Clinical trial NCT02988466
Conditions: Hematologic Malignancies
Keywords: Acute Leukemias Acute myeloid leukemia (AML) Acute lymphoblastic leukemia (ALL)/lymphoma Biphenotypic/Undifferentiated/Prolymphocytic Leukemias Myelodysplastic syndrome Chronic myelogenous leukemia Minimal Residual Disease (MRD) positive leukemia Leukemia or Myelodysplastic Syndromes (MDS) in aplasia Myeloproliferative neoplasms/myelofibrosis Relapsed large-cell lymphoma, mantle-cell lymphoma and Hodgkin lymphoma Burkitt's lymphoma Relapsed T-cell lymphoma Natural Killer cell malignancies Relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular lymphoma Lymphoplasmacytic lymphoma Relapsed multiple myeloma Bone marrow failure syndromes
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2017-01-24; Completion date: 2025-03-24
Enrollment: 78 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a single institution phase II study of a reduced intensity conditioning (RIC) followed by a haploidentical hematopoietic cell transplant (haplo-HCT) in persons with diagnosis of hematologic malignancy. Conditioning will consists of fludarabine, cyclophosphamide, melphalan and total body irradiation (TBI) preparative regimen with a melphalan dose reduction for patients ≥55 years old and those with HCT Comorbidity Index (CI) \>3. This study uses a two-stage phase II design with accrual goal of 84 patients, using 28 patients separately for arms A, C and D

Detailed description:

Arms: arm 1: Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients \<55 years old with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≤2 arm 2: Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients ≥55 years old or younger with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≥3. arm 3: Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≤2 aged ≥55 and \< 65 years old. arm 4: Reduced-intensity conditioning and transplantation of human leukocyte antigen (HLA) -haploidentical related donor stem cells for patients patients ≥65 and ≤75 years old OR any age group with hematopoietic cell transplantation Comorbidity Index (HCT-CI) ≥3.
Interventions: intervention 1: Haplo HCT <55 years old intervention 2: Haplo HCT ≥55 years old intervention 3: GVHD Prophylaxis intervention 4: Haplo HCT ≥55 and < 65 years old intervention 5: Haplo HCT ≥65 and ≤75 years old
Intervention descriptions: intervention 1: * Fludarabine (Flu)
* Cyclophosphamide (Cy)
* Melphalan (Mel)
* Total body irradiation (TBI)
* Non-T-cell depleted donor bone marrow stem cell infusion Day 0 intervention 2: * Fludarabine (Flu)
* Cyclophosphamide (Cy)
* Melphalan (Mel): Dose reduction by 30%
* Total body irradiation (TBI)
* Non-T-cell depleted donor bone marrow stem cell infusion intervention 3: * Cyclophosphamide (Cy)
* Tacrolimus (Tac)
* Mycophenolate mofetil (MMF) intervention 4: * Fludarabine (Flu)
* Cyclophosphamide (Cy)
* Melphalan (Mel)
* Total body irradiation (TBI)
* non-T-cell depleted donor bone marrow stem cells intervention 5: * Fludarabine (Flu)
* Cyclophosphamide (Cy)
* Total body irradiation (TBI)

Protocol documents:
Prot_SAP_000.pdf: 
Masonic Cancer Center, University of Minnesota 
Blood and Marrow Transplantation Program 
 
 
 
Reduced Intensity Conditioning (RIC) and Transplantation of HLA-
Haploidentical Related Hematopoietic Cells (Haplo-HCT) For 
Patients With Hematologic Malignancies 
MT2016-15 
CPRC # 2016LS092 
 
 
 
Principal Investigators: 
Mark Juckett, MD  
 
 
Co-Investigators: 
Jeffrey S. Miller, MD 
Kathryn Dusenbery, MD 
David McKenna, Jr, MD 
 
 
Biostatistician: 
Qing Cao, MS 
 
 
Version Date: 
     March 11, 2024 
Confidential 
 
 


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CPRC #2016LS092 
Revision History 
 
Revision 
Number 
Version 
Date 
Revision Summary 
Consent 
Change? 
 
06/22/2016 original to CPRC 
 
 
12/07/2016 Updated Eligibility section 4.1.5 to include LAR 
No 
 
02/17/2017 Throughout protocol clarified upper age eligibility 
criteria  
No 
 
05/02/2017 
• Throughout protocol, clarified that PBSC may be 
used if haplo donor is not a suitable candidate for 
marrow harvest 
• Corrected typo on page 12 & 13 
Yes 
(corrected 
typo on 
adult 
consent) 
 
07/18/2017 
• Edited wording on 5/2/17 clarification, per CPRC 
request 
No 
 
03/12/2018 
• Changed PI to Dr. Brunstein; fixed typo to 
removed day 28 bone marrow biopsy 
Yes 
 
09/18/2018 
• Added Dr. Najla El Jurdi to study committee 
• Revised treatment plans based on age and co-
morbidity scores. Arm B closed. Arms C and D 
added. 
• Moved standard clinical procedures to (new) 
appendix IV  
• Updated standard of care activity table, and 
moved post engraftment follow up to (new) 
appendix V 
• Revised statistics to account for closure of Arm B, 
and for new Arms C & D 
• Minor edits for clarity 
Yes 
 
05/15/2019 
• Section 7.1, 7.2, 7.3, Appendix IV: clarified the 
timing of infusion and post-transplant 
cyclophosphamide, tacrolimus and MMF in the 
event a donor undergoes more than one apheresis 
collection. 
• Dr. El Jurdi takes over as principal investigator 
Yes 
(corrected 
typo on 
consents) 
 
 
01/21/2021 
• Removed eligibility checklists 
• Eligibility – HIV+ patients will be permitted if 
patient has undetectable viral load; removed 
comorbidity index threshold for older individuals; 
allow for PBSC donor source 
• Minor edits of typographical errors 
Yes 
 
09/09/2021 
• Synopsis, Sections 3, 12.3 and 12.4 increased 
accrual goal in Arm D due to faster than expected 
enrollment 
• Edits to the synopsis and eligibility criteria to 
ensure both sections matched 
• Section 11.2 updated link to DSMP 
Yes 


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CPRC #2016LS092 
 
11/10/2021 
• Minor eligibility clarification in Synopsis, schema, 
eligibility: patients who had previous allogeneic 
transplant, autologous transplant or cellular 
therapy are only eligible for Arm D 
No 
 
03/11/2024 
• PI change 
Yes 
 
 
 
 
PI Contact Information: 
Mark Juckett, MD 
Division of Hematology/Oncology/Transplantation 
MMC 480 
420 Delaware Street SE 
Minneapolis, MN 55455 
612 625-8942 (phone) 
juck0001@umn.edu (email) 
 


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Table of Contents 
 
Study Synopsis .................................................................................................................................... 6 
Schema ................................................................................................................................................. 9 
1 
Study Objectives ........................................................................................................................ 11 
1.1 
Primary Objective............................................................................................................... 11 
1.2 
Secondary Objectives ....................................................................................................... 11 
1.3 
Transplant Related Objectives ......................................................................................... 11 
2 
Background and Rationale ....................................................................................................... 11 
3 
Study Design .............................................................................................................................. 15 
4 
Patient Selection ........................................................................................................................ 15 
4.1 
Inclusion Criteria ................................................................................................................ 15 
4.1.1 
Age, Performance Status, and Graft Criteria ......................................................... 15 
4.1.2 
Eligible Diseases ........................................................................................................ 16 
4.1.3 
Organ Function Criteria ............................................................................................. 18 
4.2 
Exclusion Criteria ............................................................................................................... 19 
5 
Donor Selection .......................................................................................................................... 19 
6 
Patient Registration in OnCore ................................................................................................ 20 
7 
Treatment Plan ........................................................................................................................... 21 
7.1 
Preparative Arm A ............................................................................................................. 22 
7.2 
Preparative Arm C ............................................................................................................. 24 
7.3 
Preparative Arm D ............................................................................................................. 26 
7.4 
Post-Transplant Cyclophosphamide (Day 3 and Day 4) ............................................. 27 
7.5 
Post-Transplant Support ................................................................................................... 28 
7.6 
Follow-up ............................................................................................................................. 28 
8 
Expected Toxicities of the Treatment Plan ............................................................................ 28 
8.1 
Preparative Regimen......................................................................................................... 28 
8.2 
Haploidentical Donor Stem Cell Infusion........................................................................ 29 
8.3 
GVHD Prophylaxis ............................................................................................................. 30 
8.4 
G-CSF .................................................................................................................................. 31 
9 
Clinical Care Evaluations .......................................................................................................... 32 


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10 
Adverse Event Documentation and Reporting .................................................................. 33 
10.1 
Event Documentation ........................................................................................................ 33 
10.2 
Adverse Event Reporting .................................................................................................. 33 
11 
Study Data Collection and Monitoring ................................................................................ 33 
11.1 
Data Collection ................................................................................................................... 33 
11.2 
Data and Safety Monitoring .............................................................................................. 34 
11.3 
Study Related Monitoring ................................................................................................. 34 
11.4 
Record Retention ............................................................................................................... 34 
12 
Statistical Considerations ..................................................................................................... 35 
12.1 
Statistical Endpoints .......................................................................................................... 35 
12.1.1 
Primary Endpoint ....................................................................................................... 35 
12.1.2 
Secondary Endpoints ................................................................................................ 35 
12.1.3 
Transplant Related Endpoints ................................................................................. 35 
12.2 
Statistical Analysis ............................................................................................................. 35 
12.3 
Design and Sample-Size Justification ............................................................................ 36 
12.4 
Toxicity Monitoring and Stopping Rules ......................................................................... 37 
12.4.1 
Treatment Related Mortality by 100 days .............................................................. 37 
12.4.2 
Grade III-IV by 100 days ........................................................................................... 37 
13 
Conduct of the Study ............................................................................................................. 38 
13.1 
Record Retention ............................................................................................................... 38 
13.2 
Ethical Considerations ...................................................................................................... 38 
13.3 
Informed Consent .............................................................................................................. 38 
14 
References .............................................................................................................................. 38 
Appendix I – Eligibility Checklist ...................................................................................................... 44 
Appendix II – Karnofsky Performance Status and Lansky Play Score ...................................... 45 
Appendix III – TBI Guidelines .......................................................................................................... 46 
Appendix IV Standard Transplant Procedures and Supportive Care ........................................ 47 
Appendix V Standard of Care Clinical Follow-up .......................................................................... 50 
 


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Study Synopsis 
Reduced Intensity Conditioning (RIC) and Transplantation of HLA-
Haploidentical Related Hematopoietic Cells (Haplo-HCT) For 
Patients with Hematologic Malignancies 
MT2016-15 
 
Study Design: 
This is a two stage phase II trial of HLA-haploidentical related hematopoietic 
cells transplant (Haplo-HCT) using a reduced intensity conditioning 
(cyclophosphamide, fludarabine, melphalan, total body irradiation) with 
modifications based on factors including age and comorbidities.  Bone marrow 
is the donor graft source. 
 
