Clinical trial NCT01685411
Conditions: Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Myelodysplastic Syndrome
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2013-01-01; Completion date: 2020-02-10
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a treatment guideline to allow routine clinical data to be collected and maintained in Oncore (clinical database) and the University of Minnesota Blood and Marrow Database as part of the historical database maintained by the department.

Detailed description:
This is a single arm trial to evaluate the efficacy of busulfan and cyclophosphamide followed by an allogeneic hematopoietic stem cell transplant (HSCT) in the treatment of hematological malignancies. The intent of this study is to provide a protocol that will use unmanipulated allogeneic hematopoietic stem cells from related and unrelated donors after a common preparative regimen.

Arms: arm 1: Patients treated with Allopurinol, Keppra, Busulfan, Cyclophosphamide, Filgrastim, antithymocyte globulin, Tacrolimus, Mycophenolate mofetil and allogeneic hematopoietic stem cell transplant infusion.
Interventions: intervention 1: Allopurinol intervention 2: Keppra intervention 3: Busulfan intervention 4: Cyclophosphamide intervention 5: Tacrolimus intervention 6: Mycophenolate mofetil intervention 7: Allogeneic hematopoietic stem cell transplant intervention 8: Filgrastim intervention 9: antithymocyte globulin
Intervention descriptions: intervention 1: Day -8 (prior to transplant): Per institutional guidelines intervention 2: Day -8 (prior to transplant): Per institutional guidelines intervention 3: Days -7 through -4 (prior to transplant): given intravenously (IV) infusion over 2 hours every 6 hours following dose, administration and pharmacokinetic monitoring per University of Minnesota institutional guidelines. intervention 4: Days -3 and -2 (prior to transplantation): given as a 2 hour intravenous infusion with a high volume fluid flush and mesna per institutional guidelines. Dosing is based on actual body weight. intervention 5: All patients (regardless of allograft source) will receive tacrolimus therapy beginning on day -3. Dosing will be monitored and altered as clinically appropriate per institutional pharmacy guidelines. Dose adjustments will be made on the basis of toxicity and/or low tacrolimus levels. Taper at day +100 for matched sibling donor (MSD) recipients, and day +180 for non-MSD recipients. Taper to zero by 10% weekly dose reduction over approximately 10 weeks. intervention 6: Day -3 (prior to transplant): Recipients of umbilical cord blood will given a dose of 3 gm/day every 8 or 12 hours (\> or = 40 kg) or 15 mg/kg 3 times per day (\< 40 kg) for up to 30 days unless no engraftment. intervention 7: Day 0 (or Day+1/+2 to accommodate weekdays): Infusion of cells from related or unrelated donor bone marrow or single or double unrelated donor umbilical cord blood. intervention 8: Beginning Day +1: Intravenously (IV) 5 mcg/kg once daily and continuing until the absolute neutrophil count is \>2500 x 10\^9/L or per institutional guidelines. intervention 9: Administered per institutional guidelines for recipients of umbilical cord blood transplant.

Protocol documents:
Prot_SAP_000.pdf: 
Masonic Cancer Center  
University of Minnesota 
Blood and Marrow Transplantation  
  
 
 
Busulfan and Cyclophosphamide Followed By Allogeneic 
Hematopoietic Cell Transplantation In Patients With 
Hematological Malignancies 
 
MT2011-20C 
CPRC #2011OC139 
 
 
 
Investigators: 
Margaret L. MacMillan, M.D. (Principal Investigator) 
John E. Wagner, Jr. M.D. 
Daniel J. Weisdorf, M.D. 
 
 
Biostatistician 
Qing Cao, M.S. 
 
 
Version Date: 
April 19, 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
Page 2 of 20 
CPRC # 2011OC139 
Revision History 
 
Revision 
# 
Version 
Date 
Detail of Changes 
Consent 
change? (Y/N) 
 
08/06/2012 
Original to CPRC and IRB  
 
1 
11/20/2014 
section 5.3.1 and 5.3.2- correct the type 
and number of donor cells to collected 
section 8 – update event reporting to new 
IRB requirements 
treatment 
appendix only – 
replace 
fludarabine with 
cyclophosphamide 
2 
01/30/2017 
Treatment plan; Section 5.0 Updated 
chemotherapy with standard departmental 
guidelines 
Section 7.0 – deleted day -1 bone marrow 
biopsy 
Updated with new 
IRB out of study 
contact language 
3 
04/19/2018 
Updated GVHD prophylaxis from CSA to 
tacrolimus per current institutional standard 
of care 
Treatment 
appendix only – 
replace CSA with 
TAC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI Contact Information: 
Margaret L. MacMillan, MD, MSc 
University of Minnesota  
Pediatric Blood and Marrow Transplant Program  
MMC 484   
420 Delaware Street SE 
Minneapolis, MN 55455 
612 626-2778 (phone) 
612-626-2815 (fax) 
macmi002@umn.edu (email) 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
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CPRC # 2011OC139 
Table of Contents 
 
Synopsis ........................................................................................................................ 4 
Treatment Plan .............................................................................................................. 5 
1.0 
Introduction......................................................................................................... 6 
2.0 
Background......................................................................................................... 6 
3.0 
Patient Selection ................................................................................................. 6 
4.0 
Registration in OnCore....................................................................................... 7 
5.0 
Treatment Plan .................................................................................................... 7 
5.1 
Preparative Regimen ........................................................................................ 7 
5.2 
GVHD Prophylaxis ............................................................................................ 8 
5.3 
Stem Cell Procurement ..................................................................................... 9 
5.4 
Stem Cell Infusion (day 0) ............................................................................... 11 
5.5 
Post-Transplant G-CSF (filgrastim) ................................................................. 11 
5.6 
Expected Treatment Related Toxicity .............................................................. 11 
5.7 
Supportive Care .............................................................................................. 11 
5.8 
Follow-Up ........................................................................................................ 12 
6.0 
Drug Procurement ............................................................................................ 12 
7.0 
Clinical Evaluations .......................................................................................... 13 
8.0 
Event Reporting ................................................................................................ 14 
9.0 
Study Data Collection and Statistical Plan ..................................................... 14 
9.1 
Trial Size Justification ..................................................................................... 14 
9.2 
Enrollment Plan ............................................................................................... 15 
9.3 
Analysis of Primary and Secondary Endpoints ................................................ 15 
9.4 
Safety Monitoring ............................................................................................ 15 
Appendix I – Performance Status Scales .................................................................. 16 
Appendix II – Expected Toxicities Of The Preparative Regimen And 
Transplantation ........................................................................................................... 17 


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CPRC # 2011OC139 
 Synopsis 
Busulfan and Cyclophosphamide Followed By Allogeneic 
Hematopoietic Cell Transplantation In Patients With 
Hematological Malignancies 
MT2011-20C 
 
This is a treatment guideline to allow routine clinical data to be collected and maintained in 
OnCore and the University Of Minnesota Blood and Marrow Database as part of the historical 
database maintained by the department. 
 
Eligible patients will include individuals who have acute leukemia and myelodysplastic syndrome, 
are ≤ 35 years of age and who have had a previous hematopoietic cell transplant (HCT) or have 
received sufficient radiation treatment to be ineligible for TBI containing preparative therapy  
 
Study Design: 
This is a single arm trial to evaluate the efficacy of busulfan and 
cyclophosphamide followed by an allogeneic hematopoietic stem cell 
transplant (HSCT) in the treatment of hematological malignancies.  The 
intent of this proposal is to provide a protocol that will use unmanipulated 
allogeneic hematopoietic stem cells from related and unrelated donors after 
a common preparative regimen.  Results will be compared to historical 
controls.  
 
Eligibility 
Criteria: 
Patients must have a diagnosis of ALL, AML or MDS, currently be in a 
complete remission and meet one of the following: 
• <45 years of age who are at least 6 months after initial HSCT 
• <45 years of age and have received sufficient radiation treatment to be 
ineligible for TBI containing preparative therapy 
Karnofsky performance status >70% or Lansky play score >50 
Adequate organ function defined as: 
 
• Cardiac: ejection fraction >45% 
• Renal: glomerular filtration rate (GFR) >40 mL/min 
• Hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, 
ascites) 
Exclusions – eligible for TBI containing prep; active uncontrolled infection 
within 1 week; pregnant or breastfeeding  
 
Endpoints 
 
 
 
Duration of long-term disease-free survival (DFS), rate of engraftment, 
incidence and severity of acute and chronic graft versus host disease 
(GVHD), treatment related toxicity and incidence of relapse.  Endpoints will 
be abstracted from routine data collected by the BMT Database. 
 
Enrollment 
2-3 patients per year 
 
 
 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
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CPRC # 2011OC139 
Treatment Plan 
 
 
Acceptable stem cell sources include: HLA-matched related or unrelated donor bone marrow 
(6/6 or 5/6 antigen match), related or unrelated peripheral blood stem cells, and related or single 
or double unrelated donor umbilical cord blood (6/6, 5/6 or 4/6 match)  
 
 
Begin levetiracetam (Keppra®)  day -8 per institutional busulfan guidelines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HSCT   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       * 
 
 
               
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
               -7 
          -6 
-5                -4      
     -3 
          -2   
 -1                0                +1         
 
 
 
 
 
 
 
 
 
                           G-CSF 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
  Tacrolimus 
 
 
 
 
 
 
           MMF       
 
 
 
 
 
 
 
     
 
Busulfan per institutional guideline for every 6 hours dosingIV) day -7 through day -4 
 
 
 
 
 
 
 
            Cyclophosphamide 60 mg/kg/day IV day -3 and -2 
 
 
 
   
                 G-CSF 5 mcg/kg/day (max 480mcg) IV starting day +1 until ANC ≥2.5 x 109/L for 3 
consecutive days  
 
* 
ATG (Atgam® - equine) will be administered to umbilical cord blood recipients only: 
30 mg/kg/dose IV every 24 hours on days -3, -2, and -1. 
 
 
Standard GVHD prophylaxis or, if eligible, an alternative GVHD prophylaxis will be used: 
 
           Tacrolimus will start day -3 for all patients and continue based on stem cell type: 
• 
For patients receiving HLA-identical sibling HCT, beginning on day +100 or 1 month after 
control of GVHD (whichever is later), Tacrolimus will be tapered by 10%/week. 
• 
For patients receiving alternate donor HCT, beginning on day +180 or 1 month after 
control of GVHD (whichever is later), Tacrolimus will be tapered by 10%/week. 
             MMF will start day -3 for all patients and continue to day +30 or 7 days after engraftment, 
whichever is later, 
 
  
 


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CPRC # 2011OC139 
1.0 
Introduction  
This treatment guideline provides a mechanism that will use unmanipulated 
allogeneic hematopoietic stem cells from related or unrelated donors after 
a common preparative regimen in patients with acute leukemia or a 
myelodysplastic syndrome (MDS) who have either had a prior HSC 
transplant or have had sufficient radiation therapy preventing the use of total 
body irradiation (TBI) as part of a transplant preparative regimen.   
 
Major endpoints are duration of long-term disease-free survival (DFS), rate 
of engraftment, incidence and severity of acute and chronic graft versus 
host disease (GVHD), treatment related toxicity and incidence of relapse.  
 
Patients will consent to allow routine registration data to be collected and 
maintained in OnCore, the Masonic Cancer Center’s (MCC) clinical 
database and specific transplant related endpoints in the University of 
Minnesota Blood and Bone Marrow Database as part of the historical 
database maintained by the department. 
 
2.0 
Background  
The treatment guideline is based on the previous University of Minnesota 
clinical trial “MT2000-12 Busulfan, Cyclophosphamide, and Melphalan 
Followed by Allogeneic Hematopoietic Cell Transplantation in Patients with 
Hematological Malignancies;” however melphalan has been omitted  to 
decrease the regimen related toxicity. 
 
3.0 
Patient Selection 
3.1 
Diagnosis of ALL, AML or MDS and currently in complete remission 
meeting one of the following: 
• <45 years of age who are at least 6 months after initial HSCT 
• <45 years of age and have received sufficient radiation treatment 
to be ineligible for TBI containing preparative therapy 
 
3.2 
Karnofsky performance status >70% or if < 16 years of age, a Lansky 
play score >50 
 
3.3 
Adequate major organ function including: 
• cardiac: left ventricular ejection fraction > 45% by ECHO/MUGA 
• renal: creatinine clearance >40 mL/min/1.73m2 
• hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, 
ascites) 
 
 


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April 19, 2018 
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CPRC # 2011OC139 
3.4 
An acceptable source of stem cells according to current University of 
Minnesota BMT program guidelines.  Acceptable stem cell sources 
include:  
• HLA-matched related or unrelated donor bone marrow (6/6 or 5/6 
antigen match)  
• HLA-matched related or unrelated donor peripheral blood stem 
cells  
•  related or single or double unrelated donor umbilical cord blood 
(6/6, 5/6 or 4/6 match)   
 
3.5 
Women of child bearing age must have a negative pregnancy test 
and all sexually active participants must agree to use effective 
contraception during study treatment  
 
3.6 
Written consent (adult or parent/guardian) 
 
3.7 
Exclusion Criteria:  
• eligible for TBI containing preparative regimen 
• active uncontrolled infection within one week of study enrollment 
• pregnant or lactating female 
 
4.0 
Registration in OnCore  
Patients will be registered to this study in OnCore after the signing of the 
consent. 
5.0 
Treatment Plan 
5.1 
Preparative Regimen 
The preparative regimen administration and adjustments will follow 
the University Of Minnesota Blood and Marrow Transplant Program 
dosing guidelines.  Appropriate age/weight dose adjustments will be 
made for pediatric patients.  The treating physician may make 
chemotherapy drug and dosage adjustments consistent with the 
standard of care as needed for patient safety.  
 
Day  
Therapy 
-8 
start allopurinol, if appropriate, and levetiracetam 
(Keppra) 
-7 
busulfan IV over 2 hours every 6 hours  
-6 
busulfan IV over 2 hours every 6 hours 
-5 
busulfan IV over 2 hours every 6 hours 
-4 
busulfan IV over 2 hours every 6 hours 
-3 
cyclophosphamide 60 mg/kg/day IV over 2 hours 
-2 
cyclophosphamide 60 mg/kg/day IV over 2 hours 
-1 
rest 
0 
Infusion of stem cells 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
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CPRC # 2011OC139 
 
As seizures have occurred following high dose busulfan, all patients 
will be treated with levetiracetam (Keppra®) beginning day -8  and 
continuing until at least 24hours after last busulfan dose per 
institutional guidelines. 
Busulfan will be administered as an IV infusion over 2 hours every 
6 hours following dose, administration and pharmacokinetic 
monitoring per University Of Minnesota institutional guidelines 
(MT2003-19S). Refer to guidelines to consider obesity dosing 
adjustment. 
 
Cyclophosphamide will be administered as a 2 hour intravenous 
infusion with a high volume fluid flush and mesna per institutional 
guidelines on days -3 and -2.   
 
Dosing is based on Actual Body Weight (ABW) unless ABW > 150% 
above Ideal Body Weight (IBW), in which case the dose should be 
computed using adjusted body weight. Refer to Cyclophosphamide 
Pharmacy Guidelines for calculating IBW based on age.  
 
Antithymocyte Globulin (Atgam -equine) will be administered to 
umbilical cord blood recipients only at a dose of 30 mg/kg/dose IV 
every 24 hours on days -3, -2, and -1.  Methylprednisone 1 mg/kg 
(no max dosing) IV will be administered prior to each dose of ATG.  
Additional steroids and/or other medications may be used as needed 
per the discretion of the treating physician.  ATG will be administered 
per institutional guidelines. 
5.2 
GVHD Prophylaxis 
Standard acute GVHD prophylaxis or, if eligible, an alternative 
GVHD prophylaxis will be used. 
 
 
5.2.1 Tacrolimus 
All patients (regardless of allograft source) will receive 
tacrolimus therapy beginning on day –3.   
 
Tacrolimus dosing will be monitored and altered as clinically 
appropriate per institutional pharmacy guidelines.  Dose 
adjustments will be made on the basis of toxicity and/or low 
tacrolimus levels.  
 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
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CPRC # 2011OC139 
Tacrolimus taper begins at day +100 for matched sibling 
donor (MSD) recipients, and day +180 for non-MSD 
recipients.  Taper to zero by 10% weekly dose reduction over 
approximately 10 weeks.   
5.2.2 Mycophenolate Mofetil (MMF) 
All patients will begin mycophenolate mofetil (MMF) on day -
3 at a dose of 15mg/kg/dose  (max 1gm) IV q8h.  Adult 
patients may be dosed at 1 gm IV q8h or 1.5 gm IV q12h (3 
grams/day)  
 
MMF dosing will be monitored and altered as clinically 
appropriate based on institutional guidelines.  Patients will be 
eligible for MMF dosing and pharmacokinetics studies. 
Use IV route between days –3 and +5, then, if tolerated, may 
change to PO between days +6 and +30.  
 
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 there is no donor engraftment, do not stop MMF.  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 according the 
institutional policy for management of slow engraftment. 
 
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 
Stem Cell Procurement 
Acceptable stem cell sources include: HLA-matched related or 
unrelated donor bone marrow (6/6 or 5/6 antigen match) and related 
or single or double unrelated donor umbilical cord blood (6/6, 5/6 or 
4/6 match).  HLA-match is determined by serology for class I 
antigens (HLA A, B) and high resolution DNA typing for class II 
(DRB1) unless parental typing is available (DR is satisfactory).   
 
5.3.1 Bone Marrow 
Unrelated donor bone marrow will be collected in the usual 
manner using established parameters determined by the 
National Marrow Donor Program.   
 
Related donor BM will be collected according to current 
institutional guidelines. 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
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CPRC # 2011OC139 
 
A minimum of 2 x 108 nc/kg bone marrow cells. 
 
No processing or manipulation of the donor marrow cells will 
be performed. 
 
5.3.2 Peripheral Blood Stem Cells 
A target of 5 x 106/kg and a minimum of 4 x 106 CD34+ cells/kg 
recipient weight will be collected by mobilized donor 
apheresis. 
 
Day 0 for stem cell infusion may be shifted to day +1 or day 
+2 to move donor collections to weekdays or to accommodate 
a third donor collection, if needed.  All associated procedures 
(i.e. G-CSF doses etc.) will shift accordingly.   
 
Guideline for mobilized apheresis: 
Day 
Donor: 
-5 
G-CSF 16 mcg/kg SQ 
-4 
G-CSF 16 mcg/kg SQ 
-3 
G-CSF 16 mcg/kg SQ 
-2 
G-CSF 16 mcg/kg SQ 
-1 
G-CSF 16 mcg/kg SQ  
apheresis 
0 
G-CSF 16 mcg/kg SQ 
apheresis 
+1 
If necessary to achieve targeted cell dose 
G-CSF 16 mcg/kg SQ  
apheresis  
 
Acetaminophen 15mg/kg/dose (max 650 mg) PO should be 
given 30 minutes before the first dose of G-CSF and continue 
every 8-12 hours for the duration of G-CSF administration.   
 
Donors may experience any of the following side effects from 
G-CSF: bone pain, headaches, body ache, fatigue, 
nausea/vomiting, insomnia, dyspnea, rash, edema or other 
complaints.  Donors experiencing intolerable symptoms (≥ 
grade 3 CTCAE v 4) attributed to G-CSF therapy should 
receive a dose reduction to 10 mcg/kg/dose. 
 
Mobilized Donor Apheresis  
Donors will undergo mobilized peripheral blood progenitor cell 
(PBPC) apheresis on days –1 and day 0 per institutional 
guidelines.     
 
In most cases the target graft cell dose will be recovered in 
two aphereses; however, rarely a third apheresis may be 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
Page 11 of 20 
CPRC # 2011OC139 
required the following day to achieve the minimum cell dose.  
More than 3 collections are not allowed.   
 
5.3.3 Umbilical Cord Blood 
Umbilical cord blood selection will be per the current 
University of Minnesota Cord Blood Unit Selection algorithm.  
One or two units may be used to obtain the minimum cell 
dose.  There will be no processing of the cells. 
 
Note:  Unlicensed UCB units will be covered by University of 
Minnesota IND BB 14797 (C. Brunstein, MD, PhD – 
sponsor/investigator) and therefore will be in compliance with 
mandatory reporting to the FDA for minimally manipulated 
UCB units. 
5.4 
Stem Cell Infusion (day 0) 
On day 0 the stem cells will be infused per cell source specific 
institutional guidelines.  
 
Recommended premedication: acetaminophen 15mg/kg/dose (max 
650 mg) PO and diphenhydramine 0.5 mg/kg/dose (max 25 mg) 
PO/IV. 
 
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 required depending on reactions to 
the product infusion.  Notify the resident physician immediately if 
patient exhibits signs or symptoms of a reaction. 
5.5 
Post-Transplant G-CSF (filgrastim) 
Beginning on day +1, patients will receive G-CSF IV 5 micrograms/kg 
once daily and continuing once daily until the ANC is >2500 x109/L 
for 3 consecutive days.  
 
G-CSF will be restarted at 5 mcg/kg/day (Max 480mcg/dose) IV if the 
ANC falls below 1000 x109/L or per institutional guidelines. 
5.6 
Expected Treatment Related Toxicity 
Refer to appendix II. 
5.7 
Supportive Care 
Patients will receive standard supportive transplant care, including 
antibacterial/antifungal/antiviral prophylaxis according to institutional 
guidelines or as modified based on clinical parameters. 
 


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April 19, 2018 
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CPRC # 2011OC139 
Patients will be eligible for any supportive care studies regarding 
infectious disease prophylaxis and management, immunoglobulin 
support, etc. as appropriate. 
5.8 
Follow-Up 
Follow-up will be according to the current University Of Minnesota 
BMT guidelines. 
 
 
6.0 
Drug Procurement 
The preparative drugs (cyclophosphamide and busulfan) and supportive 
care drugs referenced in this study are standard of care, commercially 
available and will be administered according to current institutional 
guidelines.  
 
 
 
 


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CPRC # 2011OC139 
7.0 
Clinical Evaluations 
All clinical evaluations are standard of care and will be done according to current 
institutional guidelines.  Scheduled evaluations before day 30 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 year, 2 years and 3 years may be performed (+/- 30) days of the targeted date.  
In addition, targeted days may be altered as clinically appropriate. 
 
 
Pre-BMT  
work-up 
During 
Preparative 
Regimen 
Day 0 
Day 1 to 
engraftment1 
Follow-up 
Days 31-
100 
Follow-up 
per U of MN 
BMT 
guidelines 
Written consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
daily 
 
 
Physical exam 
X 
 
 
daily 
weekly 
 
Performance status 
X 
 
 
 
Day 100 
 
Weight 
X 
 
X 
X(3) 
 
 
Height 
X 
 
 
 
 
 
GVHD evaluation 
 
 
 
daily 
weekly 
 
CMV Surveillance 
 
 
 
weekly 
weekly 
prn 
EBV Surveillance 
 
 
 
every other 
week 
every other 
week 
 
CBC, diff, platelet  
X 
daily 
 
daily 
weekly 
 
PT/PTT 
X 
 
 
 
 
 
Alk phos, AST, ALT, tot bili 
X 
weekly 
 
weekly 
 
 
Creat, BUN, Na, K, CO2 
X 
daily 
daily 
daily 
weekly 
 
Pre-BMT viral panel  
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
Pregnancy test ( FOCBP) 
X 
 
 
 
 
 
BM bx/asp 
X 
 
 
Day 21 
Day 60, 100 
6 and12 
months 
Chimerism – BM 
X 
 
 
Day 21 
Day 60, 100 
6 and12 
months 
Chimerism – PB 
X 
 
 
Day 28 
Day 100 
6 and12 
months 
EKG 
X 
 
 
 
 
 
MUGA or echo 
X 
 
 
 
 
 
Chest x-ray or CT 
X 
 
 
 
 
 
PFT’s 
X 
 
 
 
 
 
Disease eval 
X 
 
 
Day 21 
Day 100 
X 
1 -engraftment defined as absolute neutrophil count (ANC) is >2500 x109/L for 3 consecutive measurements  
 
 


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April 19, 2018 
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CPRC # 2011OC139 
8.0 
Event Reporting 
This is a treatment guideline to allow routine clinical data to be collected 
and maintained in OnCore and the University Of Minnesota Blood and 
Marrow Database as part of the historical database maintained by the 
department.  The only research element is the collection of routine clinical 
data in association with study milestones.  Therefore, the only events 
reportable to the University Of Minnesota Institutional Review Board in a 
prompt manner (within 5 business days of discovering the event) will be 
those in association with data collection.  Primarily these risks would be: 
• 
Any breach in confidentiality that may involve risk to the subject or others 
in association with the data collection 
• 
Any complaint in association with the data collection of a subject that 
cannot be resolved by the research staff  
 
Any report should be made using the Report form found on the IRB’s 
website (http://www.research.umn.edu/irb/).   
 
 
9.0 
Study Data Collection and Statistical Plan 
Specific transplant related endpoints include:  
• Days to ANC engraftment 
• Incidence of engraftment failure at day 42 
• Incidence of acute GVHD at 100 days 
• Incidence of chronic GVHD at 6 months and 1 year 
• Incidence of transplant related mortality (TRM) at 6 months and 1 
year 
• Incidence of relapse at 1 year and 2 years 
• Disease free survival at 2 year, 5 year and 10 years 
• Overall survival at 2 year, 5 year and 10 years 
 
All endpoint data will be recorded in the University of Minnesota Blood and 
Bone Marrow Database as part of the historical database maintained by the 
department. 
9.1 
Trial Size Justification 
The primary objective is to record outcomes and patient 
characteristics in the BMT database for patients using partially 
matched unrelated or related donors or umbilical cord blood as a cell 
source and are treated in a standard manner. Based on prior a prior 
study (MT2000-12), enrollment will be minimal as other transplant 
approaches and higher priority clinical trials limit accrual for this 
transplant study.  However, this study remains necessary for 
selected patient populations who lack a histocompatible related 


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April 19, 2018 
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CPRC # 2011OC139 
donor and have no more promising treatment option. No trial size 
justification is needed. 
9.2 
Enrollment Plan 
We plan to enroll 2-3 per year. 
9.3 
Analysis of Primary and Secondary Endpoints 
Cumulative incidence will be used to estimate TRM, Relapse, 
neutrophil engraftment, GVHD and engraftment failure treating non-
events as competing risks. Kaplan-Meier curves will be used to 
estimate disease-free survival and overall survival.  
9.4 
Safety Monitoring 
We have studied the regimen for patients with these diagnoses for 
the past 12 years and it has been shown to be safe. Continuous 
stopping rules are no long needed. Safety parameters will be 
monitored on a yearly basis.  
 


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CPRC # 2011OC139 
Appendix I – Performance Status Scales 
 
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 
 
REFERENCE 
Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR (1987). "The measurement of performance in 
childhood cancer patients". Cancer 60 (7): 1651–6.  
 
 
 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
Page 17 of 20 
CPRC # 2011OC139 
 
Appendix II – Expected Toxicities Of The Preparative Regimen 
And Transplantation  
 
Busulfan  
Common 
Less Common 
Rare 
• low white blood cell count with 
increased risk of infection  
• low platelet count with 
increased risk of bleeding  
• low red blood cell count 
(anemia) which may cause 
tiredness, headache, dizziness  
• hair loss or thinning, including 
face and body hair (usually 
grows back after treatment)  
• long-term or short-term 
infertility (inability to have 
children) in men and women 
 
 
• tiredness  
• sores in mouth or 
on lips  
• fever  
• nausea  
• vomiting 
• rash  
• loss of appetite  
• diarrhea  
• serious infection 
due to low white 
blood cell count  
 
 
• abnormal blood tests results which 
suggest that the drug is affecting the liver 
(Your doctor will discuss the importance of 
this finding, if any.)  
• allergic reaction with hives, itching, 
headache, coughing, shortness of breath, 
or swelling of the face, tongue, or throat  
• scarring of lung tissue, with cough, 
difficulty breathing, and shortness of 
breath that may occur after prolonged use, 
or even months or years after stopping the 
drug  
• leukemia (several years after treatment)  
• darkened skin  
• heart problems with high-dose treatment, 
most often in people with thalassemia (a 
type of genetic anemia that is present at 
birth)  
• problems with the hormone system that 
cause weakness, tiredness, poor appetite, 
weight loss, and darker skin  
• death due lung damage, bone marrow 
shutdown, sepsis (severe infection) or 
other causes  
 
 
 
Cyclophosphamide 
Common 
Less Common 
Rare 
• low white blood cell count with 
increased risk of infection  
• hair loss or thinning, including 
face and body hair (usually 
grows back after treatment)  
• nausea  
• vomiting  
• loss of appetite  
• sores in mouth or on lips  
• bleeding from bladder, with 
blood in urine  
• diarrhea  
• long-term or short-term 
infertility (inability to have 
children) in women and men 
 
• low platelet count 
with increased risk 
of bleeding  
• darkening of nail 
beds  
• acne  
• tiredness  
• infection  
• fetal changes if 
pregnancy occurs 
during 
cyclophosphamide  
 
• heart problems with high doses, with 
chest pain, shortness of breath, or swollen 
feet  
• severe allergic reactions  
• skin rash  
• scarring of bladder  
• kidney damage (renal tubular necrosis) 
which can lead to kidney failure  
• heart damage, with trouble getting your 
breath, swelling of feet, rapid weight gain  
• scarring of lung tissue, with cough and 
shortness of breath  
• second cancer, which can happen years 
after taking this drug  
• death from infection, bleeding, heart 
failure, allergic reaction, or other causes  
 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
Page 18 of 20 
CPRC # 2011OC139 
 
Anti-Thymocyte Globulin (ATG) (umbilical cord blood recipients only) 
Common 
Less Frequent 
Uncommon 
• fever 
• chills 
• low white blood cell count with 
increased risk of infection  
• pain 
• headache 
• abdominal pain 
• diarrhea 
• hypertension 
• nausea 
• low platelet count with increased 
risk of bleeding  
• peripheral edema 
• dyspnea 
• asthenia 
• hyperkalemia 
• tachycardia 
• malaise 
• dizziness 
• severe allergic reaction (anaphylaxis) 
 
 
GVHD Prophylaxis 
 
 
Mycophenolate mofetil (MMF) 
Common 
Less Common 
Rare, but may be serious 
• miscarriage 
• birth defects 
• diarrhea 
• damage to unborn baby 
• limited effectiveness of 
birth control 
• stomach pain 
• upset stomach 
• vomiting 
• headache 
• tremors 
• low white blood cell 
count with increased risk 
of infection 
• increased 
blood 
cholesterols 
• swelling of the hands, 
feet, ankles or lower legs 
• anemia 
• rash 
• difficulty falling asleep or 
staying asleep 
• dizziness 
• uncontrollable hand shakes 
• difficulty breathing 
• unusual bruising 
• fast heartbeat 
• excessive tiredness 
• weakness 
• blood in stool 
• bloody vomit 
• change in vision 
• secondary cancers, such 
as 
lymphoproliferative 
disease or lymphoma 
• Progressive 
Multifocal 
Leukoencephalopathy 
 
Tacrolimus (FK506, Prograf®) 
Common  
occurs in more than 20% of 
patients 
Less Common 
occurs in 5 to 20% of 
patients 
Rare 
occurs in fewer than 5% 
of patients 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
Page 19 of 20 
CPRC # 2011OC139 
 Kidney problems 
 Loss of magnesium, calcium, 
potassium 
 Cardiovascular: hypertension 
 Tremors 
 hyperlipidemia  
 thrombocytopenia  
 Infections 
 
 Nausea 
 Vomiting 
 Liver problems 
 Changes in how 
clearly one can think 
 Insomnia 
 Unwanted hair 
growth 
 Confusion 
 Seizures 
 Changes in vision 
 Dizziness 
 microangiopathic 
hemolytic anemia 
 post-transplant 
lymphoproliferative 
disorders 
It is very important that grapefruit or drinks with grapefruit juice are not consumed while taking 
Tacrolimus.  Grapefruit has an ingredient called bergamottin, which can affect some of the 
treatment drugs used in this study.  Common soft drinks that have bergamottin are Fresca, Squirt, 
and Sunny Delight. 
 
Hematopoietic Stem Cell Transplantation 
• 
nausea and vomiting  
• 
possible allergic reaction (including itching, hives, flushing [red face], shortness of breath, 
wheezing, chest tightness, skin rash, fever, chills, stiff muscles, or trouble breathing) 
• 
graft-versus-host-disease (GVHD) 
• 
veno-occlusive disease  
• 
mucositis,  
• 
infections (sepsis)  
 
 
UCB Infusion 
Infusion of cord blood may be associated with expected and unexpected adverse events similar 
to those seen with transfusion of fresh and cryopreserved blood products.  Expected adverse 
events include: 
• 
acute hemolytic reactions 
• 
febrile nonhemolytic reactions 
• 
allergic reactions 
• 
anaphylactoid or anaphylactic reactions 
• 
transfusion-related acute lung injury (TRALI) 
• 
DMSO toxicity 
• 
transmission of bacterial, viral or protozoal infection 
• 
fat embolism (marrow) 
• 
bleeding 
• 
transfusion-associated circulatory overload (TACO) 
• 
hypothermia 
• 
non-immunologic hemolysis 
• 
granulocyte-related complications  
 
Cardiotoxicity associated with double cord blood infusion has also been reported.   
 
 
 


MT2011-20C: Busulfan and Cyclophosphamide followed by HSCT for Heme Malignancies 
 
 
 
 
April 19, 2018 
Page 20 of 20 
CPRC # 2011OC139 
 
G-CSF 
Common 
Less Common 
Rare 
• 
none 
 
• bone and muscle pain  
• abnormal blood tests which 
suggest that the drug is 
affecting the liver  
 
• 
fast heartbeat  
• 
low blood pressure  
• 
allergic reaction (may 
include shortness of breath, 
wheezing, swelling in the 
mouth or throat, hives, 
itching, flushing, or fever)