Clinical trial NCT02162420
Conditions: Dyskeratosis Congenita Aplastic Anemia
Keywords: severe aplastic anemia Hematopoietic Stem Cell Transplant
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2015-01-10; Completion date: 2025-03-11
Enrollment: 61 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Fludarabine-based preparative regimen followed by an allogeneic hematopoietic stem cell transplant using related or unrelated donor in persons 0-70 years of age diagnosed with dyskeratosis congenita or severe aplastic anemia who have bone marrow failure characterized by a requirement for red blood cell and platelet transfusions. Three different preparative regimens are included based on disease and donor type.

Detailed description:

Arms: arm 1: Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, followed by stem cell transplant for the treatment of dyskeratosis congenita. arm 2: Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant. arm 3: Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant. arm 4: Fludarabine based preparative regimen, including alemtuzumab, cyclophosphamide, fludarabine, followed by stem cell transplant for the treatment of dyskeratosis congenita. arm 5: Fludarabine based preparative regimen which includes: cyclophosphamide, fludarabine, rabbit ATG and total body irradiation. Followed by stem cell transplant.
Interventions: intervention 1: Alemtuzumab intervention 2: Fludarabine intervention 3: Cyclophosphamide intervention 4: Total Body Irradiation intervention 5: Stem Cell Transplant intervention 6: Anti-thymocyte globulin
Intervention descriptions: intervention 1: Alemtuzumab 0.2 mg/kg IV over 2 hours on days -10 to -6 from transplant. intervention 2: Fludarabine 40 mg/m2 IV over 1 hour on days -6 to -2 from transplant. intervention 3: Cyclophosphamide 50 mg/kg IV over 2 hours on day -7 from transplant. intervention 4: TBI 200 cGy as a single fraction on day -1 from transplant. intervention 5: Stem cell transplant on day 0. intervention 6: ATG (Thymoglobulin - Rabbit ) 3 mg/kg IV on days -5 to -3 from stem cell transplant.

Protocol documents:
Prot_SAP_000.pdf: 
University of Minnesota 
Masonic Cancer Center 
Blood and Marrow Transplantation  
Department of Pediatrics  
 
 
 
 
 
 
Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita 
or Severe Aplastic Anemia 
MT2013-34C 
CPRC #2013OC127 
 
 
 
Investigators: 
Christen L. Ebens, MD, MPH (Principal Investigator) 
 
Jakub Tolar, MD, PhD 
Brian C. Betts, MD 
Angela Smith, MD 
Paul Orchard, MD 
Margaret MacMillian, MD 
John E. Wagner, MD 
Daniel Weisdorf, MD 
Kathryn E. Dusenbery MD 
Kristina M. Nelson, PharmD 
 
 
Statistician: 
Todd E. DeFor, MS 
 
 
Version Date: 
February 15, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 


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CPRC # 2013OC127 
Revision History 
 
Revision 
# 
Version 
Date 
Detail of Changes 
Consent 
change? 
(Y/N) 
 
02/05/2014 
Original to CPRC 
 
1 
01/08/2015 
Schema, sections 1, 2.11, 4.1, 5 – remove TBI from 
the DC treatment plan; 
Insert a new section 5 for donor selection/cell 
requirements  
Update protocol to current template 
yes 
2 
09/16/2016 
Clarify for SAA – second transplants will receive the 
unmatched donor preparative regimen regardless of 
donor type 
yes SAA 
3 
4/10/2017 
Revised per CPRC stipulations to include background 
and donor preferences for 2nd transplant; added link 
to CPRC DSMP 
no 
3A 
4/12/2017 
Clarified section 5.2 per IRB stipulation 
No 
4 
3/22/2018 
Section 4.5.1 and Appendix II: changed GVHD 
Prophylaxis from CSA to tacrolimus 
Yes 
(consent 
attachments) 
4A 
08/15/2018 
Sections 4.1, 4.2 & study summary, added 
fludarabine dose adjustments for pediatric patients < 
10kg; Sections 4.5.1 & 4.5.2 edited the dosing 
guideline for tacrolimus and MMF per pharmacist 
recommendation 
No 
5 
03/19/20 
Change of PI to Dr. Christen Ebens; added Brian 
Betts and Kristina Nelson to study committee 
Addition of haploidentical donor treatment arms for 
SAA and dyskeratosis congenita 
Updated diagnostic criteria for dyskeratosis congenita 
Yes 
(consents 
and new 
attachments 
for Haplo) 
6 
05/21/2020 
Edited dosing instructions to current standard of care, 
per recommendations of inpatient pharmacist 
No 
7 
02/15/2021 
Section 6, minor edits to laboratory procedures to 
remove inconsistencies from SOC orders 
No 
 
 
 
PI Contact Information: 
Christen Ebens, MD, MPH  
Hematology/Oncology and Transplantation 
Department of Pediatrics 
MMC 484 
420 Delaware Street SE 
Minneapolis, MN  55455 
612-626-8094  (phone) 
612-626-2815 (fax)  
ebens012@umn.edu(email) 


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CPRC # 2013OC127 
Table of Contents 
 
Synopsis ......................................................................................................................................................... 4 
Schema ........................................................................................................................................................... 5 
1.0 
Introduction and Rationale ................................................................................................................ 6 
2.0 
Patient Selection ................................................................................................................................ 7 
2.1 
Eligible Diseases: .......................................................................................................................... 7 
2.2 
Adequate organ function ............................................................................................................... 8 
2.3 
Age and consent ............................................................................................................................ 8 
2.4 
Exclusion Criteria: ........................................................................................................................ 9 
2.5 
Donor Selection: ........................................................................................................................... 9 
3.0 
Registration in OnCore .....................................................................................................................10 
4.0 
Treatment Plan .................................................................................................................................10 
4.1 
Dyskeratosis Congenita (DC) ......................................................................................................10 
4.2 
Severe Aplastic Anemia (SAA) ...................................................................................................12 
4.3 
Cell Infusion (day 0) ....................................................................................................................14 
4.4 
Post-Transplant G-CSF (filgrastim) .............................................................................................14 
4.5 
GVHD Prophylaxis ......................................................................................................................15 
4.6 
Follow-Up ....................................................................................................................................16 
4.7 
Supportive Care ...........................................................................................................................16 
5.0 
Donor Selection and Cell Dose Requirements .................................................................................16 
5.1 
Donor specific HLA antibodies: ..................................................................................................16 
5.2 
Donor Considerations When More Than 1 Potential Donor ........................................................17 
5.3 
Donor Considerations for 2nd Transplant ....................................................................................17 
5.4 
Cell Dose Requirements Based on Cell Source ...........................................................................17 
6.0 
Clinical Evaluations .........................................................................................................................19 
7.0 
Event Reporting ................................................................................................................................20 
8.0 
Data Collection and Statistical Plan .................................................................................................20 
8.1 
Trial Size Justification .................................................................................................................20 
8.2 
Analysis of Primary and Secondary Endpoints ............................................................................20 
8.3 
Safety Monitoring ........................................................................................................................20 
9.0 
REFERENCES .................................................................................................................................22 
Appendix I – Treatment Related Risks Dyskeratosis Congenita (Arms A and D) ........................................24 
Appendix II – Treatment Related Risks Severe Aplastic Anemia (Arms B and E).......................................26 
Appendix III – Treatment Related Risks Severe Aplastic Anemia  (Arm C) ................................................28 
Appendix IV – Transplant Related Risks – General, Regardless of Diagnosis .............................................29 


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Synopsis 
Hematopoietic Stem Cell Transplant for Patients with Dyskeratosis 
Congenita or Severe Aplastic Anemia 
MT2013-34C 
 
This study facilitates the collection and analysis of outcome data for patients with dyskeratosis 
congenita (DC) or severe aplastic anemia (SAA) undergoing a hematopoietic stem cell transplant 
(HSCT).  
 
Study Design: 
This is a treatment study using a fludarabine-based preparative regimen 
followed by a related or unrelated allogeneic hematopoietic stem cell 
transplant.  Five different preparative regimens are included based on 
disease and donor type. 
  
Patient 
Population: 
Persons 0-70 years of age diagnosed with dyskeratosis congenita or severe 
aplastic anemia who have bone marrow failure chacaterized by a requirment 
for red blood cell and platelet transfusions, or require a second transplant 
due to graft failure. 
 
Endpoints: 
Specific transplant related endpoints include incidence of: 
• neutrophil engraftment at day 42 and platelet engraftment at 1 year  
• regimen related morality at 100 days 
• acute GVHD at 100 days  
• chronic GVHD at 6 months and 1 year  
• secondary malignancies 
   
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.   
 
Enrollment  
It is anticipated that 50 patients will be enrolled over 10 years 
 
 
 




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1.0 
Introduction and Rationale 
This is a treatment study for the use of hematopoietic stem cell transplant 
(HSCT) for dyskeratosis congenita (DC) and severe aplastic anemia (SAA).  
Based on the previous University of Minnesota study MT2006-06, this 
protocol offers a conditioning regimen that is less intensive but with 
adequate immunosuppressive activity to promote engraftment of HSC from 
related and unrelated donors. The modification eliminates the total body 
irradiation (TBI) from the DC preparative regimen only. It additionally 
expands donor options with haploidentical T-replete post-transplant 
cyclophosphamide based conditioning regimens. 
 
Idiopathic severe aplastic anemia treatment focuses on disruption of an 
immune-mediated destruction of hematopoietic stem cells or the bone 
marrow niche, with either systemic immunosuppressive therapy (IST) or 
HSCT1. Historically, up-front HSCT was offered only for patients with an 
HLA-matched related donor. However, more recent compelling data 
supports equivalent overall survival (IST 82%, MUD HSCT 77%)1 and 
equivalent, if not superior, event-free-survival with HLA-matched unrelated 
donor HSCT as compared to IST2. IST is limited by non-response in 30% of 
patients3, relapse in 40%4, clonal evolution of myelodysplastic or leukemia 
clones in 20%5 and delayed recovery of cell counts (3-4 months). Additional 
improvements in HSCT outcomes have been recognized with decreased 
irradiation6 and addition of fludarabine7 in the conditioning regimen. Finally, 
the gap in outcomes between recipients of HLA-matched related donors 
and unrelated donors has been eliminated8-11. More recently, the donor pool 
has been expanded to include haploidentical donors, with results reviewed 
bu DeZern and Brodsky, 201812.  
   
Literature on HSCT in DC continues to support non-myeloablative or 
reduced intensity conditioning regimens13-15. Evidence suggests that 
radiation-free 
conditioning 
does 
not 
compromise 
hematopoietic 
engraftment16,17.It does however eliminate radiation related extra-medullary 
toxicity (especially to the lung and liver), a concern since pulmonary fibrosis 
and liver cirrhosis are a part of disease phenotype. While matched related 
donor HSCT has the best outcome in DC, success has been reported with 
alternative donor18 and haploidentical HSCT19-21. With regard to 
haploidentical donor HSCT, use of post-transplant cyclophosphamide 
(PTCy) may be particularly detrimental to patients with DC, contributing to 
pulmonary and liver toxicity and increased risk for future carcinomas. Luznik 
et al. reported on comparison of 1 versus 2 days of PTCy, showing 


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CPRC # 2013OC127 
equivalent outcomes with regard to acute graft-versus-host disease 
(GvHD)22. More recently, the Kanakry lab carefully examined exact timing 
of PTCy dosing in murine models, identifying day +4 as optimal in single 
PTCy dose regimen23. Consider the available data, should a DC patient 
require HSCT with a haploidentical donor, we will limit alkylator exposure 
by removing conditioning cyclophosphamide and adding single dose day +4 
PTCy. 
 
As bone marrow failure is the primary cause of premature deaths in DC and 
SAA patients, HSCT is an attractive option with proven potential for curing 
the BM failure associated with these diseases.  This treatment will also be 
open to SAA patients who have experienced graft failure (GF) early after 
stem cell infusion. At the University of Minnesota, the incidence of graft 
failure by day 50 is 7 – 10%, creating a necessity for 2nd transplant treatment 
options for these patients.  
 
Patients consent to allow the analysis of routine clinical data collected and 
maintained in OnCore, the Masonic Cancer Center’s (MCC) clinical 
database, and specific transplant related endpoints in the University Of 
Minnesota Blood and Bone Marrow Database as part of the historical 
database maintained by the department.   
 
Endpoints include incidence of neutrophil engraftment at day 42 and platelet 
engraftment at 1 year, regimen related morality at 100 days, acute GVHD 
at 100 days, chronic GVHD at 6 and 12 months, and secondary 
malignancies. 
2.0 
Patient Selection  
Inclusion Criteria: 
2.1 
Eligible Diseases: 
2.1.1 Dyskeratosis Congenita (DC)     
1) Diagnosis of DC: 
o 
short telomeres  
o 
pathogenic or suspected pathogenic variant(s) in a DC 
associated gene (e.g. DKC1, TERT, TERC, NOP10, NHP2, 
TCAB1, TINF2, CTC1, ACD, PARN, RTEL1, WRAP53) 
2) With evidence of BM failure defined as:  
• requirement for red blood cell and/or platelet transfusions 
or 


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• requirement for G-CSF or GM-CSF or erythropoietin 
or  
• refractory cytopenias having one of the following three 
o 
platelets <50,000/uL or transfusion dependent  
o 
absolute 
neutrophil 
count 
<500/uL 
without 
hematopoietic growth factor support 
o 
hemoglobin <9g/uL or transfusion dependent 
2) OR early myelodysplastic features 
3) With or without clonal cytogenetic abnormalities 
 
2.1.2 Severe Aplastic Anemia (SAA) primary transplant with 
1) Diagnosis of SAA: 
• Refractory cytopenias having one of the following three: 
o 
platelets <20,000/uL or transfusion dependent  
o 
absolute 
neutrophil 
count 
<500/uL 
without 
hematopoietic growth factor support 
o 
absolute reticulocyte count <20,000/uL 
2) With evidence of BM failure:  
• Refractory cytopenia defined by bone marrow 
cellularity <50% (with < 30% residual hematopoietic 
cells) 
3) OR early myelodysplastic features 
4) With or without clonal cytogenetic abnormalities 
 
2.3.3 Severe Aplastic Anemia (SAA) requiring a 2nd transplant 
• Graft failure as defined by blood/marrow chimerism 
of < 5% 
 
2.2 
Adequate organ function  
defined as: 
Cardiac:  left ventricular ejection fraction ≥ 35% with no evidence of 
decompensated heart failure 
Pulmonary:  DLCO ≥30% predicted, no supplemental oxygen 
requirement 
Renal:  Glomerular filtration rate (GFR) ≥30% predicted 
 
2.3 
Age and consent 
Age: 0-70 years 
Consent: Voluntary written consent (adult or parental/guardian) 


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2.4 
Exclusion Criteria: 
 
2.4.1 Acute hepatitis or evidence of moderate or severe portal 
fibrosis or cirrhosis on biopsy 
 
2.4.2 Pregnant or lactating 
 
2.4.3 Uncontrolled infection  
 
2.4.4 Prior radiation therapy (applies to SAA patients only) 
 
2.4.5 Diagnosis of Fanconi anemia based on DEB 
 
2.4.6 Advanced MDS or acute myeloid leukemia with >30% blasts 
 
2.5 
Donor Selection: 
2.5.1 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. 
 
2.5.2 Donor options 
• Bone marrow or peripheral blood stem cells 
o Related donor: HLA matched, 1 antigen mismatched, or 
haploidentical (matching at a minimum of one allele each of 
HLA-A, -B, -Cw, -DRB1 and -DQB1) 
 Related bone marrow or peripheral blood stem cell donors 
must meet donor criteria as outlined in the MT2012-14C: 
Procedure Guidelines for Related Hematopoietic Stem Cell 
Donors.  
 Related donors of patients with DC must have a telomere 
length within 2 standard deviations of normal 
o Unrelated donor: HLA matched or 1 antigen mismatched  
• UCB unit(s): Single or double UCB units selected according to 
Minnesota BMT program guidelines 
 
Refer to section 5 for additional donor selection preferences and 
cell doses based on source. 


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3.0 
Registration in OnCore  
Patients will be registered to this study in OnCore at the time of consent 
signing.   
 
4.0 
Treatment Plan 
All drugs will be prepared and administered per institutional guidelines, 
with the drugs, doses and scheduled modified as clinically indicated. 
Dosing is based on actual body weight (ABW) and current institutional 
guidelines. 
4.1 
Dyskeratosis Congenita (DC) 
 
 
Day 
 
ARM A: Non-haploidentical donor 
 
ARM D: Haploidentical donor 
-10 
Alemtuzumab 0.2 mg/kg IV over 2 hours 
Alemtuzumab 0.2 mg/kg IV over 2 hours 
-9 
Alemtuzumab 0.2 mg/kg IV over 2 hours 
Alemtuzumab 0.2 mg/kg IV over 2 hours 
-8 
Alemtuzumab 0.2 mg/kg IV over 2 hours 
Alemtuzumab 0.2 mg/kg IV over 2 hours 
-7 
Alemtuzumab 0.2 mg/kg IV over 2 hours 
Alemtuzumab 0.2 mg/kg IV over 2 hours 
Cyclophosphamide 50 mg/kg IV over 2 hours 
 
-6 
Alemtuzumab 0.2 mg/kg IV over 2 hours 
Alemtuzumab 0.2 mg/kg IV over 2 hours 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour  
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour  
-5 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
-4 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
-3 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
-2 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
-1 
rest 
rest 
0 
stem cell transplant 
stem cell transplant 
+4 
 
Cyclophosphamide 50 mg/kg IV over 2 hours 
 
 
Refer to appendix I for treatment related risks. 
 
 
 


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4.1.1 Conditioning Regimen for DC (Arms A and D) 
4.1.1.1 Alemtuzumab 
Alemtuzumab will be administered at doses and days 
indicated for Arms A and D via central venous catheter as 
follows:  
• Pre-medicate 30 minutes prior to Alemtuzumab infusion 
with methylprednisolone 1 mg/kg IV, (max dose = 125 mg), 
acetaminophen 15 mg/kg dose (max dose = 650 mg) 
enterally and diphenhydramine 1 mg/kg/dose (max dose = 
50 mg) enterally or IV.  
 Infuse Alemtuzumab over 2 hours. 
 Hypersensitivity orders per standard guidelines during 
Alemtuzumab administration. 
 
4.1.1.2 Cyclophosphamide 
Cyclophosphamide 50 mg/kg IV will be administered over 2 
hours on day -7 (Arm A only). 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. 
 
4.1.1.3 Fludarabine 
Fludarabine will be administered at a dose of 40 mg/m2/day x 
5 days, total dose 200 mg/m2 (days –6 to –2). For children < 
10 kg, fludarabine dosing will be 1.33 mg/kg/day x 5 days, 
total dose 6.65 mg/kg (days -6 to -2). Dosing is based on 
actual body weight. The fludarabine dose will be administered 
IV over one hour at a constant rate. If the normalized GFR is 
<70 ml/min, a 20% dose-reduction of fludarabine may be 
considered after discussion between the protocol PI, patient’s 
primary BMT physician and BMT pharmacist. 
 
 


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4.2 
Severe Aplastic Anemia (SAA) 
 
Day 
ARM C: Matched related donor 
-5 
Cyclophosphamide 50 mg/kg IV over 2 hours 
Rabbit ATG 3 mg/kg IV over 4-6 hours  
-4 
Cyclophosphamide 50 mg/kg IV over 2 hours 
Rabbit ATG 3 mg/kg IV over 4-6 hours  
-3 
Cyclophosphamide 50 mg/kg IV over 2 hours 
Rabbit ATG 3 mg/kg IV over 4-6 hours  
-2 
Cyclophosphamide 50 mg/kg IV over 2 hours 
-1 
rest 
0 
stem cell transplant 
 
 
Day 
ARM B: MUD, mMRD, UCB donor OR 
Non-Haplo 2nd transplant) 
ARM E: Haploidentical donor 
-9 
 
Rabbit ATG 0.5 mg/kg IV over 4-6 hours  
-8 
 
Rabbit ATG 2 mg/kg IV over 4-6 hours  
-7 
Cyclophosphamide 50 mg/kg IV over 2 hours 
Rabbit ATG 2 mg/kg IV over 4-6 hours  
-6 
 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
Cyclophosphamide 14.5 mg/kg IV over 2 hours 
Fludarabine 30 mg/m2 IV (1 mg/kg if <10 kg) 
over 1 hour 
-5 
 
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
Cyclophosphamide 14.5 mg/kg IV over 2 hours 
Fludarabine 30 mg/m2 IV (1 mg/kg if <10 kg) 
over 1 hour 
-4 
Rabbit ATG 3 mg/kg IV over 4-6 hours  
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
 
Fludarabine 30 mg/m2 IV (1 mg/kg if <10 kg) 
over 1 hour 
-3 
Rabbit ATG 3 mg/kg IV over 4-6 hours  
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
 
Fludarabine 30 mg/m2 IV (1 mg/kg if <10 kg) 
over 1 hour 
-2 
Rabbit ATG 3 mg/kg IV over 4-6 hours  
Fludarabine 40 mg/m2 IV (1.33 mg/kg if <10 kg) 
over 1 hour 
 
Fludarabine 30 mg/m2 IV (1 mg/kg if <10 kg) 
over 1 hour 
-1 
TBI 2 Gy 
TBI 2 Gy 
0 
stem cell transplant 
stem cell transplant 
+3 
 
Cyclophosphamide 50 mg/kg IV over 2 hours 
+4 
 
Cyclophosphamide 50 mg/kg IV over 2 hours 
Refer to Appendix II (Arms B, E) and Appendix III (Arm C) for treatment related 
risks. 


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4.2.1 Conditioning regimen for SAA (Arms B, C and E) 
4.2.1.1 Rabbit ATG (Thymoglobulin®) 
Rabbit ATG will be administered at doses and days indicated for 
Arms C, D, and E above via central venous catheter as follows:  
 Pre-medicate 
30 
minutes 
prior 
to 
ATG 
infusion 
with 
methylprednisolone 1 mg/kg IV, (max dose = 125 mg), 
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 through a 0.22 micrometer filter over 4-6 hours. 
 Hypersensitivity orders per standard guidelines during ATG 
administration. 
 
4.2.1.2 Cyclophosphamide 
Cyclophosphamide will be administered over 2 hours at the doses 
and days indicated above for Arms B, C, and E. 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. Hyperhydration is not 
required for 14.5 mg/kg cyclophosphamide doses. 
 
4.2.1.3 Fludarabine (Arms B and E only) 
For Arm B, Fludarabine will be administered at a dose of 40 
mg/m2/day x 5 days, total dose 200 mg/m2 (days –6 to –2). For 
children < 10 kg, fludarabine dosing will be 1.33 mg/kg/day x 5 
days, total dose 6.65 mg/kg (days -6 to -2).  
 
For Arm E, fludarabine will be administered at a dose of 30 
mg/m2/day x 5 days, total dose of 150 mg/m2 (days -6 to -2).  For 
children <10 kg, fludarabine dosing will be 1 mg/kg/day x 5 days, 
total dose 5 mg/kg (days -6 to -2). 
 
The fludarabine dose will be administered IV over one hour at a 
constant rate. If the normalized GFR is <70 ml/min, a 20% dose-
reduction of fludarabine may be considered after discussion between 
the protocol PI, patient’s primary BMT physician and BMT 
pharmacist. 
 
 


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4.2.1.4 Total Body Irradiation (Arms B and E only) 
2 Gy administered in a single fraction will be given at a dose rate 
between 1 and 1.9 Gy/minute prescribed to the midplane of the 
patient at the level of the umbilicus. 
 
The total body irradiation will be delivered with right and left lateral 
fields, with the patient supine on a specially designed couch. 
 
Total body irradiation will be delivered with a linear accelerator using 
6, 18, or 24 MV X-rays. 
 
Based on measurements of transverse thicknesses, aluminum 
compensators may 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). 
 
A beam “spoiler” will be used to ensure a full skin dose.  Half value 
layer lung and kidney blocks will not be utilized.  Testicular boosts 
are not given. 
4.3 
Cell Infusion (day 0) 
Refer to section 2.2 for cell source options and section 5 for selection 
considerations. 
 
On day 0 the cells will be infused per cell source specific institutional 
guidelines.  
 
Recommended Pre-medication: acetaminophen 15 mg/kg (max 
dose = 650 mg) PO and diphenhydramine 1 mg/kg (max dose 50 
mg) PO/IV with adjusted dosing for pediatric patients. 
 
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 IV for transplant related risks. 
4.4 
Post-Transplant G-CSF (filgrastim) 
Beginning on day +1 (Arms A, B, C) or day +5 (Arms D, E), patients 
will receive G-CSF SQ or IV 5 micrograms/kg once daily until post-
nadir ANC > 2000/μL for 3 consecutive days. 
 
Refer to appendix IV for G-CSF related risks. 


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4.5 
GVHD Prophylaxis 
Standard acute GVHD prophylaxis and immune suppression will be 
used; however, an alternative regimen may also be used as clinically 
appropriate. 
 
Refer to appendix IV for GVHD prophylaxis related risks. 
4.5.1 Post-transplant Cyclophosphamide (Arms D, E only) 
Cyclophosphamide will be administered over 2 hours at the 50 
mg/kg on day +4 (Arm D) or on days +3 and +4 (Arm E). 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. 
 
4.5.2 Tacrolimus (All Arms) 
Tacrolimus therapy will begin on day -3 (Arms A, B, C) or day +5 (Arms 
D, E).  Initial dosing of tacrolimus will be 0.03 mg/kg/day IV via 
continuous infusion. Goal trough levels will be 10-15 ug/mL for the first 
14 days post-transplant and then decreased to a goal of 5-10 ng/mL 
thereafter. Dose adjustments will be made on the basis of toxicity 
and/or tacrolimus levels outside of goal range. Conversion from IV to 
oral tacrolimus will be done as the patient tolerates and prior to 
discharge. Potential toxicities are detailed in Appendix II.  
The timing of the tacrolimus taper will be at the discretion of the treating 
physician, but in general: 
• Taper begins at day +100 +/- 10 days, if the patient is stably 
engrafted and has no active GVHD.   
Taper to zero by reducing dose by approximately 10% a week 
(rounded to nearest pill size), with a goal to discontinue by month 6 
post-HCT. 
 
In the presence of severe tacrolimus toxicities, other alternative 
agents may be used after review and approval by the PI. 
4.5.3 Mycophenylate Mofetil (MMF) 
Mycophenylate mofetil (MMF) therapy will begin on day -3 (Arms A, B, 
C) or day +5 (Arms D, E). Dosing of MMF will be 15 mg/kg/dose three 


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CPRC # 2013OC127 
times daily up to a max of 1gm per dose. The same dosage is used 
orally or intravenously. Consider dose modification if renal and/or 
hepatic impairment (GFR<25 mL/minute corrected). The first MMF 
pharmacokinetic time point will be obtained at day +3 (Arms A, B, C) 
or day +11 (Arms D, E). An attempt will be made to maintain an MMF 
AUC of 200 - 250 ng*hr/mL for q8h dosing and an AUC of 300-350 
ng*hr/ml for q12h dosing. Should dose adjustments be made, repeat 
AUC monitoring at steady-state should be considered. 
Stop MMF at Day +30 (Arms A, B, and C), Day +35 (Arms D and E) or 
7 days after engraftment achieved (ANC>500 x 106 neutrophils/L x 3 
days) if later than day +30 (Arms A, B, and C) or day +35 (Arms D and 
E). If sufficient acute GvHD is observed to require systemic therapy, 
MMF should be continued for 7 days after initiation of systemic therapy. 
Afterward, use of MMF is at the discretion of the treating physician.  
Refer to appendix II for risks associated with MMF. 
4.6 
Follow-Up 
Follow-up will be according to the current University Of Minnesota 
BMT follow-up guidelines as outlined in section 6. 
4.7 
Supportive Care 
Patients will receive standard supportive transplant care, including 
antibacterial/antifungal/antiviral prophylaxis according to institutional 
guidelines or as modified based on clinical parameters. 
Patients will be eligible for any supportive care studies regarding 
infectious disease prophylaxis and management, immunoglobulin 
support, etc. as appropriate. 
 
5.0 
Donor Selection and Cell Dose Requirements 
5.1 
Donor specific HLA antibodies:  
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 


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5.2 
Donor Considerations When More Than 1 Potential Donor 
• Bone marrow is preferred over peripheral blood. Peripheral blood 
is preferred over cord blood. 
• HLA-matched related donor bone marrow is optimal, followed by 
HLA-matched unrelated donor cell sources. If HLA-matched 
sources are not available, the lowest number of mismatches in 
the host-versus-graft direction is prioritized to minimize graft 
rejection. 
• 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 
5.3 
Donor Considerations for 2nd Transplant 
• In the case of 2nd transplant, the original donor source, if willing 
and available, is preferred 
• If original donor not available, any readily available graft source 
as per section 2.2 will be considered 
5.4 
Cell Dose Requirements Based on Cell Source  
5.4.1 Bone Marrow (BM) 
BM will be collected with a goal of >5.0 x 108 nucleated cells/kg 
recipient body weight per MT2012-14C (for related donor) or NMDP 
guidelines (for unrelated donor). 
5.4.2 Peripheral Blood (PB) 
CD34+ cell dose goal to infuse will be >10.0 x 106 CD34+ cells/kg 
recipient body weight.   


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Related donor: If donor is > 12 years and > 40 kg, PB will be collected 
after G-CSF mobilization per MT2012-14C. 
 
Unrelated donor:  The PB product will be collected, processed and 
shipped according to the existing protocols of the National Marrow 
Donor Program to obtain GCSF mobilized PB for primary allogeneic 
HSC transplant with unrelated donors.  
5.4.3 Umbilical Cord Blood (UCB) 
For umbilical cord blood, a minimum cell dose of ≥ 3.5 x 107 
nucleated cells/kg is required with an optimal cell dose ≥ 5 x 107 
nucleated cells/kg recipient body weight.  The unit(s) will not be 
manipulated. 
 
Unrelated unlicensed UCB unit(s) will require the recipient’s co-
enrollment on MT2011-13R (Infusion of Cell Populations from 
Unlicensed 
Umbilical 
Cord 
Blood 
Units 
– 
C 
Brunstein 
sponsor/investigator).  
 
 


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6.0 
Clinical Evaluations 
All clinical evaluations are standard of care and will be done according to current 
institutional guidelines.  Post-transplant and some pre-transplant monitoring are 
suggested guidelines and should be tailored for each patient’s clinical case. 
 
 
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 
Informed consent 
X 
 
 
 
Medical history including prior transfusions, 
alloantibodies and allergies 
X 
 
 
 
DEB and cytogenetics (unless previously documented 
negative) 
X 
 
 
 
Physical exam 
X 
daily 
weekly 
X 
Radiation Therapy consult (SAA only) 
X 
 
 
 
Neuropysch testing and QOL 
X 
As clinically indicated 
1 and 2 years 
Any other subspecialty consultations as clinically 
indicated 
X 
As clinically indicated 
X 
Height/Weight 
X 
 
 
X 
GVHD evaluation 
 
daily 
weekly  
X 
CMV Surveillance 
X 
weekly 
weekly 
prn 
EBV assessment (ATG and Alemtuzumab patients 
only) 
 
 
every 2 
weeks 
every 2 weeks 
until day 180 
Laboratory  
CBC, diff , platelet 
X 
daily 
weekly 
X 
Anti-HLA antibody testing  
X 
 
 
 
PT/PTT 
X 
As clinically indicated 
Serum chemistries 
X 
As clinically indicated 
Creatinine, Na, K, HCO3 
X 
daily 
weekly 
X 
LH, FSH and Estradiol levels for females >10 years;  
LH, FSH and  testosterone levels for males >11 years 
X 
 
Day 100 
1 and 2 years 
Free T4 and TSH 
X 
 
Day 100 
X 
Chimerism – PB 
X 
Day  28 
Day 60 
X 
Quantitative immunoglobulins 
X 
 
Day 60, 100 
X 
T cell subsets, extended profile 
X 
 
Day 60,100 
X 
Urinalysis 
X 
 
 
X 
Urine or serum pregnancy test - females of 
childbearing potential only 
X 
 
 
 
Procedures  
EKG 
X 
 
 
 
MUGA or echo as age appropriate 
X 
 
 
1 year 
PFTs if age appropriate/ pulse oximetry 
X 
 
Day 100 
1 and 2 years 
Chest CT 
X 
 
 
 
Bone Marrow Biopsy/Aspirate (with chimerism) 
X 
 
Day100 
X  
 
 


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CPRC # 2013OC127 
7.0 
Event Reporting 
The only research element is the collection and analysis of routine clinical 
data in association with study milestones.  Therefore, the only events 
reportable to the University Of Minnesota Institutional Review Board in an 
expedited manner (5 business days from discovery) will be those in 
association with data collection.  Primarily these risks would be: 
• 
Any breach in confidentiality that may involve risk to the subject or others 
in association with the data collection 
• 
Any complaint in association with the data collection of a subject that 
cannot be resolved by the research staff  
Any report should be made using the Report form found on the IRB’s 
website (http://www.research.umn.edu/irb/).   
 
8.0 
Data Collection and Statistical Plan  
Specific transplant related endpoints include incidence of: 
• neutrophil engraftment at day 42 and platelet engraftment at 1 year  
• regimen related morality at 100 days 
• acute GVHD at 100 days  
• chronic GVHD at 6 months and 1 year  
• secondary malignancies 
   
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.   
8.1 
Trial Size Justification 
Since this treatment plan among these patients has been studied 
over the last 8 years, this is now a standard of care protocol.  No trial 
size justification is needed.  
8.2 
Analysis of Primary and Secondary Endpoints  
Cumulative incidence will be used to estimate TRM, neutrophil 
engraftment, GVHD and graft failure treating non-events as 
competing risks. Kaplan-Meier curves will be used to estimate 
disease-free survival and overall survival. Chimerism will be plotted 
with box-plots and described over time. 
8.3 
Safety Monitoring  
We have studied this regimen for patients with these diagnoses for 
the past 8 years and it has been shown to be safe.  Continuous 
stopping rules are no longer needed.  Safety parameters will be 
monitored on a yearly basis through the DSMC. 
 


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CPRC # 2013OC127 
The 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 
 
 
 


MT2013-34C: HSCT for Patients with Dyskeratosis Congenita or Severe Aplastic Anemia 
 
 
 
 
 
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CPRC # 2013OC127 
9.0 
REFERENCES 
 
1. 
Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017. 
2. 
Georges GE, Storb R. Hematopoietic stem cell transplantation for acquired aplastic anemia. Curr 
Opin Hematol. 2016;23(6):495-500. 
3. 
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 transplantation : journal of the American Society 
for Blood and Marrow Transplantation. 2017;23(3):498-504. 
4. 
Schrezenmeier H, Marin P, Raghavachar A, et al. Relapse of aplastic anaemia after 
immunosuppressive treatment: a report from the European Bone Marrow Transplantation Group 
SAA Working Party. British journal of haematology. 1993;85(2):371-377. 
5. 
Socie G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli A. Late clonal diseases of treated 
aplastic anemia. Seminars in hematology. 2000;37(1):91-101. 
6. 
Deeg HJ, O'Donnell M, Tolar J, et al. Optimization of conditioning for marrow transplantation 
from unrelated donors for patients with aplastic anemia after failure of immunosuppressive 
therapy. Blood. 2006;108(5):1485-1491. 
7. 
Tolar J, Deeg HJ, Arai S, et al. Fludarabine-based conditioning for marrow transplantation from 
unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation 
study show life-threatening adverse events at predefined cyclophosphamide dose levels. Biology of 
blood and marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation. 2012;18(7):1007-1011. 
8. 
Kennedy-Nasser AA, Leung KS, Mahajan A, et al. Comparable outcomes of matched-related and 
alternative donor stem cell transplantation for pediatric severe aplastic anemia. Biology of blood 
and marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation. 2006;12(12):1277-1284. 
9. 
Hsieh MY, Chiou TJ, Hung GY, Yen HJ. Outcomes of matched sibling and alternative donor stem 
cell transplantation for 26 children with severe aplastic anemia. International journal of 
hematology. 2010;91(1):54-60. 
10. 
Buchholz S, Dammann E, Koenecke C, et al. Allogeneic stem cell transplantation from related and 
unrelated donors for aplastic anaemia in adults--a single-centre experience. Annals of hematology. 
2008;87(7):551-556. 
11. 
Yagasaki H, Takahashi Y, Hama A, et al. Comparison of matched-sibling donor BMT and 
unrelated donor BMT in children and adolescent with acquired severe aplastic anemia. Bone 
Marrow Transplant. 2010;45(10):1508-1513. 
12. 
DeZern AE, Brodsky RA. Haploidentical Donor Bone Marrow Transplantation for Severe 
Aplastic Anemia. Hematol Oncol Clin North Am. 2018;32(4):629-642. 
13. 
Gadalla SM, Sales-Bonfim C, Carreras J, et al. Outcomes of allogeneic hematopoietic cell 
transplantation in patients with dyskeratosis congenita. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow Transplantation. 
2013;19(8):1238-1243. 
14. 
Barbaro P, Vedi A. Survival after Hematopoietic Stem Cell Transplant in Patients with 
Dyskeratosis Congenita: Systematic Review of the Literature. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow Transplantation. 
2016;22(7):1152-1158. 
15. 
Fioredda F, Iacobelli S, Korthof ET, et al. Outcome of haematopoietic stem cell transplantation in 
dyskeratosis congenita. British journal of haematology. 2018;183(1):110-118. 
16. 
Marsh RA, Rao MB, Gefen A, et al. Experience with Alemtuzumab, Fludarabine, and Melphalan 
Reduced-Intensity Conditioning Hematopoietic Cell Transplantation in Patients with 
Nonmalignant Diseases Reveals Good Outcomes and That the Risk of Mixed Chimerism Depends 
on Underlying Disease, Stem Cell Source, and Alemtuzumab Regimen. Biology of blood and 
marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 
2015;21(8):1460-1470. 


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17. 
Dror Y, Freedman MH, Leaker M, et al. Low-intensity hematopoietic stem-cell transplantation 
across human leucocyte antigen barriers in dyskeratosis congenita. Bone Marrow Transplant. 
2003;31(10):847-850. 
18. 
Bizzetto R, Bonfim C, Rocha V, et al. Outcomes after related and unrelated umbilical cord blood 
transplantation for hereditary bone marrow failure syndromes other than Fanconi anemia. 
Haematologica. 2011;96(1):134-141. 
19. 
Algeri M, Comoli P, Strocchio L, et al. Successful T-cell-depleted haploidentical hematopoietic 
stem cell transplantation in a child with dyskeratosis congenita after a fludarabine-based 
conditioning regimen. Journal of pediatric hematology/oncology. 2015;37(4):322-326. 
20. 
Giardino S, Faraci M, Lanino E, et al. Successful Second Unrelated Donor Hematopoietic Stem 
Cell Transplant in a Patient With Dyskeratosis Congenital After First Graft Rejection. Exp Clin 
Transplant. 2017. 
21. 
Bhattacharyya R, Tan AM, Chan MY, Jamuar SS, Foo R, Iyer P. TCR alphabeta and CD19-
depleted haploidentical stem cell transplant with reduced intensity conditioning for Hoyeraal-
Hreidarsson syndrome with RTEL1 mutation. Bone Marrow Transplant. 2016;51(5):753-754. 
22. 
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(6):641-650. 
23. 
Wachsmuth LP, Patterson MT, Eckhaus MA, Venzon DJ, Kanakry CG. Optimized Timing of 
Post-Transplantation Cyclophosphamide in MHC-Haploidentical Murine Hematopoietic Cell 
Transplantation. Biology of blood and marrow transplantation : journal of the American Society 
for Blood and Marrow Transplantation. 2020;26(2):230-241. 
 
 


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Appendix I – Treatment Related Risks Dyskeratosis Congenita 
(Arms A and D) 
 
Alemtuzumab (Campath, Campath 1-H)  
Common 
Less Common 
Rare 
• mild allergic reaction with first 
few infusions (may include 
fever, headache, chills, itching, 
hives, nausea) 
• low white blood cell count with 
increased risk of infection 
• low platelet count with 
increased risk of bleeding 
• low red blood cell count 
• fever 
• nausea 
• vomiting  
• allergic reaction with later 
infusions (same symptoms as 
under common) 
• abdominal pain, back pain, or 
chest pain 
• headache 
• feeling tired 
• infections, which can be 
serious* 
• diarrhea 
• mouth sores 
• loss of appetite 
• shortness of breath 
• trouble sleeping 
• anxiety 
• cough 
• itching 
• rash 
• blood pressure changes 
• swelling in the hands or feet 
• abnormal blood test results 
which suggest that the drug is 
affecting the liver or kidneys   
• serious allergic reaction, with trouble 
breathing, swelling of the mouth or face, 
tightness in the throat, faintness, heart 
attack, shock, cardiac arrest 
• serious damage to the bone marrow, so 
that it stops making blood cells 
• feeling dizzy 
• rapid heart rate 
• upset stomach 
• constipation 
• muscle aches 
• sore throat 
• deaths due to allergic reactions, severe 
bone marrow damage, infections, 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 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 
 
 
 
 


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CPRC # 2013OC127 
 
 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 
 
 
 
 
 
 
 


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Appendix II – Treatment Related Risks Severe Aplastic Anemia 
(Arms B and E) 
 
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 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 
 
 
 
 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 
 
 
 
Anti-Thymocyte Globulin (ATG) 
Common 
Less Common 
Rare 
• fever 
• chills 
• leukopenia 
• pain 
• headache 
• abdominal pain 
• diarrhea 
• hypertension 
• nausea 
• thrombocytopenia 
• malaise 
• dizziness  
 
• severe allergic reaction 
(anaphylaxis) 
 


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CPRC # 2013OC127 
Anti-Thymocyte Globulin (ATG) 
Common 
Less Common 
Rare 
• peripheral edema 
• dyspnea 
• asthenia 
• hyperkalemia 
• tachycardia  
 
 
Total Body Irradiation (TBI)  
Common 
Less Common 
Rare 
• nausea and vomiting 
• diarrhea 
• cataracts 
• sterility 
• endocrinopathies 
• growth failure 
• intestinal cramps 
• mucositis 
• 
parotitis 
• 
interstitial pneumonitis 
• 
generalized mild erythema 
• 
veno-occlusive disease 
• dysphagia 
• vertebral deformities 
• nephropathy 
• risk of 2nd malignancy years later 
(when given along with 
chemotherapy) 
 
 
 
 
 


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Appendix III – Treatment Related Risks Severe Aplastic Anemia  
(Arm C) 
 
 
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 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 
 
 
Anti-Thymocyte Globulin (ATG) 
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) 
 
 
 
 


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Appendix IV – Transplant Related Risks – General, Regardless of 
Diagnosis 
 
Hematopoietic Stem Cell Transplantation – regardless of stem cell source 
• 
nausea and vomiting  
• 
possible allergic reaction (including itching, hives, flushing [red face], shortness of breath, 
wheezing, chest tightness, skin rash, fever, chills, stiff muscles, or trouble breathing) 
• 
graft-versus-host-disease (GVHD) 
• 
veno-occlusive disease,  
• 
mucositis,  
• 
infections (sepsis)  
 
Risks associated with the use of Umbilical Cord Blood 
• 
DMSO Toxicity is a possible complication of UCB infusion and occurs due to the presence of 
DMSO in the thawed product. The risk of toxicity increases with the number of units (total 
volume per kg body weight) infused. Symptoms are due to histamine release and include: 
• 
cough  
• 
flushing 
• 
rash 
• 
chest tightness 
• 
nausea and vomiting  
• 
bradycardia and tachycardia 
• 
hypertension 
 
• 
Bacterial/Endotoxin Contamination of cellular therapy products may occur, but rarely 
cause acute, severe or life threatening effects. However, the onset of high fever (>2ºC or 
>3.5ºF rise in temperature), severe chills, hypotension, or circulatory collapse during or 
immediately after infusion should suggest the possibility of bacterial contamination and/or the 
presence of endotoxin in the product. 
 
• 
Transmission of Infectious Disease may occur because cellular therapy products are 
collected from human body and/or tissues. The donor selection criteria do not totally eliminate 
the risk of transmitting the agents currently tested such as HIV, HTLV, HBV, HCV, CMV, T. 
pallidum (Syphilis), West Nile Virus, and Trypanosome (Chagas).   For some other infectious 
disease there are no routine tests to prevent disease transmission including Parvovirus spp., 
Plasmodium spp. (Malaria), the coronavirus associated with severe acute respiratory 
syndrome (SARS), and the agents of human transmissible spongiform encephalopathies 
(TSEs).  
 
 
G-CSF given to help the blood counts recover more quickly 
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)  
 
 
 
 
 


MT2013-34C: HSCT for Patients with Dyskeratosis Congenita or Severe Aplastic Anemia 
 
 
 
 
 
February 15, 2021 
Page 30 of 30 
CPRC # 2013OC127 
 
Tacrolimus   
Common 
Less Common 
Rare, but may be serious 
 kidney problems 
 loss of magnesium, 
calcium, potassium 
 high blood pressure 
 tremors 
 increases in cholesterol 
and triglyceride 
 
 nausea 
 vomiting 
 liver problems 
 changes in how clearly 
one can think 
 insomnia 
 unwanted hair growth 
 confusion 
 
seizures 
 
changes in vision 
 
dizziness 
 
red blood cell 
destruction 
It is very important that grapefruit or drinks with grapefruit juice are not consumed while 
taking Tacrolimus.  Grapefruit has an ingredient called bergamottin, which can affect some of 
the treatment drugs used in this study.  Common soft drinks that have bergamottin are Fresca, 
Squirt, and Sunny Delight.  
 
 
Mycophenolate Mofetile (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 
 
 
Arms D and E only: Post-transplant cyclophosphamide (Risks as documented in treatment 
related risks, Appendix I and II) 
 

ICF_001.pdf: