulocytes and mononuclear cells and subsequent progressive replacement by UCB 
cells.  Excluding the 4 patients who received maternal mobilized peripheral blood cells, 
the corresponding data was: median time to ANC>0.5x109/L was 9.5 days (9-17); CB-
ANC>0.5x109/L was 22 days; and full CB chimerism 54 days; median time to platelets 
>20x109/L and >50x109/L was 30 and 54 days, respectively.  The 4 who received 
maternal cells had no significant engraftment of these cells, although 3 had exclusive 
UCB chimerism, 2 of which reached full UCB engraftment (days 20 and 36).  
Replacement of the 3rd party graft by the UCB engraftment may be due to rejection by 
the UCB-derived immune system or immunization to minor histocompatibility 
antigens.18 
 
20 of 27 (74%) patients had acute GVHD (a-GVHD) of any grade after day 11 post- 
transplant; 4 of 27 (14.8%) reached grade III-IV.  Most of the patients with a-GVHD 
responded to corticosteroid therapy.  There were two deaths primarily related to a-
GVHD, one occurred in one of two patients who did not receive ATG as part of the 
preparative regimen.  DNA analysis of skin biopsies of GVHD lesions showed UCB 
DNA in several instances, but in no case were third party donor cells detected.  Only 4 
out of 20 patients at risk developed manifestions of chronic GVHD (c-GVHD), which 
was limited in all.     
 
8 deaths have been reported related to the procedure (toxicity 2; graft failure 1; GVHD 
>II 2; opportunistic infection 3).  The 2 deaths due to toxicity occurred in patients who 
received 1.2 Gy TBI without fludarabine.  One developed multi-organ failure and the 
other veno-occlusive disease.  Two of the deaths due to opportunistic infection were 
due to CMV; the other from toxoplasmosis.  With a median follow up of 10 months (1-
75) for all patients and 16 months (3-75) for the 20 living (9 surviving >2years), the 4 
year overall survival is 67% for the whole group.17       
 
2.3 
Rationale for the current study 
The applicability of BMT is limited by the availability of a matched donor.  As 
described   earlier, umbilical cord transplants provide an additional source for 
hematopoietic stem cells (HSCs).  Partially matched UCB transplants have already 
been shown to engraft with reduced acute GVHD.  The major limitation to UCB 

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transplants is delayed engraftment which is related to nucleated cell dose.  Our patient 
population is relatively older, has advanced disease, and often suffers from 
comorbidities.  Prolonged neutropenia is not tolerated, and intensive conditioning is 
necessary to induce durable disease control.  We are therefore interested in 
recapitulating the Spanish data in a patient population with more advanced disease.  
 
For patients transplanted in remission, we will use a conditioning regimen of 
fludarabine-melphalan because it is relatively well tolerated and effective in assuring 
engraftment and preventing GVHD. 11, 19    
 
For high risk patients, we will use either fludarabine-thiotepa-TBI20 or busulfan-
fludarabine21, as currently evaluated at University of Chicago. 
 
Correlative studies will include those related to engraftment and immune reconstitution. 
 
The essential differences between our proposed study and the Spanish study will be the 
following: 
 
1. Patient selection. The median age in our studies is usually over 50, more than two 
decades older than in the Spanish studies.  Age-related differences in the immune 
system may profoundly affect our outcomes. 
 
2. Differences in conditioning regimen, which are influenced by our institutional 
experience.  
 
2.4 
Preliminary Data as of February 2012 
 
We published our initial experience with reduced intensity conditioning of this regimen 
(Liu, Blood, Oct 2011 pre-published online). Overall, this regimen has been promising 
with early engraftment in the majority of subjects and cord-blood predominance later. 
We also had shifted from TBI based regimens for active disease to an alternative non-
radiation approach of disease reduction before transplant with chemotherapy and then 
at the nadir of cytopenia, using reduced intensity conditioning.  This is an approach we 
have used for matched donors with success. 
 
3.0    PATIENT ELIGIBILITY 
 
     3.1     Inclusion criteria 
 
Patients will be eligible for this study if they have any one of the diseases that are 
known to be cured after allogeneic stem cell transplantation.  For example: 
 

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1. Relapsed or refractory acute leukemia (myeloid or lymphoid)   
2. Acute leukemia in first remission at high-risk for recurrence 
3. Chronic myelogenous leukemia in accelerated phase or blast-crisis 
4. Chronic myelogenous leukemia in chronic phase intolerant, refusing, or refractory 
to TKI. 
5. Recurrent or refractory malignant lymphoma or Hodgkin lymphoma 
6. Chronic lymphocytic leukemia, refractory, relapsed or with poor prognostic features 
(based on karyotype or Ig Mutation profile) 
7. Multiple myeloma failing or not eligible for autologous transplant 
8. Myelodysplastic syndrome with high risk feature (based on accepted risk features 
such as IPSS or failure of other treatment) 
9. Chronic myeloproliferative disease with high risk features and/or failures of 
conventional treatment.  
      
  10.  Hemoglobinopathies with high risk features  (frequent vaso-occlusive crisis, stroke 
etc.).  
      
  11.  Aplastic anemia failing conventional treatment  such as immunosuppressants or not 
appropriate for conventional treatments.  
 
 
 
     3.2     Exclusion criteria 
 
Patients must be discussed and approved at the weekly Stem Cell Transplant conference after 
careful consideration of the following criteria: 
 
1. Zubrod performance status > 2 (see Appendix E) 
2.  Life expectancy is severely limited by concomitant illness 
3.  Patients with severely decreased LVEF or impaired pulmonary function tests (PFT’s) 
4.  Estimated Creatinine Clearance <50 ml/min  
5.  Serum bilirubin> 2.0 mg/dl or SGPT >3 x upper limit of normal   
6.  Evidence of chronic active hepatitis or cirrhosis 
7.  Active HIV-infection defined as positive viral load in past 6 months, not being on a 
stable anti-retroviral regimen for 6 months, and/or opportunistic infections (excluding 
treatment for responsive thrust, mycobacterium and herpes infections) 
8. Patient is pregnant 
9.  Patient or guardian not able to sign informed consent 
 
4.0    PATIENT SELECTION AND STEM CELL SOURCE 
 
     4.1    Patient selection  
 
Patients are eligible for enrollment if they are an appropriate candidate for   
transplantation, and an HLA-identical related or unrelated donor cannot be identified 
within an appropriate time frame. 
 
     4.2    Hematopoietic stem cell source 

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Umbilical cord cells will be obtained from established umbilical cord blood centers.  
Umbilical cord preparation procedure will be according to established cell lab 
procedures in accordance with FACT/FDA guidelines.  
 
     4.3    Selection of grafts 
 
4.3.1 Cord Blood. Preliminary searches of umbilical cord-blood banks will be         
performed using the patient’s HLA phenotype, as determined by molecular typing 
for class I HLA-A, B, C; and class II DR and DQ.  Preferred cord-blood units are 
those that are antigen-matched for greater than 3 of 6 HLA loci (HLA A, B, DR) 
and contain a minimum cell count of 1 x 107 nucleated cells per kilogram of the 
recipient’s body weight before freezing.  A less closely matched graft with higher 
nucleated cells will be selected over a more closely matched graft with fewer 
nucleated cells. 
 
           4.3.2     Third Party Donor. The preferred 3rd party donor will be a young, non- maternal 
HLA haploidentical relative. After appropriate evaluation as per transplant 
program critera (Appendix I) , the donor will receive G-CSF (filgrastim) 5 
mcg/kg SQ BID for four consecutive days. Apheresis will start on the morning of 
the fifth day and proceed until sufficient cells have been collected. Apheresis 
procedure will be conducted as per transplant program policy (Appendix J)  
Typically four total blood volumes (TBV) are collected. The use of pediatric 
donors is restricted to donors who are over the age of 14 and weigh more than 50 
kg. 
 
 
 
 
5.0    TREATMENT PLAN 
 
     5.1     All patients shall be registered with the Data Management Office 
 
   Register patients in theVelos system (http://velos.bsd.uchicago.edu/eres/jsp/ereslogin.jsp)  
 
     5.2     Conditioning Regimens.  
 
          5.2.1     Good Risk Patients (refer to ASBMT Criteria22):  
 
 Fludarabine-Melphalan as per institutional guidelines (See Appendix A) 
 Rabbit antithymocyte globulin (Thymoglobulin, r-ATG) 
 
  
          5.2.2     High Risk Patients (refer to ASBMT Criteria22):  
 
                  5.2.2.1  Fludarabine-Thiotepa-TBI as per institutional guidelines (See Appendix B). 

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        Rabbit antithymocyte globulin (Thymoglobulin, r-ATG) 
 
5.2.2.2  Busulfan-Fludarabine as per institutional guidelines will be considered if 
the patient is not eligible for TBI  (See Appendix C). Busulfan will be 
targeted if possible to an AUC of 4800 to 6000 per day using therapeutic 
drug monitoring 
 
 
 
        Rabbit antithymocyte globulin (Thymoglobulin, r-ATG) 
 
5.2.2.3  Cytoreductive therapy at the treating physicians discretion followed 7 – 
21 days later (although longer if clinically required) 
 
 Fludarabine-Melphalan as per institutional guidelines (See Appendix A) 
                               
 Rabbit antithymocyte globulin (Thymoglobulin, r-ATG) 
 
 
     5.3    Umbilical cord blood infusion 
 
  On day 0 or day 1 the cord blood product will be prepared and infused according to   
transplant program policy 431.02 “Infusion of Cryopreserved  Hematopoietic 
Progenitor Cells by Nurses” (see Appendix H). 
 
     5.4     Haploidentical stem cell preparation 
 
 Stem cells will be collected from a haploidentical donor. The preferred 3rd party 
donor will be a young HLA haploidentical relative. After appropriate evaluation as 
per transplant program criteria, the donor will receive G-CSF (filgrastim) 5 mcg/kg 
SQ BID daily for four consecutive days. (doses rounded to the nearest vial size) 
Apheresis will start on the morning of the fifth day and proceed until sufficient cells 
have been collected.  
      Based on Spanish experience, the maternal donor will be avoided. 
 
 After collection and prior to cryopreservation, cells will be T-cell depleted using    
the Isolex 300i CD34 depletion device. The target will be to obtain a product 
containing less than 1x104 CD3+ cells per kg of recipient body weight and no more 
than 3x106/kg CD34 positive cells.  The haploidentical cells will be infused on day 
0 or day 1 according to transplant unit policy. 
 
 As of early April 2010, the Isolex 300 CD34 depletion device is no longer 
commercially available and instead we use the Miltenyi Clinimax device which 
serves a similar purpose. An IND has been obtained that covers both the device and 
the need for all cord bloods to be licensed or fall under an FDA IND. 
   
      
 

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5.5     GVHD prophylaxis  
 
 Tacrolimus 0.03 mg/kg/day IV CI over 24 hr from 4 PM day -2 until engraftment 
or when patient is able to take PO, then tacrolimus approximately 0.09 mg/kg PO 
in 2 divided doses.  Tacrolimus should be given at full dose to maintain levels of 
5-15 ng/mL through day 180. Thereafter, tacrolimus will be tapered by 20% every 
week. 
 
 Additional GVHD prophylaxis according to standard of care. 
 
     5.6     Supportive care 
 
 Infection prophylaxis and supportive care will be as per BMT unit policy.  
 
 All patients, regardless of disease histology will receive G-CSF 5 mcg/kg 
(rounded to 300 mcg or 480 mcg, depending on patient weight) SQ daily from 
day 1 until ANC >5 x10E9/L. 
 
 Suggested premedication for rATG will consist of diphenhydramine, 
acetaminophen, and methylprednisolone.  
 
6.0     PRETREATMENT EVALUATION  (See TABLE I) 
     6.1     EVALUTION OF THE PATIENT  (The following list is to be used as a guideline, 
but can be adjusted in individual cases.  Please also refer to transplant policies.) 
 
1. Complete history and physical examination; height/weight; performance status 
2. Bone marrow biopsy and aspirate with leukemia markers, cytogenetics, flow 
cytometry 
3. CBC, differential, platelets 
4. Complete metabolic profile (including complete liver function panel); magnesium,      
phosphate, LDH, uric acid 
5. PT and PTT 
6. Hepatitis screen 
7. Serum titers for CMV, HSV, EBV 
8. HIV antibody  
9. Complete urinalysis 

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10.  Urine pregnancy test (if female) 
11.  Baseline EKG 
12.  MUGA with measurement of LVEF  
13.  Pulmonary function tests with DLCO   
   
 
   
14.  Chest X-ray  
15.  CT scan of the sinuses (without IV contrast)  
16. CT scan of chest/abdomen/pelvis (routinely without IV contrast; with IV contrast at 
the discretion of the treating physician) 
17.  HLA class I and class II molecular typing  
18.  ABO and Rh typing 
19.  Peripheral blood for chimerism studies 
20.  Lumbar puncture for cell count, protein, glucose, and cytology (in patients with         
ALL and high grade NHL, or if prior history of CNS involvement) 
21. Quantitative immunoglobulins, serum free light chains, serum and 24-hour urine 
protein electrophoresis and immunoelectrophoresis, skeletal survey (for multiple 
myeloma patients only 
22.  Any additional tests that may be required for clinical care and described in the 
transplant policies. 
23. 20 cc of blood and 5 cc of bone marrow will be stored on all recipients to be used for 
research purposes 
 
     6.2    EVALUATION OF THE DONOR  (The following list is to be used as a guideline, but 
can be adjusted in individual cases.  Please also refer to transplant policies.)   
 
1. Complete history and physical examination; performance status 
2. CBC, differential, platelets 
3. Complete metabolic panel (including complete liver function tests), magnesium, 
phosphate  
4. PT and PTT 
5. Hepatitis screen 
6. Serum titers for CMV, HSV, EBV; CMV PCR 
7. HIV antibody 
8. Complete urinalysis 
9. EKG 
10. Chest X-ray 
11. HLA Class I and Class II molecular typing 
12. ABO and Rh typing 
13.  Peripheral blood for chimerism studies 
 
 
  
7.0    EVALUATION DURING STUDY (See TABLE I) (The following list is to be used as a      
guideline, but can be adjusted in individual cases.  Please also refer to transplant policies.) 
    
     7.1    EVALUATION DURING THE FIRST 100 DAYS 
 

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 Evaluation during the first 100 days will be done as per transplant program 
guidelines.  
 Restaging of disease and engraftment studies will be performed between day 25 and 
day 35. 
 
   7.2    DAY 100 EVALUATION  (The following list is to be used as a guideline, but can be 
adjusted in individual cases.  Please also refer to transplant policies.)   
 
1. Review of systems and physical examination; performance status 
2. Bone marrow biopsy and aspirate with leukemia markers, cytogenetics, flow 
cytometry 
3. CBC, differential, platelets 
4. Complete metabolic profile (including complete liver function panel); magnesium,      
phosphate, LDH 
5. CMV, BK, EBV, adenovirus PCR 
6. Chest X-ray  
7. Pulmonary function tests with DLCO 
8. Schirmer’s test and slit lamp examination  
 
   
 
    
9. Peripheral blood for chimerism studies 
10. Quantitative immunoglobulins, serum and 24-hour urine protein electrophoresis and 
immunoelectrophoresis, skeletal survey (for multiple myeloma patients only   
11. Restaging of disease as indicated by disease specific testing 
 
     7.3     EVALUATION DAYS 100-365 (patient without chronic GVHD) 
 
 
Physical examination and screening labs at least monthly through day 365 
       Restaging of disease at Day 180 and one year after transplant; or at relapse 
 
Follow-up for patients with chronic GVHD as per chronic GVHD guidelines 
 
7.4 ANNUAL EVALUATION  (The following list is to be used as a guideline, but can       
be adjusted in individual cases.  Please also refer to transplant policies.)   
 
1. Review of systems and physical examination; performance status  
2. Bone marrow biopsy and aspirate with leukemia markers, cytogenetics, flow 
cytometry 
3. CBC, differential, platelets 
4. Complete metabolic profile (including complete liver function panel); magnesium,      
phosphate, LDH 
5. Chest X-ray  
6. Pulmonary function tests with DLCO 
7. Thyroid function tests 

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8. Schirmer’s test and slit lamp examination  
 
   
 
    
9. Peripheral blood for chimerism studies 
10. Quantitative immunoglobulins, serum and 24-hour urine protein electrophoresis and 
immunoelectrophoresis, skeletal survey (for multiple myeloma patients only   
11. Restaging of disease as indicated by disease specific testing 
 
     7.5    RESEARCH BLOOD AND BONE MARROW SAMPLES (SEE APPENDIX G) 
 
         7.5.1  Samples of blood and bone marrow will be obtained at the following time points: 
 
      
 
     Prior to admission 
 
     Day 0 (Blood) 
 
     Day 7 (Blood) 
                   Day 10(Blood) 
 
     Day 14 (Blood) 
 
     Day 28 (BM and Blood) 
      
 
     Day 100 (BM and Blood)   
 
     Day 180 (BM and Blood)   
 
     At relapse (BM and Blood) 
 
     One year and yearly thereafter (BM and Blood) 
 
7.5.2   Chimerism will be determined by molecular analysis of peripheral blood and    
bone marrow samples. Peripheral blood chimerism studies will be performed every 
two weeks for the first 100 days following haploidentical-cord blood 
transplantation. Samples of blood and bone marrow will be obtained at the 
following time points:    
 
 
     Day 14 (Blood) 
 
     Day 28 (BM and Blood) 
 
     Day 42 (Blood) 
                   Day 56 (Blood) 
 
     Day 70 (Blood) 
                   Day 84 (Blood) 
 
     Day 100 (BM and Blood)   
 
     Day 180 (BM and Blood)   
 
     At relapse (BM and Blood) 
 
     One year and yearly thereafter (BM and Blood) 
 
7.5.3    Immune reconstitution will be assessed by lymphocyte subset analysis of blood 
per transplant program guidelines. 
 
7.5.4    Bone marrow samples -2 green top tubes will be stored at the time of diagnostic 
bone marrow aspirations. Request this sample on the bone marrow requisition in the 
“Other “ section.  
 

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7.5.5 A back-up stem cell collection will be considered for patients who are in 
remission.                                      

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                                                                             Table I 
                                                      SCHEDULE OF PATIENT TESTS 
Tests & Observations 
Prior to 
Study 
Day of 
Transplant 
Day 30  
(± 1 wk)  
Post Transplant 
Day 100   
 (± 1 wk) 
Day 180 
 (± 1 wk) 
Post-Tx 
Follow-up** 
 
History and Progress Notes 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
Pulse, Blood Pressure 
X 
X 
X 
X 
X 
X 
Height/Weight/BSA 
X 
 
 
 
 
 
Performance Status 
X 
X 
X 
X 
X 
X 
Tumor Measurements 
L 
L 
L 
L 
L 
L 
Toxicity Assessment 
 
X 
X 
X 
X 
X 
AGVHD Assessment 
 
 
X 
X 
X 
 
CGVHD Assessment 
 
 
 
 
X 
X 
  Laboratory Studies 
 
 
 
 
 
 
CBC, Differential, Platelets 
X 
X 
X 
X 
X 
X 
Serum electrolytes 
X 
X 
X 
X 
X 
X 
Serum creatinine, BUN 
X 
X 
X 
X 
X 
X 
  AST, ALT, Bilirubin 
X 
 
X 
X 
X 
X 
   LDH 
X 
 
X 
X 
X 
X 
   PT/PTT 
X 
 
 
 
 
 
Hepatitis Screen  
X 
 
 
 
 
 
Serologies:  CMV, HSV, EBV  X 
 
 
 
 
 
CMV PCR 
X 
 
X 
X 
 
 
HIV Ab 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
Serum or urine HCG, if female X 
 
 
 
 
 
  Quantitative immunoglobulins 
M 
 
M 
M 
 
M 
SPEP, UPEP, SIEF, UIEF 
M 
 
M 
M 
 
M 
HLA class I and II molecular 
typing  
X 
 
 
 
 
 
ABO and Rh Typing 
X 
 
 
 
 
 

IRB#:  14736B 
 
 
 
16 
 
 
 
 
   11/19/2012 
Tests & Observations 
Prior to 
Study 
Day of 
Transplant 
Day 30  
(± 1 wk)  
Post Transplant 
Day 100   
 (± 1 wk) 
Day 180 
 (± 1 wk) 
Post-Tx 
Follow-up** 
 
  Surveillance Tests  
 
 
 
 
 
 
  ECG 
X 
 
 
 
 
X 
  MUGA with LVEF 
X 
 
 
 
 
X 
PFTs with DLCO 
X 
 
 
X 
 
X 
Thyroid function tests 
 
 
 
 
 
X 
Schirmer test and slit lamp 
exam 
 
 
 
X 
 
X 
LP with cell count, gluc. prot, 
cytology 
H 
 
 
 
 
 
Screening 
 
 
 
 
 
 
Chest x-ray, PA & Lateral 
X 
 
 
X 
 
X 
CT sinus 
X 
 
 
 
 
 
CT chest/abd/pelvis 
X 
 
L 
L 
L 
L 
Skeletal survey 
M 
 
 
M 
 
M 
Bone Marrow Asp & Biopsy 
X 
 
X 
X 
 
X 
Cytogenetics 
X 
 
X 
X 
 
X 
Flow cytometry 
X 
 
X 
X 
 
X 
Chimerism 
 
 
 
 
 
 
   Peripheral blood (20 cc min.) 
X 
 
X 
X 
X 
X 
   Bone marrow aspirate 
 
 
X 
X 
X 
X 
  Immune Reconstitution 
 
 
 
 
 
 
Peripheral blood (40 cc min.)* X 
X 
X 
X 
X 
X 
* Additional samples on day 7, day 14, day 50, day 75 and then 3 samples/year for a maximum of 5 years. 
** At one-year post-transplant, and then yearly thereafter for a maximum of 5 years from study entry, and at relapse. 
H: ALL, high grade NHL, or past history of CNS involvement 
L:  For lymphoma patients. 
M:  For multiple myeloma patients.  

IRB#:  14736B 
 
 
 
17 
 
 
 
 
   11/19/2012 
8.0    CRITERIA FOR STUDY EVALUATION 
 
 Event Free Survival 
 
Relapse will be recorded by the day of initial detection of malignant cells if these cells 
were on subsequent testing confirmed to be increasing in number. The molecular 
detection of MRD will not be taken into account for the definition of clinical recurrence. 
The diagnosis of disease recurrence will be based on clinical and pathological criteria. 
 
 Toxicity 
 
Toxicity will be scored according to NCI-CTC criteria.   
 
Acute GVHD will be scored according to the criteria proposed by Przepiorka et al. 
(Appendix F).23  
 
Chronic GVHD will be scored according to the NIH Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease:  I. Diagnosis and 
Staging Working Report (Appendix G and Appendix H).24  
 
 Definitions of Engraftment 
 
Myeloid engraftment will be defined as the first day in which the ANC is > 500/mm3 for 
three consecutive days.  Cytogenetic and chimerism studies will be performed to confirm 
donor origin. 
  
Platelet engraftment will be defined as the first day the platelet count is > 20,000/mm3 
without transfusion support for seven consecutive days.  
 
Failure to engraft will be defined as lack of evidence of hematopoietic recovery (ANC < 
500/mm3 and platelet count < 20,000/mm3) by day +35, confirmed by a biopsy revealing 
a marrow cellularity < 5%.  Graft failure will also be defined as initial myeloid 
engraftment by day +35, documented to be of donor origin, followed by a drop in the 
ANC to < 500/mm3 for more than three days, independent of any myelosuppressive 
drugs, severe GVHD, CMV, or other infection.  
 
There may be rare cases in which the haploidentical transplant is rejected, but the 
cord transplant engrafts with delay.  Loss of established haploidentical engraftment 
will be considered graft failure.  
 
Graft rejection will be defined as graft failure with documentation of return of recipient 
hematopoiesis as determined by cytogenetic and/or chimerism studies. 
 
Chimerism studies will be used to determine the percentage cord vs haploidentical donor 
engraftment. 

IRB#:  14736B 
 
 
 
18 
 
 
 
 
   11/19/2012 
9.0    STATISTICAL CONSIDERATIONS 
 
The primary endpoint of this trial is the rate of engraftment (which is the opposite of graft 
failure).  Up to 53 patients will be enrolled in the trial.  Graft failure will be monitored 
using the group sequential procedure described in O’Brien and Fleming25 to test the null 
hypothesis that the graft failure rate is < 10%, against the alternative that the rate is > 10%.  
Four interim analyses will be performed after n=10, 20, 30, and 40 patients have been 
enrolled, followed by a final analysis at n=53 using a simple z-test.  For a one-sided test at 
the overall 0.10 alpha level, the critical z-values are 3.50, 2.24, 1.87, 1.59, and 1.41, 
respectively.  Applying a continuity correction, this implies that if 5 or more of the first 10 
patients, 6 or more of the first 20, 7 or more of the first 30, or 8 or more of the first 40 
patients experience graft failure, the trial may be terminated.  The null hypothesis will also 
be rejected if, at the end of the trial, 9 or more graft failures have occurred.  Rejection of 
the null hypothesis will indicate that the graft failure rate is unacceptably high, i.e., the rate 
of engraftment is too low.  The test has 80% power if the true graft failure rate is 20%. 
 
GVHD is the secondary endpoint, and we are particularly interested in monitoring high risk 
extensive GVHD.  We will review the data after the first 5, 10, 15, and 20 patients with 
successful engraftment and without evidence of relapse reach their 18-month landmark.  
Evidence that the rate of high-risk, extensive GVHD in this subset of patients is >40% will 
lead to consideration for early stopping.  Specifically, if 4 of 5, 6 of 10, 9 of 15, or 11 of 20 
such patients develop high-risk, extensive GVHD at any time prior to 18 months, we will 
consider terminating the trial.  The probability of having these many poor outcomes (or 
more) if the true rate of GVHD is 40% is 0.087, 0.17, 0.10, and 0.13, respectively.   
 
Given the heterogeneity of the patient population included, one cannot formulate 
expectations regarding overall survival and progression-free survival (PFS).  Unless the 
above described monitoring boundaries are exceeded, the protocol will continue to accrue 
until 53 patients have been enrolled.  At the conclusion of the study, 95% confidence 
intervals will be generated for PFS, the incidence of graft failure, and the frequency of 
active and extensive GVHD.  Kaplan-Meier estimates of progression-free and overall 
survival rates will be calculated, both overall and for the good and high risk groups 
separately, and the median progression-free and overall survival times and their associated 
95% confidence intervals derived using the method described in Brookmeyer and 
Crowley.26  Descriptive statistics related to the frequency of adverse events and of changes 
in laboratory values will be generated. 
 
An independent Data and Safety Monitoring Committee will be established to review the 
data and make recommendations regarding the continuation or discontinuation of the trial.   
 
Addendum: As of March 2010, 34 patients have been accrued to the protocol and no excess 
graft failure or GVHD have been observed (Rich etal, ASH abstract 3114, 2009). The 
protocol is being modified for use of the Miltenyi column because of market supply 
reasons. But the stopping rules  no longer apply.  
Addendum 2 as of March 2012. We will expand the number of subjects to provide more 
robust estimates of outcome. The vast majority of subjects received fludarabine, melphalan 

IRB#:  14736B 
 
 
 
19 
 
 
 
 
   11/19/2012 
conditioning for AML/MDS. Of  73 subjects enrolled so far, 60 have received fludarabine 
and melphalan reduced intensity. We recently reported our experience with the first 45 
subjects receiving reduced intensity fludarabine melphalan (Liu, Blood 2011).  Only four 
of 45 had graft failure (lack of haplo and cord blood engraftment). The stopping rules 
indicate that if 8 or more of the first 40 have graft failure, the trial would be stopped. 
Engraftment will continue to be monitoried. A secondary endpoint was GVHD and the 
rates have been low and below the 40% chronic GVHD considered for stopping the trial. 
The cumulative incidence of grade II-IV GVHD was 24% and for cGVHD 6 % at one year. 
 
Since the safety of this approach has been established based on low graft failure and low 
GVHD, overall survival and progression free survival become more of interest. One year 
overall survival was 55% and progression free-survival 42%.  The majority 29 (64%) had 
AML and MDS.  In addition, 21/45 (47%) had high risk disease defined as refractory, 
untreated relapse. Expanding our sample size will allow us to generate OS and PFS 
estimates in those by disease risk (high-risk versus standard/low) and for those with 
AML/MDS.  A better estimate of efficacy is essential as future studies are now being 
planned including a randomized trial. An additional 20 subjects will accrue approximately 
87 who will receive fludarabine-melphalan divided into 46 with low to standard risk 
disease and 41 with high-risk disease (assuming the proportion in the first 45 subjects is 
maintained). This will also result in enrolling approximately 55 to 56 subjects with 
AML/MDS and of those, we estimate 30 will have low to standard risk disease. Generating 
estimates in the cohort of MDS/AML with standard risk disease has emerged as essential as 
this represents the most common transplant indication. 
 
10.0   DATA AND PROTOCOL MANAGEMENT  
 PROTOCOL COMPLIANCE Patients will be reviewed weekly during admission by the 
study investigators who will score the patient for standard endpoints. After discharge they 
will be reviewed at least once a month. 
 DATA ENTRY Data must be entered into the Protocol Data Management System before 
a course of therapy can be given.  A brief explanation for required but missing data 
should be recorded as a comment. 
 ACCURACY OF DATA COLLECTION The Study Chairman will be the final arbiter of 
toxicity should a difference of opinion exist. 
 

IRB#:  14736B 
 
 
 
20 
 
 
 
 
   11/19/2012 
11.0   CRITERIA FOR REMOVAL FROM PROTOCOL 
 At patient request. 
 Clinical progression. Such patients may be treated on other treatment protocols or at the 
investigator’s discretion. Such patients will continue to be monitored for end-points 
relating to engraftment, GVHD and immune reconstitution. 
12.0   REPORTING REQUIREMENTS 
      
 Any unexpected, life-threatening and/or serious (grade 3 or 4) toxicity or grade 3 or 4 
GVHD will be reported immediately to the Study Chairman.  The Chairman will be 
responsible for notifying the Surveillance Committee.   
 
 Expected toxicities are those listed in the consent form and include regimen-related 
toxicities, myelosuppression, opportunistic infections such as CMV reactivation, or 
GVHD.  These will not be routinely reported to the IRB even if they require 
admission. 
 
 On the other hand, such toxicities will be monitored by the PI and the transplant team 
and reported regularly at the High Risk Protocol Committee of the Cancer Center. 
 
 All deaths that are not due to the disease recurrence will be reported to the IRB. 
 
13.0   RETROSPECTIVE REVIEW 
 
As of October 2012, we plan to retrospectively analyze the results of this haplo-cord SCT 
protocol with the results of Haploidentical stem cell transplant at Peking Institute of 
Hematology in Beijing.  The analysis will focus on the AML/MDS population first. The 
main purpose of the analysis is to compare the patient characteristics, pre-transplant co-
morbidities, and outcomes of transplant from these two centers; including neutrophil, 
platelet engraftment; progression free survival, overall survival, incidence of acute GVHD, 
and chronic GVHD et al. In addition, we would like to compare the immune re-constitution 
after these two types of transplant.  The datasets will be shared between the University of 
Chicago and the Peking institute of Hematology in Beijing without identifiable patient 
information (coded), each patient will be marked by code without name or medical record 
number.  Both centers have IRB approval for the transplant protocol. The IRB has 
approved the Peking Institute of Hematology retrospective review.  
 
