Clinical trial NCT00305682
Conditions: Myeloproliferative Disorders Leukemia Lymphoma Myelodysplastic Syndromes
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2005-06-01; Completion date: 2019-12-12
Enrollment: 295 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill cancer cells. An umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving sirolimus and mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation followed by an umbilical cord blood transplant, sirolimus, and mycophenolate mofetil works in treating patients with hematologic cancer.

Detailed description:
OBJECTIVES:

Primary

* Determine the one- and two-year survival of patients with hematologic malignancies treated with a nonmyeloablative conditioning regimen comprising fludarabine, cyclophosphamide, and total-body irradiation followed by umbilical cord blood transplantation and post-transplant immunosuppression comprising sirolimus and mycophenolate mofetil.

Secondary

* Determine the six-month nonrelapse mortality of patients treated with this regimen.
* Determine the presence of chimerism in patients treated with this regimen at days 21, 60, 100, 180, and 365.
* Determine the incidence of neutrophil engraftment by day 42 in patients treated with this regimen.
* Determine the incidence of platelet engraftment by six months in patients treated with this regimen.
* Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 in patients treated with this regimen.
* Determine the incidence of chronic GVHD at one year in patients treated with this regimen.
* Determine the probability of overall survival within one or two years in patients treated with this regimen.
* Determine the probability of progression-free survival within one or two years in patients treated with this regimen.
* Determine the incidence of relapse or disease progression within one or two years in patients treated with this regimen.

OUTLINE: This is a nonrandomized study. Patients are stratified into five disease groups: 1. acute myeloid leukemia, myelodysplastic syndromes, chronic myelogenous leukemia \[CML\] in first chronic phase and second chronic phase \[CP2\] after myeloid blast crisis; 2. acute lymphoblastic leukemia, Burkitt's lymphoma, CML CP2 post lymphoid blast crisis, 3. large-cell B and T-cell lymphoma, mantle cell lymphoma; 4. chronic lymphocytic leukemia/small lymphocytic lymphoma, prolymphocytic leukemia, marginal zone B-cell lymphoma, follicular lymphoma; 5. Hodgkin's lymphoma and multiple myeloma.

* Nonmyeloablative conditioning: Patients receive fludarabine intravenously on days -6 to -2 and cyclophosphamide IV on day -6. Patients who did not undergo prior autologous transplant or who received ≤ 1 course of prior multiagent chemotherapy or no severely immunosuppressive therapy in the past 3 months also receive anti-thymocyte globulin IV on days -6 to -4. All patients also undergo total-body irradiation on day -1.
* Umbilical cord blood transplant: Patients undergo umbilical cord blood transplantation on day 0.
* Post-transplant immunosuppression: Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation. Patients also receive mycophenolate mofetil IV on days -3 to 5 and then orally on days 6-30.

After completion of study treatment, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 320 patients will be accrued for this study.

Arms: arm 1: Arm 1 - hematologic malignancy patients who have received a previous autologous transplant or ≥ 2 cycle of multiagent chemotherapy within the last 3 months previous to umbilical cord blood transplant (UCBT). Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation without anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. arm 2: Arm 2 - hematologic malignancy patients who have not been treated with prior autologous transplant or ≤ 1 cycle of chemotherapy in the 3 months previous to umbilical cord blood transplant (UCBT), and who should receive anti-thymocyte globulin as conditioning regimen. Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation with anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. arm 3: Arm 3 - patients with refractory leukemia or lymphoma who have been rendered aplastic either by induction chemotherapy or radioimmunoconjugated monoclonal antibody therapy. Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation with anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. arm 4: Arm 4 - hematologic malignancy patients enrolled in MT2006-01. Conditioning Fludarabine dose of 40 mg/m2/day x 5, cyclophosphamide and total body irradiation with or without anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. arm 5: Arm 5 - hematologic malignancy patients who have received a previous autologous transplant or ≥ 2 cycle of multiagent chemotherapy within the last 3 months previous to umbilical cord blood transplant (UCBT). Conditioning Fludarabine dose of 30 mg/m2/day x 5, cyclophosphamide and total body irradiation without anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus. arm 6: Arm 6 - hematologic malignancy patients who have not been treated with prior autologous transplant or ≤ 1 cycle of chemotherapy in the 3 months previous to umbilical cord blood transplant (UCBT), and who should receive anti-thymocyte globulin as conditioning regimen. Conditioning Fludarabine dose of 30 mg/m2/day x 5, cyclophosphamide and total body irradiation with anti-thymocyte globulin followed by umbilical cord blood transplantation, and peri-transplant Mycophenolate Mofetil and Sirolimus.
Interventions: intervention 1: anti-thymocyte globulin intervention 2: cyclophosphamide intervention 3: Fludarabine intervention 4: mycophenolate mofetil intervention 5: umbilical cord blood transplantation intervention 6: total body irradiation intervention 7: Sirolimus
Intervention descriptions: intervention 1: Equine ATG dose is 15 mg/kg intravenously (IV) every 12 hours for 6 doses on days -6, - 5, and -4. intervention 2: Cyclophosphamide 50mg/kg x 1 to be administered IV over 2 hours with high volume fluid flush on day -6. intervention 3: Fludarabine 40 mg/m2/day or 30 mg/m2/day intravenously (IV) as one hour infusion x 5 days, on day -6 to -2. intervention 4: Mycophenolate mofetil (MMF) 3 gram/day for patients who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (\<40 kilograms) will receive MMF at the dose of 15 mg/kg/dose every 8 hours. intervention 5: One or 2 UCB units may be infused to achieve the required cell dose. intervention 6: Administered Day -1, 200 cGy intervention 7: Sirolimus will be administered starting at day -3 with 8mg-12mg mg oral loading dose followed by single dose 4 mg/day with a target serum concentration of 3 to 12 mg/mL. Levels are to be monitored 3 times/week in the first 2 weeks, weekly until day +60, and as clinically indicated until day +100 post-transplantation. In the absence of acute GVHD sirolimus may be tapered starting at day +100 and eliminated by day +180 post-transplantation.

Protocol documents:
Prot_SAP_000.pdf: 
UNIVERSITY OF MINNESOTA BLOOD AND MARROW TRANSPLANT PROGRAM
TRANSPLANTATION OF UNRELATED DONOR UMBILICAL CORD BLOOD IN PATIENTS WITH
HEMATOLOGICAL MALIGNANCIES
USING A NON-MYELOABLATIVE PREPARATIVE REGIMEN
MT2005-02
CPRC #2005LS036
Principal Investigators
Claudio G. Brunstein, MD, PhD
John E. Wagner, MD
Co-Investigators
Mukta Arora, MD
Bruce R. Blazar, MD
Linda J. Burns, MD
Kathryn Dusenbery, MD
Margaret L.MacMillan, MD
Jeffrey Miller, MD
Daniel J. Weisdorf, MD
Study Statistician
Todd E. DeFor, MS
Version Date
November 8, 2013
This document contains confidential information that is the property of the Blood and Marrow
Transplant Program. Do not copy, disclose, or circulate without written authorization from
the University of Minnesota, Fairview Blood and Marrow Transplant Services Medical Director


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Revision History
Version
Date
Details of changes
Consent
change?
11/08/2013
Section 5.2.1 - Add pediatric dosing for sirolimus
Section 6 – add testing for anti-HLA antibodies
Appendix I – replace eligibility checklist with the current checklist in use reflecting
changes from 02/2013 (protocol document not previously updated) and correct wording in
arm 6
No
02/22/2013
Reduce fludarabine dose from 40 mg/m2 to 30 mg/m2 to match current practice (creating
2 new treatment arms for statistical analysis – arm 5 and arm 6) in patients other than
those co-enrolled in MT2006-01(arm 4) and those with aplasia (arm 3).
Delete year 3 follow-up visits as all transplant patients are transferred to the long-term
follow-up by the database after 2 years
For clarification and simplification - remove reference to treatment arms for statistical
analysis from all sections except registration and statistical considerations
General editing for clarity throughout
No
09/11/2012
Replace cyclosporine with sirolimus sections 5.2.1 and 8.9
Yes
05/07/2012
Update eligibility for acute lymphoblastic leukemia/lymphoma (section 3.2.1.ii) to allow
MRD and include other gene arrangements (hypodiploidy and IKZFI); modify eligibility
for CLL/SLL, marginal zone B-cell lymphoma and follicular lymphoma (section 3.2.7) to
include patients who progress within 12 months of previous CR or PR;
delete research related bloods, remove lists of procedures as in table format already;
general updating and reformatting throughout
add eligibility checklist appendix I, renumber remaining appendices
Yes
10/22/10
Revised to remove Appendix VIII: cord blood selection algorithm (U of MN Institutional
Guidelines will now be a separate document).
6/29/10
•Modified graft selection for patient co-enrolled in 2006-01 Treg study
4/23/2010
Added research bone marrow sample to section 7.0, required observations
No
02/16/2010
Section 4.1.1 and synopsis - changed eligibility criteria to include patients aged >70 but ≤75 
with a co-morbidity score ≤ 2; add co-morbidity scoring as appendix XII  
Update sections 5 ( patient registration); 9.4 (DSMP) 9.5 (SAE reporting), and delete
appendix VII (same information as in section 9.5); Removed Marcie Tomblyn from protocol
team
No
11/5/2008
Clarified immune reconstitution testing table (deleted day +28, +60, and +100 cytokine
levels and PCR)
Clarified that only subjects on Arm A will have immune reconstitution tests
Deleted appendix which had FHCRC local guidelines.
Yes
7/17/2008
Clarified immune reconstitution testing table
Yes
4/8/2008
Added immune reconstitution testing: Section 7.1.2
Yes
10/4/2007
Section 9.5 clarified definition of serious adverse events
No
7/20/2007
Eligibility section 4.2, added NK cell malignancies and Burkitt’s lymphoma in remission
Section 7.2.5 clarified to define who needs to have 24 hour creatinine clearance; removed
transferring and albumin testing
Section 7.1 and 7.3 have been made consistent in regards to chimerism studies
Section 9.5 Reporting requirement modified to include only grades 3-5
No
11/15/2006
Modified sections 7.4.11 and 7.5.11 to include the wording " For patients who received
ATG as part of the conditioning regimen” to clarify that the EBV viral load will not be
No


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CPRC#2005LS036
Version
Date
Details of changes
Consent
change?
required of all subjects.
11/1/2006
Fred Hutchinson Cancer Research Center will no longer be an affiliate in this study. All
references to FHCRC removed.
Yes
6/19/2006
Corrected typographical errors
Added table of contents
Added Appendix XI with clarification of ideal body weight formulas for U of MN and
FHCRC
Section 6.0 reworded to clarify dose-adjustment instructions
No
4/6/2006
Section 4.0 reworded to clarify eligibility based on tumor size, prior autologous transplant,
and the utilization of the PET scan for staging
Section 4.3.8, 4.3.9, and 4.3.10 added to clarify eligibility criteria
Section 4.4 added to exclude subjects with active CNS malignancy
Section 6.0 adjusted formula to adjust cyclophosphamide based on weight, and fludarabine
based on renal function and prior CNS malignancy/radiotherapy
Section 6.1.1 added CSA dose adjustment criteria
Section 9.5.1.1 added contact numbers for reporting SAEs
12/21/2005
In section 6.0 wording referring to Appendix II has been modified
In section 6.1.2 clarification of pediatric dose of MMF to be administered every 8 hours
In sections 7.3.7, 7.4.8 and 7.5.6 we have removed the required peripheral blood
chimerism studies; and table 7.1 has been similarly modified
Sections 7.2.11 and 7.2.12 pediatric pretransplant evaluation modified for children unable
to cooperate for MUGA/echocardiography and/or pulmonary function tests
Section 7.3.4 wording of CMV surveillance modified.
Title of Appendix III modified to “recommended” radiation therapy.
Appendix III modified to allow for local radiation guidelines
Title of Appendix IV modified to “recommended” supportive care.
Wording of Appendix V modified to allow for local guidelines
Appendix IX modified to reflect current protocol number
Appendix XI and XII deleted
10/28/2005
Modified MMF section 6.1.2 to read: Mycophenolate mofetil (MMF) 3 gram/day for patients
who are ≥ 40 kg divided in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF 
at the dose of 15 mg/kg.
9/7/05
Added Myeloproliferative syndromes to eligibility; Added appendix X and XI


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TABLE OF CONTENTS
Protocol Synopsis – MT 2005-02...................................................................................................................... 5
Treatment Plan.................................................................................................................................................. 6
1
Objectives................................................................................................................................................. 7
2
Background and Significance .................................................................................................................... 7
3
Patient Selection.......................................................................................................................................10
4
Patient Registration..................................................................................................................................13
5
Treatment Plan.........................................................................................................................................14
6
Required Observations .............................................................................................................................18
7
Event Monitoring and Reporting .............................................................................................................19
8
Experimental Design, Endpoints and Statistics .........................................................................................21
9
Ethical and Regulatory Considerations .....................................................................................................25
10
References ...............................................................................................................................................26
Appendix I: Eligibility Checklist......................................................................................................................29
Appendix II: Karnofsky and Lansky Performance Status Scale.........................................................................32
Appendix III: Chemotherapy Drug Information................................................................................................33
Appendix IV: Expected Treatment Related Toxicity.........................................................................................34
Appendix V: Radiation Therapy Guidelines .....................................................................................................37
Appendix VI: Co-Morbidity Scoring................................................................................................................39


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Protocol Synopsis – MT 2005-02
Transplantation of Umbilical Cord Blood from Unrelated Donors in Patients With
Hematological Diseases Using a Non-Myeloablative Preparative Regimen
Study Design:
This is a non-randomized phase II trial using a non-myeloablative
cyclophosphamide/fludarabine/TBI prep with modifications based on factors
including diagnosis, disease status, and prior treatment. One or two cords will make
up the graft.
Primary Objective:
Estimate probability of one and two year survival
Secondary
Objectives:
Six month non-relapse mortality
Chimerism at days 21,60,100,180 and 365
Incidence of neutrophil engraftment by day 42
Incidence of platelet engraftment by six months
Incidence of day 100 grade II-IV and III-IV acute GVHD
Incidence of one year chronic GVHD
Probability of one and two year progression-free survival for each diagnosis
cohort
Probability of one and two year survival for each diagnosis cohort
Incidence of one and two year relapse or disease progression for each diagnosis
cohort.
Eligible Diseases:
Hematological malignancies/diseases: acute leukemias in complete remission
(high risk CR1 or subsequent CR); chronic myelogenous leukemia (except
refractory blast crisis); myelodysplastic syndrome with severe pancytopenia or
complex cytogenetics, large-cell lymphoma, Hodgkin lymphoma and multiple
myeloma, chronic lymphocytic leukemia/small lymphocytic lymphoma, marginal
zone b-cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma,
mantle-cell lymphoma, prolymphocytic leukemia may be eligible after initial
therapy
Aplasia after induction: refractory leukemia or MDS in aplasia after
chemotherapy or radiolabeled antibody; bone marrow failure syndromes, except for
Fanconi Anemia
Eligibility Criteria:
must be <70 years old with no matched 5/6 or 6/6 sibling donor - patients ≥ 70 
but ≤ 75 are eligible if the co-morbidity scores is ≤ 2 (refer to appendix VI)
Karnofsky score > 60% (adults) or Lansky score 50 (pediatrics)
> 3 months after prior myeloablative transplant (if applicable)
UCB units will be selected according to current University of Minnesota
umbilical cord blood graft selection algorithm. One or 2 UCB units may be used
to achieve the required cell dose.
Organ Function:
Cardiac: Absence of decompensated congestive heart failure, or uncontrolled


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arrhythmia and left ventricular ejection fraction ≥ 35%
Pulmonary: DLCO > 30% predicted, and absence of O2 requirements
Liver: Transaminases < 5 x upper limit of normal and bilirubin < 3 x upper limit
of normal
Renal: Creatinine ≤ 2.0 mg/dl (adults) and creatinine clearance > 40 ml/min 
(pediatrics). All adults with a creatinine > 1.2 or a history of renal dysfunction
must have estimated creatinine clearance > 40 ml/min
Exclusion Criteria:
pregnant or breastfeeding
evidence of HIV infection or known HIV positive serology
current active serious infection
acute leukemia in relapse/persistent disease CML in refractory blast crisis
large cell lymphoma, mantle cell lymphoma and Hodgkin lymphoma that is
progressive on salvage therapy - stable disease is acceptable to move forward
provided it is non-bulky
Accrual Objective:
The accrual goal is set at 320 patients – estimated disease distribution may be found
in section 8.4
Treatment Plan
Disease/Prior Treatment Status
Preparative Regimen
CY/FLU/TBI, no ATG
hematological diseases with prior autologous
transplant, ≥ 2 cycles of multi-agent 
chemotherapy or severely
immunosuppressive therapy in the last 3
months
cyclophosphamide 50 mg/kg day -6
fludarabine 30 mg/m2 days -6 to -2*
TBI 200cGy day -1
* if co-enrolled through MT2006-01(T-reg) give
fludarabine 40 mg/m2 days -6 to -2
CY/FLU/TBI, ATG hematological diseases
with prior autologous transplant > 12 months
or ≤ 1 cycle of multi-agent chemotherapy or 
no immunosuppressive chemotherapy in the
last 3 months
cyclophosphamide 50 mg/kg day -6
fludarabine 30 mg/m2 days -6 to -2
TBI 200cGy day -1
equine ATG 15 mg/kg twice daily days -6 to -4
CY/FLU/TBI for aplasia after induction
refractory leukemia and lymphoma in aplasia
after induction chemotherapy or
radioimmunoconjugated monoclonal Ab
therapy
cyclophosphamide 50 mg/kg day -6
fludarabine 40 mg/m2 days -6 to -2
TBI 200cGy day -1


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1
Objectives
1.1
Primary Objective
Estimate probability of one and two year survival
1.2
Secondary Objectives
Six month non-relapse mortality
Chimerism at days 21, 60, 100, 180 and 365
Incidence of neutrophil engraftment by day 42
Incidence of platelet engraftment by six months
Incidence of day 100 grade II-IV and III-IV acute GVHD
Incidence of one year chronic GVHD
Probability of one and two year progression free survival for each diagnosis cohort
Probability of one and two year survival for each diagnosis cohort
Incidence of one and two year relapse or disease progression for each diagnosis cohort
2
Background and Significance
Conventional allogeneic hematopoietic stem cell (HSC) transplantation is limited by lack of rapidly
available, human leukocyte antigen (HLA)-matched donors and excess transplant-related mortality
(TRM). Umbilical cord blood (UCB) is an alternative HSC source with the advantages of relative
tolerance of HLA-disparity [1-5] and rapid availability[6]. UCB transplantation (UCBT), a standard
therapy for pediatric leukemia[2-5], is now being investigated in adults [7-10]. However, many older
patients, or those with extensive prior therapy or serious co morbidities, are unable to tolerate
conventional conditioning. Therefore, reduced intensity or non-myeloablative (NMA) regimens are
being investigated using either related or unrelated volunteer donors[11-19]. However, given many
patients will not have a suitable donor, to further extend access to allogeneic transplant we have
investigated the combined use of unrelated donor UCB as HSC source with NMA conditioning in
adults with advanced or high-risk hematologic malignancy who are ineligible for conventional
conditioning. Augmentation of graft cell dose was achieved by the combined use of 2 partially
matched units in a double unit graft for those patients without access to a satisfactory single unit [20].
Our hypothesis was that alloreactive T cells in a UCB graft consisting of either single or double units
are sufficient to effect donor engraftment after NMA conditioning.
The current experience at the University of Minnesota after NMA conditioning (MT-2000-15) in 59
high-risk adults with advanced or high-risk hematologic malignancy were analyzing factors
influencing engraftment and TRM is summarized below. Eligible patients received a non-
myeloablative (NMA) preparative regimen with single dose of cyclophosphamide 50 mg/kg on day –6,
fludarabine 40 mg/m2 daily x 5 days (days –6 to –2), and a single dose of 200 cGy of total body
irradiation (day –1) (Cy50/Flu200/TBI200). During the conduct of the study equine anti-thymocyte
globulin (ATG, ATGAM, Pharmacia) 15 mg/kg every 12 hours for 6 doses on days –3 to –1 was added
to the preparative regimen for patients (n = 12) without combination chemotherapy in the preceding 4
months or with only a single induction regimen for acute myelogenous leukemia (AML) prior to
transplant. All patients received cyclosporine-A (CSA) from day –3 for at least 3 months (aiming for a


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trough blood level of > 200 µg/l). In addition, patients received mycophenolate mofetil (MMF) 1 gram
twice daily either orally or intravenously from days –3 to 30.
In the 58 evaluable patients neutrophil recovery occurred at a median of 8 days (range 5-32) after UCB
infusion. Four patients had primary and 2 had secondary graft failure for a cumulative incidence of
sustained donor derived engraftment of 89% (95%CI: 81-97). The cumulative incidence of sustained
donor engraftment in single unit recipients was 100% as compared to 86% (95%CI: 76-96) in double
unit recipients (p = 0.17). The cumulative incidence of platelet engraftment to > 50 x 109/l by day 180
was 68% (95%CI: 53-83) overall, and 64% (95%CI: 36-92) in single unit and 69% (95%CI: 52-86) in
double unit recipients (p = 0.76).
Among engrafting patients, there was no significant difference in total donor chimerism between single
and double unit recipients. Six patients had primary or secondary graft failure. One died of infection on
day 34 whereas 5 were re-transplanted with a second UCB graft. Two of these 5 patients engrafted
with the second UCB graft whereas 3 had autologous hematopoietic recovery. Only patient’s prior
therapy had a significant association with sustained engraftment. For patients with a Prior autograft or
chemotherapy within 3 months preceding UCBT, the cumulative incidence of sustained donor
engraftment was 98% (95%CI: 94-100), compared to a 64% (95%CI: 39-89) incidence in patients who
had never had chemotherapy or whose most recent chemotherapy was at least 4 months prior to UCBT
(p = 0.03).
Thirteen of the 40 (32.5%) patients who were transplanted with 2 UCB units and had
primary donor engraftment had evidence of both donors in their BM at day 21. However, one unit
ultimately predominated in all patients. There was no predicting factor for winning unit.
The cumulative incidences of grade II-IV and III-IV acute GVHD were 63% (95%CI: 49-77) and 25%
(95%CI: 14-36) at day 100, with no significant differences between single and double unit recipients.
Of the 15 patients with grade III-IV acute GVHD, 13 had grade III and 2 had grade IV disease with
patients exhibiting involvement of the skin (n = 13), upper gut (n = 10), rectum (n = 11) and liver (n =
8). All patients with grade III-IV acute GVHD responded to therapy. The cumulative incidence of
chronic GVHD was 28% (95%CI: 16-40) at 1 year. There were no statistically significant differences
in the incidence of acute or chronic GVHD between recipients engrafted with 4/6 and 5-6/6 matched
units.
For the entire group, TRM was 19% (95%CI: 9-29) at day 180. Day 180 TRM in the older patients was
relatively low at 14% (95%CI: 4-24), and in patients with extensive prior therapy was 24% (95%CI: 8-
40), and was not significantly different to the younger or less extensively pre-treated patients,
respectively. However, patients with poor fitness at transplant work-up had a significantly increased
risk of Day 180 TRM of 44% (95%CI: 20-68) as compared to an incidence of 7% (95%CI: 0-15) in
patients with satisfactory fitness (p < 0.01). Further, of these 3 factors, Cox regression analysis
demonstrated that only poor fitness had a significant impact on TRM [relative risk 8.0 (95%CI: 2.0-32)
(p < 0.01)]. Cell dose (total NC and CD34+ dose) had no impact on day 180 TRM (data not shown).
Patients engrafting with a 5-6/6 HLA-matched unit had a day 180 TRM of 12% (95%CI: 0-24%) as
compared to 21% (95%CI: 7-35%) in patients engrafting with a 4/6 unit (p = 0.46).
The incidence of relapse or disease progression was 33% (95%CI: 20-46) at both 1 and 2 years.
Regression of relapsed or persistent disease post-transplant has been seen in patients with MDS (n =
2), CML (n = 1), intermediate and low grade NHL/CLL (n = 11), Hodgkin’s lymphoma (n = 1) and


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myeloma (n = 1). This occurred either spontaneously or with the reduction in immunosuppression,
with 4 of the NHL/CLL patients also receiving additional post-transplant rituximab.
With a median follow-up of 16 months (range 4-30), the probability of overall and progression-free
survival is 52% (95%CI: 39-65) and 41% (95%CI: 28-54) at 1 year, and 44% (95%CI: 30-58) and 35%
(95%CI: 21-49) at 2 years, respectively, with no difference between single and double unit recipients.
Cell dose (total NC and CD34+ dose) had no demonstrable impact on survival (data not shown).
Patients engrafting with a 5-6/6 HLA-matched unit had a 1 year progression-free survival of 52%
(95%CI: 32-72%) as compared to 30% (95%CI: 13-47%) in patients engrafting with a 4/6 unit (p =
0.13).
2.1
Overall Summary of Rationale for Study
These results demonstrate that UCB may be successfully used as the HSC source in this setting,
extending the experience of our group[20] and others[21-24]. Notably, the Cy50/Flu200/TBI200
preparative regimen is both NMA and effective in inducing sustained donor engraftment in the
majority of patients with an incidence comparable to that of NMA in the setting of unrelated donor
HSC transplantation[16-18]. Despite the high-risk nature of this patient population, the incidence of
TRM in this study was relatively low and comparable to reports of NMA unrelated donor HSC
transplantation[16, 17, 19]. Of the patient factors dictating NMA conditioning (older age, extensive
prior therapy and poor fitness), only poor fitness was independently associated with increased TRM in
the setting of a NMA regimen. This demonstrates that UCBT after NMA conditioning is generally well
tolerated and may be safely extended to older adults who are otherwise fit. Also, while transplantation
prior to multiple treatment regimens is ideal, NMA UCBT may offer a treatment approach for some
patients who have failed multiple prior regimens or autologous transplantation.
The aim of this study is to better assess efficacy as measured by probability of 1 year survival.
For the purpose of analysis, patients will be stratified by diagnosis into one of 5 disease groups:
1. AML/secondary AML
MDS
CML CP1
CML CP2 after myeloid BC
2. ALL/Lymphoblastic lymphoma
Burkitt’s lymphoma
CML CP2 after lymphoid BC
3. large-cell B and T-cell lymphomas
mantle cell lymphoma
4. CLL/SLL
prolymphocytic leukemia
lymphoplasmacytic lymphoma
marginal zone B-cell lymphoma
follicular lymphoma
5. Hodgkin lymphoma
multiple myeloma


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In addition, analysis will by treatment arm as assigned at the time of study entry. Treatment arms will
be added as needed to accommodate changes in the preparative regimen. A list of treatment arms for
statistical purposes is found in section 4 (Patient Registration) and section 8 (Experiment Design,
Endpoints, and Statistics).
3
Patient Selection
3.1
Age, Graft Cell Dose and Graft HLA Criteria
3.1.1
Must be <70 years old with no matched 5/6 or 6/6 sibling donor - patients ≥ 70 
and ≤ 75 years of age may be eligible if they have a Co-Morbidity score ≤ 2 (Appendix 
VI)
3.1.2
UCB units will be selected according to current University of Minnesota
umbilical cord blood graft selection algorithm. One or 2 UCB units may be used to
achieve the required cell dose.
3.1.3
The UCB graft is matched at 4-6 HLA-A, B, DRB1 antigens with the recipient.
This may include 0-2 antigen mismatches at the A or B or DRB1 loci. If 2 UCB units
are required to reach the target cell dose, each unit must be a 4-6 HLA-A, B, DRB1
antigen match to each other, as well as a 4-6 antigen match to the recipient.
3.1.4
Patients co-enrolled in MT-2006-01 Phase I Study of Infusion of Umbilical
Cord Blood Derived CD25+CD4+ T-Regulatory (Treg) Cells after Non-Myeloablative
Cord\Blood Transplantation will receive grafts composed of 2 UCB units.
3.2
Disease Criteria: All diseases listed below are advanced hematologic malignancies not
curable by conventional chemotherapy. Responses to conventional treatment range from
zero to 30% but are typically short lived [25].
3.2.1
Acute Leukemias: Must be in remission by morphology (<5% blasts). Note
cytogenetic relapse or persistent disease without morphologic relapse is acceptable.
Also a small percentage of blasts that is equivocal between marrow regeneration vs.
early relapse are acceptable provided there are no associated cytogenetic markers
consistent with relapse. (refer to exclusion criteria section 3.5 for more detailed
definition).
i.
Acute myeloid leukemia: high risk CR1 (as evidenced by preceding MDS,
high risk cytogenetics such as those associated with MDS or complex
karyotype, > 2 cycles to obtain CR or erythroblastic and megakaryocytic);
second or greater CR.
ii. Acute lymphoblastic leukemia/lymphoma: high risk CR1 as evidenced by
high risk cytogenetics (e.g. t(9;22), t(1;19),t(4;11), other MLL
rearrangements, hypodiploidy or IKZF1), > 1 cycle to obtain CR or evidence
of minimal residual disease (MRD). Patients in second or greater CR are
also eligible.


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3.2.2
Burkitt’s lymphoma in CR2 or subsequent CR
3.2.3
Natural Killer cell malignancies
3.2.4
Chronic myelogenous leukemia: all types except refractory blast crisis.
Chronic phase patients must have failed or been intolerant to Gleevec
3.2.5
Myelodysplastic syndrome: any subtype including refractory anemia (RA) if
severe pancytopenia or complex cytogenetics. Blasts must be less than 5%. If
5% or more requires induction therapy pre-transplant to reduce blast count to
≤5%.
3.2.6
Large-cell lymphoma, Hodgkin lymphoma and multiple myeloma with
chemotherapy sensitive disease that has failed or patients who are ineligible for
an autologous transplant.
3.2.7
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),
marginal zone B-cell lymphoma, follicular lymphoma, which have
progressed within 12 months of achieving a partial or complete remission.
Patients who had remissions lasting > 12 months, are eligible after at least two
prior therapies. Patients with bulky disease should be considered for debulking
chemotherapy before transplant. Patients with refractory disease are eligible,
unless has bulky disease and an estimated tumor doubling time of less than one
month.
3.2.8
Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic
leukemia are eligible after initial therapy if chemotherapy sensitive.
3.2.9
Refractory leukemia or MDS. These patients may be taken to transplant in
aplasia after induction or re-induction chemotherapy or radiolabeled antibody.
These high risk patients will be analyzed separately (Arm 3).
3.2.10 Bone marrow failure syndromes, except for Fanconi Anemia
3.2.11 Myeloproliferative syndromes
Patients who have undergone an autologous transplant >12 months prior to allogeneic
transplantation and who have not received multi-agent or immunosuppressive chemotherapy
within the preceding 3 months must receive ATG as part of the preparative regimen.


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3.3
Organ Function and Performance Status Criteria (all patients)
Adequate organ function is defined as:
3.3.1
Cardiac: Absence of decompensated congestive heart failure, or uncontrolled
arrhythmia and left ventricular ejection fraction > 35%. For children that are not
able to cooperate with MUGA and echocardiography, such should be clearly
stated in the physician’s note
3.3.2
Pulmonary: DLCO > 30% predicted, and absence of O2 requirements. For
children that are not able to cooperate with PFTs, a pulse oximetry with exercise
should be attempted. If nether test can be obtained it should be clearly stated in
the physician’s note.
3.3.3
Liver: Transaminases < 5 x upper limit of normal and bilirubin < 3 x upper limit
of normal
3.3.4
Renal: Creatinine < 2.0 mg/dl (adults) and creatinine clearance > 40 ml/min
(pediatrics). Adults with a creatinine > 1.2 or a history of renal dysfunction must
have estimated creatinine clearance > 40 ml/min.
3.3.5
Adequate performance status is defined as Karnofsky score ≥ 60% (> 16 years 
of age) or Lansky score ≥ 50 (pediatrics) (Appendix II) 
3.4
Other Inclusion Criteria (all patients)
3.4.1
If recent mold infection e.g. Aspergillus - must have minimum of 30 days of
appropriate treatment before BMT and infection controlled and be cleared by
Infectious Disease.
3.4.2
Second BMT: Must be > 3 months after prior myeloablative transplant.
3.4.3
Patients must be ineligible for autologous transplantation due to prior autologous
transplant, an inadequate autologous stem cell harvest, inability to withstand a
myeloablative preparative regimen, or clinically aggressive/high risk disease.
3.4.4
Patients are eligible for transplantation if there is no evidence of progressive
disease by imaging modalities or biopsy. Persistent PET activity, though
possibly related to lymphoma, is not an exclusion criterion in the absence of CT
changes indicating progression.
3.4.5
Patients with stable disease are eligible for transplantation if the largest residual
nodal mass is < 5 cm (approximately). For patients who have responded to
preceding therapy, the largest residual mass must represent a 50% reduction and
be < 7.5 cm (approximately).


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3.5 Exclusion Criteria
3.5.1
< 70 years with an available 5-6/6 HLA-A, B, DRB1 matched sibling donor
3.5.2
Pregnancy or breastfeeding
3.5.3
Evidence of HIV infection or known HIV positive serology
3.5.4
Current active serious infection
3.5.5
Unless in post-chemotherapy and radioimmunoconjugated antibody induced
aplasia, when he/she would be eligible, patients with acute leukemia in
morphologic relapse/ persistent disease defined as > 5% blasts in normocellular
bone marrow OR any % blasts if blasts have unique morphologic markers (e.g.
Auer rods) or associated cytogenetic markers that allows morphologic relapse to
be distinguished are not eligible.
3.5.6
CML in refractory blast crisis
3.5.7
Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is
progressive on salvage therapy. Stable disease is acceptable to move forward
provided it is non-bulky.
3.5.8
Active central nervous system malignancy
4
Patient Registration
Patient consent must be signed prior to the performance of any study related procedures or
assessments.
To be eligible for registration to this study, the patient must meet each criteria listed on the
eligibility checklist based on the eligibility assessment documented in the patient’s medical record.
4.1
Registration with the University of Minnesota Clinical Trials Office (CTO)
Upon completion of the screening evaluation, eligibility checklist and obtaining
consent, the study coordinator or designee will enroll the patient into OnCore.
At the time of registration in OnCore, the treatment arm related to statistical analysis
will be recorded using the following definitions:
Arm 1 – hematologic malignancy patients who have received a previous autologous
transplant or ≥ 2 cycle of multi-agent chemotherapy within the 3 months previous to 
UCBT; fludarabine dose of 40 mg/m2/day x 5 (suspended with February 2013 revision,
except Arm 4 will continue to mirror this treatment plan)
Arm 2 - hematologic malignancy patients who have not been treated with prior
autologous transplant or ≤ 1 cycle of chemotherapy in the 3 months previous to UCBT, 


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and who should receive ATG as part of their conditioning regimen; fludarabine dose of
40 mg/m2/day x 5 (suspended with February 2013 revision)
Arm 3 - patients with refractory leukemia or lymphoma who have been rendered
aplastic either by induction chemotherapy or radioimmunoconjugated monoclonal
antibody therapy
Arm 4 – patients co-enrolling through MT2006-01, treat per Arm 1 (fludarabine dose of
40 mg/m2/day x 5)
New with the February 2013 protocol amendment using a lower fludarabine dose
as in current practice:
Arm 5 - hematologic malignancy patients who have received a previous autologous
transplant or ≥ 2 cycle of multi-agent chemotherapy within the 3 months previous to 
UCBT; fludarabine dose of 30 mg/m2/day x 5
Arm 6 - hematologic malignancy patients who have not been treated with prior
autologous transplant or ≤ 1 cycle of chemotherapy in the 3 months previous to UCBT, 
and who should receive ATG as part of their conditioning regimen; fludarabine dose of
30 mg/m2/day x 5
4.2
Patients Who Are Registered and Do Not Begin Study Treatment
If a patient is registered to the study, and is later found not able to begin the planned
study treatment, for whatever reason, the patient will be removed from study and treated
at the physician’s discretion. Study data will be collected until the time the patient is
off study. The reason for removal from study will be clearly indicated in OnCore.
5
Treatment Plan
In order to provide optimal patient care and to account for individual medical conditions, investigator
discretion may be used in the prescribing of all supportive care drug therapy (i.e. acetaminophen,
diphenhydramine, G-CSF, antimicrobials, etc.).
For chemotherapy drug information see Appendix III. For information regarding recommended total
body irradiation (TBI) see Appendix V.
5.1
Preparative Regimen
The administration of the preparative regimen will follow institutional drug and supportive care
guidelines. Dose and/or schedule adjustments consistent with the standard of care may be
made on an individual patient basis as needed for safety.


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Day
Treatment
Day -7
Begin allopurinol (Day –7 to Day 0)
Day –6
Fludarabine 30* mg/m2 IV over 1 hour
Cyclophosphamide 50 mg/kg IV over 2 hours
Day –5
Fludarabine 30* mg/m2 IV over 1 hour
Day -4
Fludarabine 30* mg/m2 IV over 1 hour
Day –3
Fludarabine 30* mg/m2 IV over 1 hour
Day –2
Fludarabine 30* mg/m2 IV over 1 hour
Day –1
TBI 200 cGy
Day 0
UCB transplant
*Administer fludarabine at 40 mg/m2 IV for patients co-enrolled on MT2006-01 or refractory
leukemia or lymphoma who have been rendered aplastic either by induction chemotherapy or
radioimmunoconjugated monoclonal antibody therapy
Fludarabine will be administered as a 1 hour infusion per institutional guidelines on day -6
through day -2. Dose adjustments will be made for adult patients with renal impairment
defined as CrCL < 70mL/minute. Fludarabine dose MAY also be reduced to this dose if there is
prior malignancy involvement of the central nervous system with intrathecal chemotherapy
and/or cranio-spinal irradiation
Cyclophosphamide will be administered as a 2 hour intravenous infusion with a high volume
fluid flush and mesna per institutional guidelines on day -6.
TBI will be administered as a single treatment on day -1 per guidelines in appendix V.
ATG - Patients who have had exposure ≤1 cycle of combination or high dose chemotherapy in 
the three months preceding transplant will also receive ATG in the preparative regimen. Also
any patient who has had only a single induction cycle for the treatment of acute leukemia or
MDS or CML blast crisis will also receive ATG during conditioning.
Patients with a prior autologous transplant in the year prior to second transplant DO NOT require
ATG.
Equine ATG (ATGAM) 15 mg/kg IV will be administered every 12 hours for 6 doses
beginning on day -6 per institutional guidelines. Methylprednisone 1 mg/kg IV will be
administered prior to each dose of ATG per institutional guidelines. Additional steroids and/or
other medications may be used as needed per the discretion of the treating physician.
5.2
Immunosuppressive Therapies
All patients will receive prophylaxis for GVHD with 2 drugs both beginning at day -3 as
follows:
5.2.1
Sirolimus
Adult Dosing: Sirolimus will be administered starting at day -3 with 8mg-12mg mg
oral loading dose followed by single dose 4 mg/day with a target serum concentration of


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3 to 12 mg/mL by high-performance liquid chromatography (HPLC) and will be
monitored per institutional guidelines. In the absence of acute GVHD sirolimus may be
tapered starting at day +100 and eliminated by day +180 post-transplantation.
Pediatric Dosing: Sirolimus will be administered starting on day -3 with an oral loading
dose of 5 mg/m2/day (Maximum daily dose of 8 mg for 1 day followed by maintenance
dosing of 2.5 mg/m2/day (Maximum total daily dose of 4mg) as per institutional
guidelines. Target serum concentration goals are 3 to 12 mg/mL by high-performance
liquid chromatography (HPLC) and will be monitored per institutional guidelines.
Due to the long and variable half life in pediatric patients, it is recommended that
sirolimus dosing changes must not be made until 3 days after a dose change or using
best clinical judgment. In the absence of acute GVHD sirolimus may be tapered
starting at day +100.
Sirolimus is available as 0.5 mg tablet, 1 mg tablet, 2 mg tablet and 1mg/ml oral
suspension. The oral tablets and oral suspension are not bio-equivalent. No IV
formulation is available.
5.2.2
Mycophenolate mofetil (MMF)
Mycophenolate mofetil (MMF) 3 gram/day IV/PO for patients who are ≥ 40 kg divided 
in 2 or 3 doses. Pediatric patient (<40 kilograms) will receive MMF at the dose of 15
mg/kg/dose every 8 hours beginning day -3. MMF dosing will be monitored and
altered as clinically appropriate based on institutional guidelines. Patients will be
eligible for MMF dosing and pharmacokinetics studies.
Stop MMF at day +30 or 7 days after engraftment, whichever day is later, if no acute
GVHD. (Definition of engraftment is 1st day of 3 consecutive days of absolute
neutrophil count [ANC) > 0.5 x 109 /L]). If no donor engraftment, do not stop MMF.
If the patient has acute GVHD requiring systemic therapy, MMF may be stopped 7 days
after initiation of systemic therapy for acute GVHD (e.g. resolution of skin rash,
vomiting, and diarrhea).
5.3
UCB Thaw and Infusion
Cord blood products are thawed and filtered (170-micron) in the Molecular and Cellular
Therapeutics (MCT) Lab using the method of Rubinstein et al.
Infusion will be per current institutional policies. The infusion of the first UCB unit
should begin within 15 minutes, and no later than 30 minutes after arrival on the Unit.
If 2 units are used, both cords will be infused within 30-60 minutes of each other as
deemed clinically safe by the BMT attending or designee.
Vital signs will be checked before and after the infusion, and one hour post infusion per
University Of Minnesota transplant guidelines. More frequent vital signs may be


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required depending on reactions to the product infusion. Notify the resident physician
immediately if patient exhibits signs or symptoms of a reaction.
5.4
Expected Toxicities and Complications
Refer to Appendix IV
5.5
Management of Slow Engraftments or Graft Failure
Patients with ANC < 1000 any time after cord infusion will be started on G-CSF
support at 5 mcg/kg (IV/SQ)(round to vial size) daily until ANC > 2500/μL for 2 
consecutive days. Once a patient has met these criteria, the ANC will be monitored and
G-CSF restarted if ANC falls to < 1000.
If no evidence of donor engraftment on the day +21 bone marrow biopsy, notify URD
search coordinator to pursue back-up UCB and arrange day +28 bone marrow biopsy
per current institutional slow engraftment guidelines.
5.6
Supportive Care
Supportive care will be provided per University Of Minnesota institutional guidelines
for transplant patients including any supportive care research protocols.
All patients will receive standard supportive transfusion care according to transfusion
committee guidelines or as modified based on clinical parameters.
Antimicrobial prophylaxis directed towards bacteria, fungi and viruses will be per
University Of Minnesota current institutional guidelines for transplant patients.


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6
Required Observations
Scheduled evaluations for days 21, 28 may be performed (+/-3 days) from the targeted date;
assessments to be performed on day 60 and 100 may be done on (+/-) 7 days of the targeted date;
assessments on day 180, 1 and 2 years may be performed (+/- 30) days of the targeted date. In
addition, targeted days may be altered as clinically appropriate.
ACTIVITY
PRE-BMT
WORK-UP
DAY 1 TO
ENGRAFTMENT*
FOLLOW-UP
DAYS 31-100
FOLLOW-UP ( >DAY
100)
Consent
X
Medical History
X
X(1)
X(2)
X(day 180, 360, 720)
Physical Exam
X
X(1)
X(2)
X(day 180, 360, 720)
Karnofsky/Lansky
X
day 100
X(day 180, 360, 720)
PFT/DLOC
X
(As clinically
indicated)
(As clinically
indicated)
(As clinically indicated)
MUGA or Echo
X
Creatinine, Na, K
HC03
X(1)
X(2)
X(day 180, 360)
CBC/diff/plt
X
X(1)
X(2)
X(day 180, 360)
PT/PTT
X
Viral Screen
X
Serum Chemistry
X
testing for anti-HLA
antibodies
X#
Urinalysis
X
Cr Cl for adults with
creat > 1.2 or hx or
renal dysfunction
X
Pregnancy test for
FOCBP
X
BM Biopsy chimerism
X (on BM or
blood)
BM (day 21)
BM (day 100)
BM (day 180, 360, 720)
Blood chimerism
Patient and
UCB
PB (day 21, 28)
PB (day 60)
GVHD Assessment
X(1)
X(2), day 100
X (day 180, 360)
EBV Assessment
(ATG patients only)
X(3)
X(3) until day 180
Chest CT
X**
Disease Evaluation
X
X(day 28)
X(day 100)
X (day 180, 360, 720)
# obtain as soon as possible once the patient is determined to be a candidate for UCB transplantation in order to guide unit
selection
* engraftment defined as absolute neutrophil count (ANC) ≥ 5 X 108/L for 3 consecutive measurements
**Patients with a history of MDS or a history of 2 or more consecutive inductions/re-inductions to treat acute leukemia or
CML blast crisis or prolonged neutropenia of at least 2 months immediately preceding transplant should have a chest CT
without contrast to exclude occult fungal infection prior to transplant.
x(1)=perform test daily or as clinically indicated
x(2)=perform test weekly or as clinically indicated
x(3)=perform test every 2 weeks or as clinically indicated


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NOTE: In certain clinical circumstances (e.g. relapse or patients terminally ill) study tests may be omitted at the physician’s
discretion).
7
Event Monitoring and Reporting
Toxicity and adverse events will be classified according to NCI's Common Terminology Criteria for
Adverse Events V 3.0 (CTCAE) and reported on the schedule below. A copy of the CTCAE can be
downloaded from the CTEP home page http://www.eortc.be/services/doc/ctc/ctcaev3.pdf
7.1
Definitions
The following definitions are based on the Code of Federal Regulations Title 21 Part
312.32 (21CFR312.32(a)).
Adverse Event: Any untoward medical occurrence associated with the use of a drug in
humans, whether or not considered drug related.
Suspected Adverse Reaction: Any adverse event for which there is a reasonable
possibility that the drug caused the adverse event.
Life-Threatening Adverse Event Or Life-Threatening Suspected Adverse
Reaction: An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the investigator or sponsor, its occurrence places
the patient or subject at immediate risk of death.
Serious Adverse Event Or Serious Suspected Adverse Reaction: An adverse event
or suspected adverse reaction is considered “serious” if, in the view of either the
investigator or sponsor, it results in any of the following outcomes:

Death

A life-threatening adverse event

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to
conduct normal life functions

A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require
hospitalization may be considered serious when, based upon appropriate medical
judgment, they may jeopardize the patient or subject and may require medical or
surgical intervention to prevent one of the outcomes listed in this definition.
Unanticipated (unexpected) problems/events as defined by the University Of
Minnesota IRB are those that are not already described as potential risks in the consent
form, not listed in the Investigator’s Brochure or not part of an underlying disease.
UPIRTSO: Federal regulations [45CFR46.103(b)(5) and 21CFR56.108(b)(1)] require
the IRB to ensure that researchers promptly report “any unanticipated problems
involving risk to subjects or others” (UPIRTSOs). The University of Minnesota IRB
defines a UPIRTSO as any problem or event which in the opinion of the local


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researcher was unanticipated, reflects new or increased risk to the subjects and at least
possibly related to the research procedures.
In addition, the IRB has defined the following problems/events as reportable within 10
working days using the UPRITSO form found on the IRB website:

Any accidental or unintentional change to the IRB-approved protocol that increases
risk or has the potential to recur

Any deviation from the protocol taken without prior IRB review to eliminate
apparent immediate hazard to a research subject

Any publication in the literature, safety monitoring report (including Data and
Safety Monitoring Reports), interim result or other finding that indicates an
unexpected change to the risk/benefit ratio of the research

Any breach in confidentiality that may involve risk to the subject or others

Any complaint of a subject that cannot be resolved by the research staff

Any other possibly related event which in the opinion of the investigator constitutes
an unanticipated risk
Expedited (Rapid) Reporting: Certain events may require rapid notification to entities
providing patient safety oversight (e.g. IRB) as detailed in section 7.2. For the IRB this
is 10 working days.
7.2
Adverse Event Monitoring
All subjects will be monitored from the initiation of any study treatment through day
100 as it is expected that most serious adverse events will occur during this period.
After day 100, monitoring for serious adverse events will become less frequent based on
the schedule in section 6.0. However, the investigator is obligated, upon knowledge of,
to report any adverse event according to the schedule in section 7.3.
7.3
Required Reporting
The reporting period for this study is from the first dose of fludarabine through day
+100; however after day +100, the investigator must report upon knowledge any event
meeting the expedited reporting criteria below.
Agency
Criteria for reporting
Timeframe
Form to Use
Submission address/ fax
numbers
Copy AE to:
U of MN
IRB
UPIRTSO: any event which is
unanticipated, involved new or
increased risk to subjects, and was at
least possibly related to study
procedures
10 Working
Days
UMCC SAE
University Of Minnesota
IRB
MMC 820
Masonic Cancer Center SAE
Coordinator
mcc-saes@umn.edu
Other Problems or Events meeting
the definition of UPIRTSO in
section 7.1
UPIRTSO
form
MCC SAE
Coordinator
Any event meeting an early study
stopping rule per section 8.9
at time of
reporting
Early Study
Stopping Rule
Form
SAE Coordinator
mcc-saes@umn.edu
Not applicable


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The SAE Coordinator will provide the Cancer Center’s Data and Safety Monitoring
Council (DSMC) with the SAE in an appropriate format depending on the individual
SAE (as reported or in a summary format).
FOR UNLICENSED UCB UNITS ONLY: Selected expected adverse reactions
determined to be caused by or at least possibly caused by the UCB unit based on
objective evidence will be reported in an expedited manner to the FDA under
University of Minnesota IND BB-14797 (C. Brunstein, MD, PhD –
sponsor/investigator).
8
Experimental Design, Endpoints and Statistics
8.1
Primary clinical endpoint: Probability of one year survival
The principal objective of this study is to determine an estimate of one year survival among the
hematologic malignancy patients. Whereas the previous study was meant to ensure safety this
study will be used to establish more precise estimates of survival both for the group as a whole
and for patients within certain disease groups. The group of patients with refractory acute
leukemia in chemotherapy induced aplasia has not yet been tested with this regimen. The
primary objective for this third group will simply be to ensure safety through the assessment of
non-relapse mortality.
8.2
Secondary Endpoints
8.2.1
Probability of two year survival
8.2.2
One year and two year survival within

Acute myelogenous leukemia, myelodysplastic syndrome, chronic myelogenous
leukemia (CML) in first (CP1) and second chronic phase (CP2) after myeloid blast
crisis

Acute lymphoblastic leukemia, CML CP2 post lymphoid blast crisis, lymphobalstic
lymphoma, Burkitt’s and Burkitt’s like lymphoma

Large cell B and T cell lymphomas, mantle cell lymphoma

Chronic lymphocytic leukemia/small lymphocytic lymphoma, marginal zone B-cell
lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, mantle-cell
lymphoma, prolymphocytic leukemia

Hodgkin lymphoma and multiple myeloma
8.2.3
Incidence of six month non-relapse mortality
8.2.4
Chimerism values at days 21, 60, 100, 180 and 365
8.2.5
Incidence of day 42 Neutrophil Engraftment
8.2.6
Incidence of six month Platelet Engraftment


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8.2.7
Incidence of day 100 Acute GvHD and one year extensive Chronic GvHD
8.2.8
Probability of one and two year Progression-Free survival
8.2.9
Incidence of one and two year relapse
8.3
Statistical Analyses
This study will be separated into treatment arms for the purposes of analysis, with arms added
as needed to accommodate changes in the preparative regimen:
Arm1 – Hematologic malignancy patients that do not receive ATG as part of their conditioning
regimen (fludarabine dose of 40 mg/m2/day x 5).
Arm2 – Hematologic malignancy patients who do receive ATG as part of their conditioning
regimen (fludarabine dose of 40 mg/m2/day x 5).
Arm3 – Aplastic leukemia patients who are considered high risk
Arm4 – co-enrolled with MT2006-01 – treat according to Arm1 (fludarabine dose of 40
mg/m2/day x 5).
Added with the February 2013 revision:
Arm5 – Hematologic malignancy patients that do not receive ATG as part of their conditioning
regimen (fludarabine dose of 30 mg/m2/day x 5).
Arm6 – Hematologic malignancy patients who do receive ATG as part of their conditioning
regimen (fludarabine dose of 30 mg/m2/day x 5).
Survival and progression-free survival will be estimated by the Kaplan-Meier method. Non-
relapse mortality, relapse, neutrophil and platelet engraftment, acute and chronic GVHD will be
estimated by cumulative incidence using competing risk methods. 95% confidence intervals
will be used to make inferences on survival both overall as well as in the disease specific
categories. Comparisons of endpoints by various factors will be completed by the Log-rank
test.
8.4
Rationale for Sample Size
In order to achieve a precise estimate of the probability of survival at one year post transplant
we would like to have an estimate of survival with a 95% confidence interval that has a band
width of less than 0.15. We expect to enroll approximately 290 patients on arms 1, 2, 5 and 6 of
the study. Assuming that the proportion surviving at one year is 50%, the 95% confidence
interval should have a band width of approximately 0.12. This is assuming that there are no
patients lost to follow-up and that all patients have been followed for at least one year post
transplant at the time of analysis. Twenty and ten patients are expected to be enrolled on arms 4
and 3 respectively of the study. The total enrollment will therefore be approximately 320
patients.
For all arms of the study, the disease distribution is estimated as follows:

Fifty percent of patients with acute myelogenous leukemia, myelodysplastic syndrome,
chronic myelogenous leukemia (CML) in first (CP1) and second chronic phase (CP2)
after myeloid blast crisis


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
Eight percent of patients with Acute lymphoblastic leukemia, CML CP2 post lymphoid
blast crisis, lymphoblastic lymphoma, Burkitt’s and Burkitt’s like lymphoma

Seventeen percent of patients with large cell B and T cell lymphomas, mantle cell
lymphoma

Seventeen percent of patients with Chronic lymphocytic leukemia/small lymphocytic
lymphoma, marginal zone B-cell lymphoma, follicular lymphoma, lymphoplasmacytic
lymphoma, mantle-cell lymphoma, prolymphocytic leukemia

Eight percent of patients with Hodgkin’s lymphoma and multiple myeloma
Given these sample sizes, we can expect to get estimates of one year survival in the disease
specific groups with 95% confidence bands of widths 0.39, 0.28 and 0.16 for the group sizes of
25, 50 and 150, respectively.
8.5
Engraftment and Chimerism Evaluation
Hematopoietic recovery and engraftment will be evaluated with peripheral blood counts AND
chimerism studies in peripheral blood and bone marrow.
1)
Engraftment/hematopoietic recovery

Time to 1st 3 consecutive days with ANC > 5 x 108/L and percentage of patients with
neutrophil recovery by day 42 (Cumulative incidence)

Time to platelets > 20,000 (first of 3 consecutive days) with no platelet transfusions for
seven days and percentage of patients with platelet engraftment >50,000 by day 100.

Time to RBC independence (Hb > 9gms and no transfusions for 30 days)
2)
Chimerism

Chimerism studies will be performed on the blood and bone marrow. BM chimerism
days 21 and 100, at 6 months and 1 year (see table) to determine the relative
contribution of donor and recipient hematopoiesis. If the patient's peripheral blood
counts are slow to recover, ANC <5 x 108/L by day 28, or the peripheral blood counts
drop below <1.0 x 108/L after an initial recovery, the peripheral blood and bone marrow
will be evaluated at that time unless a cause has been determined (e.g., use of
Gamciclovir for treatment of CMV).

Patients diagnosed with failure of count recovery by day 42 should be reported to the
University of Minnesota Clinical Trials Office and BMT Database.
8.6
GVHD Evaluation
Patients will be staged weekly between days 0 and 100 after transplantation using standard
criteria. Patients will be assigned an overall GVHD score based on extent of skin rash, volume
of diarrhea and maximum bilirubin level. Incidence of grades II-IV and grades III-IV GVHD
by day 100 will be monitored. Patients will be rescored on day 180 and at 1 year with
additional scores as events occur.
8.7
Relapse of Disease
This will be documented at days 30, 100, 180, 360 and 720 and as clinically indicated. Patients
with leukemia and lymphoma involving the BM and multiple myeloma will have this done by
BM biopsy and additional special studies such as cytogenetics or flow cytometry as


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appropriate. Patients with lymphoma and myeloma will have radiology studies such as plain X-
rays or CT scans and/or other studies such as blood tumor markers to document presence or
absence of disease as clinically indicated.
8.8
Death Post Transplant
As the stopping rule for Arm 3 is based on non-relapse mortality up to Day 100, a death not due
to relapse prior to Day 100 must be reported to the BMT data base and the Biostatistics Team
for the appropriate review and reporting.
8.9
Monitoring Boundaries
8.9.1. Monitoring Boundaries Arm 2 with Sirolimus/MMF as GVHD prophylaxis
Monitoring guidelines for grade III-IV acute gvhd in the gvhd prophylaxis arm (Sirolimus/MMF)
were developed using the sequential probability ratio test with the level of significance and power
preset at 5% and 80% respectively.
Day 100 grade III-IV AGvHD for arm 2 (Sirolimus/MMF): Given a hypothesized gvhd rate of
20%, a maximum tolerated level of 40%, and a maximum monitoring size of 100 patients, the trial
will be halted and reviewed if 4 events occur within the first 4 patients, 5 in the first 7, 6 in the first
10, 7 in the first 14, 8 in the first 17, 9 in the first 21, 10 in the first 24, 11 in the first 27 or 12/31,
13/34, 14/38, 15/41, 16/44, 17/48, 18/51, 19/55, 20/58, 21/61, 22/65, 23/68, 24/72, 25/75, 26/79,
27/82, 28/85, 29/89, 30/92, 31/96 or 32/99.
8.9.2 Arm 3 Monitoring Guidelines for Non-Relapse Mortality
Monitoring guidelines for non-relapse mortality in arm 3 were developed using the sequential
probability ratio test with the level of significance and power preset at 5% and 80%
respectively.
Day 100 non-relapse mortality for arm 3
Given a hypothesized non-relapse mortality rate of 30%, a maximum tolerated level of 50%,
and a sample size of 20 patients, the trial will be halted and reviewed if 5 deaths occur within
the first 5 patients, 6 in the first 7, 7 in the first 9, 8 in the first 11, 9 in the first 14, 10 in the
first 16 or 11 in the first 19.
Because arms 1 and 2 have already been evaluated in a safety study, safety parameters such
non-relapse mortality and graft failure for these two arms will be evaluated in a summary
format on an annual basis by the study statistician and principal investigator.
8.9.3 Monitoring Guidelines For Primary Graft Failure At Day 42 Arms 5 And 6
Guidelines were developed separately using the sequential probability ratio test with the level
of significance and power preset at 5% and 80% respectively.
Day 42 primary graft failure
Given a hypothesized non-relapse mortality rate of 8%, a maximum tolerated level of 15%, and
a maximum sample size of 100 patients, the trial will be halted and reviewed if in either arm


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there are 5 graft failures in the first 9 patients, 6/18, 7/27, 8/36, 9/45, 10/54, 11/63, 12/72,
13/81, 14/90 or 15/99.
Because arms 1 and 2 have already been evaluated in a safety study, safety parameters such
non-relapse mortality and graft failure for these two arms will be evaluated in a summary
format on an annual basis by the study statistician and principal investigator.
8.10
Data Management
The University of Minnesota database collection staff will perform basic data management
functions associated with the study. Patient, transplant characteristics, adverse events and
disease endpoints will be verified and dual entered into the BMT Clinical Database. Computer
edit checks will be used to ensure that the data are logical and consistent. Data will be analyzed
and reported by SASTM software.
8.11
Data Collection
Standard pre- and post-transplant data will be recorded on the BMT research database,
including the occurrence of toxicity and chimerism evaluations at day 100. Patients will be
followed for relapse and death according to standard procedures. All patients will be followed
beyond the conclusion of the study per standard procedure at the University of Minnesota.
8.12
Record Retention
The investigator will retain study records in a secure facility, including source data, and all
study correspondence for at least 6 years after the study file is closed with the IRB. In addition,
the Clinical Trials Office may keep a master log of all reported and registered patients
participating in the study which may provide sufficient information to allow retrieval of the
medical records.
9
Ethical and Regulatory Considerations
9.1
Ethical Considerations
Patients are referred to the University of Minnesota Medical Center, Fairview for consideration
of hematopoietic cell transplantation. While there will be every effort to seek out and include
women and minority patients, the patient population is dependent upon the referral pattern and
the ability to identify suitable UCB donors. Women and minority patients are eligible for all
aspects of the study and their participation will be actively encouraged.
9.2
Patient Consent
The principles of informed consent described in FDA Regulations (21 CFR Part 50) will be
followed to comply with Food and Drug Administration regulations. A patient will give written
consent prior to study participation. The original consent will be retained by the investigator as
part of the study records. A copy of the consent form will be given to the patient.


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Once a potentially eligible patient and donor graft have been identified, the patient will be fully
evaluated by a physician who subsequently outlines the course of therapy. Assuming the patient
meets the medical requirements for undergoing the transplant procedure, the patient will then
be admitted to the inpatient unit where the course of therapy will again be reviewed. The risks
of the procedures to the patient will be discussed in detail. The purpose and plan of the study,
including the potential risks and benefits, will be presented as objectively as possible.
9.3
Institutional Board Review (IRB)
Before the initiation of this study, this protocol will have been reviewed and approved by the
University of Minnesota Human Subjects Committee, as defined by FDA regulations (21 CFR
Part 56).
IRB approval of any future modifications of the protocol or consent form for this study will be
given in writing.
9.4
Data Safety Monitoring
This study’s Data and Safety Monitoring Plan will be in compliance with the University of
Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan, which can be accessed at
http://www.cancer.umn.edu/exfiles/research/dandsmplan.pdf
For the purposes of data and safety monitoring, this study is classified as moderate risk (phase
II). Therefore the following requirements will be fulfilled:

The PI will complete and submit a twice yearly Trial Progress Report to the Masonic
Cancer Center Data and Safety Monitoring Council (DSMC) with the understanding more
frequent reporting may be required by the Cancer Protocol Review Committee.

The PI will comply with at least twice yearly monitoring of the project by the Masonic
Cancer Center monitoring services.

The PI will oversee the reporting of all adverse events meeting the definition of reportable
in section 7.3 to the University Of Minnesota IRB and the Masonic Cancer Center SAE
Coordinator.
In addition, at the time of the continuing review with the University Of Minnesota IRB, a copy
of the report will be submitted to the Cancer Protocol Review Committee (CPRC).
10 References
1.
Kurtzberg, J., M. Laughlin, M.L. Graham, et al., Placental blood as a source of hematopoietic
stem cells for transplantation into unrelated recipients. N Engl J Med, 1996. 335(3): 157-66.
2.
Gluckman, E., V. Rocha, A. Boyer-Chammard, et al., Outcome of cord-blood transplantation
from related and unrelated donors. Eurocord Transplant Group and the European Blood and
Marrow Transplantation Group. N Engl J Med, 1997. 337(6): 373-81.
3.
Rubinstein, P., C. Carrier, A. Scaradavou, et al., Outcomes among 562 recipients of placental-
blood transplants from unrelated donors. N Engl J Med, 1998. 339(22): 1565-1577.


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4.
Rubinstein, P., J. Kurtzberg, F. Loberiza, et al., Comparison of Unrelated Cord Blood and
Unrelated Bone Marrow Transplants for Leukemia in Children: A Collaborative Study of the
New York Blood Center and the International Bone Marrow Transplant Registry. Blood, 2001.
98: 814a.
5.
Wagner, J.E., J.N. Barker, T.E. DeFor, 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(5):
1611-8.
6.
Barker, J.N., T.P. Krepski, T.E. DeFor, et al., Searching for Unrelated Donor Hematopoietic
Stem Cells: Availability and Speed of Umbilical Cord Blood versus Bone Marrow. Biol Blood
Marrow Transplant, 2002. 8: 257-260.
7.
Laughlin, M.J., J. Barker, B. Bambach, et al., Hematopoietic engraftment and survival in adult
recipients of umbilical-cord blood from unrelated donors. N Engl J Med, 2001. 344(24): 1815-
22.
8.
Laughlin, M.J., M. Eapen, P. Rubinstein, et al., Outcomes after transplantation of cord blood
or bone marrow from unrelated donors in adults with leukemia. N Engl J Med, 2004. 351(22):
2265-75.
9.
Long, G.D., M. Laughlin, B. Madan, et al., Unrelated umbilical cord blood transplantation in
adult patients. Biol Blood Marrow Transplant, 2003. 9(12): 772-80.
10.
Barker, J.N., D.J. Weisdorf, T.E. DeFor, et al., Transplantation of Two Partially HLA-Matched
Umbilical Cord Blood Units To Enhance Engraftment in Adults with Hematologic Malignancy.
Blood, 2005. 105: 1343-1347.
11.
Giralt, S., E. Estey, M. Albitar, et al., Engraftment of allogeneic hematopoietic progenitor cells
with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without
myeloablative therapy. Blood, 1997. 89(12): 4531-6.
12.
Slavin, S., Nagler, A., Naparstek, E., et al, Nonmyeloablative Stem Cell Transplantation and
Cell Therapy as an Alternative to Conventional Bone Marrow Transplantation with Lethal
Cytoreduction for the Treatment of Malignant and Nonmalignant Hematologic Diseases.
Blood, 1998. 91(3): 756-763.
13.
Childs, R.e.a., Engraftment Kinetics after Nonmyeloablative Allogeneic Peripheral Blood Stem
Cell Transplantation: Full Donor T-Cell Chimerism Precedes Alloimmune Responses. Blood,
1999. 94(9): 3234-3241.
14.
Giralt, S., P.F. Thall, I. Khouri, et al., Melphalan and purine analog-containing preparative
regimens: reduced-intensity conditioning for patients with hematologic malignancies
undergoing allogeneic progenitor cell transplantation. Blood, 2001. 97(3): 631-7.
15.
McSweeney, P.A., D. Niederwieser, J.A. Shizuru, et al., Hematopoietic cell transplantation in
older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with
graft-versus-tumor effects. Blood, 2001. 97(11): 3390-400.
16.
Chakraverty, R., K. Peggs, R. Chopra, et al., Limiting transplantation-related mortality
following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning
regimen. Blood, 2002. 99(3): 1071-8.
17.
Niederwieser, D., M. Maris, J.A. Shizuru, et al., Low-dose total body irradiation (TBI) and
fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or
mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and
mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained
remissions in patients with hematological diseases. Blood, 2003. 101(4): 1620-9.


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18.
Maris, M.B., D. Niederwieser, B.M. Sandmaier, et al., HLA-matched unrelated donor
hematopoietic cell transplantation after nonmyeloablative conditioning for patients with
hematologic malignancies. Blood, 2003. 102(6): 2021-30.
19.
Giralt, S., B. Logan, M. Zhang, et al., Non-Ablative or Reduced Intensity Conditioning
Regimens With Volunteer Unrelated Donor Progenitor Cell Transplantation: An Analysis from
the Center for International Blood and Marrow Transplant Research Sergio Giralt,1, Brent
Logan,1*, Mei-Jie Zhang,1*, Olivia McGaha,1*, Karen Ballen,1, Christos Emmanouilides,1,
Rajneesh Nath,1*, Pablo Parker,1, David Porter,1, Brenda Sandmaier,1, Edmund Waller,1,
Juliet Barker,1, Steven Pavletic,1, and Daniel Weisdorf,1. Blood, 2004.
20.
Barker, J.N., D.J. Weisdorf, T.E. DeFor, et al., Rapid and complete donor chimerism in adult
recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity
conditioning. Blood, 2003. 102(5): 1915-1919.
21.
Rizzieri, D.A., G.D. Long, J.J. Vredenburgh, et al., Successful allogeneic engraftment of
mismatched unrelated cord blood following a nonmyeloablative preparative regimen. Blood,
2001. 98(12): 3486-8.
22.
Chao, N.J., C.X. Liu, B. Rooney, et al., Nonmyeloablative regimen preserves "niches" allowing
for peripheral expansion of donor T-cells. Biol Blood Marrow Transplant, 2002. 8(5): 249-256.
23.
Del Toro, G., P. Satwani, L. Harrison, et al., A pilot study of reduced intensity conditioning and
allogeneic stem cell transplantation from unrelated cord blood and matched family donors in
children and adolescent recipients. Bone Marrow Transplant, 2004. 33(6): 613-22.
24.
Miyakoshi, S., K. Yuji, M. Kami, et al., Successful engraftment after reduced-intensity
umbilical cord blood transplantation for adult patients with advanced hematological diseases.
Clin Cancer Res, 2004. 10(11): 3586-92.
25.
Hoffman, R., E.J. Benz, S.J. Shattil, et al., Hematology, Basic Principles and Practice. Fourth
ed. 2005, Philadelphia: Elservier - Churchill Livingstone.


Appendix I: Eligibility Checklist
MT2005-02 TRANSPLANTATION OF UNRELATED DONOR UMBILICAL CORD BLOOD IN PATIENTS WITH
HEMATOLOGICAL MALIGNANCIES USING A NON-MYELOABLATIVE PREPARATIVE REGIMEN
Eligibility Checklist – Page 29 of 39
Patient initials
Patient ID
1st 2 initials of first name + 1st 2 initials of last name
OnCore Sequence #
INCLUSION CRITERIA (answers must be yes):
Yes
No
1.
Subjects must be <70 years old.  (Subjects ages ≥ 70 and ≤ 75 may be eligible if they have a HCT-CI 
score ≤ 2)     Age 
HCT-CI score, if applicable
2.
Adequately matched UCB unit(s) selected according to the current U of MN cord blood selection
algorithm to achieve the required cell dose. Patients co-enrolled in MT-2006-01 will receive grafts
composed of 2 UCB units
3.
One of the following advanced hematologic malignancies not curable by conventional chemotherapy
(refer to section 3.2 of the protocol for disease specific eligibility requirements)
acute leukemias
Burkitt’s lymphoma in CR2 or subsequent CR
Natural Killer cell malignancies
Chronic myelogenous leukemia
Myelodysplastic syndrome
Large-cell lymphoma, Hodgkin lymphoma and multiple myeloma
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell
lymphoma, follicular lymphoma
Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia
Patients who have undergone an autologous transplant >12 months prior to allogeneic
transplantation
Refractory leukemia or MDS
Bone marrow failure syndromes (except FA)
Myeloproliferative syndromes
4.
Adequate organ function is defined as:
Organ system
requirement
value
date
cardiac
Absence of decompensated congestive
heart failure, or uncontrolled arrhythmia and
left ventricular ejection fraction > 35% - if
uncooperative child, document eligibility
%
/
/
pulmonary
DLCO > 30% predicted and absence of O2
requirements. For children not able to
cooperate with PFTs, a pulse oximetry with
exercise should be attempted
%
/
/
hepatic
Transaminases < 5 x upper limit of normal
and bilirubin < 3 x upper limit of normal
.
/
/
renal
Creatinine < 2.0 mg/dl (adults) and
creatinine clearance > 40 ml/min (pediatrics)
Adults with a creat > 1.2 or a history of
renal dysfunction must have estimated crcl
> 40 ml/min
.
mg/dl
or
.
ml/mn
/
/


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MT2005-02 TRANSPLANTATION OF UNRELATED DONOR UMBILICAL CORD BLOOD IN PATIENTS WITH
HEMATOLOGICAL MALIGNANCIES USING A NON-MYELOABLATIVE PREPARATIVE REGIMEN
Eligibility Checklist – Page 30 of 39
Patient initials
INCLUSION CRITERIA (answers must be yes):
EXCLUSION CRITERIA
(answers must be NO):
Yes
No
10.
Have an available 5-6/6 HLA-A, B, DRB1 matched sibling donor
11.
Pregnancy or breastfeeding
12.
Evidence of HIV infection or known HIV positive serology
13.
Active serious infection
14.
Acute leukemia in morphologic relapse/ persistent disease defined as > 5% blasts in normocellular
bone marrow OR any % blasts if blasts have unique morphologic markers (e.g. Auer rods) or
associated cytogenetic markers that allows morphologic relapse to be distinguished ( Unless on Arm
3)
15.
CML in refractory blast crisis
16.
Active central nervous system malignancy
Yes
No
5.
Karnofsky score > 60 or Lansky score 50% (pediatrics)
PS -
6.
If recent mold infection e.g. Aspergillus - must have minimum of 30 days of appropriate treatment
before BMT and infection controlled and be cleared by ID
- n/a, check yes
7.
Second BMT: Must be > 3 months after prior myeloablative transplant
- n/a, check yes
8.
Ineligible for autologous transplantation (due to prior autologous transplant, an inadequate
autologous stem cell harvest, inability to withstand a myeloablative preparative regimen, or
clinically aggressive/high risk disease).
9.
Patients with Lymphoma : have
*must have no evidence of progressive disease by imaging modalities or biopsy .
*Or persistent PET activity, in the absence of CT changes indicating progression
* patients with stable disease if the largest residual nodal mass is < 5 cm.
* Responsive disease with the largest residual mass having 50% reduction and be < 7.5 cm


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MT2005-02 TRANSPLANTATION OF UNRELATED DONOR UMBILICAL CORD BLOOD IN PATIENTS WITH
HEMATOLOGICAL MALIGNANCIES USING A NON-MYELOABLATIVE PREPARATIVE REGIMEN
Eligibility Checklist – Page 31 of 39
Patient initials
Please indicate which treatment ARM patient will be placed on.
Arm 3: For patients with refractory leukemia or lymphoma who have been rendered aplastic either by
induction chemotherapy or radioimmunoconjugated monoclonal antibody therapy.
Cy 50mg/kg, FLU 40 mg/m2, TBI 200
Arm 4: TReg only
Cy 50mg/kg, FLU 40 mg/m2, TBI 200
Arm 5: NO ATG For patients with hematologic malignancy patients who have received a previous
autologous transplant or ≥ 2 cycle of multi-agent chemotherapy within the 3 months previous to UCBT  
Cy 50mg/kg, FLU 30 mg/m2, TBI 200
Arm 6: ATG For patients who have NOT been treated with prior autologous transplant or < 1 cycle of
chemotherapy in the 3 months previous to UCBT.
Cy 50mg/kg, FLU 30 mg/m2, TBI 200
Date consent form signed:
Having obtained consent and reviewed each of the inclusion/exclusion criteria, I verify that this patient is:
Eligible
Ineligible
Date registered
Signature of person verifying eligibility
Date


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Appendix II: Karnofsky and Lansky Performance Status Scale
Karnofsky Performance Status Scale
Percentage
100
Normal, no complaints, no evidence of disease
90
Able to carry on normal activity; minor signs or symptoms of disease
80
Normal activity with effort; some signs or symptoms of disease
70
Cares for self; unable to carry on normal activity or do active work
60
Requires occasional assistance, but is able to care for most of his/her needs
50
Requires considerable assistance and frequent medical care
40
Disabled; requires special care and assistance
30
Severely disabled, hospitalization indicated. Death not imminent
20
Very sick, hospitalization necessary, active supportive treatment necessary
10
Moribund, fatal processes, progressing rapidly
0
Dead
________________________
REFERENCE
Karnofsky DA: Meaningful clinical classification of therapeutic responses to anti-cancer drugs. Editorial: Clin
Pharmacol Ther 2:709-712, 1961.
LANSKY PLAY PERFORMANCE STATUS SCALE
Percentage
100
Fully active, normal
90
Minor restrictions in physically strenuous activity
80
Active, but tires more quickly
70
Both greater restriction of, and less time spent in, play activities
60
Up and around, but minimal active play; keeps busy with quieter activities
50
Gets dressed but lies around much of the day, no active play; able to participate in all
quiet play and activities
40
Mostly in bed; participates in quiet activities
30
In bed; needs assistance even for quiet play
20
Often sleeping; play entirely limited to very passive activities
10
Unresponsive
0
Dead


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Appendix III: Chemotherapy Drug Information
Fludarabine (Fludara- Berlex) (F-Ara-A, fludarabine phosphate)
Formulation: Vials (lyophilized solid cake): 50 mg (25 mg/ml after reconstitution)
Storage: Between 2 and 8° centigrade (36 and 46 F)
Mixing: Adding 2 mL of sterile water for injection to the 50 mg vial, producing a solution containing 25 mg/mL (the solid
cake should fully dissolve within 15 seconds). Solutions may be further diluted in 100 or 125ml of 5% dextrose injection
or 0.9% sodium chloride injections for administration by intravenous infusion.
Stability: Once diluted, solutions should be promptly administered or stored in the refrigerator for no more than 8 hours
prior to administration.
Administration: Fludarabine is administered over a 1-hour period.
Cyclophosphamide. Cyclophosphamide is a nitrogen mustard-derivative, polyfunctional alkylating agent.
Cyclophosphamide for injection is commercially available as a sterile solution in sodium chloride or as a powder that is
reconstituted in sterile or bacteriostatic water. Institutional guidelines for handling, reconstitution and administration
should be followed. Cyclophosphamide can cause temporary hair loss, nausea, vomiting, diarrhea, and lowering of the
blood cell counts. Anti-emetics should minimize nausea and vomiting.
Formulation: parenteral 100 mg and 500 mg vials. Commercially available.
Storage: room temperature.
Mixing: i.v. drug should be mixed with sterile water for i.v. Use. Dissolves very slowly with cold water. It helps to
warm the water or to warm the vial after adding water.
Stability: i.v. Solution should be used within 12 hours of mixing.
Administration: cyclophosphamide is added to D5w and administered i.v.
Mycophenolate mofetil (cellcept®)
formulation: vials - 500 mg powder for iv injection, capsule - 250 mg blue-brown, two-piece hard gelatin capsule.
Mixing: each vial of lyophilized mycophenolate mofetil powder should be reconstituted by adding 14 ml of 5% dextrose
for injection. Once powder is dissolved, a vial should be further diluted to a final concentration of 6 mg/ml. Available in
500 mg vials.
Stability: once diluted, iv solutions should be promptly administered and stored at 25ºc for no more than 4 hours after
reconstitution.
Administration: iv mycophenolate is administered over a 2-hour period at a constant rate.
Equine ATG (atgam®) thymoglobulin (genzyme) is a purified pasteurized, gamma immune
Globulin obtained by immunization of rabbits with human thymocytes. This immunosuppressive product contains cytoxic
antibodies directed against antigens expressed on human t-lymphocytes. Institutional guidelines for handling,
reconstitution and administration should be followed.
Formulation: intravenous lyophilized powder
Storage: store in refrigerator between +2 degrees c to +8 degrees c, protect from light, do not freeze.
Mixing: 5-ml sterile water for injection as diluent.
Stability: should be used within 4 hours of reconstitution if kept at room temperature.
Administration: infusion - deliver dose over a minimum of six hours for the first dose, and over at least 4 hours for
subsequent doses.


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Appendix IV: Expected Treatment Related Toxicity
Cyclophosphamide
Common
Occurs in 21-100 people out of
every 100
Less Frequent
Occurs in 5-20 people out
of every100
Uncommon
Occurs in <5 people out of every 100
nausea/vomiting
mucositis
sterility
severe suppression of
blood counts
diarrhea
fluid weight gain/edema
alopecia
hemorrhagic cystitis
cardiomyopathy
skin rash
SIADH (Syndrome of Inappropriate Anti-
diuretic Hormone)
Fludarabine
Common
Occurs in 21-100 people out of
every 100
Less Frequent
Occurs in 5-20 people out
of every100
Uncommon
Occurs in <5 people out of every 100
severe suppression of
blood counts
diarrhea
anorexia
mucositis
nausea/vomiting
stomatitis
osteoporosis
dysuria
chills
fever
GI bleeding
peripheral edema
neurotoxicity
agitation and confusion
blurred vision
peripheral neuropathy
hearing loss
headache
cerebellar syndrome
blindness
coma
weakness
depression
insomnia
hemorrhagic cystitis (except in FA)
abnormal renal function test
autoimmune hemolytic anemia
deep venous thrombosis
aneurysms
pruritic skin rash
abnormal liver function/liver failure
constipation
transient ischemic attack
dysphagia
myalgia
arthralgia
renal failure


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Total Body Irradiation (TBI) (arms 1 and 3)
Common
Occurs in 21-100 people out of
every 100
Less Frequent
Occurs in 5-20 people out
of every100
Uncommon
Occurs in <5 people out of every 100
nausea and vomiting
diarrhea
cataracts
sterility
endocrinopathies
growth failure
intestinal cramps
mucositis
parotitis
interstitial pneumonitis
generalized mild erythema
veno-occlusive disease
dysphagia
vertebral deformities
nephropathy
risk of 2nd malignancy years later (when
given along with chemotherapy)
Anti-Thymocyte globulin (ATG) (arm 2 only)
Common
Occurs in 21-100 people
out of 100
Less Frequent
Occurs in 5-20 people out of every
100
Uncommon
Occurs in <5 people out of every
100
fever
chills
leukopenia
pain
headache
abdominal pain
diarrhea
hypertension
nausea
thrombocytopenia
peripheral edema
dyspnea
asthenia
hyperkalemia
tachycardia
malaise
dizziness
severe allergic reaction
(anaphylaxis)
Toxicities potentially associated with the UCB graft:
Potential toxicities associated with the infusion include DMSO toxicity and side effects from red cells. DMSO toxicity
and side effect of red cells may include changes in heart rate or rhythm, changes in blood pressure, fever, chills, sweats,
nausea/vomiting, diarrhea, abdominal cramping, headache, allergic reaction, presence of DMSO taste and odor,
hemoglobinuria, and acute renal failure. Due to the washing and processing steps, these toxicities are unlikely.
Risks of the Immunosuppressive Therapies:
Mycophenolate mofetil (MMF) can cause nausea and vomiting, diarrhea or constipation, a lowering of blood counts, leg
cramps, skin rash, difficulty sleeping, chemical imbalances including high blood sugar, headaches, dizziness and high
blood pressure.
Sirolimus adverse reactions
Most side-effects of sirolimus occur with prolonged use, especially when used in combination with CNIs like
tacrolimus and cyclosporine. Sirolimus alone is not associated with neurotoxicity or nephrotoxicity because of
its inability to inhibit calcineurin. Adverse reactions that resulted in rates of sirolimus discontinuation > 5%
were increased creatinine, hypertriglyceridemia and thrombotic thrombocytopenic purpura.


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CPRC#2005LS036
Sirolimus Adverse Events
Common
>20%
Occasional
5-20%
Rare
<5%
Immediate
Within 1-2 days of
receiving drug
Headache (L),
hypertension (L), nausea,
diarrhea, immuno-
suppression (L), fever,
constipation
Chest pain, insomnia,
dyspepsia, vomiting, dyspnea
Hypotension, asthma, increased
cough, flu like syndrome,
tachycardia, anorexia,
hypersensitivity reactions
(exfoliative dermatitis,
angioedema)
Prompt
Within 2-3 weeks,
prior to the next
course
Tremor (L), renal
dysfunction, elevated
creatinine/BUN, anemia,
pain (abdominal, back,
pain), hyperlipidemia,
hypercholesteremia,
hypertrigylceridemia,
hyperglycemia, peripheral
edema, weight gain,
arthralgia
Elevated LFTs (with elevated
sirolimus levels), stomatitis,
urinary tract infections, URIs,
mild thrombocytopenia,
leukopenia,
hyper/hypokalemia (L),
hypophosphatemia, rash,
hives, pruritis, delayed
wound healing or dehiscence
(L), hypomagnesaemia (L),
proteinuria
Opportunistic infections, pleural
and pericardial effusions, non-
infectious pneumonitis or
bronchiolitis-obliterans
organizing pneumonia and
pulmonary fibrosis, thrombosis,
myalgias, increased risk of CNI-
induced HUS/TTP/TMA (L)
Delayed
Any time later
during therapy,
excluding the
above conditions
Acne
Chronic renal dysfunction, renal
tubular necrosis, CHF, ascites,
arthrosis, bone necrosis,
osteoporosis
Late
Any time after
completion of
treatment
Lymphoproliferative disorders,
skin malignancies
Unknown
Frequency and
Timing
Sirolimus was embryo/fetotoxic in rats at dosages of approximately 0.2 to 0.5; clinical doses
were adjusted for body surface area. It is not known whether sirolimus is excreted in human
milk.


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Appendix V: Radiation Therapy Guidelines
All patients who have had previous radiation therapy or TBI will be seen by Radiation Oncology prior to
entrance on the protocol for approval for additional 200 cGy of TBI. TBI may be delivered by local guidelines
provided the effective dose is equivalent to what is recommended in the TBI Guidelines.
Patients ineligible for this protocol include those who have had previous irradiation to areas of the body such
that the Radiation Oncologist feels that even a relatively small dose of total body irradiation (TBI) cannot safely
be given.
If the patient has previously had total body irradiation (TBI), the radiation oncologist will have the option of
deciding whether the patient is still eligible to receive additional TBI. Based on the recommendation of the
treating Radiation Oncologist, the patient may be eligible for this protocol with modifications to the beam such
that the lungs and or kidneys are partially shielded from the radiation beam. No other organs may be shielded.
Patients who have not had previous TBI
The dose of TBI will be 200 cGy given in a single fraction on day -1.
The dose rate will be between 10-19 cGy/minute prescribed to the midplane of the patient at the level of the
umbilicus.
The TBI will be delivered with right and left lateral fields with the patient semi-recumbent in a semi-fetal
position with their arms at their sides.
Based on measurement of transverse thickness, aluminum compensators will be used to ensure that the dose
homogeneity across the fields is within 10% of the prescribed dose. Usually head/ neck, leg and lung
compensators are used (although based on calculated mid-mediastinal doses, lung compensators are often not
needed if the thickness of the arms, which partially shield the lung, are taken into the thickness consideration).
TBI will be delivered with a linear accelerator using 6, 18 or 25 MV photons. The energy used will be based on
the calculated dose to midline at points along the patient's torso. The lowest energy that give 90-100% of the
prescriptions point dose will be used.
A beam "spoiler" will be used to ensure a full skin dose.
Half value layer lung and kidney blocks will not be utilized for patients who have not previously received total
body irradiation.
Patients who have received previous TBI
The dose of TBI will be 200 cGy given in a single fraction on day -1.
The dose rate will be between 10-19 cGy/minute prescribed to the midplane of the pelvis,
The TBI will be delivered with AP and PA fields with the patient standing.
If the patient is less than 40 inches in height and requires anesthesia, he/she will be treated supine and prone on
a couch on the floor.


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One half value layer lung blocks will be used to decrease the photon contribution to the lung dose to
approximately half that of the prescription point.
The chest wall areas blocked by the 1 HVL lung blocks will be boosted with electrons of the appropriate energy
(determined by CT scanning) such that the electrons D90 is at the chest wall-lung interface. The dose to the
chest wall will be 200 cGy prescribed to Dmax.
One half value layer POSTERIOR kidney blocks will be used to decrease the photon contribution to the kidneys
to approximately 75% that of the prescription point.
TBI will be delivered with a linear accelerator using 6 MV photons.
A beam "spoiler" will be used to ensure a full skin dose.


M T 2 0 0 5- 0 2:
U C B T i n He mat ol o gical mali g n a n cies usi n g a N M A pre parati ve re gi me n
1 1/ 0 8/ 2 0 1 3
P a ge 3 9 of 3 9
C P R C # 2 0 0 5 L S 0 3 6
A p p e n di x VI: C o- M or bi dit y S c ori n g
P A TI E N T N A M E: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
W/ U D A T E: _ _ _ _ _ _ _ _ _ _ _ _ _ _
P ati e nt I D _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
T x D at e _ _ _ _/ _ _ _ _ _/ _ _ _ _ _ _ _ _ _ _ - F or d at a b a s e o nl y
CI B M T R Pr e- Tr a n s pl a nt E s s e nti al D at a
C O M O R BI D C O N DI TI O N S
I s t h er e a hi st or y of
m e c h a ni c al v e ntil ati o n ?
1�Y e s
2�N o
I s t h er e a hi st or y of pr o v e n i n v a si v e f u n g al i nf e cti o n ?
1�Y e s
2�N o
W er e t h er e
cli ni c all y si g nifi c a nt c o- e xi sti n g di s e a s e or or g a n i m p air m e nt at ti m e of p ati e nt a s s e s s m e nt pri or t o
pr e p ar ati v e r e gi m e n ?
1�Y e s – C o m pl et e t h e f oll o wi n g q u e sti o n s:
2�N o
– D O N O T N E E D T O C O M P L E T E F O L L O WI N G Q U E S TI O N S
Y e s N o N ot D o n e  
C o m or bi dit y D efi niti o n s
1 �
2 
3
Arr h yt h mi a Atri al fi brill ati o n or fl utt er, si c k si n u s s y n dr o m e, or v e ntri c ul ar 
arr h yt h mi a s
1 �
2 
3
C ar di a c C or o n ar y art er y di s e a s e §, c o n g e sti v e h e art f ail ur e, m y o c ar di al i nf ar cti o n, or E F
≤ 5 0 %
1 �
2 
3
C er e br o v a s c ul ar di s e a s e Tr a n si e nt i s c h e mi c att a c k or c er e br o v a s c ul ar a c ci d e nt
1 �
2 
3
Di a b et e s r e q uiri n g tr e at m e nt wit h i n s uli n or or al h y p o gl y c e mi c s b ut n ot di et al o n e
1 �
2 
3
H e art v al v e di s e a s e E x c e pt
mitr al v al v e pr ol a p s e
1 �
2 
3
H e p ati c,
mil d C hr o ni c h e p atiti s, bilir u bi n > U L N t o 1. 5 × U L N, or A S T/ A L T > U L N t o 2. 5 × U L N
1 �
2 
3
H e p ati c,
m o d er at e/ s e v er e Li v er cirr h o si s, bilir u bi n > 1. 5 × U L N, or A S T/ A L T > 2. 5 × U L N
1 �
2 
3
I nf e cti o n R e q uiri n g c o nti n u ati o n of a nti mi cr o bi al tr e at m e nt aft er d a y 0
1 �
2 
3
I nfl a m m at or y b o w el di s e a s e Cr o h n' s di s e a s e or ul c er ati v e c oliti s
1 �
2 
3
O b e sit y P ati e nt s wit h a b o d y m a s s i n d e x > 3 5 k g/ m 2
1 �
2 
3
P e pti c ul c er r e q uiri n g tr e at m e nt
1 �
2 
3
P s y c hi atri c di st ur b a n c e D e pr e s si o n or a n xi et y r e q uiri n g p s y c hi atri c c o n s ult or tr e at m e nt
1 �
2 
3
P ul m o n ar y,
m o d er at e D L c o a n d/ or F E V 1 6 6- 8 0 % or d y s p n e a o n sli g ht a cti vit y
1 �
2 
3
P ul m o n ar y, s e v er e D L c o a n d/ or F E V 1 ≤ 6 5 % or d y s p n e a at r e st or r e q uiri n g o x y g e n
1 �
2 
3
R e n al, m o d er at e/ s e v er e S er u m cr e ati ni n e > 2 m g/ d L or > 1 7 7 μ m ol/ L, o n di al y si s,
or pri or r e n al tr a n s pl a nt ati o n
1 �
2 
3
R h e u m at ol o gi c S L E, R A, p ol y m y o siti s, mi x e d C T D, or p ol y m y al gi a R h e u m ati c a
1 �
2 
3
S oli d t u m or, pri or Tr e at e d at a n y ti m e p oi nt i n t h e p ati e nt' s p a st hi st or y, e x cl u di n g
n o n m el a n o m a s ki n c a n c er
1 �
2 
3
Ot h er S p e cif y: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
O n e or
m or e v e s s el- c or o n ar y art er y st e n o si s r e q uiri n g
m e di c al tr e at m e nt, st e nt, or b y p a s s gr aft. E F
i n di c at e s ej e cti o n fr a cti o n; U L N, u p p er li mit of n or m al; S L E, s y st e mi c l u p u s er yt h m at o si s; R A,
r h e u m at oi d art hriti s; C T D, c o n n e cti v e ti s s u e di s e a s e; D L c o, diff u si o n c a p a cit y of c ar b o n
m o n o xi d e.
S o ur c e: Bl o o d, 2 0 0 5 O ct 1 5; 1 0 6( 8): 2 9 1 2- 2 9 1 9
P H Y SI CI A N’ S SI G N A T U R E _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
D A T E _ _ _ _ _ _ _ _ _ _ _ R e vi s e d 2/ 2 1/ 0 8