Conditions: Leukemia Myelodysplastic Syndrome Non-Hodgkin's Lymphoma
Keywords: GVHD Prophylaxis Cyclophosphamide Renal Insufficiency Hematopoietic Stem Cell Transplant 14-273
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: yes

Brief summary:
This is a pilot study which will be done in a small number of patients. The purpose of this study is to test the safety and benefit of giving a type of chemotherapy - cyclophosphamide - after the transplant to prevent graft versus host disease (GVHD) in patients with abnormal kidney function. GVHD is one of the most common complications of a stem cell transplant .

Detailed description:

Arms:
arm 1: Melphalan 70 mg/m 2/d will be administered intravenously on d-6 and -5 Fludarabine 25 mg/m 2/d will be administered intravenously on d-6 thru -2 Day -1 will be a day or rest Cyclophosphamide and mesna will be given on d+3 and +4 Siro +/- MMF will be started in those patients who are to receive it on d+5. Neupogen will begin d+7.

Interventions: intervention 1: Cyclophosphamide
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
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Page 1 of 33 
 
 
 
A Pilot Trial of GVHD Prophylaxis with Post Transplant Cyclophosphamide for  Patients 
with Renal Insufficiency Undergoing a Conventional  8/8 HLA-matched Related or 
Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplant 
PROTOCOL FACE PAGE FOR  
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal 
Investigator/Department: 
Ann Jakubowski, Ph.D., M.D.     
Medicine, BMT 
Co-Principal 
Investigator(s)/Department: 
Esperanza Papadopoulos, M.D 
Medicine, BMT           
Investigator(s)/Department: 
Juliet Barker, M.B.B.S.  
Hugo Castro-Malaspina, M.D.  
David Chung, M.D., Ph.D. 
Parastoo Dahi, M.D. 
Sergio A. Giralt, M.D. 
Boglarka Gyurkocza, M.D. 
Alan Hanash M.D., Ph.D. 
Katharine Hsu, M.D., Ph.D. 
Guenther Koehne, M.D., Ph.D.  
Heather Landau, M.D. 
Matthew Matasar, M.D. 
Craig Moskowitz, M.D. 
Jonathan Peled, M.D. 
Miguel-Angel Perales, M.D.  
Doris Ponce, M.D.  
Craig Sauter, M.D. 
Brian Shaffer, M.D. 
Gunjan Shah, M.D. 
Melody Smith, M.D. 
Roni Tamari, M.D.  
Marcel RM van den Brink, M.D., Ph.D.  
James Young, M.D. 
Elaina Preston, PA 
Ilya Glezerman M.D. 
Sean Devlin, Ph.D. 
Patrick Hilden, M.S. 
Shani Irby, NP 
Megan Scott, NP 
Shannon Andersen, NP 
Abigail Cohen, NP 
Nicole Lestrange, NP 
Allison Tucker, NP 
Tara Wolff, NP 
Sheila Kenny, NP 
Leslie Eadon Blades, NP 
Carter Hibbs, NP 
Chelsea Mintz, NP 
Medicine, BMT  
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT  
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT  
 Medicine, BMT  
Medicine, BMT  
Medicine, BMT  
Medicine, BMT 
Medicine, BMT  
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, Renal  
Epidemiology and Biostatistics  
 Epidemiology and Biostatistics   
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 


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Page 2 of 33 
 
Emily Patterson, NP 
Naomi Cazeau, NP 
Christina Kiss, NP 
Meighan Palazzo, NP 
Courtney McElrath, NP 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Consenting 
Professional(s)/Department: 
Juliet Barker, M.B.B.S.  
Hugo Castro-Malaspina, M.D.  
David Chung, M.D., Ph.D. 
Parastoo Dahi, M.D. 
Sergio A. Giralt, M.D. 
Boglarka Gyurkocza, M.D. 
Ann Jakubowski Ph.D., M.D. 
Alan Hanash M.D., Ph.D. 
Katharine Hsu, M.D., Ph.D. 
Guenther Koehne M.D., Ph.D.  
Heather Landau, M.D. 
Esperanza Papadopoulos, M.D. 
Jonathan Peled, MD 
Miguel-Angel Perales, M.D.  
Doris Ponce, M.D.  
Craig Sauter, M.D. 
Brian Shaffer, M.D. 
Gunjan Shah, M.D. 
Melody Smith, M.D. 
Roni Tamari, M.D. 
 
Marcel RM van den Brink, M.D., Ph.D.  
James Young, M.D.  
Medicine, BMT  
Medicine, BMT  
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT  
Medicine, BMT  
Medicine, BMT 
Medicine, BMT 
Medicine, BMT  
Medicine, BMT  
Medicine, BMT  
Medicine, BMT  
Medicine, BMT 
Medicine, BMT  
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
Medicine, BMT 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065


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IRB#: 14-273 A (4) 
Approved: 25 Apr 2017 
 
 
Page 3 of 33 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 5 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .................................................................................. 6 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 6 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................ 8 
4.1 
Design ................................................................................................................................. 8 
4.2 
Intervention ......................................................................................................................... 9 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 10 
5.1 Melphalan (Alkeran ®) ........................................................................................................... 10 
5.2 Fludarabine (FLUDARA ®) .................................................................................................... 11 
5.3 Cyclophosphamide (Cytoxan ®) ............................................................................................ 11 
5.4 Mesna (Mesnex®) ................................................................................................................. 12 
5.5 Sirolimus ................................................................................................................................ 12 
5.6 Mycophenolate Mofetil (CellCept®)(MMF) ............................................................................. 12 
5.7 Filgrastim/ Granulocyte-Colony Stimulating Factor (Neupogen®) .......................................... 13 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................. 13 
6.1 
Subject Inclusion Criteria ................................................................................................... 13 
6.2 
Subject Exclusion Criteria ................................................................................................. 14 
7.0 
RECRUITMENT PLAN ......................................................................................................... 15 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 15 
9.0 
TREATMENT/INTERVENTION PLAN .................................................................................. 16 
9.1 RIC  allogeneic HSCT conditioning ........................................................................................ 16 
9.2 Cyclophosphamide administration ......................................................................................... 16 
9.3 Additional GVHD prophylaxis ................................................................................................. 16 
9.4 Prophylaxis against infections ................................................................................................ 16 
9.5 Enrollment ............................................................................................................................. 17 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 17 
10.1 Post-transplant evaluation .................................................................................................... 17 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................... 19 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 23 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 25 
14.0 BIOSTATISTICS .................................................................................................................. 25 
15.0  RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 26 
15.1 Research Participant Registration ..................................................................................... 26 
15.2 Randomization .................................................................................................................. 27 


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16.0 DATA MANAGEMENT ISSUES ........................................................................................... 27 
16.1 Quality Assurance ............................................................................................................. 27 
16.2 Data and Safety Monitoring ............................................................................................... 27 
17.0 PROTECTION OF HUMAN SUBJECTS .............................................................................. 28 
17.1 Privacy .............................................................................................................................. 29 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................... 29 
17.2.1 ....................................................................................................................................... 30 
18.0 INFORMED CONSENT PROCEDURES .............................................................................. 30 
19.0 REFERENCES ..................................................................................................................... 31 
20.0 APPENDICES ...................................................................................................................... 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
This is a single center, pilot trial evaluating the safety of post transplant cyclophosphamide 
as GVHD prophylaxis alone following a conventional (unmodified) matched related or 
unrelated allogeneic hematopoietic stem cell transplant (HSCT) in patients with renal 
insufficiency.  Patients with acute lymphoblastic leukemia (ALL), acute myelogenous 
leukemia (AML), high risk forms of myelodysplastic syndrome (MDS), chronic myelogenous 
leukemia (CML) unresponsive or intolerant of TKIs, advanced myeloproliferative disease 
(MPD) and non Hodgkins lymphoma (NHL) who fulfill eligibility requirements and consent to 
treatment will receive a reduced intensity (RIC) regimen followed by infusion of a  8/8 
matched related or unrelated donor stem cell graft.   
The RIC regimen will consist of melphalan plus fludarabine.   Patients eligible for this 
protocol are those who require a conventional graft but are at high risk of renal failure and 
other complications associated with the use of standard GVHD prophylaxis including 
calcineurin inhibitors.  They will receive post transplant cyclophosphamide (50 mg/kg/day IV) 
on days +3 and +4.  Bone marrow (BM) will be the preferred choice for the graft with 
peripheral blood stem cells (PBSC) as the secondary choice.  If PBSC grafts are used, the 
CD34+ cell dose will be capped to limit the number of CD3+ cells.   
Separately in the BM and PBSC cohorts, the trial design will de-escalate the GVHD 
prophylaxis to determine whether cyclophosphamide alone can be used. The general design 
of the trial will follow the 3-by-3 design typically used in phase I dose escalation trials.    
As shown in the table below, the BM cohort will first start with sirolimus (Siro) plus 
cyclophosphamide, which can be de-escalated if excessive grade IV GVHD is not observed. 
If excessive GVHD is observed at dose level 1 (Siro+ Cyclophosphamide), a dose level -1 
will be explored and mycophenolate (MMF) will be added to the regimen. 
BM De-escalation  
Level  
Prophylaxis  
-1 
MMF + Siro+ 
Cyclophosphamide 
1 
Siro+ Cyclophosphamide 
2 
Cyclophosphamide 
 
The table below describes the de-escalation in the PBSC cohort. If excessive GVHD is 
observed in dose level 1 (MMF+Siro+ Cyclophosphamide), a dose level -1 will be explored 
and methylprednisolone will be added to the regimen. 
 
 
 
 
 
 
 
 


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Page 6 of 33 
 
PBSC De-escalation  
Level  
Prophylaxis  
-1 
Methylprednisolone+ 
MMF+ Siro+ 
Cyclophosphamide 
 
1 
MMF+ Siro+ 
Cyclophosphamide 
2 
Siro+ Cyclophosphamide 
3 
Cyclophosphamide 
 
This protocol offers a strategy for post transplant cyclophosphamide as primary GVHD 
prophylaxis and is novel in the capping of the CD34/CD3 dose and employing GVHD 
prophylaxis that is not renal toxic.   
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
1) To evaluate a safe minimal combination of GVHD prophylaxes for patients with renal 
insufficiency not appropriate for standard calcineurin inhibitor prophylaxis who receive a 
bone marrow (BM) or peripheral blood stem cell (PBSC) (with limited CD34 and T cell 
dosing) grafts.   
Secondary objectives 
1) To assess overall incidence of acute and chronic GVHD by 2 years 
2) To assess 100-day transplant-related mortality 
3) To assess the incidence of graft failure. 
4) To assess 2-year overall survival (OS) and disease-free survival (DFS) 
5)  To determine  
a) the incidence acute renal insufficiency, requiring dialysis 
b) the worsening of chronic renal insufficiency  
6)    To assess infectious complications 
7)  To evaluate the time to immune reconstitution, defined as PHA >50% LLN and 
CD4>200 
3.0 
BACKGROUND AND RATIONALE 
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after 
allogeneic hematopoietic stem cell transplantation (HSCT).  While the incidence of severe 
acute GVHD has declined over the past decade, up to 70% of patients continue to develop 
grade 2-4 acute GVHD following a well matched related or unrelated graft1.  Long-term 
immunosuppression is required in 30-40% of patients who develop GVHD1-6.   In the event of 
steroid-refractory disease, the mortality rate is in excess of 75%, often due to uncontrollable 
infectious complications7.       
 
Pharmacologic GVHD prophylaxis primarily includes the combination of a calcineurin 
inhibitor with methotrexate (MTX) or MMF1,8. Calcineurin inhibitor-based GVHD prophylaxis is 
associated with a large number of adverse effects, including nephrotoxicity4,9-12.  The use of 
calcineurin inhibitors in patients with poor renal reserve is often not feasible and potentially 
jeopardizes the individual’s ability to receive an unmodified graft.  Over the past decade, the 
Melphalan 70 mg/m2 d-6 and -5 
Fludarabine 25 mg/m2 d-6 - -2 
 


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Page 7 of 33 
 
incidence of nephrotoxicity within the first 100 days post transplant has  decreased 
dramatically.  However 43% of patients continue to develop a 2-3 fold rise in serum 
creatinine1.  Though rare, post transplant hemodialysis is required in 5% of patients1.  
Additionally, calcineurin-based prophylaxis offers suboptimal GVHD control.  Acute GVHD 
occurs in 18-40% of patients that receive an unmodified graft followed by conventional 
calcineurin inhibitor-based prophylaxis9,10. The incidence of chronic GVHD among individuals 
that receive standard pharmacologic prophylaxis ranges from 24-58%9,10.  Two large phase 
III studies have compared tacrolimus to cyclosporine in combination with MTX. Both trials 
showed a lower risk of acute GVHD for the tacrolimus arm, but similar survival9,10.  None of 
the currently used calcineurin inhibitor based acute GVHD regimens have had any significant 
impact in reducing the risk of chronic GVHD. Chronic GVHD has emerged as one of the most 
common and debilitating complications of allogeneic SCT and a major contributor to poor 
quality of life post SCT13.   
 
 
Three calcineurin inhibitor free GVHD strategies have been studied for acute GVHD 
prevention: 
1) 
T 
cell 
depletion 
of 
the 
donor 
graft2,6,14-24; 
2) 
post 
transplant 
cyclophosphamide25-29 and 3) sirolimus containing regimens30. Prospective comparisons of 
these methods are needed to determine potential benefits of one strategy over another as 
well as comparative effectiveness studies with other acute GVHD prophylaxis regimens in 
specific patient populations.  While MSKCC has expertise in TCD, which can be used in 
patients with renal insufficiency prior to transplant, the disease in many patients precludes its 
appropriateness for a potentially curative transplant.  Furthermore, although sirolimus can be 
used for patients with renal insufficiency,  it  has not demonstrated efficacy as first line 
therapy alone for acute GVHD prophylaxis in patients requiring a conventional graft.  Post 
transplant cyclophosphamide is associated with relatively low rates of grade III-IV acute 
GVHD and chronic GVHD6.  The GVHD control provided by post transplant 
cyclophosphamide is due to its ability to eliminate proliferating alloreactive T cells and 
preserve the expansion of CD4+CD25+CD127-FoxP3+ T cells (regulatory T cells or T-
regs)25-28.  Tregs are critically involved in the control of GVHD, through IL-10, TGF-beta, and 
direct cell-cell mechanisms31,32.  Conversely, calcineurin-based prophylaxis greatly impairs 
post transplant Treg expansion by suppressing vital IL-2-dependant signaling3,5,31,32.     
 
High-dose, post transplant cyclophosphamide is an effective form of GVHD prophylaxis, 
allowing for graft tolerance without sacrificing GvL.  Compared with calcineurin-based 
prophylaxis, only 5% of patients that receive post transplant cyclophosphamide develop renal 
toxicity25.  Preclinical murine transplant studies demonstrated that post transplant 
cyclophosphamide achieved successful engraftment of MHC-mismatched marrow, allowed 
for add-back donor lymphocyte infusions when challenged with a leukemia cell line, and 
controlled GVHD26,27.  In 2002, GVHD prophylaxis with high-dose post transplant 
cyclophosphamide was explored clinically in a phase I trial.  Thirteen patients received 
nonmyeloablative conditioning with fludarabine, cyclophosphamide, and TBI29.  GVHD 
prophylaxis consisted of post transplant cyclophosphamide 50 mg/kg once on day +4, and 
mycophenolate mofetil with tacrolimus beginning on day +529.  The trial demonstrated that 
post transplant cyclophosphamide was safe in combination with standard prophylaxis, 
without an unacceptable level of graft failure or relapse29.   
 
High-dose post transplant cyclophosphamide was later evaluated in a phase I/II trial of 68 
patients with high risk leukemia and lymphoid malignancies receiving grafts from HLA-
haploidentical related donors28.  The preparative regimen again consisted of fludarabine, 
cyclophosphamide, and TBI28.  High-dose cyclophosphamide was administered on day +3, or 
days +3 and +428.  MMF and tacrolimus were initiated the following day after completing the 
infusion of cyclophosphamide28.  While patients transplanted for lymphoid diseases 
performed statistically better, the overall and event-free survival was 36% and 26%.  The risk 
of relapse was 51% at 1 year28.   


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Page 8 of 33 
 
 
In 2010, GVHD prophylaxis with post transplant high-dose cyclophosphamide, without any 
additional pharmacologic immunosuppression, was studied in a phase I/II trial of  
advanced hematologic malignancies receiving BM grafts with a targeted total nucleated cell 
dose of  4 x 10 8/kg. 26 This study differed from the previous trials, in that all 117 patients 
received myeloablative conditioning with busulfan and cyclophosphamide.  Overall, the 
incidence of graft failure was low, with a total of 5 patients developing primary or secondary 
graft failure.  The day +100 cumulative incidence of grade II-IV acute GVHD for all patients 
was 43%.  The cumulative incidence of relapse at 2 years was 44%.  The OS at 2 years after 
BMT was 55%.  No significant difference in grade II-IV GVHD, relapse, or OS was observed 
between the recipients of related or unrelated donor grafts.  Additionally, the cumulative 
incidence of chronic GVHD was 10% at 2 years.  The trial demonstrated that post transplant 
cyclophosphamide alone in this protocol design offered prophylaxis for acute GVHD, limited 
chronic GVHD, facilitated stem cell engraftment, and was safe in patients with serum 
creatinine levels up to 2.5 mg/dL.    
 
In the last few years,  publications have been predominantly retrospective  but have included 
patients who received some GVHD prophylaxis (mostly including calcineurin inhibitors), 
limited if any patients with renal insufficiency, and most using bone marrow rather than PBSC 
grafts.  Two have started to limit the number of CD34+ cells in the graft as proposed in this 
study. 32-34 
 
Currently, the criteria for renal function employed in most of the transplant protocols  is a 
serum creatinine within the normal range, or if not in the normal range, a creatinine clearance 
(CrCl)  of > 50 or MDRD >  60 ml/min.   Generally, lean body mass (which is the source of 
creatinine) decreases with age. But renal function also declines, resulting in less CrCl. Serum 
creatinine in the older patients will not increase until 50% of nephrons are no longer 
functional and thus a normal creatinine is not a reliable indicator of adequate renal function. 
Because of these age-related changes and those associated with lean body mass, which can 
change significantly in patients with cancer, any elevation of creatinine is significant. Thus 
serum creatinine is not a reliable indicator of renal function in the older or debilitated patient, 
renal function is best assessed and monitored with CrCl or MDRD. For patients with reduced 
renal function, the preference for transplant at MSKCC has been to offer a TCD transplant 
which markedly reduces the need for nephrotoxic drugs that can further impact negatively on 
the renal function and transplant outcome.  For patients with persistent disease at the time of 
transplant, a TCD transplant is not an appropriate option and the general practice is to offer a 
conventional transplant which requires the use of calcineurin inhibitors for GVHD 
prophylaxis. The calcineurin inhibitors can result in the development of renal insufficiency or 
can exacerbate renal insufficiency that is already present.  If the patient is unable to receive 
a calcineurin inhibitor around the time of the transplant there is a high likelihood that they will 
develop severe GVHD which is often lethal. Thus patients with significant renal insufficiency 
are usually  not considered candidates for conventional transplants and thus may not be 
eligible for any transplant which could be curative for their disease.  The approach described 
here offers these patients an option. 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This is a single center, pilot trial evaluating the safety of post transplant cyclophosphamide  
as GVHD prophylaxis following a matched related or unrelated allogeneic hematopoietic 


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Page 9 of 33 
 
stem cell transplantation.  Patients with ALL, AML,  high risk forms of MDS, CML intolerant of 
or unresponsive to TKIs, advanced MPD,  and NHL who fulfill eligibility requirements and 
consent to treatment will receive a reduced intensity (RIC) conditioning regimen with a  8/8 
matched related or unrelated donor stem cell graft per MSKCC protocol. If  PBSC are used, 
the CD34+ cell dose will be capped to limit the number of CD3+ cells. To investigate whether 
Cyclophosphamide alone can be used as GVHD prophylaxis, both cohorts will receive 
additional prophylaxis initially which will be removed if excessive grade IV GVHD at day +100 
is not observed. The de-escalation schema will follow a 3-by-3 strategy typically used in dose 
escalation studies. Two days of posttransplant cyclophosphamide will be the main form of 
GVHD prophylaxis administered on d+3 and d+4 to all patients. Additional GVHD prophylaxis   
will be given initially until it is evident that the risk of grade IV GVHD is low. If acute grade III- 
IV GVHD  exceeds  33% in any group, the posttransplant prophylaxis in subsequent patients 
will be increased to that used in the previous cohort.  If excessive grade III-IV GVHD occurs 
in the first cohort of patients receiving PBPC grafts, methylprednisolone 0.5 mg/kg daily will 
be added to the Siro, MMF and cyclophosphamide, and an additional 3-6 patients who 
receive PBPC grafts will be treated with that regimen. If excessive grade III-IV GVHD occurs 
in the first cohort of patients receiving BM grafts MMF  will be added to the Siro.  For patients 
who develop  GVHD, immunosuppressives may be continued for longer time periods 
according to standard of care guidelines. If no GVHD develops, immunosuppression should 
begin to be tapered at approximately d100 and a plan to be off immunosuppression by 9 
months.    Patients with persistent GVHD while on Siro, MMF and topical steroid therapies 
should be treated with methylprednisolone 1-2.5 mg/kg daily.  This protocol offers a strategy 
for post transplant cyclophosphamide as GVHD prophylaxis specifically for patients at high 
risk of complications from the use of calcineurin inhibitors. Conditioning will be a RIC 
regimen.  
 
4.2 
Intervention 
Patients ineligible/inappropriate for a TCD graft or at increased risk of transplant related 
complications associated with the use of standard calcineurin inhibitor GVHD prophylaxis 
who carry a diagnosis of ALL, AML,  high risk forms of MDS, CML resistant to, intolerant to or 
progressing on TKIs, accelerated phase CML or treated blast crisis of CML, advanced MPD  
and NHL and who fulfill eligibility requirements and consent to treatment, will receive a RIC 
conditioning regimen with a 8/8 matched related or unrelated donor stem cell graft.  The RIC 
conditioning will consist of melphalan 70 mg/m 2 x 2 days plus fludarabine 25 mg/m 2 x 5 
days.  GVHD prophylaxis with posttransplant  cyclophosphamide 50 mg/kg/day on days +3 
and +4 will be given to all patients. The de-escalation of GHVD prophylaxes for the BM and 
PBSC cohorts are described in the two tables below. 
BM De-escalation  
Level  
Prophylaxis  
-1 
MMF + Siro+ 
Cyclophosphamide 
1 
Siro+ Cyclophosphamide 
2 
Cyclophosphamide 
 
PBSC De-escalation  
Level  
Prophylaxis  
-1 
Methylprednisolone+ 
MMF+ Siro+ 
Cyclophosphamide 


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1 
MMF+ Siro+ 
Cyclophosphamide 
2 
Siro+ Cyclophosphamide 
3 
Cyclophosphamide 
 
The cell dose for BM grafts will be targeted for 4 x 10 8TNC/kg, and PBPC grafts will be 
capped at 3 x 106 CD34/kg in order to limit the T cell dose.  For the groups of patients who 
are to receive Siro +/- MMF, immunosuppressive drugs will begin on d+5.  Siro trough level 
will be targeted for 3-15 mcg/ml.  Mesna will be given as per MSKCC guidelines to reduce 
the toxicity of the cyclophosphamide. Neupogen can be given beginning at d+7. 
 
 
 
 
 
 
 
 
 
 
 
 
Melphalan 70 mg/m 2/d will be administered intravenously on d-6 and -5 
Fludarabine 25 mg/m 2/d will be administered intravenously on d-6 thru -2 
Day -1 will be a day or rest  
Cyclophosphamide and mesna will be given on d+3 and +4 
Siro +/- MMF will be started in those patients who are to receive it on d+5. . 
Neupogen will begin d+7.  
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 Melphalan (Alkeran®) 
Source and pharmacology: Supplier: Glaxo Wellcome. A derivative of nitrogen mustard, an 
analog of mustard gas.  It is a polyfunctional alkylating agent that causes miscoding, 
cross-linkage of DNA, and single-strand breakage of DNA.  It inhibits cellular 
glycolysis, respiration, and protein synthesis.  It is cell cycle-phase non-specific.   
8/8


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Formulation and stability: A lyophilized powder of 50 mg melphalan and 20 mg povidone per 
vial.  Also provided is 10 ml of sterile diluent for use in reconstituting the product and a 
0.45 micron filter.    The special diluent has the following composition: Sodium citrate 
0.2 g, Propylene glycol 6.0 ml, Ethanol (95%) 0.5 ml, and sterile water 10 ml.   
Solution preparation:   
1. Vial/50 mg: Reconstitute by rapidly injecting 10 ml of the supplied diluent into the 
vial to yield a final concentration of 5 mg/ml.  
2. Shake vigorously until the solution is clear.   
3. Immediately dilute the dose to be administered in 0.9% Sodium Chloride, USP, to 
a concentration no greater than 0.45 mg/ml 
Storage and stability:  The intact packages should be stored at room temperature (15-30°C) 
protected from light. Shelf-life surveillance of the intact dosage form is ongoing.  
Constitution with the special diluent as directed results in a solution that retains at 
least 90% potency for about three hours at 30°C.  Storage at 5°C results in 
precipitation. 
Administration:  Intravenous, over 30 minutes. Complete infusion within 60 minutes of 
preparation. 
 
5.2 Fludarabine (FLUDARA®) 
Supplied as: 50mg vial  
Reconstitution directions: add 2ml of sterile water for injection to a 50mg vial; yields a final 
concentration of 25 mg/ml.  
Storage and stability:  
1. Store vials under refrigeration.  
2. Refrigerated: prepare infusion in D5W; stable for 16 days.  
3. Room temperature: prepare infusion in D5W; stable for 16 days.  
Solution Preparation:  
1. Standard iv fluid: D5W.  
2. Final infusion concentration range: up to 10mg/ml.  
3. IV piggyback volume: 50 cc.  
Clinical considerations:  
1. Hydration: during 500 cc saline.  
2. Emetic potential: low.  
3. Supportive medications: none.  
Toxicities: see Section 11.5.1 
Incompatibilities: acyclovir, amphotericin B, chlorpromazine, daunorubicin, ganciclovir, 
 
 
hydroxyzine, miconazole, prochlorperazine. 
5.3 Cyclophosphamide (Cytoxan ®) 
Supplied as: 200 mg, 500 mg, 2000 mg vials  
Reconstitution directions: add sterile water for injection to yield a final concentration of 20 
mg/ml.  
Storage and stability:  
1. Store vials at room temperature.  
2. Refrigerated: prepare infusion in D5W, stable for 28 days.  
3. Room temperature: prepare infusion in D5W: stable for 48 hours  
Solution Preparation:  
1. Standard iv fluid: D5W.  
2. Final concentration range up to: 20mg/ml.  


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3. IV piggyback volume: for doses < 1200mg/m2, infuse in 25cc D5W; for doses> 
1200mg, infuse as straight drug.  
Clinical considerations:  
1. Hydration: as per MSKCC guidelines for BMT patients receiving > 3000 mg/m2.  
2. Emetic potential: high and delayed.  
3. Supportive medications: anti-emetics and mesna.  
Toxicities: see Section 11.5.2  
  Incompatibilities: do not administer with other drugs.  
 
5.4 Mesna (Mesnex®) 
Supplied as: 200 mg/2 ml ampule, 1 gram/10 ml multi-dose vials  
Reconstitution: not applicable.  
Storage and stability:  
1. Store vials at room temperature.  
2.  Multi-dose vials may be stored and used for up to 8 days after initial entry.  
3.  Infusions prepared in D5W are stable for 48 hours when stored under refrigeration or 
at room temperature.  
Solution Preparation:  
1. Must be diluted prior to infusion  
2. Standard IV fluid: D5W.  
3. IV piggyback volume: 50ml D5W  
Usual Dosage and administration: 100% of the total cyclophosphamide dose divided into 
3 doses, and administered at 30 minutes prior to and 4 and 8 hours after the start of 
the chemotherapy. Given as IVPB over 15 minutes.  
Clinical Considerations: mesna functions solely for uroprotection to prevent hemorrhagic 
cystitis and has no cytotoxic activity.  
Toxicities: none.  
Incompatibilities: Carboplatin, Cisplatin, and Epirubicin.  
 
5.5 Sirolimus 
Indications: Immunosuppressant used in the prevention of graft-versus-host-disease (GVHD) 
following allogeneic bone marrow transplantation. 
Storage and Stability: Oral solution: Store under refrigeration, 2°C to 8°C (36°F to 46°F). 
Protect from light. A slight haze may develop in refrigerated solutions, but the quality of 
the product is not affected. After opening, solution should be used in 1 month. If 
necessary, may be stored at temperatures up to 25°C (77°F) for ≤15 days after 
opening. Product may be stored in amber syringe for a maximum of 24 hours (at room 
temperature or refrigerated). Solution should be used immediately following dilution. 
Tablet: Store at room temperature of 20°C to 25°C (68°F to 77°F). Protect from light 
Toxicities: see section 11.0 
 
5.6 Mycophenolate Mofetil (CellCept®)(MMF) 
Supplied as: 500 mg vial of powder for reconstitution. 
Reconstitution: reconstitute each 500 mg vial with 14 ml of D5W only. Gently shake the vial 
to dissolve the drug. The vial will contain 500 mg of mycophenolate in approximately 
15 ml.  


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Storage and Stability: Store at 15 -30C. Drug compatible with D5W only. A final 
concentration of 6mg/ ml must be achieved prior to administration. Reconstituted 
vials and IV preparations are stable for up to 4 hours after preparation.  
Solution Preparation:  
1. Reconstitute each 500 mg vial with 14 ml of D5W. 
2. Gently shake the vial to dissolve the drug. 
3. Drug must be further diluted to a final concentration of 6 mg/ml. A 1000 mg dose 
should be placed in 140 ml of D5W. 
4. MMF vials are stable for 4 hours at room temperature after reconstitution. 
5. Doses of MMF may begin infusion into the patient up to 4 hours after initial 
reconstitution of the vials.  
 
Clinical Considerations: administer only with D5W, over at least 2 hours. Mycophenolate is 
mutagenic, carcinogenic, and teratogenic. Precautions must be taken when handling 
this product. If medication comes in contact with skin, wash thoroughly with soap and 
water.  
Toxicities: see section 11.0 
Incompatibilities: Only compatible with D5W.  
 
5.7 Filgrastim/ Granulocyte-Colony Stimulating Factor (Neupogen®)  
Supplied as: 300 mcg/ml; 1 ml vial (300 mcg) and 1.6 ml vial (480 mcg); 300 mcg/0.5 ml pre 
filled syringe; 480 mcg/0.8 ml pre-filled syringe.  
Storage and Stability: Store in a refrigerator (2-8°C). Do not freeze. If inadvertently the 
filgrastim is exposed to freezing temperatures for up to 24 hours, it may be thawed 
and refrigerated for use. Avoid shaking. Filgrastim may be allowed to reach room 
temperature for 24 hours prior to use.  
Solution Preparation:  
1. For IV infusion, dilute filgrastim in 25-50 ml D5W.  
2. The minimum concentration must not be less than 5 mcg/ml.  
3. If the final concentration of filgrastim in solution is between 5-15 mcg/ml, albumin 2 
mg/ml must be added to the solution prior to addition of the drug.  
4. Stability (IV) once diluted in 25-50 ml of D5W, filgrastim is stable for 7 days.  
5. Stability (plastic syringe) filgrastim is stable for two weeks in BD 1 ml plastic TB 
syringes at 2-8°C.  
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
 
Age: Patients over age 18 who are deemed eligible for transplant by their treating 
physician.  
 
Disease status:  
1.  AML in ≥ 1st remission - excluding those in 1st remission with ‘good risk’ 
cytogenetic features (i.e. t(8;21), t(15;17), inv 16).   
2. Secondary AML   
3. ALL/LL in 1st remission with clinical or molecular features indicating a high risk for 
relapse; or ALL > 2nd remission   


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4. CML failing to respond to, progressing on or not tolerating appropriate TKI therapy in 
first chronic phase of disease; CML in accelerated phase, second chronic phase, or in 
CR after accelerated phase or blast crisis.   
5. Non-Hodgkins lymphoma with chemoresponsive disease in any of the following 
categories:   
a. high grade lymphomas who have failed to achieve a first CR or have relapsed 
following a 1st remission who are not candidates for autologous transplants or 
transplants requiring the use of calcineurin inhibitors.   
b. any NHL with therapy responsive disease which is considered not curable 
outside the transplant setting and not eligible/appropriate for autologous 
transplant or a higher priority protocol.   
6. Myelodysplastic syndrome (MDS): RA/RCMD with high risk cytogenetic features or 
transfusion dependence, RAEB-1 and RAEB-2 and AML evolved from MDS, who are 
not eligible for a higher priority protocol.   
7. Chronic myelomonocytic leukemia: CMML-1 and CMML-2, advanced polycythemia 
vera, and myelofibrosis.   
a.  Patients must have a healthy HLA compatible ( 8/8 molecularly matched 
related, or unrelated) donor willing to undergo BM harvesting or  PBSC 
apheresis after G-CSF administration.  BM will be the preferred graft source.     
b. Patients diagnosed with any form of acute leukemia must  have received 
induction and at least one course of consolidation chemotherapy pretransplant   
 
Patients must have a Karnofsky Performance Status > 70%   
 
Patients will have a eGFR <60 ml/min/1.73 m2  
1. Patients must have adequate organ function measured by:  Cardiac: 
asymptomatic or if symptomatic then LVEF at rest must be > 50% and must 
improve with exercise.   
2. Hepatic: ALT < 3 x ULN and total serum bilirubin < 1.5 x ULN, unless there is 
congenital benign hyperbilirubinemia 
3. Renal: eGFR > 30 ml/min/1.73 m2  
4. Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected 
for hemoglobin)   
 
Each patient must be willing to participate as a research subject and must sign an 
informed consent form.  
 
Patient must have a fully  matched related or unrelated donor willing to donate stem cells.   
6.2 
Subject Exclusion Criteria 
 
Major surgery or irradiation within two weeks.  
 
Active CNS or extramedullary malignant disease.  
 
Active and uncontrolled infection at time of transplantation including active infection with 
Aspergillus or other mold, or HIV infection 
 
Pregnant or lactating women – they are excluded, given the potential teratogenic effects 
of chemotherapy and agents used in the transplant.   
 
Male and female patients of child-bearing potential unwilling to use effective means of 
contraception   
 
HIV or HTLV I/II positive, hepatitis C or chronic active hepatitis B. 
 
Patients who have had a previous malignancy unless they are deemed by their treating 
physicians to be at low risk for recurrence. 


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 
Patient or guardian unable to give informed consent or unable to comply with the 
treatment protocol including appropriate supportive care, follow-up and research tests. 
 
 
7.0 
RECRUITMENT PLAN 
An attending physician of the  Adult BMT service will recruit and consent patients who fulfill the 
eligibility criteria as listed in Section 6.0 for this study. The estimated time to enroll the necessary 
number of patients is 5 years.     
 
This protocol will take due notice of NIH/ADAMHA policies concerning inclusion of women and 
minorities in clinical research populations. We expect that the study population will be fully 
representative of the range of patients referred for transplant without exclusion as to age, gender, 
or ethnic background.  Pregnant women are excluded from participation in this study. 
 
Any healthy family member will be considered for stem cell donation. Selection of a donor will be 
based on matching of HLA-A, B, C, and DR loci .  A prospective donor must be a 8/8 HLA match 
(HLA-A, B, C, DR, DQ) – all typing will be determined at the DNA level.  The related donors will 
provide signed informed consent to undergo a BM harvest or to receive a 5-6-day course of G-
CSF and to undergo two PBSC leukaphereses.   In addition, if the PBSC collection is determined 
to be inadequate, the donor should agree to undergo a BM harvest under general anesthesia if 
additional stem cells are needed. The related donor will undergo a medical evaluation as per the 
BMT Service. 
 
If an adequate related donor is not identified, a search will be conducted through the National 
Marrow Donor Program and individual registries.  Screening and harvests will be conducted as 
per the NMDP guidelines. The unrelated donor must be a 8/8 HLA molecular match. 
8.0 
PRETREATMENT EVALUATION 
The following tests are required within 30 days prior to beginning the conditioning regimen or 
sooner as clinically indicated. 
 Complete history and physical examination (including Karnofsky performance status) 
 CBC, comprehensive panel (defined previously), LDH, PT/PTT 
 Bone marrow aspiration, with cytogenetics and molecular studies when clinically 
indicated. Radiologic imaging studies as clinically appropriate for diseases staging. 
 Serum or urine HCG in women of childbearing potential 
 EKG 
 Urinalysis, eGFR and Renal Service consultation based on discussion with a Renal 
Service attending. 
 Chest x-ray 
 Red blood type and screen 
 STR on donor and patient  
 Serologic/PCR testing for transmittable diseases 
 Stress echocardiogram or stress MUGA and PFTs  
 
 


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9.0 
TREATMENT/INTERVENTION PLAN 
 
 
 
 
 
 
 
 
 
9.1 RIC  allogeneic HSCT conditioning 
 
Melphalan 70 mg/m2 x 2 days d -6 and -5 and fludarabine 25 mg/m2 x 5 days days -6 
thru  -2. There will be no adjustment of the chemotherapy based on renal function:  
Cell dose for BM grafts will be targeted for 4 x 108 TNC/kg, and PBSPC grafts will be 
capped at 3 x 106 CD34/kg  
 
There will be no adjustment of the chemotherapy based on renal function:   
 
Cell dose for BM grafts will be targeted for 4 x 10e8 TNC/kg, and PBSPC grafts will 
be capped at 3 x 10e6 CD34/kg. 
 
9.2 Cyclophosphamide will be administered at 50 mg/kg/day IV on days +3 and +4 post 
transplantation 
 
Dosing will be based on ideal body weight 
 
Mesna will be administered IV at 80% of the cyclophosphamide dose, in 4 divided 
doses, on days +3 and +4 post transplantation. 
 
9.3 Additional GVHD prophylaxis 
 
As shown in the tables in section 4.2, additional GVHD prophylaxes are initially 
provided. Siro standard starting dose consists of  6 mg PO loading dose, with a 
maintenance dose started 24 hours later at 2 mg PO/day. MMF dosing is 1g IV q8h 
for patients >50 kg. Both will begin on d+5 and will be titrated to standard trough 
levels. 
 
If no acute GVHD develops, Siro +/- MMF will begin being  titrated down at d+100. 
 
9.4 Prophylaxis against infections  
 
Standard of care guidelines will be followed for prophylaxis against post transplant 
infections by opportunistic organisms, including Pneumocystis jiroveci, fungal 
organisms, DNA herpesviruses and more specifically CMV. 
 


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9.5 Enrollment 
 
All patients may be entered into a new cohort level only after 3 patients have been 
treated at the previous level and survived to D+100 +/- 5 days without developing 
grade IV GVHD. 
 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
10.1 Post-transplant evaluation 
a. Clinical Assessments: Patients will receive physical examinations daily while an 
inpatient with particular attention to assessment of potential toxicities induced by 
preparatory cytoreductive therapy, including mucositis, cystitis, sepsis, pneumonia, 
veno-occlusive disease (VOD) and transplant- associated complications including graft 
failure, acute and chronic GVHD, renal insufficiency/failure, and transplant associated 
infections. Patients are closely monitored for alterations in vital signs, weight, oral and 
intravenous intake, and intestinal and urinary output. Cardiac assessments are obtained 
prior to admission to assess cardiac function and thereafter when clinically indicated. 
Pulmonary status is closely monitored when clinically indicated by radiographic and 
functional analysis. Following discharge, patients will receive physical examinations 
during outpatient visits as described in the table below. Women at risk of menstruating 
will receive hormone supplementation to prevent  bleeding during periods of 
thrombocytopenia.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedures 
Pre-
treat 
Days Post-Transplant 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
100 
6 mts 
9 
mts 
12 mts 
18 
mts 
24 
mts 
Window 
30 
(+/-) 3 
(+/-) 7 
(+/-) 14 
(+/-) 30 
Eligibility 
X 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History/Physical 
X 
 
 
 
 
 
Dental 
Evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
Chemistry/CMP 
(1) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
 
 
 
 
 
Blood Type and 
screen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology 
Testing (2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
if applicable 
(childbearing 
age) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
EKG and echo 
or MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT 
chest/abd/pelvis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT 
X 
 
 
 
 
 
Chest x-ray 
X 
 
 
 
 
 
Bone marrow 
aspirate and 
biopsy  
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X* 
X 
X 
X 
Flow 7 
lymphocyte 
panel 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X* 
X 
X* 
X* 
Peripheral 
blood 
lymphocyte 
(PBL) (3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X* 
X* 
X* 
X 
X* 
X* 
Chimerism 
(Blood and BM) 
(4) 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
Disease 
Assessment (5) 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
GvHD 
evaluation 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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*if clinically indicated 
(1) BUN, creatinine, electrolytes, glucose, total protein, albumin, AST, ALT, bilirubin, alkaline phosphatase 
(2) CMV, Herpes Zoster, Herpes Simplex, Hepatitis B, Hepatitis C, EBV, Syphilis and Toxoplasmosis 
(3) In vitro response of PBL to mitogen = PHA.  
(4) Chimerism at baseline (pretreatment)  can be either blood or bone marrow 
(5) Includes bone marrow aspirate and/or biopsy for patients with MDS, acute or chronic leukemia, CLL.  
Patients with lymphoma or extramedullary leukemia will undergo CT scans.  Radiology disease 
assessments are not needed on Day 28. 
 
 
 
 
11.0 TOXICITIES/SIDE EFFECTS 
Toxicities will be graded per the BMT Service SAE Guide using the NCI-Common 
Terminology for Adverse Events (CTCAE), version 4.0.  Patients recruited to this 
transplantation trial are individuals who are either referred by physicians or self-referred for 
marrow transplantation as a potentially curative treatment for their malignancy. Prior to 
consideration for transplant, all patients undergo a series of consultations discussing the 
risks and potential benefits of an allogeneic stem cell transplantation and the different 
procedures which will be a normal part of the transplant course. The risks and potential 
Toxicity 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 


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benefits of the transplant procedure are also discussed.  This protocol offers a strategy for 
post transplant cyclophosphamide as GVHD prophylaxis.   
 
11.1 General Description of Risks to Recipients 
Infections and hemorrhage constitute major and continuing risks throughout the period of 
marrow aplasia. These are, however, also the major risks associated with the primary 
disease. Certain opportunistic infections remain a risk in transplant patients beyond recovery 
of circulating leukocytes, for at least 9-12 months post-transplant, e.g. Pneumocystis carinii, 
cytomegalovirus and Epstein Barr virus. 
 
11.2 Melphalan 
 
Likely side effects include myelosuppression, fatigue, not sleeping well, anorexia, 
nausea, vomiting, diarrhea, mucositis weight gain and swelling, changes in blood sodium 
level, alopecia, needing transfusions of platelets and red blood cells, fever, needing 
antibiotics to treat infection, transient liver dysfunction. 
 
Less likely side effects include Late effects of these chemotherapy agents include: 
cataracts and under-activity of the thyroid gland. Both of these side effects can be easily 
treated. Renal or bladder dysfunction (increased BUN, creatinine, necrosis) may be seen. 
 
Rare but serious side effects include pulmonary fibrosis, respiratory distress has been 
rarely reported. Serious hypersensitivity reactions: Edema, rash, anaphylaxis 
11.3 Fludarabine  
 
Likely side effects include Myelosuppression, tiredness, not sleeping well, anorexia, 
nausea, vomiting, diarrhea, mucositis weight gain and swelling, changes in blood sodium 
level, alopecia, needing transfusions of platelets and red blood cells, fever, needing 
antibiotics to treat infection, jaundice and elevations of liver enzymes 
 
Less likely side effects include late effects of these chemotherapy agents include: 
cataracts and under-activity of the thyroid gland. Both of these side effects can be easily 
treated. confusion, numbness, loss of vision, loss of balance, difficulty walking 
 
11.4 Sirolimus 
 
Likely side effects include immune suppression which leads to increased risk for 
infection. This is managed with aggressive supportive care with both prophylaxis and 
treatment of infectious complications. hypertriglyceridemia, Hypercholesterolemia, mild 
thrombocytopenia, anemia, leukopenia, hypokalemia, elevated LDH, arthralgia, epistaxis, 
edema, and infections.   
 
Rare but serious side effects a syndrome of thrombotic microangiopathy, comprised of 
microangiopathic hemolytic anemia, thrombocytopenia and renal dysfunction has been 
described in association with Siro and tacrolimus use. 
 
11.5 Mycophenolate 


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 
Likely side effects include immune suppression which leads to increased risk for 
infection. This is managed with aggressive supportive care with both prophylaxis and 
treatment of infectious complications. 
 
Less likely side effects include myelosuppression, headache, insomnia, aches and pains, 
rash, nausea, anorexia and diarrhea.  
 
 Less likely side effects include a very rare side effect known as Progressive Multifocal 
Leukoencephalopathy (PML), which is a progressive disease of the nervous system that 
can cause severe disability or death.  A very small number of cases of PML have been 
reported in patients treated with MMF.  PML can cause hemiparesis, confusion, cognitive 
deficiencies and ataxia. 
Likely  
Reproductive risks: Sterility. Male patients may be offered sperm banking before admission 
for the transplant. Possibilities of preserving the ability to have children for female patients 
can be discussed with the doctor. Patients should not become pregnant or father a baby 
while on this study because the drugs in this study can affect an unborn baby. Women 
should not breast feed a baby while on this study. A pregnancy test is required of all females 
of childbearing age before starting the transplant.  
Growth factor (G-CSF): Bone pain, headache, body ache, feeling tired, swelling of 
hands/feet, nausea. These are generally mild and will go away when the growth factor is 
stopped. 
 
 
Transplant related risks 
Blood transfusions: Transfusions may induce allergic reactions. Small, subclinical 
pulmonary emboli may occur, but these rarely if ever require any intervention. Standard pre-
medications for blood products may be used before administration of the marrow graft. Fluid 
overload can be managed with diuretics. Allergic reactions of variable severity can be 
prevented or mitigated by premedication with antipyretics, antihistamines, and narcotics.  
These products may also serve as vectors of serious infection (e.g., CMV, hepatitis, AIDS). 
To circumvent this, prospective blood and marrow donors will be screened per AABB and 
FAHCT guidelines. CMV antibody (-) blood products will be used in CMV(-) individuals, 
whenever possible, regardless of the antibody status of the marrow donor. All blood products 
are irradiated (3000r, 137Cs) to circumvent the risk of GvHD caused by contaminating 
lymphocytes in the transfused fractions. 
 
Receiving BM or PBSC: The volume of the graft infused can be up to approximately 1500 
cc. Possible side effects include: changes in blood pressure, fever, headache, shortness of 
breath, chills, sweats, nausea/vomiting, bad taste in the mouth. Pre-medications are given to 
reduce these side effects. Reactions will be treated as per standard MSKCC guidelines.  
 
Graft-versus-host-disease (known as GvHD): This condition happens when the 
transplanted donor cells recognizes the patient’s body as foreign and attacks it. Approx. 30-
50% of patients receiving conventional grafts  will develop grade II-IV acute GvHD. GvHD 
can be treated with medications (either IV or tablets). A biopsy may be necessary to make 
the diagnosis of GvHD.  
 


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Acute GvHD usually occurs in the first 3 months or as immune suppressive medications are 
tapered and may cause: skin rashes, nausea, vomiting, diarrhea, hepatitis, increased risk of 
infection, ulceration of the surfaces of the oral cavity, esophagus, and intestines, and 
suppressed or delayed recovery of the hematopoietic and immune system. The incidence in 
previous reports using BM is approx. 50%, the incidence may be higher using PBPC grafts.  
 
Chronic GvHD can occur any time after the first 3 months. Approximately 50% of patients 
with acute GvHD may also develop chronic GvHD, manifested to varying degrees by 
scleroderma-like changes of the skin, cirrhosis of the liver, sclerosis of lacrimal and salivary 
ducts, chronic inflammation and scarring of the gastrointestinal tract with consequent 
malabsorption and diarrhea, chronic bronchitis, and suppression of the immune system. This 
can be treated with standard or protocol-based experimental immunosuppression, but may 
be refractory. 
 
Severe GVHD: Rarely, GvHD can be severe or deadly. Severe acute GvHD could involve a 
severe skin rash like a burn, severe vomiting and/or diarrhea, liver failure and infections or 
bleeding. Severe acute GvHD will be treated with intense immunosuppressive therapy 
according to standard clinical practice or other experimental protocol. Severe chronic GvHD 
could involve similar symptoms but may produce other symptoms such as severe skin 
changes, severe dry eyes and weight loss. 
 
Steroids, as treatment for GvHD: inability to sleep, high blood sugar, puffiness of the face, 
changes in the skin, high blood pressure, increased risk of infection, weight gain, reduced 
growth in children, thinning of the bones 
 
Infections or bleeding: Full recovery of blood counts may take months. Full recovery of the 
immune system may take months to a few years. For this reason patients will be at increased 
risk of infections and bleeding. Medications are given to reduce the chance of those 
infections.  Patients will receive treatment if they do get an infection and most infections can 
be treated successfully with antibiotics. Patients will stay in the hospital longer or be 
readmitted if found to have an infection. Patients are watched closely for bleeding and given 
platelet transfusions to prevent serious bleeding, but minor bleeding may occur. 
 
Serious infections or bleeding: Some infections are very difficult to treat, even with strong 
antibiotics. Rarely, serious infections can be passed on by the transfusion of blood products. 
Serious bleeding can happen in spite of platelet transfusions. Rarely infections or bleeding 
are lethal. 
 
Pneumocystis jiroveci prophylaxis: The risk of trimethoprim and sulfamethoxazole in the 
doses given are primarily hypersensitivity reactions and signs of folate deficiency. Any 
patient with known hypersensitivity to these compounds will not receive these drugs. The 
risks of parenteral pentamidine are primarily hypotension and hypoglycemia both of which 
will be monitored during and following administration of the drug. Hypokalemia or 
hypomagnesemia associated with prolonged QT syndrome or Torsade de pointe 
necessitates strict electrolyte monitoring. The risks of aerosolized pentamidine are mild 
bronchospasm primarily observed in (prior) tobacco abusers and easily managed with 
bronchodilator therapy. 
 
Risk of a secondary cancer may occur after chemotherapy. The risk of developing a 
secondary cancer of the skin, cervix, etc., which has been seen in other transplant studies  is 
less than 5%.  
 
Graft Failure/rejection: Stem cell  grafts may fail to grow or may start to grow and then be 
rejected by the patient’s immune system. Past experience with this type of transplant using 


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BM suggests that this may occur in ~10% of patients.  The incidence using PBSC has not 
been reported.  If graft failure occurs, it is unlikely that bone marrow will recover and a 
second transplant with stem cells from the same donor or a different donor will be needed. 
 
Progression of Disease or Relapse is a risk even if the transplant is initially successful.  
 
Worsening Kidney Function:  Since the patients on this protocol will have some degree of 
renal insufficiency and despite avoidance of nephrotoxic medications, there is a risk that the 
kidney function will deteriorate and the patient may require dialysis.  
 
Death: There is an approximately 5-10% risk of treatment related mortality within the first 
month of transplant for patients with normal renal function due to the risk of severe regimen 
related toxicity, hemorrhage, opportunistic infection, or other complications. Patients enrolled 
on this protocol may be at higher risk of complications due to their baseline renal 
insufficiency.  
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
Definition of events in the post-transplant course important for analysis and treatment. 
12.1 Engraftment and Chimerism 
Engraftment will be documented by analysis of blood cells, T cells and bone marrow cells for 
chimerism by standard cytogenetic studies at about 1 month, 100 days, 6 months, 9 months 
(if clinically indicated), and 12 months, 18 months (if clinically indicated), and 24 months post 
transplant or as needed thereafter.  
 
12.2 Graft Failure or rejection  
Primary non-engraftment is diagnosed when the patient fails to achieve an ANC 500/mm3 at 
any time in the first 28 days post-transplant. If the patient's leukemia recurs during this 
interval, the patient is scored as having refractory leukemia. In such a situation, the absence 
of donor hematopoiesis is not evaluable for graft failure or rejection. If host T-cells capable of 
specifically inhibiting donor hematopoietic progenitor growth in vitro are concurrently 
detected during graft failure, a presumptive diagnosis of immune mediated rejection is made: 
if (1) after achievement of an ANC 500/mm3, the ANC declines to <500/mm3 for more than 3 
consecutive days in the absence of relapse, or, (2) there is absence of donor cells in the 
marrow and/or blood as demonstrated by chimerism assay in the absence of relapse, a 
diagnosis of secondary graft failure is made. If, however, recurrence of host leukemia is 
detected concurrently, the patient is not evaluable for graft failure or rejection.  
 
Patients with evidence of graft failure without evidence of recurrence of host leukemia will 
have additional studies drawn to ascertain cause and define relevant histoincompatibilities. 
These analyses may include (1) Evaluation of bone marrow aspirates and biopsies for 
residual or recurrent leukemia and chimerism, when indicated, (2) Culture and/or molecular 
analyses of marrow and blood for viral pathogens potentially causing graft failure including 
CMV, HHV6 and parvovirus B 19, (3) Immunophenotypic and genetic analysis of circulating 
T-cells and NK cells to ascertain their origin and potential function, (4) Analysis of the 
functional activity of residual circulating lymphocytes Patients who suffer graft failure will be 
considered for a secondary transplant. The need for additional immunosuppression or 


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treatment for viral infection prior to the secondary transplant will be determined by the results 
obtained from chimeric and viral studies. 
12.3 Graft-versus-host-disease 
Standard BMT-CTN and IBMTR systems clinical criteria as defined by Rowlings, et al (55) 
will be used to establish and grade acute GVHD.  
 
To determine the severity of acute GVHD, data will be collected approximately weekly at 
least during the first 100 days (as per Adult BMT Service guidelines) to characterize the 
severity of symptoms and signs caused by GVHD and to evaluate possible confounding 
factors.  
 
Patients will be observed for acute and/or chronic GVHD as long as they have not received 
donor derived leukocytes infusions (DLI) for the treatment of relapse or infections. If at any 
time, a patient receives DLI, that time will represent the end-time for evaluation of GVHD. 
Graft-versus-host disease occurring after DLI infusions will be analyzed separately.  
 
Patients with moderate to severe acute GVHD (grade II-IV) will be treated  as per Adult BMT 
Service guidelines Patients failing to respond to systemic steroids will be considered for 
treatment with experimental treatments available at the time of diagnosis of GVHD.  
 
Chronic GVHD will be diagnosed and graded according to the (NIH criteria)  treated with 
standard or experimental immunosuppressive therapy. 
12.4 Infections 
The occurrence of life-threatening opportunistic infections will be evaluated according to the 
criteria established by BMT CTN (see Appendix 2),  and will be correlated  with the level of 
immune recovery. The infection-related mortality will also be  monitored. Patients will be 
considered to have died from infection if death is attributed to a recent severe infection 
and/or infection was identified at autopsy. Patients with relapsed disease before death will be 
excluded from the above definition, even if an infection was the final cause of death.  
 
12.5 Disease Relapse  
Relapse of MDS, AML and AML will be defined by an increasing number of blasts in the 
marrow over 5%, by the presence of circulating peripheral blasts,  by the presence of blasts 
in any extramedullary site, or recurrence of a cytogenetic abnormality.   Relapse of NHL will 
be determined by bone marrow evaluation (when appropriate) and imaging studies similar to 
those used for pretransplant disease evaluation.    
 
12.6 Disease-free survival 
DFS is defined as the minimum  interval of time to relapse/recurrence, to death or to the last 
follow-up, from the time of transplant. 
12.7 Overall survival 
Overall survival is defined as time from transplant to death or last follow-up.  
 


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12.8 Renal insufficiency 
Renal insufficiency is defined as a calculated eGFR <60 ml/min/1.73m2.  Those with a eGFR 
< 30 ml/min/1.73m2 will be considered ineligible. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
If at any time the research participant is found to be ineligible for the protocol as designated 
in the section on Criteria for research participant eligibility (eg a change in diagnosis), the 
research participant will be removed from the study. Also research participants may be 
removed from the study if requested by the research participant. Management will depend on 
where they are in their treatment course. Such research participants will receive appropriate 
supportive care.  
14.0 
BIOSTATISTICS 
This is a pilot study to investigate the safety of using post transplant Cyclophosphamide as 
acute GVHD prophylaxis in patients who cannot receive calcineurin inhibitors. The outcome 
for this study is day +100 grade III-IV acute GVHD.  The study will be separated into two 
cohorts determined by whether a BM or PBSC graft will be used.   Both cohorts will receive 
additional prophylaxes initially which can be removed if excessive grade III-IV GVHD at day 
+100 is not observed. When applicable, the de-escalation schema will follow a 3-by-3 
strategy typically used in dose escalation studies. Since this study includes a patient 
population previously ineligible for transplant, it is challenging to provide an accrual rate. 
However, there may be approximately 25 patients or more annually eligible for inclusion on 
this study, of whom 5-10 may receive a BM graft and 15-20 may receive a PBSC graft. 
BM Graft: 
 
The initial cohort of 3 patients who receive a bone marrow graft will receive both Siro  and 
cyclophosphamide. If no patient in the initial three develop grade III-IV GVHD, an additional 
three patients will be treated with the combination for safety confirmation.  
 
 The trial for this cohort will enroll between 2 to 6 patients. De- escalation of prophylaxes may 
occur at a later time point if excessive GVHD is not observed at this level. 
There will be six patients treated at the final combination of prophylaxses. In this cohort, the 
grade III-IV GHVD estimate and corresponding 95% exact confidence interval will be 0% 
(0%-46%) if no patient has GVHD and will be 17% (0.4%-64%) if one patient have GHVD. 
 
PBSC Graft: 
The initial cohort of 3 patients will receive Siro plus MMF and cyclophosphamide (level 1 in 
table below). The dose de-escalation scheme is as follows: 
1. If no patient in the initial 3 experiences grade III-IV GVHD at a given level, the 
next level will be studied.  
1. If one of the initial 3 experiences grade III-IV GVHD, 3 additional patients will be 
treated at that level.  


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2. If 2 or more patients experience DLTs at a given level, the previous level will be 
declared the prophylaxis strategy.   
3. In order to decide on a final prophylaxis strategy, a total of six patients must be 
treated at that level.  
The trial for this cohort will enroll between 2 to 12 patients. De- escalation of prophylaxes will 
only occur once all patients at the current level have cleared the day +100 window without 
grade III-IV GVHD 
 
PBSC De-escalation  
Level  
Prophylaxis  
 
1 
MMF+ Siro+ 
Cyclophosphamide 
2 
Siro+ Cyclophosphamide 
Using this de-escalation scheme, de-escalation to the next level is probable if the risk of 
grade III-IV GVHD is low, and the likelihood of de-escalation decreases as the risk of grade 
III-IV GVHD increases, as demonstrated in table below: 
 
De-Escelation / GVHD Risk 
True risk of grade III-IV GVHD 
.10 
.20 
.30 
.40 .50 .60 
Probability of De-Escelation 
.91 
.71 
.49 
.31 .17 .08 
 
Treatment-related mortality will be closely monitored in this high-risk patient cohort. In order 
to reduce patient risk, the following trial suspension rules will be implemented. Should more 
than 2 out of the six patients in the BM cohort die of TRM by day +100, accrual in that cohort 
will stop.  Should more than 2 out of the first six patients or four at any point in the PBSC 
cohort die of TRM by day +100, accrual in that cohort will stop.   
In addition to TRM, this trial may be temporarily suspended to evaluate the overall treatment 
strategy if >2 patients require post-transplant dialysis at any point post transplant in the 
combined BM and PBSC cohorts. 
There are a number of secondary objectives included in this protocol. These descriptive 
objectives will be evaluated separately for patients receiving BM and PBPC grafts.  
1. Cumulative incidence functions (CIF) will be used to estimate 2-year acute and 
chronic GVHD. 
2.   100-day TRM will be estimated using CIF.   
3. The incidence of graft failure will be evaluated using CIF. 
4. Overall and disease-free survival will be evaluated using Kaplan-Meier 
methodology.  
5. The proportion of patients with acute or worsening chronic renal insufficiency will 
be tabulated. Worsening chronic insufficiency is evaluated as the change in 
creatinine from the time of transplant.  
6. The proportion of patients who have infectious complications will be tabulated.  
7. Time to immune reconstitution will be summarized using CIF.   
15.0 
 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 


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Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
15.2 
Randomization 
This research study does not require a randomization. 
16.0 
DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study and will be responsible for 
patient accruals. The responsibilities of the RSA and principal investigator include project 
compliance, data collection, abstraction and entry, data reporting, regulatory monitoring, 
problem resolution and prioritization, and coordinate the activities of the protocol study team. 
The data collected for this study will be entered into The Clinical Research Data Base 
(CRDB), a secure database. Source documentation will be available to support the 
computerized patient record.  
16.1 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action.  
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb2.mskcc.org/irb/index.htm  
 


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There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center's Research Council and Institutional Review Board.  During 
the protocol development and review process, each protocol will be assessed for its level of 
risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed and the 
monitoring procedures will be established at the time of protocol activation. 
17.0 
PROTECTION OF HUMAN SUBJECTS 
The risks associated with the transplant  are those associated with the toxicities of the 
conditioning regimens,  as well as the risks of an allogeneic transplant, particularly graft 
failure, or graft vs. host disease, as detailed in Section 11.0.  
To protect against the toxicities of the cytoreductive regimens, the patient will be transplanted 
in a single room, HEPA filtered environment. Organ toxicities such as mucositis, enteritis and 
hepatic dysfunction as well as infectious complications will be treated by standard 
procedures developed for transplantation to support the patient. Blood and platelet counts 
will be supported by transfusion. Graft failure might necessitate a second transplant, after 
additional conditioning. Approaches to the diagnosis and treatment of graft failure that secure 
consistent engraftment have been developed by the transplantation services. Similarly, 
advanced treatments will be instituted in the event the patient develops graft vs. host 
disease.  
 
Despite a transplant, the patient’s disease may recur. In this case, standard and/or 
experimental therapies, such as phase I/II drugs, antibodies or cell therapies, will be 
available to the patient for consideration as treatment options.  
 
Benefits:  
A transplant is administered with curative intent. The approaches being evaluated may 
achieve this goal and may also be effective in preventing acute and chronic graft vs. host 
disease and providing transplantation as a potentially curative therapy for  patients with renal 
insufficiency.  
 
 
The results of this study will also define risks and benefits of high dose cyclophosphamide as 
GVHD prophylaxis for patients not appropriate for TCD transplantation or conventional grafts 
using standard calcineurin inhibitor prophylaxis. This may greatly accelerate further 
development of transplantation approaches employing this approach to GVHD prophylaxis.  
 
Consent Process: Participation in this study is voluntary. All patients will be required to sign a 
statement of informed consent which must conform to MSKCC IRB guidelines.  
 
Alternatives: Enrollment in this study is voluntary. Alternative treatment options will be 
presented to the patient prior to taking part in this study. Alternative treatment options may 


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include receiving treatment for the cancer with either chemotherapy or a transplant without 
being on a study; taking part in another study; or taking no treatment. 
Costs: The patient’s health plan/insurance company will need to pay for all of the costs of 
treatment in this study. The patient will be responsible for the costs of standard medical care, 
all hospitalizations and any transplant complications. Pre-authorization for the transplant will 
be cleared with the health plan/insurance company prior to admission. Patients will not be 
paid for taking part in this study.  
 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research and 
hospital records are confidential. 
17.1 
Privacy 
It is the responsibility of the Research Staff to ensure that protocol subjects receive the 
Center’s Notice of Privacy Practices. If the subject has not received one, MSK personnel 
must provide a Notice of Privacy Practices and obtain acknowledgment before the subject 
participates in the study. MSKCC’s Privacy Office may allow the use and disclosure of 
protected health information pursuant to a completed and signed Research Authorization 
form. The use and disclosure of protected health information will be limited to the individuals 
described in the Research Authorization form. A Research Authorization form must be 
completed by the Principal Investigator and approved by the IRB and Privacy Board 
(IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
An adverse event is considered serious if it results in ANY of the following outcomes:  
 
Death  
 
A life-threatening adverse event  
 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
A congenital anomaly/birth defect 
 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious 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 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE.  
 
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the event. 


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The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows:   
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
The report should contain the following information: 
Fields populated from CRDB: 
 
Subject’s initials 
 
Medical record number 
 
Disease/histology (if applicable) 
 
Protocol number and title 
Data needing to be entered: 
 
The date the adverse event occurred 
 
The adverse event 
 
The grade of the event  
 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
 
If the AE was expected 
 
The severity of the AE 
 
The intervention 
 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
 
If an amendment will need to be made to the protocol and/or consent form 
 
If the SAE is an Unanticipated Problem  
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office 
 
17.2.1  
This research study does not require an IND approval. 
18.0 
INFORMED CONSENT PROCEDURES 
The individual listed as consenting professionals have completed the mandatory Human 
Subjects Education and Certification Program. The consulting BMT attending will obtain 
consent from the patient or the patient’s guardian. The patient will sign three copies of the 


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consent. One copy will be given to the patient to keep, one will be scanned into the patient’s 
medical record and one copy will be stored in the patient’s research file. 
 
18.1 Research Authorization  
Procedures for obtaining Research Authorization: Before any protocol-specific 
procedures are carried out, investigators and/or designated staff will fully explain the 
details of the protocol, study procedures, and the aspects of patient privacy concerning 
research specific information. In addition to signing the IRB Informed Consent, all 
patients must sign the Research Authorization component of the informed consent form. 
The Research Authorization requires a separate set of signatures from the patient. The 
original signed documents will become part of the patient’s medical record, and each 
patient will receive a copy of the signed documents. 
 
 
19.0 
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Wagner JE, Santos GW, Noga SJ, et al. Bone marrow graft engineering by counterflow 
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15. 
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Kernan NA, Collins NH, Juliano L, Cartagena T, Dupont B, O'Reilly RJ. Clonable T 
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Lowenberg B, Wagemaker G, van Bekkum DW, et al. Graft-versus-host disease following 
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22. 
Jakubowski AA, Small TN, Young JW, et al. T cell depleted stem-cell transplantation for 
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Urbano-Ispizua A, Rozman C, Pimentel P, et al. Risk factors for acute graft-versus-host 
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Luznik L, Engstrom LW, Iannone R, Fuchs EJ. Posttransplantation cyclophosphamide 
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Luznik L, Jalla S, Engstrom LW, Iannone R, Fuchs EJ. Durable engraftment of major 
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29. 
Luznik L, O'Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation 
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O'Donnell PV, Luznik L, Jones RJ, et al. Nonmyeloablative bone marrow transplantation from 
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Schleuning M, Judith D, Jedlickova Z, et al. Calcineurin inhibitor-free GVHD prophylaxis with 
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32.  
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Solomon ST, Sanacore M, Zhang X, et al.  Calcineurin inhibitor-free graft-versus-host 
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20.0 
APPENDICES 
Appendix 1. BMT CTN Severity of Infection