 
14.0   REFERENCES 
 
 
1.  Confer DL. Unrelated marrow donor registries. Curr.Opin.Hematol. 1997;4:408-412. 
 
2.  Beatty PG, Clift RA, Mickelson EM et al. Marrow transplantation from related donors 
other than HLA-identical siblings. N.Engl.J.Med. 1985;313:765. 

IRB#:  14736B 
 
 
 
21 
 
 
 
 
   11/19/2012 
 
3.  Kurtzberg J, Laughlin M, Graham ML et al. Placental blood as a source of hematopoietic 
stem cells for transplantation into unrelated recipients. N.Engl.J.Med. 1996;335:157-166. 
 
4.  Barker JN, Davies SM, Defor T et al. Survival after transplantation of unrelated donor 
umbilical cord blood is comparable to that of human leukocyte antigen-matched 
unrelated donor bone marrow: results of a matched-pair analysis. Blood 2001;97:2957-
2961. 
 
5.  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. 
 
6.  Laughlin MJ, Barker J, Bambach B et al. Hematopoietic engraftment and survival in 
adult recipients of umbilical-cord blood from unrelated donors. N.Engl.J.Med. 
2001;344:1815-1822. 
 
7.   Hurley CK, Wagner JE, Setterholm MI et al.  Advances in HLA:  Practical implications 
for selecting adult donors and cord blood units.  Biol Blood Marrow Transplant 2006; 12: 
28-33.   
 
8.  Pecora AL, Stiff P, Jennis A et al. Prompt and durable engraftment in two older adult 
patients with high risk chronic myelogenous leukemia (CML) using ex vivo expanded 
and unmanipulated unrelated umbilical cord blood. Bone Marrow Transplant. 
2000;25:797-799. 
 
9.  Barker JN, Weisdorf DJ, DeFor TE et al. Transplantation of 2 partially HLA-matched 
umbilical cord blood units to enhance engraftment in adults with hematologic 
malignancy. Blood 2005;105:1343-1347. 
    10.   Scaradavou A, Sung D, Rubinstein P. Combination of low-dose allogeneic placental cord 
blood (PCB) transplants in a mouse model: improved survival rates and stable long-term 
engraftment [abstract]. Blood 2002;100, Suppl 1:#5182. 
 11.  Ballen KK, Spitzer TR, Yeap B et al.  Excellent disease-free survival after double cord 
blood transplantation using a reduced intensity chemotherapy only conditioning regimen 
in a diverse adult population.  Blood 2005;106:#2048.   
    12.  Bachar-Lustig E, Rachamim N, Li H-W, et al. Megadose of T-cell depleted bone marrow 
overcomes MHC barriers in sublethally irradiated mice. Nature Medicine 1995;1:1268-
1273. 
 13.  Aversa F, Tabilio A, Velardi A et al. Treatment of high-risk acute leukemia with T-cell 
depleted stem cells from related donors with one fully mismatched HLA haplotype. 
N.Engl.J.Med. 1998;339:1186-1193. 

IRB#:  14736B 
 
 
 
22 
 
 
 
 
   11/19/2012 
 14.  Devine SM, Stock W, Peace D et al. Transplantation of haploidentical stem cells in adult 
recipients with advanced hematological malignancies [abstract]. Blood 1999;94 
Suppl1:#4975.  
 15.  Fernandez MN, Regidor C, Cabrera R et al. Unrelated umbilical cord blood transplants in 
adults: Early recovery of neutrophils by supportive co-transplantation of a low number of 
highly purified peripheral blood CD34+ cells from an HLA-haploidentical donor. 
Exp.Hematol. 2003;31:535-544. 
    16. Fernandez MN, Regidor C, Cabrera R et al.  Unrelated single cord blood transplant 
supported by co-infusion of a low number of mobilized peripheral blood highly purified 
CD34+ cells from a third party donor after low toxicity myeloablative conditioning.  A 
strategy that makes cord blood transplant feasible for most patients.  (An "Allostem" 
Study).  Blood 2004; 104, Suppl 1:#823.     
 17.  Fernandez MN.  Unrelated single cord transplants supported by co-infusion of a low 
number of mobilized peripheral blood highly purified CD34+ cells from a third party 
donor after low toxicity myeloablative conditioning.  Biol.Blood Marrow Transplant.  
2005;11:930. 
 18.   Magro E, Regidor C, Cabrera R et al.  Co-infusion of mobilized stem cells from a third 
party donor induces early hematopoietic recovery overcoming current limitations of the 
use of a single unit of unrelated cord blood transplantation in adults.  Hematology 2006 
(in press). 
    19.   van Besien K, Devine S, Wickrema A et al.  Regimen-related toxicity after fludarabine-
melphalan conditioning:  a prospective study of 31 patients with hematologic 
malignancies.  Bone Marrow Transplant 2003; 32:471-476.    
    20.   van Besien K, Devine S, Wickrema A et al.  Safety and outcome after fludarabine-      
thiotepa-TBI conditioning for allogeneic transplantation:  a prospective study of 30 
patients with hematologic malignancies.  Bone Marrow Transplant. 2003; 32:9-13.     
    21.   de Lima M, Couriel D, Thall PF et al.  Once-daily intravenous busulfan and fludarabine: 
clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning 
regimen for allogeneic stem cell transplantation in AML and MDS.  Blood 2004; 
104:857-864.  
    22.   2006 version of the ASBMT Standardized Request for Information (RFI).  American 
Society of Blood and Marrow Transplantation (ASBMT) Website.  BMT Center 
Management, Standardized RFI.         
    23.   Przepiorka D, Weisdorf D, Martin P et al. Consensus conference on GVHD grading.  
Bone Marrow Transplant. 1995;15:825-828.  
 
 24.  Filipovich AH, Weisdorf D, Pavletic S et al.  National Institutes of Health Consensus 
Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host 

IRB#:  14736B 
 
 
 
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   11/19/2012 
Disease:  I.  Diagnosis and Staging Working Group Report.  Biol.Blood Marrow 
Transplant.  2005; 11:945-955.     
 25.  O-Brien PC, Fleming TR.  A multiple testing procedure for clinical trials.  Biometrics 
1979; 35:549-556. 
 26.  Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics 1982;38:29-41. 
 
 
 

IRB#:  14736B 
 
 
 
24 
 
 
 
 
   11/19/2012 
APPENDIX A 
 
TREATMENT PLAN 
 
FLUDARABINE – MELPHALAN  
      
 
Conditioning:  
 
 
Day -7 
Day -6  
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
 Day 0 
Fludarabine 
 
30 mg/m2   30 mg/m2  
30 mg/m2   30 mg/m2  
30mg/m2 
 
 
 Haplo 
Melphalan 
 
 
 
 
 
70 mg/m2 
70 mg/m2 
 
 and  
rATG 
1.5 mg/kg 
 
1.5 mg/kg 
 
1.5 mg/kg 
 
1.5 mg/kg 
 Cord 
 
 
 
GVHD Prophylaxis: 
Tacrolimus 0.03 mg/kg/day IV CI over 24 hr from 4 PM day -2 until engraftment or when patient is able to take PO, then tacrolimus 
approximately 0.09 mg/kg PO in 2 divided doses.  Tacrolimus should be given at full dose to maintain levels of 5-15 ng/mL through 
day 180, tapered by 20% every week thereafter. Early tapering can be given for repeated infection, poor chimerism, or high-risk 
disease. 
 
Additional GVHD prophylaxis according to standard of care. 
 
 
 
 
 
 

IRB#:  14736B 
 
 
 
25 
 
 
 
 
   11/19/2012 
APPENDIX B 
 
TREATMENT PLAN 
 
FLUDARABINE –THIOTEPA – TBI  
      
 
Conditioning:  
 
 
Day -7 
Day -6  
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0 
Fludarabine 
 
30 mg/m2   
30 mg/m2   
30 mg/m2   
30 mg/m2   
30 mg/m2 
 
 
Haplo 
Thiotepa 
 
5 mg/kg 
5 mg/kg 
 
 
 
 
 
and  
TBI 
 
 
 
 
 
  
 BID 
 
  
 BID 
 
  
 BID 
Cord 
rATG 
1.5 mg/kg 
 
1.5 mg/kg 
 
1.5 mg/kg 
 
1.5 mg/kg 
 
 
 
 
GVHD Prophylaxis: 
Tacrolimus 0.03 mg/kg/day IV CI over 24 hr from 4 PM day -2 until engraftment or when patient is able to take PO, then tacrolimus 
approximately 0.09 mg/kg PO in 2 divided doses.  Tacrolimus should be given at full dose to maintain levels of 5-15 ng/mL through 
day 180, tapered by 20% every week thereafter. Early tapering can be given for repeated infection, poor chimerism, or high-risk 
disease. 
 
Additional GVHD prophylaxis according to standard care. 
 
 

IRB#:  14736B 
 
 
 
26 
 
 
 
 
   11/19/2012 
APPENDIX C 
 
TREATMENT PLAN 
FLUDARABINE – BUSULFAN  
 
Conditioning:  
 
 
Day -7 
Day -6  
Day -5 
Day -4 
Day -3 
Day -2 
Day -1 
Day 0 
Fludarabine 
 
30 mg/m2   
30 mg/m2   
30 mg/m2   
30 mg/m2   
30 mg/m2 
 
 
Haplo 
Busulfan 
 
 
130 mg/m2 
130 mg/m2 
130 mg/m2 
130 mg/m2 
 
 
and  
rATG 
1.5 mg/kg 
 
1.5 mg/kg 
 
1.5 mg/kg 
 
1.5 mg/kg 
Cord 
 
 
 
GVHD Prophylaxis: 
Tacrolimus 0.03 mg/kg/day IV CI over 24 hr from 4 PM day -2 until engraftment or when patient is able to take PO, then tacrolimus 
approximately 0.09 mg/kg PO in 2 divided doses.  Tacrolimus should be given at full dose to maintain levels of 5-15 ng/mL through 
day 180, tapered by 20% every week thereafter. Early tapering can be given for repeated infection, poor chimerism, or high-risk 
disease. 
 
  
Additional GVHD prophylaxis according to standard care. 

IRB#:  14736B 
 
 
 
27 
 
 
 
 
   11/19/2012 
APPENDIX D 
BACKGROUND DRUG INFORMATION 
 
 
BUSULFAN 
 
AVAILABILITY 
Commercially available in 60 mg/ 10 mL ampuls. 
 
 
STORAGE & STABILITY 
Store ampuls under refrigeration at 2oC to 8oC.  The diluted solution is stable for up to 8 hours at room 
temperature (25oC), but the infusion must also be completed within that 8-hour time frame.  Dilution of 
busulfan injection in 0.9% sodium chloride is stable for up to 12 hours under refrigeration (2oC to 8oC), 
but the infusion must also be completed within that 12-hour time frame. 
 
PREPARATION 
Dilute busulfan injection in 0.9% sodium chloride injection or dextrose 5% in water per institutional 
pharmacy guidelines. 
 
ADMINISTRATION 
Intravenous busulfan should be administered via a central venous catheter per institutional guidelines. 
 
TOXICITY 
Severe myelosuppression with marrow ablation, alopecia, and mild nausea/vomiting are expected.  
Alopecia may not be completely reversible.  Liver toxicity, including severe and possibly fatal veno-
occlusive disease (<5%), may occur.  Pulmonary toxicity is rare.  Darkening of the skin may occur and 
may last several months.  Seizures may occur (<5%).  Anti-seizure prophylaxis should be administered 
per transplant guidelines.  Benzodiazepines, eg. Clonazepam (Klonopin) 1 mg PO TID, may be used.  
Busulfan causes immunosuppression with the risk of opportunistic infection even after resolution of 
neutropenia.  Busulfan is expected to cause nearly universal infertility in the doses used, although men 
may occasionally father children.  Grade III mucosities, diarrhea, and abdominal pain, hemorrhagic 
cystitis, “hand-foot syndrome” with neuropathic pain has also been reported. 
 
 
 
FILGRASTIM  (G-CSF:  Granulocyte Colony Stimulating Factor, Neupogen)   
 
AVAILABILITY 
G-CSF is commercially available in 1.0 and 1.6 mL vials containing 300 mcg and 480 mcg G-CSF, and in 
prefilled syringes containing 300 mcg/0.5 mL and 480 mcg/0.8 mL. 
 
 
STORAGE & STABILITY 
Intact vials and prefilled syringes should be stored under refrigeration.  Do not allow the drug to freeze.  
 
ADMINISTRATION 

IRB#:  14736B 
 
 
 
28 
 
 
 
 
   11/19/2012 
The daily dose of G-CSF should be injected subcutaneously in one or two sites.  The dose following 
peripheral blood stem cell infusion is 5 mcg/kg/day.  The dose of G-CSF may be rounded up to the 
nearest vial size. 
 
TOXICITY 
The most common side effect associated with G-CSF is bone pain.  Bone pain is usually reported as mild 
or moderate and, if necessary, may be treated with non-opiod or opiod analgesics. 
 
 
 
FLUDARABINE (Fludara) 
     
 
AVAILABILITY 
Fludarabine is commercially available as a white, lyophilized powder.  Each vial contains 50 mg of 
fludarabine, 50 mg of mannitol and sodium hydroxide to adjust pH.   
 
STORAGE & STABILITY 
Intact vials should be stored under refrigeration.  Reconstituted vials are stable for 16 days at room 
temperature or under refrigeration.  Solutions diluted in D5W or NS are stable for 48 hours at room 
temperature or under refrigeration. 
 
PREPARATION 
Fludarabine should be reconstituted with Sterile Water for Injection, USP or normal saline per 
institutional pharmacy guidelines.   
 
ADMINISTRATION 
Fludarabine will be administered as an IV infusion over 30 minutes. 
 
TOXICITY 
Myelosuppression, (dose-limiting toxicity), fever, mild nausea and/or vomiting, diarrhea, stomatitis, skin 
rashes, myalgia, headache, agitation, hearing loss, transient episodes of somnolence and fatigue, 
autoimmune hemolytic anemia (may be life-threatening), peripheral neuropathy, and pulmonary toxicity.  
(Both pneumonia and hypersensitivity reactions have been reported.  Fatal pulmonary toxicity has been 
described, especially when fludarabine was used in combination with pentostatin.  Severe, fatal CNS 
toxicity presenting with loss of vision and progressive deterioration of mental status was encountered 
almost exclusively after very high doses of fludarabine.  Such toxicity has only been rarely demonstrated 
at the 25-30 mg /m2 dosage of fludarabine.  Very rarely described complications include transfusion-
associated graft versus host disease.  Tumor lysis syndrome has been observed, especially in patients with 
advanced bulky disease.  Opportunistic infections (protozoan, viral, fungal, and bacterial) have been 
observed.     
 
 
 
MELPHALAN (Alkeran) 
 
AVAILABILITY 
Melphalan for IV use is commercially available in sterile 50 mg vials.  The product is a lyophilized 
powder with 20 mg povidone per vial.  Also provided is 10 mL of special diluent for use in reconstituting 
the product.  The special diluent has 0.20 g sodium citrate, 6 mL propylene glycol, 0.5 mL 95% ethanol, 
and sterile water. 

IRB#:  14736B 
 
 
 
29 
 
 
 
 
   11/19/2012 
 
 
STORAGE & STABILITY 
Intact vials should be stored at room temperature (15oC-30oC) and protected from light.  Reconstituted 
solutions are chemically and physically stable for at least 90 minutes at room temperature.  Solutions 
further diluted in 0.9% sodium chloride to a concentration of 0.1 mg/mL to 0.45 mg/mL are stable for at 
least 60 minutes.  Solutions diluted to 1 mg/mL are reported to be physically stable for at least 4 hours at 
room temperature-chemical stability of this dilution is not known.  Because of the relative instability of 
melphalan solutions, it is recommended that administration of the diluted solution be completed within 60 
minutes of reconstitution.  Reconstituted solutions should not be refrigerated. 
 
PREPARATION 
Melphalan should be prepared immediately before intended use.  Each vial is reconstituted with 10 mL of 
the special diluent to yield a concentration of 5 mg/mL.  The reconstituted solution may be diluted with 
0.9% sodium chloride to a concentration of 0.1 mg/mL to 0.45 mg/mL.   
 
ADMINISTRATION 
The total dose of melphalan will be administered by short IV infusion over 30-60 minutes, as per 
institutional pharmacy guidelines. 
 
TOXICITY 
The major toxicity of melphalan is bone marrow suppression, usually lasting four to eight weeks.  Other 
toxicities include nausea, vomiting, diarrhea, and mucositis.  Less common toxicities include pulmonary 
fibrosis, interstitial pneumonitis, vasculitis, alopecia, hemolytic anemia, and allergic reactions.  Transient 
rises in BUN and creatinine have occurred with high dose melphalan and also acute renal failure. Tissue 
necrosis may result if infiltration occurs.    
 
 
 
MYCOPHENOLATE MOFETIL (Cellcept; Myfortic; MMF) 
     
 
AVAILABILITY 
Mycophenolate mofetil is available as a Capsule, as mofetil:  CellCept®: 250 mg;  
as Injection, powder for reconstitution, as mofetil hydrochloride:  CellCept®: 500 mg [contains 
polysorbate 80]; as Powder for oral suspension, as mofetil: CellCept®: 200 mg/mL (225 mL) [provides 
175 mL suspension following reconstitution; contains phenylalanine 0.56 mg/mL; mixed fruit flavor]; as 
a Tablet, as mofetil: CellCept®: 500 mg [may contain ethyl alcohol]; and as a Tablet, delayed release, 
as mycophenolic acid: Myfortic®: 180 mg, 360 mg [formulated as a sodium salt]. 
 
STORAGE & STABILITY 
Intact vials should be stored at room temperature 15ºC to 30ºC (59ºF to 86ºF).  Store solutions at 15ºC to 
30ºC (59ºF to 86ºF) and begin infusion within 4 hours of reconstitution.  Store capsules at room 
temperature of 15ºC to 39ºC (59ºF to 86ºF).  Tablets should be stored at room temperature of 15ºC to 
39ºC (59ºF to 86ºF) and protected from light.  Store powder for oral suspension at room temperature of 
15ºC to 39ºC (59ºF to 86ºF).  Once reconstituted, the oral solution may be stored at room temperature or 
under refrigeration. Do not freeze. The mixed suspension is stable for 60 days. 
 
PREPARATION 
Mycophenolate mofetil is stable in D5W should be reconstituted per institutional pharmacy guidelines.  
 
 

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ADMINISTRATION 
Intravenous solutions of mycophenolate mofetil should be administered over at least 2 hours (either 
peripheral or central vein); do not administer intravenous solution by rapid or bolus injection.  Oral 
dosage formulations (tablet, capsule, suspension) should be administered on an empty stomach to avoid 
variability in MPA absorption. The oral solution may be administered via a nasogastric tube (minimum 8 
French, 1.7 mm interior diameter); oral suspension should not be mixed with other medications. Delayed 
release tablets should not be crushed, cut, or chewed. 
 
TOXICITY 
Pain, abdominal pain, fever, headache, infection, sepsis, asthenia, chest pain, back pain, hypertension, 
tremor, insomnia, dizziness, acne, rash, diarrhea, constipation, mild N/V, oral monoliasis, anemia, 
leukopenia, 
thrombocytopenia, 
hypochromic 
anemia, 
leukocytosis, 
peripheral 
edema, 
hypercholesterolemia, hypophosphatemia, edema, hypo or hyperkalemia, hyperglycemia, infection, 
dyspnea, cough increase, pharyngitis, bronchitis, pneumonia, UTI, hematuria, kidney tubular necrosis, 
urinary tract disorder. 
 
 
 
RABBIT ANTITHYMOCYTE GLOBULIN (Thymoglobulin, rATG) 
 
AVAILABILITY 
Antithymocyte globulin is commercially available.  Each package contains two vials:  the first vial 
contains 25 mg antithymocyte globulin, and the second vial contains > 5 mL SWFI diluent. 
 
 
STORAGE & STABILITY 
Ampuls must be refrigerated (2oC-8oC/ 36oF-46oF),).  Do not freeze.   
 
PREPARATION 
Reconstitute 25 mg vial with diluent provided by manufacturer (SWFI > 5 mL).  Roll vial gently to 
dissolve powder.  Use contents of vial within 4 hours of reconstitution.  Dilute dosage to a final 
concentration of 0.5 mg/mL in 0.9% sodium chloride injection or 5% dextrose injection.  Gently invert 
admixture 1-2 times to mix solution.  Use admixture solution immediately.  Final concentration must be 
0.5 mg/mL. 
 
ADMINISTRATION 
Infuse the first dose over at least six hours, and subsequent doses over at least 4 hours.  Infuse through a 
0.22 micron in-line filter into a high-flow vein.  Premedications include acetaminophen 650 mg PO, 
diphenhydramine 25-50 mg PO/IV, and methylprednisolone 1 mg/kg (at the initiation and half-way 
through antithymocyte globulin administration). 
 
TOXICITY 
Infusion-related toxicities, including fevers, chills, rash, dyspnea, cardiovascular (hypo- or hypertension, 
tachycardia, edema, chest pain).  In rare cases, anaphylaxis has been reported in which case the infusion 
should be terminated immediately, and emergency treatment with epinephrine and other resuscitative 
measures should be instituted.  rATG should not be administered again to this patient.  
Immunosuppression is a common feature of rATG and can result in severe infections including sepsis, 
CMV, and urinary tract infections.  Serum sickness, neutropenia (57%), thrombocytopenia (37%), 
leucopenia (57%), pain (46%), headache (40%), nausea and diarrhea (37%), peripheral edema (34%), 
systemic infection, malaise, pain, stomatitis, GI bleed, swelling or redness at injection site, myalgia, back 
pain, development of human anti-rabbit antibodies (HARA).  

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TACROLIMUS (Prograf, FK506) 
 
AVAILABILITY 
Tacrolimus is commercially available as an injection (5 mg/mL; 1 mL ampuls) and as oral capsules (0.5 
mg, 1 mg, and 5 mg). 
 
 
STORAGE & STABILITY 
Store tacrolimus capsules and injection at controlled room temperature, 15oC-30oC (59oF-86oF).   
 
PREPARATION – FOR IV USE 
Tacrolimus injection must be diluted prior to IV infusion with 0.9% sodium chloride or 5% dextrose 
injection to a concentration of 4-20 mcg/mL.  Solutions should be prepared in non-PVC plastic or glass.  
Tacrolimus injection and diluted solutions of the drug should be inspected visually for particulate matter 
and discoloration prior to administration whenever solution and container permit. 
 
ADMINISTRATION 
Oral therapy should be started as soon as possible as per protocol and 8 to 12 hours after stopping 
intravenous therapy.  Oral doses will be administered twice a day.  The conversion from IV to oral 
therapy should take into account concomitant medications (such as voriconazole). 
 
TOXICITY 
In patients receiving tacrolimus, 5% to 47% experienced anemia, 8% to 32% experienced leukocytosis, 
and 14% to 24% experienced thrombocytopenia.  Rare cases of microangiopathic hemolytic anemia have 
been reported.  Chest pain was reported in 19%.  Mild to moderate hypertension is a common adverse 
effect associated with tacrolimus therapy.  Antihypertensive therapy may be required.  The most common 
adverse effects of tacrolimus have involved the central nervous system, and include headache (37% to 
64%), tremors (48% to 56%), insomnia (32% to 64%), paresthesia (17% to 40%), and dizziness (19%).  
Tremor and headache may respond to dosage reduction.  Visual changes, agitation, anxiety, confusion, 
seizures, depression, hallucinations, myoclonus, neuropathy, psychosis, incoordination, and abnormal 
dreams have been reported in 3% to 15%.  Hyperkalemia (13% to 45%), hypokalemia (13% to 29%) 
hypophosphatemia (49%) and hypomagnesemia (16% to 48%) have been associated with tacrolimus 
therapy.  Hyperuricemia has been reported in >3%.  Gastrointestinal adverse effects included nausea 
(32% to 46%), vomiting (14% to 29%), anorexia (7% to 34%), constipation (23% to 35%), and diarrhea 
(37% to 72%).  Nephrotoxicity was reported in 38% to 52% of liver and kidney transplant patients, 
respectively.  Hematuria has been reported in greater than 3%.  Abnormal liver function tests have been 
reported in 6% to 36% of patients; ascites in 7% to 27%.   
 
Other effects reported in clinical trials include pain, fever, asthenia, back pain, and peripheral edema.  The 
incidence of hyperglycemia was 17% and may require therapy with insulin.  Other less frequently 
occurring effects include abscess, chills, peritonitis, and photosensitivity reactions.  Anaphylaxis has been 
reported in a few patients receiving intravenous tacrolimus.  Tacrolimus injection contains cremophor 
which in other drugs has been associated with anaphylaxis.  Because tacrolimus is an 
immunosuppressant, the risk of opportunistic infections is increased. 
 
 
 
 
 

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DRUG INTERACTIONS   
Tacrolimus is metabolized by cytochrome P450 3A4.  Drugs that are inhibitors (e.g. itraconazole) of 
inducers (e.g. phenytoin) of 3A4 might be expected to increase or decrease tacrolimus concentrations, 
respectively, possibly resulting in increased or decreased effects.  
 
 
 
THIOTEPA (Thioplex) 
 
AVAILABILITY 
Thiotepa is commercially available. 
 
 
STORAGE & STABILITY 
Store intact vials under refrigeration (2oC-8oC) and protect from light.  Not stable at room temperature for 
any duration of time. 
 
PREPARATION 
Dilute powder 1.5 mL SWI to a concentration of 10.4 mg/mL which is stable for 8 hours at refrigeration.  
Further dilutions in NS per institutional pharmacy guidelines. 
 
ADMINISTRATION 
Thiotepa will be administered as an IV infusion over 2 hours per institutional guidelines. 
 
TOXICITY 
Myelosuppression, anorexia, anaphylaxis, hyperuricemia.  High dose thiotepa: Severe myelosuppression, 
severe N/V, stomatitis. LFT abnormalities, hyperpigmentation, confusion.  Intrathecal thiotepa: 
Headache, nausea and vomiting.  May require dose reduction in renal impairment. 
 
  
 
 
 

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APPENDIX E 
 
ZUBROD (ECOG) SCALE OF PERFORMANCE STATUS 
 
 
 
Zubrod Status 
 
 
0 = No symptoms 
 
 
1 = Symptoms, fully ambulatory 
 
 
2 = Requires nursing assistance or equivalent; bedridden < 50% or normal day.  
 
 
3 = Bedridden > 50% or normal day 
 
 
4 = Bedfast 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX F 
 
PRZEPIORKA CRITERIA 
FOR ACUTE GVHD 
 
 
 
 
Consensus Criteria for Grading of Acute GVHD 
______________________________________________________________________________ 
 
 
              Skin 
 
               Liver 
 
                                  Gut 
______________________________________________________________________________________ 
Stage 
   1 
Rash <25%a   
 
     Bilirubin 2-3 mg/dLb 
 
Diarrhea >500 mL/dc or persistent  
 
 
 
 
 
 
 
 
     nausead 
   2 
Rash 25-50% 
 
     Bilirubin 3-6 mg/dL 
 
Diarrhea >1000 mL/d 
   3 
Rash >50% 
 
     Bilirubin 6-15 mg/dL  
Diarrhea >1500 mL/d 
   4 
Generalized erythroderma      Bilirubin >15 mg/dL 
 
Severe abdominal pain with or  
 
    with bullae 
 
 
 
 
 
    without ileus 
 
Gradee 
    I 
           Stage 1-2  
 
 None 
 
 
 
     None 
    II 
             Stage 3             or              Stage 1            or                                  Stage 1 
    III 
 
 ----                                    Stage 2-3          or                                 Stage 2-4 
    IV                    Stage 4               or              Stage 4            or                                  Stage 4 
______________________________________________________________________________________ 
 
aUse “Rule of Nines” or burn chart to determine extent of rash. 
bRange given as total bilirubin.  Downgrade one stage if an additional cause of elevated bilirubin has been 
documented. 
cVolume of diarrhea applies to adults.  For pediatric patients, the volume of diarrhea should be based on body 
surface area.  Downgrade one stage if an additional cause of diarrhea has been documented. 
dPersistent nausea with histologic evidence of GVHD in the stomach or duodenum. 
eCriteria for grading given as degree of organ involvement required to confer that grade. 
fGrade IV may also include lesser organ involvement when the Karnofsky performance status is <50%, so patients 
with Stage 4 gut GVHD are usually grade IV.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX G 
HAPLO-CORD SAMPLES 
 
Blood Samples are drawn: 
Before conditioning (plus bone marrow sample) 
Day 0 
Day 7 
Day 10 
Day 14 
Day 28  (plus bone marrow sample) 
Day 100  (plus bone marrow sample) 
Day 180  (plus bone marrow sample) 
At relapse  (plus bone marrow sample) 
One year and yearly thereafter  (plus bone marrow sample) 
 
Blood samples are ordered on a miscellaneous requisition -  
Fill in the top portion: 
Lab:  “Kovler – Jodie” 
Specimen:  “Blood” 
Examination:  “Haplo-cord study samples” 
 
On the bottom right, add: 
“Haplo-cord study samples” and date of sample 
 
On the left, give these instructions: 
“Please draw 4 green top and 1 red top tube of peripheral blood (PB). 
Send to Apheresis, tube station #663, and call Jodie at 58127, or pager 9950, for pickup”.  
 
Bone Marrow Samples: 
Bone marrow exams are performed as above (pre, days 28, 100, 180, relapse, 1 year): 
 
On the bone marrow requisition, request in the “Other Section”: 
“Please draw 2 green top tubes of BM aspirate.  Send to Apheresis, tube station #663, and call Jodie at 
58127, or pager 9950, for pick up” 
 
If the “Other Section” is used, you may also request these bone marrow samples on a miscellaneous 
requisition and attach to the bone marrow requisition.  In the Specimen field of the miscellaneous 
requisition, write “bone marrow aspirate”.   And in the lower right add:  “Please draw 2 green top tubes 
of BM aspirate.  Send to Apheresis, tube station #663, and call Jodie at 58127, or pager 9950, for pick up” 
  
 
Order Cytogenetics FISH analysis if either the haploidentical or cord donor is a sex mismatch.  
 
Additional Information: 
Peripheral blood VNTR (chimerism) will be performed every two weeks for the first 100 days following a 
Haplo-Cord transplant (on days 14, 28, 42, 56, 70, 84, 100). 
 
If any questions, please call: 
Scott Allen – 21613, or pager 9377.             Or contact Study Chair Dr. Andrew Artz 

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APPENDIX H 
 
INFUSION OF CRYOPRESERVED HEMATOPOIETIC PROGENITOR CELLS BY 
NURSES 
 
SEE ATTACHED POLICY:  431.02 
University of Chicago Medical Center 
Progenitor Cell Transplantation & Cell Therapy Program 
 
 
APPENDIX I: 
ALLO DONOR SELECTION CRITERIA 
 
SEE ATTACHED POLICY: 051.4 
University of Chicago Medical Center 
Progenitor Cell Transplantation & Cell Therapy Program 
 
 
APPENDIX J: 
APHERESIS EVALUATION AND MANAGEMENT 
 
SEE ATTACHED POLICY: 410.03 
University of Chicago Medical Center 
Progenitor Cell Transplantation & Cell Therapy Program