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
Phase: PHASE2
Conditions: Adult Lymphoblastic Lymphoma
Sponsor: University of Alabama at Birmingham

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 
 
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25. Alousi A, de Lima M. Reduced-intensity conditioning allogeneic hematopoietic stem cell 
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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.