Haploidentical Donor T-cell Replete Allogeneic Hematopoietic Cell Transplant Following Reducing Intensity Conditioning for Patients With Selected High Risk Non-Malignant Disease
Phase: PHASE2
Conditions: Sickle Cell Disease, Thalassemia, High Risk Hematologic Disorders, Cerebral Adrenoleukodystrophy, Inherited Metabolic Disorders
Sponsor: Masonic Cancer Center, University of Minnesota

Blood and Marrow Transplantation Program 
Masonic Cancer Center 
University of Minnesota 
   
 
Haploidentical Donor T-cell Replete Allogeneic Hematopoietic 
Cell Transplant following Reducing Intensity Conditioning for 
Patients with Selected High Risk Non-Malignant Disease 
 
MT2017-30 
CPRC # 2017LS101 
 
 
 
Investigators: 
Christen L. Ebens, MD, MPH (Principal Investigator) 
Paul J. Orchard, MD 
Angela R Smith, MD, MS 
John E. Wagner, MD 
Shernan Holtan, MD 
Kathryn E Dusenbery MD 
 
 
 
 
Biostatistician: 
Todd E. DeFor, MS 
 
 
Version Date: 
January 15, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 

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CPRC #2017LS101 
 
Revision History 
 
Revision 
# 
Version 
Date 
Detail of Changes 
Consent 
change? 
(Y/N) 
 
09/26/2017 Original to CPRC 
 
 
11/08/2017 Response to CRPC minor stipulations providing 
consistency in objectives throughout and 
clarifying conditioning chemotherapy dose 
modifications 
NA 
 
11/20/2017 Section 3.5.2 edited for clarity. 
Removed Dr. Weston Miller from the 
Investigator list. 
No 
1 
02/28/2018 Synopsis and section 1 – edited transplant 
objectives for consistency 
Section 6.2, 6.3, 6.4 and 6.5.3 updated standard 
of care medication orders (to current BMT 
standard practice 
Section 7.1 combined labs into “basic metabolic 
panel” 
Section 7.2 Added research lab: ATG levels 
Section 10.2.3 removed “autologous recovery by 
100 days” from stopping rules and fixed 
typographical error 
Appendix 1, clarified ATG dosing chart is also 
for ALD patients 
Yes 
1A 
03/30/2018 Edited endpoints for consistency per CPRC 
request 
No 
1B 
04/16/2018 Layout of table 6.2 edited for clarity 
No 
1C 
06/19/2018 Corrected dosing error in table 6.2 
No 
2 
09/28/2018 Updated section 6.2.1.5 for females who elect 
ovarian transposition 
Yes 
3 
03/15/2019 Eligibility: Expanded upper age eligibility to 55 
years of age, in order to make treatment 
available to older adults with non-malignant 
diseases who may benefit from a reduced 
intensity PTCy approach; removed performance 
IQ from ALD diagnosis 
Section 6.1 and 10.2.3 – the back up stem cell 
harvest can be either marrow or PBSC  
Yes  

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CPRC #2017LS101 
 
Section 9.2 updated CPRC risk determination 
4 
5/14/2019 
Throughout document clarified that the 
Haploidentical stem cells may be from either a 
related or an unrelated donor. 
No 
5 
01/15/2020 Section 4.2 Revised to allow for either PBSC or 
Bone Marrow as the stem cell source, per 
physician preference 
Updated Section 8.2, AE Reporting with IRB’s 
new Ethos system 
Removed Appendix IX, eligibility checklist, per 
current CTO SOP. Eligibility checklists will be 
only kept in Oncore. 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI Contact Information: 
Christen L. Ebens, MD, MPH 
Pediatrics – Blood and Marrow Transplant 
420 Delaware St SE, MMC 484 
Minneapolis, MN 55455 
Phone: 612-626-8094 
Email: ebens012@umn.edu 
 

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CPRC #2017LS101 
 
Table of Contents 
 
Synopsis ............................................................................................................... 6 
Schema ................................................................................................................. 7 
1.0 
Hypothesis and Objectives .......................................................................... 8 
1.1 
Hypothesis ............................................................................................... 8 
1.2 
Objective .................................................................................................. 8 
1.3 
Primary Endpoint ..................................................................................... 8 
1.4 
Secondary Endpoints ............................................................................... 8 
1.5 
Transplant Endpoints ............................................................................... 8 
1.6 
Exploratory Endpoints .............................................................................. 9 
2.0 
Background and Rationale .......................................................................... 9 
2.1 
HaploHCT: ............................................................................................... 9 
2.2 
Proposed approach ............................................................................... 15 
2.3 
Study Outcomes .................................................................................... 16 
3.0 
Patient Selection ....................................................................................... 16 
3.1 
Eligible Diseases ................................................................................... 16 
3.2 
Age, Performance Status, Consent ....................................................... 17 
3.3 
Adequate Organ Function ...................................................................... 17 
3.4 
Exclusion Criteria ................................................................................... 18 
3.5 
Donor Selection ..................................................................................... 18 
4.0 
Donor Stem Cell Mobilization and Acquisition ........................................... 19 
4.1 
Bone Marrow ......................................................................................... 19 
4.2 
Peripheral Blood  ................................................................................... 20 
5.0 
Registration in OnCore .............................................................................. 20 
6.0 
Treatment Plan ......................................................................................... 20 
6.1 
Autologous stem cell collection .............................................................. 20 
6.2 
HaploHCT Regimen ............................................................................... 22 
6.3 
Haploidentical Allogeneic Stem Cell Infusion (day 0) ............................. 25 
6.4 
GVHD Prophylaxis/Immunosuppression ................................................ 26 
6.5 
Supportive Care ..................................................................................... 27 
6.6 
Autologous Stem Cell Rescue ............................................................... 30 
6.7 
Follow-Up ............................................................................................... 30 
7.0 
Clinical Evaluations ................................................................................... 30 
7.1 
Patients .................................................................................................. 31 
7.2 
Research Labs ....................................................................................... 32 
7.3 
Donor Screening .................................................................................... 33 
8.0 
Adverse Event Monitoring and Reporting .................................................. 33 
8.1 
Event Documentation ............................................................................ 33 
8.2 
Adverse Event Reporting ....................................................................... 33 
9.0 
Study Data Collection and Monitoring ....................................................... 34 
9.1 
Data Collection ...................................................................................... 34 
9.2 
Data and Safety Monitoring ................................................................... 34 
9.3 
Study Related Monitoring....................................................................... 35 
9.4 
Record Retention ................................................................................... 35 
10.0 Statistical Considerations .......................................................................... 35 

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10.1 Primary, Secondary and Transplanted-Related Endpoints .................... 36 
10.2 Data Collection and Statistical Plan ....................................................... 37 
11.0 Conduct of the Study ................................................................................. 39 
11.1 Ethical Considerations ........................................................................... 39 
11.2 Good Clinical Practice ........................................................................... 39 
11.3 Informed Consent .................................................................................. 39 
12.0 Works Cited .............................................................................................. 39 
Appendix I -  Rabbit ATG (Thymoglobulin) dosing for ALD and RBC disorder 
patients ............................................................................................................... 43 
Appendix II – Treatment Related Risks:  Conditioning Chemotherapy ............... 45 
Appendix III – Treatment Related Risks: GVHD Prophylaxis/Immune 
Suppression ........................................................................................................ 47 
Appendix IV – Treatment Related Risks: Supportive Care ................................. 48 
Appendix V - Risks of the Anti-Oxidant/Anti-Inflammatory Regimens ................. 49 
Appendix VI – Transplant Related Risks ............................................................. 51 
Appendix VII - Performance Status ..................................................................... 52 
Appendix VIII –GVHD Scoring ............................................................................ 53 

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CPRC #2017LS101 
 
Synopsis 
Haploidentical Donor T-cell Replete Allogeneic Hematopoietic Cell Transplant 
following Reduced Intensity Conditioning for Patients with Selected High Risk 
Non-Malignant Disease  
MT2017-30 
CPRC # 2017LS101 
 
Design: 
Open label, interventional, phase II trial  
 
Objectives: 
To establish safety as measured by sustained hematopoietic 
engraftment and efficacy as measured by 1 year overall survival  
 
Key Inclusion 
Criteria: 
• 
Diagnosis of sickle cell disease (SCD), thalassemia, other high 
risk hematologic disorder, cerebral adrenoleukodystrophy (cALD) 
or other inherited metabolic disorders 
• 
Meets the disease specific criteria (detailed in section 2) 
• 
0 to 55 years of age 
• 
Available haploidentical related or unrelated donor   
 
Treatment 
Plan: 
 
Reduced intensity conditioning (RIC) with rabbit ATG, fludarabine, 
cyclophosphamide, thiotepa and low dose (2 Gy) total body 
irradiation followed by T-cell replete, unmanipulated, haploidentical 
related or unrelated donor stem cell transplant (HaploHCT) and post-
transplant cyclophosphamide (PTCy) 
 
 
Primary 
Endpoint: 
• Incidence of neutrophil recovery by day +42 
 
 
Secondary 
Endpoints: 
• Probability of overall survival at 1 year  
• Incidence of primary graft failure (neutropenic and non-
neutropenic) by day +42 
 
Transplant 
Endpoints: 
• Incidence of secondary graft failure (neutropenic and non-
neutropenic) by day +180 
• Incidence of acute graft-versus-host disease (GVHD) at 100 days 
• Incidence of chronic GVHD at 1 year 
• Incidence of transplant-related mortality at 100 days, 180 days, 
and 1 year following transplant 
 
Exploratory 
Endpoints: 
 
• 
Sorted lymphocyte chimerism at days 21, 42, 84, 100, 180, 1 and 
2 years 
• 
Description of immunological recovery by assessment of 
lymphocyte subsets and immune globulin levels at days 21, 42, 
84, 100, 180, 1 and 2 years 
• 
Impact of residual ATG on day -1 on neutrophil recovery, graft 
failure, and T cell chimerism. 
 
 
Accrual 
Objective:  
20 patients over 5 years. 
 

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1.0 
Hypothesis and Objectives 
This is a Phase II study for the use of T-cell replete reduced intensity 
conditioning (RIC) haploidentical donor allogeneic hematopoietic cell 
transplantation (HaploHCT) for individuals with high-risk non-malignant 
diseases who lack a suitable HLA-matched sibling donor. 
 
1.1 
Hypothesis 
1.1.1 Reduced intensity conditioned (RIC) HaploHCT will be safe 
and will provide acceptable rates of neutrophil engraftment in 
the setting of alternative-donor HCT.  
 
1.2 
Objective 
1.2.1 To establish the safety as measured by sustained 
hematopoietic engraftment and efficacy as measured by 1 
year overall survival of RIC followed by HaploHCT for patients 
with selected high-risk non-malignant disorders  
 
1.3 
Primary Endpoint 
1.3.1 Incidence of neutrophil recovery at day +42 
 
1.4 
Secondary Endpoints 
1.4.1 Incidence of overall survival at 1 year 
1.4.2 Incidence of primary graft failure (neutropenic and non-
neutropenic) 
 
1.5 
Transplant Endpoints 
1.5.1 Incidence of secondary graft failure (neutropenic and non-
neutropenic) 
1.5.2 Incidence of acute graft-versus-host disease (GVHD) at 100 
days 
1.5.3 Incidence of chronic GVHD at 1 year 
1.5.4 Incidence of transplant-related mortality at 100 days, 180 
days, and 1 year following transplant. 
 

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1.6 
Exploratory Endpoints 
1.6.1 Degree of mixed T cell chimerism 
1.6.2 Description of immunological recovery 
1.6.3 Impact of day -1 residual serum ATG on neutrophil recovery, 
graft failure, and T cell chimerism 
2.0 
Background and Rationale 
2.1 
HaploHCT: 
 
Haploidentical donor 
allogeneic 
hematopoietic 
cell 
transplantation 
(HaploHCT) provides unique benefits over other alternative donor (AD) 
stem cell sources, including allowance for less stringent HLA-match, rapid 
availability of stem cells, and option for future boost of cells if needed. 
Previously prohibitive rates of acute graft-versus-host disease (GVHD) with 
haploidentical matched donors have in recent years been overcome by the 
introduction of post-transplant cyclophosphamide (PTCy) on days +3 and 
+4 following HaploHCT. PTCy selectively eliminates alloreactive over 
homeostatically proliferating donor T cells, effectively reducing acute GVHD 
rates to that of matched unrelated donor HCT and allowing for adequate 
donor T cell preservation for engraftment and peripheral expansion for early 
protection against virus reactivation or infection1-3. Given recent 
improvements in outcomes for HaploHCT with PTCy, this HCT approach 
has been made available to more populations of patients4. 
 
High-risk non-malignant diseases (NMD) often lack unaffected HLA-
matched sibling donors (MSD) and must rely upon AD options for HCT. For 
many such disorders, we have yet to determine the best combination of 
conditioning and stem cell source to achieve reliable rates of engraftment, 
disease-free and overall survival. Identification of an appropriate stem cell 
donor is a barrier for many patients. For example, for sickle cell disease 
(SCD), 76% lack a MSD5. A recent publication6 reported probabilities of 
20% for identifying an 8/8 HLA-matched unrelated donor (MUD), 84% for 
7/8-HLA matched MUD, and 90% for a 5-6/6 HLA-matched UCB unit. In 
other NMD population, such as high risk cerebral adrenoleukodystrophy 
(cALD), expediency is critical to interrupt the destructive disease process. 
The time needed to identify and collect stem cells from an unrelated bone 
marrow or peripheral blood stem cell donor is prohibitive. HaploHCT 
provides a rapidly available donor option for the majority of patients lacking 
a MSD.  
 

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CPRC #2017LS101 
 
We seek to provide a reduced toxicity conditioning HaploHCT treatment 
option for these NMD patients lacking a MSD and often lacking a quickly 
available appropriate AD stem cell source.   
 
2.1.1. HaploHCT in NMD 
 
While the majority of experience with HaploHCT using PTCy is in treatment 
of leukemia, a body of literature can be compiled describing outcomes of 
this HCT strategy in NMD such as hemoglobinopathies, primary 
immunodeficiencies, and severe aplastic anemia. As reviewed in Table 1, 
conditioning regimens have been variable but largely reduced intensity or 
reduced toxicity with intensive patient immunosuppression to minimize graft 
failure (GF). GVHD prophylaxis typically includes a calcineurin inhibitor or 
mTOR inhibitor and mycophenylate mofetil (MMF) in addition to PTCy. 
 
High-risk hemoglobinopathies are the most reported on NMD group to 
undergo HaploHCT with PTCy. From Johns Hopkins University, Bolanos-
Meade et al.7 reported results in 14 adult patients with sickle cell disease 
(SCD) receiving unmanipulated bone marrow (BM) from haploidentical 
donors following conditioning with fludarabine (Flu) 30 mg/m2/d x 5 days, 
cyclophosphamide (Cy) 14.5 mg/kg/d x 2 days, anti-thymocyte globulin 
(ATG) 0.5 mg/kg x1 day and 2 mg/kg x 2 days, and a single fraction of low 
dose 2 Gy total body irradiation (TBI). GVHD prophylaxis included PTCy 50 
mg/kg/d on days +3 and +4, MMF starting on day +4 and tacrolimus or 
sirolimus starting on day +5. Median neutrophil and platelet engraftment 
were both day +24. All patients had count recovery (no aplasia), though 
rates of graft failure were high at 43%, with one patient with no detectible 
donor DNA and 5 with complete loss of donor chimerism over time, for a 
total of 6 episodes of GF in the 14 haploidentical donor transplant recipients. 
However, all 17 patients were alive at a median follow-up of 711 days (range 
244-1981) with 11 ultimately attaining disease-free survival (DFS).  
 
Over the course of enrollment, several alterations were made to the study, 
including addition of ATG after the initial 2 patients to improve engraftment, 
replacement of tacrolimus with sirolimus after the initial 10 patients to 
decrease the incidence of posterior reversible encephalopathy syndrome 
(PRES), and granulocyte-colony stimulating factor (GCSF) priming of bone 
marrow from the donors for the final 3 patients to improve engraftment. 
PRES occurred in 30% of patients receiving tacrolimus and 0 of 7 patients 
treated with sirolimus. GCSF mobilization increased the cell dose at 

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transplant from a median of 4.35 x 108 TNC/kg recipient weight, 5.24 x 106 
CD34+ cells/kg recipient weight, and 3.61 x 107 CD3+ cells/kg recipient 
weight without GCSF to 1.14 x 109 TNC/kg recipient weight, 6.02 x 106 
 
Table 1. HaploHCT with PTCy for NMD 
 
Reference   
Institution 
Patients 
Conditioning 
GVHD 
prophy 
1 yr 
OS 
(%) 
1 yr 
DFS 
(%) 
1° GF 
rate 
(%) 
Gr 2+ 
aGVHD 
(%) 
cGVHD 
(%) 
Comments 
Sickle cell disease 
Bolanos- Meade J,  
  et al., 20127 
 
Johns Hopkins, US 
14 
Flu 150 mg/m2 
Cy 29 mg/kg 
rATG 4.5 mg/kg 
TBI 200 cGy 
PTCy 
Siro 
MMF 
100 
57 
43 
0 
0 
Changes during trial: 
To decrease PRES: 
  Changed tacro to siro  
  Added GCSF to prime BM  
To decrease GF: Added ATG  
De La Fuente J, et  
  al., 20158 
 
Great Ormond, UK 
 
16 
Flu 150 mg/m2 
Cy 29 mg/kg 
rATG 4.5 mg/kg 
TT 10 mg/kg 
TBI 200 cGy 
PTCy 
Siro 
MMF 
94 
94 
0 
13 
6 
1 death (MAS2ry GF2nd   
  HCTVOD) 
Dhedin N, et al.,  
  20169 
 
Paris, France, 
London, UK, 
Vanderbillt, TN, US 
5 
 
 
 
 
7 
 
 
22 
Flu 150 mg/m2 
Cy 29 mg/kg 
rATG 4.5 mg/kg 
TBI 200 cGy 
 
Above +  
TT 10 mg/kg 
 
Above + 
Pre-HCT IST: 3 mon 
  Aza 3 mg/kg/d + HU    
  30 mg/kg/d 
TT 10 mg/kg 
PTCy 
Siro 
MMF 
 
 
 
 
 
100 
 
 
86.4 
 
 
 
 
 
100 
 
 
81.8 
20 
 
 
 
 
0 
 
 
0 
 
 
 
 
 
29 
 
 
 
 
 
0 
+50% 2ry GF triggered  
  stopping rule 
 
 
 
 
 
 
+9% 2ry GF 
Acute + chronic GVHD 18.2% 
Wiebking, et al.,  
  201710 
 
Munich, Germany 
3 
CAMPATH 0.4 mg/kg 
Flu 150 mg/m2 
Treo 42 g/m2 
TT 10 mg/kg 
Cy 29 mg/kg 
PTCy 
Tacro 
MMF 
100 
100 
0 
0 
0 
 
Thalassemia 
Anurathapan U, et  
  al., 201611 
 
Thailand 
31 
 
Pre-HCT IST:  
Two 5d cycles of    
  Flu 40 mg/m2/d + 
  Dexa 25 mg/m2/d + HU 
 
Flu 210 mg/m2 
Bu 650 mg/m2 (no  
  target AUC) 
rATG 4.5 mg/kg 
PTCy 
Tacro or    
  Siro 
95 
94 
6 
29 
16 
VOD 16% 
DOCK8 deficiency 
Shah N, et al.,  
  201712 
 
NIH, US 
7 
Flu 150 mg/m2 
Bu (cumulative  
  AUC 11,600) 
Cy 29 mg/kg 
TBI 200 cGy 
PTCy 
Tacro 
MMF 
86 
86 
0 
57 (all gr, 
max gr3 
in 1) 
0 
1 death (d+165 worsening of  
  pre-existing pulmonary  
  fibrosis, possible COP) 
Severe aplastic anemia 
Clay J, et al., 
201413 
 
King’s College,UK 
 
4 SAA 
4 primary GF  
  following  
  1st HCT 
Flu 150 mg/m2 
Cy 29 mg/kg 
TBI 200 cGy 
PTCy 
Tacro 
MMF 
75 
75 
25 
13 
0 
2 patients with DSA developed  
  1° GF and died of sepsis  
Esteves I, et al.,  
  201514 
 
Brazil 
16 SAA 
Flu 150 mg/m2 
Cy 28 mg/kg 
TBI 200-600 cGy 
PTCy 
Tacro or  
  CSA 
MMF 
67 
67 
0 
13 
(2/15 
alive at 
d+30) 
23 
(3/13 
alive at 
d+100) 
5 deaths from infection, 1  
  before engraftment 
2ry GF in 2 
Jaiswal SR, et al.,  
  201515 
 
New Delhi, India 
10 SAA 
Flu 150 mg/m2 
Cy 30 mg/kg 
Mel 120 mg/m2 
hATG 45 mg/kg 
PTCy 
CSA +/-  
  siro 
MMF 
60 
60 
0 
13 
13 
4 deaths: ARDS (2), HLH (1),  
  aGVHD (1) 
DeZern, et al.,  
  201716 
 
Johns Hopkins, US 
 
13 SAA 
 
Flu 150 mg/m2 
Cy 29 mg/kg 
rATG 4.5 mg/kg 
TBI 200 cGy 
PTCy 
Tacro 
MMF 
100 
100 
0 
15 
8 
9 / 13 with evidence of clonality  
  pre-HCT, 0/13 post-HCT 
15% with delayed engraftment  
  (later than d+42) 
No 2ry GF 
Wiskott-Aldrich syndrome 

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CPRC #2017LS101 
 
Kreetapirom P, et  
  al., 201717 
 
Thailand 
1 
Flu 210 mg/m2 
Bu 320 mg/m2 (no  
  target AUC) 
rATG 4.5 mg/kg 
PTCy 
CSA 
MMF 
Yes 
Yes 
No 
Gr 1 
0 
CMV reactivation, bronchiolitis 
obliterans 
Mixed NMD 
Klein OR, et al.,  
  201618 
 
Johns Hopkins, US 
IPEX (1) 
 
XIAP (1) 
CGD (1) 
GT (1) 
CAMPATH, Flu, Cy, Mel,  
  TBI 
CAMPATH, Flu, Mel, TBI 
CAMPATH, Flu, Mel, TBI 
CAMPATH, Flu, TBI 
PTCy 
Tacro 
MMF 
100 
100 
0 
0 
0 
XIAP patient developed VOD 
IPEX patient developed late 2ry 
GF (>2 years post-HCT), 
required a 2nd haploHCT 
 
Prophy, prophylaxis; yr, year; OS, overall survival; PFS, progression free survival; GF, graft failure; Gr, grade; aGVHD, acute graft-versus-
host disease; cGVHD, chronic graft-versus-host disease; Flu, fludarabine; Cy, cyclophosphamide; rATG, rabbit anti-thymocyte globulin; 
TBI, total body irradiation; PTCy, post-transplant cyclophosphamide; siro, sirolimus; MMF, mycophenylate mofetil; tacro, tacrolimus; PRES, 
posterior reversible encephalopathy syndrome; GCSF, granulocyte-colony stimulating factor; BM, bone marrow; TT, thiotepa; MAS, 
macrophage activation syndrome; HCT, hematopoietic cell transplantation; VOD, veno-occlusive disease; treo, treosulfan; IST, 
immunosuppressive therapy; dexa, dexamethasone; HU, hydroxyurea; Bu, Busulfan; AUC, area under the curve; COP, cryptogenic 
organizing pneumonia; SAA, severe aplastic anemia; DSA, donor specific antibodies; CSA, cyclosporine; hATG, horse anti-thymocyte 
globulin; ARDS, acute respiratory distress syndrome; HLH, hemophagocytic lymphohistiocytosis; IPEX, immune dysregulation, 
polyendocrinopathy, X-linked syndrome; XIAP, X-linked inhibitor of apoptosis; CGD, chronic granulomatous disease; GT, Glanzmann’s 
thrombasthenia; Mel, melphalan; haploHCT, haploidentical donor hematopoietic cell transplantation 
 
CD34+ cells/kg recipient weight, and 1.09 x 108 CD3+ cells/kg recipients 
weight with GCSF. No haploidentical BM recipients developed acute or 
chronic GVHD. Three infections were noted including 1 CMV reactivation 
(no disease development), one case of EBV viremia (responded to a single 
dose of rituximab), and one patients with RSV upper respiratory tract 
infection as well as tuberculosis identified from a bronchoscopy specimen 
(patients recovered). In summary, the first report of 14 SCD patients 
undergoing HaploHCT with PTCy revealed this approach to be feasible with 
excellent survival and GVHD risk, low rates of infectious complications, but 
high rates of graft failure. 
 
De La Fuente et al.8 described promising preliminary data on 16 pediatric 
recipients (13 SCD, 3 Thalassemia) of HaploHCT. Transplant conditioning 
included those agents above in the Johns Hopkins protocol (Flu 150 mg/m2, 
Cy 29 mg/kg, TBI 2 Gy, and ATG 4.5 mg/kg), but differed by the addition of 
thiotepa (TT) 10 mg/kg. Patients received GCSF primed BM. GVHD 
prophylaxis was unchanged, including PTCy 50 mg/kg on days +3 and 4, 
MMF, and sirolimus. All engrafted, though one patient developed secondary 
graft failure attributed to macrophage activation syndrome, underwent an 
autologous HCT for rescue, developing veno-occlusive disease (VOD) after 
the 2nd conditioning regimen and ultimately died. Neutrophil engraftment 
was achieved at a median of 17 days, platelet engraftment at 32 days. Acute 
GVHD (grade >/= 2) was observed in 2 patients (1 skin, 1 gut) and chronic 
GVHD in 1 patient. Median time to sirolimus discontinuation was 124 days 
as patients demonstrated excellent donor chimerism (un-separated donor 
peripheral blood chimerism of >/=95% in 93.3% and CD3+ donor chimerism 
>/= 95% in 73.3% of patients at day +28).  
 

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An alternative approach to improve upon the Johns Hopkins / Bolanos-
Meade7 outcomes included enhanced pre-conditioning immunosuppression 
as described by Anurathapan, et al11. Thirty-one severe thalassemia 
patients (median age of 10 years) received 2 courses of pre-transplant 
immunosuppression consisting of Flu 40 mg/m2/day and dexamethasone 
25 mg/m2/day x 5 days (cycles started at day-68 and day -40 pre-
transplant). The conditioning phase of therapy included Flu 210 mg/m2, 
busulfan (Bu) 130 mg/m2, and ATG 3.5 mg/kg. Patients received GCSF 
mobilized peripheral blood stem cell grafts. GVHD prophylaxis included 
PTCy 50 mg/kg on days +3 and 4, 60 days of MMF and 6-12 months of 
either tacrolimus or sirolimus. No complications were identified during the 
pre-transplant immune suppression. Primary graft failure was low at 6% with 
median neutrophil recovery on day +14. One-year overall survival was 95% 
with disease-free survival of 94%. 
 
Dhedin et al.9 recently expanded upon De la Fuente8. In a systematic 
approach to HaploHCT, Dhedin et al. transplanted the first 5 SCD patients 
using the Johns Hopkins approach, however with 3 of 5 patients 
demonstrating graft failure, they transitioned to a 2nd strategy, where 
thiotepa 10 mg/kg was added to the conditioning regimen (the De la Fuente 
approach). Of 7 patients treated with Flu, Cy, ATG, TT, and TBI 2 Gy, all 
engrafted (median time to neutrophil recovery 25 days), 2 had viral 
reactivation, 2 had >grade 2 acute GVHD, but no chronic GVHD. 
Subsequently, similar to the Anurathapan approach, pre-transplant 
immunosuppression was intensified by the addition of 3 months of 
azathioprine, hydroxyurea, and hypertransfusion pre-transplant. All 22 
patients transplanted by this final strategy engrafted (median time to 
neutrophil recovery of 17 days) though two (9%) had secondary graft failure 
and three died of infectious complications/MAS. GVHD rates were low 
(cumulative incidence of acute and chronic GVHD of 18.2%). Overall 
survival in this latter group declined to 86.4% and event-free survival 81.8%.  
 
Combined, the above experience in HaploHCT for hemogobinopathies 
outlines the need for higher intensity conditioning than the Johns Hopkins 
approach to achieve reliable donor engraftment in NMD patient population 
who have not previously been exposed to myelo- or immunosuppressive 
therapies (as compared to patients with malignancies) but highlights the 
potentially lethal infectious risks of excess immune suppression.  
 
 

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2.1.2 MSD-HCT and non-Haplo AD-HCT for NMD 
 
2.1.2.1 Outcomes in the literature  
For most diseases amenable to treatment with HCT, including NMD, an 
unaffected MSD is the standard against which AD-HCT is compared. Using 
the example of SCD, modern outcomes on large cohorts MSD-HCT 
following MAC show overall survival ranging from 91-100%, event-free 
survival from 82-91%, and graft failure at or less than 8%19-24. Earlier trials 
informed need for strong immunoablation (patients heavily transfused and 
alloimmunized placing them at high risk of graft failure) and targeted 
supportive care (against neurologic complications) to achieve such 
remarkable results. There is very little published data on the use of AD-HCT 
(unrelated donor, URD or umbilical cord blood, UCB) in SCD or other high-
risk hemoglobinopathies. Using MAC, MUD BMT for 27 adult thalassemia 
patients in Italy yielded an overall survival (OS) of 79% with graft failure rate 
of 13%25. However, the chance of finding a MUD in the registry depends on 
the patient’s ethnicity and is as low as 19% in African Americans and 27% 
in Southeast Asians26. 
 
Another important finding of early trials of MSD-HCT for SCD was resolution 
of symptoms with stable mixed donor chimerism27, 28. This suggested that 
less intensive RIC regimens may be adequate for cure of this devastating 
disorder29. Unfortunately, there have not been consistent positive results 
from RIC in hemoglobinopathies, regardless of donor source. Jacobsohn et 
al.30 reported in 2004 on 13 patients with NMD undergoing RIC with a 
regimen of Flu, Bu, and ATG. Of these 13, 3 were transplanted for SCD (2 
MSD, 1 MUD) and 1 for thalassemia (MUD). Of these 4 patients, 2 died (one 
of chronic GVHD, one of infection) and 2 lived, though with graft failure and 
persistent SCD. Similarly, Horan et al. 200531 reported on 4 patients (3 
SCD, 1 thalassemia) receiving conditioning with fludarabine, ATG, and low 
dose total body irradiation. Unfortunately, 3 of 4 had graft failure with 
withdrawal of immunosuppression, with one dying following a 2nd alloHCT 
and one experiencing a subsequent stroke. Only one promising report of 
RIC [Flu, Bu, ATG, total lymphocyte irradiation (TLI)] in hemoglobinopathies 
was published by Krishnamurti, et al. 2008,32 showing 100% OS of 7 
patients with stable donor engraftment and DFS in 6 of 7. Two national trials 
for RIC URD HCT in patients with severe SCD are underway: the SCURT 
trial (NCT00745420) and the STRIDE trial (NCT01565616). The probability 
of finding an adequately matched UCB unit for HCT is better than finding an 
HLA-matched URD, but the rates of graft failure are higher with this source. 

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In fact, the SCURT trial closed enrollment on the UCBT arm due to the high 
incidence of GF (5/8 patients)33.  
 
2.1.2.2 Outcomes at the University of Minnesota 
Our experience at the University of Minnesota mirrors the findings in the 
literature, with excellent outcomes for MAC + MSD but need for 
improvement for RIC + AD regimens. We conducted 5 consecutive trials 
from 1996 to 2015, including 36 pediatric and young adult patients 
undergoing HCT for high risk red blood cell disorders including SCD, 
thalassemia, and Diamond-Blackfan Anemia) These trials included two 
different MAC regimens (n=11, Bu, Cy, ATG and Flu, Bu) and two different 
RIC regimens (n=25), Flu, Cy, CAMPATH,TBI and Flu, Bu, ATG, TLI). In 
general, MAC was used for patients with MSD and RIC for those with AD. 
While 1 year DFS following 1st HCT was respectable for MSD receiving 
MAC including busulfan, cyclophosphamide, and ATG at 88%, DFS for AD-
HCT with RIC was disappointing at 56%.  
 
2.2 
Proposed approach  
The objectives of our study are to use haploidentical donors to expand stem 
cell graft options for high-risk non-malignant diseases such as RBC disorder 
patients with often limited or no donor options and provide an expeditious 
pathway to alloHCT and for cALD patients requiring urgent intervention to 
halt the disease process. Excellent outcomes with MSD regimens preclude 
enrollment in this HaploHCT trial for those patients with a suitable MSD. 
Further, with the Johns Hopkins HaploHCT conditioning regimen 
(fludarabine  150 mg/m2, cyclophosphamide 29 mg/kg, and TBI 2 Gy) as a 
baseline, we plan to reduce rates of GF by intensifying conditioning with the 
addition of thiotepa, maintain recipient lymphodepletion with serotherapy 
(rabbit ATG with precision dosing based on weight and absolute lymphocyte 
count34), and infuse unmanipulated haploidentical donor stem cells followed 
by PTCy 50 mg/kg on days +3 and +4 for GVHD prophylaxis along with a 
combination of MMF and sirolimus. 
 
Supportive care will be specific to the patient’s diagnosis. For high risk RBC 
disorder patients, we will use hydroxyurea and hypertranfusion to maintain 
a hgb >10 for the month prior to admission for alloHCT to reduce recipient 
bone marrow activity/inflammation. Immediately prior to admission, a simple 
or exchange transfusion may be indicated for sickle cell disease patients to 
achieve a HgbS <30%. Once conditioning starts, we will maintain hgb >9 
g/dL, platelets >50,000/mm3, Magnesium >1.5 mEq/L, provide anti-seizure 

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prophylaxis with keppra while on immunosuppression, and tight blood 
pressure control to avoid neurologic complications such as PRES or 
cerebrovascular accident.  
 
For cALD patients, supportive care will include use of anti-oxidant / anti-
inflammatory medications from day -10 (prior to initiation of conditioning) 
until day +100 (N-acetylcysteine, celecoxib, Vitamin E, and alpha lipoic 
acid). In addition, through conditioning and until sirolimus is discontinued, 
cALD patients will be maintained on Keppra for seizure prophylaxis. 
Concurrent treatment for pre-existing or suspected adrenal insufficiency will 
be provided, including maintenance hydrocortisone dosing and stress-
dosing when indicated. 
 
2.3 
Study Outcomes 
The primary objective of this study is to demonstrate safety as measured by 
timely neutrophil engraftment (by day +42) and secondary objective to 
demonstrate efficacy as measured by 1 year overall survival for RIC 
HaploHCT with PTCy for selected high risk non-malignant diseases. 
3.0 
Patient Selection  
3.1 
Eligible Diseases 
3.1.1 Sickle Cell Disease (SCD) 
• If diagnosis of SCD must meet one or more of the following 
disease characteristics: 
o Stroke, CNS hemorrhage or a neurologic event 
lasting longer than 24 hours, or abnormal 
cerebral MRI or cerebral arteriogram or MRI 
angiographic 
study 
and 
impaired 
neuropsychological testing 
o Acute chest syndrome with a history of recurrent 
hospitalizations or exchange transfusions 
o Recurrent vaso-occlusive pain 3 or more 
episodes per year for 3 years or more years or 
recurrent priapism, 
o Impaired 
neuropsychological 
function 
and 
abnormal cerebral MRI scan 
o Stage I or II sickle lung disease, 

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o Sickle 
nephropathy 
(moderate 
or 
severe 
proteinuria or a glomerular filtration rate [GFR] 
30-50% of the predicted normal value) 
o Bilateral proliferative retinopathy and major 
visual impairment in at least one eye 
o Osteonecrosis 
of 
multiple 
joints 
with 
documented destructive changes 
o Requirement for chronic transfusions  
o RBC alloimmunization 
 
3.1.2 Transfusion Dependent Alpha- or Beta-Thalassemia 
3.1.3 Other Non-Malignant Hematologic Disorders  
Transfusion dependent or involve other potential life-threatening 
cytopenias, including but not limited to Paroxysmal Nocturnal 
Hemoglobinuria, Glanzmann’s Thrombasthenia, Severe Congenital 
Neutropenia and Shwachman-Diamond Syndrome  
3.1.4 cALD 
• Diagnosis of ALD by abnormal plasma very long chain 
fatty acid (VLCFA) profile or ABCD1 gene mutation 
• Cerebral disease on MRI 
• Absence of a Major Functional Disability (cortical 
blindness, loss of communication, wheelchair 
dependence) on the ALD Neurologic Function Scale 
 
3.1.5 Other inherited metabolic disorders 
Any other inherited metabolic disorder for which alloHCT is 
indicated and for whom, in the opinion of the treating physician, the 
patient’s best treatment option is with a haploidentical donor 
following non-myeloablatve conditioning. 
3.2 
Age, Performance Status, Consent 
Age:  0-55 years 
Performance Status:  Karnofsky ≥ 70%, Lansky play score ≥ 70 
Consent:  voluntary written consent (adult or parental/guardian) 
3.3 
Adequate Organ Function 
Renal:  Creatinine <2.0 mg/dl for adults or glomerular filtration rate > 
50 ml/min for children 

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Hepatic:  Bilirubin and ALT <3 times the upper limit of institutional 
normal 
Cardiac:  Absence of decompensated congestive heart failure, or 
uncontrolled arrhythmia and left ventricular ejection fraction > 40%.   
3.4 
Exclusion Criteria  
• Availability of a suitable HLA-matched related donor 
• Uncontrolled infection  
• Pregnant or breastfeeding 
• HIV positive 
3.5 
Donor Selection  
3.5.1 Donors regardless of match and selection criteria must: 
• Not be affected by the same disease making the patient 
eligible for alloHCT. Disease carriers may be permitted 
depending on the clinical situation. 
• Meet donor criteria as outlined in University of Minnesota 
protocol MT2012-14C: Procedure Guidelines for Related 
Hematopoietic Stem Cell Donors; or NMDP requirements for 
unrelated donors. 
 
3.5.2 Match-specific Criteria: 
HLA mismatched or haploidentical related or unrelated donors: The 
donor and recipient must be haploidentical at a minimum of one 
allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, 
HLA-DRB1, and HLA-DQB1.  
 
Donor-specific anti-HLA antibody testing requirement: Testing for 
antibodies targeting donor specific HLA antigens at HLA-A, B, C, 
DRB1, DQ and DP will be completed as per institutional standards. 
 
When more than one donor is available, the donor with the lowest 
number of HLA allele mismatches will be chosen, unless there is an 
HLA cross-match incompatibility or a medical reason to select 
otherwise, in which case donor selection is the responsibility of the 
PI. In cases where there is more than one donor with the least degree 
of mismatch, donors will be selected based on the most favorable 
combination of the factors below.  
 

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Donor selection criteria in decreasing order of priority: 
1. Absence of donor-specific HLA antibodies is preferred [negative 
flow cytometric cross-match assay or the mean fluorescence 
intensity (MFI) of any anti-donor HLA antibody by solid phase 
immunoassay <1000]. If donor-specific anti-HLA antibodies 
cannot be avoided, the risks will be discussed with the patient and 
consenting parent/guardian and options including debulking or 
deferring transplant will be considered. 
2. The lowest number of mismatches in the host-versus-graft 
direction is prioritized to minimize graft rejection. 
3. If more than one donor with the same degree of HLA match, 
absent or equivalent donor-specific anti-HLA antibodies, and 
equivalent host-versus-graft allele mismatches, the following 
prioritization will be used: 
a. Homozygous normal donor is preferable to heterozygote 
(carrier) 
b. ABO-compatible donor is preferable to ABO-incompatible 
donor 
c. CMV status 
1) For a CMV seronegative patient, prefer a CMV 
seronegative donor 
2) For a CMV seropositive patient, prefer a CMV seropositive 
donor 
d. Younger donor is preferable to older, avoiding those >55 
years of age if possible 
e. Male donor preferred over nulliparous female donor over 
multiparous female donor 
 
4.0 
Donor Stem Cell Mobilization and Acquisition  
Per physician preference, either peripheral blood stem cells or bone marrow may 
be utilized as a stem cell source. 
4.1 
Bone Marrow 
Haploidentical related donor BM will be collected according to 
current institutional guidelines (University of Minnesota protocol 
MT2012-14C: Procedure Guidelines for Related Hematopoietic 
Stem Cell Donors). Unrelated donors will be collected per NMDP 
SOPs. 
 

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A minimum of 2 x 108 total nucleated cells/kg recipient weight will be 
collected with a goal of 8-16 x 108 total nucleated cells/kg recipient 
weight. 
 
Bone marrow will be red cell depleted in cases of ABO 
incompatibility. 
4.2 
Peripheral Blood  
PBSC will be collected and processed per institutional guidelines 
(University 
of 
Minnesota 
protocol 
MT2012-14C: 
Procedure 
Guidelines for Related Hematopoietic Stem Cell Donors). Unrelated 
donors will be collected per NMDP SOPs. 
 
A minimum of 4 x 106 CD34+/kg unprocessed cells will be collected 
with a goal of 7-10 x 106 CD34+/kg unprocessed cells. 
 
5.0 
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 eligibility assessment documented in the patient’s 
medical record.  A copy of the eligibility checklist is under attachments within 
the study in OnCore.    
 
6.0 
Treatment Plan 
Dose and/or schedule modifications based on weight (i.e. for pediatric 
patients), clinical issues or current institutional practice are permitted at the 
discretion of the treating physician in collaboration with BMT pharmacists. 
All drugs will be prepared and administered per institutional guidelines, with 
the drugs, doses and scheduled modified as clinically indicated.   
 
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 therapy (i.e. acetaminophen, diphenhydramine, G-CSF, 
antimicrobials, etc).    
6.1 
Autologous stem cell collection 
We plan to pre-emptively collect autologous bone marrow or G-CSF 
mobilized peripheral blood from the initial 5 patients enrolled on this protocol 
to rescue any cases of aplastic graft failure. Should no episodes of aplastic 

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graft failure occur, subsequent autologous stem cell collection will take 
place on an individualized patient basis.  
 
For autologous bone marrow collection, the patient will be admitted on day 
-12 and will be hydrated overnight and transfused as needed to achieve hgb 
>9-10, platelet count >50,000, and INR/PTT ≤1.5 x ULN. The following day 
(day -11), the patient will undergo a bone marrow harvest and Hickman line 
placement (if needed). Collected bone marrow (goal of 2 x 108 TNC/kg) will 
be counted, processed and cryopreserved. GCSF will not be used for 
mobilization in hemoglobinopathy patients given risk of leukocytosis 
triggering a veno-occlusive crisis.  
 
Alternatively, non-hemoglobinopathy patients may undergo leukapheresis 
to obtain peripheral blood stem cells after GCSF mobilization.  
Leukapheresis (for the collection of PBSCs) will be performed per 
institutional standard with adaptations for small children as outlined below. 
In patients without an appropriate double-lumen leukapheresis-grade 
catheter in place, this may be accomplished through a percutaneously 
placed temporary leukapheresis-grade catheter or two large bore peripheral 
IVs, which is/are then removed following completion of the leukapheresis.  
 
Patients will be primed with filgrastim (Neupogen, G-CSF) 10 mg/kg/QAM 
for 5 days before planned leukapheresis. Peripheral CD34 enumeration 
should be undertaken on the morning of the 4th day of filgrastim before 
pheresis catheter placement. If the peripheral CD34 count is >/= 10 x 10^6/L 
(and/or viable CD34% >/= 1% of viable CD45%) pheresis cathether 
placement can proceed (if needed) with leukopheresis the following day. 
Following each leukapheresis, the cells will be processed and 
cryopreserved per institutional standards. Prior to cryopreservation, an 
aliquot of each collection will be analyzed for cell count and 
immunophenotype. The target for the leukapheresis will be 6 x 10^6 viable 
CD34+ cells/kg, with acceptable range of 2 -10 x 10^6 CD34+ cells/kg. This 
may require up to two days of leukapheresis.  
 
For patients smaller than 10 kg, the leukapheresis procedure established 
for adults will be modified. During the procedure, a set volume of blood is 
contained in the tubing and apparatus. For larger children and adults, this 
represents less than 10% of their total blood volume and is usually well 
tolerated. However, in very small children, the extracorporeal blood volume 
may be >10% of their total blood volume and this may cause clinically 

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significant hypovolemia. For patients for whom the extracorporeal blood 
volume is >10% of their total blood volume, the machine will be primed with 
irradiated packed red blood cells.  
Leukapheresis can be safely accomplished in the outpatient setting for 
patients >22 kg. Smaller children will be admitted to the inpatient unit 
following pheresis catheter placement for leukopheresis. 
6.2 
HaploHCT Regimen 
Day 
Drug 
Dose and route 
Refer to 
section: 
-9 to -6 
(variable 
# of days) 
Rabbit ATG* 
(Thymoglobulin) 
IV over 6 hours with pre-meds 
Continue methylprednisolone per 
taper through day -2. 
Specific dose and number of days 
per ATG nomogram 
6.3.1.1 
Appendix I 
-7 
Thiotepa 
5 mg/kg IV Q12H x 2 doses 
6.3.1.2 
-6 
Cyclophosphamide 14.5 mg/kg IV over 2 hours  
6.3.1.3 
MESNA 
14.5 mg/kg IV via continuous 
infusion 
Fludarabine 
30 mg/m2 IV over 1 hour (if <10 
kg, 1 mg/kg) 
6.3.1.4 
-5 
Cyclophosphamide 14.5 mg/kg IV over 2 hours  
6.3.1.3 
MESNA 
14.5 mg/kg IV via continuous 
infusion 
Fludarabine 
30 mg/m2 IV over 1 hour 
6.3.1.4 
-4 
Fludarabine 
30 mg/m2 IV over 1 hour  
6.3.1.4 
-3 
Fludarabine 
30 mg/m2 IV over 1 hour  
6.3.1.4 
-2 
Fludarabine 
30 mg/m2 IV over 1 hour  
6.3.1.4 
-1 
TBI** 
2 Gy as a single dose 
6.3.1.5 
0 
Stem cell infusion 
6.4 
+3 
Cyclophosphamide 50 mg/kg IV over 2 hours  
6.5.1 
MESNA 
50 mg/kg IV via continuous 
infusion 
+4 
Cyclophosphamide 50 mg/kg IV over 2 hours  
6.5.1 
MESNA 
50 mg/kg IV via continuous 
infusion 
* Rabbit ATG dosing (daily dose and number of days) will be determined according to 
the ATG dosing nomogram (Appendix I) as described below in section 6.2.2.  
**See alternate study calendar in section 6.2.1.5 for females who elect Ovarian 
transposition  

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6.2.1 Conditioning regimen  
6.2.1.1 Rabbit ATG (Thymoglobulin) 
Rabbit ATG mg/kg IV will be administered via central venous 
catheter as follows:  
 Pre-medicate 
30 
minutes 
prior 
to 
ATG 
infusion 
with 
methylprednisolone 1 mg/kg IV, acetaminophen 15 mg/kg dose 
(max dose = 650 mg) enterally and diphenhydramine 1 
mg/kg/dose (max dose = 50 mg) enterally or IV.  
 Infuse ATG daily at 9 am through a 0.22 micrometer filter over 6 
hours. 
 Hypersensitivity orders per standard guidelines during ATG 
administration. 
 ATG dose and number of doses as per ATG nomogram 
(Appendix I). First dose to be given on day -9. 
6.2.1.2 Thiotepa 
Thiotepa 5 mg/kg IV Q12H x 2 doses to be administered via central 
venous catheter over 2 hours per institutional guidelines.  
6.2.1.3 Cyclophosphamide 
Cyclophosphamide 14.5 mg/kg IV will be administered over 2 hours 
on days -6 and -5. Cyclophosphamide dosing is calculated based on 
actual body weight (ABW). Refer to cyclophosphamide institutional 
standards regarding dosing for obese patients.  
Alterations to dosing should be discussed with the BMT pharmacist.  
 
Uroprotection 
with 
mesna 
and 
hyperhydration 
per 
cyclophosphamide 
institutional 
guidelines. 
 
Potassium 
supplementation in fluids to be adjusted based on patient need and 
serial serum potassium measurements. 
6.2.1.4 Fludarabine 
Fludarabine 30 mg/m2 IV will be administered over 1 hour on days -
6 to -2. For children <10 kg, use a weight based fludarabine dose of 
1 mg/kg. If the adjusted creatinine clearance is < 70 ml/min, dose-
reduce Fludarabine by 20%. Alterations to dosing should be 
discussed with the BMT pharmacist. 

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6.2.1.5 Total body irradiation (TBI) 
Total body irradiation of 2 Gy will be administered in a single fraction 
on day -1.  
 
The total body irradiation will be delivered with right and left lateral 
fields, with the patient supine on a specially designed couch. 
  
Based on measurements of transverse thicknesses, aluminum 
compensators will be used to ensure that the dose homogeneity 
across the field 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). 
  
Total body irradiation will be delivered with a linear accelerator 
using 6, 18, 24 MV X-rays.  The energy used will be based on the 
calculated dose to the midline at points up and down the patient’s 
torso.  The lowest energy that gives 90-100% of the prescription 
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. 
 
Ovarian transposition/radiation shielding and testicular radiation 
shielding will be considered for appropriate candidates.  
 
Men who request testicular shielding will also be treated with AP 
and PA total body radiation beams prescribed at midline at 
midpelvis and treated with 6MV photons at a dose rate of 10-19 
cGy /minute instead of the rt/lt lateral beams. Lung compensators 
will be used to keep the lung dose within 10% of prescription. A 
beam spoiler will be used. 
 
Females who elect to have Ovarian transposition/radiation 
shielding will be treated according to the study calendar below: 
 
Day 
Drug 
Dose and route 
Refer to 
section: 
-10 
TBI 
2 Gy as a single dose 
6.3.1.5 
-9 to -6 
(variable 
# of days) 
Rabbit ATG* 
(Thymoglobulin) 
IV over 6 hours with pre-meds 
Continue methylprednisolone per 
taper through day -2. 
Specific dose and number of days 
per ATG nomogram 
6.3.1.1 
Appendix I 

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Day 
Drug 
Dose and route 
Refer to 
section: 
-7 
Thiotepa 
5 mg/kg IV Q12H x 2 doses 
6.3.1.2 
-6 
Cyclophosphamide 14.5 mg/kg IV over 2 hours  
6.3.1.3 
MESNA 
14.5 mg/kg IV via continuous 
infusion 
Fludarabine 
30 mg/m2 IV over 1 hour (if <10 
kg, 1.17 mg/kg) 
6.3.1.4 
-5 
Cyclophosphamide 14.5 mg/kg IV over 2 hours  
6.3.1.3 
MESNA 
14.5 mg/kg IV via continuous 
infusion 
Fludarabine 
30 mg/m2 IV over 1 hour 
6.3.1.4 
-4 
Fludarabine 
30 mg/m2 IV over 1 hour  
6.3.1.4 
-3 
Fludarabine 
30 mg/m2 IV over 1 hour  
6.3.1.4 
-2 
Fludarabine 
30 mg/m2 IV over 1 hour  
6.3.1.4 
-1 
Rest 
0 
Stem cell infusion 
6.4 
+3 
Cyclophosphamide 50 mg/kg IV over 2 hours  
6.5.1 
MESNA 
50 mg/kg IV via continuous 
infusion 
+4 
Cyclophosphamide 50 mg/kg IV over 2 hours  
6.5.1 
MESNA 
50 mg/kg IV via continuous 
infusion 
* Rabbit ATG dosing (daily dose and number of days) will be determined according to 
the ATG dosing nomogram (Appendix I) as described below in section 6.2.2.  
 
Females who undergo ovarian transposition will be treated with AP and PA total 
body radiation beams  prescribed at midline at midpelvis and treated with 6MV 
photons at a dose rate of 10-19 cGy /minute instead of the rt/lt lateral beams.   
Lung compensators will be used to keep the lung dose within 10% of 
prescription. The transposed ovary will be blocked with 5HVL cerrebend blocks. 
Ovarian location will be determined by ultrasound and marked at the time of 
transposition. A beam spoiler will be used.  On day -8 the oophorpexy will be 
reversed.   
 
Refer to Appendix II for risks associated with this treatment plan.  
 
6.3 
Haploidentical Allogeneic Stem Cell Infusion (day 0) 
On day 0 the stem cells will be infused per cell source specific 
institutional guidelines.  
 

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Recommended 
Pre-medication: 
acetaminophen 
15 
mg/kg 
(maximum 650 mg) PO and diphenhydramine 0.5 mg/kg (maximum 
25 mg) PO/IV. 
 
Vital signs will be checked before and after the infusion, and one hour 
post infusion per University Of Minnesota transplant guidelines.  
More frequent vital signs may be required depending on reactions to 
the product infusion.   
 
Refer to Appendix VI for risks associated with transplant. 
6.4 
GVHD Prophylaxis/Immunosuppression 
6.4.1 Post-transplant Cyclophosphamide: 
Cyclophosphamide 50 mg/kg IV will be administered over 1 hour on 
days +3 and +4. Cyclophosphamide dosing is calculated based on 
actual body weight (ABD) . Refer to cyclophosphamide institutional 
standards regarding dosing for obese patients.  Alterations to dosing 
should be discussed with the BMT pharmacist. Uroprotection with 
mesna and hyperhydration per cyclophosphamide institutional 
guidelines. 
 
Refer to Appendix III for risks associated with cyclophosphamide and 
mesna. 
6.4.1 Sirolimus: 
Patients will receive sirolimus therapy beginning on day +5.  Dosing of 
sirolimus will be per the University of Minnesota Pediatric BMT 
Program guidelines. The target trough sirolimus level will be 10-15 
ng/mL for the first 4 months post-HCT and 10 ng/mL from 4-12 months 
post-HCT. 
Empiric dose adjustments when administered concurrently with anti-
fungal –azoles should be considered. 
The timing of the sirolimus taper will be at the discretion of the treating 
physician, but in general begins at d+365. Patients with <50% CD3+ 
donor chimerism at 1 year post-transplant should be considered for 
prolonged sirolimus use with a target trough of 5-10 ng/mL. 
 
Refer to Appendix III for risks associated with sirolimus. 

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6.4.2 Mycophenylate Mofetil (MMF):  
Patients will receive mycophenylate mofetil (MMF) therapy beginning 
on day +5.  Dosing of MMF will be 1 gram three times daily (total daily 
dose 3 grams/day) if the recipient is >50 kg, or 15 mg/kg/dose three 
times daily if the recipient is ≤50 kg.  The same dosage is used orally 
or intravenously. Consider dose modification if renal and/or hepatic 
impairment (GFR<25 mL/minute corrected). Consider consulting the 
pediatric BMT pharmacist when changing MMF doses or routes of 
administration.  
MMF pharmacokinetics are not required, but may be obtained when 
clinically indicated.  Consult with the pediatric BMT pharmacist for AUC 
interpretations and dose adjustments when necessary.  
Stop MMF at Day +35 or 7 days after engraftment achieved (ANC>500 
x 106 neutrophils/L x 3 days), whichever is later. If sufficient GVHD is 
observed to require systemic therapy, MMF should be continued for 7 
days after GVHD is controlled (e.g. resolution of skin rash, vomiting, 
and diarrhea).  
 
Refer to Appendix III for risks associated with MMF. 
6.5 
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.  
 
Refer to Appendix IV for side effects associated with supportive care 
medications. 
 

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Specific Supportive Care as follows: 
6.5.1 All patients 
 
6.5.1.1 
Radiation Shielding 
Consider ovarian transposition and radiation shielding or 
testicular radiation shielding. This should be discussed and 
interested patients should meet with radiation oncology and/or 
gynecology to discuss prior to transplant.  
 
6.5.1.2 
Seizure Prophylaxis 
Patients will receive Levetiracetam (Keppra) for seizure 
prophylaxis starting at initiation of conditioning (day -9) and 
continuing until discontinuation of sirolimus.  
 
6.5.1.3 
GCSF  
On day +5 or once ANC declines below 1000 x 109/L 
(whichever occurs later), patients will start G-CSF support at 
5 mcg/kg/dose (IV/SQ) daily until ANC ≥ 2500/mm3 for 2 
consecutive days. Once a patient has met these criteria, the 
ANC will be monitored and G-CSF re-dosed if the ANC falls 
to <1000 x 109/L.  
6.5.2 Hemoglobinopathy patients 
6.5.2.1 Pre-Transplant Therapy  
• Hydroxyurea – Beginning at least 1 months prior to 
transplant (preferably 2-3 months) until admitted for 
conditioning. 
 
Hydroxyurea (HU) 30 mg/kg enterally. If subjects are 
already taking HU for their underlying disease, they will 
continue their regular home dose until admission to the 
hospital for conditioning.  
 
• Hypertransfusion 
(SCD 
only) 
- 
Packed 
RBC 
transfusions will be increased to achieve a goal 
hemoglobin of 10 g/dL for one month prior to transplant. 
 
• Exchange Transfusion (SCD only) - For patients not on 
a chronic transfusion protocol and having a hemoglobin S 

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level >30%, a partial exchange transfusion will be 
performed with a goal of reducing the hemoglobin S level 
to 30% or lower prior to the beginning of conditioning.  
6.5.2.2 Transfusion guidelines (SCD only): 
 
• Anemia - Transfusion of packed red blood cells will be 
administered as needed to maintain a hemoglobin of 9-10 
gm/dL through day 100.  
• Thrombocytopenia - Transfusion of platelets will be 
administered to maintain the platelet count >50,000.  
6.5.3 cALD patients 
 
• N-acetylcysteine (NAC) - Beginning on day -10 and 
continuing through day +100.  
 
NAC 70 mg/kg/dose IV, every 6 hours (while inpatient) and 
3 times daily (once outpatient). While inpatient, patients 
will receive NAC on a target schedule of 02:00, 08:00, 
14:00 and 20:00 and drug will be administered over 15-30 
minutes. While outpatient, patients will receive NAC "TID" 
and infusion rates may vary. 
 
• Celecoxib - Beginning on day -10 and continuing through 
day +100. 
 
 
Dosed by patient weight: 
>25 kg: Celecoxib 100 mg PO twice daily 
≥ 10 kg and ≤ 25 kg: Celecoxib 50 mg PO twice daily 
 
Note:  Recommended hold/dose adjustment parameters:  
serum creatinine > 2.5 x baseline; ALT or AST > 3x ULN; 
hemorrhage; uncontrolled hypertension. 
 
• Vitamin E - Beginning on day -10  and continuing through 
day +100. 
 
Vitamin E 450 IU PO daily 
 

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• Alpha Lipoic Acid - Beginning on day -10  and continuing 
through day +100. 
 
Alpha Lipoic Acid 200 mg PO twice daily. 
 
Refer to Appendix V for risks associated with this supportive care 
plan. 
6.6 
Autologous Stem Cell Rescue 
Infusion of autologous stem cells will be considered by the treating 
physician and protocol PI for any of the following indications: 
• Lack of neutrophil engraftment by day +42 in the absence of 
serious infectious complications 
• Lack of neutrophil engraftment by day +35 concurrent with 
serious infectious complication 
 
The autologous stem cells will be stored for two years, then, either 
discarded, or, if the patient “opts-in” to specimen storage, may be 
de-identified and used in future research.  
6.7 
Follow-Up 
Patients will be followed for 2 years post-transplant according to the current 
University of Minnesota BMT follow-up as outlined in section 6.  
 
Follow-up after 2 years will be per the University of Minnesota standard 
hematopoietic stem cell transplantation protocol for long-term follow-up.   
 
7.0 
Clinical Evaluations 
All clinical evaluations are standard of care and will be done according to current 
institutional guidelines and disease specific guidelines. Post-transplant and some 
pre-transplant monitoring may be tailored for each patient’s clinical case. 
 
Scheduled evaluations after screening and until engraftment may be performed +/-
3 days from the targeted date; assessments performed after engraftment and 
through day 100 may be done +/-7 days of the targeted date.   After day 100 
assessments may be done +/- 30 days of the targeted date.  In addition, targeted 
days may be altered as clinically appropriate. 

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7.1 
Patients  
 
Pre-
transplant  
work-up 
Days in Reference to the transplant 
Day 1 to 
engraftment 
Follow-up 
Days 31-100 
6 months, 1 
and 2 years 
MD/NC to ensure that Hydroxyurea is 
started at least one month prior to 
transplant for RBC disorder patients 
X 
 
 
 
Informed consent 
X 
 
 
 
Medical history 
X 
daily 
weekly 
X 
Physical exam 
X 
daily 
weekly 
X 
Radiation Therapy consult (discuss 
testicular or ovarian shielding as 
appropriate) 
X 
 
 
 
Performance status 
X 
 
X(100) 
X 
Height/Weight 
X 
 
 
 
GVHD evaluation 
 
daily 
weekly  
X 
Toxicity Assessment 
 
daily 
weekly 
X 
Gynecology Consult (Females only if 
interested in ovarian transposition and 
radiation shielding) 
X 
 
 
 
Neuropsychological testing 
X* 
 
 
1, 2 yrs 
(also at 6 mo 
for cALD) 
Laboratory  
CBC, diff  
X 
daily 
weekly 
X 
Platelet 
X 
daily 
weekly 
X 
PT/PTT 
X 
As clinically indicated 
Ferritin 
X 
 
X (100) 
X 
Ferriscan and/or Liver Biopsy 
As 
clinically 
indicated 
 
 
 
ABO, Coombs 
X 
 
 
 
Red cell antibody studies, Red cell Antigen 
typing (phenotype) (RBC disorder patients) 
X 
 
 
 
Reticulocyte count 
X 
 
X (100) 
X 
Basic metabolic panel 
X 
daily 
weekly 
X 
Urinalysis and NM GFR 
X 
 
 
 
Adenovirus, EBV and CMV DNA PCR 
X 
weekly 
weekly 
X 
Free T4 and TSH 
X 
 
X (100) 
X 
LH, FSH, Anti-mullerian hormone (AMH) 
and Estradiol levels for females >10 yr; LH, 
FSH and testosterone levels for males >11 
yr 
X 
 
 
X 
Urine or serum pregnancy test 
X 
 
 
 
Semen analysis and storage (if desired) 
X 
 
 
 
Lymphocyte subsets (extended profile 
including B and NK populations) 
 
Day 21 
Days 42, 84, 
100 
X 

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Pre-
transplant  
work-up 
Days in Reference to the transplant 
Day 1 to 
engraftment 
Follow-up 
Days 31-100 
6 months, 1 
and 2 years 
Immune globulin levels (IgG, A, M, E) 
 
Day 21 
Days 42, 84, 
100 
X 
Bone marrow biopsy/aspirate 
As clinically indicated 
Donor chimerism -- BM 
As clinically indicated 
Sorted lineage donor chimerism per clinical 
standard- PB  
X 
Day 21 
Days 42, 84, 
100 
X 
Donor chimerism (CD71+)– PB (send out to 
UCSF) for RBC disorder patients 
X 
Day 28 
Days 60, 100 
X 
Procedures 
EKG 
X 
As clinically 
indicated 
As clinically 
indicated 
X 
MUGA or echo 
X 
As clinically 
indicated 
X (100) 
X 
Chest x-ray  
X 
 
 
 
PFT’s 
X 
 
 
X 
Sickle Cell Disease Only 
Exchange Transfusion (ask MD if indicated, 
see section 6.5 for details) 
X 
 
 
 
Cerebral MRI and MRA 
X 
As clinically indicated 
Hemoglobin S level 
X 
 
X (100) 
X 
Hematology 
consult 
for 
exchange 
transfusion prior to transplant (ask MD if 
indicated) 
X 
 
 
 
Neurology Evaluation (e.g. If history of 
stroke or abnormal MRI) 
as 
clinically 
indicated  
 
 
 
Thalassemia Only 
Hemoglobin electrophoresis 
X 
 
X (100) 
X 
* For cALD, previous neuropsychological testing may be used for pre-transplant baseline 
evaluation 
7.2 
 Research Labs 
ATG (Thymoglobulin) PK Sampling - a blood sample will be 
obtained to characterize individual Thymoglobulin PK parameters. 
Thymoglobulin concentrations as well as anti-Thymoglobulin 
antibodies will be determined. 
 
 
Day ‐1 
PK sample – 1.0 mL 
EDTA tube  
X 
 
The study CRA will pick up the sample and deliver to the 
Translational Therapy lab (TTL).  TTL will batch ship the sample to 
Utrecht University Lab in the Netherlands. 
Centrifuge the tube immediately after collection, at 3-5°C for 15 
minutes at 3500 rpms to separate the plasma. 

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Immediately following centrifugation, transfer the supernatant to a 
pre-chilled 0.5 mL Microtube Screw Cap vial (approx. 0.33 mL of 
plasma). Freeze at approx. -80 C until shipment. 
 
Tube labels will have the protocol number and sample name pre-
printed.  The following information on the label must be filled in by 
the site using the appropriate source documents for completion:   
• Date sample was drawn 
• Time the sample was drawn (24:00 hour clock) 
• Patient number 
 
The label should be placed vertically on the tube (not horizontally) 
so all of the information can be read.   
7.3 
Donor Screening 
Marrow or peripheral blood donors will undergo screening 
evaluations based on the current recommendations and procedures 
of the University of Minnesota and National Marrow Donor Program.   
8.0 
Adverse Event Monitoring and Reporting 
8.1 
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.  
 
8.2 
Adverse Event Reporting  
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 
Within 5 
business 
days of 
event 
discovery 
 
 RNI 
 ETHOS system 
 
SAE 
Coordinator 
mcc-
saes@umn.edu 

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Agency 
Criteria for reporting 
Timeframe 
Form 
to Use 
Submission 
address/ fax 
numbers 
Copy to: 
harm  For a complete list refer to 
http://www.research.umn.edu/irb/g
uidance/ae.html#.VC7xraI0-sh  
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 
 
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). 
 
9.0 
Study Data Collection and Monitoring 
9.1 
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. 
9.2 
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 
http://z.umn.edu/dmsp  
 
For the purposes of data and safety monitoring, this phase II study is 
classified as high risk.  Therefore the following requirements will be 
fulfilled: 
▪ 
The Masonic Cancer Center Data and Safety Monitoring 
Council (DSMC) will review the trial’s progress quarterly 

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▪ 
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 8.2 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). 
9.3 
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. 
9.4 
Record Retention  
The investigator will retain study records for at 6 years after the study 
file is closed with the IRB.   
 
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. 
10.0   Statistical Considerations  
This is a treatment Phase II study for the use of T-cell replete reduced 
intensity conditioning (RIC) haploidentical donor allogeneic hematopoietic 
cell transplantation (HaploHCT) for individuals with high-risk non-
malignant diseases who lack a suitable HLA-matched sibling donor. 
 

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10.1 Primary, Secondary and Transplanted-Related Endpoints 
The primary objective of this phase II trial is to estimate the rate of 
donor neutrophil engraftment by day +42, defined as ANC > 500 
(0.5x109/L) for three consecutive measurements.  
 
Secondary endpoints include: 
• Incidence of overall survival at 1 year 
• Incidence of primary graft failure defined as failure to reach 
ANC>500 prior to day +42 with >50% donor myeloid cells 
 
Transplant related endpoints include: 
• Incidence of secondary graft failure at 6 months, 1 and 2 
years, defined at any time after day +42, as either 
- Graft failure with autologous recovery (non-neutropenic). 
Based on underlying disease, but may include consideration 
of Hgb S percentage exceeding that of the donor and ongoing 
transfusion dependence) 
- Aplastic graft failure (neutropenic), with bone marrow 
cellularity <10% and ongoing transfusion dependence 
• Incidence of acute graft-versus-host disease (GVHD) at 100 
days 
• Incidence of chronic GVHD at 1 year 
 
• Incidence of transplant-related mortality at 100 days, 180 
days, and 1 year following transplant 
 
Exploratory endpoints include: 
• Sorted lymphocyte chimerism at days 21, 42, 84, 100, 180, 1 
and 2 years 
• Description of immunological recovery (lymphocyte subsets 
and immune globulin levels) at days 21, 42, 84, 100, 180, 1 
and 2 years 
• Impact of day -1 residual serum ATG on neutrophil recovery, 
graft failure, and T cell chimerism. 
 
All endpoint data will be recorded in the University of Minnesota Blood and 
Bone Marrow Database as part of the historical database maintained by 
the department.   
 
 

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10.2 Data Collection and Statistical Plan 
10.2.1 
Statistical Analysis  
Cumulative incidence will be used to estimate incidence of 
engraftment, graft failure, treating late death (>day +21) as a 
competing risk (Lin, 1997). Kaplan-Meier curves will be used to 
estimate disease-free and overall survival (Kaplan & Meier, 1958). 
Hall-Wellner confidence bands will be obtained for both disease-free 
and overall survival estimates. Chimerism will be described with 
medians, ranges, interquartile ranges (IQR) and respective box 
plots. Immunological recovery will be descriptive over time in a 
similar fashion. The association of ATG with neutrophil recovery and 
graft failure may be measured with Fine and Gray regression or a 
simple Chi-square test. Its association with chimerism at specified 
time-points will be assessed by the general-Wilcoxon test but may 
be more descriptive in format using simple box-plots. 
10.2.2  
Sample Size 
The overall sample size of 20 patients is based on Simon’s optimal 
two-stage design assuming a type-I error of 5% and 80% power. The 
null hypothesis or the rate considered unworthy of further 
investigation is ≤ 50% engraftment. The alternative hypothesis or the 
rate considered worthy of further investigation is ≥80%.  
 
After enrollment of 7 patients, the trial will be terminated if 4 or fewer 
achieve neutrophil recovery. If we reach the second stage, the study 
will go on to enroll an additional 13 patients for a total sample size of 
20 patients. If 14 or more patients engraft out of 20 patients, the 
regimen will be considered worthy of further study. We expect to 
accrue 4-5 patients per year. Therefore, we anticipate completion of 
enrollment within 4-5 years. 
10.2.3  
Safety Monitoring and Stopping Rules 
Aplastic graft failure defined as lack neutrophil engraftment, 
treatment-related mortality by day 100 and Grade III-IV acute GHVD 
by day 100 will be monitored using early stopping rules. Stopping 
rules were developed based on adaptation of the Pocock stopping 
boundaries (Pocock, 1977). In the event that a stopping boundary is 
crossed, study accrual will halt, the IRB and study committee will be 
notified and the study plan will be reviewed.   
 

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1) Aplastic graft failure by day +42 
The goal is to construct a boundary based on excessive failure by 
day 42 such that the probability of early stopping is at most 10% if 
the expected rate is equal to 10% and our sample size is 20.  With 
these stipulations, the study will be stopped if there is failure in 2 out 
of 2 patients, 3 out of 8 patients, 4 out of 14 patients or 5 at any time.  
If the actual probability of failure is 30%, the probability of reaching 
the boundary will be 80%. 
 
If no aplastic graft failure is identified in the initial five RBC disorder 
or initial five cALD disorder patients, pre-Haplo HCT autologous stem 
cell collection can be discontinued. 
 
2) Treatment-related mortality by day +100 
The goal is to construct a boundary based on excessive mortality by 
day 100 such that the probability of early stopping is at most 10% if 
the expected rate is equal to 20% and our sample size is 20.  With 
these stipulations, the study will be stopped if there is mortality in 3 
out of 4 patients, 4 out of 7 patients, 5 out of 10 patients, 6 out of 13 
patients, 7 out of 17 patients or 8 at any time.  If the actual probability 
of failure is 40%, the probability of reaching the boundary will be 
68%. 
 
3) Grade III-IV Acute GVHD by day +100 
The goal is to construct a boundary based on excessive GVHD by 
day 100 such that the probability of early stopping is at most 10% if 
the expected rate is equal to 20% and our sample size is 20.  With 
these stipulations, the study will be stopped if there is GVHD in 3 out 
of 4 patients, 4 out of 7 patients, 5 out of 10 patients, 6 out of 13 
patients, 7 out of 17 patients or 8 at any time.  If the actual probability 
of failure is 40%, the probability of reaching the boundary will be 
68%. 
 
Note. We understand that the inclusion of stopping rules may slightly 
reduce the overall power of the trial. 
 
 

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11.0  Conduct of the Study 
11.1 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.  
11.2 Good Clinical Practice 
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.   
11.3 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. 
12.0 
Works Cited 
1. 
Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow 
transplantation for hematologic malignancies using nonmyeloablative 
conditioning and high-dose, posttransplantation cyclophosphamide. Biology of 
blood and marrow transplantation : journal of the American Society for Blood and 
Marrow Transplantation. 2008;14:641-650. 
2. 
Kasamon YL, Luznik L, Leffell MS, et al. Nonmyeloablative HLA-haploidentical 
bone marrow transplantation with high-dose posttransplantation 
cyclophosphamide: effect of HLA disparity on outcome. Biology of blood and 
marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation. 2010;16:482-489. 

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CPRC #2017LS101 
 
3. 
McCurdy SR, Kanakry JA, Showel MM, et al. Risk-stratified outcomes of 
nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation 
cyclophosphamide. Blood. 2015;125:3024-3031. 
4. 
Kanakry CG, Fuchs EJ, Luznik L. Modern approaches to HLA-haploidentical 
blood or marrow transplantation. Nat Rev Clin Oncol. 2016;13:132. 
5. 
Walters MC, Patience M, Leisenring W, et al. Barriers to bone marrow 
transplantation for sickle cell anemia. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow 
Transplantation. 1996;2:100-104. 
6. 
Justus D, Perez-Albuerne E, Dioguardi J, Jacobsohn D, Abraham A. Allogeneic 
donor availability for hematopoietic stem cell transplantation in children with 
sickle cell disease. Pediatr Blood Cancer. 2015;62:1285-1287. 
7. 
Bolanos-Meade J, Fuchs EJ, Luznik L, et al. HLA-haploidentical bone marrow 
transplantation with posttransplant cyclophosphamide expands the donor pool for 
patients with sickle cell disease. Blood. 2012;120:4285-4291. 
8. 
de la Fuente J, O'Boyle F, Harrington Y, et al. Haploidentical BMT with a post-
infusion of stem cells cyclophosphamide approach is feasible and leads to a high 
rate of donor engraftment in haemoblobinopathies allowing universal application 
of transplantation. Blood. 2015;126:4317. 
9. 
Dhedin N, de la Fuente J, Bernaudin F, et al. Haploidentical bone marrow 
transplant with post-transplant cytoxan plus thiotepa improves donor engraftment 
in patients with sickle cell anemia: Results of an international multicenter learning 
collaborative. Blood. 2016;128:1233. 
10. 
Wiebking V, Hutker S, Schmid I, Immler S, Feuchtinger T, Albert MH. Reduced 
toxicity, myeloablative HLA-haploidentical hematopoietic stem cell transplantation 
with post-transplantation cyclophosphamide for sickle cell disease. Annals of 
hematology. 2017;96:1373-1377. 
11. 
Anurathapan U, Hongeng S, Pakakasama S, et al. Hematopoietic stem cell 
transplantation for homozygous beta-thalassemia and beta-
thalassemia/hemoglobin E patients from haploidentical donors. Bone Marrow 
Transplant. 2016;51:813-818. 
12. 
Shah NN, Freeman AF, Su H, et al. Haploidentical Related Donor Hematopoietic 
Stem Cell Transplantation for Dedicator-of-Cytokinesis 8 Deficiency Using Post-
Transplantation Cyclophosphamide. Biology of blood and marrow transplantation 
: journal of the American Society for Blood and Marrow Transplantation. 
2017;23:980-990. 
13. 
Clay J, Kulasekararaj AG, Potter V, et al. Nonmyeloablative peripheral blood 
haploidentical stem cell transplantation for refractory severe aplastic anemia. 
Biology of blood and marrow transplantation : journal of the American Society for 
Blood and Marrow Transplantation. 2014;20:1711-1716. 
14. 
Esteves I, Bonfim C, Pasquini R, et al. Haploidentical BMT and post-transplant 
Cy for severe aplastic anemia: a multicenter retrospective study. Bone Marrow 
Transplant. 2015;50:685-689. 
15. 
Jaiswal SR, Chatterjee S, Mukherjee S, Ray K, Chakrabarti S. Pre-transplant 
sirolimus might improve the outcome of haploidentical peripheral blood stem cell 
transplantation with post-transplant cyclophosphamide for patients with severe 
aplastic anemia. Bone Marrow Transplant. 2015;50:873-875. 
16. 
DeZern AE, Zahurak M, Symons H, Cooke K, Jones RJ, Brodsky RA. Alternative 
Donor Transplantation with High-Dose Post-Transplantation Cyclophosphamide 
for Refractory Severe Aplastic Anemia. Biology of blood and marrow 

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Page 41 of 53 
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transplantation : journal of the American Society for Blood and Marrow 
Transplantation. 2017;23:498-504. 
17. 
Kreetapirom P, Hongeng S, Manuyakorn W, et al. Successful HLA haploidentical 
HSCT with post-transplant cyclophosphamide in Wiskott-Aldrich syndrome. Bone 
Marrow Transplant. 2017;52:913-914. 
18. 
Klein OR, Chen AR, Gamper C, et al. Alternative-Donor Hematopoietic Stem Cell 
Transplantation with Post-Transplantation Cyclophosphamide for Nonmalignant 
Disorders. Biology of blood and marrow transplantation : journal of the American 
Society for Blood and Marrow Transplantation. 2016;22:895-901. 
19. 
Vermylen C, Cornu G, Ferster A, et al. Haematopoietic stem cell transplantation 
for sickle cell anaemia: the first 50 patients transplanted in Belgium. Bone 
Marrow Transplant. 1998;22:1-6. 
20. 
Walters MC, Patience M, Leisenring W, et al. Stable mixed hematopoietic 
chimerism after bone marrow transplantation for sickle cell anemia. Biology of 
blood and marrow transplantation : journal of the American Society for Blood and 
Marrow Transplantation. 2001;7:665-673. 
21. 
Bernaudin F, Socie G, Kuentz M, et al. Long-term results of related myeloablative 
stem-cell transplantation to cure sickle cell disease. Blood. 2007;110:2749-2756. 
22. 
Panepinto JA, Walters MC, Carreras J, et al. Matched-related donor 
transplantation for sickle cell disease: report from the Center for International 
Blood and Transplant Research. British journal of haematology. 2007;137:479-
485. 
23. 
Lucarelli G, Gaziev J, Isgro A, et al. Allogeneic cellular gene therapy in 
hemoglobinopathies--evaluation of hematopoietic SCT in sickle cell anemia. 
Bone Marrow Transplant. 2012;47:227-230. 
24. 
Bhatia M, Jin Z, Baker C, et al. Reduced toxicity, myeloablative conditioning with 
BU, fludarabine, alemtuzumab and SCT from sibling donors in children with 
sickle cell disease. Bone Marrow Transplant. 2014;49:913-920. 
25. 
La Nasa G, Caocci G, Argiolu F, et al. Unrelated donor stem cell transplantation 
in adult patients with thalassemia. Bone Marrow Transplant. 2005;36:971-975. 
26. 
Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic 
stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371:339-348. 
27. 
Krishnamurti L, Kharbanda S, Biernacki MA, et al. Stable long-term donor 
engraftment following reduced-intensity hematopoietic cell transplantation for 
sickle cell disease. Biology of blood and marrow transplantation : journal of the 
American Society for Blood and Marrow Transplantation. 2008;14:1270-1278. 
28. 
Hsieh MM, Wu CJ, Tisdale JF. In mixed hematopoietic chimerism, the donor red 
cells win. Haematologica. 2011;96:13-15. 
29. 
Hsieh MM, Kang EM, Fitzhugh CD, et al. Allogeneic hematopoietic stem-cell 
transplantation for sickle cell disease. The New England journal of medicine. 
2009;361:2309-2317. 
30. 
Jacobsohn DA, Duerst R, Tse W, Kletzel M. Reduced intensity haemopoietic 
stem-cell transplantation for treatment of non-malignant diseases in children. 
Lancet. 2004;364:156-162. 
31. 
Horan JT, Liesveld JL, Fenton P, Blumberg N, Walters MC. Hematopoietic stem 
cell transplantation for multiply transfused patients with sickle cell disease and 
thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-
thymocyte globulin. Bone Marrow Transplant. 2005;35:171-177. 
32. 
Krishnamurti L, Bunn HF, Williams AM, Tolar J. Hematopoietic cell 
transplantation for hemoglobinopathies. Curr Probl Pediatr Adolesc Health Care. 
2008;38:6-18. 

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33. 
Kamani NR, Walters MC, Carter S, et al. Unrelated donor cord blood 
transplantation for children with severe sickle cell disease: results of one cohort 
from the phase II study from the Blood and Marrow Transplant Clinical Trials 
Network (BMT CTN). Biology of blood and marrow transplantation : journal of the 
American Society for Blood and Marrow Transplantation. 2012;18:1265-1272. 
34. 
Admiraal R, van Kesteren C, Jol-van der Zijde CM, et al. Association between 
anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric 
haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic 
cohort analysis. Lancet Haematol. 2015;2:e194-203. 
 
 
 

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Appendix I -  Rabbit ATG (Thymoglobulin) dosing for 
ALD and RBC disorder patients 
Patient 
Weight (kg)@ 
Absolute 
Lymphocyte Count# 
Cumulative 
dose (mg/kg)& 
Number of 
doses 
Daily dose 
(mg/kg) 
5 
0.1 
10 
4 
2.5 
5 
0.5 
10 
4 
2.5 
5 
1 
10 
4 
2.5 
5 
2 
10 
4 
2.5 
5 
3 
10 
4 
2.5 
5 
4 
10 
4 
2.5 
7.5 
0.1 
8 
4 
2.0 
7.5 
0.5 
9 
4 
2.3 
7.5 
1 
10 
4 
2.5 
7.5 
2 
10 
4 
2.5 
7.5 
3 
10 
4 
2.5 
7.5 
4 
10 
4 
2.5 
10 
0.1 
7 
4 
1.8 
10 
0.5 
8 
4 
2.0 
10 
1 
9 
4 
2.3 
10 
2 
10 
4 
2.5 
10 
3 
10 
4 
2.5 
10 
4 
10 
4 
2.5 
15 
0.1 
6 
3 
2.0 
15 
0.5 
6 
4 
1.5 
15 
1 
7 
4 
1.8 
15 
2 
8 
4 
2.0 
15 
3 
10 
4 
2.5 
15 
4 
10 
4 
2.5 
20 
0.1 
5 
2 
2.5 
20 
0.5 
5 
3 
1.7 
20 
1 
6 
3 
2.0 
20 
2 
8 
4 
2.0 
20 
3 
10 
4 
2.5 
20 
4 
10 
4 
2.5 
25 
0.1 
4 
2 
2.0 
25 
0.5 
5 
2 
2.5 
25 
1 
5 
3 
1.7 
25 
2 
6 
3 
2.0 
25 
3 
9 
4 
2.3 
25 
4 
10 
4 
2.5 
30 
0.1 
4 
2 
2.0 
30 
0.5 
4.5 
2 
2.3 
30 
1 
5 
2 
2.5 
30 
2 
6 
3 
2.0 

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Patient 
Weight (kg)@ 
Absolute 
Lymphocyte Count# 
Cumulative 
dose (mg/kg)& 
Number of 
doses 
Daily dose 
(mg/kg) 
30 
3 
8 
4 
2.0 
30 
4 
10 
4 
2.5 
35 
0.1 
3.5 
2 
1.8 
35 
0.5 
4 
2 
2.0 
35 
1 
5 
2 
2.5 
35 
2 
6 
3 
2.0 
35 
3 
7.5 
3 
2.5 
35 
4 
10 
4 
2.5 
40 
0.1 
3 
2 
1.5 
40 
0.5 
3.5 
2 
1.8 
40 
1 
4 
2 
2.0 
40 
2 
5 
2 
2.5 
40 
3 
6 
3 
2.0 
40 
4 
10 
4 
2.5 
50 
0.1 
3 
2 
1.5 
50 
0.5 
3 
2 
1.5 
50 
1 
4 
2 
2.0 
50 
2 
5 
2 
2.5 
50 
3 
6 
3 
2.0 
50 
4 
8 
4 
2.0 
60 
0.1 
2.5 
2 
1.3 
60 
0.5 
3 
2 
1.5 
60 
1 
3 
2 
1.5 
60 
2 
4 
2 
2.0 
60 
3 
5 
2 
2.5 
60 
4 
7.5 
3 
2.5 
70 
0.1 
2.5 
1 
2.5 
70 
0.5 
2.5 
2 
1.3 
70 
1 
3 
2 
1.5 
70 
2 
4 
2 
2.0 
70 
3 
5 
2 
2.5 
70 
4 
6 
3 
2.0 
80 
0.1 
2 
1 
2.0 
80 
0.5 
2.5 
1 
2.5 
80 
1 
3 
2 
1.5 
80 
2 
4 
2 
2.0 
80 
3 
5 
2 
2.5 
80 
4 
6 
3 
2.0 
@Recipient’s weight in kilograms; #Absolute lymphocyte count (x103/uL) determined 
from the CBC diff obtained prior to first ATG dose on day -10 or -9; &Cumulative dose 
is an estimate; actual dose is determined by last two columns, number of doses x 
daily dose. For patients whose weights and/or ALC between those shown in the 
nomogram, round to the closest value (rounding up if at midpoint).  
 

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Appendix II – Treatment Related Risks:  Conditioning 
Chemotherapy 
 
Fludarabine 
Common  
Less Common 
Rare 
• low white blood cell count with 
increased risk of infection  
• low platelet count with 
increased risk of bleeding  
• low red blood cell count 
(anemia) with tiredness and 
weakness 
• tiredness (fatigue)  
• nausea  
• vomiting  
• fever and chills 
• infection 
• pneumonia  
• diarrhea  
• loss of appetite 
• weakness 
• pain 
• numbness and tingling in 
hands and/or feet related to 
irritation of nerves  
• changes in vision  
• agitation  
• confusion 
• clumsiness 
• seizures 
• coma  
• cough  
• trouble breathing  
• intestinal bleeding 
• weakness  
• death due to effects on the 
brain, infection, bleeding, 
severe anemia, skin blistering, 
or other causes 
 
Cyclophosphamide 
Common  
Less Common 
Rare 
• low white blood cell count with 
increased risk of infection  
• hair loss or thinning, including 
face and body hair (usually 
grows back after treatment)  
• nausea  
• vomiting  
• loss of appetite  
• sores in mouth or on lips  
• bleeding from bladder, with 
blood in urine  
• diarrhea  
• long-term or short-term 
infertility (inability to have 
children) in women and men 
• low platelet count (mild) with 
increased risk of bleeding  
• darkening of nail beds  
• acne  
• tiredness  
• infection 
• fetal changes if pregnancy 
occurs while taking 
cyclophosphamide  
• heart problems with high 
doses, with chest pain, 
shortness of breath, or swollen 
feet 
• severe allergic reactions 
• skin rash  
• scarring of bladder 
• kidney damage (renal tubular 
necrosis) which can lead to 
kidney failure 
• heart damage, with trouble 
getting your breath, swelling of 
feet, rapid weight gain 
• scarring of lung tissue, with 
cough and shortness of breath 
• second cancer, which can 
happen years after taking this 
drug 
• death from infection, bleeding, 
heart failure, allergic reaction, 
or other causes 
 
Mesna is administered before, during and after the cyclophosphamide to protect 
against bladder damage.   
Mesna 
Common 
Less Common 
Rare, but may be serious 
• bad taste when taken by 
mouth (may recommend 
taking it with a strong-flavored 
beverage)  
• nausea or vomiting 
• mild diarrhea  
• headache  
• loss of appetite  
• flu-like symptoms (fever, 
flushing, dizziness)  
• fast heartbeat  
• low blood pressure  
• allergic reaction (may include 
shortness of breath, wheezing, 
swelling in the mouth or throat, 

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Mesna 
Common 
Less Common 
Rare, but may be serious 
• cold symptoms (sore throat, 
runny nose)  
• feeling tired or sleepy 
hives, itching, flushing, or 
fever)  
 
Thiotepa 
Common 
Less Common 
Rare, but may be serious 
• low white blood cell count with 
increased risk of infection  
• low platelet count with 
increased risk of bleeding  
• nausea  
• vomiting  
• loss of appetite  
• temporary or permanent 
sterility (inability to have 
children)  
• tiredness (fatigue)  
• anemia (low red blood cell 
count)  
• dizziness  
• headache  
• fever  
• pain where the drug was 
injected  
• hair loss, thinning or brittle 
hair (including hair on the face 
or body)  
• blurred vision  
• confusion  
• allergic reaction with itching, 
hives (welts), swelling in 
throat, wheezing, dizziness, or 
shortness of breath  
• second type of cancer  
• death from infection, bleeding, 
or other cause  
 
Rabbit ATG (Thymoglobulin) 
Common 
Less Common 
Rare 
• fever 
• chills 
• leukopenia 
• pain 
• headache 
• abdominal pain 
• diarrhea 
• hypertension 
• nausea 
• thrombocytopenia 
• peripheral edema 
• dyspnea 
• asthenia 
• hyperkalemia 
• tachycardia  
• malaise 
• dizziness  
• severe allergic reaction 
(anaphylaxis) 
 
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) 
 
 

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Appendix III – Treatment Related Risks: GVHD 
Prophylaxis/Immune Suppression 
Risks of post-transplant cyclophosphamide and mesna are as above in Appendix 
II. 
 
 
Mycophenolate Mofetil (MMF) 
Common 
Rare, but may be serious 
• constipation 
• stomach pain or swelling 
• nausea 
• vomiting 
• difficulty falling asleep or staying asleep 
• pain, especially in the back, muscles, or joints 
• uncontrollable shaking of a part of the body 
• headache 
• rash 
 
 
• diarrhea 
• swelling of the hands, arms, feet, ankles, or lower legs 
• difficulty breathing 
• chest pain 
• fast heartbeat 
• dizziness 
• fainting 
• lack of energy 
• pale skin 
• black and tarry stools 
• red blood in stools 
• bloody vomit 
• vomit that looks like coffee grounds 
• yellowing of the skin or eyes 
 
 
Sirolimus 
 
 
Common  
Less Common 
Rare 
• Headache  
• Hypertension 
• Nausea 
• Diarrhea 
• immuno-suppression 
• fever 
• constipation 
• Tremor  
• renal dysfunction 
• elevated creatinine/BUN, 
anemia 
• pain (abdominal, back, pain) 
• hyperlipidemia 
• hypercholesterolemia 
• hypertrigylceridemia, 
hyperglycemia 
• peripheral edema 
• weight gain 
• arthralgia 
• Acne 
• Chest pain 
• Insomnia 
• Dyspepsia 
• Vomiting 
• Dyspnea 
• Elevated LFTs (with elevated 
sirolimus levels) 
• Stomatitis 
• urinary tract infections 
• URIs 
• mild thrombocytopenia 
• leukopenia 
• hyper/hypokalemia  
• hypophosphatemia 
• rash, hives, pruritis,  
• delayed wound healing or 
dehiscence 
• hypomagnesaemia  
• proteinuria 
• Hypotension 
• Asthma 
• increased cough 
• flu like syndrome 
• tachycardia 
• anorexia 
• hypersensitivity reactions (exfoliative 
dermatitis, angioedema) 
• Opportunistic infections 
• pleural and pericardial effusions 
• non-infectious pneumonitis or 
bronchiolitis-obliterans organizing 
pneumonia and pulmonary fibrosis 
• thrombosis 
• myalgias 
• increased risk of CNI-induced 
HUS/TTP/TMA) 
• Chronic renal dysfunction 
• renal tubular necrosis 
• CHF 
• Ascites 
• arthrosis 
• bone necrosis 
• osteoporosis 
• Lymphoproliferative disorders 
• skin malignancies 

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Appendix IV – Treatment Related Risks: Supportive Care 
 
G-CSF 
Common  
Less Common 
Rare 
• none  
• bone and muscle pain  
• abnormal blood tests which 
suggest that the drug is 
affecting the liver  
• fast heartbeat  
• low blood pressure  
• allergic reaction (may include 
shortness of breath, wheezing, 
swelling in the mouth or throat, 
hives, itching, flushing, or fever)  
•  
 
 
Hydroxyurea 
Common 
Less Common 
Rare 
• Cough or hoarseness 
• fever or chills 
• lower back or side pain 
• painful or difficult urination 
 
• Black, tarry stools 
• blackening of the fingernails 
and toenails 
• blood in the urine or stools 
• pinpoint red spots on the skin 
• sores in the mouth and on the 
lips 
• unusual bleeding or bruising 
• Confusion 
• convulsions (seizures) 
• difficulty with urination 
• dizziness 
• headache 
• joint pain 
• seeing, hearing, or feeling 
things that are not there 
• swelling of the feet or lower 
legs 
 
 

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Appendix V - Risks of the Anti-Oxidant/Anti-Inflammatory 
Regimens 
 
Levetiractem (Keppra) is used to prevent seizures during times of increased risk. 
Keppra will be started on from day -9, with the start of conditioning, until sirolimus 
is discontinued. Risks of Keppra include hallucinations; fever, chills, body aches, 
flu symptoms; weakness, lack of coordination; increasing or worsening seizures; 
and nausea, stomach pain, loss of appetite, itching, dark urine, clay-colored stools, 
jaundice (yellowing of the skin or eyes).  Less serious side effects include 
dizziness, spinning sensation; drowsiness; feeling irritable; headache; runny nose, 
sore throat; or neck pain. 
 
N-acetylcysteine can cause nausea, vomiting, and diarrhea or constipation. 
Rarely, it can cause rashes, fever, headache, drowsiness, low blood pressure, 
and liver problems. 
When inhaled, it can also cause swelling in the mouth, runny nose, drowsiness, 
clamminess, and chest tightness. 
N-acetyl cysteine has an unpleasant odor that may make it hard to take. 
 
 
Celecoxib: 
Common 
Less Common 
Rare 
• cough  
• fever 
• rash 
• sneezing 
• sore throat  
 
• vomiting  
• heartburn 
• nausea 
• diarrhea  
• stomach pain 
• wheezing  
• headache  
• tiredness (fatigue), weakness  
• increased sensitivity of skin 
to sunlight (higher risk of 
sunburn) 
• loss of appetite  
• liver function test changes 
• bloating or swelling, 
especially of the legs and 
feet* 
• peptic (stomach) ulcers  
• bleeding from the stomach or 
intestines 
• abnormal blood tests which 
suggest that the drug is 
affecting the liver 
 
• decreased hearing  
• vision changes  
• double vision  
• hepatitis (liver inflammation) 
• liver damage, which may 
cause yellow skin or eyes 
(jaundice)  
• rash and itching  
• high blood pressure 
• low white blood cell count with 
increased risk of infection  
• low platelet count with 
increased risk of bleeding  
• low red blood cell count 
(anemia) and tiredness  
• urinary tract infection 
• kidney damage (usually gets 
better after medicine is 
stopped) 
• kidney failure  
• blood in urine  
• stroke (higher risk with long 
term use) 
• heart attack (higher risk with 
long term use)  
• anxiety  
• severe allergic reaction with 
trouble breathing, raised itchy 

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CPRC #2017LS101 
 
Celecoxib: 
Common 
Less Common 
Rare 
welts on the skin, or swelling 
of the face, mouth, or throat 
• heart attack or stroke  
 
 
Vitamin E may cause allergic skin reactions (inflammation or itching), blurred 
vision, changes in cholesterol levels, changes in insulin resistance, diarrhea, 
dizziness, fatigue, flu-like symptoms, headache, heart conditions, increased risk 
of death, increased risk of fainting or falls, increased risk of heart failure, 
increased risk of high blood pressure in pregnancy, increased risk of stroke, 
increased risk of tuberculosis, kidney dysfunction, nausea, severe response to 
infection (in preterm babies), sexual dysfunction, stomach pain, vision loss, and 
weakness. 
 
Alpha Lipoic Acid is generally safe, but may cause a rash or lower blood sugar.  
People at risk for thiamine deficiency should take a thiamine supplement.   
 
 
 

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Appendix VI – Transplant Related Risks  
 
Hematopoietic Cell Transplantation – regardless of stem cell source 
With the cell infusion 
• 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) 
 
As result of transplant  
• 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 
 
Additional Risks associated with the using a Haploidentical Donor 
Based on previous experience at this instutition and others there is lower 
transplant related mortality (TRM), a greater chance of disease relapse but 
similar overall survival when compared with other transplants using a related or 
unrelated matched donor. 
 
 
 

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Appendix VII - Performance Status 
Karnofsky Performance Status Scale (≥ 16 years) 
 
Lansky Score (children < 16 years) 
Lansky 
Score 
Performance Status 
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 
Able to carry on normal activity 
and to work; no special care 
needed. 
  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.  
Unable to work; able to live at 
home and care for most 
personal needs; varying 
amount of assistance needed. 
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 personal needs. 
50 
Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires 
equivalent of institutional or 
hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospital admission is 
indicated although death not imminent. 
20 
Very sick; hospital admission necessary; 
active supportive treatment necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead