Clinical trial NCT02065154
Conditions: Leukemia Lymphoma Myelodysplastic Syndrome Myelofibrosis Severe Aplastic Anemia Allogeneic Transplant
Keywords: acute myeloid leukemia AML acute lymphoblastic leukemia ALL chronic myeloid leukemia CML chronic lymphocytic leukemia CLL non-Hodgkin lymphoma NHL Hodgkin lymphoma HL myelodysplastic syndrome MDS myelofibrosis severe aplastic anemia
Sponsor: University of Alabama at Birmingham
Start date: 2013-08-27; Completion date: 2022-04-01
Enrollment: 39 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to assess the effects of cyclophosphamide (cytoxan) in the post transplant setting to prevent onset of acute graft-versus-host disease (GVHD). The primary objective is to determine the incidence of grade II-IV acute GVHD following Allogeneic (allo) Hematopoeitic Cell Transplant (HCT) using post-transplant cyclophosphamide (cytoxan) for patients with human leukocyte antigen (HLA) matched unrelated (MUD) and mismatched unrelated (MMUD) donors. Other objectives for this study will be the determination of disease-free survival (DFS) and overall survival (OS) following allo HCT and assess the safety of post-transplant cyclophosphamide (cytoxan) for MUD and MMUD transplantation. Disease recurrence and time to recurrence in patients receiving post-transplant cyclophosphamide compared to historical control without post-transplant cyclophosphamide (cytoxan) will also be evaluated. Other objectives will be to determine the time of onset, severity, responsiveness to treatment, organs involved of acute and chronic GVHD as well as observation of Immune Reconstitution over time.

Detailed description:
he main purpose of this study is to assess the effects of cyclophosphamide (cytoxan) in the post transplant setting to prevent onset of acute graft-versus-host disease (GVHD). The primary objective is to determine the incidence of grade II-IV acute GVHD following Allogeneic (allo) Hematopoeitic Cell Transplant (HCT) using post-transplant cyclophosphamide (cytoxan) for patients with human leukocyte antigen (HLA) matched unrelated (MUD) and mismatched unrelated (MMUD) donors. Other objectives for this study will be the determination of disease-free survival (DFS) and overall survival (OS) following allo HCT and assess the safety of post-transplant cyclophosphamide (cytoxan) for MUD and MMUD transplantation. Disease recurrence and time to recurrence in patients receiving post-transplant cyclophosphamide compared to historical control without post-transplant cyclophosphamide (cytoxan) will also be evaluated. Other objectives will be to determine the time of onset, severity, responsiveness to treatment, organs involved of acute and chronic GVHD as well as observation of Immune Reconstitution over time.

Arms: arm 1: Cyclophosphamide (Cytoxan)
Interventions: intervention 1: Cyclophosphamide
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Phase II Clinical Trial of the Use of Post-Transplant 
Cyclophosphamide for Graft Versus Host Disease 
(GvHD) Prophylaxis Following Matched Unrelated 
Donor (MUD) 
Hematopoietic Stem Cell Transplant (HSCT) 
PI: OMER JAMY, MD 
NCT 02065154 
November 22, 2017


UAB BMTCT Program 
UAB 1286 – Post Transplant CTX Version  
Protocol Version 1.6 dated 11/22/2017 
 
 
 
 
 
Phase II Clinical Trial of the Use of Post-Transplant 
Cyclophosphamide for Graft Versus Host Disease (GvHD) 
Prophylaxis Following Matched Unrelated Donor (MUD)  
Hematopoietic Stem Cell Transplant (HSCT) 
 
Bone Marrow Transplantation and Cellular Therapy Program 
University of Alabama at Birmingham 
Protocol Version 1.6 dated 11/22/2017 
                                                   Protocol Version 1.5 dated 09/21/2017 
                                                   Protocol Version 1.4 dated 08/23/2017 
Protocol Version 1.3 dated 01/21/2015 
Previous Version 1.2 dated 05/16/2014 
Protocol Version 1.1 dated 2/20/2013 
Previous Version 1.0 dated 11/7/2012 
 
 
 
 
 
 
 
Principal Investigator 
Racquel Innis-Shelton, M.D. 
Co-investigators 
Ravi Bhatia, M.D. 
Ayman Saad, MD 
Donna Salzman, M.D. 
Antonio Di Stasi, M.D. 
Luciano Costa, M.D. 
Ruby F. Meredith, MD, Ph.D. 
Lawrence Lamb, Ph.D. 
. 
Protocol Writing Committee 
Shin Mineishi, M.D. 
Racquel Innis-Shelton, M.D. 
Ayman Saad, M.D. 
Melissa N. Gazi, MPH 
Lisa D. Williams, RN 
Protocol Statistician  
Sejong Bae, Ph.D. 


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Table of Contents 
1 BACKGROUND ..........................................................................................................................1 
1.1 Allogeneic Stem Cell Transplantation in Hematologic Malignancies ....................................1 
1.2 Post-Transplant Cytoxan as a GVHD Prophylaxis for Haploidentical Transplant .................2 
1.3 Post-Transplant Cytoxan as a GVHD Prophylaxis for Matched Transplant ..........................2 
2 OBJECTIVES AND ENDPOINTS ..............................................................................................2 
2.1 Primary Objective ...................................................................................................................2 
2.2 Secondary Objectives ..............................................................................................................2 
2.3 Primary Endpoint ....................................................................................................................3 
2.4 Secondary Endpoints ..............................................................................................................3 
3 PATIENTS ELIGIBILITY CRITERIA .......................................................................................3 
3.1 Inclusion Criteria ....................................................................................................................3 
3.2 Exclusion Criteria ...................................................................................................................4 
4 STUDY TREATMENT ................................................................................................................5 
4.1 Preparative Regimens .............................................................................................................5 
4.2 Study Treatment Schedule for Myeloid Diseases ...................................................................6 
4.3 Study Treatment Schedule for ALL or high-risk NHL patients ≤ 40 years old ......................6 
4.4 Study Treatment Schedule for ALL or high-risk NHL patients ≥ 40 years old ......................7 
4.5 Study Treatment Schedule for Lymphoma patients ................................................................7 
5 MEDICATIONS ...........................................................................................................................7 
5.1 Cyclophosphamide ..................................................................................................................7 
5.2 Fludarabine .............................................................................................................................8 
5.3 Busulfan ..................................................................................................................................8 
5.4 Anti-Seizure prophylaxis ........................................................................................................8 
5.5 GVHD prophylaxis .................................................................................................................9 
5.5.1 Cyclophosphamide ......................................................................................................9 
5.5.2 Mycophenolate Mofetil ...............................................................................................9 
5.5.3 Tacrolimus ..................................................................................................................9 
5.6 Filgrastim ................................................................................................................................9 
5.7 Infection Prophylaxis ..............................................................................................................9 
5.7.1 Recommended fungal prophylaxis ............................................................................10 
5.7.2 HSV / VZV Prophylaxis .............................................................................................10 
5.7.3 CMV (Cytomegalovirus) preemptive therapy ...........................................................10 
5.7.4 PCP (Pneumocystic pneumonia) prophylaxis...........................................................10 
5.7.5 PCR testing ...............................................................................................................10 
6 DRUG INFORMATION ............................................................................................................10 
6.1 Cyclophosphamide (Cytoxan) ..............................................................................................10 
6.2 Fludarabine (Fludara) ............................................................................................................11 
6.3 Busulfan (Busulfex) ..............................................................................................................13 
6.4 Tacrolimus (Prograf) .............................................................................................................14 
6.5 Mycophenolate Mofetil (MMF, Cellcept) ............................................................................17 
6.6 Filgrastim (Neupogen) ..........................................................................................................19 


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6.7 Total Body Irradiation (TBI) ................................................................................................20 
7 ALLOGENEIC STEM CELL INFUSION ..................................................................................21 
7.1 Stem Cell Source...................................................................................................................21 
7.2 PBSC Mobilization and Collection .......................................................................................22 
7.3 Stem Cell Dosing ..................................................................................................................22 
8 REQUIRED OBSERVATIONS ..................................................................................................22 
8.1 Pre-Transplant Observations (within 35 days prior to study registration / day of final 
transplant evaluation).  .................................................................................................................  22 
8.2 Post-Transplant Required Observations and Follow-up Plan ...............................................22 
8.3 Assessment of GVHD ...........................................................................................................23 
9 STATISTICAL CONSIDERATIONS .........................................................................................23 
9.1 Sample Size ...........................................................................................................................23 
9.2 Analysis Methods..................................................................................................................24 
10 ADVERSE EVENT REPORTING ..............................................................................................24 
10.1 Definitions of Adverse Events with Commercially Available Agents .................................24 
10.2 Required Adverse Events Reporting .....................................................................................25 
10.3 Hematologic Toxicity and Definition of Primary Engraftment Failure ................................25 
10.4 Serious Adverse Event Reporting Procedures ......................................................................26 
11 DATA SAFETY AND MONITORING PROCEDURES ...........................................................26 
11.1 Data and Safety Monitoring Procedures ...............................................................................26 
11.2 Quality Assurance and Audits...............................................................................................27 
REFERENCES .................................................................................................................................29 
Appendix A: Performance Scores .....................................................................................................33 
Appendix B: Study Calendars ...........................................................................................................34 
Appendix C: Grading of Acute Graft versus Host Disease ..............................................................42 
Appendix D: Grading of Chronic Graft versus Host Disease ...........................................................43 


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1 
BACKGROUND 
 
1.1 
Allogeneic Stem Cell Transplantation in Hematologic Malignancies 
Allogeneic hematopoietic stem cell transplantation (allo HCT) has become widely used as a 
possible curative option for many hematologic malignancies.1, 2 Although the HLA matching 
techniques have improved significantly over the last several years, including DNA typing, the 
incidence of graft versus host disease (GVHD) of unrelated donor (MUD) transplant, particularly, 
mismatched unrelated donor (MMUD) transplant is still higher then matched related donor 
transplant.3-5  The high incidence of GVHD is associated with lower survival.4    Efforts have been 
made to improve the result of MUD and MMUD transplantation; however, none of these efforts 
have been very successful. 
 
Anti-thymocyte globulin (ATG) has been used for many years for prevention of GVHD6, 7, but a 
systematic review showed it is not associated with significant reduction in  non-relapse mortality.8 
The benefit of reduced incidence of GVHD is unfortunately offset by increased risk of infections9 
and increased risk of non-relapse mortality (NRM). Thus the use of ATG for GVHD 
prophylaxis has become controversial.10 The main prophylactic regimens for prevention of GVHD 
after allo HCT are based on pharmacologic agents such as calcineurin inhibitors and 
methotrexate.11 These agents have narrow therapeutic window and are often associated with 
adverse effects such as severe mucositis with methotrexate and renal impairment with 
calcineurin inhibitors.11 
 
Alemtuzumab (Campath-1H) has also been introduced for GVHD treatment12 and prophylaxis13, 
14, but because of its significant immune suppression, the patient becomes more susceptible to 
infections. Also, because of the significant T-cell suppression effect which may continue for 
months after the stem  cell  transplant,  the  patients  may  gradually  lose  the  donor   chimeric 
component which may predispose them to relapse. Thus, the use alemtuzumab for GVHD 
prophylaxis has become controversial15. 
For these reasons, the optimal regimen for prevention of GVHD in MUD and MMUD 
transplantation has yet to be identified. 


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1.2 
Post-Transplant Cytoxan as a GVHD Prophylaxis for Haploidentical Transplant 
Haploidentical HCT has traditionally been done as a T-cell depleted transplant to avoid the high 
risk of GVHD by the alloreactive donor T-cells.16-18 However, risk of engraftment failure and 
poor immune reconstitution remained barriers for significant survival improvement.18 
Johns Hopkins group has used post-transplant Cyclophosphamide (Cytoxan) with T-cell replete 
haploidentical HCT to prevent GVHD.19, 20 They developed this method based on animal 
experiments. Post-transplant Cytoxan was shown to be effective in preventing GVHD in 
haploidentical HCT. These favorable data has been reproduced.21, 22 The benefit of post- transplant 
Cytoxan has also been shown with the use of non-myeloablative regimens with haploidentical 
HCT.20, 23 
 
1.3 
Post-Transplant Cytoxan as a GVHD Prophylaxis for Matched Transplant 
Post-transplant Cytoxan (after myeloablative By/Cy preparative regimen) has also been tested 
before as a sole GVHD prophylaxis regimen after T-cell replete allogeneic bone marrow transplant  
(not PBSC)  with matched related  and  MUD.24  The 100-day and 2-year  non-relapse 
mortality (NRM) in this study were 9% and 17% respectively.24 
 
We hypothesize that post-transplant Cytoxan at a lower dose (than that used in haploidentical 
HCT) is effective in preventing GVHD in the setting of MUD and MMUD after myeloablative 
transplant. Because the HLA disparity in these 2 settings is not as much as in haploidentical 
transplant, we will use the post-transplant Cytoxan, 50 mg/kg for one dose, instead of the two 
doses in the original haploidentical transplant regimens. 
 
2 
OBJECTIVES AND ENDPOINTS 
 
2.1 
Primary Objective 
The primary objective is to determine the incidence of grade II-IV acute GVHD following allo 
HCT using post-transplant cyclophosphamide for patients with human leukocyte antigen (HLA) 
matched unrelated (MUD) donors. 
 
2.2 
Secondary Objectives 
 To determine disease-free survival (DFS) and overall survival (OS) following allo 
HCT using post-transplant cyclophosphamide for patients with HLA matched 
unrelated (MUD) donors. 


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 To assess the safety of post-transplant cyclophosphamide for MUD transplantation. 
 To evaluate disease recurrence and time to recurrence in patients receiving post- 
transplant cyclophosphamide compared to historical control without post-transplant 
cyclophosphamide. 
 To determine the time of onset, severity, responsiveness to treatment, organs involved 
of acute and chronic GVHD. 
 Observation of Immune Reconstitution over time. 
 
2.3 
Primary Endpoint 
The primary study endpoint is grade II-IV acute GVHD. 
 
2.4 
Secondary Endpoints 
 
OS at one-year post-transplant. 
 
 
DFS at one-year post-transplant. 
 
 
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 support for 7 days. 
 
 
Relapse rate at 2 years post-transplant. 
 
3 
PATIENTS ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
1) Disease Criteria: patients must meet diagnostic criteria of acute myeloid leukemia 
(AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), 
chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), Hodgkin 
lymphoma (HL), myelodysplastic syndrome (MDS), myelofibrosis, or severe aplastic 
anemia. Patients will be allowed on study if they are deemed eligible for allo HCT 
regardless of remission status. 
 
2) Age Criteria: 19 to 65 years in age. 
 
3) Organ Function Criteria: All organ function testing should be done within 28 days of 
study registration. 


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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 (diffusing capacity of the lung 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: 
o Serum bilirubin 1.5 upper limit of normal (ULN) 
o Aspartate transaminase (AST)/alanine transaminase (ALT) 2.5 ULN 
o Alkaline phosphatase 2.5 ULN 
 
8) Performance status: Karnofsky ≥ 70%., 
 
9) 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. 
 
10) Patient has a suitable and willing HLA-8/8 matched unrelated donor identified. 
 
3.2 
Exclusion Criteria 
1) Patient is NOT a candidate for myeloablative regimen. 
2) Non-compliant to medications. 
3) No appropriate caregivers identified. 
4) HIV1 (Human Immunodeficiency Virus-1) or HIV2 positive 
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) Pregnancy or Breastfeeding. 
10) Prior autologous or allogeneic stem cell transplant. 


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4 
STUDY TREATMENT 
We are going to use this method for various diagnoses so this GVHD prophylaxis regimen will 
be included in the following preparative regimens. 
 
4.1 
Preparative Regimens 
 
1) Fludarabine / Busulfan regimen is a modified Fludarabine plus Busulfan preparative 
regimen that will be used for myeloid malignancy and severe aplastic anemia. In the 
myeloablative regimen of fludarabine plus busulfan, the target AUC (area under the 
concentration curve) of busulfan is typically 20 - 24,000 μM⋅min. Since we are   adding 
post-transplant cytoxan to this regimen, we will use a busulfan target AUC of 20,000. 
Patients will receive MESNA and hydration for prophylaxis of hemorrhagic cystitis per 
standard practice. Seizure prophylaxis will be administered per standard practice while 
on busulfan. 
 
2) Total body irradiation (TBI) / Cytoxan regimen will be used for ALL or aggressive 
NHL or HL in young patients (patients </= 40 years old) with no major comorbidities. 
The standard myeloablative regimen for those patients is TBI 1,200 cGy and Cytoxan 
60 mg/kg x 2 days. In our study, TBI dose will be the same, but the 2 doses of pre- 
transplant Cytoxan will be 35 mg/kg, in addition to post-transplant Cytoxan of 50 
mg/kg on Day +3. Thus the total dose of Cytoxan is unchanged in this regimen. Patient 
will receive MESNA and hydration for prophylaxis of hemorrhagic cystitis per standard 
practice. 
 
3) TBI / Fludarabine regimen will be used for ALL or aggressive NHL or HL in patients 
who are older than 40 years or at any age with major comorbidities that portends high 
NRM with fully myeloablative Cy/TBI. These patients will receive Fludarabine 40 
mg/m2 x 4 doses plus TBI 1,000 cGy instead of usual 1,200 cGy. Post-transplant Cytoxan 
of 50 mg/kg on Day +3 will be given. Patient will receive MESNA and 
hydration for prophylaxis of hemorrhagic cystitis per the transplant physician’s clinical 
practice standard. 


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4) Fludarabine/Melphalan regimen may be used for NHL or HL patients. These patients 
will receive Fludarabine 40 mg/m2 x 4 doses plus melphalan 140 mg/m2 x one dose. 
Post-transplant Cytoxan of 50 mg/kg on Day +3 will be given. Patient will receive 
MESNA and hydration for prophylaxis of hemorrhagic cystitis per the transplant 
physicians clinical practice standard. 
 
 
4.2 
Study Treatment Schedule for Myeloid Diseases 
Flu/Bu - Preparative Regimen #1 
 
Day -6 (+/- 2 days) Admit to Hospital  
Day -5 (+/- 2 days) Busalfan 3.2mg/kg and Fludarabine 40 mg/m2 IV 
Day -4 (+/- 2 days) Busulfan- 3.2mg/kg, Fludarabine 40 mg/m2 
IV Day -3(+/- 2 days) Busulfan PK directed dosing IV, Fludarabine 40 mg/m2  
IV Day -2 (+/- 2 days) Busulfan PK directed dosing IV, Fludarabine 40 mg/m2 
Day -1 (+/- 2 days) Rest Day(s) 
Day 0 Transplant 
Day +3 Cyclophosphamide 50mg/kg IV 
 
 
 
4.3 
Study Treatment Schedule for ALL or high-risk NHL patients ≤ 40 years old 
TBI / Cy – Preparative Regimen #2 
Day -6 (+/- 2 days) TBI 200cGy/ fraction (2 fractions) 
Day -5 (+/- 2 days) TBI 200cGy/ fraction (2 fractions) 
Day -4 (+/- 2 days) TBI 200cGy/Fraction (2 fractions) 
Day -3 (+/- 2 days) Cyclophosphamide 35 mg/kg IV 
Day -2 (+/- 2 days) Cyclophosphamide 35 mg/kg IV 
Day -1 (+/- 2 days) Rest day(s) 
Day 0    Transplant 
Day +3 Cyclophosphamide 50mg/kg IV 


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4.4 
Study Treatment Schedule for ALL or high-risk NHL patients ≥ 40 years old 
Flu / TBI – Preparative Regimen #3 
 
Day -7 (+/- 2 days) 
Fludarabine 40 mg/m2 IV 
Day -6 (+/- 2 days) 
Fludarabine 40 mg/m2 IV 
Day -5 (+/- 2 days) Fludarabine 40 mg/m2 IV 
Day -4 (+/- 2 days) 
Fludarabine 40 mg/m2 IV 
Day -3 (+/- 2 days) TBI 200cGy/fraction (2 fractions) 
Day -2 (+/- 2 days) TBI 200cGy/fraction (2 fractions) 
Day -1 (+/- 2 days) TBI 200cGy/fraction (1 fraction) 
Day 0 
Transplant 
Day +3 Cyclophosphamide 50mg/kg IV 
 
4.5 
Study Treatment Schedule for Lymphoma patients 
Flu/Mel – Preparative Regimen #4 
Day -5 (+/- 2 days) 
Fludarabine 40 mg/m2 IV 
Day -4 (+/- 2 days) 
Fludarabine 40 mg/m2 IV 
Day -3 (+/- 2 days)   Fludarabine 40 mg/m2 IV 
Day -2 (+/- 2 days) 
Fludarabine 40 mg/m2 IV 
Day -1 (+/- 2 days) 
Melphalan 140 mg/m2 IV 
Day 0 
Transplant 
Day +3 Cyclophosphamide 50mg/kg IV 
Rituximab may be added to this regimen (at the physician’s discretion) on days -6, +1, and/or +8 
for lymphoma not in CR at the time of transplant. 
 
 
5 
MEDICATIONS 
 
5.1 
Cyclophosphamide 
Cyclophosphamide (35mg/kg) IV will be administered in preparative regimen #2 as noted 
above. 
 
Cyclophosphamide (50mg/kg) IV will be administered at day +3 as GVHD prophylaxis in 
all 3 treatment plans. 
 
Cyclophosphamide will be infused over 2 hours. 


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Cyclophosphamide will be dosed based on actual body weight unless patient is greater than 
40% above IBW in which case we will use adjusted body weight. 
 
Ideal Body Weight is calculated as follows: 
Males: IBW= 50 + {[(Ht in cm x 0.39) – 60] x 2.3} 
Females: IBW= 45.5 + {[(Ht in cm x 0.39) – 60] x 2.3} 
Adjusted ideal body weight is calculated as follows: 
Ideal Weight + (Actual Weight-Ideal Weight) x 0.4 
 
If actual weight is lower than ideal weight, we will use actual weight. 
 
Mesna will be administered as an adjuvant for cyclophosphamide metabolites. Dosing will 
follow standard practice. 
 
5.2 
Fludarabine 
Fludarabine (40 mg/m2/day) IV will be administered in preparative regimens #1 and #3 as 
noted above. 
 
Fludarabine will be dosed based on actual body weight unless patient is greater than 40% 
above IBW in which case we will use adjusted body weight calculated as noted above. 
 
Fludarabine will be given by 1hour IV infusion. 
 
 
5.3 
Busulfan 
Busulfan IV will be administered in preparative regimen #1 as noted above. 
 
Busulfan IV will start at approximately 9 am and be given over 3 hours via IV infusion. 
 
Busulfan pharmacokinetics (PK) study will be done on day 5 (test dose) 
Busulfan PK will be adjusted to target AUC of 20,000 μM⋅min. 
 
5.4 
Melphalan 
Melphalan IV will be administered in preparative regimen #4 as noted above. 
Melphalan IV will be infused over 30 to 40 minutes. 
Melphalan will be dosed on actual BSA unless actual weight is greater than adjusted IBW. 
If actual weight is greater than adjusted IBW then melphalan will be dosed using adjusted 
IBW. 


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5.5 
Anti-Seizure prophylaxis 
Anti-seizure prophylaxis will be administered as per standard practice. 
 
5.6 
GVHD prophylaxis 
GVHD prophylaxis consists of post-transplant cyclophosphamide, mycophenolate mofetil 
(MMF), and tacrolimus. Patients will not receive immunosuppressive therapy between days 0 
and +5 for concern of mitigating the immunosuppressive effect of post-transplant Cytoxan, 
which is administered on Day +3, unless determined by treating physician that there is a need 
based on clinical status. 
 
5.6.1 Cyclophosphamide 
Cytoxan will be administered on Day +3 at 50mg/kg IV over 2 hours single dose. 
 
5.6.2 Mycophenolate Mofetil 
MMF will be administered starting day +5. Dosing will start at 15 mg/kg Q8h IV with a 
maximum dose of 1g Q8h IV, then change to PO when patient can tolerate PO intake. 
MMF will be continued till day +35 unless there is active GVHD. 
 
5.6.3 Tacrolimus 
Tacrolimus will be administered starting on day +5. Dosing will follow therapeutic 
standards for GVHD prophylaxis. Tacrolimus will be continued till day +100 with taper 
starting on +100 unless there is active GVHD. 
 
 
5.7 
Filgrastim 
Filgrastim (G-CSF) will be administered beginning Day +5 at approximately 5 mcg/kg rounding 
to the nearest vial size according to the ranges listed below. Treatment will continue until 
engraftment. 
 
Weight Range 
G-CSF dose 
Up to 60kg 
Use 300mcg Vial 
61 kg to 96 kg 
Use 480mcg Vial 
97 kg to 120 kg 
Use two 300mcg vials 
121 kg to 156 kg 
Use one 300 mcg vial and one 480 mcg vial 
157 kg to 192 kg 
Use two 480 mcg vials 
 
5.8 
Infection Prophylaxis 
Antibacterial, antiviral and antifungal coverage during neutropenia until engraftment will be at 
the discretion of the transplant physician’s clinical practice standards. 


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The following is a suggested prophylaxis regimen: 
 
5.8.1 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). 
 
5.8.2 HSV / VZV Prophylaxis 
Herpes simplex virus / Herpes zoster virus (HSV/VZV) infection prophylaxis will be 
done using Acyclovir or valganciclovir daily until day +365 post-transplant. 
 
5.8.3 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. 
 
5.8.4 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. 
 
5.8.5 PCR testing 
PCR testing for HHV6 and Adenovirus will be sent weekly (+/- 3 days) starting 
approximately Day +20 and continue until day 100. 
PCR testing for EBV will be sent every 2 weeks (+/- 3 days) starting approximately Day 
+20 until day 100. 
 
6 
DRUG INFORMATION 
 
6.1 
Cyclophosphamide (Cytoxan) 
Chemical Characteristics 
Cyclophosphamide monohydrate (cyclophosphamide) is a synthetic antineoplastic drug 
chemically recognized as 2-[bis(2-cholorethyl) amino] tetrahydro-2H-1,3,2-oxazaphosphorine 2- 
oxide monohydrate. The molecular formula of cyclophosphamide is C7H15Cl2N2O2P·H2O with a 
molecular weight of 279.1. 


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Available Forms 
IV cyclophosphamide is available as a sterile white crystalline powder. Cyclophosphamide is 
stored in a single dose vial with 500mg of the powder. 
 
Storage and Handling 
Unopened vials should be stored at or below 25°C (77°F). 
 
 
Toxicity 
Common side effects of cyclophosphamide include: nausea, vomiting, alopecia, leucopenia, 
interstitial pneumonitis, interstitial pulmonary fibrosis, anaphylactic reactions, amenorrhea, 
hemorrhagic cystitis, oligospermia or azoospermia and suppression of immune responses. Less 
common side effects include: secondary malignancies in patients diagnosed with a primary 
malignancy, fetal harm when administered to pregnant women, acute cardiac toxicity, congestive 
heart failure, hemorrhagic myocarditis, hemopericardium and possible cross sensitivity with 
other alkylating agents. 
 
Administration 
Cyclophosphamide for parenteral use must be prepared by either adding 0.9% sodium chloride 
solution, if injected directly, or sterile water, if infused. Constituted in water, cyclophosphamide 
is hypotonic hence should not be injected directly. Solutions of cyclophosphamide with sodium 
chloride solution may be injected, intravenously, intramuscularly, intraperitoneally, or 
intrapleurally. 
Constituted cylophosphamide is physically and chemically stable for 24 hours at room temperature 
or six days refrigerated. Prepared solutions do not contain any microbial preservative; hence 
sterility of the solutions should be monitored. 
 
6.2 
Fludarabine (Fludara) 
Chemical Characteristics 
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. 


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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. 
 
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). 
 
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 tachycardia, myocardial infarction, deep venous thrombosis, 
phlebitis, transient ischemic attack, aneurysm, cerebrovascular accident, arthralgia, tumor lysis 
syndrome. 
 
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. 


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Reconstituted IV fludarabine contains no antimicrobial preservative hence should be utilized 
within 8 hours of reconstitution. DO NOT infuse concomitantly with another intravenous solution 
of unknown compatibility. 
 
6.3 
Busulfan (Busulfex) 
Chemical Characteristics 
Busulfan is a bifunctional alkylating agent known chemically as 
1,4-butanediol, 
dimethanesulfonate with a molecular formula of CH3SO2O(CH2)4OSO2CH3 and a molecular 
weight of 246 g/mole. 
 
Available Forms 
IV busulfan (Busulfex) is supplied as a clear, colorless, sterile solution in 10-mL single-use glass 
vials each containing 60 mg of busulfan at a concentration of 6 mg/mL for intravenous use. 
IV busulfan is packaged in a tray pack of 8 vials. 
 
 
Storage and Handling 
Unopened vials of Busulfex must be stored under refrigerated conditions between 2°-8°C (36°- 
46°F). 
 
Toxicity 
Toxicities reported as more than 10% incidence are: 
Tachycardia, hypertension, edema, thrombosis, chest pain, vasodilation, hypotension, 
insomnia, fever, anxiety, headache, chills, pain, dizziness, depression, confusion, rash, pruritus, 
alopecia, hypomagnesemia, hyperglycemia, hypokalemia, hypocalcemia, hypophosphatemia, 
nausea, mucositis/stomatitis, vomiting, anorexia, diarrhea, abdominal pain, 
dyspepsia, 
constipation, xerostomia, rectal disorder, abdominal fullness, myelosuppression, neutropenia, 
thrombocytopenia, lymphopenia, anemia, hyperbilirubinemia, ALT increase, veno-occlusive 
disease, jaundice, injection site inflammation, injection site pain, weakness, back pain, myalgia, 
arthralgia, creatinine increased, oliguria, rhinitis, lung disorder, cough, epistaxis, dyspnea, 
pneumonia, hiccup, pharyngitis, infection, allergic reaction. 


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Toxicities with expected incidences are 1% to 10% are: 
Arrhythmia, cardiomegaly, atrial fibrillation, ECG abnormality, heart block, heart failure, 
pericardial effusion, tamponade, ventricular extrasystoles, hypervolemia, lethargy, hallucinations, 
agitation, delirium, encephalopathy, seizure, somnolence, cerebral hemorrhage, vesicular rash, 
vesiculobullous rash, skin discoloration, maculopapular rash, acne, exfoliative dermatitis, 
erythema nodosum, hyponatremia, ileus, weight gain, hematemesis, pancreatitis, prothrombin 
time increase, hepatomegaly, hematuria, dysuria, hemorrhagic cystitis, BUN increase, asthma, 
alveolar hemorrhage, hyperventilation, hemoptysis, pleural effusion, sinusitis, atelectasis, 
hypoxia. 
Administration 
IV busulfan must be diluted prior to use with either NS or D5W. The diluent quantity should be 
10 times the volume of Busulfex, so that the final concentration of busulfan is approximately 0.5 
mg/mL. 
Infusion pumps should be used to administer the diluted busulfan solution. DO NOT infuse 
concomitantly with another intravenous solution of unknown compatibility. Warning: Rapid 
infusion of IV busulfan has not been tested and is not recommended. 
 
Follow the institutional guidelines for more detailed preparation and administration procedures 
of busulfan. 
 
6.4 
Melphalan 
Chemical Characteristics 
Melphalan is a phenylalanine derivative of nitrogen mustard. Melphalan is a bi-functional 
alkylating agent that is active against selected human neoplastic diseases. It is known chemically 
as 4-[bis(2-chloroethyl)amino]-L -phenylalanine. The molecular formula is C13 H18 Cl2 N2 O2. 
Available Forms 
Melphalan for Injection is supplied in a carton containing one single-use clear glass vial of 
freeze-dried melphalan hydrochloride equivalent to 50 mg melphalan and one 10-mL clear glass 
vial of sterile diluent (NDC 0173-0130-93). 


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Storage and Handling 
Store at controlled room temperature 15° to 30°C (59° to 86°F) and protect from light. Procedures 
for proper handling and disposal of anticancer drugs should be considered. 
 
Toxicity 
The most common side effect is bone marrow suppression leading to leukopenia, 
thrombocytopenia, and anemia. Gastrointestinal disturbances such as nausea and vomiting, 
diarrhea, and oral ulceration occur infrequently. Hepatic disorders ranging from abnormal liver 
function tests to clinical manifestations such as hepatitis and jaundice have been reported. Hepatic 
veno-occlusive disease has been reported. 
 
Other reported adverse reactions include skin hypersensitivity, skin ulceration at injection site, 
skin necrosis rarely requiring skin grafting, maculopapular rashes, vasculitis, alopecia, hemolytic 
anemia, allergic reaction, pulmonary fibrosis (including fatal outcomes), and interstitial 
pneumonitis. Temporary significant elevation of the blood urea has been seen in the early stages 
of therapy in patients with renal damage. Subjective and transient sensation of warmth and/or 
tingling. 
 
Administration 
Parenteral drug products should be visually inspected for particulate matter and discoloration prior 
to administration whenever solution and container permit. If either occurs product should not be 
used. Care should be taken to avoid possible extravasation of melphalan and in cases of poor 
peripheral venous access, consideration should be given to use of a central venous line. 
 
Melphalan for injection must be reconstituted by injecting 10 mL of the supplied diluent directly 
into the vial of lyophilized powder. This provides a 5-mg/mL solution of melphalan. 
Dose to be administered in diluted in 0.9% Sodium Chloride Injection, USP, to a concentration 
not greater than 0.45 mg/mL.  Administer the diluted product over a minimum of 15 minutes. 


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6.5 
Tacrolimus (Prograf) 
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). 
 
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. 
 
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). 
 
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. 
 
Administration 
Tacrolimus (Prograf 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. 
 
6.6 
Mycophenolate Mofetil (MMF, Cellcept) 
Chemical Characteristics 
CellCept (mycophenolate mofetil) is the 2-morpholinoethyl ester of mycophenolic acid (MPA); 
an immunosuppressive agent; inosine monophosphate dehydrogenase (IMPDH) inhibitor. The 
chemical name for mycophenolate mofetil (MMF) is 2-morpholinoethyl (E)-6-(l,3-dihydro-4- 
hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has 
an 
empirical formula of C23H31NO7 a molecular weight of 433.50. 
Mycophenolate mofetil is a white to off-white crystalline powder. It is slightly soluble in water 
(43 µg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at pH 3.6). It is 
freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. The apparent 
partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa values for 
mycophenolate mofetil are 5.6 for the morpholino group and 8.5 for the phenolic group. 
Mycophenolate mofetil hydrochloride has a solubility of 65.8 mg/mL in D5W. The pH of the 
reconstituted solution is 2.4 to 4.1. 
 
Available Forms 
CellCept is available for oral administration as capsules containing 250 mg of mycophenolate 
mofetil, tablets containing 500 mg of mycophenolate mofetil, and as a powder for oral suspension, 
which when constituted contains 200 mg/mL mycophenolate mofetil 


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Toxicity 
Toxicities reported as more than 20% incidence are: 
Hypertension, hypotension, peripheral edema, chest pain, tachycardia, pain, headache, insomnia, 
fever, dizziness, anxiety, rash, hyperglycemia, hypercholesterolemia, hypomagnesemia, 
hypokalemia, hypocalcemia, hyperkalemia, abdominal pain, nausea, diarrhea, constipation, 
vomiting, anorexia, dyspepsia, urinary tract infection, leukopenia, anemia, leukocytosis, 
thrombocytopenia, liver function tests abnormality, ascites , back pain, weakness, tremor, 
paresthesia, abnormal kidney function, dyspnea, respiratory tract infection, pleural effusion, 
cough, lung disorder, sinusitis, infection, sepsis, lactate dehydrogenase increase. 
 
Toxicities with expected incidences are 3% to 20% are: 
Angina, arrhythmia, arterial thrombosis, atrial fibrillation, atrial flutter, bradycardia, cardiac arrest, 
cardiac failure, CHF, extrasystole, facial edema, hyper-/hypovolemia, pallor, palpitation, 
pericardial effusion, peripheral vascular disorder, postural hypotension, supraventricular 
extrasystoles, supraventricular tachycardia, syncope, thrombosis, vasodilation, vasospasm, 
venous pressure increased, ventricular extrasystole, ventricular tachycardia, chills with fever, 
confusion, delirium, depression, emotional lability, hallucinations, hypoesthesia, malaise, 
nervousness, psychosis, seizure, somnolence, thinking abnormal, vertigo , acne, alopecia, 
bruising, cellulitis, fungal dermatitis, hirsutism, petechia, pruritus, skin carcinoma, skin 
hypertrophy, skin ulcer, vesiculobullous rash, acidosis, alkalosis, Cushing's syndrome, 
dehydration, diabetes mellitus, gout, hypercalcemia, hyper-hypophosphatemia, hyperlipemia, 
hyperuricemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, hypothyroidism, 
parathyroid disorder, abdomen enlarged, dysphagia, esophagitis, flatulence, gastritis, 
gastroenteritis, gastrointestinal hemorrhage, gastrointestinal moniliasis, gingivitis, 
gum 
hyperplasia, ileus, melena, mouth ulceration, oral moniliasis, stomach disorder, stomach ulcer, 
stomatitis, xerostomia, weight gain/loss, impotence, nocturia, pelvic pain, prostatic disorder, 
scrotal edema, urinary frequency, urinary incontinence, urinary retention, urinary tract disorder, 
coagulation disorder, hemorrhage, neutropenia, pancytopenia, polycythemia, prothrombin time 
increased,   thromboplastin   time   increase,   alkaline   phosphatase   increased,     bilirubinemia, 


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cholangitis, cholestatic jaundice, GGT increased, hepatitis, jaundice, liver damage, transaminases 
increase, abscess, arthralgia, hypertonia, joint disorder, leg cramps, myalgia, myasthenia, neck 
pain, neuropathy, osteoporosis, amblyopia, cataract, conjunctivitis, eye hemorrhage, lacrimation 
disorder, vision abnormality, deafness, ear disorder, ear pain, tinnitus, albuminuria, creatinine 
increased, dysuria, hematuria, hydronephrosis, oliguria, pyelonephritis, renal failure, renal tubular 
necrosis, apnea, asthma, atelectasis, bronchitis, epistaxis, hemoptysis, hiccup, hyperventilation, 
hypoxia, respiratory acidosis, pharyngitis, pneumonia, pneumothorax, pulmonary edema, 
pulmonary hypertension, respiratory moniliasis, rhinitis, sputum increased, voice alteration, thirst. 
 
Administration 
Oral dosage formulations (tablet, capsule, suspension) should be administered on an empty 
stomach to avoid variability in MPA absorption. The oral solution may be administered via a 
nasogastric tube (minimum 8 French, 1.7 mm interior diameter); oral suspension should not be 
mixed with other medications. Delayed release tablets should not be crushed, cut, or chewed. 
Intravenous solutions should be administered over at least 2 hours (either peripheral or central 
vein); do not administer intravenous solution by rapid or bolus injection. 
 
6.7 
Filgrastim (Neupogen) 
Chemical Characteristics 
Neupogen is the trademark name for filgrastim, representing recombinant methionyl human 
granulocyte colony-stimulating factor (r-methHuG-CSF). Neupogen is a 175 amino acid protein 
produced by recombinant DNA technology utilizing Escherichia coli (E. coli). Neupogen has 
molecular weight 18,800 daltons and an amino acid sequence similar to that of natural human 
DNA except for the additional methonine at the N-terminal, necessary for expression in E. coli. 
 
Available Forms 
Neupogen is marketed as a sterile, clear, colorless preservative-free liquid. It is packaged in vials 
and prefilled syringes. The vials are single-dose, preservative-free and contain 300 mcg/mL of 
filgrastim. The prefilled syringes are single-dose, preservative free and hold 600mcg/mL of 
filgrastim. 


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Storage and Handling 
Neupogen must be stored refrigerated at 2° to 8°C (36° TO 46°F). Avoid shaking. 
 
 
Preceding injection, neupogen must reach room temperature for at most 24 hours. Discard any 
vials or prefilled syringes left at room temperature for more than 24 hours. Avoid use if particulate 
matter or discoloration is observed prior to administration 
 
Toxicity 
Common side effects include: nausea, vomiting, skeletal pain, spontaneous reversible elevations 
in uric acid, lactate dehydrogenase and alkaline phosphatase, alopecia, palpable splenomegaly 
and petechiae. Other side effects include: diarrhea, neutropenic fever, mucositis, fever, fatigue, 
thrombocytopenia, anorexia, dyspnea, headache, epistaxis, transfusion reaction, cough, skin rash, 
chest pain, generalized weakness, sore throat, stomatitis, pain, myocardial infarctions, 
constipation, arrhythmias, hypotension, hemorrhagic events, renal insufficiency, capillary leak 
syndrome, hepatomegaly, arthralgia, osteoporosis, cutaneous vaculitis, hematuria/proteinuria, 
exacerbation of some pre-existing skin disporders, splenic rapture, sickle cell crisis, sweet’s 
syndrome and decreased bone density. 
 
Administration 
Neupogen may be administered as an IV or a subcutaneous infusion. It is recommended that 
neupogen be administered at least 24 hours after bone marrow infusion, with dosage 
modifications determined by neutrophil response. 
 
If necessary, neupogen maybe diluted in 5% dextrose with addition of Albumin(human) to prevent 
absorption to plastic materials. Dilution to final concentration less than 5mcg/mL is not 
recommended at any time. Do not dilute with saline as product may precipitate. 
 
When using either vials or prefilled syringes, do not save unused drugs for later administration. 
Dispose of all unused portions. 
 


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6.8 Total Body Irradiation (TBI) 
Toxicity 
 
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. 
 
7 
ALLOGENEIC STEM CELL INFUSION 
 
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. 
Besides the use of steroid use for pre-medication (per our program standards), patients will not 
receive any immunosuppression, including steroid, tacrolimus, sirolimus, or mycophenolate 
mofitle (unless definitely indicated per the attending physician) between day 0 and day 5 for 
concern of mitigating the immunosuppressive effect of post-transplant Cytoxan (given on day 
+3). 
 
7.1 
Stem Cell Source 
The source of donor stem cells will be peripheral blood stem cells (PBSC) or bone marrow 
(BM). PBSC will be preferred.  Cord blood will not be allowed. 


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7.2 
PBSC Mobilization and Collection 
PBSC mobilization and collection procedures and BM collection procedures will follow 
institutional practice. 
 
7.3 
Stem Cell Dosing 
For PBSC infusions: The recommended stem cell dose is 4-8 X 106 CD34 cells/kg recipient 
weigh. The minimum accepted stem cell dose is 2 X 106 CD34 cells/kg recipient weight. 
 
For marrow infusions: The recommended stem cell dose is 4-8 X 108 mononuclear cells/kg 
recipient weigh. The minimum accepted stem cell dose is 2 X 108 mononuclear cells/kg recipient 
weight. 
 
8 
REQUIRED OBSERVATIONS 
Please see appendix B for study calendars. 
 
8.1 
Pre-Transplant Observations (within 35 days prior to study registration / day of final 
transplant evaluation). 
 History and physical exam (include Karnofsky Score within 14 days prior to 
registration) 
 Creatinine, AST, ALT, Alk Phos., and Total bilirubin 
 Echocardiogram or MUGA 
 Pulmonary function testing: FVC, FEV1, DLCO (corrected for hemoglobin). 
 Unilateral bone marrow aspirate and biopsy, morphology and cytogenetics. (ALL and 
AML will be performed within 28 days prior to registration) 
 Cerebrospinal fluid examination, if required, will be based on the transplant 
physician’s clinical practice standards. 
 
8.2 
Post-Transplant Required Observations and Follow-up Plan 
 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 have not demonstrated disease progression by that time 
point. In addition, a unilateral marrow aspirate will also be collected whenever a 
relapse is suspected. 
 
 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 +100 (±14), Day +180 (±21) and at 1 year (±45) post-transplant. 
 
 Patients need to be seen in clinic at least once a week until day 100 post-transplant 
and have acute GVHD assessment weekly (±3 days). Then they need to be seen at 


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least once a month (±14 days) until 1 year after transplant to have chronic GVHD 
assessment. 
 
 The patient will be followed at least for 2 years after transplant. The follow up 
interval is determined as clinically necessary. 
 
 The patient who relapsed after transplant will be followed only for survival. 
 
 
8.3 
Assessment of GVHD 
Acute GVHD typically occurs after engraftment of the stem cells. Clinical assessment for acute 
GVHD will start after infusion of the stem cells. There are 2 grading systems for acute GVHD; 
the modified Keystone (Glucksberg) consensus criteria (grades I-IV)25, 26 and CIBMTR criteria 
(grades A-D)27. Both systems were shown to equally predict survival.28, 29 
The Glucksberg criteria will be followed in assessment of acute GVHD and the highest grade 
will be recorded (appendix C). 
Chronic GVHD is graded based on clinical manifestations of organ systems based on the NIH 
Consensus data and CIBMTR grading guidelines utilizing UAB BMTCT form for recording. 
(appendix D) 
 
9 
STATISTICAL CONSIDERATIONS 
 
9.1 
Sample Size 
This is a single-center phase II study whose primary aim is to show an improvement in incidence 
of acute GVHD grade II-IV after myeloablative MUD/MMUD all HCT from 57 %. The base 
line (historical) incidence of 57% is based on the data of a systematic analysis of CIBMTR 
(Center of International Blood and Marrow transplant Research) data that showed the incidence 
of grade II-IV acute GVHD after myeloablative MUD/MMUD all HCT to be 50-63%.30 With 
complete follow-up of all patients (which is expected), a maximum of 45 patients would supply 
80% power and a significance level of .05 for the null hypothesis of a GVHD rate of 57% if the 
true rate is 37%. We have augmented the sample size to 48 to account for patients who become 
non-evaluable or may lose follow-up. Non-evaluable patients are those who were registered for 
the study but did not receive stem cell transplant. It is expected the enrollment may be completed 
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9.2 
Analysis Methods 
A Simon two stage optimum design will be used.  In the first stage 17 patients will be assessed. 
If nine or more of them experience grade II - IV GVHD the study will be stopped with the 
conclusion that the GVHD rate is not less than 57%. Otherwise, an additional twenty-eight 
patients will be accrued for a total of 45. If twenty-one or more of them experience GVHD we 
will conclude that the GVHD is not less than 57%. Otherwise we will conclude that the GVHD 
rate is less than 57%. This plan will provide a probability of .05 of concluding that the GVHD 
rate less than 57% if it is 57% and a probability of 80% of concluding that the rate is less than 
57% if it is actually 37%. The expected sample size will be 24.8 under the null and 41.2 under 
the alternative hypothesis. If the null hypothesis is true and the GVHD rate is 57%, we will have 
a 72% probability of stopping early after 17 patients are assessed. The method of Koyama and 
Chen will be used to compute estimated GVHD rates and a 95% confidence interval. This 
method takes proper account of the Simon two stage design. 
 
10 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. Post-transplant, regimen related toxicity / adverse events will be reported 
through day 100. Following day 100, patients will still be followed for relapse and overall 
survival. 
 
10.1 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 


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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. 
 
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: 
 
The current NCI Agent-Specific Adverse Event List (provided in the Drug Information 
Section of this protocol); or 
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. 
 
10.2 Required Adverse Events Reporting 
Therapy for hematological malignancies, with or without stem cell transplantation, 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 stem cell transplantation for hematological malignancies. 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. 
 
10.3 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. 


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10.4 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 
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 (BMTCT) 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 BMTCT Program. 
 
11 DATA SAFETY AND MONITORING PROCEDURES 
 
11.1 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. 


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In addition to the Cancer Center DSMB, BMTCT 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 
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, Day 100 
all-cause mortality, and incidence of engraftment failure.) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
These meetings are to be documented by the 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. 
 
11.2 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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Hahn T, Wolff SN, Czuczman M, Fisher RI, Lazarus HM, Vose J et al. The role of 
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Transplantation 2001; 7(6): 308-31. 
 
3. 
Ho VT, Kim HT, Liney D, Milford E, Gribben J, Cutler C et al. HLA-C mismatch is 
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4. 
Petersdorf EW, Gooley T, Malkki M, Horowitz M, for The 
International 
Histocompatibility Working Group in Hematopoietic Cell T. Clinical significance of 
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transplantation from unrelated donors. Tissue antigens 2007; 69 Suppl 1: 25-30. 
 
5. 
Woolfrey A, Klein JP, Haagenson M, Spellman S, Petersdorf E, Oudshoorn M et al. HLA-
C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood 
stem cell transplantation. Biology of blood and marrow transplantation : journal of the 
American Society for Blood and Marrow Transplantation 2011; 17(6): 885-92. 
 
6. 
Al-Kadhimi Z, Gul Z, Rodriguez R, Chen W, Smith D, Mitchell A et al. Anti-Thymocyte 
Globulin (Thymoglobulin), Tacrolimus, and Sirolimus as Acute Graft-versus-Host Disease 
Prophylaxis for Unrelated Hematopoietic Stem Cell Transplantation. Biology of blood and 
marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation 2012; 16: 16. 
 
7. 
Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR et al. Standard 
graft-versus-host disease prophylaxis with or without anti-T-cell globulin in 
haematopoietic cell transplantation from matched unrelated donors: a randomised, open- 
label, multicentre phase 3 trial. The lancet oncology 2009; 10(9): 855-64. 
 
8. 
Kumar A, Mhaskar AR, Reljic T, Mhaskar RS, Kharfan-Dabaja MA, Anasetti C et al. 
Antithymocyte globulin for acute-graft-versus-host-disease prophylaxis in patients 
undergoing allogeneic hematopoietic cell transplantation: a systematic review. Leukemia 
2012; 26(4): 582-8. 
 
9. 
Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino PE, di Bartolomeo P et al. 
Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from 
unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo 
(GITMO). Blood 2001; 98(10): 2942-7. 


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10. 
Appelbaum FR, Bacigalupo A, Soiffer R. Anti-T cell antibodies as part of the preparative 
regimen in hematopoietic cell transplantation--a debate. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow Transplantation 
2012; 18(1 Suppl): S111-5. 
 
11. 
Storb R, Antin JH, Cutler C. Should methotrexate plus calcineurin inhibitors be considered 
standard of care for prophylaxis of acute graft-versus-host disease? Biology of blood and 
marrow transplantation: journal of the American Society for Blood and Marrow 
Transplantation 2010; 16(1 Suppl): S18-27. 
 
12. 
Gutierrez-Aguirre CH, Cantu-Rodriguez OG, Borjas-Almaguer OD, Gonzalez-Llano O, 
Jaime-Perez JC, Solano-Genesta M etal. Effectiveness of subcutaneous low-dose 
alemtuzumab and rituximab combination therapy for steroid-resistant chronic graft- 
versus-host disease. Haematologica 2012; 97(5): 717-22. 
 
13. 
Xhaard A, Hermet E, Bay JO, Peffault de Latour R. [Use of monoclonal antibodies in 
prophylaxis and treatment of acute and chronic graft-versus-host disease in 2011]. Bull 
Cancer 2011; 98(8): 889-99. 
 
14. 
Nagi W, Lim ZY, Krishnamurthy P, Potter V, Tindell V, Reiff-Zall L et al. Alemtuzumab 
based reduced intensity conditioning allogeneic haematopoietic stem cell transplantation 
for myelofibrosis. Leuk Res 2011; 35(8): 998-1000. 
 
15. 
Poire X, van Besien K. Alemtuzumab in allogeneic hematopoetic stem cell transplantation. 
Expert opinion on biological therapy 2011; 11(8): 1099-111. 
 
16. 
Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S et al. Full haplotype- 
mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute 
leukemia at high risk of relapse. J Clin Oncol 2005; 23(15): 3447-54. 
 
17. 
Reisner Y, Hagin D, Martelli MF. Haploidentical hematopoietic transplantation: current 
status and future perspectives. Blood 2011; 118(23): 6006-17. 
 
18. 
Fuchs EJ, Huang XJ, Miller JS. HLA-haploidentical stem cell transplantation for 
hematologic malignancies. Biology of blood and marrow transplantation : journal of the 
American Society for Blood and Marrow Transplantation 2010; 16(1 Suppl): 3. 
 
19. 
Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA- 
haploidentical bone marrow transplantation for hematologic malignancies 
using 
nonmyeloablative conditioning and high-dose, post transplantation cyclophosphamide. 
Biology of blood and marrow transplantation: journal of the American Society for Blood 
and Marrow Transplantation 2008; 14(6): 641-50. 
 
20. 
Munchel A, Kesserwan C, Symons HJ, Luznik L, Kasamon YL, Jones RJ et al. 
Nonmyeloablative, HLA-haploidentical bone marrow transplantation with high dose, post-
transplantation cyclophosphamide. Pediatr Rep 2011; 22(3). 


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21. 
Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, Holland HK et al. 
Haploidentical Transplantation Using T-Cell Replete Peripheral Blood Stem Cells and 
Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies Who 
Lack Conventional Donors Is Well Tolerated and Produces Excellent Relapse-Free 
Survival: Results of A Prospective Phase II Trial. Biology of blood and marrow 
transplantation : journal of the American Society for Blood and Marrow Transplantation 
2012; 31: 31. 
 
22. 
Bilmon IA, Kwan J, Gottlieb D, Kerridge I, McGurgan M, Huang G et al. Haploidentical 
bone marrow transplants for hematological malignancies using non-myeloablative 
conditioning therapy and post-transplant immunosuppression with cyclophosphamide: 
results from a single Australian centre. Intern Med J 2012; 30(10): 1445-5994. 
 
23. 
Kasamon YL, Luznik L, Leffell MS, Kowalski J, Tsai HL, Bolanos-Meade J et al. 
Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose 
posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biology of 
blood and marrow transplantation : journal of the American Society for Blood and Marrow 
Transplantation 2010; 16(4): 482-9. 
 
24. 
Luznik L, Bolanos-Meade J, Zahurak M, Chen AR, Smith BD, Brodsky R et al. High- 
dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host 
disease. Blood 2010; 115(16): 3224-30. 
 
25. 
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical 
manifestations of graft-versus-host disease in human recipients of marrow from HL-A- 
matched sibling donors. Transplantation 1974; 18(4): 295-304. 
 
26. 
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 
Consensus Conference on Acute GVHD Grading. Bone marrow transplantation 1995; 
15(6): 825-8. 
 
27. 
Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ et al. 
IBMTR Severity Index for grading acute graft-versus-host disease: retrospective 
comparison with Glucksberg grade. British journal of haematology 1997; 97(4): 855-64. 
 
28. 
Martino R, Romero P, Subira M, Bellido M, Altes A, Sureda A et al. Comparison of the 
classic Glucksberg criteria and the IBMTR Severity Index for grading acute graft-versus- 
host disease following HLA-identical sibling stem cell transplantation. International Bone 
Marrow Transplant Registry. Bone marrow transplantation 1999; 24(3): 283-7. 
 
29. 
Cahn JY, Klein JP, Lee SJ, Milpied N, Blaise D, Antin JH et al. Prospective evaluation of 
2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de 
Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and 
International Bone Marrow Transplant Registry (IBMTR) prospective study. Blood 2005; 
106(4): 1495-500. 


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30. 
Jagasia M, Arora M, Flowers ME, Chao NJ, McCarthy PL, Cutler CS et al. Risk factors 
for acute GVHD and survival after hematopoietic cell transplantation. Blood 2012; 119(1): 
296-307. 
 
31. 
Kaplan EL MP. Nonparametric estimation from incomplete observations. Journal of 
American Statistical Association 1958; 53: 457–481. 
 
32. 
Gray RJ. A Class of K-Sample Tests for Comparing the Cumulative Incidence of a 
Competing Risk. The Annals of Statistics 1988; 16(5): 1141-1154. 


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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 1286 – Post Transplant CTX 
34 
 
 
Appendix B: Study Calendars 
Study Calendar for Fludarabine/Busulfan Conditioning Regimen 
 
 
Procedures 
Screening Period 
Day −35 prior to Study 
Registration 
 
    Tx. 
Follow-Up Phase 
-5 
-4 
-3 
-2 
-1 
Day 0 
+3 
+5 
Day 30 
(±7) 
Day 100 
(±14) 
Day 180 
(±21) 
Day 365 
(±45) 
2 
Years 
Inclusion/ Exclusion criteria, 
Informed Consent, Medical and 
Treatment History 
X 
Physical Exam, and Vital Signs 
X 
X 
X 
X 
X 
Pulmonary Function Test and 
Echocardiogram or MUGA 
X 
HIV1 and HIV2 labs and 
Pregnancy Test 
X 
Karnofsky status1 
X 
Bone marrow aspirate and 
biopsy4, morphology and 
cytogenetics 
X2 
X 
X 
X 
Immune Reconstitution and 
Chimerism Studies 
X 
X 
X 
X 
CBC/Diff 5; Liver Function 
Panel, , Renal Function Panel 
X 
X 
X 
X 
X 
Stem cell Infusion3 
X 
HHV6 PCR, EBV PCR, 
Adenovirus PCR and CMV 
PCR8 
X 
Infection Prophylaxis10 
X 
GvHD Assessments 6, 7 
X 
Mycophenolate Mofetil9 
X 
Tacrolimus9 
X 
X 
Cyclophosphamide 
X9 
Fludarabine11 
X 
X 
X 
X 
Busulfan12 
X 
X 
X 
X 
Filgrastim (G-CSF) 13 
X 
Assess for Disease Progression 
and Survival Status 
X 


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Study Calendar for Fludarabine/Busulfan Conditioning Regimen 
 
 
1. Karnofsky Performance Score will be assessed within 14 days prior to registration. 
2. A unilateral bone marrow aspirate and biopsy will be performed within 28 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 unilateral bone marrow aspirate will be collected whenever relapse is suspected. Patients that relapse will be followed for survival. 
5. Post Transplant - Neutrophil engraftment is defined as the first of 3 consecutive days with an absolute neutrophil count (ANC) > 500/µL. 
6. Acute GVHD will be assessed weekly (±3 days) till 100 days post-transplant. 
7. Chronic GVHD will be assessed monthly (±14 days) till 1 year post transplant. 
8. Starting approx. Day +20 post transplant collect and send the following. HHV6 PCR and Adenovirus PCR once a week until Day 100. EBV PCR once every 2 weeks until day 100. CMV 
PCR once a week until Day 100 for pts. when either the pt. or the donor is seropositive for CMV pre-transplant. 
9. GVHD prophylaxis will consist of Cyclophosphamide (50mg/kg IV) starting on day +3. Mycophenolate Mofetil (15mg/kg Q8h IV) and Tacrolimus drip (dose dependent on Voriconazole 
use) both starting on day +5. MMF will stop by day +35.  Patients will convert to oral tacrolimus when tolerated. Tacrolimus will begin taper at approximately day +100 to end by Day +100 if 
no signs of active GVHD. 
10. Recommended infection prophylaxis: Voriconazole 200 mg PO BID starting on day 0 and continue through day 75. Acyclovir starting day 0 until at least day +365. Bactrim starting day 
+30 and continuing until off immunosuppression or at the discretion of the attending physician. 
11. Fludarabine dosed at 40mg/m2 IV 
12. Busulfan dosing will be based on pharmacokinetics. 
13. G-CSF (at approx. 5mcg/kg) will begin on Day 5 and continue until engraftment. 


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Study Calendar for TBI / Cytoxan Conditioning Regimen 
 
 
Procedures 
Screening Period 
Day −35 prior to Study 
Registration 
Conditioning Phase Day 
Tx. 
Follow-Up Phase 
-6 
-5 
-4 
-3 
-2 
-1 
Day 0 
+3 
+5 
Day 30 
(±7) 
Day 100 
(±14) 
Day 180 
(±21) 
Day 365 
(±45) 
2 Years 
Inclusion/ Exclusion criteria, 
Informed Consent, Medical and 
Treatment History 
X 
Physical Exam, and Vital Signs 
X 
X 
X 
X 
X 
Pulmonary Function Test and 
Echocardiogram or MUGA 
X 
HIV1 and HIV2 labs and Pregnancy 
Test 
X 
Karnofsky status1 
X 
Bone marrow aspirate and biopsy4, 
morphology and cytogenetics 
X2 
X 
X 
X 
Immune Reconstitution and 
Chimerism Studies 
X 
X 
X 
X 
CBC/Diff 5; Liver Function Panel, 
GGT, Renal Function Panel 
X 
X 
X 
X 
X 
Stem cell Infusion3 
X 
HHV6 PCR, EBV PCR, Adenovirus 
PCR and CMV PCR8 
X 
Infection Prophylaxis10 
X 
GvHD Assessments 6, 7 
X 
Mycophenolate Mofetil9 
X 
Tacrolimus9 
X 
Cyclophosphamide 
X11 
X11 
X9 
TBI12 
X 
X 
X 
Filgrastim (G-CSF) 13 
X 
Assess for Disease Progression and 
Survival Status 
X 


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Study Calendar for TBI / Cytoxan Conditioning Regimen 
 
 
1. Karnofsky Performance Score will be assessed within 14 days prior to registration. 
2. A unilateral bone marrow aspirate and biopsy will be performed within 28 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 unilateral bone marrow aspirate will be collected whenever relapse is suspected. Patients that relapse will be followed for survival. 
5. Post-Transplant - Neutrophil engraftment is defined as the first of 3 consecutive days with an absolute neutrophil count (ANC) > 500/µL. 
6. Acute GVHD will be assessed weekly (±3 days) till 100 days post-transplant. 
7. Chronic GVHD will be assessed monthly (±14 days) till 1 year post transplant. 
8. Starting approx. Day +20 post-transplant collect and send the following. HHV6 PCR and Adenovirus PCR once a week until Day 100. EBV PCR once every 2 weeks until day 100. CMV 
PCR once a week until Day 100 for pts. when either the pt. or the donor is seropositive for CMV pre-transplant. 
9. GVHD prophylaxis will consist of Cyclophosphamide (50mg/kg IV) starting on day +3. Mycophenolate Mofetil (15mg/kg Q8h IV) and Tacrolimus drip (dose dependent on Voriconazole 
use) both starting on day +5. MMF will stop by day +35.  Patients will convert to oral tacrolimus when tolerated. Tacrolimus will begin taper at approximately day +100 to end by Day +180 if 
no signs of active GVHD. 
10. Recommended infection prophylaxis: Voriconazole 200 mg PO BID starting on day 0 and continue through day 75. Acyclovir starting day 0 until at least day +365. Bactrim starting day 
+30 and ending continuing until off immunosuppression or at the discretion of the attending physician. 
11. Cyclophosphamide as a conditioning regimen will be administered on day-3(35mg/kg IV) and day -2 (35mg/kg IV). 
12. TBI 200cGY/fraction x2 each day 
13. G-CSF (at approx. 5mcg/kg) will begin on Day 5 and continue until engraftment. 


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Study Calendar for TBI / Fludarabine Conditioning Regimen 
 
 
Procedures 
Screening Period 
Day −35 prior to Study 
Registration 
Conditioning Phase Day 
Tx. 
Follow-Up Phase 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
Day 0 
+3 
+5 
Day 30 
(±7) 
Day 100 
(±14) 
Day 180 
(±21) 
Day 365 
(±45) 
2 
Year 
Inclusion/ Exclusion criteria, 
Informed Consent, Medical and 
Treatment History 
X 
Physical Exam, and Vital Signs 
X 
X 
X 
X 
X 
Pulmonary Function Test and 
Echocardiogram or MUGA 
X 
HIV1 and HIV2 labs and Pregnancy 
Test 
X 
Karnofsky status1 
X 
Bone marrow aspirate and biopsy4, 
morphology and cytogenetics 
X2 
X 
X 
X 
Immune Reconstitution and 
Chimerism Studies 
X 
X 
X 
X 
CBC/Diff 5; Liver Function Panel, 
GGT, Renal Function Panel 
X 
X 
X 
X 
X 
Stem cell Infusion3 
X 
HHV6 PCR, EBV PCR, Adenovirus 
PCR and CMV PCR8 
X 
Infection Prophylaxis10 
X 
GvHD Assessments 6, 7 
X 
Mycophenolate Mofetil9 
X 
Tacrolimus9 
X 
X 
Cyclophosphamide 
X9 
Fudarabine11 
X 
X 
X 
X 
TBI12 
X-2 
X-2 
X-1 
Filgrastim (G-CSF) 13 
X 
Assess for Disease Progression and 
Survival Status 
X 


UAB BMTCT Program 
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Study Calendar for TBI / Fludarabine Conditioning Regimen 
 
 
1. Karnofsky Performance Score will be assessed within 14  days prior to registration. 
2. A unilateral bone marrow aspirate and biopsy will be performed within 28 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 unilateral bone marrow aspirate will be collected whenever relapse is suspected. Patients that relapse will be followed for survival. 
5. Post-Transplant - Neutrophil engraftment is defined as the first of 3 consecutive days with an absolute neutrophil count (ANC) > 500/µL. 
6. Acute GVHD will be assessed weekly (±3 days) till 100 days post-transplant. 
7. Chronic GVHD will be assessed monthly (±14 days) till 1 year post transplant. 
8. Starting approx. Day +20 post-transplant collect and send the following. HHV6 PCR and Adenovirus PCR once a week until Day 100. EBV PCR once every 2 weeks until day 100. CMV 
PCR once a week until Day 100 for pts. when either the pt. or the donor is seropositive for CMV pre-transplant. 
9. GVHD prophylaxis will consist of Cyclophosphamide (50mg/kg IV) starting on day +3. Mycophenolate Mofetil (15mg/kg Q8h IV) and Tacrolimus drip (dose dependent on Voriconazole 
use) both starting on day +5. MMF will stop by day +35.  Patients will convert to oral tacrolimus when tolerated. Tacrolimus will begin taper at approximately day +100 to end by Day +180 if 
no signs of active GVHD. 
10. Recommended infection prophylaxis: Voriconazole 200 mg PO BID starting on day 0 and continue through day 75. Acyclovir starting day 0 until at least day +365. Bactrim starting day 
+30 and ending continuing until off immunosuppression or at the discretion of the attending physician. 
11. Fludarabine dose 40mg/m2/day. 
12. TBI 200cGy/fraction x 2 on days -3 and -2. TBI 200cGy/fraction x1 on day -1. 
13. G-CSF (at approx. 5mcg/kg) will begin on Day 5 and continue until engraftment. 


UAB BMTCT Program 
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Version 1.5 September 21, 2017 
40 
 
 
 
 
Study Calendar for Fludarabine / Melphalan Conditioning Regimen 
 
 
Procedures 
Screening Period 
Day −35 prior to Study 
Registration 
Conditioning Phase Day 
Tx. 
Follow-Up Phase 
-5 
-4 
-3 
-2 
-1 
Day 0 
+3 
+5 
Day 30 
(±7) 
Day 100 
(±14) 
Day 180 
(±21) 
Day 365 
(±45) 
2 
Years 
Inclusion/ Exclusion criteria, 
Informed Consent, Medical and 
Treatment History 
X 
Physical Exam, and Vital Signs 
X 
X 
X 
X 
X 
Pulmonary Function Test and 
Echocardiogram or MUGA 
X 
HIV1 and HIV2 labs and 
Pregnancy Test 
X 
Karnofsky status1 
X 
Bone marrow aspirate and 
biopsy4, morphology and 
cytogenetics 
X2 
X 
X 
X 
Immune Reconstitution and 
Chimerism Studies 
X 
X 
X 
X 
CBC/Diff 5; Liver Function 
Panel, , Renal Function Panel 
X 
X 
X 
X 
X 
Stem cell Infusion3 
X 
HHV6 PCR, EBV PCR, 
Adenovirus PCR and CMV 
PCR8 
X 
Infection Prophylaxis10 
X 
GvHD Assessments 6, 7 
X 
Mycophenolate Mofetil9 
X 
Tacrolimus9 
X 
Cyclophosphamide 
X9 
Fludarabine11 
X 
X 
X 
X 
Melphalan12 
X 
Filgrastim (G-CSF) 13 
X 
Assess for Disease Progression 
and Survival Status 
X 


UAB BMTCT Program 
UAB 1286 – Post Transplant CTX 
Version 1.5 September 21, 2017 
41 
 
 
 
 
Study Calendar for Fludarabine/Melphalan Conditioning Regimen 
 
 
1. Karnofsky Performance Score will be assessed within 14 days prior to registration. 
2. A unilateral bone marrow aspirate and biopsy will be performed within 28 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 unilateral bone marrow aspirate will be collected whenever relapse is suspected. Patients that relapse will be followed for survival. 
5. Post-Transplant - Neutrophil engraftment is defined as the first of 3 consecutive days with an absolute neutrophil count (ANC) > 500/µL. 
6. Acute GVHD will be assessed weekly (±3 days) till 100 days post-transplant. 
7. Chronic GVHD will be assessed monthly (±14 days) till 1 year post transplant. 
8. Starting approx. Day +20 post-transplant collect and send the following. HHV6 PCR and Adenovirus PCR once a week until Day 100. EBV PCR once every 2 weeks until day 100. CMV 
PCR once a week until Day 100 for pts. when either the pt. or the donor is seropositive for CMV pre-transplant. 
9. GVHD prophylaxis will consist of Cyclophosphamide (50mg/kg IV) starting on day +3. Mycophenolate Mofetil (15mg/kg Q8h IV) and Tacrolimus drip (dose dependent on Voriconazole 
use) both starting on day +5. MMF will stop by day +35. Patients will convert to oral tacrolimus when tolerated. Tacrolimus will begin taper at approximately day +100 to end by Day +180 
if no signs of active GVHD. 
10. Recommended infection prophylaxis: Voriconazole 200 mg PO BID starting on day 0 and continue through day 75. Acyclovir starting day 0 until at least day +365. Bactrim starting day 
+30 and ending continuing until off immunosuppression or at the discretion of the attending physician. 
11. Fludarabine dose 40mg/m2/day. 
12. Melphalan dose 140mg/m2 on day -1 . 
13. G-CSF (at approx. 5mcg/kg) will begin on Day 5 and continue until engraftment. 


UAB BMTCT Program 
UAB 1286 – Post Transplant CTX 
Version 1.5 Dated September 21, 2017 
42 
 
 
 
 
 
 
 
Appendix C: Grading of Acute Graft versus Host Disease 
 
(Per modified Glucksberg criteria = Keystone criteria)26 
Stages of organ involvement 
Skin 
1 
Maculopapular eruption involving less than 25% of the body surface 
2 
Maculopapular eruption involving 25-50% of the body surface 
3 
Generalized erythroderma 
4 
Generalized erythroderma with bullous formation. 
GI 
1 
> 500 ml of liquid stool/day or biopsy-proven upper GI involvement 
2 
> 1,000 ml of stool/day 
3 
> 1,500 ml of stool/day 
4 
Severe abdominal pain with or without ileus 
Liver 
1 
Bilirubin is 2 -2.9 mg/dl 
2 
Bilirubin is 3 - 5.9 mg/d1 
3 
Bilirubin is 6 - 14.9 mg/dl 
4 
Bilirubin is  > 15 mg/dl 
 
 
Overall grading of acute GVHD by organ staging. 
Skin 
GI 
Liver 
I 
1-2 
None 
None 
II 
3 or 
1 
or 
1 
III 
--- 
2-4 
2-3 
IV* 
4 
--- 
4 
*If Karnofsky performance status < 30%, then grade IV. 


UAB BMTCT Program 
UAB 1286 – Post Transplant CTX 
Version 1.5 Dated September 21, 2017 
43 
 
 
Was a specific therapy used to treat or prevent cGVHD ? 
 Yes 
No 
 
 
 
 
 
Prophylaxis - Prophylaxis is defined as standard preventive immunosuppression ;  still considered prophylaxis if continued after GVHD diagnosis 
Treatment - Treatment is defined as local or systemic therapy started with the onset of signs and symptoms of GVHD 
Treatment Started:   
_/  
/  
  Was Treatment Dose Increased?   
 No 
 Yes 
 Date:   
 
Tapering Therapy ?  
 No   
 Yes  
 
 Taper Started on:  
 
 Ongoing  or Stop Date:  
 
 
 
Appendix D: Grading of Chronic Graft versus Host Disease 
 
 
 
 
 
 
 
 
 
 
 
 CSA (Cyclosporin) 
 FK 506 (Tacrolimus, Prograf) 
 ECP (extra-coporeal photopheresis) 
 MMF (Mycophenolate Mofetil , Cellcept) 
 Corticosteroids (Systemic) 
 MTX (Methotrexate) 
 PUVA 
 Other   
 
 
Assessments 
 
Onset of cGVHD was: 
Stage of cGVHD: 
  Progressive ( acute progressed directly to chronic ) 
 Limited: Localized skin involvement resembling localized 
scleroderma with or without liver involvement; no other 
organ involvement. 
  Interrupted (acute resolved; then chronic developed ) 
  de novo ( never developed acute GVHD ) 
 Extensive: Generalized skin and/or multiple organ 
involvement. – generalized skin involvement; or, 
– liver histology showing chronic aggressive hepatitis, 
bridging necrosis or cirrhosis; or, 
– involvement of eye: Schirmer’s test with < 5 mm wetting; or 
– involvement of minor salivary glands or oral mucosa 
demonstrated on labial biopsy; or 
– involvement of any other target organ 
  Chronic Flare (symptoms reactivated within 30 days of 
drug tapering or discontinuation) 
 
 
Overall Severity of cGVHD 
 Mild – signs and symptoms of cGVHD do not interfere substantially with function and do not progress once appropriately 
treated with local therapy or standard systemic therapy (first line therapy). 
 Moderate – signs and symptoms of cGVHD interfere somewhat with function despite appropriate therapy or are progressive 
through first line systemic therapy. 
 Severe – signs and symptoms of cGVHD limit function substantially despite appropriate therapy or are progressive through 
second line therapy. 
 
 
 
 
 
 
 
Clinical Signature 
Date 
Pt. Name:  
  MR#  
 Inpt 
 Outpt 
Transplant Date:   
/  
/  
 
MRD     MUD     PBSC     Marrow 
Research Study: 
 
  
 
Date of last GvHD Assessment:   
/  
/  
 
Date of GvHD Assessment:   
/  
/  
 
Has Chronic GVHD Occurred this period? 
 Yes   No 
If yes, Date of onset:   
Site:  
Has Chronic GVHD Resolved this period    Yes 
 Date :   
  No  
 Continue Form 
   
    
   
   
   
   
   
   
   
   
    
  
  
  
  
  
  
  
 
  
 
 
Biopsy Performed: 
 No    Yes  
Tissue: 
Date: 
Results: 
 Positive 
 Negative 

ICF_001.pdf: 
Phase II Clinical Trial of the Use of Post-Transplant 
Cyclophosphamide for Graft Versus Host Disease 
(GvHD) Prophylaxis Following Matched Unrelated 
Donor (MUD) 
Hematopoietic Stem Cell Transplant (HSCT) 
PI: OMER JAMY, MD 
NCT 02065154 
March 13, 2015