This study is designed to estimate disease-free survival (DFS) at 1 year post-
transplant.  Since the goal is to estimate the DFS at a long-term time-point (1 
year post-transplant), the design has a planned interim analysis without 
suspension of accrual for futility when 15 subjects have been enrolled on arms 
A, C and D.  
 
Primary Objective Probability of 1 year disease-free survival (DFS) 
 
Secondary 
Objectives: 
• Incidence of day 100 grade II-IV and grade III-IV acute graft versus-host-
disease (GVHD)  
• Probability of 6 month, 1 and 2 year treatment related mortality (TRM) 
• Probability of 1 and 2 year relapse incidence 
• Incidence of serious fungal and viral infections at day 100 and 1 year post-
HCT 
  
Transplant 
Related 
Objectives: 
• Incidence of neutrophil recovery by day +30 
• Incidence of platelet recovery by day +60  
• Donor cell engraftment (chimerism) at day +21, +60, +100, +180 and + 365 
• Incidence of 1 and 2 year chronic GVHD 
• Probability of 1 and 2 year GVHD and relapse-free survival (GRFS) 
• Probability of 2 year DFS 
• Probability of 1 and 2 year overall survival (OS) 
 
Treatment Plan 
Arm A: haplo-HCT in patients with HCT-CI ≤2* <55 years old:  
- Fludarabine (Flu) 30 mg/m2 IV Days -6, -5, -4, -3, -2 
- Cyclophosphamide (Cy) 30 mg/kg IV Day -6 
- Melphalan (Mel) 100 mg/m2 IV Days -5 
- Total body irradiation (TBI) 200cGy Days -2, -1 
- Day 0 Infuse non-T-cell depleted donor bone marrow stem cells 
CLOSED: Arm B: haplo-HCT in patients ≥55 years old (or younger with HCT-
CI ≥3*): 
- Fludarabine (Flu) 30 mg/m2 IV Days -6, -5, -4, -3, -2 
- Cyclophosphamide (Cy) 30 mg/kg IV Day -6 
- Melphalan (Mel) 70 mg/m2 IV Days -5 
- TBI 200cGy Days -2, -1 
- Day 0 Infuse non-T-cell depleted donor bone marrow stem cells  
* HCT-CI calculator: http://www.qxmd.com/calculate-online/hematology/hct-ci 
 
Arm C: haplo-HCT in patients with HCT-CI ≤2* aged ≥55 and < 65 years old: 
- Fludarabine (Flu) 30 mg/m2 IV Days -6, -5, -4, -3, -2 
- Cyclophosphamide (Cy) 30 mg/kg IV Day -6 


MT2016-15:  RIC Haplo-HCT for Hematologic Malignancies 
 
 
 
 
 
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CPRC #2016LS092 
- Melphalan (Mel) 70 mg/m2 IV Days -5 
- TBI 200cGy Days -2, -1 
- Day 0 Infuse non-T-cell depleted donor bone marrow stem cells  
* HCT-CI calculator: http://www.qxmd.com/calculate-online/hematology/hct-ci 
 
 
Arm D: haplo-HCT in patients ≥65 and ≤75 years old OR any age group with 
HCT-CI ≥3* OR patients who had previous allogeneic transplant, autologous
transplant or cellular therapy:  
- -Fludarabine 30 mg/m2 IV Days -6, -5, -4, -3, -2 
- -Cyclophosphamide 30 mg/kg IV Day -6 
- -TBI 200cGy Days -2, -1 
* HCT-CI calculator: http://www.qxmd.com/calculate-online/hematology/hct-ci 
 
 
GVHD Prophylaxis (all patients): 
- Cyclophosphamide (Cy) 50 mg/kg IV Days +3, +4 
- Tacrolimus (Tac) IV or PO beginning Day +5 (or sirolimus, if intolerant) 
- Mycophenolate mofetil (MMF) beginning Day +5 
Eligible 
Diseases: 
• Acute 
leukemia in complete remission, myelodysplastic syndrome, 
myeloproliferative neoplasm or chronic myelogenous leukemia with <5% 
blasts in bone marrow by morphology;  
• Chemotherapy sensitive: chronic lymphocytic leukemia/small lymphocytic 
lymphoma; follicular lymphoma; marginal zone lymphoma; mantle cell 
lymphoma; diffuse large B-cell lymphoma; Hodgkin’s lymphoma, Burkitt’s 
lymphoma; T-cell lymphoma, natural killer cell malignancies and multiple 
myeloma eligible for an allogeneic transplantation 
 
Selected 
patients 
may 
be 
eligible 
in 
post-chemotherapy 
and 
radioimmunoconjugate- induced aplasia 
 
Selected patients in CR, but with positive immunophenotypic (flow cytometry) or 
molecular evidence of minimal residual disease (MRD) may be eligible if recent 
chemotherapy has not resulted in MRD negative status. 
 
Age, PS and 
Graft 
Requirements: 
• ≤ 75 years of age 
• Karnofsky performance status of ≥70% or Lansky play score ≥ 70% 
• A related haploidentical bone marrow/PBSC donor with up to 2 or 3 HLA locus-
mismatches 
• The donor and recipient must be HLA identical for at least one haplotype 
(using high resolution DNA based typing) at the following genetic loci: HLA-A, 
HLA-B, HLA-C, and HLA-DRB1. 
 
Other Inclusion 
Criteria: 
• Adequate liver and renal function  
• Absence of decompensated congestive heart failure, or uncontrolled 
arrhythmia and left ventricular ejection fraction ≥ 40% 
• DLCOcorr > 40% predicted, and absence of O2 requirements 
• > 6 months after prior autologous transplant (if applicable) 
• Patients who are HIV+ must have undetectable viral load. All HIV+ patients 
must be evaluated by Infectious Disease (ID) and a HIV management plan 
establish prior to transplantation 
 


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Exclusion 
Criteria: 
• 
≤ 75 years with an available 5-6/6 HLA-A, B, DRB1 matched sibling donor 
• 
Pregnancy or breastfeeding 
• 
Current active and uncontrolled serious infection 
• 
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). 
• 
CML in blast crisis 
• 
Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that is 
progressive on salvage therapy. Stable non-bulky disease is acceptable. 
• 
Active central nervous system malignancy 
• 
Less than 3 months since prior myeloablative transplant (if applicable); less 
than 6 months since prior autologous transplant (if applicable)  
• 
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. 
 
Donor 
Requirements 
Donor Selection: 
• 
Donors must be HLA-haploidentical relatives of the patient, defined as having 
a shared HLA haplotype between donor and patient at HLA-A, -B, -C, and -
DRB1. 
• 
Eligible donors (14-70 years old) include biological children, siblings or half 
siblings, or parents, able and willing to undergo bone marrow harvesting or 
PBSC collection.  
• 
For donors <18 years, the maximum recipient weight (actual body weight) 
should not exceed 1.25 times the donor weight (actual body weight)1 In 
addition, bone marrow product volume should be limited to 20 ml/kg donor 
weight for donors <18 years. 
 
Donor Prioritization Schema: 
In the event that two or more eligible donors are identified, the following order 
of priority is suggested: 
• 
 Medically fit to donate 
• 
 Absence of recipient donor-specific anti-HLA antibodies (DSA) 
• 
 Donor age 18-40 years is prioritized over donor age < 18, then > 40, with 
donors <70 preferred. If multiple 18-40 year old donors are available, the 
youngest donor is prioritized.  
• 
 Lack of major ABO incompatibility 
• 
 For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative 
donor 
• 
 Lack of minor ABO incompatibility 
• 
 Male donor or non-parous female preference for male patients.  
 
 
Enrollment: 
The accrual goal :  94 patients (28 patients separately for arms A and C; and 38 
patients in Arm D) 
 
 
 


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Schema 
ARM A:  reduced-intensity conditioning and transplantation of HLA-haploidentical 
related donor stem cells for patients <55 years old with HCT Comorbidity Index* 
(HCT-CI) ≤2 
 
 
 
 
 
 
 
 
 
 
CLOSED ARM B:  reduced-intensity conditioning and transplantation of HLA-
haploidentical related donor stem cells for patients ≥55 years old or younger with HCT 
Comorbidity Index* (HCT-CI) ≥3. 
 
 
 
 
 
 
 
 
 
 
 
-8 
-4 
-5 
-2 
-3 
0 
-1 
+40 
+30 
+20 
+10 
+5 
+60 
+50 
+180 
   Flu 30 mg/m
2/day          CY 50 mg/kg/day 
TBI 2Gy/day 
BM infusion 
Tac 
MMF 
G-CSF 
-7 -6 
CY 30 mg/kg 
Mel 100 mg/m2 
-8 
-4 
-5 
-2 
-3 
0 
-1 
+40 
+30 
+20 
+10 
+5 
+60 
+50 
+180 
  Flu 30 mg/m
2/day          CY 50 mg/kg/day 
TBI 2Gy/day 
BM infusion 
Tac 
MMF 
G-CSF 
-7 -6 
CY 30 mg/kg 
Mel 70 mg/m2 


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ARM C: Haplo-HCT in patients with HCT-CI ≤2* aged ≥55 and < 65 years old: 
 
 
 
 
 
 
 
 
 
 
ARM D: haplo-HCT in patients ≥65 and ≤75 years old OR any age group with HCT-CI ≥3* or 
patients who had previous allogeneic transplant, autologous transplant or cellular 
therapy: 
 
 
 
 
 
 
 
 
 
 
* HCT-CI calculator: http://www.qxmd.com/calculate-online/hematology/hct-ci 
 
 
-8 
-4 
-5 
-2 
-3 
0 
-1 
+40 
+30 
+20 
+10 
+5 
+60 
+50 
+180 
  Flu 30 mg/m
2/day          CY 50 mg/kg/day 
TBI 2Gy/day 
BM infusion 
Tac 
MMF 
G-CSF 
-7 -6 
CY 30 mg/kg 
Mel 70 mg/m2 
-8 
-4 
-5 
-2 
-3 
0 
-1 
+40 
+30 
+20 
+10 
+5 
+60 
+50 
+180 
  Flu 30 mg/m
2/day          CY 50 mg/kg/day 
TBI 2Gy/day 
BM infusion 
Tac 
MMF 
G-CSF 
-7 -6 
CY 30 mg/kg 
 


MT2016-15:  RIC Haplo-HCT for Hematologic Malignancies 
 
 
 
 
 
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1 Study Objectives 
1.1 
Primary Objective 
The primary objective is to estimate probability of the 1 year disease free 
survival (DFS) after a HLA-haploidentical related hematopoietic cells transplant 
(Haplo-HCT) 
using 
a 
reduced 
intensity 
cyclophosphamide/fludarabine/melphalan/total 
body 
irradiation 
(TBI) 
conditioning with modifications based on factors including age and 
comorbidities in patients with a hematologic malignancy.  
1.2 
Secondary Objectives 
Secondary objectives are: 
• Incidence of day 100 grade II-IV and grade III-IV acute graft versus-host-
disease (GVHD)  
• Probability of 6 month, 1 and 2 year treatment-related mortality (TRM) 
• Probability of 1 and 2 year relapse incidence 
• Incidence of serious fungal and viral infections at day 100 and 1 year post-
HCT 
1.3 
Transplant Related Objectives 
• Incidence of neutrophil recovery by day +30 
• Incidence of platelet recovery by day +60  
• Donor cell engraftment (chimerism) at day +21, +100, +180 and + 365 
• Incidence of 1 and 2 year chronic GVHD 
• Probability of 1 and 2 year GVHD and relapse-free survival (GRFS) 
• Probability of 2 year DFS 
• Probability of 1 and 2 year overall survival (OS) 
2 Background and Rationale 
Allogeneic (allo) hematopoietic cell transplantation (HCT) is widely used as a 
curative therapy for number of hematological malignancies.  Reduced intensity 
conditioning (RIC) opened opportunities for older patients and those with comorbid 
conditions to be eligible for potentially curable transplantation.2-6  
However, donor availability still remains significant challenge for large number of 
patients as HLA-identical matched sibling (MSD) or adult unrelated donor (MUD) 
is available only for about 60% of the patients.7  In addition, the data from the 
National Marrow Donor Program (NMDP) indicate that median time from donor 
search to adult MUD transplant is about 3-4 months.  This time delay increases 
the risk of malignancy relapse in some patients with aggressive diseases.2, 3   


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Since adult MUD is generally not readily available for many patients with 
hematological malignancies who are in need for urgent HCT, recent years number 
of transplant centers widely expended the use of alternative graft sources such as 
umbilical cord blood (UCB) or haploidentical grafts. 2-6, 8-12 Although UCB is timely 
available for most of the Caucasian patients, its availability is significantly less for 
ethnic minorities such as African Americans or Asians.  Furthermore, significantly 
high cost of UCB as compared to other donor sources remains an additional 
limitation.  
In contrast, lower cost and easy accessibility of haploidentical transplantation 
(haplo-HCT) makes it an attractive alternative graft source. First-degree relative 
haploidentical donor is available for more than 95% of individuals with average 
such donor number of 2.7.7, 13 Initial experience with haplo-HCT using T-cell 
replete allograft was disappointing with unacceptably high incidence of severe graft 
versus host disease (GVHD) and transplant-related mortality (TRM) in about half 
of the patients.14-16 However, when T-cells were depleted and reduced-intensity 
conditioning (RIC) regimen was used there was an excessive risk of graft failure. 
Engraftment was improved with mega-doses of CD34 + cells (over 10x106cells/kg) 
infusion and/or when full intensity conditioning regimen was used.10, 13, 17 On the 
other hand T-cell depleted myeloablative regimen was associated with significantly 
increased mortality from serious infections/unacceptable immune reconstitution as 
reported by the European Group for Blood and Marrow Transplantation (EBMT) 
among 266 acute leukemia patients with 2-year TRM ranging between 36-61±10% 
depending on remission status at transplant.17 Subsequently, in order to minimize 
GVHD risk without significantly affecting immune reconstitution following haplo-
HCT several strategies were undertaken most of which are still in developmental 
stage. One such approach is to augment the immune reconstitution after T-cell 
depleted haplo-HCT by infusion of pathogen-specific T-cells,18-22 T-cells 
engineered to express suicide genes,23-25 regulatory T-cells (Tregs),26, 27 or to 
perform alloreactive donor T-cell ex-vivo photodepletion.28, 29 Another approach is 
to perform selective allodepletion in T-cell replete haplo-HCT by ex vivo anergy 
induction by costimulation blockade,30, 31 ex vivo selective depletion of T-cells,32-34 
or use of high-dose post-transplant cyclophosphamide (PT-Cy).11, 35-38 PT-Cy 
approach was pioneered by Johns Hopkins University (JHU) group using RIC 
regimen consisting of Flu 30 mg/m2/day IV daily from Days  -6 to -2, Cy 14.5 mg/kg 
IV on Day -6 and -5, and 200 cGy TBI in a single fraction on Day -1 
(Flu150Cy29TBI200). 1, 39-41 PT-Cy has been shown to promote in vivo depletion 
of alloreactive T-cells that helps reducing both graft rejection and GVHD rates after 
transplantation.42 In recent years PT-Cy approach either in a setting of RIC 
(Flu150Cy29TBI200 or other regimens) or myeloablative conditioning has become 
widely used in many transplant centers given its easy accessibility and lower 


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cost.11, 36, 43-50  Munchel and colleagues reported 87% sustained engraftment, 27% 
grades II-IV acute GVHD and 13% chronic GVHD rates in 210 haplo-
HCT(Flu150Cy29TBI200)/PT-Cy recipients with 5-year TRM of 18%, relapse 
incidence of 55% and overall survival (OS) of 35%.35  The same group most 
recently reported better engraftment rate and OS after Haplo-HCT when younger 
donors (<40 years old) are selected for bone marrow donation.40  They identified 
in that study that the yield of CD34+ dose (>2.5 x106/kg, in some cases 4-8 
x106/kg) is higher in younger donors.40  Ciurea and colleagues compared the 
clinical outcomes of 65 recipients of melphalan, fludarabine and thiotepa 
conditioning regimen and haplo-HCT with T-cell replete BMT/PT-Cy versus T-cell 
depleted peripheral blood HCT and demonstrated superiority of T-cell replete 
BMT/PT-Cy with statistically significant improvement of 1-year NRM (16% vs. 42%, 
p=0.03), chronic GVHD rate (8% vs. 18%, p=0.03), progression free (PFS) (45% 
vs. 21%, p=0.03) and OS (66% vs. 30%, p=0.02).36   
Several recent studies also suggest improvement of immune reconstitution with 
preserved memory T-cells when PT-Cy is used in T-cell replete haplo-HCT.35, 37 
Brunstein et al. compared the outcomes of patients with haplo-BM/PT-Cy (BMT 
CTN 0603, n=50) and UCB transplantation (BMT CTN 0604, n=50) after RIC in 
Blood and Marrow Transplant Clinical trials Network (BMT-CTN) 2 parallel 
multicenter phase 2 trials.9  Eligibility criteria for the two trials were the same and 
included patients up to 70 years with hematological malignancies.  The target 
accrual of 50 patients per trial was achieved in just 20 months (16 months faster 
than expected).  The primary endpoint of the study was to determine overall 
survival 180 days after BMT, with examination of neutrophil and platelet recovery, 
graft failure, acute GVHD, chronic GVHD, incidence of infections, transplant 
related mortality, time to relapse, and progression free survival as secondary 
endpoints.  Recipients of haplo-HCT were conditioned with Flu150Cy29TBI200 
and UCB recipients received Flu 40mg/m2 Days -6 to -2, Cy 50 mg/kg Day -6 and  
TBI 200 cGy Day -1 (Flu200/Cy50/TBI200).  GVHD prophylaxis for haplo-HCT 
consisted of Cy 50 mg/kg IV on Days +3 and +4 followed by MMF and tacrolimus 
beginning on Day +5.  UCB recipients received MMF and CSA beginning on Day 
-3 for GVHD prophylaxis. The 1-year probabilities of OS and DFS were 54% and 
46% after double UCB transplantation (n =50) and 62% and 48%, respectively, 
after haplo-HCT (n = 50). The cumulative incidence of neutrophil recovery at day 
56 was 94% after dUCB and 96% after Haplo-HCT. The cumulative incidence of 
grade II-IV acute GVHD at Day 100 was 40% after UCB and 32% after haplo-HCT.  
The 1-year cumulative incidences of TRM and relapse after UCB transplantation 
were 24% and 31%, respectively, and those for haplo-HCT were 7% and 45%, 
respectively.  


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This set the stage for current ongoing BMT-CTN 1101 a multicenter, randomized 
phase III trial that aims to compare 2-year PFS between haplo and UCB graft 
sources. Despite haplo-HCT/PT-Cy after Flu150Cy29TBI200 conditioning 
resulting into low TRM and survival comparable to MSD or MUD transplant in some 
recent reports,11, 41, 48 high risk of relapse ranging between 45-60% still remains 
the major challenge of haplo-HCT/PT-Cy particularly for AML diagnosis.1, 36, 40, 43   
Efforts to reduce relapse by using full intensity conditioning regimens with haplo-
HCT/PT-Cy in younger patients lowered the risk of post-transplant AML relapse to 
20-45% without substantial increase in TRM in some reports.45, 50  However, since 
myeloablative conditioning is not an option for older patients and for those with 
higher comorbidities (HCT-CI ≥3) due to an acceptably high risk of TRM,  strategies 
identifying novel RIC regimen platforms that can reduce the risk of relapse and 
improve survival after haplo-HCT/PT-Cy are in great demand for those >55 years 
old or with comorbidities.  Most recently Flu/Mel and Flu/Busulfan RIC regimens 
were compared in matched adult donor alloHCT setting for AML/MDS, and 
significantly lower relapse rate and better survival was observed in those receiving 
Flu/Mel conditioning regimen.51  Intensification of Flu150/Cy50/TBI 200 RIC 
regimen in another study with addition of 5-10 mg/kg Thiotepa and increasing the 
those of TBI to total 400 cGy (200 cGy day -2 and -1) resulted into low 2-year 
relapse rate of 11% with TRM of 17% and encouraging 2-year DFS rate of 66% in 
patients receiving UCB allograft for hematological malignancies.52  The group from 
MD Anderson Cancer Center (MDACC) recently reported their experience with 
haplo-HCT/PT-Cy with use of Flu 40 mg/m2 Day -6 to -3, Melphalan (Mel) 140 
mg/m2 Day -8 and either Thiotepa 5 mg/kg Day -7 or TBI 200 cGy (FM140) 
conditioning regimen where Mel dose was reduced to 100 mg/m2 (FM100) in 
patients 55 years and older. 49, 50 Despite reported low 1-year relapse rates of 11-
19% with FM regimen in these studies, prolonged course of intensive immune 
suppression (MMF through Day +90 and Tac through Day +180) was required in 
order to minimize the risk of excessive acute GVHD.49, 50 Since high dose of Mel 
exposure per kilogram of body weight (>3.5mg/kg) has been previously shown to 
increase the risk of oral mucositis and subsequent acute GVHD rate in alloHCT 
recipients,53  51% grade II-IV acute GVHD rate, despite intensive GVHD 
prophylaxis, at least in part can be explained by higher dose of Mel (FM140) use 
in MDACC study.49  
We hypothesize that intensification of Flu150/Cy29/TBI 200 haplo-HCT/PT-Cy RIC 
regimen with addition of low dose Mel of 100 mg/m2 Day -5 (70 mg/m2 for patients 
≥55 years and HCT-CI ≥3) and total TBI dose increase to 400 cGy (200 cGy Day 
-2 and -1) can successfully reduce the risk of relapse and improve DFS after haplo-
HCT without substantially increasing the risk of TRM.  Therefore, we propose to 


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conduct a phase II study using RIC regimen platform Flu 30 mg/m2 IV Days -6 to -
2, Cy 30 mg/kg IV Day -6; Mel 100 mg/m2 IV Days -5 and TBI 200cGy Days -2 and 
-1 (Flu150/Cy30/Mel100/TBI400) followed by haplo-HCT/PT-Cy and tacrolimus (or 
sirolimus), mycophenolate mofetil GVHD prophylaxis for patients with 
hematological malignancies where Mel dose reduction to 70 mg/m2 IV Day -5 will 
be 
used 
in 
patients 
≥55 
years 
old 
and 
those 
with 
HCT-CI 
≥3 
(Flu150/Cy30/Mel70/TBI400).  
3 Study Design 
This is a single institution phase II study of a reduced intensity conditioning (RIC) 
followed by a haploidentical hematopoietic cell transplant (haplo-HCT) in persons 
with diagnosis of hematologic malignancy.   
 
Conditioning will consists of fludarabine, cyclophosphamide, melphalan and total 
body irradiation (TBI) preparative regimen with a melphalan dose reduction for 
patients ≥55 years old and those with HCT Comorbidity Index (CI) ≤ 2. No 
melphalan will be given to subjects age ≥ 65 - ≤ 75 or subjects of any age with a 
CI of ≥3. 
 
This study uses a two-stage phase II design with accrual goal of 94 patients, using 
28 patients separately for arms A and C;  and 38 patients in Arm D (arm B has 
been closed).  
4 Patient Selection 
Study entry is open to persons less than 75 years of age, regardless of gender, 
race or ethnic background.  While there will be every effort to seek out and include 
females and minority patients, the patient population is expected to be no different 
than that of a similar studies at the University of Minnesota. 
4.1 Inclusion Criteria 
4.1.1 
Age, Performance Status, and Graft Criteria 
• Must be <75 years old with no 7/8 or 8/8 HLA-matched sibling 
donor. We recommend counseling patients ≥ 65 about the higher 
risk of non-relapse mortality (NRM), especially in the context of co-
morbidities  
• Adequate performance status is defined as Karnofsky score ≥ 70% 
(> 16 years of age) or Lansky score ≥ 70 (pediatrics) (Appendix II) 
• Patients and selected donor must be HLA typed at high resolution 
using DNA based typing at the following HLA-loci: HLA-A, -B, -C and 


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DRB1. Donors must be HLA-haploidentical relatives including, but not 
limited to, children, siblings, or parents, defined as having a shared 
HLA haplotype between donor and patient at HLA-A, -B, -C, and -
DRB1. 
Refer to donor selection in section 5.  
4.1.2 Eligible Diseases 
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). 
Acute myeloid leukemia (AML): second or greater complete remission 
(CR); first CR (CR1) in patients ≥60 years old; CR1 in <60 years old that 
is NOT considered as favorable risk.   
• Favorable risk AML is defined as having one of the following: 
• t(8,21) without cKIT mutation 
• inv(16) or t(16;16) without cKIT mutation  
• Normal karyotype with mutated NPM1 but FLT3-ITD wild type 
• Normal karyotype with double mutated CEBPA 
• Acute prolymphocytic leukemia (APL) in first molecular remission 
at the end of consolidation 
Acute lymphoblastic leukemia (ALL)/lymphoma: second or greater 
CR; CR1 unable to tolerate consolidation chemotherapy due to 
chemotherapy-related toxicities; CR1 high-risk ALL.    
High risk ALL is defined as having one of the following: 
• Evidence of high risk cytogenetics, e.g. t(9;22), t(1;19), t(4;11), 
other MLL rearrangements, IKZF1 
• Recipient age 30 years and older at diagnosis 
• White blood cell counts of greater than 30,000/mcL (B-ALL) or 
greater than 100,000/mcL (T-ALL) at diagnosis 
• CNS leukemia involvement during the course of disease 
• Slow cytologic response (>10% lymphoblasts in bone marrow on 
Day 14 of induction therapy) 


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• Evidence of persistent immonophenotypic or molecular minimal 
residual disease (MRD) at the end of induction and consolidation 
therapy 
Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or 
subsequent CR. 
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 chemotherapy for cytoreduction to 
≤5% prior to transplantation. 
Chronic myelogenous leukemia in chronic or accelerated phase.  
Chronic phase patients must failed at least two different TKIs, been 
intolerant to all available TKIs or have T315I mutation. 
MRD positive leukemia (AML, ALL or accelerated/blast phase 
CML). Selected patients in morphologic CR, but with positive 
immunophenotypic (flow cytometry) or molecular evidence of MRD may 
be eligible if recent chemotherapy has not resulted in MRD negative 
status.  
Leukemia or MDS in aplasia. These patients may be taken to 
transplant if after induction therapy they remain with aplastic bone 
marrow and no morphological or flow-cytometry evidence of disease ≥ 
28 days post-therapy. These high risk patients will be analyzed 
separately. 
Myeloproliferative neoplasms/myelofibrosis. 
Relapsed large-cell lymphoma, mantle-cell lymphoma and Hodgkin 
lymphoma that is chemotherapy sensitive and has failed or ineligible 
for an autologous transplant.  
Burkitt’s lymphoma in CR2 or subsequent CR. 
Relapsed T-cell lymphoma that is chemotherapy sensitive in CR/PR 
that has failed or ineligible for an autologous transplant. 
Natural Killer cell malignancies.  
Relapsed 
chronic 
lymphocytic 
leukemia/small 
lymphocytic 
lymphoma (CLL/SLL), marginal zone B-cell lymphoma, follicular 
lymphoma, which have progressed within 12 months of achieving a 


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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 bulky 
disease and an estimated tumor doubling time of less than one month.  
Lymphoplasmacytic lymphoma is eligible after initial therapy if 
chemotherapy sensitive. 
Relapsed multiple myeloma that is chemotherapy sensitive and has 
failed or ineligible for an autologous transplant.  
Bone marrow failure syndromes, except for Fanconi Anemia. 
4.1.3 Organ Function Criteria 
 
Adequate organ function is defined as:  
Cardiac: Absence of decompensated congestive heart failure, or 
uncontrolled arrhythmia and left ventricular ejection fraction > 40%.  For 
children 
that 
are 
not 
able 
to 
cooperate 
with 
MUGA 
and 
echocardiography, such should be clearly stated in the physician’s note 
Pulmonary: DLCO, FEV1, FVC > 40% 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 provider’s note.  
Liver: Transaminases < 5 x upper limit of normal (ULN) and total bilirubin 
≤ 2.5 mg/dL except for patients with Gilbert’s syndrome or hemolysis.  
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/1.73m2. 
4.1.4 Patients who are HIV+ must have undetectable viral load. All HIV+ 
patients must be evaluated by Infectious Disease (ID) and a HIV 
management plan establish prior to transplantation. 
4.1.5 Patients who had previous allogeneic transplant, autologous transplant 
or cellular therapy are only eligible for Arm D 
4.1.6 Sexually active females of childbearing potential and males with 
partners of child-bearing potential must agree to use adequate birth 
control during study treatment.   


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4.1.7 Voluntary written consent (adult; Legally Authorized Representative on 
behalf of cognitively impaired adult; or parent/guardian with presentation 
of the minor information sheet, if appropriate) 
4.2 Exclusion Criteria 
4.2.1 ≤ 75 years with an available 5-6/6 HLA-A, B, DRB1 matched sibling 
donor 
4.2.2 Pregnant or breast feeding. The agents used in this study include 
Pregnancy Category D: known to cause harm to a fetus.  Females of 
childbearing potential must have a negative pregnancy test prior to 
starting therapy.  
4.2.3 Current active and uncontrolled serious infection 
4.2.4 Less than 3 months since prior myeloablative transplant (if applicable); 
less than 6 months since prior autologous transplant (if applicable)  
4.2.5 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. 
4.2.6 CML in blast crisis 
4.2.7 Large cell lymphoma, mantle cell lymphoma and Hodgkin disease that 
is progressing on salvage therapy. Stable non-bulky disease is 
acceptable. 
4.2.8 Active central nervous system malignancy 
5 Donor Selection 
Donor selection will be in compliance with 21 CFR 1271.  Donors will be evaluated, 
consented and enrolled via the University of Minnesota related donor protocol 
(MT2012-14C); however information in this protocol (including match criteria, 
donor selection priority if more than 1 available donor, cell collection target) 
overrules that protocol. While bone marrow is preferred, peripheral blood is an 
acceptable graft source for those haploidentical donors who are not suitable 
candidates for general anesthesia for bone marrow harvest, such as, but not 
limited to the elderly or morbidly obese, or per discussion with the treating 
physician. Total volume required will be the same as above requirements for 
marrow. 
In addition to meeting the criteria in MT2012-14C the following must be met: 


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5.1 Must be HLA-haploidentical relatives of the patient (biological parents, 
siblings, half-siblings or offspring), defined as having a shared HLA haplotype 
between donor and patient at HLA-A, -B, -C, and -DRB1 
5.2 14 to 70 years of age 
5.3 For donors less than 18 years of age, the maximum recipient weight (actual 
body weight) should not exceed 1.25 times the donor weight (actual body 
weight) and bone marrow product volume should be limited to 20 ml/kg donor 
weight. 
5.4 
Negative for HIV and active hepatitis B  
5.5 
Not pregnant - females of childbearing potential must have a negative 
pregnancy test  within 7 days of marrow collection 
Donor Prioritization Schema 
In the event that two or more eligible donors are identified, the following order of 
priority is suggested: 
• Medically fit to donate 
• Absence of recipient donor-specific anti-HLA antibodies (DSA). Positive 
DSA is defined as a positive crossmatch test of any titer (by complement-
dependent cytotoxicity or flow cytometric testing) or the presence of DSA to 
the high expression loci HLA-A, - B, -C, or -DRB1 with mean fluorescence 
intensity >1000 by solid phase immunoassay. 
• Donor age 18-40 is prioritized over donor age < 18, then >40, with donors 
<70 preferred. If multiple 18-40 year old donors are available, the youngest 
donor is prioritized.  
• Lack of major ABO incompatibility 
• For cytomegalovirus (CMV) seronegative recipients, a CMV seronegative 
donor 
• Lack of minor ABO incompatibility 
• Male donor or non-parous female are preferable.  
6 Patient Registration in OnCore 
Registration will occur after the patient/parent/guardian has signed the subject 
consent and eligibility is confirmed. To be eligible for registration to this study, the 
patient must meet each criteria listed on the eligibility checklist based on the 


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eligibility assessment documented in the patient’s medical record.  A copy of the 
eligibility checklist is under attachments within the study in OnCore. 
Donors will be registered onto the University of Minnesota Related Donor protocol 
“Procedure Guidelines For Related Hematopoietic Stem Cell Donors” (MT2012-
14C) 
Patients will be registered in OnCore by the Masonic Cancer Center’s Clinical Data 
Associates (CDA’s). 
At the time of registration in OnCore, the patient will be assigned to Arm A, Arm C, 
or Arm D: 
ARM A:  <55 years old with HCT-CI ≤2 (Flu150/Cy30/Mel100/TBI400) 
Closed 
- 
ARM 
B: 
 
≥55 
years 
old 
or 
younger 
with 
HCT-CI 
≥3 
(Flu150/Cy30/Mel70/TBI400) 
Arm C: patients with HCT-CI ≤2 aged ≥55 and < 65 years old 
Arm D: patients ≥65 and ≤75 years old OR any age group with HCT-CI ≥3 or  
patients who had previous allogeneic transplant, autologous transplant or cellular 
therapy 
7 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, antimicrobials, etc.). 
 
All patients will receive allopurinol 300 mg/day (for peds -150 mg/m2/day) PO, 
unless known allergy ending one day after the last dose of chemotherapy or TBI 
(may continue longer if clinically indicted). 
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. 
 
All drugs used in this study are commercially available by prescription. 
 
 


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7.1 Preparative Arm A  
< 55 years of age and CI ≤2 
Treatment 
Day 
Treatment 
Protocol 
Section  
Day –6 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
Cyclophosphamide 30  mg/kg IV over 2 hours 
Mesna IV (see below for dose and schedule) 
7.1 
Day -5 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
Melphalan 100 mg/ m2 IV over 15-20 minutes (give at 
least 24 hours after cyclophosphamide) 
7.1 
Day -4 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
7.1 
Day -3 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
7.1 
Day -2 
Fludarabine 30 mg/m2 IV over 30-60 minutes  
TBI 200 cGy 
7.1 
Appendix III 
Day -1 
TBI 200 cGy 
Appendix III 
Day 0* 
Non-T-cell depleted bone marrow* 
Appendix IV  
Day 3 
Cyclophosphamide 50 mg/kg IV 
Mesna IV (see section 7.4 for dose and schedule) 
7.4 
Day 4 
Cyclophosphamide 50 mg/kg IV 
Mesna IV (see section 7.4 for dose and schedule) 
7.4 
Day 5 
Begin tacrolimus (or sirolimus), mycophenolate 
mofetil, and G-CSF 
Appendix IV 
*(Peripheral blood is an acceptable graft source only for those haploidentical donors who are 
not suitable candidates for general anesthesia for bone marrow harvest, such as, but not limited 
to the elderly or morbidly obese). Refer to Appendix IV for note on timing of infusion if donor 
requires additional apheresis 
Fludarabine is administered as a 30-60 minute 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 
Pre-Transplant Cyclophosphamide Hydration prior to cyclophosphamide will 
be given according to recommended institutional standards, starting 12 hours 
prior to cyclophosphamide. 
Mesna dose will be 100% of the cyclophosphamide dose being given and 
divided into 5 doses.  20% of the total dose will be give prior to the start of 
cyclophosphamide, and then 3, 6, 9, and 12 hours after the start of 
cyclophosphamide.   


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Cyclophosphamide 30 mg/kg will be administered as a 2 hour intravenous 
infusion on Day –6.  Cyclophosphamide dosing is calculated based on ABW 
(actual weight) unless ABW is >150% of the IBW (Ideal Body Weight).  Then 
the dose should be computed using adjusted body weight.  
Ideal body weight is calculated using 50kg + [2.3kg x(height in inches – 60)] for 
men; 45.5kg + [2.3kg x(height in inches – 60)] for women.   
Adjusted body weight = IBW + 0.5(ABW-IBW).  
Melphlan is administered on Day –5 and at least 24 hours after the Day -6 
cyclophosphamide dose. The melphalan dose will be calculated based on 
Actual Body Weight.  High-dose Melphalan is administered via a central venous 
catheter following reconstitution with the provided sterile diluent.  High-dose 
melphalan should be administered diluted with sodium chloride and infused 
over 15-20 minutes. Vigorous maintenance hydration (> 1500ml/m2/day) will 
be administered with high dose melphalan starting 4 hours prior and continuing 
for at least 10 hours following the dose (day –5). 
 
TBI 200 cGy will be administered on Day -2 and Day -1.  Refer to appendix III. 
Haploidentical Marrow Infusion will be administered on Day 0 per institutional 
standard of care.  Refer to appendix IV. 
 
 


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7.2 Preparative Arm C  
Patients with HCT-CI ≤2 aged ≥55 and < 65 years old 
Treatment 
Day 
Treatment 
Protocol 
Section  
Day –6 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
Cyclophosphamide 30  mg/kg IV over 2 hours 
Mesna IV (see below for dose and schedule) 
7.2 
Days -5 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
Melphalan 70 mg/ m2 IV over 15-20 minutes (give at 
least 24 hours after cyclophosphamide) 
7.2 
Day -4 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
7.2 
Day -3 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
7.2 
Day -2 
Fludarabine 30 mg/m2 IV over 30-60 minutes and  
TBI 200 cGy 
7.2 
Appendix III 
Day -1 
TBI 200 cGy 
Appendix III 
Day 0* 
Non-T-cell depleted bone marrow* 
Appendix IV  
Day 3 
Cyclophosphamide 50 mg/kg IV 
Mesna IV (see section 7.4 for dose and schedule) 
7.4 
Day 4 
Cyclophosphamide 50 mg/kg IV 
Mesna IV (see section 7.4 for dose and schedule) 
7.4 
Day 5 
Begin tacrolimus (or sirolimus), mycophenolate mofetil, 
and G-CSF 
Appendix IV 
*(Peripheral blood is an acceptable graft source only for those haploidentical donors who are 
not suitable candidates for general anesthesia for bone marrow harvest, such as, but not limited 
to the elderly or morbidly obese). Refer to Appendix IV for note on timing of infusion if donor 
requires additional apheresis 
 
Fludarabine 30 mg/m2/day will be administered over 30-60 minutes intravenous 
infusion on Days –6 through –2 for a total dose of 150 mg/m2.  Fludarabine will 
be dosed according to the recipient’s actual body weight.  For patients who 
have an estimated or measured creatinine clearance < 70 ml/min/1.73 m2, or 
either prior CNS disease, prior brain radiation, or prior intrathecal 
chemotherapy, the fludarabine dose should be reduced by 20%.  Fludarabine 
dosing is based on the last creatinine clearance prior to the start of conditioning.  
The fludarabine dose should be the same on Days -6 to -2, even if the patient’s 
creatinine changes.   
Fludarabine must be administered before cyclophosphamide on Day -6 and 
before melphalan on Day -5. 


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Pre-Transplant Cyclophosphamide Hydration prior to cyclophosphamide will 
be given according to recommended institutional standards, starting 12 hours 
prior to cyclophosphamide. 
Mesna dose will be 100% of the cyclophosphamide dose being given and 
divided into 5 doses.  20% of the total dose will be given prior to the start of 
cyclophosphamide, and then 3, 6, 9, and 12 hours after the start of 
cyclophosphamide.   
Cyclophosphamide 30 mg/kg will be administered as a 2 hour intravenous 
infusion on Day –6.  Cyclophosphamide dosing is calculated based on ABW 
(actual weight) unless ABW is >150% of the IBW (Ideal Body Weight).  Then 
the dose should be computed using adjusted body weight. Ideal body weight is 
calculated using 50kg + [2.3kg x(height in inches – 60)] for men; 45.5kg + [2.3kg 
x(height in inches – 60)] for women.  Adjusted body weight = IBW + 0.5(ABW-
IBW).  
Melphalan 70 mg/m2 over 15-20 minutes will be administered on Day –5. 
Melphalan dose will be calculated based on Actual Body Weight. High-dose 
Melphalan is administered via a central venous catheter following reconstitution 
with the provided sterile diluent. High-dose melphalan should be administered 
diluted with sodium chloride and infused over 15-20 minutes. Vigorous 
maintenance hydration (> 1500ml/m2/day) will be administered with high dose 
melphalan starting 4 hours prior and continuing for at least 10 hours following 
the dose (day –5). 
TBI 200 cGy will be administered on Day -2 and Day -1.  Refer to appendix III. 
Haploidentical Marrow Infusion will be administered on Day 0 per institutional 
standard of care.  Refer to appendix IV. 
 
 


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7.3 Preparative Arm D  
Patients ≥65 and ≤75 years old OR any age group with HCT-CI ≥3 or 
patients who had previous allogeneic transplant, autologous transplant 
or cellular therapy 
 
Treatment 
Day 
Treatment 
Protocol 
Section  
Day –6 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
Cyclophosphamide 30  mg/kg IV over 2 hours 
Mesna IV (see below for dose and schedule) 
7.3 
Days -5 
Fludarabine 30 mg/m2 IV over 30-60 minutes, then 
7.3 
Day -4 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
7.3 
Day -3 
Fludarabine 30 mg/m2 IV over 30-60 minutes 
7.3 
Day -2 
Fludarabine 30 mg/m2 IV over 30-60 minutes and  
TBI 200 cGy 
7.3 
Appendix III 
Day -1 
TBI 200 cGy 
Appendix III 
Day 0* 
Non-T-cell depleted bone marrow* 
Appendix IV 
Day 3 
Cyclophosphamide 50 mg/kg IV 
Mesna IV (see section 7.4 for dose and schedule) 
7.4 
Day 4 
Cyclophosphamide 50 mg/kg IV 
Mesna IV (see section 7.4 for dose and schedule) 
7.4 
Day 5 
Begin tacrolimus (or sirolimus), mycophenolate mofetil, 
and G-CSF 
Appendix IV 
*(Peripheral blood is an acceptable graft source only for those haploidentical donors who are 
not suitable candidates for general anesthesia for bone marrow harvest, such as, but not limited 
to the elderly or morbidly obese). Refer to Appendix IV for note on timing of infusion if donor 
requires additional apheresis 
 
Fludarabine 30 mg/m2/day will be administered over 30-60 minutes intravenous 
infusion on Days –6 through –2 for a total dose of 150 mg/m2.  Fludarabine will 
be dosed according to the recipient’s actual body weight.  For patients who 
have an estimated or measured creatinine clearance < 70 ml/min/1.73 m2, or 
either prior CNS disease, prior brain radiation, or prior intrathecal 
chemotherapy, the fludarabine dose should be reduced by 20%.  Fludarabine 
dosing is based on the last creatinine clearance prior to the start of conditioning.  
The fludarabine dose should be the same on Days -6 to -2, even if the patient’s 
creatinine changes.   
Fludarabine must be administered before cyclophosphamide on Day -6. 


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Pre-Transplant Cyclophosphamide Hydration prior to cyclophosphamide will 
be given according to recommended institutional standards, starting 12 hours 
prior to cyclophosphamide. 
Mesna dose will be 100% of the cyclophosphamide dose being given and 
divided into 5 doses.  20% of the total dose will be given prior to the start of 
cyclophosphamide, and then 3, 6, 9, and 12 hours after the start of 
cyclophosphamide.   
Cyclophosphamide 30 mg/kg will be administered as a 2 hour intravenous 
infusion on Day –6.  Cyclophosphamide dosing is calculated based on ABW 
(actual weight) unless ABW is >150% of the IBW (Ideal Body Weight).  Then 
the dose should be computed using adjusted body weight. Ideal body weight is 
calculated using 50kg + [2.3kg x(height in inches – 60)] for men; 45.5kg + [2.3kg 
x(height in inches – 60)] for women.  Adjusted body weight = IBW + 0.5(ABW-
IBW).  
TBI 200 cGy will be administered on Day -2 and Day -1.  Refer to appendix III. 
Haploidentical Marrow Infusion will be administered on Day 0 per institutional 
standard of care.  Refer to appendix IV. 
7.4 Post-Transplant Cyclophosphamide (Day 3 and Day 4) 
Hydration and uroprotection will be given according to our institutional 
standards.  
Cyclophosphamide 50mg/kg will be given as an IV infusion over 1-2 hours 
(depending on volume) on Days 3 post-transplant (between 60 and 72 hours 
after marrow infusion) and on Day 4 post-transplant (approximately 24 hours 
after Day 3 cyclophosphamide).   
Cyclophosphamide dosing is calculated based on ABW (actual weight) unless 
ABW is >150% of the IBW (Ideal Body Weight).  Then the dose should be 
computed using adjusted body weight.  
Ideal body weight is calculated using 50kg + [2.3kg x(height in inches – 60)] for 
men; 45.5kg + [2.3kg x(height in inches – 60)] for women.   
Adjusted body weight = IBW + 0.5(ABW-IBW).  
Mesna should accompany post-transplantation cyclophosphamide.  Mesna will 
be dosed the same way as when it was given with the pre-transplantation 
cyclophosphamide (section 7.1 or 7.2). 


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7.5 Post-Transplant Support 
Standard Post transplant supportive care, including GVHD prophylaxis, growth 
factor support, and management of slow engraftment/graft failure are outlined 
in Appendix IV. 
7.6 Follow-up  
Patients will be followed for 2 years post-transplant per the standard of care 
schedule in section 9 and appendix V.   
Follow-up after 2 years will transition to the University of Minnesota standard 
hematopoietic stem cell transplantation protocol for long-term follow-up and 
data collection.  
8 
Expected Toxicities of the Treatment Plan 
8.1 Preparative Regimen 
Fludarabine 
Common 
Less Common 
Rare 
• 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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Cyclophosphamide 
Common 
Less Common 
Rare 
• 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) 
 
 
Melphalan 
Common 
Less Common 
Rare 
• 
nausea (at higher doses)  
• 
vomiting (at higher doses)  
• 
low white blood cell count 
with increased risk of 
infection  
• 
low platelet count with 
increased risk of bleeding  
• 
anemia (low red blood cell 
count) with symptoms like 
tiredness, paleness, or 
trouble catching breath 
 
• short-term or long-term 
infertility (inability to have 
children)  
• weakness 
 
• 
severe allergic reaction  
• 
loss of appetite  
• 
scarring (fibrosis) or 
inflammation of lungs  
• 
hair loss, including face and 
body hair  
• 
rash  
• 
itching  
• 
second type of cancer (may 
happen years after 
treatment)  
• 
death from lung damage or 
other causes  
 
Total Body Irradiation 
Common  
Less Common 
Rare 
• nausea and vomiting 
• diarrhea 
• cataracts 
• sterility (inability to have 
children) 
• endocrinopathies 
(hormone imbalance due 
to damage to the 
endocrine gland)  
• stunted growth in children 
• intestinal cramps 
• mucositis (mouth sores) 
• parotitis (swelling and 
inflammation of the parotid 
gland) 
• interstitial pneumonitis 
(explained below in the damage 
to vital organs section) 
• generalized mild reddening of 
the skin 
• veno-occlusive disease (VOD - 
explained below in the damage 
to vital organs section) 
• dysphagia (difficulty 
swallowing) 
• deformities of the 
backbone (vertebrae)  
• nephropathy (numbness 
or tingling in hands 
and/or feet) 
• risk of 2nd malignancy 
years later (when given 
along with 
chemotherapy) 
 
8.2 
Haploidentical Donor Stem Cell Infusion  
With the cell infusion 


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• 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) 
 
General transplant related risks  
• slow recovery of blood counts   
• graft failure 
• Graft-Versus-Host Disease (GVHD)  
• other complications including: 
o damage to the vital organs  
o serious infections  
o relapse of disease or a new blood cancer  
o risk to the unborn 
8.3 GVHD Prophylaxis 
Tacrolimus   
Common 
Less Common 
Rare, but may be serious 
 kidney problems 
 loss of magnesium, calcium, 
potassium 
 high blood pressure 
 tremors 
 increases in cholesterol and 
triglyceride 
 
 nausea 
 vomiting 
 liver problems 
 changes in how clearly one 
can think 
 insomnia 
 unwanted hair growth 
 confusion 
 
seizures 
 
changes in vision 
 
dizziness 
 
red blood cell destruction 
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. 
 
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 
• 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 


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Mycophenolate mofetil (MMF) 
Common 
Less Common 
Rare, but may be serious 
• tremors 
• low white blood cell count 
with increased risk of 
infection 
• increased blood 
cholesterols 
• swelling of the hands, feet, 
ankles or lower legs 
• secondary cancers, such as 
lymphoproliferative disease or 
lymphoma 
• Progressive Multifocal 
Leukoencephalopathy 
8.4  G-CSF 
Common 
Less Common 
Rare, but may be serious 
none 
• local irritation at injection site 
• ache or pain inside the bones 
• increased levels of liver enzymes 
• uric acid in the blood 
• low number of platelets in the blood 
• allergic reaction, low fever 
• enlargement of the spleen and even 
splenic rupture  
• worsening of pre-existing skin rashes,  
• hair loss  
• inflammation of a blood vessel in the skin 
 
 


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9 
Clinical Care Evaluations 
Scheduled evaluations after screening and until engraftment may be performed +/-
3 days from the targeted date.  Day 100 and subsequent assessments may be 
done +/- 30 days of the targeted date.  In addition, targeted days may be altered 
as clinically appropriate. 
Activity 
Pre-BMT 
Work-Up 
Day 1 To 
Engraftment1 
Follow-Up Days 
42-100 
Follow-Up ( >Day 100 
through Day 720) 
Consent 
X 
 
 
 
Medical History 
X 
weekly 
 
 
Physical Exam 
X 
weekly 
 
 
RT consultation 
X 
 
 
 
Karnofsky/Lansky 
X 
 
 
 
GVHD Assessment 
 
weekly start day 7 
weekly, day 100 
 
CBC/diff/plt3 
X 
daily 
 
 
PT/INR 
X 
 
 
 
Viral Screen 
X 
 
 
 
PRA (panel reactive 
antibody) 
X 
 
 
 
Comprehensive 
metabolic panel 
X 
 
 
 
Urinalysis 
X 
 
 
 
eGFR for adults with 
creat > 1.2 or hx or 
renal dysfunction 
X 
 
 
 
Pregnancy test (females 
of childbearing potential) 
X 
 
 
 
BM Biopsy 
X 
BM (day 21)  
 
 
BM chimerism  
 
BM (day 21) 
 
 
Blood chimerism  
Patient and 
donor 
PB (day 21) 
 
 
PFT/DLCO 
X 
 
 
 
MUGA or Echo 
X 
 
 
 
Chest CT 
X2 
 
 
 
Disease Evaluation4 
X 
X(day 21 to 28) 
X (day 100) 
X (day 360, 720) 
1 
engraftment defined as absolute neutrophil count (ANC) ≥ 5 X 108/L for 3 consecutive 
measurements  
2 
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. 
3 
If ANC<500 diff will not be calculated 
4 
With approval from the medical team, disease assessments may be performed at an outside 
institution 
NOTE: In certain clinical circumstances (e.g. relapsed or terminally ill patients) study tests may be 
omitted at the physician’s discretion).This will not be considered a deviation. 


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10 Adverse Event Documentation and Reporting 
Toxicity and adverse events will be classified according to NCI's Common 
Terminology Criteria for Adverse Events V 4.0 (CTCAE).  A copy of the CTCAE 
can 
be 
downloaded 
from 
the 
CTEP 
home 
page 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html  
10.1 Event Documentation  
Transplant related outcomes and events will be recorded in the Blood and 
Marrow Transplantation (BMT) database.   
Events requiring prompt reporting to the University of Minnesota Institutional 
Review Board (IRB), early stopping rule events, and protocol deviations will be 
documented in OnCore.  
10.2 Adverse Event Reporting  
The SAE Coordinator will provide the Masonic 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). 
11 
Study Data Collection and Monitoring 
11.1 Data Collection  
This study will track SAE’s, stopping rule events, and clinical deviations using 
The Online Enterprise Research Management Environment (OnCoreTM), a web 
based Oracle® database utilizing study specific electronic case report forms.   
All transplant related outcomes and complications will be recorded in the Blood 
and Marrow Transplantation (BMT) database. 
Agency 
Criteria for reporting 
Timeframe 
Form to 
Use 
Submission 
address/ fax 
numbers 
Copy to: 
U of MN IRB 
Events requiring prompt reporting including, but not 
limited to unanticipated death of a locally enrolled 
subject(s); new or increased risk; any adverse event  
that require a change to the protocol or consent 
form or any protocol deviation that resulting in harm  
For a complete list refer to 
http://www.research.umn.edu/irb/guidance/ae.htm
l#.VC7xraI0-sh  
Within 5 
business 
days of 
event 
discovery 
 
Report 
Form 
irb@umn.edu 
 
SAE Coordinator 
mcc-saes@umn.edu 
Masonic 
Cancer 
Center SAE 
Coordinator 
Events that impact the early study stopping rules. 
At time of 
reporting 
Event 
Form 
SAE Coordinator 
mcc-
saes@umn.edu 
n/a 


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11.2 Data and Safety Monitoring  
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring 
Plan (DSMP), which can be accessed at https://z.umn.edu/dsmp . 
For the purposes of data and safety monitoring, this phase II study is classified 
as moderate risk.  Therefore the following requirements will be fulfilled: 
 The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) 
will review the trial’s progress twice yearly 
 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 submission of all reportable adverse events per the 
definition of reportable in section 9.2 to the Masonic Cancer Center’s SAE 
Coordinator and the University of Minnesota IRB.   
 
In addition, at the time of the continuing review with the University of Minnesota 
IRB, a copy of the report with any attachments will be submitted to the Cancer 
Protocol Review Committee (CPRC). 
11.3 Study Related Monitoring  
The investigator will permit study-related monitoring, audits, and inspections by 
the IRB, government regulatory bodies, and University of Minnesota 
compliance groups.  The investigator will make available all study related 
documents (e.g. source documents, regulatory documents, data collection 
instruments, study data, etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.) will be available for trial related monitoring, audits, or regulatory 
inspections. 
11.4 Record Retention  
The investigator will retain study records for at 6 years after the study file is 
closed with the IRB and FDA.   
In addition, the Clinical Trials Office (CTO) will keep a master log of all patients 
participating in the study with sufficient information to allow retrieval of the 
medical records for that patient.  
Please contact the CTO before destroying any study related records. 


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12 
Statistical Considerations 
12.1 
Statistical Endpoints 
12.1.1 Primary Endpoint 
The primary endpoint is the probability of disease-free survival (DFS) by 
1 year post-transplant.  An event will be defined as death or a relapse. 
12.1.2 Secondary Endpoints 
• Probability of Grade II-IV and Grade III-IV aGVHD at 180 days 
• Probability of treatment-related mortality (TRM) at 6 months, 1 and 2 
years 
• Probability of relapse at 1 and 2 years  
• Probability of serious fungal and viral infections at day +100 and 1 year 
post-HCT 
12.1.3 Transplant Related Endpoints 
The following endpoints are not stressed but will be abstracted from the 
BMT database: 
• Probability of neutrophil recovery by day +30 
• Probability of platelet recovery by day +60 
• Proportion of donor cell engraftment (chimerism) at days +21, 
+100, +180 and +365 
• Probability of 1 and 2 year chronic GVHD 
• Probability of 1 and 2 year GVHD and relapse-free survival (GFRS) 
• Probability of 2-year DFS 
• Probability of 1 and 2 year overall survival (OS) 
 
12.2 
Statistical Analysis 
Arm B has been closed due to higher toxicity but we will analyze as intended 
to estimate endpoints under previous eligibility and conditioning. In order to 
reduce treatment-related mortality, future enrollment of patients previously 
eligible for arm B will be placed into two separate arms (C and D) based on age 
and HCT-CI with reduced conditioning in arm D. Eligibility for Arm C will 
primarily be changed to allow only patients aged 55-64 with HCT-CI≤2. The 
conditioning will remain the same. In Arm D, eligible patients will be age 65-75 
or have and HCT-CI ≥3 but Melphalan will be completely removed from the 
conditioning. Analysis will be performed separately for arms A, C and D as we 
are not certain if the disease-free survival will differ between the two groups. It 
is possible that PBSC will be used as a donor source but this is unexpected. 
These patients will be evaluated separately in a descriptive format. Otherwise 


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for the primary target study population, Kaplan-Meier curves will be used to 
estimate the probability of DFS, OS and GFRS along with respective 95% 
confidence intervals. Cumulative incidence will be used to estimate the 
probabilities of GVHD, relapse, infection, and neutrophil and platelet recovery 
treating non-event deaths as competing risks. The probability of TRM will be 
estimated in a similar manner but treating relapse as the competing risk. 
Ninety-five percent confidence intervals will be estimated from respective 
standard errors. The proportion of donor chimerism (classified as ≥70% donor 
cells at various time-points will be estimated among patients who have survived 
to the evaluated time-point). Descriptive plots and measures will also be used 
to evaluate chimerism as a continuous measure. Medians, ranges and inter-
quartile ranges will be given for actual chimerism values. Analyses will be 
performed and plots generated using SAS 9.3 (SAS Institute, Cary, NC) and/or 
R 3.5.1.  
12.3 Design and Sample-Size Justification 
This study is designed as a two-stage phase II trial to estimate disease-free 
survival (DFS) by one year post-transplant. We will potentially enroll 28 patients 
with one interim analysis (without pause in enrollment) at 15 subjects in each 
arm (A and  C) and 38 in Arm D. Since the goal is to estimate the DFS at a 
long-term time-point (1 year), we ran a simulated exponential model 10,000 
times based on complete follow-up and a one-sided log-rank test through 1 
year with interim analysis based on accrual of 15 subjects with incomplete 
follow-up to generate sample size and power estimates.  
 
When 15 subjects have been enrolled, we will discontinue the trial if the 
projected kaplain-meier curve has an estimated 1 year DFS of <32%. 
Assuming the null hypothesis of 30% DFS is true, we have a 42% chance of 
stopping the trial early due to futility which may vary depending on the rate of 
accrual. Assuming the alternative hypothesis of 60% DFS by 1 year, we have 
overall power of approximately 79%. Due to the number of comparisons, the 
Bonferonni correction for multiple comparisons has been employed (type-I 
error = 0.0167 (0.05/3)) to maintain an experiment-wise type-I error of 0.05.   
 
We expect to complete the study after 2-3 years of enrollment plus 1 year of 
follow-up after the last enrolled patients.  
 
08/19/21: Arm D has been accruing faster than expected (currently at 25 
patients with final enrollment of 28 patients). Given that Arm D has been shown 
to be efficacious with 1 year DFS of 52% (95% CL, 30-70%) and safe (2 TRM 
stopping rule events and 2 Grade III-IV aGVHD stopping rule events), we 


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CPRC #2016LS092 
propose to increase enrollment to 38 patients in Arm D. This will provide a more 
precise estimate of DFS for Arm D. Thirty-eight patients would decrease the 
95% confidence limit width by approximately 7%. 
 
12.4 Toxicity Monitoring and Stopping Rules 
Monitoring guidelines are developed to monitor excess toxicity using a 
continuous monitoring strategy based on an adaptation of Pocock stopping 
boundaries56.  In the event that a stopping rule is triggered, enrollment will be 
halted and the event reviewed by the study committee prior to re-initiation of 
enrollment.  
08/19/21: Given limited stopping rule events to date, continuous monitoring will 
cease after enrollment of 28 patients on Arm D. Safety measures including 
stopping rule events will subsequently be monitored by the DSMC on a 
quarterly basis for Arm D. Other arms will be monitored on a continuous basis. 
 
12.4.1 Treatment Related Mortality by 100 days 
Stopping rules were developed for excessive non-event mortality (TRM) 
by day 100 post-transplant. The goal is to construct a boundary based 
on TRM such that the probability of early stopping is at most 10% if the 
true rate is equal to 12% and our sample size is 28. Given these 
parameters, the upper stopping boundary for TRM is 2 deaths out of 2 
patients, 3 out of 6, 4 out of 11, 5 out of 16 or 6 out of 21 or 7 out of 27. 
The probability of early stopping of TRM if the true probability is 30% is 
80%. 
 
12.4.2 Grade III-IV by 100 days 
Stopping rules were developed for excessive grade III-IV aGVHD by day 
100 post-transplant. The goal is to construct a boundary based on 
GVHD such that the probability of early stopping is at most 10% if the 
true rate is equal to 13% and our sample size is 28. Given these 
parameters, the upper stopping boundary for GVHD is 2 events out of 2 
patients, 3 out of 6, 4 out of 10, 5 out of 15 or 6 out of 20, 7 out of 26 or 
8 at any time. The probability of early stopping of GVHD if the true 
probability is 30% is 77%. 
 
Due to additional stopping rules, it is understood that the overall power 
may be slightly reduced for this study. 


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13 
Conduct of the Study 
13.1 
Record Retention  
The study will be conducted in accordance with the appropriate regulatory 
requirement(s).  Essential clinical documents will be maintained to demonstrate 
the validity of the study and the integrity of the data collected.  Master files 
should be established at the beginning of the study, maintained for the duration 
of the study and retained according to the appropriate regulations.   
13.2 Ethical Considerations  
The study will be conducted in accordance with ethical principles founded in 
the Declaration of Helsinki.  The IRB will review all appropriate study 
documentation in order to safeguard the rights, safety and well-being of the 
patients.  The study will only be conducted at sites where IRB approval has 
been obtained.  The protocol, consent, written information given to the patients, 
safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB by the investigator.   
13.3 Informed Consent  
All potential study participants will be given a copy of the IRB-approved consent 
to review. The investigator or designee will explain all aspects of the study in 
lay language and answer all questions regarding the study. If the participant 
decides to participate in the study, he/she will be asked to sign and date the 
consent document. In the case of minor patients, the parent/guardian will be 
required to sign and date the parental consent form and the minor, if 8 years or 
older will be presented with a minor information sheet. 
Patients who refuse to participate or who withdraw from the study will be treated 
without prejudice.  
14 
References 
1. 
McCurdy SR, Kanakry JA, Showel MM, Tsai HL, Bolanos-Meade J, Rosner GL et al. Risk-
stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose 
posttransplantation cyclophosphamide. Blood 2015; 125(19): 3024-31. 
2. 
Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell 
transplantation: marrow or umbilical cord blood? Blood 2003; 101(11): 4233-44. 
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Confer D, Robinett P. The US National Marrow Donor Program role in unrelated donor 
hematopoietic cell transplantation. Bone marrow transplantation 2008; 42 Suppl 1: S3-S5. 
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Ballen KK, Spitzer TR, Yeap BY, McAfee S, Dey BR, Attar E et al. Double unrelated reduced-
intensity umbilical cord blood transplantation in adults. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow Transplantation 2007; 
13(1): 82-9. 


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5. 
Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. Rapid and complete 
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Brunstein CG, Barker JN, Weisdorf DJ, DeFor TE, Miller JS, Blazar BR et al. Umbilical cord 
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7. 
Gladstone DE, Zachary AA, Fuchs EJ, Luznik L, Kasamon YL, King KE et al. Partially 
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of blood and marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation; 19(4): 647-52. 
8. 
Misawa M, Kai S, Okada M, Nakajima T, Nomura K, Wakae T et al. Reduced-intensity 
conditioning followed by unrelated umbilical cord blood transplantation for advanced 
hematologic malignancies: rapid engraftment in bone marrow. International journal of 
hematology 2006; 83(1): 74-9. 
 
9. 
Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J et al. Alternative donor 
transplantation after reduced intensity conditioning: results of parallel phase 2 trials using 
partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood 
grafts. Blood; 118(2): 282-8. 
10. 
Chang YJ, Xu LP, Liu DH, Liu KY, Han W, Chen YH et al. Platelet engraftment in patients 
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transplantation: effects of CD34+ cell dose and disease status. Biol Blood Marrow Transplant 
2009; 15(5): 632-8. 
11. 
Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK et al. T-cell-replete HLA-
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transplantation cyclophosphamide results in outcomes equivalent to those of 
contemporaneous HLA-matched related and unrelated donor transplantation. Journal of 
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suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-
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selective allodepletion approach for the treatment of HLA-mismatched and matched donor-
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differentially affects CD4+ Tregs versus CD4+ effector T cells from patients with chronic graft-
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32. 
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depletion and reduced intensity conditioning: a phase II study. Haematologica; 97(10): 1523-
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33. 
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transplantation 2007; 39(12): 751-7. 
34. 
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reconstitution after haploidentical hematopoietic cell transplantation: impact of reduced 
intensity conditioning and CD3/CD19 depleted grafts. Leukemia; 25(1): 121-9. 
35. 
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Nonmyeloablative, HLA-haploidentical bone marrow transplantation with high dose, post-
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36. 
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outcomes using a T cell replete graft compared with T cell depleted haploidentical 
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of the American Society for Blood and Marrow Transplantation; 18(12): 1835-44. 
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transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning 
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Haploidentical (mini-haplo) Blood or Marrow Transplantation (BMT) with High-Dose Post-
Transplant Cyclophosphmade (PTCy) for Acute Myeloid Leukemia (AML): Donor Age 
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tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res; 47(1-3): 65-
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grafts. Blood 2011; 118(2): 282-8. 
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Castagna L, Crocchiolo R, Furst S, Bramanti S, El Cheikh J, Sarina B et al. Bone marrow 
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Transplantation 2014; 20(5): 724-9. 
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Unmanipulated haploidentical bone marrow transplantation and post-transplant 
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update. Bone marrow transplantation 2015; 50 Suppl 2: S37-9. 
47. 
Cieri N, Greco R, Crucitti L, Morelli M, Giglio F, Levati G et al. Post-transplantation 
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Stem Cells. Biology of blood and marrow transplantation : journal of the American Society for 
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Kanate AS, Mussetti A, Kharfan-Dabaja MA, Ahn KW, DiGilio A, Beitinjaneh A et al. 
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Haploidentical Stem Cell Transplantation for Lymphoma with Melphalan-Based Conditioning. 
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Gaballa S, Ge I, El Fakih RO, Brammer JE, Wang SA, Lee DA et al. Results of a Two-Arm 
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Damlaj M, Alkhateeb HB, Partain DK, Almasri J, Hefazi M, Hashmi SK et al. Fludarabine 
Busulfan Compared to Fludarabine Melphalan Is Associated with Increased Relapse Risk in 
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Annual Meeting Abstracts) 2015 126: 736(23). 
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Kosuri S, Hilden P, Devlin SM, Yoo Y, Lauer E, Peled JU et al. High Progression-Free 
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Disease after a Novel Intermediate Intensity Conditioning Regimen. Biology of Blood and 
Marrow Transplantation 2016; 22(3): S76-S77. 
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Vokurka S, Steinerova K, Karas M, Koza V. Characteristics and risk factors of oral mucositis 
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Appendix I – Eligibility Checklist  
Removed – Eligibility checklists are kept in Oncore 


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Appendix II – Karnofsky Performance Status and Lansky Play Score 
For patients 16 years of age and older: 
Karnofsky Performance Scale 
Percent 
Description 
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 to 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 indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
For patients < 16 years of age: 
Lansky 
Score 
Play Score 
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 activity 
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 but 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 
No play; does not get out of bed 
0 
Unresponsive 
 
 


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Appendix III – TBI 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.   
The total dose of TBI will be 400 cGy.  Each fraction will be 200 cGy given on Day -2 and 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, 10, or 18 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 gives 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. 
Updated 9/23/16  by Kathryn Dusenbery, MD 
 
 
 
 


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Appendix IV Standard Transplant Procedures and Supportive Care 
Haploidentical Donor Marrow Collection and Infusion (Day 0) 
On Day 0, patients will receive unprocessed marrow unless there is an ABO 
incompatibility. In case of major ABO incompatibility red blood cells will be depleted from 
the donor marrow using institutional practice.  In case of minor ABO incompatibilities 
donor marrow plasma depletion and IV hydration will be used per institutional standard 
practice.   
Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated cells/kg 
recipient IBW, and a recommended minimum yield of 2.5 x 108 nucleated cells/kg of 
recipient IBW.  If ABO incompatible, then a target of 6 x 108/kg will be collected to allow 
for cell losses during RBC removal as needed.  We recommend taking no more than 10 
mL per aspirate.  Marrow nucleated cell count will be calculated after collection of 500 ml 
marrow, which will be used to calculate requited total bone marrow volume harvest as 
below.  
If bone marrow collection volume exceeding 20 ml/kg of donor actual body weight is 
required, donor hemoglobin/hematocrit (Hb/Hct) should be checked STAT during bone 
marrow harvest procedure to document that Hct remains ≥25. Fluids and colloid such as 
albumin will be infused to the donor as necessary. Unrelated donor RBC transfusions can 
be considered in some cases if clinically indicated.  
In addition to calculating the total nucleated cell dose/kg, a sample of the product to be 
infused will be sent for flow cytometry to determine the content of CD34+cells.  The use 
of cryopreserved marrow is not permitted.   
Calculation:  
Total bone marrow volume required = (4 x 108 nucleated cells/kg x Recipient IBW (kg)) / 
(Marrow nucleated cell count – Peripheral blood WBC count)  
E.g. Required total bone marrow volume for 50 kg IBW recipient: (4 x 108 cells/kg x 50 
kg)/( 25 x 106/mL marrow count - 5 x 106/mL PB WBC count) = 2 x 1010/2 x 107=1000 
mL 
Peripheral blood is an acceptable graft source for those haploidentical donors who are 
not suitable candidates for general anesthesia for bone marrow harvest, such as, but not 
limited to the elderly or morbidly obese. Peripheral blood is also acceptable at the 
discretion of treating physician and the BMT team for underlying diseases with higher risk 
of engraftment failure including but not limited to those with myeloproliferative 
neoplasms/myelofibrosis and hypercellular marrow. Total volume required will be the 
same as above requirements for marrow. Peripheral blood may supplement bone marrow 
graft if cell dose requirement is not met. 


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Note that if a related donor undergoes a second apheresis session to collect the target 
number of peripheral blood stem cells, the product should be held at MCT until both 
collections have been completed. The entire collection yield should be infused on the 
same day, the patient in effect has two “Day 0s” (a rest day, then an infusion day) and 
the days of post-transplant cyclophosphamide should be adjusted accordingly to be days 
+3 and +4 post-stem cell infusion. The start of tacrolimus and MMF should also be 
adjusted accordingly in this circumstance.   
 
GVHD Prophylaxis and Growth Factor Support (begin Day 5) 
All patients will receive prophylaxis for GVHD with two drugs both beginning at Day 5 as 
follows: 
Tacrolimus 
Tacrolimus will be given at a dose of 0.03 mg/kg/day IV as a continuous infusion.  
When tolerated, tacrolimus may be changed to PO dosing at 0.12 mg/kg/day PO 
divided into two doses.  Initial IV and/or PO dose may be adjusted as clinically 
necessary to achieve desired goal levels.  
Tacrolimus prophylaxis will begin on Day +5 post-transplant.  Serum levels of 
tacrolimus will be measured around Day +7 and then should be checked twice 
weekly thereafter and the dose adjusted accordingly to maintain a trough level of 
5-15 ng/mL for a minimum of 90 days, followed by taper through Day +180 in the 
absence of GVHD. Tacrolimus may be continued if active GVHD is present.   
Sirolimus (trough level of 3-12 ng/ml) may be substituted for tacrolimus if the 
patient is intolerant of tacrolimus.  
Mycophenolate Mofetil (MMF) 
MMF will be given at a dose of 15 mg/kg PO TID (based upon actual body weight) 
with the maximum total daily dose not to exceed 3 grams (1 g PO TID).  MMF 
prophylaxis will begin on Day +5 post-transplant and will be discontinued after the 
last dose on Day +35, or may be continued if active GVHD is present.  
Growth Factor Support 


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G-CSF will be given beginning on Day +5 at a dose of 5 mcg/kg/day (rounding to 
the nearest vial dose is allowed), until absolute neutrophil count (ANC) is ≥ 
1,500/mm3 for three consecutive measurements on 3 different days.  G-CSF may 
be restarted to maintain ANC > 1,000/mm3.  G-CSF may be given by IV or 
subcutaneously. 
 
 
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. 
Acute and chronic GVHD will be staged and treated using current University of Minnesota 
BMT program GVHD protocols  
Antimicrobial prophylaxis directed towards bacteria, fungi and viruses will be per 
University Of Minnesota current institutional guidelines for transplant patients.  
Management of Slow Engraftment 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 +21/28 bone marrow biopsy, notify the 
unrelated donor (URD) search coordinator to pursue back-up graft and arrange a follow-
up bone marrow biopsy per current institutional slow engraftment guidelines. 
 
 


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Appendix V Standard of Care Clinical Follow-up 
 
Suggested clinical care activities for post transplant follow-up. Missed assessments will not be 
considered study deviations. 
Activity 
Day 1 To 
Engraftment1 
Follow-Up Days 
42-100 
Follow-Up ( ≥Day 100 
through Day 720) 
Medical History 
 
 
X (day 180, 360, 720) 
Physical Exam 
 
 
X (day 180, 360, 720) 
Karnofsky/Lansky 
 
 
X (day100, 180, 360, 
720) 
GVHD Assessment 
 
 
X (day 100, 180, 360) 
CBC/diff/plt2 
 
weekly 
X (day 180, 360, 720) 
Basic metabolic panel  
daily 
 
 
Comprehensive 
metabolic panel 
weekly 
weekly 
X (day 180, 360, 720) 
BM Biopsy 
 
 
BM (day100, 360, 
720) 
BM chimerism  
 
 
BM (day 100, 360, 
720) 
1 
engraftment defined as absolute neutrophil count (ANC) ≥ 5 X 108/L for 3 consecutive 
measurements  
2 
If ANC<500 diff will not be calculated 
 
After two years post transplant, patients will transition to the BMT Database protocol for long term 
follow up. 
 
 

ICF_001.pdf: