Clinical trial NCT01991457
Conditions: Adult Lymphoblastic Lymphoma
Keywords: ALL
Sponsor: University of Alabama at Birmingham
Start date: 2013-08-27; Completion date: 2022-08-23
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this research is to test if the conditioning regimen, fludarabine and total body irradiation (FluTBI), can lead to a safer and more effective stem cell transplant treatment regimen for ALL patients older than 40 years of age and/or younger patients with high risk medical conditions. The primary objective is to establish the efficacy of allo HCT in older ALL patients using myeloablative FluTBI conditioning regimen. The investigators are also assessing the safety and toxicity of allo HCT in older ALL patients using myeloablative FluTBI conditioning regimen.

Detailed description:

Arms: arm 1: Fludarabine, Total Body Irradiation (TBI) Fludarabine: 40 mg/m2 X 4 days TBI: TBI 2 Gy 2 times a day X 3 days
Interventions: intervention 1: Fludarabine intervention 2: Total Body Irradiation
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_002.pdf: 
Single Arm Phase II Study of Myeloablative 
Allogeneic Hematopoietic Stem Cell Transplantation 
for Acute Lymphoblastic Leukemia (ALL) in Older 
Patients Using Fludarabine and Total Body Irradiation 
(FluTBI) Regimen
PI: OMER JAMY, MD 
NCT # 01991457
December 09 2018


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Single Arm Phase II Study of Myeloablative Allogeneic Hematopoietic Stem Cell 
Transplantation for Acute Lymphoblastic Leukemia (ALL) in Older Patients Using 
Fludarabine and Total Body Irradiation (FluTBI) Regimen 
 
Bone Marrow Transplantation and Cellular Therapy Program 
University of Alabama at Birmingham 
Protocol Version 4.0 Dated 09/12/2018 
Protocol Version 3.0 Dated 11/22/2017 
Protocol Version 2.0 Dated 03/10/2017 
Protocol Version 1.3 Dated 06/30/2014 
Protocol Version 1.2 Dated 12/18/2013 
Protocol Version 1.1 Dated 3/15/2013 
Protocol Version 1.0 Dated 11/5/2012 
 
Principal Investigator 
Donna Salzman, M.D. 
 
Co-investigators 
Racquel Innis-Shelton, M.D. 
Antonio Di Stasi, M.D. 
Ruby F. Meredith, MD, PhD 
Lawrence Lamb, Ph.D. 
                Luciano J Costa, M.D., PhD 
 
 
 
Protocol Statistician  
Alan Cantor, Ph.D. 
 
 
 
 
 


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1 
BACKGROUND .................................................................................................................... 4 
1.1 
Allogeneic Hematopoietic Stem Cell Transplantation (allo HCT) for Acute 
Lymphoblastic Leukemia (ALL) .................................................................................................... 4 
1.2 
Conditioning regimens for allo HCT in ALL ..................................................................... 5 
1.3 
Reduced-intensity allo HCT in ALL................................................................................... 5 
1.4 
Conditioning regimen with FluTBI .................................................................................... 6 
2 
OBJECTIVES AND ENDPOINTS ........................................................................................ 7 
2.1 
Primary Objective: .............................................................................................................. 7 
2.2 
Secondary Objectives: ........................................................................................................ 7 
2.3 
Primary Endpoints .............................................................................................................. 7 
2.4 
Secondary Endpoints .......................................................................................................... 7 
3 
PATIENTS ELIGIBILITY CRITERIA .................................................................................. 8 
3.1 
Inclusion Criteria ................................................................................................................ 8 
3.2 
Exclusion Criteria ............................................................................................................... 9 
4 
STUDY TREATMENT .......................................................................................................... 9 
4.1 
Conditioning regimen ......................................................................................................... 9 
4.2 
Allogeneic Stem Cell Collection and Infusion ................................................................. 10 
4.3 
Maintenance treatment after transplant ............................................................................. 11 
4.4 
GVHD prophylaxis ........................................................................................................... 11 
4.5 
Infection Prophylaxis ........................................................................................................ 11 
4.5.1 
Recommended Fungal Prophylaxis .......................................................................................................... 11 
4.5.2 
HSV / VZV Prophylaxis ........................................................................................................................... 12 
4.5.3 
CMV (Cytomegalovirus) preemptive therapy .......................................................................................... 12 
4.5.4 
PCP (Pneumocystic pneumonia) prophylaxis ........................................................................................... 12 
4.5.5 
PCR testing ............................................................................................................................................... 12 
5 
DRUG INFORMATION ...................................................................................................... 12 
5.1 
Fludarabine ....................................................................................................................... 12 
5.2 
Total Body Irradiation (TBI) ............................................................................................ 14 
5.3 
Tacrolimus ........................................................................................................................ 15 
5.4 
Methotrexate ..................................................................................................................... 16 
5.5 
Thymoglobulin® (Anti-thymocyte Globulin [Rabbit]) (rATG) ....................................... 17 
5.5.1 
Chemical Characteristics .......................................................................................................................... 17 
5.5.2 
Available Forms ....................................................................................................................................... 18 
5.5.3 
Storage and Handling ............................................................................................................................... 18 
5.5.4 
Toxicity .................................................................................................................................................... 18 
6 
REQUIRED OBSERVATIONS ........................................................................................... 19 
6.1 
Pre-Transplant (within 35 days prior to study registration / day of final transplant 
evaluation)..................................................................................................................................... 19 
6.2 
Post-transplant required observations and follow-up plans .............................................. 19 
7 
STATISTICAL CONSIDERATIONS.................................................................................. 20 
7.1 
Sample Size ....................................................................................................................... 20 
7.2 
Analysis Methods.............................................................................................................. 20 
8 
ADVERSE EVENT REPORTING....................................................................................... 21 
8.1 
Definitions of Adverse Events with Commercially Available Agents ............................. 21 
8.2 
Required Adverse Events Reporting ................................................................................. 22 
8.3 
Hematologic toxicity and Definition of Primary Engraftment Failure ............................. 22 
8.4 
Serious Adverse Event Reporting Procedures .................................................................. 22 
9 
DATA SAFETY MONITORING......................................................................................... 23 


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9.1 
Data and Safety Monitoring Procedures ........................................................................... 23 
9.2 
Quality Assurance and Audits .......................................................................................... 24 
APPENDIX A:  PERFORMANCE SCORES .............................................................................. 29 
APPENDIX B: STUDY CALENDAR ......................................................................................... 30 
 
 
 


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1 
Background 
1.1 
Allogeneic Hematopoietic Stem Cell Transplantation (allo HCT) for Acute 
Lymphoblastic Leukemia (ALL) 
 
Although acute lymphoblastic leukemia (ALL) in children has become curable in 80% of cases,1 
the treatment outcome of adult ALL have been poor with cure rate of 30-40%.2 This discrepancy 
may be explained, at least partially, by the difference in cytogenetic abnormality profile between 
children and adult ALL.3 In Adult ALL, the complete remission rate is 70-90% with upfront 
therapy, but relapse rate thereafter is high. Thus long term survival can only be achieved in 30-
40% of patients, and around 10% in patients above the age 60.3, 4 In order to improve outcome of 
adult ALL, allo HCT has been used as a consolidation for patients in the 1st complete remission 
(CR).5-7 Advanced age and limited performance status are associated with increased non-relapse 
mortality (NRM). Data from the European Group for Blood and Marrow transplantation (EBMT) 
showed NRM rate of about 30% in adult ALL after allo HCT.8 
Results of the international trial of adult ALL (MRC UKALL XII/ECOG E2993) showed superior 
outcome for allo HCT in adult patients with standard-risk ALL in CR1 when compared with 
autologous HCT. The study enrolled ALL patients between 15 and 49 year old (the upper limit has 
been changed to 54 years) and proceed to allogeneic HCT if HLA matched sibling donor is 
available. Conditioning regimen was total body irradiation (TBI) 1320 cGy＋Etoposide 60 mg/kg. 
Patients in remission with no matched sibling were randomized to either chemotherapy 
maintenance or autologous HCT. They reported that relapse rate was significantly lower in cases 
with a donor compared to the ones without a donor in the analysis on Philadelphia chromosome 
negative (Ph-) cases, thus supported the presence of graft-versus leukemia (GVL) effect. In the 
standard risk cohort, patients with a donor showed better survival (62% vs. 52%, P = 0.02). In the 
high-risk cohort (age older than 35, or high WBC count at the time of diagnosis – more than 
100,000/µl in B-lineage, more than 30,000/µl in T-lineage), however, survival was not 
significantly different as NRM was high in the transplanted patients (41% vs. 35%, P = 0.2).9 In 
this study, the NRM rate was 20% and 39% in the young (< 35 years) and older patients underwent 
HCT, respectively.9 It was suggested from this result that advantage of transplant may be more 
apparent if NRM can be decreased in older age group by using less toxic conditioning regimens.  


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1.2 
Conditioning regimens for allo HCT in ALL 
The conditioning regimen being used most often for ALL has been the combination of 
cyclophosphamide (Cy) and total body irradiation (TBI) called CyTBI. The BuCy regimen, which 
replaced TBI of CyTBI with busulfan (Bu) has been shown to have comparable outcome to CyTBI 
in acute myelogenous leukemia (AML)10, but inferior outcome in pediatric ALL.11 The 
combination of TBI and etoposide (Etp) has been associated with less relapse rate than CyTBI in 
second CR.12 In addition, a randomized trial for pediatric ALL showed that TBICyEtp was superior 
to BuCyEtp in unrelated donor transplant with 3-year event-free survival (EFS) of 57% and 20% 
for both groups respectively (P=0.04). This randomized prospective study suggests that TBI has 
more favorable outcome compared to Bu in pediatric patients with ALL undergoing allo HCT. The 
City of Hope (COH) group has also reported EtpTBI regimen (TBI dose of 1320 cGy) in adult 
ALL.13 These reports provide evidences for efficacy of TBI-based containing regimens in adult 
ALL.  
 
1.3 
Reduced-intensity allo HCT in ALL 
In reduced-intensity transplant (RIT), less intense conditioning is used with less regimen-related 
toxicity, but anti-tumor effect is more dependent on GVL effect, as the anti-tumor activity of 
conditioning regimen itself is reduced.  GVL may be less effective in ALL compared to myeloid 
tumors, such as AML and myelodysplastic syndrome (MDS).14, 15 For this reason, recurrence of 
disease may be more of a concern.  There is paucity of data of RIT in ALL. Arnold et al reported 
22 cases of RIT for ALL using FluBu2 (fludarabine/busulfan) with or without ATG (anti-
thymoglobulin).  Among the cases who received RIT as the first transplant (11 cases) or second 
transplant (11 cases), 3 and 1 cases survived for a long time, respectively. All these 4 cases were 
transplanted at remission.16 Martino et al reported 27 cases who received RIT for ALL.17 A total 
of 23 out of 27 cases received a conditioning regimens based on Flu (90-150 mg/m2)-Melphalan 
(Mel) (140mg/m2).  Two-year overall survival (OS) was 31%, and cumulative incidence of 
progression was 70% in cases without GVHD, 35% in cases with GVHD, thus suggesting the 
presence of GVL effect in ALL. Only 5 cases relapsed out of 15 cases who received RIT at CR.17 
A multi-center retrospective analysis of 33 cases of RIT for ALL in Japan was published by 
Hamaki et al.18 Conditioning regimens were either FluBu2 or FluMel in most of the cases. The 
disease status at transplant was CR1 (13), CR2 (6) or non-remission (14), and 14 cases of Ph+ 


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ALL were included. The 2-year progression-free survival (PFS) and OS were 19% and 30%, 
respectively. PFS at 1-year was 31% in cases in CR1/CR2 at the time of transplant, and 29% in 
cases not in CR18. Another study reported data of 43 patients of ALL in CR2 who underwent RIT 
after conditioning regimen of Flu (90 mg/m2) Cy (1050 mg/m2) Bu (8 mg/kg).19 Regimen-related 
toxicity was acceptable, but relapse rate was as high as 70%, and OS at 3 years post-transplant was 
30%.  Mohty et al published a retrospective analysis of 97 patients who underwent RIT for ALL 
from EBMT20.  It is difficult to assess the conditioning regimens in this study as they used various 
regimens, but OS and relapse rate (RR) at 2 years were 52% and 40% in cases transplanted at CR1, 
27% and 63% in cases who had the transplant beyond CR1, 20% and 49% in cases transplanted at 
non-remission. For non-remission cases, the NRM was as high as 44%. The COH group reported 
their preliminary data of promising results of FluMel conditioning (Flu 125mg/m2 and Mel 
140mg/m2).21 FluMel regimen has also been used to salvage patients who relapsed after initial allo 
HCT.22 Higher dose of Flu of 160 mg in combination with Mel and thiotepa was shown to be 
feasible conditioning regimen for allo HCT.23 Another study reported the outcome of 51 patients 
with ALL who were > 50 years old or younger with high risk disease. In this study, patients 
underwent allo HCT using conditioning regimen of Flu TBI 2 Gy.24 The study showed 3-year 
overall survival of 34%. The 3-year relapse rate was 40% and the NRM was 28%. Thus the use of 
reduced intensity regimen for ALL has become out of favor for high relapse rate that forfeits the 
benefit of reduced NRM.  
1.4 
Conditioning regimen with FluTBI 
Most commonly used myeloablative conditioning regimen for relatively young patients with 
hematologic malignancies are CyTBI or BuCy. High-dose Cy may result in or contribute to severe 
regimen-related toxicities such as cardiac toxicity, hemorrhagic cystitis, and sinusoidal obstruction 
syndrome (SOS) previously known as veno-occlusive disease (VOD) of liver. Fludarabine is less 
toxic and more immunosuppressive (thus facilitating engraftment) compared to high-dose Cy.25 
Based on these findings FluBu4 regimen has been developed by replacing Cy of BuCy with Flu. 
Busulfan dose in this regimen is myeloablative (4-day dosing), as opposed to 2-day regimen of Bu 
in RIT regimen, FluBu2.26 This regimen was reported to be safe and well tolerated than full 
intensity myeloablative regimens. The use of myeloablative regimen of FluTBI (8 Gy) was shown 
to result in successful engraftment in patients with AML with acceptable NRM rate.27  However, 


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the addition of melphalan to FluTBI regimen resulted in significantly high NRM of 40% in a 
retrospective data from Japan.28  
Since the use of TBI-based conditioning was shown to be more appropriate for ALL, a combination 
of Flu TBI may be more effective and better tolerated than Flu Mel or Flu Bu regimens for ALL. 
We will investigate the safety and efficacy of a myeloablative regimen of Flu TBI 12 Gy regimen 
for ALL patients who are not eligible for Cy TBI conditioning regimen.  
 
2 
Objectives and Endpoints  
2.1 
Primary Objective:  
To establish the efficacy of allo HCT in older ALL patients using myeloablative FluTBI 
conditioning regimen.  
2.2 
Secondary Objectives:  
To assess the safety and toxicity of allo HCT in older ALL patients using myeloablative FluTBI 
conditioning regimen.  
2.3 
Primary Endpoints 
The primary study endpoint is disease-free survival (DFS) at one year post-transplant.  
2.4 
Secondary Endpoints 
 One-year overall survival. 
 Regimen related toxicity within the first 100 days post-transplant.  
 Time to neutrophil and platelet engraftment. Neutrophil engraftment is defined as the first of 
3 consecutive days with an absolute neutrophil count (ANC) > 500/µL.  Platelet engraftment 
is defined as the first of 3 consecutive days with a platelet count > 20,000/µL without platelet 
transfusion for 7 days.    
 Incidence and severity of acute and chronic GVHD. 
 Immune Reconstitution over time. 
 Relapse rate at 2 years post-transplant.  


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3 
Patients Eligibility Criteria 
3.1 
Inclusion Criteria 
1) Disease Criteria: 
 ALL in complete remission (CR) at the time of transplant. Remission is defined as 
“less than 5.0% bone marrow lymphoblasts by morphology,” as determined by a 
bone marrow aspirate obtained within 2 weeks of study registration.   
 Philadelphia chromosome positive ALL is allowed. 
 Lymphoid blastic crisis of CML will be included (provided that patients achieve 
CR).  
2) Age Criteria: Equal or above age 40 and up to 65 years.  If younger than 40, there must be 
comorbidities which preclude the patient to undergo CyTBI conditioning regimen.  
3) Organ Function Criteria: All organ function testing should be done within 35 days of study 
registration.  
4) Cardiac: Left ventricular ejection fraction (LVEF) ≥ 50% by MUGA (Multi Gated 
Acquisition) scan or echocardiogram.  
 
5) Pulmonary: FEV1 (Forced expiratory volume in 1 second) and FVC (Forced vital capacity) 
≥ 50% predicted, DLCO (alveolar diffusion capacity for carbon monoxide) (corrected for 
hemoglobin) ≥ 50% of predicted.  
 
6) Renal: The estimated creatinine clearance (CrCl) must be equal or greater than 
60 mL/min/1.73 m2 as calculated by the Cockcroft-Gault Formula:  
            CrCl = (140-age) x weight (kg) x 0.85 (if female)/72 x serum creatinine (mg/dL). 
7) Hepatic:  
 Serum bilirubin 2.0 g/dL 
 Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5  ULN 
 Alkaline phosphatase  2.5  ULN 
8) Performance status: Karnofsky ≥ 70%  
9)  Consent:  Patient must be informed of the investigational nature of this study in accordance 
with institutional and federal guidelines and have the ability to provide written informed 
consent prior to initiation of any study-related procedures, and ability, in the opinion of the 
principal investigator, to comply with all the requirements of the study. 


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10) Presence of a willing adult HLA-matched sibling (excluding identical twin) or HLA-matched 
unrelated donor meeting all the criteria for routine allo HSCT. All donors will be evaluated for 
eligibility and suitability per the standard of care according to the FACT and NMDP guidelines.   
3.2 
Exclusion Criteria 
1) Non-compliant to medications. 
2) No appropriate caregivers identified. 
3) HIV1 (Human Immunodeficiency Virus-1) or HIV2 positive 
4) Active life-threatening cancer requiring treatment other than ALL 
5) Uncontrolled medical or psychiatric disorders. 
6) Uncontrolled infections, defined as positive blood cultures within 72 hours of study entry, 
or evidence of progressive infection by imaging studies such as chest CT scan within 14 
days of registration.  
7) Active central nervous system (CNS) leukemia 
8) Preceding allogeneic HSCT 
9) Receiving intensive chemotherapy within 21 days of registration. Maintenance type of 
chemotherapy will be allowed.  
 
4 
Study Treatment 
4.1 
Conditioning regimen 
The transplantation conditioning regimen will be fludarabine and TBI (1200 cGy) as 
follows: 
Day -7   Fludarabine 40 mg/m2 IV (Intravenous),  
Day -6   Fludarabine 40 mg/m2 IV 
Day -5   Fludarabine 40 mg/m2 IV 
Day -4   Fludarabine 40 mg/m2 IV   
Day -3   TBI 2 Gy x 2  
Day -2   TBI 2 Gy x 2 
Day -1   TBI 2 Gy x 2,  
Day 0     Transplant 
 
 
 
Fludarabine 


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 Fludarabine dose (40 mg/m2/day) will be based on adjusted ideal body weight if the actual 
body weight is > ideal body weight. 
o Adjusted ideal body weight = ideal weight + (actual Weight-ideal weight) x 0.4. 
o If actual weight is lower than ideal weight, we will use actual weight. 
 Fludarabine will be given by 30 minutes IV infusion on days -7 to -4.  
  
Total Body Irradiation (TBI) 
 TBI is given at the total dose of 12 Gy, divided in 6 fractions over 3 days between day -3 and 
day -1.  
 10 mg of dexamethasone IV will be given daily during TBI.  
4.2 
Allogeneic Stem Cell Collection and Infusion  
Stem Cell Source  
 The source of donor stem cells will be peripheral blood stem cells (PBSC) or bone marrow 
(BM). Cord blood will not be allowed.   
 
Stem Cell Mobilization/Collection  
 PBSC mobilization and collection procedures and BM collection procedures will follow 
the institutional practice.  
 
Stem cell infusion: 
 
PBSC from a related donor should be infused into the patient on the same day of collection. 
However, given the logistics of unrelated donor collections, unrelated PBSC may be 
infused within 48h of collection.   
o For PBSC: The recommended stem cells dose is 3.5-10 x 106 CD34 cells/kg 
recipient weight.  
 
o For marrow infusions: The recommended cell dose is > 2.0 x 108 mononuclear 
cells/kg recipient weight.   
 
o Note: The day of the stem cell/marrow infusion will be defined as day 0. If more 
than one day of infusion is required, then these days are defined as day 0a, day 0b 
accordingly.  The first day after the last stem cell infusion will be defined as day 1. 
 


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4.3 
Maintenance treatment after transplant 
Patients with Philadelphia positive ALL, will receive tyrosine kinase inhibitors after transplant 
per NCCN guidelines.29   
Patients may also receive post transplant intrathecal antimetabolite therapy using cytarabine 
based on disease characteristics and the patient’s history of CNS prophylaxis at the discretion of 
the treating physician and standard practice. 
 
4.4 
GVHD prophylaxis 
 GVHD prophylaxis will be tacrolimus (0.03 mg/kg/day beginning on day -3) and methotrexate 
(5 mg/m2 on days 1, 3, 6, and 11). Patients will be converted to oral tacrolimus when tolerated. 
Tacrolimus will be continued until day +100 and then tapered if there is no evidence of active 
GVHD. Tacrolimus serum level will be followed up per institutional practice.  
 Leucovorin 5 mg/m2 IV every 6 hours x4 doses on days 2, 4, 7, and 12 is optional if severe 
mucositis.  
 Matched unrelated donor recipients will receive, in addition to above, rabbit anti-thymocyte 
globulin (rATG) IV at 1.5 mg/kg on days -7, -6, and -5 for a total rATG dose of 4.5mg/kg. If 
unable to receive rATG the use of horse derived ATG is allowed per physician discretion.  
 
 The use of Mycophenolate Mofetil (MMF) and other appropriate immunosuppressive agents 
are allowed in high risk patients at the discretion of the transplant physician. 
4.5 
Infection Prophylaxis  
Antibacterial, antiviral and antifungal coverage during neutropenia until engraftment will be at 
the discretion of the transplant physician’s clinical practice standards. 
 
The following is a suggested prophylaxis and monitoring regimen:  
4.5.1 Recommended Fungal Prophylaxis   
Patients will receive Voriconazole 200 mg PO BID until day +75 post-transplant. For patients 
who develop elevated liver enzymes (AST or ALT > 2.5 x ULN or total bilirubin > 2.5 x ULN), 
micafungin 50mg IV/day may replace voriconazole until AST, ALT and/or total bilirubin decline 
to grade I level (<2.5x ULN).  
 


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4.5.2 HSV / VZV Prophylaxis 
Herpes simplex virus / Herpes zoster virus (HSV/VZV) infection prophylaxis will be done using 
Acyclovir or valacyclovir daily until day +365 post-transplant.  
4.5.3 CMV (Cytomegalovirus) preemptive therapy   
In all cases in which  either the patient or donor are seropositive for CMV pre-transplant, CMV-
antigenemia or quantitative PCR testing will be obtained from blood weekly, starting from the 
time of neutrophil engraftment until at least day 100.  Patients whose CMV PCR or antigenemia 
assays become positive post-transplant shall be treated per the transplant physician’s clinical 
practice standard.  
4.5.4 PCP (Pneumocystic pneumonia) prophylaxis 
PCP prophylaxis should be initiated approximately day +30 post-transplant, provided the patient 
has met the engraftment criteria for neutrophils and platelets. Primary PCP prophylaxis shall be 
trimethoprim-sulfamethoxazole (TMP-SMX) single strength daily for 5 days a week or double 
strength (Bactrim DS) PO once a day for 2 or 3 days a week (preferred PCP prophylaxis). If 
intolerant to TMP-SMX, pentamidine 300 mg inhaler (or IV) every 4 weeks, dapsone 100 mg 
once a day or atovaquone (Mepron) 1500 mg PO daily may be used.  
4.5.5 PCR testing 
PCR testing for HHV6 and Adenovirus will be sent weekly starting approximately Day +20 until 
day 100.   
PCR testing for EBV will be sent every 2 weeks starting approximately Day +20 until day 100.  
5 
Drug Information 
5.1 
Fludarabine 
5.1.1. Chemical Characteristics 


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Fludarabine phosphate (fludarabine) is an antimetabolite with chemical name 9H-Purin-6-amine, 
2-fluoro-9-(5-0-phosphono- 0-D-arabino-furanosyl) (2-fluoro-ara-AMP). The molecular formula 
is C10H13FN5O7P with molecular weight of 365.2.  
 
5.1.2. Available Forms 
IV Fludarabine is packaged as a white lyophilized solid cake in a vial. Each vial has 50mg 
fludarabine phosphate and only one vial is enclosed per carton.  
5.1.3. Storage and Handling 
Unopened vials of fludarabine should be stored at 20° to 25°C (68° TO 77°F); excursions permitted 
between 15° to 30°C (59° TO 86°F). 
 
5.1.4. Toxicity 
Toxicities reported as more than 10% incidence are:   
Myelosuppression (neutropenia, thrombocytopenia, and anemia), fever and chills, infections, 
nausea and vomiting, pain, weakness, cough, pneumonia, dyspnea, diarrhea, anorexia, rash, edema.  
Toxicities with expected incidences between 1% and 10% are:  
Malaise, stomatitis, myalgia, paresthesia, visual disturbance, gastrointestinal bleeding, upper 
respiratory infection, diaphoresis, dysuria, urinary infection, sinusitis, hearing loss, hyperglycemia, 
headache, pharyngitis, hemoptysis, esophagitis, mucositis, hematuria, osteoporosis, alopecia, 
anaphylaxis, hemorrhage, dehydration, sleep disorder, depression, cerebellar syndrome, impaired 
mentation, allergic pneumonitis, epitaxis, bronchitis, hypoxia, liver failure, abnormal liver 
function,  cholelithiasis, ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, 
respiratory failure, constipation, dysphagia, pruritus, seborrhea, renal failure, abnormal, renal 
function test, protenuria, hesitancy, angina, congestive, heart failure, arrhythmia, supraventricular 


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tachycardia, myocardial infarction, deep venous thrombosis, phlebitis, transient ischemic attack, 
aneurysm, cerebrovascular accident, arthralgia, tumor lysis syndrome.  
 
5.1.5. Administration 
IV fludarabine is prepared by adding sterile water to the white solid cake. Reconstituted in 2mL 
of sterile water, the solid cake produces a solution with approximate concentration of 25mg/mL 
fludarabine phosphate. Follow the institutional guidelines for further preparation and 
administration procedures of fludarabine.  
 
Reconstituted IV fludarabine contains no antimicrobial preservative hence should be utilized 
within 8 hours of reconstitution. It should NOT be infused concomitantly with another intravenous 
solution of unknown compatibility.  
5.2 
Total Body Irradiation (TBI)  
TBI will be administered per standard of care procedure as implemented by radiation oncologists. 
TBI alone for post-pubescent patients with dose/fractionation not exceeding 2 Gy x 6 is well within 
the tolerance of most normal organs for < 5% risk of severe late toxicity (organ failure or major 
dysfunction) by 5 years. Notable exceptions are risk of cataract development, bone marrow 
suppression, ovarian and testicular dysfunction. Also, there is a small risk of second malignancy.  
The most common acute effects include nausea, vomiting, diarrhea and painful swelling of the 
parotid glands.  
When TBI is given in conjunction with other therapies in the transplant setting, there is  additional 
risk of side effects including loss of appetite,   dry mouth, difficult or painful swallowing , headache, 
stomatitis (sore throat/mouth), altered skin integrity, hair loss,  swelling, increased risk for 
infection and/or bleeding, possible lung failure, dry cough, fatigue, anxiety, fever, possible liver 
failure, lung scarring, loss of vision, shortness of breath,  sterility, heartburn, cystitis, sleep 
disturbances altered gastrointestinal and genitourinary function,  neuropathy,  fistulas, altered 
endocrine function, pericarditis and increased risk of a second cancer. Overall, the incidence of 
most major toxicity when radiation is given in conjunction with other therapy as outlined above is 
still low,  rare, serious side effects are possible. 
 


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5.3 
Tacrolimus 
5.3.1. Chemical Characteristics 
Tacrolimus is a macrolide immunosuppressant produced by Stretocyces Tsukubaensis. Tacrolimus 
has an empirical formulation of C44H69NO12-H2O and a formula weight of 822.05. Tacrolimus 
appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble 
in ethanol, and very soluble in methanol and chloroform. Tacrolimus inhibits T-lymphocyte 
activation, although the exact mechanism of action is not known. Experimental evidence suggests 
that tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, 
calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin 
inhibited.  This effect may prevent the dephosphorylation and translocation of nuclear factor of 
activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the 
formation of lymphokines (such as interleukin-2, gamma interferon). The net result is the 
inhibition of T-lymphocyte activation (i.e., immunosuppression). 
 
5.3.2. Available Forms 
 Tacrolimus is available for oral administration as capsules (tacrolimus capsules) containing the 
equivalent of 0.5 mg, 1mg  and  5mg of anhydrous tacrolimus. Inactive ingredients include lactose, 
hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate. The 0.5 mg and 
1 mg capsule shell contains gelatin and titanium dioxide, and the 5-mg capsule shell contains 
gelatine, titanium dioxide, and ferric oxide. Tacrolimus is also available as a sterile solution 
(tacrolimus injection) containing the equivalent of 5mg anhydrous tacrolimus in 1 ml for 
administration by IV infusion only. Each mL contains polyoxyl 60 hydrogenated castor oil (HCO-
60), 200 mg, and dehydrated alcohol, USP, 80.0% v/v.  
 
5.3.3. Storage and Handling 
Tacrolimus capsules should be stored at room temperature between 15° and 30°C (59° and 86°F). 
Tacrolimus injection should be stored between 5° and 25°C (41° and 77°F). 
 
5.3.4. Toxicity 
Possible side effects of tacrolimus include: depressed kidney function, high blood sugar, high 
blood potassium, skin rash, headache, nausea, vomiting. Less common side effects are loss of 
appetite, sleep disturbances, vivid dreams, hallucinations, high blood pressure, seizure, decreased 


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level of consciousness, anemia, agitation, tremors, irritability, slurred speech, tingling in the hands 
and feet, pain in the palms and soles of the feet, weakness, and abnormal blood cell levels. All of 
these side effects are reversible by reducing the dose or discontinuing the drug. Rare fatal cases of 
severe allergic reactions have been reported in patients receiving cyclosporine and it is possible 
that similar reactions could also occur in patients receiving tacrolimus. 
 
5.3.5. Administration 
Tacrolimus injection) must be diluted with NS or D5W before use. Tacrolimus is administered as 
a continuous infusion. Oral preparation will be administered on empty stomach every 12 hours.  
 
5.4 
Methotrexate 
5.4.1. Chemical Characteristics 
Methotrexate is a folate antimetabolite that inhibits DNA synthesis. Methotrexate irreversibly 
binds to dihydrofolate reductase, inhibiting the formation of reduced folates, and thymidylate 
synthetase, resulting in inhibition of purine and thymidylic acid synthesis. Methotrexate is cell 
cycle specific for the S phase of the cycle. It is also used as the immunosuppressive agent, or to 
prevent/treat GVHD.  The effect of this agent can be antagonized with the administration of 
leucovorin.  
 
5.4.2. Available Forms 
Methotrexate Injection, USP is available in 50, 100, 200, and 250 mg single-dose vials of sterile, 
isotonic liquid containing no preservatives for parenteral administration. 
 
Each 25 mg/mL, 2 mL (50 mg) vial contains methotrexate sodium equivalent to 50 mg 
methotrexate. Inactive ingredients are sodium chloride for isotonicity and sodium hydroxide and, 
if necessary, hydrochloric acid to adjust pH to approximately 8.5. 
 
Each 25 mg/mL, 4 mL (100 mg) vial contains methotrexate sodium equivalent to 100 mg 
methotrexate. Inactive ingredients are sodium chloride for isotonicity and sodium hydroxide and, 
if necessary, hydrochloric acid to adjust pH to approximately 8.5. 
 


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Each 25 mg/mL, 8 mL (200 mg) vial contains methotrexate sodium equivalent to 200 mg 
methotrexate. Inactive ingredients are sodium chloride for isotonicity and sodium hydroxide and, 
if necessary, hydrochloric acid to adjust pH to approximately 8.5. 
Each 25 mg/mL, 10 mL (250 mg) vial contains methotrexate sodium equivalent to 250 mg 
methotrexate. Inactive ingredients are sodium chloride for isotonicity and sodium hydroxide and, 
if necessary, hydrochloric acid to adjust pH to approximately 8.5. 
 
Methotrexate sodium is also available in 20 mg vial of lyophilized powder. Methotrexate sodium 
for injection should be reconstituted with an appropriate sterile, preservative free medium such as 
NS or D5W. Reconstitute the 20 mg vial to a concentration no greater than 25 mg/mL.  
Reconstitute immediately prior to use.  
 
5.4.3. Storage and Handling 
Store at controlled room temperature, 20-25○C (68-77○ F); excursions permitted to 15-30○C (59-
86○F). Protect from light.  
 
5.4.4. Toxicity 
The most frequently reported adverse reactions associated with methotrexate use as GVHD 
prophylaxis include ulcerative stomatitis, leucopenia and suppressed hematopoiesis, nausea, and 
abdominal distress. Other frequently reported adverse effects are malaise, undue fatigue, chills, 
and fever, dizziness and decreased resistance to infection. Methotrexate may be associated with 
increased rates of pulmonary complications after transplantation. The risk of infections is due to 
the suppression of hematopoiesis after transplantation.  
    
5.5 
Thymoglobulin® (Anti-thymocyte Globulin [Rabbit]) (rATG) 
5.5.1 Chemical Characteristics 
Thymoglobulin® (Anti-thymocyte globulin [rabbit]) is a purified, pasteurized, gamma immune 
globulin obtained by immunization of rabbits with human thymocytes. Gamma immune globulin 
or Immunoglobulins are heavy plasma proteins, often with added sugar chains on N-terminal. 


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5.5.2 Available Forms 
Thymoglobulin (Anti-thymocyte Globulin [Rabbit]) is available as sterile, lyophilized powder to be 
reconstituted with Sterile Water for Injections, EP.  
Each package contains one 10 mL vial. The reconstituted preparation contains approximately 5 mg/mL 
of Thymoglobulin of which >95% is rabbit gamma immune globulin (IgG). The reconstituted solution 
has a pH of 7.0 ± 0.4. Human red blood cells are used in the manufacturing process to deplete cross-
reactive antibodies to non T-cell antigens. The manufacturing process is validated to remove or 
inactivate potential exogenous viruses. All human red blood cells are from US registered or FDA 
licensed blood banks. A viral inactivation step (pasteurization, i.e., heat treatment of active ingredient 
at 60oC/10 hours) is performed for each lot. 
5.5.3 Storage and Handling 
Store in refrigerator between +2°C and +8°C (36°F to 46°F). A higher temperature of ≤37°C during 
transport for a total excursion time of ≤10 days will do the product no harm.  Protect from light.  Do 
not freeze.  Do not use after the expiration dated indicated on the label.  Any unused drug remaining 
after infusion must be discarded.  
5.5.4 Toxicity 
Thymoglobulin adverse events are generally manageable or reversible. The most frequent 
reported adverse events (more than 25% of patients) include: fever, chills, leukopenia, pain, 
headache, abdominal pain, diarrhea, hypertension, nausea, thrombocytopenia, peripheral edema, 
dyspnea, asthenia, hyperkalemia, tachycardia, and infection. 
Serious immune-mediated reactions have been reported with the use of Thymoglobulin and 
consist of anaphylaxis or severe cytokine release syndrome (CRS). Fatal anaphylaxis has been 
reported. Severe, acute infusion-associated reactions (IARs) are consistent with CRS and can 
cause serious cardiorespiratory events and/or death. IARs may occur as soon as the first or 
second infusion during a single course of Thymoglobulin treatment. During post-marketing 
surveillance, fever, rash, arthralgia and/or myalgia have been reported to occur 5 to 15 days after 
onset of Thymoglobulin therapy, indicating possible serum sickness. These symptoms are 
manageable with corticosteroid treatment. Infections, reactivation of infection, sepsis, 
malignancies including post-transplant lymphoproliferative disorder (PTLD) and other 
lymphomas as well as solid tumors have been reported after Thymoglobulin administration in 
combination with multiple immunosuppressive agents. 


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6 
Required Observations  
Please see appendix B for a study calendar.   Calendar needs updating to match 
6.1 
Pre-Transplant (within 35 days prior to study registration / day of final transplant 
evaluation).  
6.1.1  History and physical exam (include Karnofsky Performance Score within 14 days prior to 
registration) 
6.1.2 Creatinine, AST, ALT, Alk Phos., and Total bilirubin  
 
6.1.3 Echocardiogram or MUGA 
6.1.4 Pulmonary function testing: FVC, FEV1, DLCO (corrected for hemoglobin). 
6.1.5 Unilateral bone marrow aspirate and biopsy (within 35 days of registration), morphology 
and cytogenetics.  
6.1.6 Cerebrospinal fluid examination is not required, unless clinically indicated. 
6.2 
Post-transplant required observations and follow-up plans  
6.2.1. Bone marrow aspirate and biopsy specimen shall be collected for morphology examination 
and cytogenetics at day +30 (±7), +100 (±14), and 1 year (±45) post-transplant for all patients 
who are clinically stable and who have not demonstrated disease progression by that time 
point. In addition, a unilateral marrow aspirate will also be collected whenever a relapse is 
suspected.   
6.2.2. Immune Reconstitution and Chimerism studies will be performed per BMT standard and/or 
as clinically indicated.  The recommended timing of the labs is at Day +30 (±7), Day +60 
(±7), Day +100 (±14), Day +180 (±21) and at 1 year (±45) post-transplant. 
6.2.2. Patients need to be seen in clinic at least once a week until day 100 post-transplant and have 
acute GVHD assessment (using consensus criteria30) weekly (±3 days). Then they need to 
be seen at least once a month (±14 days) until 1 year after transplant to have chronic GVHD 
assessment.  
6.2.3. Adverse Event and Toxicity monitoring will be performed at each visit date.   
6.2.4. The patient will be followed at least for 2 years after transplant for survival and relapse. The 
follow up interval is determined as clinically necessary.   
6.2.5. The patient who relapsed after transplant will be followed only for survival.   
 


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7 
Statistical Considerations 
7.1 
Sample Size  
This is a single center, single arm phase II study whose primary aim is to show an improvement in 
one-year DFS to 75% from an historical rate of ~ 45%. The estimated 1-year OS of ALL patients 
≥ 20 years old undergoing allo HCT in first or subsequent CR is 55-65% according to the data of 
the Center for International Blood and Marrow Transplant Research (CIBMTR).31 CIBMTR did 
not report DFS in this subset of adult patients. Patients with ALL who are ≥ 35 years old are known 
to have high-risk disease and lower survival.3 A French study excluded patients who are ≥ 50 years 
from allo HCT and these patients (≥ 50 years) were randomized to either consolidation autologous 
HCT (auto HCT) or chemotherapy alone. The median DFS in this subset (≥ 50 years old) was 14 
months and 3-year DFS was 24%.32, 33 According to these data, we estimate that the 1-year DFS 
in patients ≥ 40 years old who receive allo HCT to be ~ 45%. We hypothesize that reduced toxicity 
myeloablative conditioning using FluTBI will improve this 1-year DFS to 75%. A maximum total 
of 16 evaluable patients will be enrolled to have a probability of .05 or less of concluding that the 
one year DFS rate exceeds 45% if it really is 45% and a probability of at least .80 of concluding 
that the one year DFS rate exceeds 45% if it is really .75%. We plan to enroll a total of 20 patients 
to allow for non-evaluable patients (patients who sign consent and do not get transplant). 
  
We estimate enrolling 7-8 patients per year in the UAB transplant program.   
7.2 
Analysis Methods  
Since all subjects will be followed for at least one year or until death, whichever is sooner, one 
year DFS can be thought of as a dichotomous (yes/no) variable.  Thus a two stage design based on 
a binomially distributed random variable is appropriate.  We have chosen a two stage design which 
will accrue 6 subjects in the first stage.  If one or fewer achieve one year DFS the study will be 
terminated with the conclusion that the one year DFS rate does not exceed 45%.  Otherwise, an 
additional 10 will be accrued for a total of 16.  If 10 or fewer of these 16 achieve one year DFS we 
will conclude that the one year DFS rate does not exceed 75%.  Otherwise we will conclude that 
it does exceed 45%.  If the one year DFS rate is really 45%, the probability of concluding that it 
exceeds 45% (alpha) is 4.9%.  If the one year DFS rate is really 75% the probability of concluding 
that it does not exceed 45% (beta) is 19%. Note that this is not a MiniMax or Optimum design as 


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described by Simon.  Those designs would have provided for an unacceptably high probability of 
early stopping for futility with a reasonably good one year DFS rate such as 60%.   One year DFS 
will be estimated using the method of Koyama and Chen (ref) which provides proper estimates 
and confidence intervals following two stage designs.  Disease-free survival and overall survival  
over time will be estimated with Kaplan-Meier methods34 with standard errors computed based on 
Greenwood’s formula. Rates of relapse and acute and chronic graft-versus-host disease (all 
secondary objectives) will be estimated using the cumulative incidence methods described in Ruan 
and Gray.35 Engraftment (secondary objective) will be summarized with the sample proportion of 
patients who engraft along with a corresponding exact 95% confidence interval, while regimen 
related toxicities (secondary objective) will be tabulated by category. 
8 
Adverse Event Reporting   
Adverse events occurring following study registration, but prior to beginning transplant therapy 
will not be reported. Protocol related therapy does not begin until patients are admitted for their 
bone marrow transplant.    Regimen related toxicity and adverse events will be monitored for and 
reported if required through day 100. Adverse Event and Toxicity assessments will be performed 
at each study visit per the study calendar. Following day 100, patients will still be followed for 
relapse and overall survival.  
8.1 
Definitions of Adverse Events with Commercially Available Agents 
This trial utilizes commercially available agents for transplant therapy for patients with 
hematological malignancies.  Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source.  In some cases, an agent obtained commercially may 
be used for indications not included in the package label.  In this case, the agent is still considered 
to be a commercial agent and the procedures described below should be followed. 
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject whether or not it may have a causal relationship with this treatment.  An AE includes 
significant exacerbation of any baseline medical condition including, but not limited to, the disease 
under study. Reporting requirements may include the following considerations: 1) the 
characteristics of the adverse event including the grade (severity); 2) the relationship to the study 
therapy (attribution); and 3) the prior experience (expectedness) of the adverse event. 


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Expected events are those that have been previously identified as resulting from administration of 
the agent.  For commercially available agents, an adverse event is considered unexpected, for 
reporting purposes only, when either the type of event or the severity of the event is not listed in 
either of the following:  
 The current NCI Agent-Specific Adverse Event List (provided in the Drug Information Section 
of this protocol). 
 The drug package insert (for treatments with commercially available agents). 
 
Except where otherwise specified, Common Terminology Criteria for Adverse Events (CTCAE) 
v.4 will be used to grade adverse events in this study.   
 
8.2 
Required Adverse Events Reporting 
Therapy for ALL, with or without allo HCT, is associated with significant toxicity.  These 
toxicities are generally viewed as an anticipated consequence of therapy rather than an adverse 
event.  To summarize, adverse events with severity grades 1, 2, 3, and all expected grade 4 
toxicities will not be reported to the IRB, as they are expected in patients undergoing allo HCT for 
ALL. Only unexpected grade 4 non-hematologic toxicity events with a possible, probable or 
definite relation to the study and all grade 5 events will be reported to IRB.  
8.3 
Hematologic toxicity and Definition of Primary Engraftment Failure 
Failure to achieve a neutrophil count > 500/µL within 35 days of the stem cell infusion will be 
defined as primary engraftment failure and reported as an adverse event. If primary engraftment 
failure occurs, an action to obtain neutrophil recovery (such as the use of growth factors or stem 
cell boost) will be allowed. Neutrophil count recovery will continue to be monitored in these 
patients until they reach statistical endpoint.  
8.4 
Serious Adverse Event Reporting Procedures 
 All serious adverse events (SAE) which require reporting must be reported immediately (i.e. 
within 24 hours of awareness) to the Principal Investigator or designee, followed by written 
documentation to the IRB from the PI (including the PI’s or designee’s medical summary of the 


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SAE) within 7 days of the PI’s knowledge of occurrence.  A serious adverse event (SAE) is defined 
as: Any adverse event (experience) occurring that results in ANY of the following outcomes: 
 
1) Death. 
 
2) A life-threatening adverse drug experience. 
 
3) Inpatient hospitalization or prolongation of existing hospitalization. 
 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 
5) A congenital anomaly/birth defect. 
 
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
medical judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition (FDA, 21 CFR 
312.32; ICH E2A and ICH E6). 
 
The research staff of Bone Marrow Transplant-Cell Therapy (BMT-CT) Program will coordinate 
the reporting process between the investigators and IRB as well as other applicable reporting 
agencies (FDA, CTEP, and NIH). Copies of all correspondence and reporting documents will be 
maintained in a regulatory file held by the research staff of BMT-CT Program.  
9 
 Data Safety Monitoring 
9.1 
Data and Safety Monitoring Procedures 
The Data and Safety Monitoring Board (DSMB) of The University of Alabama at Birmingham 
Comprehensive Cancer Center is the DSMB for this study.  This committee is responsible for the 
quarterly review and monitoring the study’s scientific progress, accrual rate and any serious 
adverse events. 
 
In addition to the Cancer Center DSMB, BMT-CT Program will form a Data and Safety 
Monitoring Committee (DSMC) for the study.  This committee will be composed of the PI, co-
investigator(s), data manager or study coordinator and other members of the study staff involved 


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in the conduct of the trial.  During the committee’s quarterly meeting, the PI will discuss matters 
related to: 
Enrollment rate relative to expectations, characteristics of participants 
Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
Adherence to protocol (protocol deviations) 
Completeness, validity and integrity of study data 
Retention of study participants 
 
These meetings are to be documented by data manager or study coordinator using the Protocol 
Specific Data and Safety Monitoring Report (DSMR), signed by the PI or co-investigator.  The 
completed DSMR is to be sent to DSMB. 
 
Similarly, protocol deviations are to be documented using the Notice of Protocol Deviation Form 
and requires the signatures of either data manager or study coordinator and the PI or co-investigator. 
These reports are to be sent to the IRB within 7 calendar days of awareness of the event and on a 
quarterly basis to the DSMB with the Protocol Specific DSMR. 
 
9.2 
Quality Assurance and Audits 
The Quality Assurance Review Committee (QARC) of The University of Alabama at Birmingham 
Comprehensive Cancer Center performs quality assurance audits of investigator-initiated clinical 
trials. Audits provide assurance that trials are conducted in compliance with the protocol. Further, 
they ensure that study data are collected, documented and reported in compliance with Good 
Clinical Practices (GCP) Guidelines and regulatory requirements. 
 
A QARC audit of each clinical trial is conducted annually. Audits occur within the month of the 
study’s initial IRB approval (provided the trial is open, and study accrual is greater than five 
subjects). 
 
All audit findings are reported by QARC to the DSMB. These findings are followed-up by the 
DSMB until they have been resolved. 
 


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The DSMB can also request QARC for a ‘for cause’ audit of the trial if the board identifies a need 
for a more rigorous evaluation of study-related issues.  
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory authority, 
the PI must immediately inform the IRB/DSMB that such a request has been made. 


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References 
 
1. Gaynon PS, Angiolillo AL, Carroll WL, et al. Long-term results of the children's cancer group 
studies for childhood acute lymphoblastic leukemia 1983-2002: a Children's Oncology Group 
Report. Leukemia 2010;24(2): 285-97. 
2. Annino L, Vegna ML, Camera A, et al. Treatment of adult acute lymphoblastic leukemia (ALL): 
long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood 2002;99(3): 863-71. 
3. Alvarnas JC, Brown PA, Aoun P, et al. Acute lymphoblastic leukemia. J Natl Compr Canc Netw 
2012;10(7): 858-914. 
4. Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive 
consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 
8811. Blood 1995;85(8): 2025-37. 
5. Yanada M, Matsuo K, Suzuki T, Naoe T. Allogeneic hematopoietic stem cell transplantation as 
part of postremission therapy improves survival for adult patients with high-risk acute 
lymphoblastic leukemia: a metaanalysis. Cancer 2006;106(12): 2657-63. 
6. Bachanova V, Weisdorf D. Unrelated donor allogeneic transplantation for adult acute 
lymphoblastic leukemia: a review. Bone Marrow Transplant 2008;41(5): 455-64. 
7. Hahn T, Wall D, Camitta B, et al. The role of cytotoxic therapy with hematopoietic stem cell 
transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review. 
Biol Blood Marrow Transplant 2006;12(1): 1-30. 
8. Chaidos A, Kanfer E, Apperley JF. Risk assessment in haemotopoietic stem cell transplantation: 
disease and disease stage. Best Pract Res Clin Haematol 2007;20(2): 125-54. 
9. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute 
lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic 
transplantation in first complete remission, and an autologous transplantation is less effective than 
conventional consolidation/maintenance chemotherapy in all patients: final results of the 
International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008;111(4): 1827-33. 
10. Ringdén O, Labopin M, Tura S, et al. A comparison of busulphan versus total body irradiation 
combined with cyclophosphamide as conditioning for autograft or allograft bone marrow 
transplantation in patients with acute leukaemia. Acute Leukaemia Working Party of the European 
Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 1996;93(3): 637-45. 
11. Davies SM, Ramsay NK, Klein JP, et al. Comparison of preparative regimens in transplants 
for children with acute lymphoblastic leukemia. J Clin Oncol 2000;18(2): 340-7. 
12. Marks DI, Forman SJ, Blume KG, et al. A comparison of cyclophosphamide and total body 
irradiation with etoposide and total body irradiation as conditioning regimens for patients 


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                                                                                                                                                             Version 4.0, dated September 12, 2018 
 
Page 27 of 30 
undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete 
remission. Biol Blood Marrow Transplant 2006;12(4): 438-53. 
13. Snyder DS, Nademanee AP, O'Donnell MR, et al. Long-term follow-up of 23 patients with 
Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic bone 
marrow transplant in first complete remission. Leukemia 1999;13(12): 2053-8. 
14. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow 
transplantation. Blood 1990;75(3): 555-62. 
15. Gale RP, Horowitz MM. Graft-versus-leukemia in bone marrow transplantation. The Advisory 
Committee of the International Bone Marrow Transplant Registry. Bone Marrow Transplant 
1990;6 Suppl 1: 94-7. 
16. Arnold R, Massenkeil G, Bornhäuser M, et al. Nonmyeloablative stem cell transplantation in 
adults with high-risk ALL may be effective in early but not in advanced disease. Leukemia 
2002;16(12): 2423-8. 
17. Martino R, Giralt S, Caballero MD, et al. Allogeneic hematopoietic stem cell transplantation 
with reduced-intensity conditioning in acute lymphoblastic leukemia: a feasibility study. 
Haematologica 2003;88(5): 555-60. 
18. Hamaki T, Kami M, Kanda Y, et al. Reduced-intensity stem-cell transplantation for adult acute 
lymphoblastic leukemia: a retrospective study of 33 patients. Bone Marrow Transplant 2005;35(6): 
549-56. 
19. Gutierrez-Aguirre CH, Gomez-Almaguer D, Cantu-Rodríguez OG, et al. Non-myeloablative 
stem cell transplantation in patients with relapsed acute lymphoblastic leukemia: results of a 
multicenter study. Bone Marrow Transplant 2007;40(6): 535-9. 
20. Mohty M, Labopin M, Tabrizzi R, et al. Reduced intensity conditioning allogeneic stem cell 
transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from 
the European Group for Blood and Marrow Transplantation. Haematologica 2008;93(2): 303-6. 
21. Stein A, O’Donnell M, Snyder D, et al. Reduced-intensity stem cell transplantation for high-
risk acute lymphoblastic leukemia. Biology of blood and marrow transplantation 2007;13(2): 134. 
22. Devine SM, Sanborn R, Jessop E, et al. Fludarabine and melphalan-based conditioning for 
patients with advanced hematological malignancies relapsing after a previous hematopoietic stem 
cell transplant. Bone Marrow Transplant 2001;28(6): 557-62. 
23. Ciurea SO, Saliba RM, Hamerschlak N, et al. Fludarabine, melphalan, thiotepa and anti-
thymocyte globulin conditioning for unrelated cord blood transplant. Leuk Lymphoma 
2012;53(5): 901-6. 
24. Ram R, Storb R, Sandmaier BM, et al. Non-myeloablative conditioning with allogeneic 
hematopoietic cell transplantation for the treatment of high-risk acute lymphoblastic leukemia. 
Haematologica 2011;96(8): 1113-20. 


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25. Alousi A, de Lima M. Reduced-intensity conditioning allogeneic hematopoietic stem cell 
transplantation. Clin Adv Hematol Oncol 2007;5(7): 560-70. 
26. Kroger N, Bornhauser M, Ehninger G, et al. Allogeneic stem cell transplantation after a 
fludarabine/busulfan-based reduced-intensity conditioning in patients with myelodysplastic 
syndrome or secondary acute myeloid leukemia. Ann Hematol 2003;82(6): 336-42. 
27. Stelljes M, Bornhauser M, Kroger M, et al. Conditioning with 8-Gy total body irradiation and 
fludarabine for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. 
Blood 2005;106(9): 3314-21. 
28. Nakamura Y, Mori T, Kato J, et al. [Allogeneic hematopoietic stem cell transplantation with 
fludarabine, melphalan, and total body irradiation as a conditioning for elderly patients with 
myeloid malignancies]. Rinsho Ketsueki 2012;53(3): 318-22. 
29. Alvarnas JC, Brown PA, Aoun P, et al. Acute lymphoblastic leukemia. J Natl Compr Canc 
Netw 2012;10(7): 858-914. 
30. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD 
Grading. Bone Marrow Transplant 1995;15(6): 825-8. 
31. Pasquini MC WZ. Current use and outcome of hematopoietic stem cell transplantation: 
CIBMTR Summary Slides. Available at: http://www.cibmtr.org 2011. 
32. Fiere D, Lepage E, Sebban C, et al. Adult acute lymphoblastic leukemia: a multicentric 
randomized trial testing bone marrow transplantation as postremission therapy. The French Group 
on Therapy for Adult Acute Lymphoblastic Leukemia. J Clin Oncol 1993;11(10): 1990-2001. 
33. Sebban C, Lepage E, Vernant JP, et al. Allogeneic bone marrow transplantation in adult acute 
lymphoblastic leukemia in first complete remission: a comparative study. French Group of 
Therapy of Adult Acute Lymphoblastic Leukemia. J Clin Oncol 1994;12(12): 2580-7. 
34. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat 
Assoc . 1958;53: 457-81. 
35. Ruan PK, Gray RJ. Analyses of cumulative incidence functions via non-parametric multiple 
imputation. Statistics in medicine 2008;27(27): 5709-24. 
 
 


UAB BMTCT Program                                                                                                                                              UAB 1285- FluTBI                                                       
 
     
                                                                                                                                                             Version 4.0, dated September 12, 2018 
 
Page 29 of 30 
Appendix A:  Performance Scores 
 
Karnofsky Performance Score 
100% – normal, no complaints, no signs of disease 
90% – capable of normal activity, few symptoms or signs of disease 
80% – normal activity with some difficulty, some symptoms or signs 
70% – caring for self, not capable of normal activity or work 
60% – requiring some help, can take care of most personal requirements 
50% – requires help often, requires frequent medical care 
40% – disabled, requires special care and help 
30% – severely disabled, hospital admission indicated but no risk of death 
20% – very ill, urgently requiring admission, requires supportive measures or treatment 
10% – moribund, rapidly progressive fatal disease processes 
0% – death. 


UAB BMTCT Program                                                                                                                                              UAB 1285- FluTBI                                                                                                                                     
                  
Version 4.0, dated September 12, 2018 
 
Page 30 of 30 
Appendix B: Study Calendar  
Procedures 
Screening Period  
Within 35 days of 
Study Registration / 
Day of Final 
Transplant 
Evaluation 
Conditioning Phase 
 
Follow-Up Phase 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
Day 
0 
+1 
+3 
+6 
+11 
Day 
30 
(±7) 
Day 
100   
(±14) 
Day 
180 
(±21) 
Day 
365 
(±45) 
2 
Years 
Eligibility criteria, Informed Consent and 
medical/treatment  history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary function test and 
Echocardiogram or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV1 and HIV2 labs and Pregnancy Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Function Panels, Renal function and 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam , Vital Signs and Karnofsky 
Status1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Bone Marrow aspirate and biopsy2, 
morphology and cytogenetics 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
X4 
 
X4 
 
Immune Reconstitution / Chimerism 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
Stem cell Infusion 
 
 
 
 
 
 
 
 
X3 
 
 
 
 
 
 
 
 
 
GVHD Prophylaxis- Tacrolimus5  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
GVHD Prophylaxis- Methotrexate6 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
GVHD Prophylaxis – rATG11 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine9 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Body Irradiation10 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Acute GVHD assessment7 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
 
 
 
Chronic GVHD assessment8 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Adverse Events and Toxicity Monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. Karnofsky Performance Score will be assessed within 14 days prior to registration. 
2. A bone marrow aspirate and biopsy will be performed within 35 days of registration to assess morphology and cytogenetics. 
3. If stem cell infusion requires more than one day, then the first day after the last stem cell infusion will be defined as day 1. 
4. A bone marrow aspirate will be collected whenever relapse is suspected. Patients that relapse will be followed for survival. 
5. Tacrolimus (0.03mg/kg/day) will be given starting day -3. Patients will convert to oral tacrolimus when tolerated. Tacrolimus will be continued till day +100 and tapered if there  
are no signs of active GVHD.  
6. Methotrexate 5mg/m2 will be given on day 1, 3, 6 and 11. If sever mucositis develops, Leucovorin 5mg/m2 on day 4,7,and 12 if severe  mucositis develops 
7. Acute GVHD will be assessed weekly (±3 days) till 100 days post-transplant. 
8. Chronic GVHD will be assessed monthly (±14 days) till 1 year post transplant. 
9. Fludarabine 40 mg/m2/day 
10. Total Body Irradiation 200cGy/fraction x 2 on days -3.-2 and -1. 
11. rATG (1.5mg/kg on Day -7, -6, and -5) given for MUD patients only. 
 

ICF_003.pdf: 
Single Arm Phase II Study of Myeloablative 
Allogeneic Hematopoietic Stem Cell Transplantation 
for Acute Lymphoblastic Leukemia (ALL) in Older 
Patients Using Fludarabine and Total Body Irradiation 
(FluTBI) Regimen 
PI: OMER JAMY, MD 
NCT # 01991457 
December 09, 2018


Page 1 of 12
UAB 1285 – FluTBI
Protocol v.4.0 - Consent dated 09/12/2018
Informed Consent Document
TITLE OF RESEARCH:
Single Arm Phase II Study of Myeloablative Allogeneic
Hematopoietic Stem Cell Transplantation for Acute 
Lymphoblastic Leukemia (ALL) in Older Patients Using 
Fludarabine and Total Body Irradiation (FluTBI) Regimen
PROTOCOL NO:
IRB -130515007
UAB #1285
INVESTIGATOR:
 Donna Salzman, M.D.
CO-INVESTIGATORS:
Raquel Innis-Shelton, M.D.
  Lawrence Lamb, Ph.D.
  Ruby Meredith, M.D.
  Antonio Di Stasi, M.D.
  Luciano Costa, M.D., Ph.D.
SPONSOR:
UAB Comprehensive Cancer Center
Purpose of the Research
You are being invited to participate in this research trial because you are going to 
receive a stem cell transplant from a matched brother or sister, or an unrelated donor to treat 
your leukemia. The goal of this research is to evaluate a pre-transplant (conditioning) regimen 
for stem cell transplant patients with high-risk disease that provides an anti-leukemia effect 
with fewer side effects. The conditioning regimen being used in this trial is the drug Fludarabine 
and total body irradiation (FluTBI). The use of FluTBI for cancer treatment has been approved 
by the FDA (U.S. Food and Drug Administration). We are studying the combination of 
Fludarabine and total body irradiation in stem cell transplant patients which has not been FDA 
approved.
Many transplant centers use full intensity conditioning treatments such as CyTBI 
(Cyclophosphamide and total body irradiation) as a standard pre-treatment for transplantation, 
but severe drug-related side effects remain a major cause of death. Fludarabine, though less 
effective when compared to Cyclophosphamide, has less drug-related side-effects. Fewer drug 
related side effects is a potential benefit for patients who are older or have high-risk disease. 
This study will continue to test if this new conditioning treatment, FluTBI, can lead to a 
safer and more effective stem cell transplant treatment approach for patients 40 to 65 years of 
UAB IRB
Approved
26-Sep-2018
until
08-May-2019


Page 2 of 12
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age and/or younger patients with high risk disease. This is a phase II clinical trial that will enroll 
approximately 20 patients, all of whom will be enrolled at UAB. You will be followed for a 
minimum of 2 years after your transplant as part of this study; this is the same transplant 
follow-up as you would have whether you are on the study or not on the study.
Explanation of Procedures
For your stem cell transplant, you (the recipient) will get FluTBI chemotherapy, followed 
by an infusion of blood stem cells collected from a donor who is a suitable match. You will have 
a separate consent form that describes the transplant process and you will be able to ask your 
doctors and nurses questions about that consent before you make your decision.
If you decide to take part in this phase 2 clinical research trial you will receive treatment 
using full-intensity chemotherapy and radiation followed by stem cell transplant. Full intensity 
means you will receive high doses of chemo-radiotherapy, as a pre-treatment, before your 
transplant. The high dose chemo-radiotherapy is given to kill as many cancer cells as possible; 
however it will also destroy your bone marrow’s ability to make blood cells. It must be followed 
by a stem cell transplant to restore your bone marrow function. 
You may be eligible to take part in this research study if your disease is in remission. To 
be eligible you should meet at least the following inclusion criteria:
•
40 to 65 years of age. Participants younger than 40 years of age may participate 
if they have other medical condition which prevents them from participating in 
more aggressive conditioning regimens.
•
You have a suitable donor available, who may be related or unrelated to you.
•
Your heart, lung, liver, and kidney function tests are acceptable.
•
You must be well enough to undergo full intensity conditioning.
There are conditions that might exclude you. If you are HIV positive, or have any active 
infections, for example, you would not be eligible for this study. If female, you cannot be 
pregnant or breastfeeding. You may not take part if you have another active life threatening 
cancer that requires treatment other than stem cell transplant or if your disease involves the 
central nervous system (CNS), which is your brain and spinal cord. Your research doctor will 
review with you in more detail the eligibility criteria that may apply to you.
If you decide to participate in this study you will receive FluTBI as your chemotherapy 
regimen starting 7 days before your transplant. You and your study doctors and nurses will 
review the clinical information for the transplant. In preparation to receive your stem cell 
transplant the following test will be performed as transplant standard of care whether you are 
on the study or not. We will use the information from your medical record to evaluate this trial 
only if you decide to participate.
Pre-Transplant (within 35 days prior to transplant admission)
You will have the following standard evaluations and tests:


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
Complete history and physical examination (including blood tests).

Heart function test (either Echocardiogram or MUGA).

Lung function test (called Pulmonary Function Tests or PFTs).

Pregnancy test, if you are a female who could become pregnant.

Blood sample to check Creatinine, AST, ALT, Alk Phos., and Total bilirubin
Pre-Transplant 
You will have a standard procedure called a bone marrow aspirate and biopsy. This is to 
collect a sample of your bone marrow and evaluate your current disease condition. 
Pre-Transplant, Conditioning Regimen
In this research study, subjects enrolled will receive the FluTBI pre-treatment (the 
conditioning regimen) beginning with Fludarabine for 4 days. Each day’s total Fludarabine dose 
is given on Days -7 to -4, prior to your transplant on Day 0. You will receive total body 
irradiation (TBI) for 3 days. Total dose of TBI is given on Days -3 to -1, prior to your transplant 
on Day 0. The FluTBI treatment is summarized in the following table.
Chemotherapy drugs-FluTBI
Day, Pre-Transplant
Fludarabine
Total Body Irradiation
Day -7
1st dose IV
Day -6
2nd dose IV
Day -5
3rd dose IV
Day -4
4th dose IV
Day -3
1st dose 
Day -2
2nd dose 
Day -1
3rd dose 
Day 0
Transplant-Stem cell infusion
You will receive medication according to the center’s institutional guidelines to helps relieve 
some of the side effects of chemo-radiotherapy.
Transplant Day
On Day 0, the day of your transplant, you will receive your donor stem cell (cells which 
will eventually develop into white blood cells, red blood cells and platelets). Donor stem cells 
may be from a donor’s blood or bone marrow. Your transplant is performed exactly the same 
way it would if you are on the study or not.
After Day 0, you will be given: antibiotics, anti-viral and anti-fungal medication to help 
prevent infections, or if necessary to fight infections; blood transfusions to increase the number 


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of red blood cells in your system; platelet transfusions to assist in helping your blood to clot; 
and nutritional and general support, according to the study protocol (and the transplant 
center’s institutional guidelines).
Post-Transplant, Required Observations and Follow-up
Following your transplant you will have regularly scheduled evaluations as part of your 
standard medical care to monitor your health and how well your transplant has replaced your 
bone marrow’s cells. The follow up visits are scheduled as medically necessary; however, the 
study will require visits at least once a week visits until day +100 after your transplant.
From day +100 to one year (day +365) clinic visit will be required at least once per 
month. 
For this study, you will be followed for 2 years after your transplant, after which follow-
up for your disease is encouraged till at least 5 years post-transplant. The follow-up visits will be 
determined by your doctors as medically necessary, but with the additional requirements of 
this study you will have to have the following minimum:

Acute GVHD (graft-versus-host disease) assessments at least once a week until day +100 
and then chronic GVHD assessment at least once per month until 1 year after your 
transplant. 

Immune reconstitution and chimerism studies will be performed. These studies will 
monitor how well your body cells are recovering.  The recommended timing of the labs 
is at Day +30 (±7), Day +60 (±7), Day +100 (±14), Day +180 (±21) and at 1 year (±45) 
post-transplant.

At least three bone marrow aspirate and biopsy tests after your transplant, on days +30, 
+100, and at 1 year, if your disease has not relapsed (progressed) by that time and you 
are able to tolerate the procedure. In addition, a marrow aspirate will also be collected 
whenever a relapse is suspected. Every effort will be made to do these tests when they 
are scheduled as part of your standard care.
Your participation in the study will end after the follow-up period is complete 2 years after your 
transplant.
Drugs for GVHD (graft-versus-host disease) Prevention
GVHD is where the donor stem cells treat the recipient’s body as “foreign” and attack 
cells in the recipient’s body. GVHD is one of the common complications with allogeneic stem 
cell transplant, (where you receive cells from another person). It can affect organ tissues such 
as skin, stomach, intestines, lungs, liver and others.
The following drugs, thymoglobulin, (rATG), Atgam, methotrexate, tacrolimus and 
Leucovorin are permitted under the protocol. Your study doctor may prescribe any combination 
of these drugs to try to prevent GVHD (GVHD prophylaxis), or help reduce its severity if you do 


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develop GVHD. The specific drugs that you receive will depend on both your study doctors’ 
judgment for what is best for you and the transplant center’s standard medical practice 
Drugs for Prevention of Infection
After your transplant, your immune system is severely weakened and slowly improves 
over many weeks or months. There are a number of different drugs available that your study 
doctor may prescribe to try to prevent infections. The specific drugs that you receive will 
depend on both your study doctors’ judgment for what is best for you and your transplant’s 
standard medical practices.
Risks and Discomforts
There is a possibility that Fludarabine may be less effective than other chemotherapy 
regimens in treating your disease. The specific medication used in this study and the known 
side effects which you may experience are listed below:
Fludarabine
Drug-related side effects observed in more than 10% of adult patients treated with 
Fludarabine 
in 
previous 
clinical 
trials 
include 
decreased 
bone 
marrow 
function 
(myelosuppression), fever and chills, infections, nausea and vomiting, pain, weakness, cough, 
pneumonia, (shortness of breath) dyspnea, diarrhea, anorexia, rash, edema. 
Side effects observed in less than 10% of adult patients (general weakness) malaise, 
(oral inflammation) stomatitis, (muscle pain) myalgia, (abnormal sensations) paresthesia, visual 
disturbance, gastrointestinal bleeding, upper respiratory infection, (excessive sweating) 
diaphoresis, (painful urination) dysuria, urinary infection, sinusitis, hearing loss, hyperglycemia, 
headache, (sore throat) pharyngitis, (spitting blood) hemoptysis, (swelling of the esophagus) 
esophagitis, mucositis, (blood in urine) hematuria, osteoporosis, (hair loss) alopecia, (serious 
allergic reaction) anaphylaxis, hemorrhage, dehydration, sleep disorder, depression, (lack of 
coordination) cerebellar syndrome, impaired mentation, allergic pneumonitis, (nose bleeds) 
epistaxis, bronchitis, hypoxia, liver failure, abnormal liver function, (gallstones) cholelithiasis, 
ARDS, respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, respiratory failure, 
constipation, dysphagia, (itching) pruritus, (dandruff) seborrhea, renal failure, abnormal renal 
function test, (protein in urine) proteinuria, hesitancy, angina, congestive heart failure, 
arrhythmia, (rapid heart rate) supraventricular tachycardia, myocardial infarction, deep venous 
thrombosis, (swelling of a vein) phlebitis, transient ischemic attack, aneurysm, (stroke) 
cerebrovascular accident, (joint pain) arthralgia, tumor lysis syndrome. 
Total Body Irradiation
Possible side effects of total body radiation include; loss of appetite, nausea, vomiting, 
diarrhea, (dry mouth) xerostomia, (difficulty in swallowing) dysphagia, headache, (swelling in 
the mouth/throat) stomatitis, altered skin integrity, (hair loss) alopecia, swelling, increased risk 
for infection and/or bleeding, possible lung failure, dry cough, fatigue, anxiety, fever, possible 


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liver failure, lung scarring, loss of vision, shortness of breath, (permanent dilation of small 
vessels causing red lesions) telangiectasia, testicular damage, ovarian damage, premature 
menopause, sterility, heartburn, cystitis, sleep disturbances altered gastrointestinal and 
genitourinary function,  radiation pneumonitis, neuropathy, fistulas, altered endocrine function, 
and increased risk of a second cancer. 
Anti-Graft-Versus-Host Disease Medications
GVHD is due to immune cells (lymphocytes) from the donor attacking the recipient’s 
organs. The acute form of GVHD may cause redness of the skin, nausea, vomiting, diarrhea, 
and/or liver problems. The chronic form of GVHD may cause dryness of the eyes and/or mouth, 
and/or breathing problems. It may cause tightness and/or scarring of the skin, weight loss, 
diarrhea, and/or difficulty swallowing. Either one of the forms of GVHD can range from mild to 
severe to life threatening. Severe GVHD is commonly the cause of death for patients who have 
serious and fatal complications, after their transplant.
During your transplant process you will receive standard of care medications to help 
prevent and/or decrease GVHD. These are listed in the tables below.
Tacrolimus 
Likely
(“Likely” refers to a side 
effect that is expected to 
occur in more than 20% of 
patients.)
Less likely
(“Less likely” refers to a side 
effect that is expected to 
occur in 20% or fewer 
patients.)
Rare, but serious
(These possible risks have 
been reported in rare 
occurrences, typically less 
than 2% of patients. They may 
be serious if they occur.)
Low red blood cell counts
Loss of appetite
Diarrhea
High potassium levels
High blood pressure
Nausea
Fever
Headache
High blood sugar
Hair loss
Vomiting
Tingling sensation in the 
extremities
Itching
Rash
Abdominal pain
Confusion
Painful joints
Increased sensitivity to light
Blurred vision
Insomnia(unable to sleep)
Jaundice (yellowing of skin 
and eyes)
Kidney injury
Seizures
These side effects are usually reversible by reducing the dose or discontinuing the drug.


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Methotrexate
Likely
(“Likely” refers to a side 
effect that is expected to 
occur in more than 20% of 
patients.)
Less likely
(“Less likely” refers to a side 
effect that is expected to 
occur in 20% or fewer 
patients.)
Rare, but serious
(These possible risks have 
been reported in rare 
occurrences, typically less 
than 2% of patients. They 
may be serious if they occur.)
High levels of liver enzymes
Nausea
Vomiting
Loss of appetite
Diarrhea
Mouth sores
Sensitivity to sunlight
Increased risk of sunburns
Decrease number of red and 
white blood cells and 
platelets
Hair loss
Dizziness
Skin redness, tenderness, 
darkening, and peeling 
Blurred vision
Allergic reaction
Damage to nerve tissue
Kidney damage
Seizures
Decreased lung function 
Decreased liver function- 
temporary
Bone and tissue damage
Loss of memory, 
concentration, balance, and 
walking
Thymoglobulin
Likely
(“Likely” refers to a side effect that is expected 
to occur in more than 25% of patients.)
Less likely but serious
(“Less likely” refers to a side effect that is 
expected to occur in 25% or fewer patients.)
Fever 
Chills 
Decreased platelets and white blood cells 
Pain
Headache
Abdominal pain
Diarrhea
High blood pressure
Nausea
Swelling 
Difficulty breathing 
Weakness
High potassium
Rapid heartbeat
Infection
Severe or life threatening allergic 
reaction
Lymphomas (i.e. cancers of the immune 
system)


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Information for Women of Childbearing Potential or Men Capable of Fathering a Child
If you are a female of childbearing age, you must not be pregnant at the time you enter 
the study, or at any time during the study. This study could potentially harm your unborn child. 
You must avoid becoming pregnant during the study. Before you enter the study, the study 
doctor will discuss the most appropriate methods to use to avoid pregnancy. All female subjects 
must commit to using these precautions throughout their participation in the study. If you 
enter the study and then think you might be pregnant you must tell the study doctor right 
away. After your participation in the study is complete, if you plan on becoming pregnant you 
should speak with your study doctor regarding when it is safe to proceed.
For females, if there is ANY chance that you can get pregnant, you must either agree to 
not have vaginal intercourse or you must use at least TWO types of birth control (one from 
each list below or two from the “highly effective” list below) AT THE SAME TIME. You must use 
two types at the same time for medical reasons. You must talk to the doctor before changing 
any birth control pills. You should not breastfeed an infant while on the study.
Highly Effective Methods
Additional Effective Methods
Intrauterine device (IUD)
Tubal ligation (Tubes Tied)
Partner’s vasectomy
Latex condom
Diaphragm
Cervical Cap
For males, all men must use medically acceptable birth control while taking part in the 
study, as the effects on sperm are not known. Male patients should not donate blood, semen or 
sperm during therapy. It is possible you may be a candidate to freeze (cryopreserve) sperm for 
future use. Discuss this option with the doctor. Cryopreservation is not part of this study.
Again, all subjects must commit to using these precautions throughout their 
participation in the study. You should talk to your study doctor so they can advise you, based on 
the program’s clinical practices, when it’s safe for you to make any changes.
Benefits 
You may not receive any personal benefits from being in this study. If you do not benefit 
personally, you participation in this research study will provide the investigators with important 
information to help design safer and more effective treatment for other patients with the same 
types of cancers. 
Alternatives 
If you decide not to participate in the study, you may still be able to undergo allogeneic 
stem cell transplantation, but not as part of this study.


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If you decide not to undergo allogeneic stem cell transplantation, you may choose to 
continue chemotherapy or other non-transplant treatment. Or you may choose to receive 
palliative care (to relieve suffering and improve you quality of life, but not to cure your disease). 
Your doctor will discuss these choices and what other options may be available.
Confidentiality
Any information gathered during this procedure will be kept confidential to the extent 
permitted by law. However, research information that identifies you may be shared with the 
UAB Institutional Review Board (IRB) and others who are responsible for ensuring compliance 
with law and regulations related to research, including people on behalf of UAB Bone Marrow 
Transplantation and Cellular Therapy Program; the U.S. Food and Drug Administration (FDA); 
and the Office for Human Research Protections (OHRP). The information from the research may 
be published for scientific purposes; however, your identity will not be given out.
If any part of this study takes place at the University of Alabama Hospital this consent 
document will be placed in your file at that facility. The document will become part of your 
medical record chart. Your medical record will indicate that you are on a clinical trial and will 
provide the name and contact information for the principal investigator. Information relating to 
this study, including your name, medical record number, date of birth and social security 
number, may be shared with the billing offices of UAB and UAB Health System affiliated entities 
and its billing agents so that the costs for clinical services can be appropriately paid for by either 
the study account or by the patient/patient’s insurance. 
Study records that have your name will be kept private. You will not be identified by 
name in any publications related to this study. Your records will be given a unique code 
number. The key to the code will be kept in a locked file in the Research and Data Management 
offices of the BMTCT program.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by the U.S. Law. This website will not include information that can identify you. At 
most, the website will include a summary of the results. You can search this website at any 
time. 
Voluntary Participation and Withdrawal 
Taking part in this study is completely voluntary. You do not have to participate if you 
don’t want to. You may also leave the study at any time. If you leave the study before it is 
finished, there will be no penalty to you, and you will not lose any benefits to which you are 
otherwise entitled. 
You are free to withdraw from this research study at any time. Your choice to leave the 
study will not affect your relationship with this institution. However, you should return to see 


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the study doctor for safety reasons so you can be taken off the study drugs and referred for 
follow-up care.
You may be removed from the study without your consent if the investigator ends the 
study, if the study doctor decides it is not in the best interest of your health, or if you are not 
following the study rules.
As a rule, the researchers will not continue to use or disclose information about you, but 
will keep it secure until it is destroyed.  Sometimes, it may be necessary for information about 
you to continue to be used or disclosed, even after you have canceled your permission or the 
study is over.
You may withdraw your consent by writing the BMT research Office at UAB BMT 
Research office-West Pavilion Room 392-619 19th Street South – Birmingham, AL 35249-6979.
Cost of Participation
There is no cost to you to participate in this research study. You will be responsible for 
the cost of standard of care treatment for your disease. The charges for your transplant will be 
billed to you and/or your insurance provider in the usual manner. 
If you are in Medicare Advantage (Medicare managed care plan), you should contact 
someone at your plan before you start a clinical trial. They can provide more information about 
additional costs you could incur from participating in clinical trials.
Payment for Participation in Research
You will not receive any payment for taking part in this research study.
Payment for Research-Related Injuries
UAB and the UAB Comprehensive Cancer Center have not provided for any payment if 
you are harmed as a result of taking part in this study. If such harm occurs, treatment will be 
provided. However, this treatment will not be provided free of charge.
Significant New Findings
You will be told by your doctor or study staff if new information becomes available that 
might affect your choice to stay in the study. If new information is provided to you after you 
have joined the study, it is possible that you may be asked to sign a new consent form that 
includes the new information. 


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UAB 1285 – FluTBI
Protocol v.4.0 - Consent dated 09/12/2018
Questions 
If you have any questions, concerns or complaints about the research or a research-
related injury, including available treatments, please contact Dr. Donna  Salzman at (205)934-
1908 or at UAB paging (205)934-3411. 
If you have questions about your rights as a research participant, or concerns or 
complaints about the research, you may contact the Office of the IRB (OIRB) at (205)934-3789 
or 1-855-860-3789. Regular hours for the ORIB are 8:00a.m. to 5:00p.m. CT, Monday through 
Friday. You may also call this number in the event the research staff cannot be reached or you 
wish to talk to someone else. 
Legal Rights
You are not waiving any of your legal rights by signing this informed consent document. 
Signatures 
Your signature below indicates that you agree to participate in this study. You will receive a 
copy of this signed document.
Print Name of Participant
Date
Signature of Participant
Date
Signature of Principal Investigator or Other Person Obtaining Consent                    Date
Signature of Witness                               
Date


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UAB 1285 – FluTBI
Protocol v.4.0 - Consent dated 09/12/2018
University of Alabama at Birmingham
AUTHORIZATION FOR USE/DISCLOSURE OF
PROTECTED HEALTH INFORMATION (PHI) FOR RESEARCH
Participant Name:  
UAB IRB Protocol Number: IRB-130515007 
Principal Investigator:  Donna Salzman M.D.
Research Protocol: Single Arm Phase II Study of 
Myeloablative 
Allogeneic 
Hematopoietic 
Stem 
Cell 
Transplantation for Acute Lymphoblastic Leukemia (ALL) 
in Older Patients Using Fludarabine and Total Body 
Irradiation (FluTBI) Regimen  
Sponsor:  UAB Comprehensive Cancer Center
What is the purpose of this form?  You are being asked to sign this form so that UAB may use and release your protected 
health information for research.  Participation in research is voluntary.  If you choose to participate in the research, you must 
sign this form so that your protected health information may be used for the research.
Why do the researchers want my protected health information?  The researchers want to use your protected health 
information as part of the research protocol listed above and as described to you in the informed consent.
What protected health information do the researchers want to use?  All medical information, including but not limited to 
information and/or records of any diagnosis or treatment of disease or condition, which may include sexually transmitted 
diseases (e.g., HIV, etc.) or communicable diseases, drug/alcohol dependency, etc.; all personal identifiers, including but not 
limited to your name, social security number, medical record number, date of birth, dates of service, etc.; any past, present, 
and future history, examinations, laboratory results, imaging studies and reports and treatments of whatever kind, including 
but not limited to drug/alcohol treatment, psychiatric/psychological treatment; financial/billing information, including but not 
limited to copies of your medical bills,  and any other information related to or collected for use in the research protocol, 
regardless of whether the information was collected for research or non-research (e.g., treatment) purposes.
Who will disclose, use and/or receive my protected health information?  All Individuals/entities listed in the informed consent 
documents, including but not limited to, the physicians, nurses and staff and others performing services related to the research 
(whether at UAB or elsewhere); other operating units of UAB, HSF, UAB Highlands, Children’s of Alabama, Eye Foundation 
Hospital, and the Jefferson County Department of Health, as necessary for their operations; the IRB and its staff; the sponsor of 
the research and its employees and agents, including any CRO; and any outside regulatory agencies, such as the Food and Drug 
Administration, providing oversight or performing other legal and/or regulatory functions for which access to participant 
information is required.
How will my protected health information be protected once it is given to others?  Your protected health information that is 
given to the study sponsor will remain private to the extent possible, even though the study sponsor is not required to follow 
the federal privacy laws. However, once your information is given to other organizations that are not required to follow federal 
privacy laws, we cannot assure that the information will remain protected.
How long will this Authorization last?  Your authorization for the uses and disclosures described in this Authorization does not 
have an expiration date.
Can I cancel this Authorization?  You may cancel this Authorization at any time by notifying the Principal Investigator, in 
writing, referencing the research protocol and IRB Protocol Number. If you cancel this Authorization, the study doctor and staff 
will not use any new health information for research. However, researchers may continue to use the protected health 
information that was provided before you cancelled your authorization.
Can I see my protected health information?  You have a right to request to see your protected health information. However, to 
ensure the scientific integrity of the research, you will not be able to review the research information until after the research 
protocol has been completed.
Signature of participant: 
Date: 
or participant's legally authorized representative: 
Date: 
Printed Name of participant’s representative: 
________
Relationship to the participant: