Clinical trial NCT01790295
Conditions: Primary Myelofibrosis Post Polycythemia Vera Myelofibrosis Post Essential Thrombocythemia Myelofibrosis
Keywords: Myelofibrosis Stem cell transplant Ruxolitinib
Sponsor: John Mascarenhas
Start date: 2013-11-01; Completion date: 2017-10-26
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out if giving the study drug Ruxolitinib (INC424) prior to a combination of other chemotherapeutic drugs (Fludarabine and Busulfan) before infusing another person's hematopoietic stem cells (bone marrow transplantation) will be successful in people who have advanced primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF), collectively known as myelofibrosis (MF). MF is a disorder in which bone marrow tissue develops in abnormal sites because the bone marrow itself undergoes fibrosis or scarring. This study plans to evaluate whether adding the drug Ruxolitinib will further aid in reducing pre-transplant spleen size, improve physical performance levels and reduce adverse events (side effects) related to the transplant. Ruxolitinib is a drug that is approved by the FDA for the treatment of patients with advanced forms of myelofibrosis. Using Ruxolitinib prior to stem cell transplantation is experimental.

Detailed description:
A two- stage Simon Phase II study will be conducted in each of two groups of patients: related and unrelated donor transplants. In each donor transplant group, the first stage of this design will include 11 patients evaluated for death or graft failure by 100 days post-transplant. In each stratum, we will enroll additional patients (up to 20%) of stratum total to take into account exclusions due to donor failure (such as donor deemed unsuitable for stem cell donation due to medical or other reasons) only. Those patients who have toxicities related to Ruxolitinib and not been able to reach HCT due to these toxicities will be included in the estimation of overall failure rates. Only those patients who are excluded based on donor related issues without any regimen related complications will be excluded from the estimation of failure rates. However, all data on these patients will be reported.

Arms: arm 1: Ruxolitinib (INC424) tablets will be started 62 days (day -67) prior to start of conditioning chemotherapy. The starting dose of Ruxolitinib will be determined according to baseline platelet count and will be modified according to platelet count at follow-up. The drug will be given in the maximum tolerated dose as defined in the protocol for 56 days, followed by 4 days of taper, and will be stopped completely at the planned start of conditioning therapy (starting on day -5) i.e. 5 days prior to stem cell infusion. The drug will be supplied as 5 mg tablets.
Interventions: intervention 1: Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)
Intervention descriptions: intervention 1: Ruxolitinib (INC424) tablets will be started 60 days (day -65) prior to start of conditioning chemotherapy. The starting dose of Ruxolitinib will be determined according to baseline platelet count and will be modified according to platelet count at follow-up. The drug will be given in the maximum tolerated dose as defined in the protocol for 56 days, followed by 4 days of taper, and will be stopped completely at the planned start of conditioning therapy (starting on day -5) i.e. 5 days prior to stem cell infusion. The drug will be supplied as 5 mg tablets.

Protocol documents:
Prot_SAP_ICF_000.pdf: 
Myeloproliferative Disorders-Research Consortium (MPD-RC)
MPD-RC Protocol 114
Exploring the Potential of Dual Kinase JAK 1/2 Inhibitor Ruxolitinib (INC424) 
with Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients 
with Myelofibrosis
NCT#01790295
Version Date: 08-08-2016


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Myeloproliferative Disorders-Research Consortium (MPD-RC) 
MPD-RC Protocol 114 
Exploring the Potential of Dual Kinase JAK 1/2 Inhibitor Ruxolitinib (INC424) with 
Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients with 
Myelofibrosis 
Mandatory Companion Protocol MPD-RC 107 
IND# 116275 
Health Canada CTA# 166732 
EudraCT# (Pending) 
Study Co-Chairs: 
Vikas Gupta, MD, FRCP, FRCPath 
Associate Professor, Department of Medicine 
University of Toronto, and 
Staff Physician, Leukemia / BMT Program 
Princess Margaret Cancer Centre 
Toronto, Canada, M5G 2M9 


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Adam Mead, MD 
Honorary Consultant Haematologist 
LRF Senior Bennett Fellow 
Haematopoietic Stem Cell Biology Laboratory 
Weatherall Institute of Molecular Medicine 
University of Oxford 
John Radcliffe Hospital 
Headington, Oxford OX3 9DS 
Sponsor/Investigator: 
John Mascarenhas, MD 
Mount. Sinai School of Medicine 
One Gustave L. Levy Place 
New York, New York 10029 
 
Co-Investigator: Statistician 
Amylou C. Dueck, PhD. 
Mayo clinic 
13400 E. Shea Blvd. 
Scottsdale, AZ 85259 
  
 
 
 
 
 
 
Co-Investigator: 
Rona Weinberg, PhD 
MPD-RC Tissue Bank North America 
New York Blood Center 
Data Management 
Gianni Tognoni, MD 
IRCCS Istituto di Ricerche Farmacologiche  
Mario Negri 
Via La Masa, 19  
20156 Milano  
 
Co-Investigator: 
Alessandro Rambaldi, MD 
MPD-RC Tissue Bank Europe 
Azienda Ospedaliera Papa Giovanni XXIII 
Piazza OMS- Organizzazione Mondiale della Sanità,1  
24127 Bergamo 
Version History 
 
Version #5                               08/08/2016 
                              
Version #4 
 
11/10/2014 
Version #3 
 
06/10/2014 
Version #2 
 
04/19/2013 
Version #1 
 
10/01/2012 


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Trial Centers  
 
Emory Hospital 
Amelia Langston, MD. 
1365 Clifton Rd. NE  
Atlanta, GA 30322 
 
Guy’s and St Thomas’ NHS Foundation Trust 
Claire Harrison, Consultant Haematologist  
Department of Hematology  
St. Thomas’ Hospital  
Lambeth Palace Road London SE1 7EH 
 
Heart of England NHS Foundation Trust 
Joanne Claire Ewing  
Birmingham Heartlands Hospital 
Bordesley Green East 
Birmingham, UK B9 5SS 
 
Mayo Clinic – Arizona 
Ruben A. Mesa, MD 
13400 E Shea BLVD  
Scottsdale, AZ 85259 
 
 
Icahn School of Medicine at Mount Sinai 
John Mascarenhas, MD 
One Gustave L. Levy Place, Box 1079 
New York, NY 10029 
 
Northwestern University 
John P Galvin, MD, MS, MPH 
676 North St. Clair Street 
Chicago, IL 60611 
 
Ohio State University  
Rebecca Klisovic, MD.  
B420 Starling Loving Hall 
320 W. 10th Avenue 
Columbus OH 43210 
 
 
 
 
 
 
 
 Princess Margaret Cancer Centre 
Vikas Gupta, MD, FRCP, FRCPath 
Toronto, Canada, M5G 2M9 
 
 
 
 
 
     
  University of Oxford  
Adam Mead, MD 
John Radcliffe Hospital 
Weatherall Institute of Molecular Medicine 
University of Oxford 
Oxford OX3 9DS 
 
Wake Forest Baptist Health 
Dmitriy Berenzon, MD 
Medical Center Boulevard 
Winston-Salem, NC 27157 
 
 
 
 


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MPD-RC Clinical Consortium (Project 6)  
John Mascarenhas, MD 
Icahn School of Medicine at Mount Sinai  
Division of Hematology/Oncology, Box 1079 
One Gustave L. Levy Place 
New York, New York 10029 
 
 
MPD-RC Central Coordinating Office 
 
Ronald Hoffman, MD 
Icahn School of Medicine at Mount Sinai  
One Gustave L. Levy Place 
Box 1079 
New York, New York 10029 
 
 
Adverse Event Reporting 
Lonette Sandy 
MPD-RC Central Coordinating Office 
 
 
Data Management 
 
 
 
Gianni Tognoni, MD 
           
 
 
             IRCCS Istituto di Ricerche Farmacologiche  
Mario Negri 
Via La Masa, 19  
20156 Milano  
 
 
 
MPD-RC Tissue Bank North America 
 
Rona Weinberg, PhD 
New York Blood Center 
 
MPD-RC Tissue Bank Europe 
 
 
Alessandro Rambaldi, MD 
Laboratorio Paolo Belli USC Ematologia 
 
Online Patient Registration 
 
 
http:/www.mpdrc.org 
 


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SCHEMA – TREATMENT PLAN 
 
N.B. Schema not drawn to scale. 
 
I. Ruxolitinib 
Ruxolitinib (INC424) tablets will be started on day -65 prior to the planned infusion of stem 
cells. The starting dose of Ruxolitinib will be determined according to baseline platelet count 
(Table SCH- A 
Starting dose assignmentTable SCH- A) and will be modified according to 
platelet count (Table SCH- B) at follow-up. The drug will be given in the maximum tolerated 
dose as defined (Table SCH- B) in the protocol until day -10, followed by 4 days of tapering 
starting on day -9 (Table SCH- C). Ruxolitinib will be stopped completely on day -5, on the 
planned start day of conditioning therapy. The drug will be supplied as 5 mg tablets.  


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Table SCH- A Starting dose assignment 
Baseline Platelet count 
Starting dose of Ruxolitinib 
>200 x 109/L 
20 mg BID (Four 5 mg tablets twice daily) 
100- 200 x 109/L 
15 mg BID (three 5 mg tablets twice daily) 
50-99  x 109/L 
10 mg BID (two 5 mg tablets twice daily) 
Platelet count will be monitored once a week, and if platelet count falls below <50 x 109/L, then 
platelet count will be monitored twice weekly. At follow-up, the dose of Ruxolitinib will be 
modified (increased or decreased) according to the Table SCH- B. The goal will be to continue 
the drug with a platelet transfusion if necessary. The drug should only be stopped if there is a 
concern regarding bleeding.   
Table SCH- B Dose adjustment according to platelet count at follow-up (prior to start of 
conditioning therapy) 
Platelet count at the 
follow-up 
Dose at the time of follow-up 
20 mg BID 
15 mg BID 
10 mg BID 
5 mg BID 
>200 x 109/L 
No change 
20 mg BID 
15 mg BID 
10 mg BID 
100-200 x 109/L 
15 mg BID 
No change 
15 mg BID 
10 mg BID 
50-99  x 109/L 
10 mg BID 
10 mg BID 
No Change 
10 mg BID 
25-49 x 109/L 
5 mg BID 
5 mg BID 
5 mg BID 
No change 
<25 x 109/L 
5 mg BID 
+ Platelet  
transfusion 
per investigator 
discretion 
5 mg BID 
+ Platelet  
transfusion  
per investigator 
discretion 
5 mg BID 
+ Platelet 
transfusion 
per investigator 
discretion 
5 mg BID 
+ Platelet 
transfusion 
per investigator 
discretion 
 
Table SCH- C Tapering schedule of Ruxolitinib 
Dose 
prior 
to day -9 
Day -9 
Day -8 
Day -7 
Day -6 
Day -5 
20 mg BID 
15 mg BID 
10 mg BID 
5 mg BID 
5 mg daily None 
15 mg BID 
10 mg BID 
10 mg BID 
5 mg BID 
5 mg daily None 
10 mg BID 
10 mg BID 
10 mg BID 
5 mg BID 
5 mg daily None 
5 mg BID 
5 mg BID 
5 mg BID 
5 mg BID 
5 mg daily None 
 


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II. Conditioning therapy  
Prior to start of conditioning, transplant physician should ensure that after completion of 
Ruxolitinib and prior to start of conditioning, patient meets the following criteria: 
1. ECOG Performance status 0-2 
2. Blasts in PB <20% 
3. Adequate renal function with creatinine <1.5 x Institutional ULN 
4. Adequate hepatic function with AST/ALT <2.5 x IULN and Bilirubin <1.5 x IULN 
5. Absence of active uncontrolled infection or any other concurrent illness which in the 
Investigator’s opinion puts the patient at excessive risk of transplant related toxicities. 
 
 
The conditioning therapy will be: 
IV Fludarabine 40 mg/m2 IV over 30 minutes once daily x 4 days for days -5 to -2 
IV Busulfan 2.0 mg/ KG of body weight IV over 2 hours once daily for 4 consecutive days for 
days -5 to -2. 
*If actual body weight is > 30% ideal body weight (IBW), use adjusted body weight (ABW) 
for calculating the dose of fludarabine and busulfan 
Fludarabine and Antithymocyte Globulin (Rabbit) – will be dosed according to the patient’s 
actual body weight, unless the patient weighs more than 130% of IBW, in which the dose 
will be based on an adjusted body weight. 
IBW:  Estimated ideal body weight in (kg) 
 Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet. 
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. 
ABW: Estimated adjusted body weight (kg) 
If the actual body weight is greater than 30% of the calculated IBW, calculate the 
adjusted body weight  
ABW = IBW + 0.4(actual weight - IBW) 
III. GVHD prophylaxis 
a. IV Calcineurin inhibitor [IV cyclosporine (per institutional practice) or IV tacrolimus 
(per institutional practice)] starting on day -2, until engraftment or when the patient is 
able to take PO, then switched to PO doses. Cyclosporine or tacrolimus will be given 
according to institutional practice.  The doses should be adjusted to keep trough levels of 
cyclosporine between 200-400 μg/L or tacrolimus 8–12 ng/ml. Cyclosporine or 
tacrolimus will be continued through day 180 and subsequently in the absence of GvHD, 
tapered by 25% every 2 weeks thereafter.  The use of cyclosporine or tacrolimus will be 
decision of the transplant center. 
b. Methotrexate 10mg/m2 on day +1, then 5 mg/m2 on day +3 and day +6, Dose of 
methotrexate should be modified if necessary according to creatinine clearance (Table 
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Table SCH- D Methotrexate dose modification 
Calculated Creatinine Clearance (mls/min) 
% Methotrexate Dose Reduction 
>70 
0% 
50-70 
25% 
30-49 
50% 
<30 
100% i.e no methotrexate 
 
c. Thymoglobuline (ATG). Patients undergoing unrelated donor or mismatched related 
donor transplantation will be given additional GvHD prophylaxis with low-dose 
thymoglobuline** (0.5 mg / KG of body weight on day -3, 2.0 mg/ KG of body weight 
on day -2, and 2.0 mg/ KG of body weight on day -1).  
** If actual body weight is > 30% ideal body weight (IBW), use adjusted body weight 
(ABW) for calculating the dose of ATG as detailed above.  
STUDY DESIGN 
A two- stage Simon Phase II study will be conducted in each of two groups of patients: related 
and unrelated donor transplants. In each donor transplant group, the first stage of this design will 
include 11 patients evaluated for death or graft failure by 100 days post transplant.  In each 
stratum, we will enroll additional patients (up to 20%) of stratum total to take into account 
exclusions due to donor failure (such as donor deemed unsuitable for stem cell donation due to 
medical or other reasons) only. Those patients who have toxicities related to Ruxolitinib and not 
been able to reach HCT due to these toxicities will be included in the estimation of overall 
failure rates. Only those patients who are excluded based on donor related issues without any 
regimen related complications will be excluded from the estimation of failure rates. However, all 
data on these patients will be reported.  
Unrelated transplants: Based on data from the MPD-RC 101 study (31), there are 15 observed 
failures (as defined above) among 34 patients by day 100 (44%; of patients died or experienced 
graft failure by day 100) who received matched unrelated donor transplants. Based on these 
preliminary data, we will not pursue a regimen with a failure rate of 50% or greater in this trial.  
A minimax two-stage design will be used to test the null hypothesis that the 100 day failure rate 
as defined above is ≥50% versus the alternative that this failure rate is ≤25%. If the regimen is 
actually not safe, there is a 0.04 probability of concluding that it is (the target for this value was 
0.050). If the regimen is actually safe, there is a 0.19 probability of concluding that it is not (the 
target power is 80%). After testing the regimen in 11 patients in the first stage, the trial will be 
terminated if there are 6 or more failures within 100 days.  If the trial goes on to the second 
stage, a total of 26 patients will be studied. If the total number of failures is 9 or more, the 
regimen will be rejected.  
The unrelated arm has been temporarily on hold while the research team performed the Stage I 
analysis to decide whether or not the unrelated arm was deemed to be re-opened for enrollment 
or not. Based on the data gathered on stage I, 14 patients have been enrolled in the unrelated arm. 
According to the stopping rules stated on the “Study Design”  section of the protocol, 6 or more 


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failures out of the first 11 enrollments are required for the unrelated arm to be permanently 
closed. A failure is defined as no engraftment or graft rejection or death before 100 days post- 
transplant. 
The data revealed 4 failures in the first 11 patients and 7 patients were alive and engrafted at 100 
days. The result of the analysis confirms that that the unrelated arm does not meet the stopping 
rule for the first stage. 
 Therefore, this new amendment is the official opening of stage 2 of MPD-RC 114, and once this 
amendment has gone through all the regulatory approvals. The Research team will be enrolling 
12 patients in the unrelated arm in order to complete the study. 
Related transplants: Based on data from the MPD-RC 101 study (31), there are 4 observed 
failures (as defined above) among 32 patients (12.5%) who received matched related donor 
transplants in this group of patients.  
A minimal (and optimal) two-stage design to test the null hypothesis that the 100 day failure rate 
as defined above is ≥25% versus the alternative that this failure rate is ≤10%. If the regimen is 
actually not safe, there is a 0.04 probability of concluding that it is (If the regimen is actually 
safe, there is a 0.18 probability of concluding that it is not (the target power is 80%).  
After testing the regimen in 11 patients in the first stage, the trial will be terminated if there are 3 
or more failures within 100 days.  If the trial goes on to the second stage, a total of 50 patients 
will be studied. If the total number of failures is 8 or more, the regimen will be rejected.  
We would like to inform that the related arm has met the stopping rule stated above and that this 
arm will be permanently closed. 
 


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TABLE OF CONTENTS 
1 
OBJECTIVES ................................................................................................................. 17 
1.1 
PRIMARY ............................................................................................................................ 17 
1.2 
SECONDARY ....................................................................................................................... 17 
2 
BACKGROUND ............................................................................................................. 18 
2.1 
MYELOFIBROSIS ................................................................................................................. 18 
2.2 
JAK INHIBITORS IN MYELOFIBROSIS .................................................................................. 18 
2.3 
BIOLOGY AND SAFETY OF RUXOLITINIB (INC424) ............................................................ 18 
2.4 
ALLOGENEIC TRANSPLANTATION IN MYELOFIBROSIS AND BARRIERS TO SUCCESSFUL 
OUTCOMES ......................................................................................................................... 20 
2.5 
STUDY RATIONALE ............................................................................................................. 22 
2.6 
CHALLENGES OF COMBINING RUXOLITINIB IN A TRANSPLANT STRATEGY .......................... 22 
3 
PATIENT SELECTION ................................................................................................ 23 
3.1 
INCLUSION CRITERIA (PATIENT SHOULD MEET ALL THE CRITERIA) .................................... 23 
3.2 
EXCLUSION CRITERIA ........................................................................................................ 23 
3.3 
SUBJECT RECRUITMENT AND SCREENING .......................................................................... 24 
3.4 
EARLY WITHDRAWAL OF SUBJECTS .................................................................................. 24 
3.4.1 When and How to Withdraw Subjects ....................................................................... 24 
3.4.2 Data Collection and Follow-up for Withdrawn Subjects .......................................... 25 
4 
TREATMENT PLAN ..................................................................................................... 26 
4.1 
STUDY DRUG (RUXOLITINIB), PACKAGING, LABELLING, SUPPLY AND STORAGE .............. 26 
4.1.1 Packaging and labeling ............................................................................................. 26 
4.1.2 Receiving Drug Supply, Receipt, Storage and Return ............................................... 26 
4.1.3 Return or Destruction of Study Drug ........................................................................ 27 
4.2 
STARTING DOSE, DOSE ADJUSTMENT AND TAPERING SCHEDULE OF RUXOLITINIB ........... 27 
4.3 
CONDITIONING THERAPY ................................................................................................... 29 
4.4 
GVHD PROPHYLAXIS ........................................................................................................ 30 
4.5 
GRAFT SOURCE .................................................................................................................. 31 
4.6 
SUPPORTIVE CARE ............................................................................................................. 31 
4.7 
STUDY FOLLOW-UP ............................................................................................................ 31 
5 
REGISTRATION PROCEDURES ............................................................................... 33 
5.1 
REGISTRATION REQUIREMENTS .......................................................................................... 33 
5.1.1 Site Registration with MPD-RC ................................................................................ 33 
5.1.2 Correlative Biomarker Study (MPD-RC 107) ........................................................... 33 
5.2 
INFORMED CONSENT .......................................................................................................... 33 
5.3 
MPD-RC REGISTRATION PROCEDURES .............................................................................. 34 
6 
PHARMACEUTICAL INFORMATION ..................................................................... 35 
6.1 
STUDY DRUG-RUXOLITINIB (INC424) .............................................................................. 35 
6.2 
FLUDARABINE .................................................................................................................... 38 
6.3 
BUSULFAN (BUSULFEX®) ................................................................................................... 38 


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7 
CORRELATIVE BIOMARKER STUDIES ................................................................ 46 
7.1 
CENTRAL MORPHOLOGICAL REVIEW OF BONE MARROW ASPIRATE SMEARS AND BIOPSIES 
FOR PATIENTS ENTERING MPD-RC TREATMENT STUDIES ................................................ 46 
7.1.1 Bone Marrow and Peripheral Blood Histopathology ............................................... 46 
7.1.2 Cytogenetics and FISH Cytogenetic and FISH Requirements .................................. 47 
7.2 
SCHEDULE OF SAMPLES FOR CORRELATIVE STUDIES ......................................................... 49 
7.2.1 Samples to be Collected ............................................................................................. 49 
7.2.2 Collection of Biomarker Samples .............................................................................. 53 
7.3 
SHIPPING SAMPLES FOR CORRELATIVE STUDIES ................................................................ 53 
7.4 
CLONALITY ........................................................................................................................ 54 
7.5 
MPN ASSOCIATE SYMPTOMS AND QUALITY OF LIFE ........................................................ 54 
7.6 
BIOMARKER EVALUATIONS ............................................................................................... 55 
8 
STUDY CALENDAR ..................................................................................................... 57 
8.1 
SCREENING AND ENROLLMENT .......................................................................................... 57 
8.2 
DONOR ASSESSMENT ......................................................................................................... 58 
8.3 
ASSESSMENTS PRIOR TO START OF CONDITIONING THERAPY (DAY-65 TO DAY -5) ............ 58 
8.4 
ASSESSMENTS FROM START OF CONDITIONING (DAY -5) TO POST BMT FOLLOW-UP (+48 
MONTHS) ............................................................................................................................ 62 
9 
MEASUREMENT OF EFFECT ................................................................................... 67 
10 
STUDY DESIGN ............................................................................................................. 68 
10.1 STATISTICAL CONSIDERATIONS ......................................................................................... 68 
10.2 DEFINITIONS OF ENDPOINTS .............................................................................................. 68 
10.3 ANALYSIS PLAN ................................................................................................................. 69 
10.4 ANTICIPATED STUDY DURATION AND TIME LINES .............................................................. 69 
11 
ADVERSE EVENTS ...................................................................................................... 70 
11.1 REPORTING OF NON-SERIOUS ADVERSE EVENTS ............................................................... 70 
11.2 REPORTING OF SERIOUS ADVERSE EVENTS ....................................................................... 70 
11.2.1 EC/IRB Notification by Investigator ......................................................................... 71 
11.2.2 Notifications by Sponsor ........................................................................................... 71 
11.2.3 MPD-RC Reporting of Suspected Unexpected Serious Adverse Reactions .............. 71 
11.2.4 MPD-RC Reporting of SUSARs ................................................................................ 71 
11.2.5 When to report ........................................................................................................... 72 
11.2.6 How to report ............................................................................................................ 72 
11.3 GRADING AND RELATIONSHIP ASSESSMENT OF ADVERSE EVENTS .................................... 73 
11.4 MONITORING OF ADVERSE EVENTS ................................................................................... 74 
11.5 IMMEDIATELY REPORTABLE ADVERSE EVENTS ................................................................. 74 
11.6 EXCEPTIONS FOR DEFINITIONS OF SERIOUS ADVERSE EVENTS .......................................... 75 
11.7 SAFETY MONITORING ........................................................................................................ 76 
11.7.1 Medical Monitoring ................................................................................................... 76 
11.7.2 Monitoring Plan and Period of Observation............................................................. 76 
12 
REGULATORY REQUIREMENTS ............................................................................ 77 
12.1 GOOD CLINICAL PRACTICE ................................................................................................ 77 


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12.2 ETHICAL CONSIDERATIONS ................................................................................................ 77 
12.3 PATIENT INFORMATION AND INFORMED CONSENT ............................................................ 77 
12.4 PATIENT CONFIDENTIALITY ............................................................................................... 77 
12.5 PROTOCOL COMPLIANCE ................................................................................................... 78 
12.6 MANAGEMENT OF INFORMATION ....................................................................................... 78 
12.7 DRUG ACCOUNTABILITY .................................................................................................... 79 
12.8 SOURCE DOCUMENTS ........................................................................................................ 79 
12.9 CASE REPORT FORMS (CRF) ............................................................................................. 79 
12.10 PREMATURE CLOSURE OF THE STUDY ............................................................................... 82 
12.11 RECORD RETENTION .......................................................................................................... 82 
12.12 ENDPOINT VERIFICATION ................................................................................................... 82 
13 
REFERENCES ................................................................................................................ 83 
14 
INFORMED CONSENT ................................................................................................ 86 


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APPENDICES 
Appendix 1 
Dynamic International Prognostic Scoring System for Myelofibrosis (DIPSS) 118 
Appendix 2 
Transfusion Dependency .................................................................................... 119 
Appendix 3 
Definition of Unfavorable Karyotype ................................................................. 120 
Appendix 4 
IWG-MRT criteria for response assessment ....................................................... 121 
Appendix 5 
Myeloproliferative Neoplasm symptom assessment form (MPN-SAF) and 
Brief Fatigue Inventory (BFI) ..............................................................................123 
Appendix 6 
EORTC QLQ-C30 (VERSION 3) ...................................................................... 125 
Appendix 7 
FACT-BMT (VERSION 4) ................................................................................ 127 
Appendix 8 
Patient Global Impression of change (PGIC) ..................................................... 130 
Appendix 9 
Regimen Related Toxicity:  Bearman Toxicity Criteria ..................................... 131 
Appendix 10  Assesment of acute and chronic GvHD .............................................................. 133 
Appendix 11  Request for Release of Nonconforming HCT/Ps ................................................ 134 
 
 


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LIST OF TABLES 
Table SCH- A 
Starting dose assignment..................................................................................... 6 
Table SCH- B 
Dose adjustment according to platelet count at follow-up (prior to start of 
conditioning therapy) ..........................................................................................6 
Table SCH- C 
Tapering schedule of Ruxolitinib ........................................................................ 6 
Table SCH- D 
Methotrexate dose modification ......................................................................... 8 
 
Table 1 
Supply and Storage of study drugs ............................................................................ 26 
Table 2 
Starting dose assignment ........................................................................................... 27 
Table 3 
Dose adjustment according to platelet count at follow-up (prior to start of 
conditioning therapy) .................................................................................................28 
Table 4 
Tapering schedule of Ruxolitinib .............................................................................. 28 
Table 5 
Conditioning therapy schedule .................................................................................. 30 
Table 6 
Methotrexate dose modification ................................................................................ 30 
Table 7 
Busulfex Dosing Nomogram ..................................................................................... 39 
Table 8 
Steady State Pharmacokinetic Parameters Following Busulfex® (busulfan) 
Infusion (0.8 mg/kg; N=59) ........................................................................................40 
Table 9 
Summary of the Incidence (≥20%) of Non-Hematologic Adverse Events through 
BMT Day +28 in Patients who Received Busulfex Prior to Allogeneic 
Hematopoietic Progenitor Cell Transplantation .........................................................41 
Table 10 
Correlative Studies Sample Collection Schedule ...................................................... 50 
Table 11 
Biomarker Evaluations .............................................................................................. 56 
Table 12 
Schedule of assessments prior to start of conditioning therapy ................................ 61 
Table 13 
Schedule of Assessments from start of conditioning to post BMT follow-up .......... 65 
Table 14 
Definitions of Adverse Event Severity Categories .................................................... 74 
Table 15 
Adverse Event Relationship to Treatment Guidelines .............................................. 74 
Table 16 
CRF Form Submission Schedule .............................................................................. 80 


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LIST OF ABBREVIATIONS 
ABW 
Adjusted body weight
ACD 
Acid Citrate Dextrose
AIBW 
Adjusted ideal body weight
ALT 
Alanine transaminase
AST 
Aspartate transaminase
ATG 
Antithymocyte globulin
AUC 
Area under the curve
BD 
Becton, Dickinson and Company
BFI 
Brief Fatigue Inventory 
BM 
Bone marrow 
BMT 
Bone marrow transplant
BUN 
Blood urea nitrogen
CBC 
Complete blood count
CI 
Clinical improvement
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
Clearance 
Cmax 
Maximum plasma concentration
CMV 
Cytomegalovirus
CR 
Complete remission
CRA 
Clinical research associate
CRF 
Case report form
CRP 
C-reactive protein
CTCAE 
Common Terminology Criteria for Adverse Events
DIPSS 
Dynamic International Prognostic Scoring System
DARF 
Drug Accountability Record Form
DMA 
Dimethylacetamide
DSMB 
Data and Safety Monitoring Board
EBV 
Epstein-Barr virus
EC 
Ethics Committee
ECG 
Electrocardiogram
EDTA 
Ethylenediaminetetraacetic acid
ESR 
Erythrocyte sedimentation rate
ET 
Essential thrombocythemia
EU 
European Union
EWB 
Emotional well-being
FACT-BMT 
Functional Assessment of Cancer Therapy-Bone Marrow Transplant 
FISH 
Fluorescence in situ hybridization
FWB 
Functional well-being
GCP 
Good Clinical Practice
G-CSF 
Granulocyte colony stimulating factor
GST 
Glutathione S-transferase
GvHD 
Graft versus host disease
Hb 
Hemoglobin  
Hct 
Hematocrit 
HCT 
Hematopoietic cell transplantation
HIPAA 
Health Insurance Portability and Accountability Act
HIV 
Human immunodeficiency virus
HLA 
Human leukocyte antigen
HSV 
Herpes simplex virus
IB 
Investigator’s Brochure
IBW 
Ideal body weight
ICH 
International Conference on Harmonisation
IPSS 
International Prognostic Scoring System


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LIST OF ABBREVIATIONS 
IRB 
Institutional Review Board
IWG-MRT 
International Working Group for Myelofibrosis Research and Treatment
JAK1 
Janus kinase 1 gene
JAK2 
Janus kinase 2 gene
JAK2V617F 
Mutation in JAK2 kinase
JAK3 
Janus kinase 3 gene
LASA 
Linear analog scale assessment 
MDS 
Myelodysplastic syndrome
MF 
Myelofibrosis
MPD-RC 
Myeloproliferative Disorders Research Consortium  
MPN 
Myeloproliferative Neoplasm
MPN-SAF 
Myeloproliferative Neoplasm Symptom Assessment Form 
MRN 
Medical record number
MTD 
Maximally tolerated dose 
NCI 
National Cancer Institute
NRM 
High non-relapse mortality
NSAID 
Nonsteroidal Anti-inflammatory Drugs
OS 
Overall Survival
PB 
Peripheral blood
PD 
Progressive disease
PFS 
Progression-free survival
PGIC 
Patient Global Impression of Change
PIN 
Patient identification number
PMF 
Primary myelofibrosis 
PPK 
Population pharmacokinetic
PR 
Partial remission
PT 
Prothrombin time
PTT 
Partial thromboplastin time
PV 
Polycythemia Vera
PWB 
Physical well-being
QC 
Quality control
QOL 
Quality of life
RIC 
Reduced intensity conditioning
RRT 
Regimen-related toxicities
SAE 
Serious adverse event
SD 
Stable disease
SFWB 
Social/family well being
SGOT 
Serum glutamic oxaloacetic transaminase
SMAC 
Sequential Multiple Analyzer with Computer
SUSAR 
Suspected unexpected serious adverse drug reaction
TB ID 
Tissue bank ID number
TOI 
Trial Outcome Index
TRM 
Transplant-related mortality
TSH 
Thyroid stimulating hormone 
TYK2 
Tyrosine kinase 2 gene
USP 
United States Pharmacopeia
V 
Volume of distribution
VOD 
Veno-occlusive disease
WBC 
White blood cell 
WHO 
World Health Organization
 


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1 
OBJECTIVES 
1.1 
Primary 
To determine the feasibility of combining Ruxolitinib (INC424) with a RIC regimen likely to 
produce success post transplantation, success being defined as patient being alive, and without 
graft failure at day 100-post allogeneic stem cell transplantation in patients who receive 
(a) related donor transplant and in those who receive (b) an unrelated donor transplant. 
1.2 
Secondary 
1. Neutrophil and platelet recovery 
2. Non-relapse mortality (NRM) at +100 days and 1-year 
3. Acute and chronic GvHD at 1-year 
4. Chimerism studies at +30, +60 and +100 days post-transplant 
5. Remission status according to IWG-MRT criteria (1) at day +100, and 6 and 12 
months post-transplant 
6. Relapse/progression (defined as per IWG-MRT criteria) (1) at 1-year post transplant  
7. Progression-free survival at 1-year  
8. Overall Survival at 1-year  
9. Impact of allogeneic stem cell transplant on myelofibrosis associated symptoms and 
overall quality of life  
10. Expression profiling and measurements of cytokines prior to start of Ruxolitinib, 
prior to start of chemotherapy for conditioning, day +30 and day +100 post-transplant 
11. Association of cytokines levels with acute and chronic GvHD 
12. Impact of somatic mutations such as CALR and ASXL1 on outcome of transplant 
 


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2 
BACKGROUND 
2.1 
Myelofibrosis 
Myelofibrosis is a chronic clonal myeloproliferative disorder characterized by variable degree of 
blood cytopenias and/or cytosis, a leucoerythroblastic blood picture, megakaryocytic 
hyperplasia, reactive marrow fibrosis and extramedullary hematopoiesis.  Myelofibrosis is a 
heterogenous disease and the survival of patients can vary from 2 years to over 10 years based on 
various prognostic factors such as age >65 years, presence of constitutional symptoms, 
hemoglobin less than 10.0 gm/dL, leukocyte count >25 x 109/l, and circulating blast cells ≥1%. 
Based on International Prognostic Scoring System (IPSS) (2), presence of 0, 1, 2, and ≥3 factors 
are categorized as low-risk, intermediate-1 risk, intermediate-2 and high-risk disease. The 
median survival of patients with low or intermediate -1 risk disease is 135 and 95 months, 
respectively and these patients are usually treated with observation alone. The median survival of 
patients with intermediate-2 and high-risk disease is 48 months and 27 months, respectively, and 
these patients are usually considered suitable candidates for medical interventions including 
allogeneic transplantation or experimental drug therapy trials. IWG-MRT group further looked at 
the validity of above risk factor in follow-up of disease course and showed that the above risk 
factors are also valid at the time of follow-up and have subsequently proposed dynamic IPSS 
(DIPSS)(3). Further refinement of DIPSS has recently been proposed by DIPSS-plus score, 
which takes into account additional prognostic impact of cytogenetics, transfusion dependency 
and thrombocytopenia (4). 
2.2 
JAK inhibitors in myelofibrosis 
Since the discovery of JAK2V617F mutation in patients with myeloproliferative neoplasms 
(MPNs), there has been considerable interest in the drug development in this area.  JAK2V617F 
mutation is present in approximately 50% of patients with MF. Another 10-12% of patients have 
other mutations such as MPL515 or exon 12 mutation. Irrespective of the mutation status, a key 
feature of MPNs is dysregulation of JAK/STAT signaling. Data from reported and ongoing 
studies have shown that JAK inhibitors are effective in ameliorating the symptoms related to 
splenomegaly, constitutional symptoms, and improvement in HRQOL scores in patients with 
myelofibrosis (5, 6). These agents appear to be equally effective in patients with MF irrespective 
of their mutation status. 
2.3 
Biology and Safety of Ruxolitinib (INC424)  
Several JAK inhibitors are in clinical development at present.  Among the various agents in 
clinical development, Ruxolitinib is most advanced and has the largest experience in terms of 
safety and toxicity. Based on results of two phase 3 pivotal studies, (COMFORT-I and 
COMFORT-II), ruxolitinib has been approved by the FDA in the United States and Health 
Canada, in Canada.  
Overview of Biological properties of Ruxolitinib 
A key feature of MPNs is dysregulation of JAK/STAT signaling. The JAK/STAT pathway is 
involved in normal hematopoiesis, inflammation and immune function (7). The four members of 
the JAK family – JAK1, JAK2, JAK3 and Tyk2 are non-receptor tyrosine kinases that play a 


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central role in signal transduction initiated by cytokines (interleukins and interferon signaling), 
growth factors and hormones. Specifically: 
JAK1 – role in lymphopoiesis and cytokine response; ubiquitously expressed 
JAK2 – role in erythropoiesis; ubiquitously expressed 
JAK3 – role in lymphocyte development and proliferation and immune response; 
expressed primarily in hematopoietic cells 
TYK2 – role in mediation of cytokine signals; ubiquitously expressed 
Ruxolitinib represents a novel, potent, and selective inhibitor of JAK1 and JAK2. Ruxolitinib 
potently inhibits JAK1 and JAK2 and yet it does not significantly inhibit a broad panel of 26 
kinases and does not inhibit JAK3 at clinically relevant concentrations. Various clinical trials in 
patients with myelofibrosis have shown their efficacy in reduction of spleen size, inhibition of 
inflammatory cyokines and improvement in QOL scores in patients with myelofibrosis (6). 
Additional details as to the in vivo pharmacology of Ruxolitinib may be found in the 
Investigator’s Brochure (IB, Edition 10, release date 29th September 2011). 
Single and multiple-dose pharmacokinetic studies have been conducted in multiple species and 
are reported in IB. Following oral, single-dose administration of Ruxolitinib capsules, the drug is 
absorbed rapidly and peak plasma concentrations are reached within 1–3 hours. After attaining 
Cmax at approximately 2 hours after administration, the plasma concentrations declined with a 
mean terminal phase distribution half-life of approximately 3–5 hours. There is no significant 
food effect on absorption or exposure. Ruxolitinib is metabolized in the liver by the cytochrome 
(CYP) P450 metabolizing enzyme system, predominantly by 3A4 isoenzyme. Thus a dose 
reduction of Ruxolitinib by 50% has been proposed in the clinical trials in patients who are on 
CYP3A4 inhibitors as concomitant medication. The pharmacokinetics of Ruxolitinib has been 
evaluated in patients with renal impairment (mild, moderate or severe). The pharmacokinetics 
and pharmacodynamics of Ruxolitinib are similar in patients with normal renal function and 
those with mild, moderate and severe renal impairment (IB).  
Safety and efficacy in phase I/II clinical trials in patients with myelofibrosis 
The results of phase I/II trial in patients with myelofibrosis were recently published (6). A total 
of 153 patients were enrolled in this trial. Various dosing schedules were investigated in this 
trial. These dosage schedules included 25 mg BID, 10 mg BID and 15 mg BID. The dose of 
Ruxolitinib was further adjusted according to platelet counts. This study demonstrated marked 
and durable reduction in spleen size. The majority of patients had a ≥25% reduction in spleen 
size on therapy (70% in 10 mg BID; 82% in 15 mg BID and 77% in 25 mg BID cohort). 
Responses occurred quickly within 1-2 months of therapy. Spleen reduction occurred regardless 
of presence / absence of JAK2V617F mutation status.  
MPNs are usually associated with weight loss and cachexia. This is probably related to 
dysregulation and abnormal elevation of a variety of pro-inflammatory cytokines, which may 
result in weight loss and wasting seen in patients with myelofibrosis. In the reported phase I/II 
trial, weight gain was observed in most patients. In addition, this trial demonstrated improvement 
in QOL, which was rapid, with in 1 month of therapy. A specific modified myelofibrosis 
symptom assessment form (MFSAF) developed by Mesa and colleagues was used to investigate 
a range of constitutional symptoms related to splenomegaly and elevated cytokines. 
Symptomatic improvement was similar among the patients receiving 10 mg, 15 mg and 25 mg 


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BID doses, with improvements in abdominal discomfort and pain seen with accompanying 
reduction in spleen size. Improvement in functional status and ability to walk was observed as 
soon as 1 month of therapy. In summary, this study demonstrated that Ruxolitinib was associated 
with prompt and marked reduction in spleen size, gains in total body weight, improvements in 
ECOG performance scores, and improvements in constitutional symptoms, which can be 
debilitating in this patient population.  
Tolerability and side effects of Ruxolitinib 
Non-hematologic toxicities 
Ruxolitinib is well tolerated and non-hematologic adverse events were uncommon. Most 
common side effects were diarrhea (5.9%), fatigue (4.3%), headache (3.3%), and peripheral 
edema (2.6%). Details of side effects are in IB. The majority of these toxicities were Grade 1/2 
CTCAE toxicity. Grade 3/4 non-hematologic toxicities included fatigue (1.3%), asthenia (2%), 
fever (0.7%), anxiety (1.3%) and insomnia (1.3%). Further two Phase 3 trials with drug have 
been completed (COMFORT-1 and COMFORT-II). COMFORT-I is randomized, double blind 
placebo controlled trial and COMFORT-II is randomized comparison of Ruxolitinib with best 
supportive therapy. Data from COMFORT-I trial shows that non-hematologic toxicity profile of 
INC424 was very similar to placebo.  
Hematologic toxicities 
Hematologic toxicity consisted primarily of anemia and thrombocytopenia. Thrombocytopenia 
appeared to be dose related and occurring less frequently in the 15 mg BID group (3% grade 3) 
than the 25 mg BID group (23% grade 3; 6% grade 4).  
2.4 
Allogeneic transplantation in myelofibrosis and barriers to successful outcomes 
HCT is the only curative treatment for patients with myelofibrosis. HCT using conventional 
intensity conditioning is associated with significant mortality (35–45%)  (8-10). Several studies 
have reported encouraging results of RIC in patients with myelofibrosis with favorable impact on 
Transplant-related Mortality (TRM) (11-13). The main attraction of this approach is to decrease 
the risk of TRM and ability to offer transplant to older patients and those with co-morbidities, 
which otherwise would have precluded the candidacy for transplantation. Both conventional and 
reduced intensity transplants are associated with significant risk of graft failure and graft-versus-
host disease (GvHD) in patients with myelofibrosis (14, 15).  
A high mortality and morbidity in myelofibrosis patients undergoing HCT is related to multiple 
factors: 
1. Graft failure 
2. GvHD 
3. Regimen-related toxicities 
4. Poor performance status 
 
Graft failure 
Patients with myelofibrosis undergoing HCT have a higher risk of graft failure in the range of 
10–20%. This appears very high in comparison to other hematologic malignancies, where the 
risk of graft failure is usually <5%. High risk of graft failure in these patients is probably related 
to splenomegaly, and increased risk of alloimmunization resulting from multiple blood 


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transfusions prior to the transplant procedure. Splenectomy prior to transplant is associated with 
earlier neutrophil and platelet recovery. However, this procedure is associated with significant 
surgery related morbidity and mortality (approximately 10%) (16, 17). As discussed above, 
treatment with Ruxolitinib results in prompt and marked reduction in spleen size.  This property 
of Ruxolitinib may decrease the risk of graft failure in these patients.   
GvHD 
GvHD is one of the most frequent and serious complications after HCT. The incidence of acute 
and chronic GvHD in HCT has been reported in the range of 50–80% depending on age of 
patient, type of donor and graft source with a higher incidence reported for use of PBSCT. 
Adverse impact of active GvHD on general and mental health, functional impairments, activity 
limitation, and pain has been widely reported in the BMT literature (18). Patients with MPN and 
particularly myelofibrosis have high cytokine levels, which lead to constitutional symptoms and 
significant debilitation in these patients (6, 19). Several convergent lines of evidence have 
suggested that inflammatory cytokines act as mediators of acute GvHD. Most of the clinical 
manifestations of GvHD may in fact be due to the dysregulated production of cytokines by T 
cells and other inflammatory cells. The complex interactions among cytokines and their cellular 
targets suggest that individual cytokines may play an important and distinctive role in the 
pathophysiology of GvHD. Perturbation of the cytokine network may function as a final 
common pathway of target organ damage, and the rapid onset of severe, acute GvHD can be 
considered a 'cytokine storm'(20). Ongoing trials with JAK inhibitors such as INC424 show a 
rapid down regulation of cytokine levels due to anti-JAK1 mediated effect (6). This property 
results in rapid improvement in constitutional symptoms. Down regulation of cytokine may be of 
particular interest in patients undergoing HCT as this may result in decreased incidence of 
GvHD.   
Regimen-related toxicities 
Patients with myelofibrosis undergoing HCT are at significant risk of regimen-related toxicities. 
Of note among these toxicities are liver toxicity (8, 11). In 53 patients undergoing HCT at 
Princess Margaret Hospital, it was noted a ≥ Grade 2 Bearman hepatic toxicity (bilirubin level 
>102.6 mmol) in 44% of patients in first 6 weeks after transplantation (21) (data presented at 
International MPD conference in NY on November 3, 2011, manuscript submitted) and was 
associated with inferior survival due to high non-relapse mortality in these patients. This liver 
toxicity appears very high in comparison to other myeloid malignancies such as acute myeloid 
leukemia and myelodysplastic syndromes reported Princess Margaret Hospital (22). Although 
the exact mechanisms of this increased liver toxicity in myelofibrosis patients undergoing HCT 
are not well understood at present; a possible explanation may be involvement of the liver by the 
underlying MPN. Comparisons of myeloablative conditioning and RIC in patients with 
myelofibrosis show a reduction in mucositis and hepatic toxicity in patients with myelofibrosis 
undergoing RIC (14). Treatment with a JAK inhibitor prior to transplant conditioning may result 
in decreasing the burden of myeloproliferation in liver and may contribute towards decreasing 
the liver related regimen-related toxicities.  
Poor performance status 
Most myelofibrosis patients undergoing HCT have advanced disease at the time of HCT. 
Performance and functional status of these patients can be further compromised due to 
symptomatic splenomegaly, constitutional symptoms, and anemia. It has been shown that poor 


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pre-transplant performance status is an independent predictor of high TRM and poor survival in 
patients with myelofibrosis (15). As highlighted above, JAK inhibitors can potentially decrease 
the spleen size, down regulate cytokine levels resulting in improvement in constitutional 
symptoms and potentially can improve the performance status of the patient. 
Improvement in pre-transplant performance status and possible potential of beneficial impact on 
GvHD make these agents attractive for exploring their potential in the transplant related 
strategies of myelofibrosis patients undergoing HCT.  
2.5 
Study rationale 
Unlike BCR-ABL inhibitors, current JAK inhibitors do not lead to good partial or complete 
remission, and do not appear to have curative potential. HCT on the other hand has curative 
potential, but is associated with significant morbidity and mortality. 
High non-relapse mortality (NRM) due to regimen-related toxicities (RRT), graft failure and 
graft versus host disease (GvHD), are major barriers to the success of allogeneic hematopoietic 
cell transplantation (HCT) in patients with myelofibrosis. Treatment with Ruxolitinib (INC424) a 
dual kinase JAK 1/2 inhibitor prior to reduced intensity conditioning (RIC) may lead to reduction 
of pre-transplant spleen size, improvement in performance scores, and decrease in inflammatory 
cytokines levels, which may have beneficial impact on TRM in patients with myelofibrosis. 
2.6 
Challenges of combining Ruxolitinib in a transplant strategy 
As highlighted above, Ruxolitinib is associated with hematologic toxicities consisting of anemia 
and thrombocytopenia. Thrombocytopenia appeared to be dose related and occurring less 
frequently in the 15 mg BID group (3% grade 3) than 25 mg BID group (23% grade 3; 6% grade 
4). These properties can result in delayed hematological recovery. These toxicities are reversible. 
In view of these toxicities, the ideal timing of Ruxolitinib would be prior to the transplant. The 
proposed timing of Ruxolitinib in this study is 60 days prior to start of conditioning. This 
provides a sufficient time for the impact of Ruxolitinib on reduction of spleen size, reduction in 
pro-inflammatory cytokines and improvement in QOL scores and performance scores. 
Ruxolitinib taper will start on day -9 and drug will be stopped completely at start of conditioning 
therapy (5 days prior to stem cell infusion). Given the short half of drug (3–5 hours), the 
likelihood of impact on donor cells will be very low. 


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3 
PATIENT SELECTION 
3.1 
Inclusion Criteria (Patient should meet all the criteria) 
1. 
Documented diagnosis of primary myelofibrosis according to WHO criteria or 
post PV myelofibrosis or post ET myelofibrosis as per IWG-MRT criteria (23)  
2. 
Age 18–70 years  
3. 
Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) criteria (3) 
(Appendix 1)  
OR 
Intermediate-1 risk disease with one of the following additional unfavorable 
features known to impact the survival adversely 
a. Red cell transfusion dependency (4)  
b. Unfavorable Karyotype (4)  
c. Platelet count <100 x 109/l (4)  
[See Appendix 2 and Appendix 3 for definition of transfusion dependency (24) 
and unfavorable karyotype (25, 26)] 
4. 
Blasts in the PB and BM < 10% prior to study enrollment  
5. 
Availability of a suitable matched related (6/6 or 5/6) or unrelated donor (10/10 or 
9/10 antigen or allele matched).  
6. 
Able to give informed written consent 
7. 
ECOG Performance status of 0-2.  
8. 
Life expectancy >3 months 
9. 
Off all MF-directed therapy including investigational agents for at least 2 weeks 
prior to study enrollment and recovered from all toxicities* 
10. 
Adequate organ function 
a. Adequate renal function – creatinine <1.5 x IULN 
b. Adequate hepatic function – AST/ALT <2.5 x IULN, Total Bilirubin 
<1.5 x IULN 
c. Adequate hematopoietic function – Platelet ≥ 50 x 109/l and ANC ≥ 1.0 
x 109/l 
d. LVEF >40% (MUGA or echocardiogram) OR Normal per Institutional 
standard 
e. Adequate pulmonary function with DLCO >50% 
* A patient who has been on stable dose of Ruxolitinib and has received ruxolitinib ≤6 
months prior to the study entry will be considered potentially eligible for the study with 
the caveat that there is no evidence of loss of response (>5cm increase in spleen size 
from the nadir). 
3.2 
Exclusion Criteria 
1. 
Any previous JAK2 inhibitor treatment prior to study enrolment, with the 
exception of Ruxolitinib  
2. 
Hypersensitivity to JAK inhibitor 


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3. 
Clinical or laboratory evidence of cirrhosis  
4. 
Prior allogeneic transplant for any hematopoietic disorder 
5. 
>20% blast in the PB or BM prior to HCT or had leukemic transformation (>20% 
blasts in PB or BM any time prior to HCT) 
6. 
Syngeneic donor 
7. 
Cord Blood transplant 
8. 
Active uncontrolled infection  
9. 
H/o another malignancy within 5-years of date of HCT except h/o basal cell or 
squamous cell carcinoma of skin or PV or ET 
10. Known HIV positive 
11. Pregnancy at the time of BMT 
12. Any other concurrent illness which in investigator’s opinion puts the patient at 
excessive risk of treatment related toxicities  
13. Unable to give informed consent 
14. Active infection with hepatitis A,B or C virus 
15. Subjects who require therapy with a strong CYP3A4 inhibitor prior to enrollment 
to  this study 
3.3 
Subject Recruitment and Screening 
Subjects will be recruited and screened for the study from the clinical services of the MPD-RC 
Clinical Study Centers. 
3.4 
Early Withdrawal of Subjects 
3.4.1 When and How to Withdraw Subjects 
In accordance with the Declaration of Helsinki and the guidelines of the country of the 
participating MPD-RC Clinical Study Center, each subject is free to withdraw from the study at 
any time.  An investigator also has the right to withdraw a subject from the study in the 
event of the patient suffering an intercurrent illness, adverse events, or other reasons concerning 
the health or well-being of the patient, or in the case of lack of cooperation by the patient. All 
serious adverse reactions need to be followed up until resolution and information returned to 
study coordinators. 
Should a subject decide to withdraw after administration of study drug, or should the 
investigator decide to withdraw the subject, all efforts should be made to complete and 
report the observations up to the time of withdrawal as thoroughly as possible. A final 
evaluation,  the reason for, and the date of withdrawal must be recorded on the CRF. The last 
visit for each subject will be defined as a study discontinuation/ end-of-study visit, which will 
occur 30 (±7 days) days after time of withdrawal.  
Subjects with clinically significant abnormal laboratory values as determined by the investigator 
or who have ongoing clinically significant treatment related adverse events during their last 
scheduled clinical evaluation will be monitored and treated until resolution or stabilization is 
achieved; or, in the event that the subject’s condition is not likely to improve because of disease 
progression, until the cause of the abnormal test result or adverse event can be determined. 


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3.4.2 Data Collection and Follow-up for Withdrawn Subjects 
The reason for and date of withdrawal from study drug treatment; and the reason for and date of 
withdrawal from the study will be recorded on the case report form (CRF). If a subject 
withdraws consent, every attempt will be made to determine the reason. If the reason for 
withdrawal is an adverse event or a clinically significant abnormal laboratory test result, 
monitoring will continue until the event has resolved or stabilized, until the subject is referred 
to the care of a local health care professional, or until a determination of a cause unrelated to 
the study drug or study procedure is made. The specific event or test result(s) must be recorded 
on the CRF. All evaluations will be performed, according to the protocol, 30 days (+/- 7 days) 
after the last day the patient takes the study drug. A subject will be considered to be lost to 
follow-up if all of the following criteria have been met: 
1. More than three phone calls to the subject are unanswered. 
2. A next of kin is contacted and no information is available. 
3. The referring physician is contacted and no information is available. 
4. A telegram or certified letter is unanswered. 
 
Subjects who experience secondary graft failure or failure to meet the primary objective will 
continue to be followed every 6 months for progression of disease and survival until the end of 
the study.  The progression of disease and survival data can be collected via telephone call or 
through the e-medical record system. See section 4.7 for more details. 
 
 
 
 
 


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4 
TREATMENT PLAN 
4.1 
Study Drug (Ruxolitinib), Packaging, Labelling, Supply and Storage 
4.1.1 Packaging and labeling 
Ruxolitinib investigational drug is provided as 5 mg tablets. Ruxolitinib 5 mg tablets are 
packaged in bottles. For centers in the US, the study medication is referenced as ruxolitinib 5 mg 
tablet on the bottle.  For centers outside the US, the study medication is referenced as INC424 
5 mg tablet on the bottle.  Medication labels will be in the local language and comply with the 
legal requirements of each country.  They will include storage conditions for the drug and the 
medication number, but no information about the subject. 
4.1.2 Receiving Drug Supply, Receipt, Storage and Return 
The Company will manufacture, package and label study drug and provide a central depot for 
study drug distribution and return to each of the MPD-RC Clinical Centers. Collaborating 
Institutions will request study drug based on instructions provided by the MPD-RC Consortium.  
Before an MPD-RC Institution can receive study drug, protocol specific regulatory documents 
must be submitted to the MPD-RC Central Coordinating Office. (See section 5.1.1 regarding 
required regulatory documents necessary)  
Ruxolitinib must be received by a designated person at the MPD-RC study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated assistants have access. Upon receipt, the Ruxolitinib should be stored according to the 
instructions specified on the drug labels. An inventory must be performed and a drug receipt log 
filled out and signed by the person accepting the shipment.  It is important that the designated 
study staff counts and verifies that the shipment contains all the items noted in the shipment 
inventory.  Any damaged or unusable study drug in a given shipment will be documented in the 
study files.  The investigator must notify the study sponsor of any damaged or unusable study 
treatments that were supplied to the investigator’s site.  
Ruxolitinib supply is for Investigational use and must be used for this trial only.  Under no 
circumstances should the investigator or any site personnel supply study drug to other 
investigators, subjects, clinics, or allow supplies to be used other than specified by the protocol. 
Once a participating site is approved by the MPD-RC and open for recruitment, request for drug 
supply for one patient would be sent immediately to Incyte in the United States and Novartis 
outside the United States to authorize drug shipment directly to the participating site. Subsequent 
study drug supplies will be sent upon request/ new patient enrollment. 
Table 1 
Supply and Storage of study drugs 
Study drugs 
Supply 
Storage 
Ruxolitinib 
Centrally supplied by Incyte (US) 
and Novartis (Outside the US) 
 
Refer to study drug label 
 
The study drug should be stored, under adequate security, in the pharmacy at the study center.  
Store Ruxolitinib at room temperature between 68°F and 77°F (20°C and 25°C). 


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4.1.3 Return or Destruction of Study Drug  
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
consumed, and drug remaining.  This reconciliation will be logged on the drug accountability 
form (signed and dated).  Any discrepancies noted will be investigated, resolved, and 
documented prior to return or destruction of unused study drug.  Drug destroyed on site will be 
documented in the study files. (See section 5.1, a copy of the participating study Centers drug 
destruction policy and procedure must be on file with the MPD-RC) 
4.2 
Starting Dose, Dose Adjustment and Tapering Schedule of Ruxolitinib 
Ruxolitinib (INC424) tablets will be started on day -65 prior to the planned stem cell infusion. 
The starting dose of Ruxolitinib will be determined according to the baseline platelet count 
(Table 2) and will be modified according to the platelet count at follow-up (Table 3). The drug 
will be given in the maximum tolerated dose as defined (Table 3) in the protocol until day -10, 
followed by 4 days of tapering starting on day -9 (Table 4), and will be stopped completely on 
day –5, on the day of planned start of conditioning therapy (starting on day -5).  If there is a 
delay in the availability of the donor or a delay in the start of the transplant conditioning regimen 
for any reason, contact the study PI to discuss.  The dose of ruxolitinib should not be tapered in 
that instance until the date of the start of the conditioning regimen is known with certainty. 
The drug will be supplied as 5 mg tablets. 
Table 2 
Starting dose assignment 
Baseline Platelet count 
Starting dose of Ruxolitinib 
>200 x 109/L 
20 mg BID (Four 5 mg tablets twice daily) 
100- 200 x 109/L 
15 mg BID (three 5 mg tablets twice daily) 
50-99 x 109/L 
10 mg BID (two 5 mg tablets twice daily) 
 
Platelet count will be monitored once a week, and if platelet count falls below 50 x 109/L, then 
platelet count will be monitored twice weekly. At follow-up, the dose of Ruxolitinib will be 
modified (increased or decreased) according to Table 3. The drug should only be stopped if there 
is a concern regarding bleeding.  


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Table 3 
Dose adjustment according to platelet count at follow-up (prior to start of 
conditioning therapy) 
Platelet count at the 
follow-up 
Dose at the time of follow-up 
20 mg BID 
15 mg BID 
10 mg BID 
5 mg BID 
>200 x 109/L 
No change 
20 mg BID 
15 mg BID 
10 mg BID 
100-200 x 109/L 
15 mg BID 
No change 
15 mg BID 
10 mg BID 
50-99 x 109/L 
10 mg BID 
10 mg BID 
No Change 
10 mg BID 
25-49 x 109/L 
5 mg BID 
5 mg BID 
5 mg BID 
No change 
<25 x 109/L 
5 mg BID 
+ Platelet  
transfusion 
per investigator 
discretion 
5 mg BID 
+ Platelet  
transfusion  
per investigator 
discretion 
5 mg BID 
+ Platelet 
transfusion 
per investigator 
discretion 
5 mg BID 
+ Platelet 
transfusion 
per investigator 
discretion 
 
Table 4 
Tapering schedule of Ruxolitinib 
Dose prior 
to Day -9 
Day -9 
Day -8 
Day -7 
Day -6 
Day -5 
20 mg BID 
15 mg BID 
10 mg BID 
5 mg BID 
5 mg OD 
None 
15 mg BID 
10 mg BID 
10 mg BID 
5 mg BID 
5 mg OD 
None 
10 mg BID 
10 mg BID 
10 mg BID 
5 mg BID 
5 mg OD 
None 
5 mg BID 
5 mg BID 
5 mg BID 
5 mg BID 
5 mg OD 
None 
 
Rationale for using a lower platelet count threshold 
In the published phase 1/2 study with INC424 (6) and recently completed two phase 3 studies 
(Registration trials, COMFORT-I and COMFORT-II), eligibility criteria is platelet count ≥100 x 
109/l. In this study, we have chosen baseline platelet count ≥50 x 109/l as eligibility criteria so as 
to give the benefit of this treatment to majority of patients with myelofibrosis. The patients 
undergoing allogeneic transplantation are usually higher risk patients and it is estimated that 
approximately 25% of patients undergoing allogeneic transplant will have baseline platelet count 
<100 x 109/l (31).  
Rationale for not withholding study drug for grade 3–4 thrombocytopenia 
In the COMFORT-1 and COMFORT-2 trials, Ruxolitinib was withheld at platelet count <50 x 
109/l. In this study, study drug will not be withheld for grade 3-4 thrombocytopenia unless there 


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is a serious bleeding complication. In the drug trials patients are on study medication for a very 
long period of time, which can vary from several months to years. In comparison, in the 
transplant trial, patients are on study medication for 56 days and then medication will be tapered. 
To get the maximum benefit of this strategy, it will beneficial to modify the dosage and continue 
the study medication with additional platelet transfusions if necessary. 
Management of patients with ruxolitinib withdrawal syndrome 
Severe reactions have been reported to occur uncommonly following abrupt ruxolitinib 
withdrawal. The dose tapering strategy in this protocol is designed to minimize the risk of such 
reactions. Patients considered to be at high risk of ruxolitinib withdrawal syndrome, such as 
those with highly proliferative disease, should be closely monitored during the tapering period 
prior to commencement of conditioning therapy. Short-term courses of corticosteroids have been 
used to moderate the withdrawal of ruxolitinib and may be considered as part of a tapering 
strategy at the investigators discretion. In the unlikely event that patients develop a withdrawal 
syndrome requiring conditioning to be deferred, this will be classified as a protocol failure. 
4.3 
Conditioning Therapy 
If HCT is delayed because of donor related issues, patient will still be considered eligible for 
HCT.   These patients should continue on Ruxolitinib as per protocol, and proceed to transplant 
once donor issues are resolved.  Prior to start of conditioning therapy, transplant physician 
should ensure that the patient meets the following criteria: 
 
a. ECOG Performance status 0-2 
b. Blasts in PB <20% 
c. Adequate renal function with creatinine <1.5 x Institutional ULN 
d. Adequate hepatic function with AST/ALT <2.5 x IULN and Bilirubin <1.5 x IULN 
e. Absence of active uncontrolled infection or any other concurrent illness which in the 
Investigator’s opinion puts the patient at excessive risk of transplant related toxicities. 
 
A patient not meeting the above criteria will be counted as failure; and treating physician should 
discuss this patient with one of the study co-chairs.  
 
Conditioning therapy will be as follows: 
Initiate anticonvulsant prophylactic therapy prior to busulfan treatment as per institutional 
practice. 
IV Fludarabine 40 mg/m2 IV over 30 minutes once daily x 4 days for days -5 to -2. 
IV Busulfan 2.0 mg/ KG of body weight IV over 2 hours once daily for 4 consecutive days for 
days -5 to -2. 
*If actual body weight is > 30% ideal body weight (IBW), use adjusted body weight (ABW) for 
calculating the dose of fludarabine and busulfan 
Fludarabine and Antithymocyte Globulin (Rabbit) – will be dosed according to the patient’s 
actual body weight, unless the patient weighs more than 130% of IBW, in which the dose will 
be based on an adjusted body weight. 
IBW: Estimated ideal body weight in (kg) 


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Males: IBW = 50 kg + 2.3 kg for each inch over 5 feet. 
Females: IBW = 45.5 kg + 2.3 kg for each inch over 5 feet. 
ABW: Estimated adjusted body weight (kg) 
If the actual body weight is greater than 30% of the calculated IBW, calculate the adjusted 
body weight  
ABW = IBW + 0.4(actual weight - IBW) 
Table 5 
Conditioning therapy schedule 
Treatment 
Day -5
Day -4
Day -3
Day–2 Day–1 Day 0
Fludarabine 
X 
X 
X 
X 
 
 
Busulfan 
X 
X 
X 
X 
 
 
ATG 
(only if unrelated donor) 
 
 
X 
X 
X 
 
 
4.4 
GvHD Prophylaxis 
a. IV Calcineurin inhibitor [IV cyclosporine (per institutional practice) or IV 
tacrolimus (per institutional practice)] starting on day -2, until engraftment or when 
the patient is able to take PO, then switched to PO doses. Cyclosporine or tacrolimus 
will be given per institutional practice.  The doses should be adjusted to keep trough 
levels of cyclosporine between 200-400 μg/L or  tacrolimus 8-12 ng/ml. 
Cyclosporine or tacrolimus will be continued through day 180 and subsequently in 
the absence of GvHD, tapered by 25% every 2 weeks thereafter. The use of 
cyclosporine or tacrolimus is according to the choice of the transplant center.  
b. Methotrexate 10 mg/m2 on day +1, then 5 mg/m2 on day +3 and day +6, dose of 
methotrexate should be modified if necessary according to creatinine clearance 
(Table 6 Methotrexate dose modification)  
Table 6 
Methotrexate dose modification 
Calculated Creatinine Clearance (mls/min) 
% Methotrexate Dose Reduction 
>70 
0% 
50-70 
25% 
30-49 
50% 
<30 
100% (no methotrexate) 
 
c. Thymoglobuline (ATG) - Antithymocyte Globulin (Rabbit). Patients undergoing 
unrelated donor or mismatched related donor transplantation will be given additional 
GvHD prophylaxis with low-dose thymoglobuline** (0.5 mg / KG of body weight 
on day -3, 2.0 mg/ KG of body weight on day -2, and 2.0 mg/ KG of body weight on 


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day -1).  Patients will be premedicated with acetaminophen, antihistamine, and 
corticosteroids as per institutional practice. 
** If actual body weight is > 30% ideal body weight (IBW), use adjusted body weight (ABW) 
for calculating the dose of ATG as detailed above. 
4.5 
Graft Source 
Peripheral blood (PB) will be the recommended graft source; however, bone marrow (BM) will 
be acceptable depending on the donor or registry choice. 
The recommended doses for the graft are:  
PB graft: 4 x 106 CD34+ cells/ Kilogram of body weight of recipient;  
BM graft: 3 x 108 Total nucleated cells (TNC)/ Kilogram of body weight of recipient 
If the PB graft dose is <2 x 106 CD34+ cells / Kilogram of body weight of recipient or BM graft 
is <1 x 108 TNC / Kilogram of body weight of recipient; the graft will be treated as non-
conforming product.  
Each transplant center will follow the guidelines of their respective country regarding safe use of 
cellular therapy products.  
A graft which is considered nonconforming nature due to either low cell dose or any other reason 
will be released after signing a form by the transplant physician confirming the nature of non-
conformance. A sample of non-conformance letter is attached in the Appendix 11. 
In case of nonconforming product, the transplant physician will report to MPD-RC about the 
nature of non-conformance; and this information will be collected in the study database.  
4.6 
Supportive Care 
Each transplant center will follow local policies for supportive care for decisions regarding use 
of antibacterial, antifungal and antiviral prophylaxis. It is mandatory that if a center uses anti-
fungal prophylaxis with an agent which is strong inhibitor of CYP3A4 (drugs such as 
voriconazole or posaconazole), these should not be started before day -2 as there is drug 
interaction with Ruxolitinib and these drugs are likely to increase the levels of Ruxolitinib. 
In case there is a clinical need to give these medications along with Ruxolitinib, then dose of 
Ruxolitinib should be reduced by 50%. 
4.7 
Study follow-up 
All the patients enrolled in the study will continue to be monitored as per study schedule until 
last enrolled patient has reached a follow up of 2 years.  There will be an annual follow-up for 
survival to a maximum of 4 years total from study start to finish. 
Treatment in this trial will be defined as any point after enrollment whether actively receiving 
ruxolitinib or post stem cell infusion. Subjects who discontinue study treatment due to toxicity or 
require additional intervention for protocol defined graft failure or relapse/disease progression 
will have a 30 day follow up visit and then will continue to be followed every 6 months from the 
EOT (end of treatment) for survival and progression of disease until the end of the trial (after last 


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enrolled patient completes 2 years of follow up).  The survival and progression of disease data 
can be collected via telephone call or medical record. 


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5 
REGISTRATION PROCEDURES 
5.1 
Registration requirements  
Only MPD-RC Approved Transplant Centers may participate and register patients to this study. 
5.1.1 Site Registration with MPD-RC 
Before an MPD-RC Institution can enroll patients, protocol specific regulatory documents 
must be submitted to the MPD-RC Central Coordinating Office via E-mail (PDF file preferred) 
or fax: 
MPD-RC Central Coordinating Office 
Alicia Orellana 
Research Protocol Manager 
Phone: (212) 241-0481 
Fax: (212) 876-5276 
E-mail: alicia.orellana@mssm.edu 
Required Protocol Specific Regulatory Documents (E-mailed by PDF format preferred): 
1. Submit a copy of IRB approval for MPD-RC 114 
2. Submit a copy of the IRB approved consent form for MPD-RC 114 
3. Submit a copy of the CV and medical license of the Research Pharmacist 
4. Submit a copy of the site’s drug destruction policy 
5. Submit a copy of a signed and dated CV and medical license of the Principal 
Investigator and Co-Is 
6. Submit a copy of Form FDA 1572 as completed by the Principal Investigator 
7. Submit a copy of the Investigational Drug Order Form (will be provided to the 
site by the MPD-RC once we receive items 1-6) 
BEFORE Study Drug Shipment 
Before Study Drug can be shipped to the MPD-RC Center to begin accruing patients, the above 
regulatory documents will be required and forwarded to the MPD-RC Central Office to the 
attention of the Regulatory Coordinator, as noted above. 
5.1.2 Correlative Biomarker Study (MPD-RC 107) 
There is a correlative science biomarker study for which participation is mandatory (MPD-RC 
protocol 107).  The patient must be enrolled in the mandatory companion biomarker study in 
order to participate in this treatment study (MPD-RC 114). 
5.2 
Informed Consent 
The patient must be aware of the neoplastic nature of his/her disease, as well as of the expected 
life expectancy at his/her stage of disease (according to DIPSS Scoring System, Appendix 1). 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the therapy, alternatives, potential benefits, side effects, risks, and 
discomforts. Human protection committee approval of this protocol and of its consent form is 
required. 


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5.3 
MPD-RC registration procedures 
This study uses the MPD-RC on-line Patient Registration system (www.mpd-rc.org). 
Registration will be accepted only through users of the MPD-RC database. Registration must 
occur prior to the initiation of therapy.  
Confirm eligibility criteria (Section 3) and complete the on-line Registration Worksheet. Access 
the online Patient Registration system via the patient registration icon on the MPD-RC 
Information Systems IS Application main menu. If the registering clinical research associate 
(CRA) requires assistance he/she may consult the on-line help file located under the Help 
menu of the MPD-RC application.  
When the patient is registered to MPD-RC tissue bank protocol #107 and then onto #114, a 
patient identification number will be generated.  Registration will not be completed if eligibility 
requirements are not met for the selected trial. 
The registering institution will receive a Confirmation of Registration email from the database 
that should be printed and included in the patient chart. If a registering institution needs to 
correct the registration form, contact the MPD-RC Data Management Center: E-mail: 
mpdtrials@mpdrc.org 


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6 
PHARMACEUTICAL INFORMATION 
6.1 
Study Drug-Ruxolitinib (INC424) 
Therapeutic Classification: 
Ruxolitinib 
phosphate 
is 
a 
kinase 
inhibitor 
with 
the 
chemical 
name 
(R)-3-(4-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile 
phosphate and a molecular weight of 404.36. Ruxolitinib phosphate has the following structural 
formula: 
 
 
 
Ruxolitinib phosphate is a white to off-white to light pink powder and is soluble in aqueous 
buffers across a pH range of 1 to 8.  
Ruxolitinib Tablets are for oral administration. Each tablet contains ruxolitinib phosphate 
equivalent to 5 mg, 10 mg, 15 mg, 20 mg and 25 mg of ruxolitinib free base together with 
microcrystalline cellulose, lactose monohydrate, magnesium stearate, colloidal silicon dioxide, 
sodium starch glycolate, povidone, and hydroxypropyl cellulose. 
Dosing Information  
Recommended Starting Dose – (See section 4.2, Table 2) 
Dose Adjustment with Concomitant Strong CYP3A4 Inhibitors 
On the basis of pharmacokinetic studies in healthy volunteers, when administering Ruxolitinib 
with strong CYP3A4 inhibitors (such as but not limited to boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
voriconazole) these CYP3A4 inhibitors should be avoided during the 62 days of ruxolitinib 
administration.  


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Method of Administration 
Ruxolitinib is dosed orally and can be administered with or without food.  The dose should be 
taken at the same time each day with a window of ±3 hours. If a dose is missed, the patient 
should not take an additional dose, but should take the next usual prescribed dose. 
When discontinuing Ruxolitinib therapy for reasons other than thrombocytopenia, gradual 
tapering of the dose of Ruxolitinib may be considered, for example by 5 mg twice daily each 
week. 
For patients unable to ingest tablets, Ruxolitinib can be administered through a nasogastric tube 
(8 French or greater) as follows: 
 Suspend one tablet in approximately 40 mL of water with stirring for approximately 10 
minutes. 
 Within 6 hours after the tablet has dispersed, the suspension can be administered through 
a nasogastric tube using an appropriate syringe. 
The tube should be rinsed with approximately 75 mL of water. The effect of tube feeding 
preparations on Ruxolitinib exposure during administration through a nasogastric tube has not 
been evaluated. 
Pharmaceutical Data 
Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2, which 
mediate the signaling of a number of cytokines and growth factors that are important for 
hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal 
transducers and activators of transcription) to cytokine receptors, activation and subsequent 
localization of STATs to the nucleus leading to modulation of gene expression. 
Side Effects: 
Adverse reactions occurring in patients on Ruxolitinib in the double-blind, placebo-controlled 
study during randomized treatment includes contusion, ecchymosis, hematoma, injection site 
hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, 
petechiae, purpura, dizziness, postural dizziness, vertigo, balance disorder, Meniere's Disease, 
labyrinthitis, urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney 
infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present, weight increased, 
abnormal weight gain, herpes zoster and post-herpetic neuralgia. Rare case reports of progressive 
multifocal encephalopathy have been reported. 
Description of Selected Adverse Drug Reactions  
Anemia  
In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher 
anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of 
anemia. In patients receiving Ruxolitinib, mean decreases in hemoglobin reached a nadir of 
approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually 
recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This 


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pattern was observed in patients regardless of whether they had received transfusions during 
therapy.  
In the randomized, placebo-controlled study, 60% of patients treated with Ruxolitinib and 38% 
of patients receiving placebo received red blood cell transfusions during randomized treatment. 
Among transfused patients, the median number of units transfused per month was 1.2 in patients 
treated with Ruxolitinib and 1.7 in placebo treated patients. 
Thrombocytopenia  
In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, 
the median time to onset was approximately 8 weeks. Thrombocytopenia was generally 
reversible with dose reduction or dose interruption. The median time to recovery of platelet 
counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of 
patients receiving Ruxolitinib and to 4.0% of patients receiving control regimens. 
Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients 
receiving Ruxolitinib and 0.9% of patients receiving control regimens. Patients with a platelet 
count of 100 X 109/L to 200 X 109/L before starting Ruxolitinib had a higher frequency of Grade 
3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L 
(16.5% versus 7.2%).  
Neutropenia  
In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Ruxolitinib because of 
neutropenia. 
Additional Data from the Placebo-controlled Study  
25.2% of patients treated with Ruxolitinib and 7.3% of patients treated with placebo developed 
newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The 
incidence of greater than or equal to grade 3 elevations in ALT was observed in 1.3% of 
ruxolitinib treated patients and 0% in placebo treated patients 
Ruxolitinib with 1.3% Grade 3 and no Grade 4 ALT elevations. 
17.4% of patients treated with Ruxolitinib and 6.0% of patients treated with placebo developed 
newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The 
incidence of Grade 2 AST elevations was 0.6%.  
Ruxolitinib with no Grade 3 or 4 AST elevations. 
16.8% of patients treated with Ruxolitinib and 0.7% of patients treated with placebo developed 
newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 
cholesterol elevations was 0.6% for Ruxolitinib with no Grade 3 or 4 cholesterol elevations. 
Clinical Applications:  
FDA approved indication: Ruxolitinib is indicated for treatment of patients with intermediate 
or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera 
myelofibrosis and post-essential thrombocythemia myelofibrosis. 
Health Canada approved indication: Ruxolitinib is indicated for the treatment of 
splenomegaly and/or its associated symptoms in adult patients with primary myelofibrosis (also 
known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-
essential thrombocythemia myelofibrosis.  


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6.2 
Fludarabine 
Therapeutic Classification 
Fludarabine is the 2-fluoro, 5-phosphate derivative of vidarabine. 
Dosing Information: 
Doses of 25 mg/m2/day (30-minute infusion) for 5 days every 4 weeks has been effective 
previously treated patients with chronic lymphocytic leukemia; in non-Hodgkin's lymphoma, a 
loading dose of 20 mg/m2 intravenously followed by a continuous intravenous infusion of 30 
mg/m2/24 hours for 48 hours, has been effective; dose reductions are suggested in renal 
insufficiency. 
Pharmaceutical Data 
Following intravenous administration, fludarabine phosphate is rapidly dephosphorylated to 
2-fluoro-vidarabine, which subsequently enters tumor cells and is phosphorylated to the active 
triphosphate derivative; peak plasma levels of 2-fluoro-vidarabine have ranged from 0.3 to 0.9 
mcg/mL following a short infusion of 25 mg/m2 fludarabine; 24% of a dose of fludarabine is 
recovered in the urine as 2-fluoro-vidarabine; the elimination half-life of 2-fluoro-vidarabine is 9 
hours. 
Side effects 
Myelosuppression, particularly neutropenia, is the predominant adverse effect; a severe 
neurotoxicity has been observed, mainly with higher doses; other adverse effects include nausea, 
vomiting, diarrhea, fever, ulcers, loss of appetite, swelling or water retention, muscle aches, 
nervousness, hearing loss, fatigue, stomatitis, skin rash, and somnolence; pneumonitis has been 
reported in 1 patient. 
Clinical Applications 
Intravenous fludarabine has been highly effective as a single agent in heavily pretreated patients 
with chronic lymphocytic leukemia; the drug has also produced responses in patients with 
non-Hodgkin's lymphoma and acute leukemia when combined with other chemotherapeutic 
agents; however, neurotoxicity has been a major concern, especially when used at high doses. 
6.3 
Busulfan (Busulfex®) 
Therapeutic Classification 
Busulfan is a bifunctional alkylating agent known chemically as 1, 4-butanediol, 
dimethanesulfonate. Busulfex® (busulfan) Injection is intended for intravenous administration. It 
is supplied as a clear, colorless, sterile, solution in 10 mL single use vials. Each vial of Busulfex 
contains 60 mg (6 mg/mL) of busulfan, the active ingredient, a white crystalline powder with a 
molecular formula of CH3SO2O(CH2)4OSO2CH3 and a molecular weight of 246 g/mole. 
Busulfan is dissolved in N,N-dimethylacetamide (DMA) 33% vol/vol and Polyethylene Glycol 
400, 67% vol/vol. The solubility of busulfan in water is 0.1 g/L and the pH of Busulfex diluted to 
approximately 0.5 mg/mL busulfan in 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP as recommended for infusion reflects the pH of the diluent used and ranges from 
3.4 to 3.9. 
Busulfex is intended for dilution with 0.9% Sodium Chloride Injection, USP or 5% Dextrose 
Injection, USP prior to intravenous infusion. 


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Dosing 
Based on the results of this 24-patient clinical trial, a suggested dosing regimen of Busulfex in 
pediatric patients is shown in the following dosing nomogram: 
Table 7 
Busulfex Dosing Nomogram 
Patient's Actual Body Weight (ABW) 
Busulfex Dosage 
≤12 kgs 
1.1 (mg/kg) 
>12 kgs 
0.8 (mg/kg) 
 
The usual adult dose is 0.8 mg/kg of ideal body weight or actual body weight, whichever is 
lower, administered every six hours for four days (a total of 16 doses). For obese, or severely 
obese patients, Busulfex should be administered based on adjusted ideal body weight. Ideal body 
weight (IBW) should be calculated as follows (height in cm, and weight in kg): IBW (kg; 
men)=50+0.91× (height in cm -152); IBW (kg; women)=45+0.91× (height in cm -152). Adjusted 
ideal body weight (AIBW) should be calculated as follows: AIBW= IBW +0.25× (actual weight 
-IBW). Cyclophosphamide is given on each of two days as a one-hour infusion at a dose of 
60 mg/kg beginning on BMT day –3, no sooner than six hours following the 16th dose of 
Busulfex. 
Busulfex clearance is best predicted when the Busulfex dose is administered based on adjusted 
ideal body weight. Dosing Busulfex based on actual body weight, ideal body weight or other 
factors can produce significant differences in Busulfex (busulfan) Injection clearance among 
lean, normal and obese patients. 
Busulfex should be administered intravenously via a central venous catheter as a two-hour 
infusion every six hours for four consecutive days for a total of 16 doses. All patients should be 
premedicated with phenytoin as busulfan is known to cross the blood brain barrier and induce 
seizures. Phenytoin reduces busulfan plasma AUC by 15%. Use of other anticonvulsants may 
result in higher busulfan plasma AUCs, and an increased risk of VOD or seizures. In cases where 
other anticonvulsants must be used, plasma busulfan exposure should be monitored. Antiemetics 
should be administered prior to the first dose of Busulfex and continued on a fixed schedule 
through administration of Busulfex. Where available, pharmacokinetic monitoring may be 
considered to further optimize therapeutic targeting. 
Pharmaceutical Data 
The pharmacokinetics of Busulfex was studied in 59 patients participating in a prospective trial 
of a Busulfex-cyclophosphamide preparatory regimen prior to allogeneic hematopoietic 
progenitor stem cell transplantation. Patients received 0.8 mg/kg Busulfex every six hours, for a 
total of 16 doses over four days. Fifty-five of fifty-nine patients (93%) administered Busulfex 
maintained AUC values below the target value (<1500 µM·min). 


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Table 8 
Steady State Pharmacokinetic Parameters Following Busulfex® (busulfan) 
Infusion (0.8 mg/kg; N=59) 
 
Mean
CV (%)
Range 
Cmax (ng/mL) 
1222 
18 
496-1684 
AUC (µM·min) 
1167 
20 
556-1673 
CL (mL/min/kg)* 
2.52 
25 
1.49-4.31 
*Clearance normalized to actual body weight for all patients. 
Busulfex pharmacokinetics showed consistency between dose 9 and dose 13 as demonstrated by 
reproducibility of steady state Cmax and a low coefficient of variation for this parameter. 
In a pharmacokinetic study of Busulfex in 24 pediatric patients, the population pharmacokinetic 
(PPK) estimates of Busulfex for clearance (CL) and volume of distribution (V) were determined. 
For actual body weight, PPK estimates of CL and V were 4.04 L/hr/20 kg (3.37 mL/min/kg; 
interpatient variability 23%); and 12.8 L/20 kg (0.64 L/kg; interpatient variability 11%). 
Distribution, Metabolism, Excretion 
Studies of distribution, metabolism, and elimination of Busulfex have not been done; however, 
the literature on oral busulfan is relevant. 
Distribution  
Busulfan achieves concentrations in the cerebrospinal fluid approximately equal to those in 
plasma. Irreversible binding to plasma elements, primarily albumin, has been estimated to be 
32.4±2.2%, which is consistent with the reactive electrophilic properties of busulfan. 
Metabolism  
Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and 
by glutathione S-transferase (GST) catalysis. This conjugate undergoes further extensive 
oxidative metabolism in the liver. 
Excretion  
Following administration of 14C-labeled busulfan to humans, approximately 30% of the 
radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in 
feces. The incomplete recovery of radioactivity may be due to the formation of long-lived 
metabolites or due to nonspecific alkylation of macromolecules. 
Side Effects 
Dimethylacetamide (DMA), the solvent used in the Busulfex formulation, was studied in 1962 as 
a potential cancer chemotherapy drug. In a Phase 1 trial, the maximum tolerated dose (MTD) 
was 14.8 g/m2/d for four days. The daily recommended dose of Busulfex contains DMA 
equivalent to 42% of the MTD on a mg/m2 basis. The dose-limiting toxicities in the Phase 1 
study were hepatotoxicity as evidenced by increased liver transaminase (SGOT) levels and 
neurological symptoms as evidenced by hallucinations. The hallucinations had a pattern of onset 
at one day post completion of DMA administration and were associated with EEG changes. The 
lowest dose at which hallucinations were recognized was equivalent to 1.9 times that delivered in 
a conditioning regimen utilizing Busulfex 0.8 mg/kg every 6 hours ×16 doses. Other 
neurological toxicities included somnolence, lethargy, and confusion. The relative contribution 


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of DMA and/or other concomitant medications to neurologic and hepatic toxicities observed with 
Busulfex is difficult to ascertain. 
Treatment with Busulfex at the recommended dose and schedule will result in profound 
myelosuppression in 100% of patients, including granulocytopenia, thrombocytopenia, anemia, 
or a combined loss of formed elements of the blood. 
Adverse reaction information is primarily derived from the clinical study (N=61) of Busulfex 
and the data obtained for high-dose oral busulfan conditioning in the setting of randomized, 
controlled trials identified through a literature review. 
Busulfex Clinical Trials 
In the Busulfex (busulfan) Injection allogeneic stem cell transplantation clinical trial, all patients 
were treated with Busulfex 0.8 mg/kg as a two-hour infusion every six hours for 16 doses over 
four days, combined with cyclophosphamide 60 mg/kg ×2 days. Ninety-three percent (93%) of 
evaluable patients receiving this dose of Busulfex maintained an AUC less than 1,500 µM·min 
for dose 9, which has generally been considered the level that minimizes the risk of HVOD. 
Table 9 
Summary of the Incidence (≥20%) of Non-Hematologic Adverse Events 
through BMT Day +28 in Patients who Received Busulfex Prior to 
Allogeneic Hematopoietic Progenitor Cell Transplantation 
Non-Hematological Adverse Events* 
Percent Incidence (%) 
BODY AS A WHOLE 
 
  Fever 
80 
  Headache 
69 
  Asthenia 
51 
  Chills 
46 
  Pain 
44 
  Edema General 
28 
  Allergic Reaction 
26 
  Chest Pain
26 
  Inflammation at Injection Site
25 
  Back Pain 
23 
CARDIOVASCULAR SYSTEM
 
  Tachycardia 
44 
  Hypertension 
36 
  Thrombosis 
33 
  Vasodilation 
25 
DIGESTIVE SYSTEM 
 
  Nausea 
98 
  Stomatitis (Mucositis) 
97 
  Vomiting 
95 
  Anorexia 
85 
  Diarrhea 
84 
  Abdominal Pain 
72 
  Dyspepsia 
44 


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Non-Hematological Adverse Events* 
Percent Incidence (%) 
  Constipation 
38 
  Dry Mouth 
26 
  Rectal Disorder 
25 
  Abdominal Enlargement 
23 
METABOLIC AND NUTRITIONAL SYSTEM
 
  Hypomagnesemia 
77 
  Hyperglycemia 
66 
  Hypokalemia 
64 
  Hypocalcemia 
49 
  Hyperbilirubinemia 
49 
  Edema 
36 
  SGPT Elevation 
31 
  Creatinine Increased 
21 
NERVOUS SYSTEM 
 
  Insomnia 
84 
  Anxiety 
72 
  Dizziness 
30 
  Depression 
23 
RESPIRATORY SYSTEM
 
  Rhinitis 
44 
  Lung Disorder 
34 
  Cough 
28 
  Epistaxis 
25 
  Dyspnea 
25 
SKIN AND APPENDAGES
 
  Rash 
57 
  Pruritus 
28 
*Includes all reported adverse events regardless of severity (toxicity grades 1-4) 
The following sections describe clinically significant events occurring in the Busulfex clinical 
trials, regardless of drug attribution.  
Hematologic  
At the indicated dose and schedule, Busulfex produced profound myelosuppression in 100% of 
patients. Following hematopoietic progenitor cell infusion, recovery of neutrophil counts to 
≥500 cells/mm3 occurred at median day 13 when prophylactic G-CSF was administered to the 
majority of participants on the study. The median number of platelet transfusions per patient on 
study was 6, and the median number of red blood cell transfusions on study was 4. Prolonged 
prothrombin time was reported in one patient (2%). 
Gastrointestinal  
Gastrointestinal toxicities were frequent and generally considered to be related to the drug. Few 
were categorized as serious. Mild or moderate nausea occurred in 92% of patients in the 
allogeneic clinical trial, and mild or moderate vomiting occurred in 95% through BMT Day +28; 


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nausea was severe in 7%. The incidence of vomiting during Busulfex administration (BMT Day 
–7 to –4) was 43% in the allogeneic clinical trial. Grade 3-4 stomatitis developed in 26% of the 
participants, and Grade 3 esophagitis developed in 2%. Grade 3-4 diarrhea was reported in 5% of 
the allogeneic study participants, while mild or moderate diarrhea occurred in 75%. Mild or 
moderate constipation occurred in 38% of patients; ileus developed in 8% and was severe in 2%. 
Forty-four percent (44%) of patients reported mild or moderate dyspepsia. Two percent (2%) of 
patients experienced mild hematemesis. Pancreatitis developed in 2% of patients. Mild or 
moderate rectal discomfort occurred in 24% of patients. Severe anorexia occurred in 21% of 
patients and was mild/moderate in 64%. 
Hepatic  
Hyperbilirubinemia occurred in 49% of patients in the allogeneic BMT trial. Grade 3/4 
hyperbilirubinemia occurred in 30% of patients within 28 days of transplantation and was 
considered life-threatening in 5% of these patients. Hyperbilirubinemia was associated with 
graft-versus-host disease in six patients and with hepatic veno-occlusive disease in 5 patients. 
Grade 3/4 SGPT elevations occurred in 7% of patients. Alkaline phosphatase increases were 
mild or moderate in 15% of patients. Mild or moderate jaundice developed in 12% of patients, 
and mild or moderate hepatomegaly developed in 6%. 
Hepatic veno-occlusive disease  
Hepatic veno-occlusive disease (HVOD) is a recognized potential complication of conditioning 
therapy prior to transplant. Based on clinical examination and laboratory findings, hepatic veno-
occlusive disease was diagnosed in 8% (5/61) of patients treated with Busulfex in the setting of 
allogeneic transplantation, was fatal in 2/5 cases (40%), and yielded an overall mortality from 
HVOD in the entire study population of 2/61 (3%). Three of the five patients diagnosed with 
HVOD were retrospectively found to meet the Jones' criteria. 
Graft-versus-host disease  
Graft-versus-host disease developed in 18% of patients (11/61) receiving allogeneic transplants; 
it was severe in 3%, and mild or moderate in 15%. There were 3 deaths (5%) attributed to 
GVHD. 
Edema  
Patients receiving allogeneic transplant exhibited some form of edema (79%), hypervolemia, or 
documented weight increase (8%); all events were reported as mild or moderate. 
Infection/Fever  
Fifty-one percent (51%) of patients experienced one or more episodes of infection. Pneumonia 
was fatal in one patient (2%) and life-threatening in 3% of patients. Fever was reported in 80% 
of patients; it was mild or moderate in 78% and severe in 3%. Forty-six percent (46%) of patients 
experienced chills. 
Cardiovascular  
Mild or moderate tachycardia was reported in 44% of patients. In 7 patients (11%) it was first 
reported during Busulfex administration. Other rhythm abnormalities, which were all mild or 
moderate, included arrhythmia (5%), atrial fibrillation (2%), ventricular extrasystoles (2%), and 
third degree heart block (2%). Mild or moderate thrombosis occurred in 33% of patients, and all 
episodes were associated with the central venous catheter. Hypertension was reported in 36% of 


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patients and was Grade 3/4 in 7%. Hypotension occurred in 11% of patients and was Grade 3/4 
in 3%. Mild vasodilation (flushing and hot flashes) was reported in 25% of patients. Other 
cardiovascular events included cardiomegaly (5%), mild ECG abnormality (2%), Grade 3/4 left-
sided heart failure in one patient (2%), and moderate pericardial effusion (2%). These events 
were reported primarily in the post-cyclophosphamide phase. 
Pulmonary  
Mild or moderate dyspnea occurred in 25% of patients and was severe in 2%. One patient (2%) 
experienced severe hyperventilation; and in 2 (3%) additional patients it was mild or moderate. 
Mild rhinitis and mild or moderate cough were reported in 44% and 28% of patients, 
respectively. Mild epistaxis events were reported in 25%. Three patients (5%) on the allogeneic 
study developed documented alveolar hemorrhage. All required mechanical ventilatory support 
and all died. Non-specific interstitial fibrosis was found on wedge biopsies performed with video 
assisted thoracoscopy in one patient on the allogeneic study who subsequently died from 
respiratory failure on BMT Day +98. Other pulmonary events reported as mild or moderate, 
included pharyngitis (18%), hiccup (18%), asthma (8%), atelectasis (2%), pleural effusion (3%), 
hypoxia (2%), hemoptysis (3%), and sinusitis (3%). 
Neurologic  
The most commonly reported adverse events of the central nervous system were insomnia 
(84%), anxiety (75%), dizziness (30%), and depression (23%). Severity was mild or moderate 
except for one patient (1%) who experienced severe insomnia. One patient (1%) developed a 
life-threatening cerebral hemorrhage and a coma as a terminal event following multi-organ 
failure after HVOD. Other events considered severe included delirium (2%), agitation (2%), and 
encephalopathy (2%). The overall incidence of confusion was 11%, and 5% of patients were 
reported to have experienced hallucinations. The patient who developed delirium and 
hallucination on the allogeneic study had onset of confusion at the completion of Busulfex 
(busulfan) Injection. The overall incidence of lethargy in the allogeneic Busulfex clinical trial 
was 7%, and somnolence was reported in 2%. One patient (2%) treated in an autologous 
transplantation study experienced a seizure while receiving cyclophosphamide, despite 
prophylactic treatment with phenytoin. 
Renal  
Creatinine was mildly or moderately elevated in 21% of patients. BUN was increased in 3% of 
patients and to a Grade 3/4 level in 2%. Seven percent of patients experienced dysuria, 15% 
oliguria, and 8% hematuria. There were 4 (7%) Grade 3/4 cases of hemorrhagic cystitis in the 
allogeneic clinical trial. 
Skin  
Rash (57%) and pruritus (28%) were reported; both conditions were predominantly mild. 
Alopecia was mild in 15% of patients and moderate in 2%. Mild vesicular rash was reported in 
10% of patients and mild or moderate maculopapular rash in 8%. Vesiculo-bullous rash was 
reported in 10%, and exfoliative dermatitis in 5%. Erythema nodosum was reported in 2%, acne 
in 7%, and skin discoloration in 8%. 


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Metabolic  
Hyperglycemia was observed in 67% of patients and Grade 3/4 hyperglycemia was reported in 
15%. Hypomagnesemia was mild or moderate in 77% of patients; hypokalemia was mild or 
moderate in 62% and severe in 2%; hypocalcemia was mild or moderate in 46% and severe in 
3%; hypophosphatemia was mild or moderate in 17%; and hyponatremia was reported in 2%. 
Other  
Other reported events included headache (mild or moderate 64%, severe 5%), abdominal pain 
(mild or moderate 69%, severe 3%), asthenia (mild or moderate 49%, severe 2%), unspecified 
pain (mild or moderate 43%, severe 2%), allergic reaction (mild or moderate 24%, severe 2%), 
injection site inflammation (mild or moderate 25%), injection site pain (mild or moderate 15%), 
chest pain (mild or moderate 26%), back pain (mild or moderate 23%), myalgia (mild or 
moderate 16%), arthralgia (mild or moderate 13%), and ear disorder in 3%. 
Deaths  
There were two deaths through BMT Day +28 in the allogeneic transplant setting. There were an 
additional six deaths BMT Day +29 through BMT Day +100 in the allogeneic transplant setting. 
Post-Marketing Experience 
The following adverse reactions (reported as MedRA terms) have been identified during post-
approval use of Busulfex (busulfan) Injection: febrile neutropenia; tumor lysis syndrome; 
thrombotic micro-angiopathy (TMA); severe bacterial, viral (e.g., cytomegalovirus viraemia) and 
fungal infections; and sepsis. Because these reactions are reported voluntarily from a population 
of uncertain size, it is not always possible to establish a causal relationship to drug exposure. 
Clinical Applications 
Busulfex® (busulfan) Injection is indicated for use in combination with cyclophosphamide as a 
conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for 
chronic myelogenous leukemia. 


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7 
CORRELATIVE BIOMARKER STUDIES 
The correlative biomarker study (MPD-RC 107) will evaluate a series of biomarkers at 
baseline (at study entry), day -37 (pre-transplant), day +100 (post-transplant), after months 6, 12, 
24 (post-transplant) and either at the time of relapse/progression or at termination of study (that is 
off study drug for any reason). 
7.1 Central Morphological Review of Bone Marrow Aspirate Smears and Biopsies for 
Patients Entering MPD-RC Treatment Studies 
7.1.1 Bone Marrow and Peripheral Blood Histopathology 
(See MPD-RC protocol 107, for more detailed information) 
At baseline (entry into the trial), at day +100 (post-transplant), and at the end of 6, 12, 24 
months (post-transplant), and at termination of study for any reason the following bone 
marrow aspiration and biopsy specimens must be obtained and submitted for central 
review: 
 three  (3)  air-dried,  unstained  bone  marrow  aspirate  slides  (if available) 
 four (4) unstained peripheral blood films (thin smears) 
 two (2) air dried unstained bone marrow biopsy touch preps for patients with no 
aspirate sample (these are made with 8 touches per slide – 4 horizontal touches in 2 
rows on the slide) 
Additionally: 
 three (3) unstained paraffin-fixed bone marrow biopsy slides each containing at least 2 
sections 
 one (1) stained H & E biopsy slide  
 one (1) biopsy slide stained for iron  
 one (1) biopsy slide stained with the silver for reticulin fibrosis stain should be 
submitted for confirmatory cytologic and cytochemical studies. These should be 
submitted together with the final institutional pathology, cytochemistry, and immuno-
phenotyping reports (if possible). 
 
Bone marrow studies should be repeated at day 100, and at the end of 6, 12 and 24 months 
following treatment and aspirate and biopsy specimens as described above again submitted for 
central review. They should also be repeated if relapse occurs or transformation to MDS, 
myelofibrosis or acute leukemia is suspected. 
The histopathology slides may be batch shipped every 3 Months to Dr. Weinberg in North 
America or Dr. Salmoiraghi in Europe. 
There must be an adequate amount of marrow biopsy specimen in each smear.  The above 
requirements are considered minimal.  Contact the MPD-RC Study Chair with any 
questions. 
Identify each slide with the patient’s MPD-RC patient ID number, protocol number, time 
point, and type of sample. Pack carefully in protective slide cartons (not cardboard 
folders), and mail to: 


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(North America) 
Rona Singer Weinberg, Ph. D 
New York Blood Center 
310 East 67th Street, Room 2-44 
New York, New York 10065 
Phone: (212) 570-3488 
Fax: (212) 570-3495 
rweinberg@nybloodcenter.org 
Laboratory Phone: (212) 570-3412 
Laboratory Fax: (212) 570-3495 
MPDLab@nybloodcenter.org 
Office hours: Monday through Friday 9AM to 5PM EST. Accepting samples Monday through 
Friday (up until 12 noon on Fridays only). For shipments to be received at other times, 
contact Dr. Weinberg in advance of collection of samples and shipment. 
Or 
(Europe) 
Dr. Silvia Salmoiraghi 
MPD-RC Tissue Bank 
Azienda Ospedaliera Papa Giovanni XXIII 
Laboratorio Paolo Belli USC Ematologia 
Torre 7, Ingresso 55, piano 1 
Piazza OMS- Organizzazione Mondiale della Sanità,1 
24127 Bergamo 
Phone: +39 035-2673769 
lab.paolobelli@hpg23.it 
 
Office hours: Monday through Friday 9AM to 5PM. Accepting samples Monday through Friday 
(up until 12 noon on Fridays only). For shipments to be received at other times, contact the. 
Office in advance of collection of samples and shipment. 
 
Send a de-identified copy of the institutional bone marrow aspiration and biopsy report 
generated at your institution as soon as it is complete to the MPD-RC central laboratory in New 
York or Bergamo, Italy. This report must include differential cell counts on the marrow aspirate, 
if performed. 
7.1.2 Cytogenetics and FISH Cytogenetic and FISH Requirements 
Diagnostic and follow up cytogenetics and or FISH will be performed by local institutional 
laboratories. All karyotypes will be centrally reviewed (see below). To ensure uniformity of 
cytogenetic preparations all participating local laboratories must adhere to the following 
requirements established by the central karyotype review committee. 


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General Inclusion Criteria for Conventional Cytogenetics 
1. Banding level 300 or more and structural aberrations are accepted at 400 or higher 
banding level or confirmed by FISH. 
2. Minimum requirements for baseline assessments:  From each patient, bone marrow 
(PV, ET) and or unstimulated PB (PMF) specimen must be set up into two, preferably 
three, different cultures (direct, 24 hrs with and without marrow max media). Every 
effort should be made to obtain the growth of cells that are cytogenetically abnormal. 
3. 20 metaphase evaluated from two or more cell cultures or from marrow max culture 
only. 
4. Only G-banding of chromosomes is acceptable. Other banding methods are not 
acceptable. 
5. Analysis of cell at 300 band resolution, or low quality banding, irrespective of the 
findings, to be complemented with FISH screening for subtle aberrations, including 
del(20)(q11q13) with D20S108 probe. 
6. ISCN 2009 must be used to describe the karyotype. 
7. Aberrations classified as clonal should be present in at least 2 cells by G-banding or 
confirmed by FISH. 
8. Unusual or novel findings should be fully characterized by FISH using appropriate 
probes. 
9. Three karyotypes (and metaphase cells) from each patient must be uploaded 
electronically into the MPD-RC database to document the stated cytogenetic 
diagnosis.  The karyotypes are uploaded either as TIFF or JPEG files. 
FISH studies, IF POSSIBLE and recommended 
10. Case normal by G banding, if possible, ought to be screened for cryptic changes by 
interphase 
FISH 
using 
a 
MPN 
panel 
of 
12 
probes: 
CEP1(1q12)/1q21, 
5p15.2/5q31(EGR1), CEP7/7q31, CEP8, CEP9/9p21, RB1 at 13q14, P53/CEP17, 
20q12/D20S108. 
11. FISH studies are performed on BM or PB on interphase cells processed directly (no 
culture) using Abbott Molecular FISH probes. A minimum of 200 cells at baseline 
should be scored by two individuals. Image of FISH results should be uploaded as 
JPEG or TIFF file into the MPD-RC database. 
Central Karyotype Review Committee consists of Vesna Najfeld, Ph.D., Director, Tumor 
Cytogenetics, The Mount Sinai Medical Center, NY (chair) Elisabeth Nacheva, MD, Ph.D, FRC 
Path, Director of Cytogenetics, UCL Medical School, Royal Free Campus, London, UK, 
Cristina Mecucci, MD, PhD, Director of Cytogenetic laboratory, University of Perugia, Perugia, 
Italy and Ursula Giussani, Ph.D., Director of Laboratorio di Genetica Medica, Bergamo, Italy. 
Central karyotype review committee will have biannual teleconferences for central karyotype 
review and will meet annually or to resolve difficult karyotypes, perform QC, discuss 
correlative studies with hematological response and other biomarkers. Karyotypes that were not 
uploaded or faxed pictures of karyotypes cannot be reviewed.  


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One of the QC indicators is a proper entry and submission of cytogenetic forms and karyotypes 
by the institutional cytogenetic laboratories. If the local laboratory fails two consecutive 
specimens (poor quality of chromosome banding, missed abnormality, wrong ISCN 
nomenclature) or lack of entering cytogenetic results into MPD- RC, the laboratory will be 
informed, and the third failure will result in placing the local laboratory on probation and the 
institutional PI will be informed. If required, either the central lab in NY or other MPD-RC 
approved cytogenetic lab will perform the studies from the institution whose cytogenetic lab is 
placed on probation. Each institution in the RC will receive quarterly information regarding the 
cytogenetic entry results on the MPD-RC database. 
For any questions please call Joe Tripodi MS, Cytogenetic Research Coordinator, Mount Sinai 
Medical Center: 212 241-8801 or Dr. Vesna Najfeld at 212 241-8801. 
7.2 
Schedule of Samples for Correlative Studies 
7.2.1 Samples to be collected 
The following samples noted in Table 10 are to be collected at baseline (entry onto trial), day -65 
(pre-transplant), day -37 (pre-transplant), day -5 (pre-transplant), day +30 (post-transplant) at day 
+100 (post-transplant), the end of month 6 (post-transplant), end of month 12 (post-transplant), 
end of month 24 (post-transplant), and at relapse or off treatment for any reason. 


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Table 10 
Correlative Studies Sample Collection Schedule 
 
Sample 
 
Baseline
Day 
-65 
Day 
-37 
Day 
-5 
Day 
+30 
Day 
+100 
End of 
6 
Months 
End of 
12 
months 
End of 
24 
Months 
Relapse/ 
off 
treatment4 
Bone Marrow 
Aspirate 
Histopathology1 
Three (3) air dried unstained slides 
X 
 
 
 
 
X 
X 
X 
X 
X 
Aspirate 
Cytogenetics2 
At local institution, upload data 
and karyotypes to the website1. If 
no aspirate, provide peripheral 
blood karyotypes. Karyotype at 
follow up only need to be repeated 
if abnormal prior to transplant 
X 
 
 
 
 
X 
X 
X 
X 
X 
Aspirate 
Biomarkers3 
2 to 5 mL of bone marrow aspirate 
in a green top, heparinized tube 
(BD catalog #366480) 
X 
 
 
 
 
X 
X 
X 
X 
X 
Biopsy 
Histopathology1 
One (1) H & E stain 
X 
 
 
 
 
X 
X 
X 
X 
X 
One (1) Iron stain 
X 
 
 
 
 
X 
X 
X 
X 
X 
One (1) Silver impregnated reticulin 
stain 
X 
 
 
 
 
X 
X 
X 
X 
X 
Three (3) Unstained paraffin-
fixed slides each with at least 2 
sections 
X 
 
 
 
 
X 
X 
X 
X 
X 
Three (3) air-dried, unstained 
bone marrow aspirate slides (if 
available) 
X 
 
 
 
 
X 
X 
X 
X 
X 
If no aspirate, two (2) air dried 
unstained touch preps, 8 
touches/slide, 2 horizontal 
X 
 
 
 
 
X 
X 
X 
X 
X 


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Sample 
 
Baseline
Day 
-65 
Day 
-37 
Day 
-5 
Day 
+30 
Day 
+100 
End of 
6 
Months 
End of 
12 
months 
End of 
24 
Months 
Relapse/ 
off 
treatment4 
Peripheral Blood 
Histopathology1 
Four (4) Unstained peripheral blood 
films, thin smears 
X 
 
 
 
 
X 
X 
X 
X 
X 
Cytogenetics2 
If no BM aspirate karyotypic 
analysis1 
X 
 
 
 
 
X 
X 
X 
X 
X 
Biomarkers3 
Hematocrit  ≤  32,  37  mL: 
 
 
 
 
 
 
 
 
 
 
Three (3) ACD: yellow 
(BD #364606; 8.5 mL) 
X 
 
 
 
 
X 
X 
X 
X 
X 
One(1) EDTA: lavender  
(BD #366450; 8.5 mL) 
X 
 
 
 
 
X 
X 
X 
X 
X 
One (1) sodium citrate: light blue 
(BD #366415; 4.5 mL) 
X 
 
 
 
 
X 
X 
X 
X 
X 
Hematocrit > 32, 67 mL: 
 
 
 
 
 
 
 
 
 
 
Five(5) ACD: yellow 
(BD #364606; 8.5 mL) 
X 
 
 
 
 
X 
X 
X 
X 
X 
One(1) EDTA: lavender  
(BD #366450; 8.5 mL) 
X 
 
 
 
 
X 
X 
X 
X 
X 
Four (4) sodium citrate: light blue 
(BD #366415; 4.5 mL) 
X 
 
 
 
 
X 
X 
X 
X 
X 
Cytokines 
Two (2) ACD: yellow  
(BD #364606; 8.5 mL) 
 
X5 
X 
X 
X 
X 
 
 
 
 


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Sample 
 
Baseline
Day 
-65 
Day 
-37 
Day 
-5 
Day 
+30 
Day 
+100 
End of 
6 
Months 
End of 
12 
months 
End of 
24 
Months 
Relapse/ 
off 
treatment4 
Other 
Nails3 
2 clippings (pre-treatment, at 
enrollment only) 
X 
 
 
 
 
 
 
 
 
 
 
1 All slides must be registered via the MPC-RC website (consult the MPD-RC website under the tissue bank section for 
diagram on labeling slides) the day they are collected and prior to shipment.  All slides MUST BE LABELED properly. 
Labels are to include the patient’s tissue bank ID number (TB ID), protocol number (e.g., Protocol 114), time of study (e.g., 
baseline, 6 months), type of specimen (e.g., BM biopsy, BM aspirate, blood), type of stain (e.g., Iron, H& E).  For unstained 
slides, use a pencil to label the slides.  All slides are to be shipped to the tissue bank laboratory in a labeled slide box.  The label 
on the box is to include the patient’s TB ID, protocol number, and time of study.    Slides may be shipped in batches together 
with the local institution’s histopathology report.  All slides are shipped to Dr. Rona Singer Weinberg (North America) or Dr. 
Silvia Salmoiraghi (Europe). See MPD-RC 107, Section 5.0 Procurement for additional labeling and shipping information. 
2 Cytogenetic analyses are performed as a standard of care at the institution where the patient is being treated.  Karyotypic 
analysis of unstimulated bone marrow after direct 24 and 48 hours, if available, or peripheral blood shall be performed.  
Karyotypic analysis using G-banding technology is required. Data and karyotypes are uploaded to the website. See MPD-RC 
107, Section 5.0 Procurement for additional reporting information. 
3 All tissue samples must be registered via the MPC-RC website the day they are collected and prior to shipment.  
All tubes, and envelopes (nails) must be labeled with patient patient’s tissue bank ID number (TB ID), protocol number (e.g., 
Protocol 114), sample ID number (provided by the data bank at the time of registration), time of study (e.g., baseline, 6 months), 
type of specimen (e.g., BM biopsy, BM aspirate, blood) and date of collection. 
4 At relapse/progression or off treatment as defined in section 4.7. If the subject experiences secondary graft failure or fails to meet 
the primary objective after transplant, the patient will be followed every 6 months for survival until the end of the study.  The 
survival data can be collected via telephone call. 
5 Cytokines collected on Day -65 must be collected BEFORE start of study drug treatment 


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Fresh blood and bone marrow are to be shipped at ambient temperature and must be shipped 
the day that they are collected. 
Nails are to be shipped at ambient temperature and may be shipped together with blood and bone 
marrow samples or subsequently. 
All slides are to be shipped to the tissue bank laboratory in a labeled slide box.  The label on the 
box is to include the patient’s TB ID, protocol number, and time point of study.  Slides may be 
shipped in batches together with the local institution’s histopathology report.  All slides are 
shipped to Dr. Rona Singer Weinberg (North America) or Dr. Silvia Salmoiraghi (Europe). For 
additional labeling and shipping information (see Protocol 107 section 5.0 Procurement). 
7.2.2 Collection of Biomarker Samples 
Please see Table 10 for various time points for collection of samples (also see Protocol 107, 
Appendix 10.3 for the time points to obtain samples).  The samples will be separated as follows. 
Bone Marrow 
Bone marrow aspirate samples will be collected for histopathology, biomarkers, and 
cytogenetics/FISH. For biomarkers and cytogenetics, obtain a total of 3-7 mL of aspirated bone 
marrow. Samples are to be divided as follows: 
 2-5 mL of bone marrow aspirate in a green top, heparinized tube (BD catalog number 
366480) to be sent to tissue bank 
 1-2 mL of bone marrow aspirate for Cytogenetics to be done locally 
Peripheral Blood: (use sterile technique)  
Up to 67 mL of blood: 
 For hematocrit ≤ 32, 37 mL of blood:  three ACD (yellow top) tubes (BD catalogue 
number 364606; 8.5 mL tubes), one EDTA (lavender top) tube (BD catalog number 
366450), and one sodium citrate (light blue top) tube (BD catalogue number 366415, 
4.5 mL). 
 For hematocrit  32, 67 mL of blood: Five ACD (yellow top) tubes (BD catalogue 
number 364606; 8.5 mL tubes), one EDTA (lavender top) tube (BD catalog number 
366450), and four sodium citrate (light blue top) tubes (BD catalogue number 366415, 
4.5 mL). 
Nail Clippings: 
Two nail clippings are to be obtained from each patient during the initial entry onto the protocol.  
Clippings are to be placed in a paper envelope and the envelope is to be sealed.   The sealed 
envelope may be stored and shipped at room temperature.  
7.3 
Shipping Samples for Correlative Studies 
All shipments must be sent by overnight courier for delivery before 10 AM or morning 
delivery the next day.  For Friday shipments (to arrive on Saturday), notify the 
laboratory prior to collection of tissue and shipment.  For shipments sent on Friday for 


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Saturday delivery be certain to request Saturday AM delivery directly to the lab.  It is not 
possible for lab personnel to go to the courier’s office for pickup. See section 7.1 for 
shipping address. 
7.4 
Clonality 
Applicable to informative females = probable 50 – 60% of patients.  Sample amount for this 
test is already included in the samples being collected.  No further sample collection needs to 
be done for this test. 
7.5 
MPN Associate Symptoms and Quality of Life 
We will measure myelofibrosis associated symptoms, general QOL, treatment-relevant QOL and 
related symptoms prior to start of conditioning therapy (days -65 and -9, pre-transplant); from 
start of conditioning and post BMT follow-up (days -5, +30, and +100; months +6, +12, and 
yearly afterwards); and at time of relapse/progression and study termination for any reason. See 
sections Table 12 and Table 13 for schedules. 
The following instruments will be used to measure QOL: 
MPN-SAF: 
The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) was developed as a 
simple, concise set of 18 questions to assess constitutional symptoms and QOL in 
myeloproliferative neoplasms including MF, PV and ET (Appendix 5). Administered along with 
the 10- item Brief Fatigue Inventory (BFI) (27) it has been validated against the EORTC QLQ-
C30 and available in multiple languages (English, Italian, Swedish, French, German, Dutch and 
Spanish). Additionally, this measure has become the standard uniform symptom assessment tool 
for MPN patients participating in clinical trials and aids in guiding clinical decisions, particularly 
in situations where objective and subjective patient complaints are discrepant. The assessment 
evaluates the following parameters on a linear analog self-assessment scale (LASA 0-10 scale): 
fatigue (from the BFI), catabolic/proliferative symptoms (night-sweats, itching, bone pain, fever, 
weight-loss), pulmonary symptoms (dyspnea, cough, insomnia), splenomegaly, pain mobility, 
and gastrointestinal effects. All of the symptoms are assessed on a clear linear scale, which has 
been proven to be valid in measuring symptoms in cancer patients with single item scales for 
fatigue, pain, stress, and anorexia (28). 
EORTC QLQ-C30: 
The EORTC-QLQ-C30 version 3.0 (Aaronson, et al 1993) (Appendix 6) is included as an 
instrument for co-validation on these trials, and redundant capture of impact of information for 
impact of protocol therapy on patient’s symptoms, mood, and quality of life. The initial EORTC 
QLQ-C36 questionnaire, later shortened and validated with 30 questions, has the following 
advantages namely being a) cancer specific b) multidimensional in structure c) appropriate for 
self- administration d) applicable across a range of cultural settings. This instrument has been 
thoroughly validated for serial use in cancer clinical trial setting, and is available in standard and 
validated translations for Italian, French, Swedish, and German (all languages required for the 
enrolling centers on these trials). This instrument although highly valid for a portion of the 
symptom changes we wish to capture with this trial, nevertheless is not as comprehensive for 
MPN specific symptoms and hence the need for both instruments to be administered. 


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FACT-BMT: 
The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) is a 50-
item validated self-report questionnaire specifically designed to test the quality of life in BMT 
patients (Appendix 7) (29).  The FACT-BMT is composed of five subscales including physical 
well-being (PWB), social/family well-being (SFWB), emotional well-being (EWB), functional 
well-being (FWB), and additional concerns specific to patients undergoing BMT.  Each question 
has response categories of “Not at all”, “A little bit”, “Somewhat”, “Quite a bit”, and “Very 
much”.  Higher scores identify better quality of life.  It is able to be completed in 5-10 min and 
may be performed in interview format or self-administered.  Question composition assesses how 
the patient feels today and over the previous seven days.  The questionnaire will be scored 
according to the published scoring algorithm and the following scales and subscales will be 
utilized in the current study:  FACT-BMT (PWB + SFWB + EWB + FWB + Additional 
concerns), FACT-G (PWB + SFWB + EWB + FWB), Trial Outcome Index (TOI; PWB + FWB 
+ Additional concerns), PWB, SFWB, EWB, FWB, and Additional concerns. 
Global Assessment of Change:  
The Patient Global Impression of Change (PGIC) is a 7-point scale used by patients to rate the 
change in their emotional or physical condition or overall quality of life (Appendix 8) (30). It 
assesses symptom by gauging whether the patient feels (1) Very much improved, (2) Much 
improved, (3) Minimally improved, (4) No change, (5) Minimally worse, (6) Much worse, (7) 
Very much worse. Categorization of patients into these three groups will use the patient’s 
response during the second administration to the physical condition item of the Global 
Impression of Change.  Worsening will include “Very much worse”, “Moderately worse”, and 
“A little worse”.  
The same battery of QOL questionnaire will be administered at all the time points as 
mentioned above.  
7.6 
Biomarker Evaluations   
The biomarkers that will be monitored in this trial at baseline (at trial entry), day -37 (pre-
transplant), day +100 (post-transplant), after months 6, 12, 24 (post-transplant), and at time of 
relapse/progression or at the termination of the patients receiving study medication are listed in 
Table 10Error! Reference source not found..  In each disease stratum the proportions of 
patients on each treatment arm who are abnormal at baseline will be estimated and changes 
over time will be examined. The JAK2V617F allele burden will be monitored at baseline (at 
trial entry), day +100 (post-transplant), and at the end of 6, 12, 24 months (post-transplant) and 
at relapse/progression or at the termination of the patients receiving study medication. The 
cytogenetics and bone marrow histopathology will be performed at baseline (at trial entry), 
day +100 (post-transplant), and at the end of 6, 12, 24 months (post-transplant) and at time of 
relapse/progression or at the termination of the patients receiving study medication. The 
hematopoietic cell clonality will be performed in select female patients who are informatives at 
baseline (at trial entry), remission, progression/relapse, 12 and 24 months (post-transplant) and 
termination of treatment. The anticipated effects of the treatments provided on the various 
biomarkers are summarized in Table 11. 


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Table 11 
Biomarker Evaluations 
Test 
Result 
Modulation 
Clonality 
Clonal 
Polyclonal JAK2V617F 
Allele 
High 
Low or absent 
Cytogenetics 
Abnormal 
Normal 
Bone Marrow Histopatholgy 
Abnormal Morphology 
Normalization 


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8 
STUDY CALENDAR 
8.1 
Screening and Enrollment 
Baseline Data 
All patients should be assessed for their eligibility in the study.  At this time, the following procedures 
should be performed and appropriately recorded into the source notes: 
 Patient Informed Consent 
 History, physical examination, and transfusion history 
 Vital signs 
 Body Surface area 
 ECOG performance status 
 ECG 
 Splenic size by clinical examination and maximum length by ultrasound examination. 
 CBC (Complete Blood Count / Differential) 
 Biochemistry screen (AST, ALT, T Bili, D Bili, alk. phosphatase, albumin, total protein, 
Ca+2, Phosphorous, LDH, creatinine, BUN, chloride, potassium, sodium, glucose, uric acid, 
CO2 total) 
 PT/PTT and INR 
 Thyroid function tests T3, T4, TSH 
 Negative serum pregnancy test 
 Bone marrow aspirate and biopsy 
 Cytogenetics 
 Biomarker blood samples for MPD-RC 107 
 Blood sample for JAK2V617F 
 Concomitant medication 
 Nail Clippings 
 MUGA / ECHO scan 
 Pulmonary Function test (PFT) 
 Urinalysis 
 CD34+ (peripheral blood) 
 Class I and II antigens (molecular typing) 
 PB Chimerism studies 
 ABO and Rh typing 
 Infectious disease screen: 
o Serum CMV, HSV, EBV 
o Hepatitis A, B, and C tests 
Study requirements must be performed within 14 days prior to registration except for 
the following: 
 bone marrow, cytogenetics, and infectious disease screen which must be done 
within 28 days prior to registration 
 MUGA/ECHO scan and pulmonary function test which must be done within 2 
months prior to registration 
 JAK2V617F; Class I and II antigens (molecular typing); PB Chimerism studies, 
and ABO and Rh typing do not have to be repeated if already performed  


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8.2 
Donor Assessment 
Donor work up will be done according to the institution’s standard of care, and the following 
information will be captured in the eCRFs: 
 Donor’s age 
 Donor’s sex 
 If donor is female, number of pregnancies 
 Donor type (related, unrelated) 
 Donor blood group 
 Donor rhesus factor 
 Donor HLA typing 
 Donor Antibodies and Antigens 
 Donor Cytokines (if administered or not) 
8.3 
Assessments prior to start of conditioning therapy (Day-65 to Day -5) 
Day -65 
Subjects will be seen by the Study Doctor and the following procedures will be performed: 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, concomitant medications, measurement of weight, blood 
pressure, heart rate 
 ECOG status 
 Completion of brief surveys (Symptom assessment package) about symptoms 
 CBC, Biochemistry 
 Cytokine profile (must be collected before start of study drug treatment) 
Days -63, -55, -48, -41, -34, -27, -20, -13 
These visits are only required if platelet count drops to <50,000/uL or <50 x 109/L. The 
following test will be performed: 
 CBC 
Days -58, -51, -44, -30, -23, & -16 
During these study visits, the following tests and procedures will be performed: 
 CBC, Biochemistry 
 An assessment for any signs of harmful effects the drug or any additional problems 
caused by the medical treatment 
 Patients’ condition will be assessed to determine if dose of Ruxolitinib needs to be 
adjusted 


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Day -37 
During this study visit, study subjects will meet with the study doctor and the following tests and 
procedures will be performed: 
 CBC, Biochemistry 
 Cytokine profile 
 An assessment for any signs of harmful effects the drug or any additional problems 
caused by the medical treatment 
 Condition will be assessed to determine if dose of Ruxolitinib needs to be adjusted, and if 
are having a positive response to Ruxolitinib 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications you are taking, measurement of your weight, blood 
pressure, heart rate 
 ECOG status 
 Review of the Ruxolitinib medication to ensure patients have been compliant with taking 
the medication 
 Evaluation of patients’ condition to determine if they are responding well to the study 
drug treatment 
Day -9 (Ruxolitinib tapering) 
Day -9 will begin the start of the 4 days of tapering (reducing the amount) of the Ruxolitinib 
drug until it is stopped completely on day -5, at the start of the conditioning therapy prior to the 
stem cell  transplant. 
During the Day -9 study visit, the following tests and procedures will be performed: 
 CBC, Biochemistry 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications you are taking, measurement of your weight, blood 
pressure, heart rate 
 ECOG status 
 Completion of brief surveys (Symptom assessment package) about symptoms 
 Pregnancy test - Serum HCG: for women of childbearing potential.  Women will not be 
allowed to participate if they are pregnant or nursing. Both men and women who are able 
to have children must agree to use an effective form of birth control (hormonal or barrier 
method of birth control, or abstinence) from the time of screening and throughout their 
participation in the study.  
 Review and instruct patients on the tapering schedule of the Ruxolitinib study drug. 
 
If study subjects begin taking Ruxolitinib, and then need to discontinue taking the medication 
due to harmful effects it is causing and don’t proceed with receiving a bone marrow transplant 
for any reason (i.e. donor drops out) OR have disease progression, they will have an end of study 
visit, 30 days after having taken the last dose of study medication.  During this study visit the 
following tests and procedures will be performed: 


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 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications you are taking, measurement of your weight, blood 
pressure, heart rate 
 ECOG status 
 CBC, Biochemistry 
 The harmful effects of the drug that patients are experiencing caused by the medical 
treatment will be assessed.  
If study subjects begin taking Ruxolitinib, and then need to discontinue taking the medication 
due to harmful effects it is causing, BUT proceed with receiving a bone marrow transplant, they 
will continue to be followed in the study. 
Should study subjects complete the Ruxolitinib portion of the therapy, they will be required to be 
hospitalized for approximately a month for the Reduced Intensity Conditioning and Bone 
Marrow Transplant.  In the first five days they will receive the reduced intensity conditioning 
regimen, the purpose of which is to improve their myeloproliferative disorder and to suppress 
immunity so that the stem cell transplant is not rejected by their immune system. Depending on 
whether the study subjects will receive stem cells from a related or unrelated donor, they will be 
assigned to one of the two following study treatment conditioning regimens: Fludarabine with 
busulfan OR fludarabine with busulfan and ATG.  ATG is only given to subjects undergoing 
unrelated donor transplantation. 
Fludarabine will be given by IV infusion (through a needle placed in the vein) daily for 4 days 
(Days -5 to -2).  Busulfan will then be given by IV infusion into a vein, daily for 4 days (Days -5 
to -2). To allow convenient administration of these two study drugs, study subjects will receive 
these drugs through a central line. See section 4.3 and Table 5 for conditioning therapy 
instructions. 
If stem cells are received from an unrelated or mismatched donor, study subjects will be given an 
additional study drug named “anti-thymocyte globulin” or ATG, on 3 consecutive days before 
the stem cells are given (Days -3 to -1). This drug further weakens the immune system to reduce 
the chances of rejection of the transplant (graft), as well as reducing the chance that the graft 
cells attack the body’s cells, a condition known as graft-versus-host disease. ATG is only given 
to subjects undergoing unrelated donor transplantation. See section 4.4 and Table 5 for further 
details. 


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Table 12 
Schedule of assessments prior to start of conditioning therapy 
All study visits after Day -65 and before Day-9 have a window of ± 2 days. 
Assessments 
Baseline a Day -65 
(Start of 
RUX) 
Day -63, -55, 
-48, -41, -34, 
-27, -20, -13 b 
Day 
-58 
Day 
-52 
Day 
-44 
Day 
-37 
Day 
-30 
Day 
-23 
Day 
-16 
Day -9 
(RUX 
tapering) 
End of 
Treatment 
visit k 
30 Day 
Follow-up 
visit l 
Off-
treatment 
follow-up m
Informed 
consent/eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Concomitant 
Medications 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Transfusion History c 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Physical Examination 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Palpable Spleen Size 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Co-morbidity 
evaluation d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG status 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
MUGA scan / ECHO 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT  
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom assessment 
package & QOL 
Instruments  
 
X e 
 
 
 
 
 
 
 
 
X 
 
 
 
Samples for Cytokines f 
 
X f 
 
 
 
 
X f 
 
 
 
 
 
 
 
Serum Pregnancy test 
(non-menopausal only) 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC (Complete Blood 
Count/ Differential) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biochemistry g 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Infectious disease 
screen h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD34+ (peripheral 
blood) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/PTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thyroid function tests 
(T3, T4, TSH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Class I and II antigens 
(molecular typing) 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
ABO and Rh typing 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow 
Aspirate and Biopsy i 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytogenetics 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
JAK 2 mutation 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
PB Chimerism studies 
X a 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematological 
toxicities 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Non-hematological 
toxicities 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Infectious 
Complications 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Study Drug 
accountability 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Dose adjustment of 
INC424 (if required) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Tapering schedule of 
INC424  
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Research samples for 
MPD-RC tissue bank j 
X j 
 
 
 
 
 
 
 
 
 
 
X j 
 
 
IWG response 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Survival and 
Progression of disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
Every 6 months 
from treatment 
d/c


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a 
Study requirements must be performed within 14 days prior to registration except for the following: 
 
bone marrow, cytogenetics, and infectious disease screen which must be done within 28 days prior to 
registration 
 
MUGA/ECHO scan and pulmonary function test which must be done within 2 months prior to registration 
 
JAK2V617F; Class I and II antigens (molecular typing); PB Chimerism studies and ABO and Rh typing do not 
have to be repeated if already performed 
b 
only required if  platelet count drops to <50,000/uL or <50 x 109/L 
c 
Blood and platelet transfusions in the preceding 3 months 
d 
Co-morbidity evaluation by HCI-CI criteria as described by Sorror et al.  
e 
Symptom assessment package and QOL instruments to be done before start of study drug treatment. 
f 
Sample needs to be shipped to reference laboratory, please see Table 10  
g 
AST, ALT. T Bili, D Bili, alkaline phosphatase, albumin, total protein, Ca+2, Phosphorous, LDH, PT/PTT, CO2 
total, creatinine, BUN, potassium, sodium, glucose, uric acid level 
h 
infectious disease screen includes:  Serum CMV, HSV, EBV; Hepatitis A, B, and C 
i 
Sample needs to be shipped to reference laboratory, please see Table 10 
j 
MPD-RC research samples specified in Table 10. Samples need to be shipped to reference laboratory, please see 
Table 10 
k 
End of treatment as defined in section 4.7 
l 
this visit occurs 30 days (±7 days) after end of treatment. Treatment defined in section 4.7. 
m 
please see as described in section 4.7  
8.4 
Assessments from start of conditioning (Day -5) to post BMT follow-up (+48 
months) 
Day -5 study requirements 
During Day -5, when study subjects will begin the additional chemotherapy regimen, they will 
have the following additional tests and procedures performed: 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications they are taking, measurement of their weight, 
blood pressure, heart rate 
 ECOG status 
 Completion brief surveys (Symptom assessment package) about symptoms 
 CBC, Biochemistry 
 Cytokine profile  
 Research samples for MPD-RC Tissue Bank 
 Study subjects will be assessed for any signs of harmful effects from the study drug or 
any additional problems caused by the medical treatment 
 Evaluation of the study subjects’ condition to determine if they responded well to the 
study drug treatment 
Reduced Intensity Transplant (Standard of Care) 
Two days after the last dose of fludarabine and busulfan, on the day of transplant (Day 0), the 
donor stem cells will be infused (through the central IV line).  
Day 0 study requirements (Day of Transplant) 
During Day 0, study subjects will have the following additional tests and procedures performed 
before the transplant: 
 A physical examination 
 CBC, Biochemistry 
 They will be assessed for any signs of harmful effects the drug or any additional 
problems caused by the medical treatment 


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Post-Transplant (Standard of Care) 
Immediately after the Reduced Intensity transplant, study subjects will receive two FDA 
approved standard drugs to reduce the risks of graft versus host disease - tacrolimus/cyclosporine 
and methotrexate. Beginning the 2 days before the transplant (day -2) and continuing for at least 
180 days after the transplant, study subjects will take the drug known as tacrolimus to reduce the 
activity of the immune system and to lower the risk of transplant rejection.  Tacrolimus will be 
given by an intravenous infusion only for the first 3 days.  Then, for the remaining 180 days, 
study subjects will take tacrolimus orally as a tablet. They will take tacrolimus tablets twice a 
day (the number of tablets taken depends on their weight) or IV cyclosporine per institutional 
practice. These drugs will help prevent the body from rejecting the cells received from the donor. 
Methotrexate will be given intravenously on days 1, 3 and 6 after transplant.  This drug will help 
prevent the body from rejecting the cells received from the donor.  If a study subject’s disease 
were to return or persist after reduced intensity transplant, or if their body does not successfully 
“take” (accept) the transplanted donor cells, the study subject may receive additional infusions of 
stem cells from their donor at two-month intervals without any study treatment conditioning 
regimen. 
If the transplant is an effective treatment of the underlying myeloproliferative neoplasm, it will 
result in production of normal blood.  It usually takes approximately two to three weeks for the 
donor stem cells to produce blood. During this time, study subjects will be dependent on 
transfusion of blood and platelets and will need antibiotics to prevent and/or treat infections. 
They will remain in the hospital until the blood counts are fully recovered and they are in good 
clinical condition. Usually this means a hospital stay of at least three or four weeks after the 
transplantation. 
After the transplantation, they will be seen regularly by the study doctor to have frequent blood 
tests, similar to the ones in the Ruxolitinib phase.   
Post-transplant study requirements (Day +30 to Month +48) 
After the stem cell transplant, and after treatment in the hospital, study subjects will be seen by 
the study doctor and study team at specific intervals: Day +30, +60, +100, 6 months, 12 months, 
18 months, 24 months, 36 months, and 48 months.  At all of these study visits, the following 
tests and procedures will be performed: 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications, measurement of weight, blood pressure, heart rate 
 ECOG status 
 CBC, Biochemistry 
 They will be assessed for any signs of harmful effects of the drug or any additional 
problems caused by the medical treatment 
 They will be assessed to see whether or not their body is experiencing Graft Versus Host 
Disease (GVHD), a side effect of bone marrow or stem cell transplantation.  In cases of 
GVHD, the new donor cells treat the body as “foreign” and launch an attack against it.  
Additionally, on these specific study visits, the following additional tests and procedures will be 
done: 


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Day +30   
 Cytokine profile  
 Symptom assessment package 
 ABO and Rh typing  
 PB Chimerism studies  
Day +60 
 ABO and Rh typing 
 PB Chimerism studies 
Day +100 
 Symptom assessment package 
 Cytokine profile  
 Bone marrow aspiration/biopsy/cytogenetics/clonality 
 Research samples for the MPD-RC Tissue Bank 
 PB Chimerism studies  
 Evaluation of their condition to determine if they are responding well to the study drug 
treatment 
+6 months and +12 months 
 Symptom assessment package 
 JAK2 V617F blood test  
 Research samples for the MPD-RC tissue bank  
 Bone marrow aspiration/biopsy/cytogenetics/clonality 
 PB Chimerism studies  
 Evaluation of their condition to determine if they are responding well to the study drug 
treatment 
+18 months 
 Evaluation of their condition to determine if they are responding well to the study drug 
treatment 
+24 months 
 Symptom assessment package 
 JAK2 V617F blood test  
 Research samples for the MPD-RC tissue bank  
 Bone marrow aspiration/biopsy/cytogenetics/clonality 
 PB Chimerism studies  
 Evaluation of their condition to determine if they are responding well to the study drug 
treatment 
+36 months and +48 months 
 Symptom assessment package 
 JAK2 V617F blood test  
 PB Chimerism studies  
 Evaluation of their condition to determine if they are responding well to the study drug 
treatment 


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Table 13 
Schedule of Assessments from start of conditioning to post BMT follow-up  
All study visits after Day 0 have a window of ±2 days. 
Assessments 
Day 
-5 
Day 
0a 
Day 
+30 
Day 
+60 
Day 
+100 
After 
+6 
months
After 
+12 
months
After 
+18 
months
After 
+24 
months
After 
+36 
months 
After 
+48 
months 
End of 
Treatment 
visit j 
30 Day 
Follow-
up visit k 
Off-
treatment 
follow-up l 
Limited Re-assessment 
of Eligibility criteria b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Co-morbidity evaluation 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG status 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Palpable Spleen Size 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Transfusion history 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Symptom assessment 
package & QOL 
Instruments 
X c 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Samples for Cytokines d 
X d 
 
X d 
 
X d 
 
 
 
 
 
 
 
 
 
CBC (complete blood 
count / differential) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biochemistry e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ABO and Rh typing 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
JAK 2 mutation 
 
 
 
 
 
X 
X 
 
X 
X 
X 
 
 
 
Research samples for 
MPD-RC tissue bank f 
 
 
 
 
X f 
X f 
X f 
 
X f 
 
 
X f 
 
 
Bone Marrow Aspirate 
and Biopsy g 
 
 
 
 
X g 
X g 
X g 
 
X g 
 
 
X g 
 
 
Cytogenetics h 
 
 
 
 
X h 
X h 
X h 
 
X h 
 
 
X h 
 
 
Hematological toxicities 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Non-hematological 
toxicities 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Regimen-related 
toxicities (RRT) i   
(see Appendix 9) 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Infectious Complications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Engraftment and graft 
failure 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
PB Chimerism studies 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
GvHD assessment  
(See Appendix 10) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
IWG response 
assessment 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Survival and Progression 
of disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
Every 6 
months from 
treatment d/c
a 
Day 0 is counted as day of stem cell infusion 
b 
See protocol section 4.3 
c 
Symptom assessment package & QOL Instruments to be done before start of condition therapy 
d  
Sample needs to be shipped to reference laboratory, please see Table 10 
e 
AST, ALT. T Bili, D Bili, alkaline phosphatase, albumin, total protein, Ca+2, Phosphorous, LDH, PT/PTT, CO2 total, 
creatinine, BUN, potassium, sodium, glucose, uric acid level 
f 
MPD-RC research samples specified in Table 10. Samples need to be shipped to reference laboratory, please see Table 10 
g 
Sample needs to be shipped to reference laboratory, please see Table 10 
h 
Repeat cytogenetics only if there is an abnormality at baseline 
i 
RRT assessed according to Bearman Criteria 
j 
End of treatment as defined in section 4.7 
k 
this visit occurs 30 days (±7 days) after end of treatment. Treatment defined in section 4.7. 
l 
please see as described in section 4.7.  
 
 
 


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8.5 
Off-treatment Assessments 
See definition of off-treatment in section 4.7. 
During the off-treatment visit, the following tests and procedures will be performed: 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, concomitant medications, weight, blood pressure, heart rate 
 ECOG status 
 Bone marrow aspiration/biopsy/cytogenetics/clonality 
 Research samples for the MPD-RC Tissue Bank 
 CBC, Biochemistry 
 They will be assessed for any signs of harmful effects of the drug or any additional 
problems caused by the medical treatment 
30 days (±7 days) after the off-treatment visit, the following tests will be performed: 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, concomitant medications, weight, blood pressure, heart rate 
 ECOG status 
 CBC, Biochemistry 
 They will be assessed for any signs of harmful effects of the drug or any additional 
problems caused by the medical treatment 
Subjects who come off treatment will be followed every 6 months for survival and disease 
progression data via telephone call or review of medical records. This data will be collected from 
the end of treatment to the end of the trial. 


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9 
MEASUREMENT OF EFFECT 
Hematological recovery: Neutrophil recovery will be defined as first of the three consecutive 
days with neutrophil count ≥0.5 x 109/l. Platelet recovery will be defined as first of the 7 days 
with platelet count ≥20 x 109/l, without platelet transfusion support and both maintained for 30 
days without transfusion support or myeloid cytokine support. 
Graft failure: Graft failure will be defined as failure to achieve hematological recovery 
(primary) or a decline in peripheral blood counts after achieving a sustained hematological 
recovery to below threshold levels defined as neutrophil count ≥0.5 x 109/l and platelets ≥20 x 
109/l in the absence of platelet transfusion or lack of sustained neutrophil count and platelets at 
the above range in the absence of a reversible cause of drop in blood counts (e.g treatment of 
CMV infection with ganciclovir or other active infection). 
NRM: will be defined as death in first 30 days due to any cause, and subsequently death due to 
any cause without the recurrence or progression of myelofibrosis. Cumulative incidence of NRM 
will be calculated taking relapse/progression as competing event.  
Acute and chronic GvHD: will be defined according to standard criteria. Cumulative incidence 
of acute and chronic GvHD will be calculated and death due to any cause will be considered as 
competing event.  
Remission status: will be defined according to IWG-MRT criteria and will be categorized as 
complete remission (CR), partial remission (PR), clinical improvement (CI), progressive disease 
(PD), and stable disease (SD) (Appendix 4).  
Relapse: Only the patients who achieve CR or PR will be eligible for analysis of relapse. A 
patient with CR or PR is considered to have undergone relapse when he or she no longer fulfills 
the criteria for even CI. This will be calculated as cumulative incidence with NRM as competing 
event (Appendix 4, IWG-MRT response criteria). 
Progression-free survival: PFS will be estimated for all patients. Failure will include death, 
progressive disease or relapse. Death due to any cause, progressive disease or relapse (whichever 
earlier) will be considered as events for this analysis.   
Overall survival: OS will be estimated for all patients with death due to any cause as event.  
 
See Appendix 4 for IWG-MRT criteria for response assessment (from Tefferi et al., 2006) 


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10 STUDY DESIGN 
10.1 
Statistical Considerations 
A two- stage Simon Phase II study will be conducted in each of two groups of patients: related 
and unrelated donor transplants. In each donor transplant group, the first stage of this design will 
include 11 patients evaluated for death or graft failure by 100 days post-transplant.  In each 
stratum, we will enroll additional patients (up to 20%) of stratum total to take into account 
exclusions due to donor failure (such as donor deemed unsuitable for stem cell donation due to 
medical or other reasons) only. Those patients who have toxicities related to Ruxolitinib and not 
been able to reach HCT due to these toxicities will be included in the estimation of overall 
failure rates. Only those patients who are excluded based on donor related issues without any 
regimen related complications will be excluded from the estimation of failure rates. However, all 
data on these patients will be reported.  
Unrelated transplants: Based on data from the MPD-RC 101 study (31), there are 15 observed 
failures (as defined above) among 34 patients by day 100 (44%; of patients died or experienced 
graft failure by day 100) who received matched unrelated donor transplants. Based on these 
preliminary data, we will not pursue a regimen with a failure rate of 50% or greater in this trial.  
A minimax two-stage design will be used to test the null hypothesis that the 100 day failure rate 
as defined above is ≥50% versus the alternative that this failure rate is ≤25%. If the regimen is 
actually not safe, there is a 0.04 probability of concluding that it is (the target for this value was 
0.050). If the regimen is actually safe, there is a 0.19 probability of concluding that it is not (the 
target power is 80%). After testing the regimen in 11 patients in the first stage, the trial will be 
terminated if there are 6 or more failures within 100 days.  If the trial goes on to the second 
stage, a total of 26 patients will be studied. If the total number of failures is 9 or more, the 
regimen will be rejected.  
Related transplants: Based on data from the MPD-RC 101 study (31), there are 4 observed 
failures (as defined above) among 32 patients (12.5%) who received matched related donor 
transplants in this group of patients.  
A minimax (and optimal) two-stage design to test the null hypothesis that the 100 day failure rate 
as defined above is ≥25% versus the alternative that this failure rate is ≤10%. If the regimen is 
actually not safe, there is a 0.04 probability of concluding that it is (If the regimen is actually 
safe, there is a 0.18 probability of concluding that it is not (the target power is 80%).  
After testing the regimen in 11 patients in the first stage, the trial will be terminated if there are 3 
or more failures within 100 days.  If the trial goes on to the second stage, a total of 50 patients 
will be studied. If the total number of failures is 8 or more, the regimen will be rejected.  
All calculations from PASS 2008 (NCSS, J. Hintze, Kaysville, Ut.).  
10.2 
Definitions of Endpoints 
See section 9 for definitions. 


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10.3 
Analysis Plan 
The primary objective of this study is to estimate the proportion of patients who experience graft 
failure or death by day 100 post transplant in patients who receive (a) related donor transplant 
and in those who receive (b) an unrelated donor transplant. In each of these two groups, if the 
study continues to the completion of the second stage of the two stage designs, we will estimate 
the failure rate with exact 95% Clopper Pearson confidence intervals in each group separately.  
Baseline patient characteristics, disease history, and treatment related variables will be 
summarized separately for each strata defined by donor type using descriptive summary statistics 
and graphical approaches.  
Secondary endpoints, including the proportion of patients who are ‘cured’ (with resolution of 
splenomegaly and normalization of blood counts), will be presented along with 95% confidence 
intervals for each stratum separately.  Duration of cure will be summarized in these patients. 
Rates of transplant-related mortality and 95% confidence intervals will be presented. Progression 
free survival and overall survival will be presented using Kaplan-Meier cumulative survival 
curves.  
Biomarker Analysis: Biomarkers will be assessed prior to transplant (before pre transplant 
treatment) and at 6, 12, and 24 months post-transplant. Rates of normalization for each 
individual marker and for combinations of one or more of these markers will be estimated 
(separately in each of the two strata).  Descriptive statistics and graphical displays of the 
distributions in relation to survival and other post-transplant events will be provided at each time 
point. For each patient, a graph of each marker over time will be provided.  Methods for 
longitudinal data analysis will also be used to examine the time course of marker changes in 
these patients. 
Quality of Life Analysis: Approaches similar to those described for the analyses of biomarkers 
will be used to examine quality of life over time in this study.  
10.4 
Anticipated study duration and time lines 
The goal of this trial is to accrue 82–86 patients (76 evaluable patients + extra 10–15% patients 
for patient attrition due to donor unavailability, donor being declared unfit for donation or patient 
not been able to reach transplant for any reason) over 18 months. Approximately half of 
recruitment would be from North America (US and Canada) and half of recruitment would be 
from Europe. It is anticipated that the study will open at 15–20 centers in North America and 
Europe. We anticipate that by January 2013, at least 3 centers will start enrolling patients, by 
April 2013, >75% of the participating centers will start enrolment. The last patients entered will 
be followed for 2 years with annual follow up thereafter, for a maximum of 4 years of follow up 
from the start of the study period.  


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11 ADVERSE EVENTS 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product/biologic (at any dose), or medical device and 
which does not necessarily have to have a causal relationship with this treatment. This includes 
the onset of new illness and the exacerbation of pre-existing conditions. An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom or disease temporally associated with the use of a medicinal product whether or not 
considered related to the medicinal product: 
 occurring in the course of the use of a drug, biological product, or device; 
 associated with, or observed in conjunction with product overdose, whether accidental or 
intentional; 
 associated with, or observed in conjunction with product abuse, and/or 
 associated with, or observed in conjunction with product withdrawal. 
All adverse events must be recorded in the subject's medical records and on the electronic Case 
Report Form.  The onset and end dates, severity, duration, effect on study drug administration 
(e.g. discontinuation), relationship to study drug, and administration of any other drug(s) to treat 
this event will be recorded for each adverse event.  The severity of the adverse event and 
relationship to study drug will be assessed according to specific guidelines. 
11.1 
Reporting of non-Serious Adverse Events 
An adverse event should initially be entered under the “Immediate AE Reporting” (Part A) 
section in the Adverse Events Form found in the MPD-RC database. 
Additional information can be entered under the “Intermediate (Part B) AE Reporting” section 
of the Adverse Events form. Updates on all AEs must be provided every two weeks by the 
investigators to the coordinating center using the “Intermediate (Part B) AE Reporting” section. 
The clinical course of the AE is “concluded” when either the AE has reached a resolution or it 
becomes a chronic disorder not prone to further evolution. When the AE is “concluded”, the 
investigator is required to inform the coordinating center by completing the “Final (Part C) AE 
Reporting” section of the Adverse Events Form.  
11.2 
Reporting of Serious Adverse Events 
A serious adverse event must be reported to the Data Monitor at the MPD-RC Central Office 
within 24 hours of the event following the appropriate MPD-RC Standard Operating Procedures 
(SOP): 
 SOP 2-1: Serious Adverse Event (SAE) reporting – USA sites 
 SOP 2-2: Serious Adverse Event (SAE) reporting – EU sites 
 SOP 2-3: Serious Adverse Event (SAE) reporting – Canada site 
 


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11.2.1 EC/IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) must be submitted to the 
local institutional IRB according to the institution’s policy. Copies of each report and 
documentation of IRB notification and receipt will be kept in the Clinical Investigator’s binder. 
11.2.2 Notifications by Sponsor 
FDA 
The MPD-RC Data Center and Regulatory Coordinator will receive reports of SAEs through the 
coordinating office. The MPD-RC as study sponsor shall notify the FDA by telephone or by 
facsimile transmission of any unexpected fatal or life-threatening experience associated with the 
use of the drug as soon as possible but no later than 7 calendar days from the sponsor’s original 
receipt of the information.(1-800-332-0178) of any unexpected fatal or life-threatening 
experience associated with the use of the drug as soon as possible but no later than 7 calendar 
days from the sponsor’s original receipt of the information. All other unexpected, serious 
adverse events that are considered related to study treatment will be reported on a MedWatch 
form by the Study Sponsor to the FDA within 15 calendar days.   If a previous adverse event 
that was not initially deemed reportable is later found to fit the criteria for reporting, the 
study sponsor will submit the adverse event in a written report to the FDA as soon as possible, 
but no later than 15 calendar days from the time the determination is made. 
Europe 
The sponsor is responsible for the prompt notification to all concerned investigator(s), the 
Research Ethics Committees and competent authorities (e.g. MHRA) of each concerned Member 
State / Country of findings that could adversely affect the health of subjects, impact on the 
conduct of the trial or alter the competent authority’s authorization to continue the trial in 
accordance with Directive 2001/20/EC and other regulations as appropriate. In each country a PI 
designate will be utilized to facilitate this process. 
Novartis/Incyte 
The MPD-RC or designee (i.e Consorzio Mario Negri Sud) will report all serious adverse 
events (SUSAR) to the safety office at Novartis Healthcare Pvt. Ltd within 15 days of first 
notification of the SAE irrespective of causality and in parallel with submission to the FDA or 
equivalent European regulatory bodies. 
 
11.2.3 MPD-RC Reporting of Suspected Unexpected Serious Adverse Reactions 
(SUSARs) Regulatory Bodies and Ethics Committees 
All suspected adverse reactions related to an investigational medicinal product (the tested 
IMP) which occurs in the concerned trial, and that are both unexpected and serious (SUSARs) 
are subject to expedited reporting. These events should be reported by the individual 
investigators to the MPD-RC. 
11.2.4 MPD-RC Reporting of SUSARs 
MPD-RC, or designee, should report all the relevant safety information previously described to 
the concerned competent authorities and to the Ethics Committee concerned. MPD-RC or 


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designee shall inform all investigators concerned of relevant information about SUSARs that 
could adversely affect the safety of subjects. All SUSAR reports will also be reported to the 
FDA, European Research Ethics Committees and competent authorities (e.g. MHRA) of each 
concerned Member State / Country and Incyte/Novartis. 
11.2.5 When to report 
Fatal or life-threatening SUSARs 
The MPD-RC should notify the Competent Authorities and the Research Ethics Committees/ 
IRBs as soon as possible but no later than 7 calendar days after the sponsor has first knowledge 
of the minimum criteria for expedited reporting. In each case relevant follow-up information 
should be sought and a report completed as soon as possible. It should be communicated to the 
Competent Authorities and the Ethics Committee within an additional eight calendar days. 
Non-fatal and non-life-threatening SUSARs 
All other SUSARs and safety issues must be reported to the competent authority and the Ethics 
Committee in the concerned countries as soon as possible but no later than 15 calendar days 
after the sponsor has first knowledge of the minimum criteria for expedited reporting. Further 
relevant follow-up information should be given as soon as possible. 
11.2.6 How to report 
To ensure subject safety, every SAE, regardless of suspected causality must be reported per 
protocol to the MPD-RC Central Office within 24 working hours of learning of its occurrence.  
The SAE should be reported in the Web-based data entry system (WBDES) on the “Immediate 
AE Reporting” (Part A) e-form and also on a Medwatch form 3500A. A signed and dated 
Medwatch 3500A should be emailed to the MPD-RC Data Monitor, Study Chair, Safety Officer, 
and PI of Project 6. At the time of the initial report the following information at minimum should 
be provided: 
 Study identifier 
 Study Center 
 Subject number 
 A description of the event 
 Date of onset 
 Current status 
 Whether study treatment was discontinued 
 The reason why the event is classified as serious 
 Investigator assessment of the association between the event and study treatment 
 Investigational agent dose 
Significant new information on ongoing serious adverse events should be provided promptly to 
the study sponsor by entering the information into the database on the “Intermediate (Part B) AE 
Reporting” e-form. Update on all SAEs must be provided every two weeks (15 days) by the 
investigators to the coordinating center using the “Intermediate (Part B) AE Reporting” e-form.   
The clinical course of the SAE is “concluded” when either the AE has reached a resolution or it 
becomes a chronic disorder not prone to further evolution. When the AE is “concluded”, the 


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investigator is required to inform the coordinating center using the “Final (Part C) AE 
Reporting” e-form.  
Minimum criteria for initial expedited reporting of SAEs 
Information on the final description and evaluation of an adverse reaction report may not be 
available within the required time frames for reporting. For regulatory purposes, initial 
expedited reports should be submitted by the Sponsor within the time limits as soon as the 
minimum following criteria are met: 
a) 
A suspected investigational medicinal product, 
b) An identifiable subject (e.g. study subject code number), 
c) 
An adverse event assessed as serious and unexpected, and for which there is a reasonable 
suspected causal relationship, 
d) An identifiable reporting source, and, when available and applicable: 
- 
a unique clinical trial identification (the sponsor's trial protocol code number) 
- 
a unique case identification (i.e. sponsor's case identification number). 
Follow-up reports of SAEs 
In case of incomplete information at the time of initial reporting, all the appropriate information 
for an adequate analysis of causality should be actively sought from the reporter or other 
available sources. The sponsor should report further relevant information after receipt of follow-
up reports. In certain cases, it may be appropriate to conduct follow-up of the long-term 
outcome of a particular reaction. 
Format of the SUSARs reports 
Electronic reporting should be the expected method of the Sponsor for expedited reporting 
of SUSARs to the competent authority. In that case, the format and content as defined by the 
Guidance of the Competent Authorities should be adhered to. The CIOMS-I form is a widely 
accepted standard for expedited adverse reactions reporting. However, no matter what the 
form or format used, it is important that the basic information/data elements described in 
annex 3 of the EU directive or as per country requirement, when available, be included in any 
expedited report (some items may not be relevant, depending on the circumstances). 
11.3 
Grading and Relationship Assessment of Adverse Events 
Any adverse event will be graded for severity according to the definitions in Table 14Table 14. 
All the toxicities related in the phase prior to stem cell infusion (during the phase of Ruxoltinib 
administration and taper off) will be defined according to CTCAE v4 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf) 
In the post-transplant period in first 6 weeks, transplant related regimen-related toxicities will be 
defined according to Bearman’s criteria (Appendix 9); which are widely used in BMT literature. 
Grading of acute and chronic graft-versus-host disease will be done according to NIH criteria 
(Appendix 10).  
All other toxicities in the post-transplant period will be graded according to CTCAE v 4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf) 


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Table 14 
Definitions of Adverse Event Severity Categories 
Mild (1) 
Awareness of sign, symptom or event, but easily tolerated. 
Moderate (2) 
Discomfort enough to cause interference with usual activity 
and may warrant intervention 
Severe (3) 
Incapacitating with inability to do usual activities or 
significantly affects clinical status, and warrants intervention. 
Life Threatening (4) 
Immediate risk of death. 
Fatal (5) 
Fatal 
 
The Investigator must assess the relationship of any adverse effect to the use of study drug, 
based on available information, using the following guidelines noted in Table 15. 
Table 15 
Adverse Event Relationship to Treatment Guidelines 
Not related (1) 
No temporal association, or the cause of event has been 
identified or the drug cannot be implicated 
Unlikely (2) 
A doubtful association exists 
Possibly Related (3) 
Temporal association, but other etiologies are likely the cause.  
However, involvement of the drug cannot be excluded. 
Probably Related (4) 
Temporal association, other etiologies are possible but 
unlikely. 
Definitely (5) 
Definite causal relationship identified 
 
11.4 
Monitoring of Adverse Events 
Patients having adverse events will be monitored with relevant clinical assessments and 
laboratory tests as determined by the Investigator.  ALL adverse events must be followed to 
satisfactory resolution or stabilization of the event(s). 
11.5 
Immediately Reportable Adverse Events 
Any serious adverse event, whether or not deemed drug-related or expected, must be reported by the 
physician within 24 hours to adverse event monitoring committee.  
Time frame for monitoring Serious Adverse Event 
Allogeneic transplant is a complex modality and where a patient can continue to have serious 
adverse events from the events related to the transplant procedure for life long. For this study, 
reportable period for the adverse and serious adverse events would be from the start of Ruxolitinib 
to 100 days after the transplant. The new intervention is this study is use of Ruxolitinib which will 


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be used for prior to the transplant, and therefore 100 days post-transplant will be a reasonable period 
to monitor any SAE related to Ruxolitinib.  
A patient undergoing transplant may continue to have various serious adverse events such as 
chronic GVHD, infectious complications, disease relapse or progression related to the transplant 
procedure itself for an indefinite duration. Information about all these events will be captured in 
the Electronic case report form (MPD-RC Database) and will be reported with the final study 
report.  The Reporting of post-100 AE and SAEs is to the Drug manufacturer Phamacovigilance 
group is optional. Events of this category still need to be circulated to the participating sites as 
stated in the contract. In these cases the sites have the responsibility to report to their IRB’s as 
per their institution’s guidelines.  
However, if the event is deemed a SUSAR even after 100 days of treatment, the MPD-RC is 
expected to report this event to the Drug manufacturer Pharmacovigilance group, the IRB and 
the participating sites, even if at the this point the event is not treatment related, and is most 
likely GVHD related.  
All events happening to the patients should be recorded in the E-CRF in the MPD-RC database  
and will be part of the study final report. 
Reports of all serious adverse events, including deaths must be communicated to the appropriate 
Institutional Review Board or ethical review committee and/or reported in accordance with local 
law and regulations. 
Definition of serious adverse event 
A serious adverse event (SAE) is any adverse drug or biologic or device experience occurring at 
any dose that results in any of the following outcomes: 
a. death; 
b. life-threatening AE (that places the subject, in the view of the initial reporter, at 
immediate risk of death from the AE as it occurs, ie, suicidal ideation/suicide attempt); 
c. persistent or significant disability/incapacity; 
d. required in-patient hospitalization, or prolonged hospitalization; 
e. congenital anomaly or birth defect; 
f. other serious (important medical events) 
 
Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects she is pregnant while participating in this study, she 
must inform her treating physician immediately and permanently discontinue study drug.  The 
pregnancy must be followed through delivery for SAEs. 
11.6 
Exceptions for Definitions of Serious Adverse Events 
The following will not be considered serious adverse events: 
Any event that results in hospitalization or prolongs an existing hospitalization will not be 
considered a serious adverse event if the only reason for that hospitalization or prolongation was 
for: 
a. transfusion of blood products 
b. administration of study procedures 


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c. placement of a permanent intravenous catheter 
d. hospice placement for terminal care 
e. out-patient hospitalization for procedures such as elective day surgery or hospitalization 
due to convenience purposes, e.g. transportation difficulties. 
11.7 
Safety Monitoring 
This trial will be monitored by the MPD-RC Data Safety Monitoring Board according to the 
established Charter.   
Data Safety Monitoring Board 
An External Data and Safety Monitoring Board has been established. All members have 
experience and expertise in clinical trials. DSMB members are not directly involved in any phase 
of MPD-RC clinical trials and they have no major financial or intellectual conflict of interest that 
would prevent them from objectively reviewing the interim data and providing advice to the 
Trials Steering Committees and the Clinical Advisory Group. They function independently of all 
other individuals, processes, and progress to ensure study integrity, monitor patient safety 
(providing quarterly safety reports), evaluate the results of interim analysis to assess efficacy, 
and make recommendations about protocol amendments and early termination to the Trials 
Steering Committees. The External Data Safety and Monitoring Board must meet at least two 
times a year. 
The DSMB statistician will possess a copy of the treatment codes for un-blinding purposes if 
required by the members of the board. 
11.7.1 Medical Monitoring 
It is the responsibility of the local institutional Principal Investigator to oversee the safety of the 
study at his/her site. This safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above, as well as the construction and implementation of a 
site data and safety-monitoring plan.  Medical monitoring will include a regular assessment 
of the number and type of serious adverse events. 
11.7.2 Monitoring Plan and Period of Observation 
The monitoring plan for this study is maintained by the MPD-RC and contains the following 
elements: 
 This study will be conducted according to the policies and procedures of the 
MPD-RC; 
 All MPD-RC provided drug supplies will be returned to the MPD-RC or are to be 
disposed in accordance with procedure agreed to by investigator and the MPD-RC. 


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12 REGULATORY REQUIREMENTS 
See Section 5.1.1 regarding required regulatory documents. All protocol amendments will 
be generated through and distributed by the MPD-RC Central Coordinating Office, which will 
also maintain records of IRB approval, amendments, SAEs, and annual reviews. 
12.1 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonisation 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator should be thoroughly familiar with the appropriate use of the study drug as described 
in the protocol and Investigator’s Brochure.  Essential clinical documents should be maintained 
to demonstrate the validity of the study and the integrity of the data collected.  Master files 
should be established at the beginning of the study, maintained for the duration of the study and 
retained according to the appropriate regulations. 
12.2 
Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
This protocol and any amendments should be submitted to a properly constituted independent 
EC or IRB, in agreement with local legal prescriptions, for formal approval of the study 
conduct.  The decision of the EC/IRB concerning the conduct of the study should be made in 
writing to the investigator and a copy of this decision should be provided to the MPD-RC 
Central Office before commencement of this study.  The investigator should provide a list of 
EC/IRB members and their affiliate to the MPD-RC Central Office. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  See section 13 for a copy of the Subject Informed Consent Form.  This consent form 
should be submitted with the protocol for review and approval by the EC/IRB for the study.  
The consent of a subject, using the EC/IRB-approved consent form, must be obtained before a 
subject is allowed to participate.  This consent form must be signed by the subject or legally 
acceptable surrogate, and the investigator obtaining the consent. 
12.3 
Patient Information and Informed Consent 
After the study has been fully explained, written informed consent should be obtained from 
either the patient or his/her guardian or legal representative prior to study participation. The 
method of obtaining and documenting the informed consent and the contents of the consent 
should comply with ICH-GCP and all applicable regulatory requirement(s). 
12.4 
Patient Confidentiality 
Information about study subjects should be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
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 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
The patient has the right to revoke their authorization for use of their PHI. In the event that 
a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to 
obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of their 
scheduled study period. 
12.5 
Protocol Compliance 
The investigator should conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB and the appropriate regulatory authority (ies). Changes 
to the protocol will require approval of the MPD-RC and written IRB approval/favorable 
opinion prior to implementation, except when the modification is needed to eliminate an 
immediate hazard(s) to patients.  The MPD-RC will submit all protocol modifications to the 
regulatory authority (ies) in accordance with the governing regulations. Any departures from the 
protocol must be fully documented in the source documents. 
12.6 
Management of Information 
The MPD-RC at Mount Sinai will maintain sponsorship authority at the Icahn School of 
Medicine at Mount Sinai and all other participating sites. 
Eligibility criteria will be confirmed using the electronic CRF. All inclusion and exclusion 
criteria are listed; the investigator is obliged to fill in all items. Subjects are enrolled in the study 
only if he/she fulfills all inclusion and no exclusion criteria. 
IRB approval for each site will be submitted to the MPD-RC Central Coordinating Office 
via e-mail (PDF file preferred) or fax: 
MPD-RC Central Coordinating Office 
Regulatory Coordinator 
                                                             Alicia Orellana 
Office hours: Monday through Friday 9AM to 5PM EST/EDT 
Upon receipt of these documents and confirmation of certification of the study investigators, the 
site will be granted access to the online registration system and case report forms (section 12.9).  
In addition, all protocol amendments will be generated through and distributed by the MPD-RC 
Central Coordinating Office, which will also maintain records of IRB approval, amendments, 
SAEs, and annual reviews. 
Serious adverse event reporting is detailed in section 11.2.  
Protocol deviations will be reported to the MPD-RC Regulatory Coordinator:  
Office hours: Monday through Friday 9AM to 5PM 
The MPD-RC principal investigators will be notified as soon as possible (and within 7 days) of 
reporting, and will be responsible for granting approval. 


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The MPD-RC will monitor study progress on an on-going basis; this will include electronic and 
telephone correspondence between the central coordinating office and with individual 
investigators at other sites. 
12.7 
Drug Accountability 
Accountability for the study drug at all study sites is the responsibility of the MPD-RC.  The 
responsible investigator at each participating center will ensure that the study drug is used 
only in accordance with this protocol, drug accountability records indicating the drug’s 
delivery date to the site, inventory at the site, use by each patient, and return.  
Accountability records will include dates, quantities, lot numbers, expiration dates (if 
applicable), and patient numbers. 
12.8 
Source Documents 
Source data includes all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in source documents. Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, 
subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or  magnetic  media,  x-rays,  subject  
files,  and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. 
12.9 
Case Report Forms (CRF) 
The study CRF is the primary data collection instrument for the study.  All data requested 
on the CRF must be recorded. The CRFs may be found online at the MPD-RC website at . 
www.marionegri.it  The CRF Form Submission schedule is listed below:  


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Table 16 
CRF Form Submission Schedule 
MPD-RC 
#114 
Form# 
MPD-RC #114 FORM NAME 
CRF SUBMISSION SCHEDULE 
00 
Parameter List 
@ Registration 
01 
ENROLLMENT 
@ Registration 
02 
PB & BM Report 
Baseline, day -65 from the start of study drug, day 
+100 after BMT,  month +6, +12, +24, +36, +48 
after BMT, @ time of relapse/progression and study 
termination for any reason 
03 
Cytogenetic 
Baseline, day -65 (start of study drug), day +100 
after BMT,  month +6, +12, +24, +36, +48 after 
BMT, @ time of relapse/progression and study 
termination for any reason 
04 
BASELINE 
Within 1 week after registration 
05 
Pre-Transplant Patient Status 
After Registration 
06 
HLA Typing Form 
Before transplant 
07 
Pre-Conditioning 
DOSE 
DRUG 
ADMINISTRATION 
Weekly until BMT 
08 
Pre transplant follow-up day -65,  
Day -65 
09 
Pre transplant follow-up day -58, 
-51, -44, -30, -23, & -16 
Day -58, -51, -44, -30, -23, & -16  
10 
Pre transplant follow-up day -9 
Day -9 
11 
Conditioning Regimen 
Pre-BMT 
12 
Characteristics of Graft 
@ BMT 
13 
DONOR'S LYMPHOCYTES 
INFUSION (DLI) 
After BMT 
14 
GVHD Prophylaxis 
After BMT 
15   
Post-transplant Follow-up +30 days 
After BMT @ +30 days 
16   
Post-transplant Follow-up +100 
days 
After BMT @ +100 days 
17   
Post-transplant Follow-up +6 
months 
After BMT @ +6 months 


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MPD-RC 
#114 
Form# 
MPD-RC #114 FORM NAME 
CRF SUBMISSION SCHEDULE 
18   
Post-transplant Follow-up +12 
months 
After BMT @ +12 months 
19 
Post-transplant Follow-up +18 
months 
After BMT @ +18 months 
20   
Post-transplant Follow-up +24 
months 
After BMT @ +24 months 
21 
Post-transplant Follow-up +36 
months 
After BMT @ +36 months 
22 
Post-transplant Follow-up +48 
months 
After BMT @ +48 months 
23 
Additional Follow-up visit not 
planned in study protocol 
After BMT as needed  
24 
Follow-up visit after drug 
interruption 
Within 2 weeks of drug interruption 
25 
Adverse Event Form 
Immediately report all SAE’s and complete all non-
reportable A/E’s Monthly 
26 
Outcome event Malignancy 
Monthly and when/if it occurs  
27 
Outcome event Pregnancy-Abortion 
Monthly and when/if it occurs 
28 
Off treatment notice 
Within 2 weeks going off treatment 
29 
Death notification form 
Immediately 
30 
End of study 
Within 2 weeks of completing study 
31 
EORTC QLQ-C30 
Pre-registration, days -5, +30, and +100; months 
+6, +12, +24, +36, +48, @ time of 
relapse/progression and study termination for any 
reason 
32 
FACT BMT 
Pre-registration, days -5, +30, and +100; months 
+6, +12, +36, +48, @ time of relapse/progression 
and study termination for any reason 
33 
MPN-SAF 
Pre-registration, days -5, +30, and +100; months 
+6, +12, +36, +48, @ time of relapse/progression 
and study termination for any reason 


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MPD-RC 
#114 
Form# 
MPD-RC #114 FORM NAME 
CRF SUBMISSION SCHEDULE 
34 
Exploratory questions and patient 
feedback 
Pre-registration, days -5, +30, and +100; months 
+6, +12, +36, +48, @ time of relapse/progression 
and study termination for any reason 
 
12.10 Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the MPD-RC Trial Steering 
Committee there is sufficient reasonable cause. Written notification documenting the reason 
for study termination will be provided to the investigator by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
 Determination of unexpected, significant, or unacceptable risk to patients 
 Failure to enter patients at an acceptable rate 
 Insufficient adherence to protocol requirements 
 Insufficient complete and/or evaluable data 
 Plans to modify, suspend or discontinue the development of the study drug 
12.11 Record Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years 
after the last approval of a marketing application in their country and until there are no pending 
or contemplated marketing applications in their country or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  These 
documents must be retained at least 2 years following completion of the last follow-up on 
patients on active study.  These documents should be retained for a longer period if required by 
an agreement with the sponsor.  In such an instance, it is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
12.12 Endpoint Verification 
The endpoint validation committee will centrally review and validate all end points following 
pre-defined criteria (Section 9 and Appendix 4). All the clinical events included in the primary 
and secondary endpoints will be validated by an ad hoc committee of expert clinicians 
blinded to the treatment assigned. Copies of physicians’ and hospital records and death 
certificates will be reviewed by a Primary Endpoint Committee for event validation. Each event 
will be independently evaluated by two evaluators. Disagreement between the two evaluators 
will be addressed by the chairman of the committee. 


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13 REFERENCES 
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Blood. 2006;108(5):1497-503. Epub 2006/05/06. 
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Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, et al. New prognostic 
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Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A, et al. A dynamic 
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Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS Plus: A 
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Pardanani A, Vannucchi AM, Passamonti F, Cervantes F, Barbui T, Tefferi A. JAK 
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Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol 
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Ballen KK, Shrestha S, Sobocinski KA, Zhang MJ, Bashey A, Bolwell BJ, et al. Outcome 
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Daly A, Song K, Nevill T, Nantel S, Toze C, Hogge D, et al. Stem cell transplantation for 
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11. Kroger N, Holler E, Kobbe G, Bornhauser M, Schwerdtfeger R, Baurmann H, et al. 
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12. Rondelli D, Barosi G, Bacigalupo A, Prchal JT, Popat U, Alessandrino EP, et al. 
Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in 


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intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia. Blood. 
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13. Merup M, Lazarevic V, Nahi H, Andreasson B, Malm C, Nilsson L, et al. Different 
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Serum interleukin (IL)-1, IL-2, sIL-2Ra, IL-6 and thrombopoietin levels in patients with 
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20. Ferrara JL, Reddy P. Pathophysiology of graft-versus-host disease. Semin Hematol. 
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21. Wong KM, Atenafu EG, Kim DDH, Kuruvilla J, Lipton JH, Messner HA, et al. Incidence, 
Risk Factors for Early Hepatotoxicity and Its Impact on Survival in Patients with 
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Meeting Abstracts. 2011;118(21):1951-. 
22. Khabori MA, El-Emary M, Xu W, Guyatt G, Galal A, Kuruvilla J, et al. Impact of intensity 
of conditioning therapy in patients aged 40-60 years with AML/myelodysplastic syndrome 
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23. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 
2008 World Health Organization criteria and point-of-care diagnostic algorithms. 
Leukemia. 2008;22(1):14-22. 
24. Gale RP, Barosi G, Barbui T, Cervantes F, Dohner K, Dupriez B, et al. What are RBC-
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25. Hussein K, Pardanani AD, Van Dyke DL, Hanson CA, Tefferi A. International Prognostic 
Scoring System-independent cytogenetic risk categorization in primary myelofibrosis. 
Blood.115(3):496-9. 
26. Tam CS, Abruzzo LV, Lin KI, Cortes J, Lynn A, Keating MJ, et al. The role of cytogenetic 
abnormalities as a prognostic marker in primary myelofibrosis: applicability at the time of 
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30. Cella D. What do global quality-of-life questions really measure? Insights from Hobday et 
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31. Rondelli, D., Goldberg, J. D., Marchioli, R., Isola, L., Shore, T. B., Prchal, J. T., ... & 
Hoffman, R. (2011, November). Results of phase II clinical trial MPD-RC 101: allogeneic 
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14 INFORMED CONSENT 
TITLE OF RESEARCH STUDY: 
Title: Exploring the Potential of Dual Kinase JAK 1/2 Inhibitor Ruxolitinib (INC424) with 
Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients with 
Myelofibrosis (IND#116275) 
PRINCIPAL 
INVESTIGATOR 
(HEAD 
RESEARCHER) 
NAME 
AND 
CONTACT 
INFORMATION: 
Name: (Name of Principal Investigator) 
Physical Address: (Participating Site Address) 
Mailing Address: (Participating Site Address) 
Phone: (Participating site phone) 
WHAT IS A RESEARCH STUDY? 
A research study is when scientists try to answer a question about something that we don’t know 
enough about.  Participating may not help you or others.   
People volunteer to be in a research study.  The decision about whether or not to take part is 
totally up to you. You can also agree to take part now and later change your mind. Whatever you 
decide is okay.  It will not affect your ability to get medical care at (Participating site).   
Someone will explain this research study to you. Please take your time and read this Informed 
Consent Form carefully before you decide whether or not to take part in this research study.  Ask 
the study doctor or a member of the study staff any questions you may have about this study.   
You may also like to take a copy of this form home to review it with your family and friends.   
Feel free to ask all the questions you want before you decide.  Any new information that 
develops during this research study, which might make you change your mind about 
participating, will be given to you promptly. 
Basic information about this study will appear on the website http://www.ClinicalTrials.gov.  
There are a few reasons for this:  the National Institutes of Health (NIH) encourages all 
researchers to post their research; some medical journals only accept articles if the research was 
posted on the website; and, for research studies the U.S. Food and Drug Administration (FDA) 
calls "applicable clinical trials” a description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include 
information that can identify you. At most, the Web site will include a summary of the results. 
You can search this Web site at any time. 
PURPOSE OF THIS RESEARCH STUDY: 
The purpose of this study is to find out if adding the study drug Ruxolitinib (INC424) prior to a 
combination of other chemotherapeutic drugs (Fludarabine and Busulfan) and then giving you a 
donor’s blood cells (bone marrow transplantation) will be successful in people who have 


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advanced primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or 
post-essential thrombocythemia myelofibrosis (PET-MF), collectively known as myelofibrosis 
(MF).  MF is a disorder in which bone marrow tissue develops in abnormal sites because the 
bone marrow itself undergoes fibrosis or scarring.  This study plans to add the drug Ruxolitinib 
to further aid in reducing pre-transplant spleen size, improve physical performance levels and 
reduce adverse events (side effects) related to the transplant.  Ruxolitinib is a drug that is 
approved by the Federal Drug Administration (FDA) for the treatment of patients with advanced 
forms of myelofibrosis. Using Ruxolitinib prior to stem cell transplantation is experimental.   
You qualify to take part in this research because you have a blood disorder called myelofibrosis 
(MF), or myelofibrosis following polycythemia vera (PV), or following essential 
thrombocythemia (ET), and need a stem cell transplant. 
Funds for conducting this research are provided by the Myeloproliferative Disorders Research 
Consortium (MPD-RC) through a grant provided by the National Cancer Institute (NCI).  
Additional funds are being provided by Incyte Pharmaceuticals.  Incyte will provide study drug 
in the United States and Novartis will provide study drug outside the United States.  
 
LENGTH OF TIME AND NUMBER OF PEOPLE EXPECTED TO PARTICIPATE 
Your participation in this research study is expected to last for an unspecified length of time.  
After the transplantation you will be seen regularly in the clinic, the visits becoming less frequent 
as time progresses.  Your medical condition will be followed yearly or until a time that you 
might experience a relapse of your disease.  
The number of people expected to take part in this research study at (Participating site) is (sites’ 
number). The total number of people expected to take part in this multi-center international 
research study is between 82 and 86, the number dependent upon the number of patients with 
appropriate donors.  Approximately half of the recruitment would be from North America (US 
and Canada) and half of recruitment would be from Europe.  
 
DESCRIPTION OF WHAT’S INVOLVED: 
If you agree to participate in this research the following information describes what may be 
involved.  You will first give consent to be enrolled in the MPD-RC mandatory Biomarker Study 
(MPD-RC #107 – “Correlative Biomarker Study for MPD-RC Treatment Studies in the 
Philadelphia Chromosome Negative MPD”).  This study allows us to collect your biological 
research specimens (blood, bone marrow, nails) at certain time points during the study.     
 
Screening Phase 
If you agree to participate in this study, you will be asked to sign this informed consent before 
any tests are performed.  After you sign the informed consent form, you will have what are 
called “screening tests”. These tests will help the study doctor decide if you are eligible to 
continue to participate in the study.   
You will be asked questions about your medical history, including your transfusion history and 
about any medications you are currently taking or have taken in the past.  In addition, you will 


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have the following tests performed.  They may be done on different days depending on when 
they can be scheduled. You will have the following tests and procedures performed: 
 A review of your medical history and a complete physical exam: your study doctor will 
ask you a series of questions.  He or she will examine your entire body.  He or she will 
use a stethoscope (a device placed on your skin to allow the doctor to hear better) to 
listen to your heart, lungs, and belly.  He or she will feel your entire body, including your 
neck, trunk, arms, and legs.   
 Measurements of your vital signs: heart rate, breathing rate, blood pressure, temperature, 
weight, and height. 
 Body surface area: the surface area of your body will be measured to be used in 
calculating the amount of medication you are to receive. 
 ECOG performance status:  rating scale to rate your ability to perform daily functions. 
 Electrocardiograms (ECGs): measure the electrical activity of your heart. For this test, 
you will be asked to lie down while 12 sticky pads are applied to each of your arms and 
legs and to your chest.  The ECG will last about five minutes. 
 Spleen measurement: through palpation (feeling with the hands) or through an ultrasound 
if necessary.  Ultrasound technology uses sound waves to reflect off of soft tissues to 
create an image based upon the computer’s interpretation of the waves’ reflections.  The 
sonographer will use a gel to help transmit the sound waves through the wand.  It is cool 
and rather gooey – but not uncomfortable and the procedure does not last long. 
 ECHO / MUGA scan: The function of your heart will be monitored using either a 
procedure called an echocardiogram or a MUGA (Multigated Acquisition Scan). An 
echocardiogram (ECHO) is a standard ultrasound examination with no known harmful 
effects. Images of your heart are taken using a small device about the size of a bar of soap 
("transducer") that is attached to a computer. A slippery gel is spread over the area being 
examined, and the transducer is pressed firmly against the skin and moved across the area 
being examined. 
 
A MUGA scan shows the motion of the heart and how well it pumps the blood. It is 
performed by injecting a small amount of imaging material into your blood stream (arm) 
and a camera (computer) will collect the data. Blood flow in your heart and heart rate will 
show on the screen and is observed and measured by a doctor. This will tell you how 
efficiently your heart is pumping the blood. 
 Pulmonary Function Test (PFT): Pulmonary function tests measure how well the lungs 
take in and exhale air and how efficiently they transfer oxygen into the blood. 
 Urinalysis: you will be asked to provide a sample of your urine to determine how well 
your kidneys are working. 
 Blood Tests: (Approximately a total of 23 tablespoons of blood will be collected from a 
vein in your arm with a needle): 
o Complete blood count (approx. 1 ½ tsp. blood): complete blood count monitors the 
blood levels; red blood cells, white blood cells, platelets and other components of the 
blood. 
o Blood chemistries (approx. 1 ½ tsp. blood): tests creatinine, glucose, bilirubin, 
and other chemicals in the blood that indicate how well the liver and kidneys are 


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functioning and to check for side effects and sedimentation rate (checks for 
inflammation). 
o Thyroid Function (approx. 1 ½ tsp. blood): the thyroid is one of the largest 
endocrine glands in the body. This gland is found in the neck and controls how 
quickly the body uses energy, makes proteins, and controls how sensitive the 
body should be to other hormones.  This blood test checks how well the thyroid 
gland is functioning.   
o JAK2 V617F (1½ tsp. blood): blood test to check for the JAK2 V617F mutation in 
your blood.   
o Pregnancy test (approx. 1 tsp. blood) - Serum HCG: for women of childbearing 
potential.  Women will not be allowed to participate if they are pregnant or 
nursing. Both men and women who are able to have children must agree to use an 
effective form of birth control (hormonal or barrier method of birth control, or 
abstinence) from the time of screening and throughout their participation in the 
study.  
o Extra Blood and nail clippings: Up to 4 2/3 Tbsp. of blood will be collected for 
research purposes for the biomarker study.  Nail clippings: 2 clippings will only 
be gathered once (at pre-study visit).  Your nail clippings will provide normal 
material, like DNA, for comparison with the abnormal material from your blood 
and/or bone marrow.  
o CD34+ test (2 tsp. blood) – to test for markers in the blood. 
o PT/PTT (0.5 tsp. blood) – a test to determine how quickly your blood clots. 
o Class I and II antigens - molecular typing (approx. 3 tsp. blood) – a test to type 
the molecules that control the immune response, and that are targets in 
transplantation rejection. 
o ABO and Rh typing (approx. 1-2 tsp. blood) - Blood type tests done before a 
person gets a blood transfusion. Human blood is typed by certain markers (called 
antigens) on the surface of red blood cells. 
o Chimerism studies (2 teaspoons) – To have a baseline of engraftment before the 
transplant 
o Serum CMV, HSV, EBV (approx. 1 tsp. blood) – to test for viruses of the herpes 
family. 
o Hepatitis A, B, and C tests (approx. 2 tsp. blood) – to detect current or previous 
hepatitis infection; an inflammation of the liver, most commonly caused by a viral 
infection (Hepatitis A, B, C). 
 Bone marrow aspiration/biopsy/cytogenetics/clonality: Bone marrow aspiration, also 
called bone marrow sampling, is the removal by suction (through a needle placed into the 
bone) of fluid from the soft, spongy material that lines the inside of most bones (marrow). 
(Approx. 1 ½ tsp.)  During a bone marrow aspiration/biopsy an area of the hip is numbed 
and a needle is placed through the skin and into the hip bone.  A small sample of bone 
marrow and bone is withdrawn.  The bone marrow will be examined to see if it is 
abnormal.  
It is important that you tell your study doctor about any medications you are taking including 
over-the-counter medications, vitamins, herbal medications, and alternative medicines.  You may 
need to stop some of your medicines in order to be able to take part in this study. 
 


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Ruxolitinib Pre- Hematopoietic cell transplantation (HCT) Phase of Study (Experimental) 
After the screening visit if it is determined that you qualify to take part in this study, the 
following will take place during the Pre-allogeneic Hematopoeitic Cell Transplantation (HCT) 
phase of the study. Allogeneic hematopoeitic cell transplantation is a procedure in which some of 
the blood forming cells (the stem cells) from a donor are collected from the blood or from the 
bone marrow and are transplanted into the patient (the recipient). Prior to the transplant, you will 
receive treatment with chemotherapy. You will receive the study drug Ruxolitinib (INC424) 
60 days (day -65) before receiving your conditioning regimen with the drugs Fludarabine and 
Busulfan. This chemotherapy that is given immediately prior to your transplant is called the 
conditioning or preparative regimen, the purpose of which is to help eliminate your disease prior 
to the infusion of donor stem cells and to suppress immune reactions. Ruxolitinib will be given at 
the maximum tolerated dose for 56 days (day -65 to day -10), followed by 4 days (day -9 to 
day -6) of tapering (reducing the amount) of the drug until it is stopped completely at the start of 
the conditioning therapy (day -5) prior to stem cell infusion. The term ‘reduced intensity’ 
transplant does not necessarily mean a safer transplant or one with less risks and side effects. 
Reduced intensity applies to strength of the drugs being used to prepare your body for the 
transplant.  You will receive medication (cyclosporine or tacrolimus with methotrexate) to help 
prevent Graft Versus Host Disease (GVHD), which will be discussed more fully later in this 
section.  If you are receiving an unrelated donor or mismatched related donor transplantation you 
will additionally receive the drug Thymoglobulin (ATG) to aid in preventing GVHD.  You will 
then receive a stem cell transplant from a donor.   
 
Ruxolitinib (INC424) 5mg tablets (taken by mouth) will be started 60 (day -65) days prior to 
start of conditioning chemotherapy. The dose of ruxolitinib will be determined according to 
baseline platelet count and will be modified according to platelet count at your follow-up visit.   
If there is a delay in the availability of the donor or a delay in the start of the transplant 
conditioning regimen for any reason, your dose of Ruxolitinib will not be tapered in that instance 
until the date of the start of the conditioning regimen is known with certainty. 
Your platelet counts will be monitored once a week, and if your platelet count falls below 50 x 
109/L, then your platelet count will be monitored twice weekly. At follow-up, the dose of 
Ruxolitinib will be modified (increased or decreased). 
After 8 weeks (56 days) of Ruxolitinib treatment, the Ruxolitinib taper will be started (day -9) 
with the goal of stopping the Ruxolitinib at the start of your conditioning therapy.  
 
Study requirements prior to the start of conditioning therapy: 
During the time you are receiving the study medication (Weeks 1-8 and during the Ruxolitinib 
taper period) you will have the following tests and procedures performed during the below stated 
time points.  During certain visits, you will be asked to return all study medication in the bottles 
provided no matter whether you take all the capsules or not to measure compliance; empty 
bottles should also be brought back to the clinic.  
Do not forget to tell your study doctor if you start taking any new medicines, feel unwell or want 
to take part in a new study run by another doctor. 


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Day -65 
You will be seen by the study doctor on day -65 and the following procedures will be performed: 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications you are taking, measurement of your weight, blood 
pressure, heart rate 
 You will have a brief assessment about your ability to perform activities of daily living 
(ECOG) 
 You will be asked to complete brief surveys (Symptom assessment package) about your 
symptoms 
 Routine blood will be drawn for hematology, chemistry – 2 teaspoons 
 Blood will be drawn for cytokine profile – 2 teaspoons 
 You will be assessed for any signs of harmful effects the drug or any additional problems 
caused by the medical treatment 
 
Days -58, -51, -44, -30, -23 & -16 
At each study visit you will have the following tests and procedures performed: 
 Routine blood will be drawn for hematology, chemistry – 2 teaspoons 
 You will be assessed for any signs of harmful effects the drug or any additional problems 
caused by the medical treatment 
 Your condition will be assessed to determine if your dose of Ruxolitinib needs to be 
adjusted 
 
Day -37 
During this study visit, you will meet with the study doctor and the following tests and 
procedures will be performed: 
 Routine blood will be drawn for hematology, chemistry – 2 teaspoons 
 Blood will be drawn for cytokine profile – 2 teaspoons 
 You will be assessed for any signs of harmful effects the drug or any additional problems 
caused by the medical treatment 
 Your condition will be assessed to determine if your dose of Ruxolitinib needs to be 
adjusted, and if you are having a positive response to Ruxolitinib 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications you are taking, measurement of your weight, blood 
pressure, heart rate 


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 You will have a brief assessment about your ability to perform activities of daily living 
(ECOG) 
 Review of the Ruxolitinib medication you have been taking to ensure you have been 
compliant with taking the medication 
 Evaluation of your condition to determine if you are responding well to the study drug 
treatment 
 
Day -9 (Ruxolitinib tapering) 
Day -9 will begin the start of the 4 days of tapering (reducing the amount) of the Ruxolitinib 
drug until it is stopped at the start of the conditioning therapy prior to the stem cell transplant. 
During the Day -9 study visit, the following tests and procedures will be performed: 
 Routine blood will be drawn for hematology, chemistry – 2 teaspoons 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications you are taking, measurement of your weight, blood 
pressure, heart rate 
 You will have a brief assessment about your ability to perform activities of daily living 
(ECOG) 
 You will be asked to complete brief surveys (Symptom assessment package) about your 
symptoms 
 Pregnancy test (approx. 1 tsp. blood) - Serum HCG: for women of childbearing potential.  
Women will not be allowed to participate if they are pregnant or nursing. Both men and 
women who are able to have children must agree to use an effective form of birth control 
(hormonal or barrier method of birth control, or abstinence) from the time of screening 
and throughout their participation in the study. 
 Review and instruct you on the tapering schedule of the Ruxolitinib study drug. 
 
Should you complete the Ruxolitinib portion of your therapy, you will be required to be 
hospitalized for approximately a month, and this may mean time away from work.  
 
If you do not already have a device called an “intravenous (IV) central line” implanted in your 
chest, you will have one surgically inserted as part of the routine standard of care for the 
administration of the chemotherapy you will receive for the treatment of your disease.  You will 
be seen by a surgeon for this procedure who will explain it to you in detail and answer any 
questions that you may have.  You will be asked sign a separate consent for this standard 
procedure.  
 
This central line will remain in place for several months so that we will not have to continually 
stick you for administration of medication or blood draws. 
 


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Information on Donor Stem Cells 
For the transplant procedure in this research study, peripheral blood stem cells (blood from a 
vein) or bone marrow stem cells from either related donors (family members, if available) or 
unrelated donors will be used. Stem cells are immature or undeveloped cells which will 
eventually develop into white blood cells, red blood cells and platelets. Although peripheral 
blood stem cells are preferred for Reduced Intensity Transplants, like the one you will have, 
there may be times when only stem cells from bone marrow can be obtained.  When a family 
donor is not available, unrelated donor stem cells (either from bone marrow or peripheral blood) 
may be obtained from outside organizations. These donor stem cells are provided to the study 
team after thorough quality testing.  
Your donor will be asked to sign a separate consent form, explaining the risks of stem cell 
collection.  This consent will be provided to the donor by the hospital as part of their standard 
procedures. 
In cases where an unrelated donor or a slightly mismatched donor is used, there is a higher 
chance for rejection of the donor stem cells. Rejection is when your body’s immune system 
(defense system) attacks the “foreign” donor stem cells.  A needle is placed in the donor’s veins 
of the arm, and blood is collected at a steady rate. Blood (which includes stem cells and other 
blood cells) will be collected from the body into a machine which separates stem cells from the 
other blood cells. This is so that the stem cells can be collected into a bag to be given to you. 
Each collection procedure takes three to four hours.  
 
Reduced Intensity Conditioning Regimen (Standard of Care) 
After the stem cells have been collected, you will be admitted to the hospital for approximately a 
month. In the first five days you will receive the reduced intensity conditioning regimen, the 
purpose of which is to improve your myeloproliferative disorder and to suppress your immunity 
so that the stem cell transplant is not rejected by your own immune system. Depending on 
whether you will receive stem cells from a related or unrelated donor, you will be assigned to 
one of the two following study treatment conditioning regimens: Fludarabine with busulfan OR 
fludarabine with busulfan and ATG.  ATG is only given to subjects undergoing unrelated donor 
transplantation.   
 
Fludarabine is given by IV infusion (through a needle placed in the vein) daily for 4 days.  
Busulfan is then given by IV infusion into a vein, daily for 4 days. To allow convenient 
administration of these two study drugs, you will receive these drugs through a central line which 
is located in your chest (this is described above).  
 
If you receive stem cells from an unrelated or mismatched donor, you will be given an additional 
study drug named “anti-thymocyte globulin” or ATG, on 3 consecutive days before the stem 
cells are given. This drug further weakens your immune system to reduce the chances of you 
rejecting the transplant (graft), as well as reducing the chance that the graft cells attack your 
body’s cells, a condition known as graft-versus-host disease (as explained in the risks section). 
ATG is only given to subjects undergoing unrelated donor transplantation. 


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This conditioning regimen is summarized in the following table, where “Day 0” is the day of 
stem cell transplantation: 
 
Day -5 Day -4 Day -3 Day–2 
Day–1 
Day 0 
Fludarabine 
X 
X 
X 
X 
 
 
Busulfan 
X 
X 
X 
X 
 
 
ATG (only 
if unrelated 
donor) 
 
 
X 
X 
X 
 
 
Day -5 study requirements 
During Day -5, when you will begin the additional chemotherapy regimen, you will have the 
following additional tests and procedures performed: 
 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications you are taking, measurement of your weight, blood 
pressure, heart rate 
 You will have a brief assessment about your ability to perform activities of daily living 
(ECOG) 
 You will be asked to complete brief surveys (Symptom assessment package) about your 
symptoms 
 Routine blood will be drawn for hematology, chemistry – 2 teaspoons 
 Blood will be drawn for cytokine profile – 2 teaspoons 
 You will be assessed for any signs of harmful effects the drug or any additional problems 
caused by the medical treatment 
 Evaluation of your condition to determine if you are responding well to the study drug 
treatment 
 
Reduced Intensity Transplant (Standard of Care) 
Two days after your last dose of fludarabine and busulfan, on the day of transplant (Day 0 on the 
table above), the donor stem cells will be infused (through the central IV line).  These stem cells 
will eventually develop into white blood cells, red blood cells, and platelets in your body.   
 
Day 0 study requirements 
During Day 0, when you will have the stem cell transplant, you will have the following 
additional tests and procedures performed: 
 A physical examination 
 Routine blood will be drawn for hematology, chemistry – 2 teaspoons 


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 You will be assessed for any signs of harmful effects the drug or any additional problems 
caused by the medical treatment 
 
Post-Transplant (Standard of Care) 
Immediately after the Reduced Intensity transplant, you will receive two FDA approved standard 
drugs to reduce the risks of graft versus host disease (explained in risk section). These drugs are 
called tacrolimus and methotrexate. Beginning the 2 days before the transplant (day -2) and 
continuing for at least 180 days after the transplant, you will take the drug known as tacrolimus 
which is used to reduce the activity of the your immune system and so lower the risk of 
transplant rejection.  Tacrolimus will be given to you by an intravenous infusion only for the first 
3 days.  Then, for the remaining180 days, you will take tacrolimus orally (by mouth), as a tablet. 
You will take tacrolimus tablets twice a day, and the number of tablets you will take depends on 
your weight. This drug will help prevent your body from rejecting the cells you received from 
your donor. Methotrexate will be given intravenously on days 1, 3 and 6 after transplant.  This 
drug will help prevent your body from rejecting the cells you received from your donor. 
 
All the standard medical care used after standard transplants, including antibiotics, intravenous 
nutrition, graft versus host disease prevention and transfusions of red cell and platelets, will be 
used after your Reduced Intensity Transplant as needed. After the reduced intensity transplant, 
the testing used to evaluate the success of the study treatment will be similar to that used for 
regular transplants. If your disease were to return or persist after reduced intensity transplant, or if 
your body does not successfully “take” (accept) the transplanted donor cells, you may receive 
additional infusions of stem cells from your donor at two-month intervals without any study 
treatment conditioning regimen. 
 
If the transplant is an effective treatment of the underlying myeloproliferative neoplasm, it will 
result in production of normal blood.  It usually takes approximately two to three weeks for the 
donor stem cells to produce blood. During this time, you will be dependent on transfusion of 
blood and platelets and will need antibiotics to prevent and/or treat infections. You will remain in 
the hospital until your blood counts are fully recovered and you are in good clinical condition. 
Usually this means a hospital stay of at least three or four weeks after the transplantation. 
 
After the transplantation, you will be seen regularly by your study doctor to have frequent blood 
tests, similar to the ones explained in the Ruxolitinib phase.   
 
Post-transplant study requirements (Day +30 to Month +48) 
After your stem cell transplant, and after your treatment in the hospital, you will be seen by the 
study doctor and study team at specific intervals: Day +30, +60, +100, 6 months, 1 year, 18 
months, 24 months, 36 months, 48 months.  At all of these study visits, the following tests and 
procedures will be performed: 


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 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications you are taking, measurement of your weight, blood 
pressure, heart rate 
 You will have a brief assessment about your ability to perform activities of daily living 
(ECOG) 
 Routine blood will be drawn for hematology, chemistry – 2 teaspoons 
 You will be assessed for any signs of harmful effects the drug or any additional problems 
caused by the medical treatment 
 
 You will be assessed to see whether or not your body is experiencing Graft Versus Host 
Disease (GVHD), a side effect of bone marrow or stem cell transplantation.  In cases of 
GVHD, the new donor cells treat the body as “foreign” and launch an attack against it.   
 
Additionally, on these specific study visits, the following additional tests and procedures will be 
done: 
Day +30  
 Blood will be drawn for cytokine profile – 2 teaspoons 
 You will be asked to complete brief surveys (Symptom assessment package) about your 
symptoms 
 ABO and Rh typing (approx. 1-2 tsp. blood) - Blood type tests done before a person gets 
a blood transfusion. Human blood is typed by certain markers (called antigens) on the 
surface of red blood cells 
 Chimerism studies (to analyze the transplant) – 2 teaspoons  
 
Day +60  
 ABO and Rh typing (approx. 1-2 tsp. blood) - Blood type tests done before a person gets 
a blood transfusion. Human blood is typed by certain markers (called antigens) on the 
surface of red blood cells 
 Chimerism studies (to analyze the transplant) – 2 teaspoons   
 
Day +100 
 You will be asked to complete brief surveys (Symptom assessment package) about your 
symptoms 
 Blood will be drawn for cytokine profile – 2 teaspoons 
 Research samples for the MPD-RC tissue bank - small sample of your blood (about 4 
tablespoons) and an additional 3 teaspoons of bone marrow will be taken to look for these 
certain molecules in the blood called “biomarkers” 
 Bone marrow aspiration/biopsy/cytogenetics/clonality: Bone marrow aspiration, also 
called bone marrow sampling, is the removal by suction (through a needle placed into the 
bone) of fluid from the soft, spongy material that lines the inside of most bones (marrow). 
(Approx. 1 ½ tsp.)  During a bone marrow aspiration/biopsy an area of the hip is numbed 
and a needle is placed through the skin and into the hip bone.  A small sample of bone 


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marrow and bone is withdrawn.  The bone marrow will be examined to see if it is 
abnormal 
 Chimerism studies (to analyze the transplant) – 2 teaspoons 
 Evaluation of your condition to determine if you are responding well to the study drug 
treatment 
 
Day +180 (6 months) 
 You will be asked to complete brief surveys (Symptom assessment package) about your 
symptoms 
 JAK2 V617F (1½ tsp. blood): blood test to check for the JAK2 V617F mutation in your 
blood   
 Research samples for the MPD-RC tissue bank - small sample of your blood (about 4 
tablespoons) and an additional 3 teaspoons of bone marrow will be taken to look for these 
certain molecules in the blood called “biomarkers” 
 Bone marrow aspiration/biopsy/cytogenetics/clonality: Bone marrow aspiration, also 
called bone marrow sampling, is the removal by suction (through a needle placed into the 
bone) of fluid from the soft, spongy material that lines the inside of most bones (marrow). 
(Approx. 1 ½ tsp.)  During a bone marrow aspiration/biopsy an area of the hip is numbed 
and a needle is placed through the skin and into the hip bone.  A small sample of bone 
marrow and bone is withdrawn.  The bone marrow will be examined to see if it is 
abnormal 
 Chimerism studies (to analyze the transplant) – 2 teaspoons 
 Evaluation of your condition to determine if you are responding well to the study drug 
treatment 
 
+12 months 
 You will be asked to complete brief surveys (Symptom assessment package) about your 
symptoms 
 JAK2 V617F (1½ tsp. blood): blood test to check for the JAK2 V617F mutation in your 
blood   
 Research samples for the MPD-RC tissue bank - small sample of your blood (about 4 
tablespoons) and an additional 3 teaspoons of bone marrow will be taken to look for these 
certain molecules in the blood called “biomarkers” 
 Bone marrow aspiration/biopsy/cytogenetics/clonality: Bone marrow aspiration, also 
called bone marrow sampling, is the removal by suction (through a needle placed into the 
bone) of fluid from the soft, spongy material that lines the inside of most bones (marrow). 
(Approx. 1 ½ tsp.)  During a bone marrow aspiration/biopsy an area of the hip is numbed 
and a needle is placed through the skin and into the hip bone.  A small sample of bone 
marrow and bone is withdrawn.  The bone marrow will be examined to see if it is 
abnormal 
 Chimerism studies (to analyze the transplant) – 2 teaspoons   
 Evaluation of your condition to determine if you are responding well to the study drug 
treatment 
 


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+18 months  
 The study doctor will evaluate your condition to determine if you are responding well to 
the study drug treatment 
+24 months 
 You will be asked to complete brief surveys (Symptom assessment package) about your 
symptoms 
 JAK2 V617F (1½ tsp. blood): blood test to check for the JAK2 V617F mutation in your 
blood   
 Research samples for the MPD-RC tissue bank - small sample of your blood (about 4 
tablespoons) and an additional 3 teaspoons of bone marrow will be taken to look for these 
certain molecules in the blood called “biomarkers” 
 Bone marrow aspiration/biopsy/cytogenetics/clonality: Bone marrow aspiration, also 
called bone marrow sampling, is the removal by suction (through a needle placed into the 
bone) of fluid from the soft, spongy material that lines the inside of most bones (marrow). 
(Approx. 1 ½ tsp.)  During a bone marrow aspiration/biopsy an area of the hip is numbed 
and a needle is placed through the skin and into the hip bone.  A small sample of bone 
marrow and bone is withdrawn.  The bone marrow will be examined to see if it is 
abnormal 
 Chimerism studies (to analyze the transplant) – 2 teaspoons   
 Evaluation of your condition to determine if you are responding well to the study drug 
treatment 
 
+36 months and +48 months 
 You will be asked to complete brief surveys (Symptom assessment package) about your 
symptoms 
 JAK2 V617F (1½ tsp. blood): blood test to check for the JAK2 V617F mutation in your 
blood   
 Chimerism studies (to analyze the transplant) – 2 teaspoons   
 Evaluation of your condition to determine if you are responding well to the study drug 
treatment 
 
Off-Treatment 
In the case you begin taking the study drug, Ruxolitinib, and then need to discontinue taking the 
medication due to harmful effects it is causing, you have disease progression, or you have 
disease relapse after the bone marrow transplant, you will have an off-treatment visit, and a 
follow up visit, 30 days after you have taken the last dose of study medication.  During the off-
treatment visit, the following tests and procedures will be performed: 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications you are taking, measurement of your weight, blood 
pressure, heart rate 
 You will have a brief assessment about your ability to perform activities of daily living 
(ECOG) 


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 Bone marrow aspiration/biopsy/cytogenetics/clonality: Bone marrow aspiration, also 
called bone marrow sampling, is the removal by suction (through a needle placed into the 
bone) of fluid from the soft, spongy material that lines the inside of most bones (marrow). 
(Approx. 1 ½ tsp.)  During a bone marrow aspiration/biopsy an area of the hip is numbed 
and a needle is placed through the skin and into the hip bone.  A small sample of bone 
marrow and bone is withdrawn.  The bone marrow will be examined to see if it is 
abnormal 
 Research samples for the MPD-RC tissue bank - small sample of your blood (about 4 
tablespoons) and an additional 3 teaspoons of bone marrow will be taken to look for these 
certain molecules in the blood called “biomarkers” 
 Routine blood will be drawn for hematology, chemistry – 2 teaspoons 
 The harmful effects of the drug that you are experiencing caused by the medical 
treatment will be assessed. 
During the 30-day follow-up visit, the following tests will be performed: 
 A physical examination including a review of current medical conditions, transfusion 
history, spleen palpation, medications you are taking, measurement of your weight, blood 
pressure, heart rate 
 You will have a brief assessment about your ability to perform activities of daily living 
(ECOG) 
 Routine blood will be drawn for hematology, chemistry – 2 teaspoons 
 The harmful effects of the drug that you are experiencing caused by the medical 
treatment will be assessed. 
After you come off treatment, the research team will follow you every 6 months via telephone or 
your medical records to collect your disease status. 
 
Note on additional Mandatory Sub-Study / Genetic testing 
Your participation in genetic testing is a mandatory part of this study and may help to better 
understand which MPD patients may benefit from the study treatment in the future. 
Segments of the DNA called genes are responsible for passing particular traits such as eye color 
from parents to children.  The genes which pass along your traits direct cells in your body to 
make proteins some of which may play a role in the development of disease such as MPD.  The 
study of gene mutations and variations in genes may help scientist to predict which patients with 
MPD are most likely to respond to specific treatments.  In this study, genetic testing will be 
performed in order to learn more about factors which may predict response to the study drug 
treatment pre-transplant. 
The doctors at (Participating site), working with other cancer researchers, are attempting to 
better understand the causes of myeloproliferative neoplasms and to develop improved methods 
for the diagnosis and treatment of these diseases. You will be asked to read and sign a consent 
form for that mandatory study called “Correlative Biomarker Study for MPD-RC Treatment 
Studies in the Philadelphia Chromosome Negative MPD”.   
 


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As part of this research study, the study team is asking you to participate in an additional 
research study where a small sample of your blood (an additional 3 teaspoons of bone marrow 
and about 4 tablespoons of blood) will be taken to look for these certain molecules in the blood 
called “biomarkers”. Because these extra blood and bone marrow samples will be collected at the 
same time as regularly scheduled blood and bone marrow tests, you will not undergo any 
additional procedures. These blood and bone marrow samples will be collected for research 
purposes only. You are also being asked to provide two nail clippings.  These samples will be 
used to test and analyze the behavior and activity of molecules (the smallest unit of a substance 
that can exist alone and retain the character of that substance) and genes (the basic biological unit 
of hereditary) that may change as by- products of the disease itself.  Your nail clippings will 
provide normal material like DNA for comparison with the abnormal material from your blood 
and/or bone marrow.  This information may provide us with a better understanding of what 
causes the disease and how to develop better treatments.  You will not receive the results from 
research on your sample. 
That study will only collect blood, bone marrow, and nail samples to determine genetic 
characteristics.  
These samples will be sent to special laboratories at the New York Blood Center for careful 
study and analysis.  Your samples will be sent to these laboratories using a unique code that does 
not identify you by name, address or social security number.  Researchers with access to your 
samples will not be able to identify you.  The code linking the sample to your name would be 
stored at (Participating site) and known only to your doctor and a limited number of research 
personnel at (Participating site).  The research will not have any effect on your care; therefore, 
the results of the genetic testing will not be placed into your medical records.  If you discontinue 
from the trial, regardless of the reason (patient, investigator or sponsor decision), no further 
genetic samples will be collected. However, we will continue to use data previously generated 
from the genetic samples collected prior to the date of discontinuation. 
 
These samples will be obtained at the following times: 
 At diagnosis or before starting study treatment  
 Day +100 following Reduced intensity transplant 
 Day +180 following Reduced intensity transplant 
 Month +12 following Reduced intensity transplant 
 Month +24 following Reduced intensity transplant 
 If/when your disease comes back (recurrence of disease) 
 
The blood and bone marrow samples we collect would normally be obtained at these times 
during your treatment and/or routine follow-up.  Blood and bone marrow samples for this study 
will be drawn only when these samples are being obtained for clinical purposes.  Therefore, you 
will not have to undergo any additional procedures to participate in this study.   
Nail clippings will be obtained only once at diagnosis or before starting treatment. 
 
Any information derived directly or indirectly from the future research, as well as any patents, 
diagnostic tests, drugs, or biological products developed directly or indirectly as a result of this 


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research, are the sole property of the Sponsor (and its successors, licensees, and assigns) and may 
be used for commercial purposes. You have no right to this property or to any share of the profits 
that may be earned directly or indirectly as a result of this research. However, in signing this 
form and donating a blood sample or tumor tissue specimen for future research, you do not give 
up any rights that you would otherwise have. 
 
You may wish to obtain professional genetic counseling before signing this informed consent so 
that you are fully aware of the implications.     
 
YOUR RESPONSIBILITIES IF YOU TAKE PART IN THIS RESEARCH: 
If you decide to take part in this research study you will be responsible for the following things: 
complying with requirements of the study, taking prescribed medications, use of effective birth 
control, and regular attendance at study visits. 
COSTS OR PAYMENTS THAT MAY RESULT FROM PARTICIPATION: 
There is no additional cost to you for participating in this research study other than those costs 
associated with the treatment of your disease. You or your insurance company will be 
responsible for the costs of your study doctor visits and all of the standard study treatments and 
procedures, including the hospital visits, x-rays, and blood tests. This is because this standard 
care would be the same even if you were not participating in this study.  
The sponsor of this study will pay for the mandatory sub-study blood tests. The sponsors of this 
study will pay for the biomarker sub-study blood tests and for the study medication, Ruxolitinib 
(INC424). 
Your insurance company must be contacted to pre-authorize the stem cell procedure and all the 
study treatments in this study. If your insurance company does not authorize these study 
treatments, you may choose not to participate in this research study.  The study doctor will 
discuss these options with you. If your insurance company does not authorize the stem cell 
transplant, and no alternative payment arrangement is made, and you choose to go ahead with the 
procedure, you would be responsible for the bill, which would be approximately $120,000.  
Please speak to the study doctor and with the financial/billing representative before proceeding 
with this research study. 
POSSIBLE BENEFITS: 
It is important to know that you may not get any benefit from taking part in this research.  Others 
may not benefit either. If you respond to the study treatment ruxolitinib plus the conditioning 
regimen of fludarabine and busulfan, you may have improvement of your disease. The 
knowledge learned from this research study may be helpful to other people with 
myeloproliferative disorders.  No direct benefit can be promised as a result of your participation 
in this research study. 
REASONABLY FORESEEABLE RISKS AND DISCOMFORTS: 


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While on this research study, you are at risk for certain known side effects associated with the 
study medication you will be taking.  There may also be other side effects that we can't predict or 
that are unknown at this time which could be serious, permanent or, in some cases, result in 
death. Therefore, it is very important that you communicate any and all symptoms that you 
experience to your study doctor.  Medications can be given to you to make side effects less 
serious and less uncomfortable.  If you do experience side effects, we can withhold or stop your 
study drug.  Many side effects go away shortly after the study drug is stopped, but in some cases 
side effects can be serious, long lasting or permanent.  You should also tell your study doctor 
about any other medications that you are taking. While on this research study, you may 
experience the following side effects:  
Infections:  
Because the immune system (body’s defense system) will be weakened for long periods of time 
after the transplant you will be at risk for infection. To prevent this, antibiotics, antifungal, and 
antiviral medicines will be given for several months after transplantation.  
Graft Versus Host Disease (GVHD): 
GVHD is a side effect of bone marrow or stem cell transplantation.  In cases of GVHD, the new 
donor cells treat the body as “foreign” and launch an attack against it.  The most common sites of 
attack by cells causing GVHD are the skin, liver, and gastrointestinal tract.  If it occurs within 
100 days after transplant it is called acute GVHD.  If it occurs later it is called chronic GVHD.  
Symptoms of GVHD can range from mild to severe, and when severe, GVHD can be fatal.  All 
these organs can be minimally, moderately, or severely affected by graft versus host disease, 
together or separately.   
Symptoms of GVHD that may occur include: 
 Skin rash 
 Liver disease (including jaundice) 
 Nausea, vomiting, diarrhea 
 Temporary darkening of the skin and hardening and thickening patches of skin and tissue 
under the skin (occurs with chronic GVHD) 
 Weight loss 
 Lung disease (chronic GVHD) 
Graft versus host disease is observed after regular transplants and also after Reduced Intensity 
Transplants. The risks of acute GVHD after non-myeloablative and reduced-intensity transplants 
appear lower than after fully ablative (standard) transplant. This is felt to be due to a lower injury 
of healthy tissues. Some patients develop serious GVHD and may need treatment with drugs 
called immunosuppressants and a few patients may experience fatal GVHD.  The overall risk of 
suffering any significant grade of GVHD has been estimated to be 15 to 75%.  Fatal acute 
GVHD after Reduced Intensity Transplant is relatively rare occurring in less than 10% of 
patients. The use of more intensive graft versus host disease treatment (a drug given to prevent 
disease or infection) can be used to address severe graft versus host disease in reduced intensity 
transplants. 
Disease relapse/persistence (return of MPN) and failure to engraft:  
Preliminary studies show that most patients experience engraftment which is successful "take" 
(acceptance) of donor cells, and many achieve 100% donor cells in their bone marrow together 


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with remission of their myeloproliferative disease.   However, because the study treatment 
conditioning regimen used in this study is much less intense, two problems may result from the 
use of Reduced Intensity Transplants.  The first is the persistence or return of the 
myeloproliferative neoplasm (IM) after transplantation, and the other is lack of or partial "take" 
of the donor stem cells.  Both problems can be addressed by infusing more cells from the donor 
into the recipient.  Immune cells can cause a reaction against tumors called graft-versus-tumor 
effect.  The purpose of infusing more donor cells will be to take maximum advantage of this 
effect.   
 
Transplant risks: 
Likely:  
 Lowered white blood cell count that may lead to infection. This can be treated with blood 
products (transfusions) and/or antibiotics. 
 Lowered platelets, which may lead to an increase in bruising or bleeding. This can be 
treated with blood products (transfusions) and/or antibiotics. 
 Lowered red blood cells, which may cause anemia, tiredness, or shortness of breath. This 
can be treated with blood products (transfusions) and/or antibiotics. 
 Tiredness 
 shortness of breath 
 fever 
 chills  
 increased risk of infections 
 loss of appetite and/or weight loss 
 diarrhea 
 nausea 
 vomiting 
 weakness 
 dizziness 
 muscle aches 
 rash 
 itching 
 elevated liver function tests 
 high blood pressure 
 difficulty sleeping 
 nervousness 
 trembling or muscle twitching 
 hair thinning or partial hair loss 
Less likely, but serious:  
 Kidney damage 
 lung damage (scarring of the lung) 
 liver damage 
 mouth and throat sores 


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 hives, including severe rash leading to sloughing of skin and mucous membranes 
(redness and flaking of skin) 
 gastrointestinal bleeding (stomach and intestines) which could cause blood when 
vomiting or black tarry stools 
 serious disturbances of the immune system which can result in life threatening infections, 
red blood cell destruction by the immune system, failure to resume production of red 
blood cells which could be fatal 
 too much sugar in the blood 
 bladder irritation where blood may be present in the urine 
 temporary unsteadiness when walking 
 hypertension (high blood pressure) 
 heart damage 
 chest pain 
 hearing loss 
 feelings of extreme stress 
 depression or confusion 
 seizures (Most seizures last from 30 seconds to 2 minutes and do not cause lasting harm. 
A seizure is uncontrolled electrical activity in the brain, which may produce physical 
convulsions like shaking and trembling, mental changes like confusion, or a combination 
of symptoms.)  
 Veno-occlusive disease: One of the problems seen after standard allogeneic transplants is 
the formation of blood clots in the small blood vessels of the liver. This complication is 
called veno-occlusive disease or VOD and can result in serious damage to the liver. The 
type of transplant used in this study is called non-myeloablative, which is less toxic than 
a standard transplant. Although VOD may still happen after non-myeloablative 
transplants it is less common. 
Less likely, but not serious:  
 Tingling of the fingers and/or toes 
 weight gain and/or swelling 
 insomnia 
 Headache 
 metallic taste in mouth 
 rash and hives 
 facial swelling 
 muscle/joint aches  
 pains in abdomen, chest or bones 
 enlargement of spleen,  
 increased or decreased potassium in the blood (may cause irregular heart beat, muscle 
cramping, weakness, difficulty breathing) 
 decreased amounts of the blood chemical phosphate (there are no symptoms of low 
phosphate, unless the values are extremely low.  Then you may notice trouble breathing 
or other respiratory problems, confusion, irritability) 
 inflamed (redness and swelling) throat or tongue which may cause a burning sensation 
 sensitivity to light 


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 blurred vision  
 ringing ears 
 painful or difficult urination.   
Drug Side Effects 
Risks of Ruxolitinib: 
The risks of ruxolitinib may not be fully known, and may vary depending upon the disease you 
are being treated for.   Therefore, you will be informed of the important symptoms or medical 
events (called “adverse events”) that have occurred frequently in patients who had serious blood 
conditions called myelofibrosis (MF) and polycythemia vera (PV).    You will also be informed 
of any adverse events that were rare but serious and might have been related to the study drug.   
During your participation, you will be given any new information that may affect your 
willingness to start or continue in the study. 
You should discuss the risks listed here with your Study Doctor.  Many side effects go away 
shortly after the study drug is stopped, but in rare cases they may be serious, long lasting, and/or 
permanent, and may even cause death. If you experience any of the described symptoms or have 
any other problems, you must immediately tell the appropriate study staff member or the Study 
Doctor.  If you feel that these symptoms or side effects are life threatening seek medical 
assistance immediately. 
The following adverse events were reported as common side effects (occurring in at least 1%) or 
very common (occurring in at least 10%) of patients who were treated with ruxolitinib for MF or 
for PV.   
Very Common (at least 10%) 
 Anemia (low red blood cells 
 Thrombocytopenia (low platelets) 
 Bruising 
 Neutropenia (low white blood cells) 
 Raised ALT and AST (blood proteins that may indicate mild liver damage) 
 Hypercholesterolemia (increase in cholesterol) 
 Hypertriglyceridemia (increase in triglycerides) 
 Dizziness 
 Headache 
 Urinary tract infections 
 Weight gain 
Common (more than 1% but less than 10%) 
 Flatulence (gas) 
 Constipation 
 Herpes Zoster (shingles) 
 Hypertension (high blood pressure) 


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Ruxolitinib may cause low blood cell counts (white blood cells, red blood cells and platelets). If 
your white blood cell count becomes low while you take the drug, this means you may have an 
increased chance of getting an infection, including urinary tract infections and viral infections. 
You will be checked for any signs of infection before starting ruxolitinib and any serious 
infections should be treated before you start ruxolitinib; your physician will check you carefully 
for signs of infection while you are being treated. You also may become anemic (low red blood 
cell count) while you take the drug, and that may cause you to feel fatigued or short of breath. If 
your platelet count becomes low while you take the drug, it may lead to bleeding and/or bruising. 
In some people taking ruxolitinib, the decrease in blood cell counts have been severe.  In most 
cases, low blood cell counts can be reversed by stopping the study drug temporarily or reducing 
the dose; you will be checked often for this side effect while on study.  If your blood cell counts 
do not recover quickly, the study drug may be stopped for a longer duration to allow the blood 
cell counts to recover.  
Uncommon:  (occurring in fewer than 1% of patients)  
These events are events that were uncommon, but occurred during ruxolitinib treatment and are 
potentially serious. 
 Non-melanoma skin cancers (NMSCs) are skin cancers such as basal cell cancer or 
squamous cell cancer that usually develop on the sun-exposed areas of skin, and 
commonly require surgery to remove.   NMSCs have been reported in patients with MF 
or PV who were treated with ruxolitinib. Most of these patients had histories of extended 
treatment with medications known to increase the risk of NMSC, and had NMSC or pre-
cancerous skin lesions before being treated with ruxolitinib. It is not known whether or 
not ruxolitinib contributed to these cases of NMSC.  Periodic skin examination is 
recommended for patients who are at increased risk for skin cancer. 
(The following conditions have occurred in patients with MF who were treated with ruxolitinib)  
 Tuberculosis (TB) has occurred in a small number of patients (less than 1%) with MF 
who were treated with ruxolitinib, but it is not known whether this was due to MF, 
ruxolitinib, or other factors that are known to increase the risk of tuberculosis (such as 
diabetes, bronchitis, asthma, smoking, emphysema, or steroid use).  Tell your study 
doctor if you have been treated for TB in the past, or have ever had a positive skin test for 
TB.  An increase in systolic blood pressure was noted on at least one occasion in more 
MF patients treated with ruxolitinib than patients treated with comparison drugs (31% vs. 
20%), but the average changes in blood pressure very small, generally occurred only once 
over the treatment period, and their meaning was not clear. 
 About one week following interruption or discontinuation of ruxolitinib, some patients 
with MF experienced a return of symptoms (such as fatigue, bone pain, fever, itching, 
night sweats, weight loss, or an enlarged spleen).  There have been cases of MF patients 
stopping ruxolitinib during another ongoing illness who became more severely ill, but it 
was not clear whether stopping ruxolitinib therapy contributed to the patients’ conditions 
worsening.  When stopping ruxolitinib therapy, your doctor may choose to gradually 
decrease the dose of ruxolitinib. 
 A rare disease called progressive multifocal leukoencephalopathy (PML) has been 
reported during ruxolitinib treatment for MF. PML comes from a viral infection that 


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causes brain damage and can be fatal.  It is unknown whether this was due to ruxolitinib 
treatment since PML has occurred in patients with blood cancers, including MF, who 
were not treated with ruxolitinib.  Tell your study doctor immediately if you have any of 
the following symptoms or if anyone close to you notices that you have any of these 
symptoms: confusion or problems thinking, loss of balance or problems walking, 
clumsiness, difficulty speaking, decreased strength or weakness on one side of your body, 
blurred and/or loss of vision. 
 
Risks of Fludarabine:   
Likely:  
 Lowered white blood cell count that may lead to infection. This can be treated with blood 
products (transfusions) and/or antibiotics. 
 Lowered platelets, which may lead to an increase in bruising or bleeding. This can be 
treated with blood products (transfusions) and/or antibiotics. 
 Lowered red blood cells, which may cause anemia (less hemoglobin (protein in red blood 
cells that carries oxygen) to carry oxygen to your tissues), tiredness, or shortness of 
breath. This can be treated with blood products (transfusions) and/or antibiotics 
 Fever 
 Nausea 
 Vomiting 
 Mouth or throat sores 
 Diarrhea 
 Ulcers 
 Loss of appetite 
 Swelling or water retention 
 Skin rashes 
 Muscle aches 
 Nervousness 
 Hearing loss 
 Sleepiness 
 Fatigue 
 
Risks of Busulfan: 
Common Side Effects: 
 Anxiety 
 Back pain 
 Constipation 
 Diarrhea 
 Dizziness 
 Dry mouth 
 Flushing or hot flashes 


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 Headache 
 Hiccup 
 Indigestion 
 Loss of appetite 
 Mild fever or chills 
 Mild redness or swelling at the injection site 
 Minor cough or sore throat 
 Muscle or joint pain 
 Nausea 
 Runny nose 
 Tiredness or weakness 
 Trouble sleeping 
 Vomiting. 
Severe Side Effects: 
 Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; 
swelling of the mouth, face, lips, or tongue) 
 Black, tarry stools 
 Blurred vision or other vision changes 
 Chest pain 
 Confusion 
 Decreased amount of urine, painful urination, or blood in the urine 
 Depression 
 Fainting 
 Fast or irregular heartbeat 
 Hallucinations 
 Missed menstrual period 
 Red, swollen, or blistered skin 
 Seizures 
 Severe or persistent pain, redness, or swelling at the injection site 
 Severe or persistent cough 
 Severe or persistent dizziness or headache 
 Severe or persistent nausea, vomiting, or diarrhea 
 Shortness of breath or trouble breathing 
 Signs of infection (eg, persistent fever, chills, or sore throat) 
 Sores in the mouth or trouble swallowing 
 Unusual bruising or bleeding (eg, nosebleed) 
 Unusual pain or swelling of the legs or calves 
 Unusual stomach pain, swelling, or weight gain 
 Vomit that looks like coffee grounds 
 Yellowing of the skin or eyes. 
Risks of Tacrolimus (Prograf):   
Likely:  


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 High blood pressure 
 Lowered white blood cell count that may lead to infection. This can be treated with blood 
products (transfusions) and/or antibiotics. 
 Lowered platelets, which may lead to an increase in bruising or bleeding. This can be 
treated with blood products (transfusions) and/or antibiotics. 
 Lowered red blood cells, which may cause anemia, tiredness, or shortness of breath. This 
can be treated with blood products (transfusions) and/or antibiotics 
 Chest pain 
 Headache 
 Tremors 
 Insomnia 
 Tingling of the fingers and toes which can cause clumsiness or stumbling 
 Nervousness, or anxious feelings 
 Abnormal blood chemistries: changes in your blood calcium, sodium, albumin (protein), 
potassium, and/or magnesium 
 Excess body hair 
 Nausea 
 Vomiting 
 Constipation  
 Diarrhea 
 Appetite loss 
 Kidney damage 
 Decreased urination 
 Abnormal liver function 
 Pain  
 Fever 
 Loss of strength and energy 
 Weakness 
 Back pain 
 Swollen ankles or fingers 
 Gum disease 
 High blood sugar.  
Less likely:  
 High potassium in the blood.  Diuretics that spare potassium such as triamterene (found 
in Dyazide and Maxzide), amiloride (found in Moduretic), and spironolactone 
(Aldactone) are not recommended. 
 Confusion 
 Seizures (Most seizures last from 30 seconds to 2 minutes and do not cause lasting harm. 
A seizure is uncontrolled electrical activity in the brain, which may produce physical 
convulsions like shaking and trembling, mental changes like confusion, or a combination 
of symptoms.)  
 Sadness 
 Hallucinations 
 Shock like muscle contractions 


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 Numbness 
 Irrational thoughts 
 Temporary unsteadiness when walking 
 Strange dreams 
Aluminum hydroxide, which is found in many antacids, binds tacrolimus in the stomach. 
Aluminum-containing antacids should not be taken with tacrolimus. 
The destruction of tacrolimus by the body may be prevented by a large number of drugs, 
resulting in higher blood levels of tacrolimus, and possibly increasing its side effects. Such drugs 
include bromocriptine (Parlodel), cimetidine (Tagamet), cisapride (Propulsid), clarithromycin 
(Biaxin), cyclosporine (Sandimmune; Neoral), danazol (Danacrine), diltiazem (Cardizem; 
Tiazac), erythromycin, fluconazole (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral), 
metoclopramide (Reglan), methylprednisolone (Medrol), nicardipine (Cardene), troleandomycin 
(Tao), and verapamil (Calan; Isoptin; Verelan; Covera-HS). Grapefruit juice also may have a 
similar effect on tacrolimus and should be avoided completely receiving this medication. 
Other drugs can stimulate the break-down of tacrolimus, decreasing its blood concentration and 
possibly reducing its effectiveness.  Such drugs include carbamazepine (Tegretol), nifedipine 
(Procardia; Adalat); phenobarbital, phenytoin (Dilantin), rifabutin, and rifampin.  
The study doctor will monitor the subject very closely for side effects.  Doses will be adjusted if 
serious side effects occur.   
Risks of methotrexate:  
Likely:   
 Lowered white blood cell count that may lead to infection. This can be treated with blood 
products (transfusions) and/or antibiotics. 
 Lowered platelets, which may lead to an increase in bruising or bleeding. This can be 
treated with blood products (transfusions) and/or antibiotics. 
 Lowered red blood cells, which may cause anemia, tiredness, or shortness of breath. This 
can be treated with blood products (transfusions) and/or antibiotics 
 Inflammation (redness, swelling, burning) of the mouth, (gums, tongue, throat)  
 Inflammation (swelling, burning) of the intestine, especially the small intestine 
 Nausea 
 Vomiting, sometimes with blood 
 Diarrhea 
 Loss of appetite 
 Mouth sores 
 Itching 
 Rash 
 Sun sensitivity  
 Drowsiness 
 Blurred vision 
 Ringing in ears 
 Low energy 
 Seizures.  


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Less likely: 
 Pale stools 
 Headache 
 Back pain and rigidity. 
Less Likely, But Serious:  
 Liver disease 
 Lung disease (which may not be fully reversible) 
 Kidney problems 
 Bladder problems 
 Low sperm counts 
 Diabetes 
Folic acid may decrease response to methotrexate. NSAIDs (nonsteroidal anti-inflammatory 
drugs), which are anti-inflammatory pain medications like ibuprofen, Motrin, or Advil may 
increase methotrexate blood levels.  Other drugs can increase or decrease effectiveness of this 
drug.  Patients should not take any folic acid or NSAIDs while on this research study and should 
tell their study doctor before taking any other drugs or vitamins. 
Risks of anti-thymocyte globulin (ATG): 
Likely: 
 Fever 
 Chills 
Rarely: 
 Hypotension (low blood pressure) 
 Allergic reaction (shortness of breath) 
 Cause the occurrence of lymphoma (cancer of your immune system) after transplantation 
Risk of secondary malignancy 
A number of established chemotherapeutic agents have a known risk of causing secondary 
cancers and/or leukemias.  Certain agents in use today, not currently known to be associated with 
this risk may be shown at a later time to result in the development of these secondary cancers 
and/or leukemias. 
Pregnancy Risks 
The effects of the drugs used in this research study on the fetus are unknown.  For this reason, to 
take part in this study, women who are capable of bearing children and men who are capable of 
fathering a child and who are heterosexually active must use an effective means of birth control 
throughout the study.  You must notify the study doctor if you suspect that you or your partner 
may be pregnant.   
Risks of clipping nails 
There are no risks to clipping nails.   
Potential Medication Interaction 


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Because some medications (either sold with or without prescriptions) can potentially reduce the 
effectiveness and/or enhance the side effects of ruxolitinib, you should tell your study doctor 
about any new treatments or medications you may be taking. This includes all prescription or 
sold without prescription medications, health food supplements, vitamins or herbal remedies, 
acupuncture or other alternative therapies.  
 
OTHER POSSIBLE OPTIONS TO CONSIDER: 
You may choose not to join this research study without any penalty. The choice is totally up to 
you.  There may be other treatment options that are available to you instead of participating in 
this research study.  These include other non-study treatments for IM, or taking medications to 
help your symptoms only.  You may also decide to use a standard conditioning regimen instead 
of a reduced intensity regimen.  There may also be other research studies available at 
(participating site) or another hospital.  Your study doctor should explain these other options, 
including the possible risks and benefits of these other options before you make the decision to 
participate in this research study.  You may also choose not to receive treatment for 
myeloproliferative disorders.  
 
If you choose not to participate in this research study, you may continue treatments that have 
already been prescribed or you may choose to receive no treatment.  Your doctor will discuss 
your options with you.  If you choose not to participate in this research study, other choices are 
available to you. 
 
IN CASE OF INJURY DURING THIS RESEARCH STUDY: 
If you are injured or made sick from taking part in this research study, medical care will be 
provided. Generally, this medical care will be billed to you and/or your health care insurance in 
the ordinary manner and you will be responsible for all treatment costs not covered by your 
insurance, including deductibles, co-payments, and coinsurance. This does not prevent you from 
seeking payment for injury related to malpractice or negligence. Contact the investigator for 
more information.  
ENDING PARTICIPATION IN THE RESEARCH STUDY: 
You may stop taking part in this research study at any time without any penalty. This will not 
affect your ability to receive medical care at (Name of site) or to receive any benefits to which 
you are otherwise entitled. 
If you decide to stop being in the research study, please contact the Principal Investigator or the 
research staff. 
You may also withdraw your permission for the use and disclosure of any of your protected 
information for research, but you must do so in writing to the Principal Investigator at the 
address on the first page. Even if you withdraw your permission, the Principal Investigator for 
the research study may still use the information that was already collected if that information is 
necessary to complete the research study. Your health information may still be used or shared 


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after you withdraw your authorization if you should have an adverse event (a bad effect) from 
participating in the research study. 
 
Samples will be banked from this research study.  If you wish to withdraw your specimen from 
use in research, you must do so in writing to the Principal Investigator of the study. 
 
Withdrawal without your consent: The study doctor, the sponsor or the institution may stop your 
involvement in this research study at any time without your consent. This may be because the 
research study is being stopped, the instructions of the study team have not been followed, the 
investigator believes it is in your best interest, or for any other reason. If specimens or data have 
been stored as part of the research study, they too can be destroyed without your consent 
This research involves the research use of genetic testing to diagnose the presence of a genetic 
variation linked to a predisposition to a genetic disease or disability in the subject or the subject’s 
offspring.  You have the right to withdraw consent to use of the tissue for future use at any time, 
and the Principal Investigator should be contacted to withdraw consent.  If you have consented to 
storage of the tissue sample and you would like to withdraw your consent, you may do so at any 
time.  A member of the study team who is storing the sample will promptly destroy the sample or 
portions that have not already been used for research. 
 
CONTACT PERSON(S): 
If you have any questions, concerns, or complaints at any time about this research, or you think 
the research has hurt you, please contact the office of the research team and/or the Principal 
Investigator at phone number (sites’ phone number). 
This research has been reviewed and approved by an Institutional Review Board. You may reach 
a representative of the Program for the Protection of Human Subjects at (Participating site) at 
telephone number (sites’ phone number) during standard work hours for any of the following 
reasons: 
 Your questions, concerns, or complaints are not being answered by the research 
team. 
 You cannot reach the research team. 
 You are not comfortable talking to the research team. 
 You have questions about your rights as a research subject. 
 You want to get information or provide input about this research. 
DISCLOSURE OF FINANCIAL INTERESTS: 
None. 
 
MAINTAINING CONFIDENTIALITY – HIPAA AUTHORIZATION: 
As you take part in this research project it will be necessary for the research team and others to 
use and share some of your private protected health information. Consistent with the federal 


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Health Insurance Portability and Accountability Act (HIPAA), we are asking your permission to 
receive, use and share that information. 
What protected health information is collected and used in this study, and might also be 
disclosed (shared) with others?  
As part of this research project the researchers will collect your name, address including zip 
code, telephone number, date of birth, sex, race, and ethnicity. 
The researchers will also get information from your medical record (includes hospital record 
from (Participating site) and referring physician’s records) 
During the study the researchers will gather information by:  
 taking a medical history (includes current and past medications or therapies, illnesses, 
conditions or symptoms, family medical history, allergies, etc.) 
 doing a physical examination that generally also includes blood pressure reading, 
heart rate, breathing rate and temperature 
 completing the tests and procedures explained in the description section of this 
consent such as CT scans, pulmonary function tests, X-rays, ECGs, pregnancy test 
results, urinalysis, bone marrow aspirate/biopsy, nail clippings, flow cytometry, 
Chimerism test results, Hepatitis A, B, C, results, CMV, HSV, and EBV virus results, 
blood typing results, class I and II antigen results, and pathology results 
 reviewing genetic tests 
Why is your protected health information being used? 
Your personal contact information is important to be able to contact you during the study. Your 
health information and the results of any tests and procedures being collected as part of this 
research study will be used for the purpose of this study as explained earlier in this consent form. 
The results of this study could be published or presented at scientific meetings, lectures, or other 
events, but would not include any information that would let others know who you are, unless 
you give separate permission to do so. 
The Principal Investigator may also use and share the results of these tests and procedures to 
treat you.  
The research team and other authorized members of (Participating site) workforce may use and 
share your information to ensure that the research meets legal, institutional or accreditation 
requirements. For example, the (Participating site) Program for the Protection of Human 
Subjects is responsible for overseeing research on human subjects, and may need to see your 
information. If you receive any payments for taking part in this study, the (Participating site) 
Center Finance Department may need your name, address, social security number, payment 
amount, and related information for tax reporting purposes.  If the research team uncovers abuse, 
neglect, or reportable diseases, this information may be disclosed to appropriate authorities.  
Who, outside (Participating site), might receive your protected health information? 
As part of the study, the Principal Investigator, study team and others in the (Participating site) 
workforce may disclose your protected health information, including the results of the research 
study tests and procedures, to the following people or organizations: (It is possible that there may 
be changes to the list during this research study; you may request an up-to-date list at any time 
by contacting the Principal Investigator.) 


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 Research data coordinating office and/or their representative(s) who will be 
responsible for collecting results and findings from all the centers: 
Myeloproliferative Disorders Research Consortium Data Management Center  
 Outside laboratory who will be performing laboratory analysis for all the research 
centers involved in this project: Myeloproliferative Disorders Central Laboratory 
located at the New York Blood Center in North America and at MPD-RC Tissue 
Bank, Laboratorio Paolo Belli in Europe. 
 The manufacturer of the drug Ruxolitinib, Incyte and Novartis Pharmaceuticals. 
 The sponsoring government agency and/or their representative who need to 
confirm the accuracy of the results submitted to the government or the use of 
government funds: In the USA this is the National Cancer Institute (NCI), in 
Europe this will be the individual regulatory authorities for examples the MHRA.  
 A Data Safety Monitoring Board or other committee that will monitor the study 
on an ongoing basis for safety.  This will include the (Participating site) 
Institutional Review Board (IRB) and the Myeloproliferative Disorders Research 
Consortium Data and Safety Monitoring Board. 
 The United States Food and Drug Administration. 
 United States Department of Health and Human Services and the Office of 
Human Research Protection. 
In all disclosures outside of (Participating site), you will not be identified by name, social 
security number, address, telephone number, or any other direct personal identifier unless 
disclosure of the direct identifier is required by law. Some records and information disclosed 
may be identified with a unique code number. The Principal Investigator will ensure that the key 
to the code will be kept in a locked file, or will be securely stored electronically. The code will 
not be used to link the information back to you without your permission, unless the law requires 
it, or rarely if the Institutional Review Board allows it after determining that there would be 
minimal risk to your privacy. It is possible that a sponsor or their representatives, a data 
coordinating office, a contract research organization, will come to inspect your records. Even if 
those records are identifiable when inspected, the information leaving the institution will be 
stripped of direct identifiers.  Additionally, the monitors, auditors, the IRB, the Food and Drug 
Administration will be granted direct access to your medical records for verification of the 
research procedures and data. By signing this document you are authorizing this access. We may 
publish the results of this research. However, we will keep your name and other identifying 
information confidential. 
For how long will (Participating site) be able to use or disclose your protected health 
information?  
Your authorization for use of your protected health information for this specific study does not 
expire. 
Will you be able to access your records? 
During your participation in this study, you will have access to your medical record and any 
study information that is part of that record. The investigator is not required to release to you 
research information that is not part of your medical record. 
Do you need to give us permission to obtain, use or share your health information? 


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NO! If you decide not to let us obtain, use or share your health information you should not sign 
this form, and you will not be allowed to volunteer in the research study. If you do not sign, it 
will not affect your treatment, payment or enrollment in any health plans or affect your eligibility 
for benefits. 
 
Can you change your mind? 
You may withdraw your permission for the use and disclosure of any of your protected 
information for research, but you must do so in writing to the Principal Investigator at the 
address on the first page. Even if you withdraw your permission, the Principal Investigator for 
the research study may still use your protected information that was already collected if that 
information is necessary to complete the study. Your health information may still be used or 
shared after you withdraw your authorization if you should have an adverse event (a bad effect) 
from being in the study. If you withdraw your permission to use your protected health 
information for research that means you will also be withdrawn from the research study, but 
standard medical care and any other benefits to which you are entitled will not be affected. You 
can also tell us you want to withdraw from the research study at any time without canceling the 
Authorization to use your data. 
If you have not already received it, you will also be given the (Participating site) Notice of 
Privacy Practices that contains more information about how (Participating site) uses and 
discloses your protected health information. 
It is important for you to understand that once information is disclosed to others outside 
(Participating site), the information may be re-disclosed and will no longer be covered by the 
federal privacy protection regulations. However, even if your information will no longer be 
protected by federal regulations, where possible, (Participating site) has entered into agreements 
with those who will receive your information to continue to protect your confidentiality. 
If as part of this research project your medical records are being reviewed, or a medical history is 
being taken, it is possible that HIV-related information may be revealed to the researchers.  If 
that is the case, the information in the following box concerns you.  If this research does not 
involve any review of medical records or questions about your medical history or conditions, 
then the following section may be ignored.   


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Signature Block for Capable Adult 
Your signature below documents your permission to take part in this research and to the use and 
disclosure of your protected health information. A signed and dated copy will be given to you. 
DO NOT SIGN THIS FORM AFTER THIS DATE

 
 
 
 
Signature of subject 
 
Date and Time 
 
 
Printed name of subject 
 
 
 
Person Explaining Study and Obtaining Consent  
 
 
 
Signature of person obtaining consent 
 
Date and Time 
 
 
Printed name of person obtaining consent 
 
 
 
 
 
 
 
If the individual cannot read, a witness is required to observe the consent process and document 
below: 
My signature below documents that the information in the consent document and any other written 
information was accurately explained to, and apparently understood by, the subject, and that consent was 
freely given by the subject. 
 
 
 
Signature of witness to consent process 
 
Date and Time 
 
 
Printed name of person witnessing consent process 
 
 


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APPENDICES 
Appendix 1 
Dynamic International Prognostic Scoring System for Myelofibrosis 
(DIPSS) 
 
Risk Factors at any time of disease management – Selected for Significant Association with 
Shorter Survival 
No. 
Prognostic Factor 
Score 
1 
Age > 65 years 
1 
2 
Presence of Constitutional symptoms 
(weight loss >10% of the baseline value in the year 
preceding MF diagnosis and/or unexplained fever or 
excessive sweats persisting for more 
than 1 month) 
1 
3 
Hemoglobin (Hb) < 10g/dL 
2 
4 
WBC count > 25 x 109/L 
1 
5 
Blood blasts ≥1 
1 
 
 
 
Definition of the Risk Groups of the Prognostic Scoring System of Myelofibrosis 
Risk Group 
Score 
Median Survival 
Months (95% CI) 
Low 
0 
Not reached 
Intermediate - 1 
1-2 
9.8 yrs 
Intermediate - 2 
3-4 
4.8 yrs 
High 
≥5 
2.3 yrs 
 


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Appendix 2 
Transfusion Dependency  
RBC-transfusion dependence is defined as recently described by a panel with expertise on 
Myeloproliferative disorders (Gale et al, Leukemia Research, 2011). This is defined as an 
average RBC-transfusion-frequency of ≥2 units of RBC transfusion every 28 days (in the 
absence of active bleeding or chemotherapy) over at least the 84 days immediately prior to study 
entry. 
 


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Appendix 3 
Definition of Unfavorable Karyotype 
 
Unfavorable karyotypes in myelofibrosis associated with poor prognosis 
Unfavorable karyotype includes:  
 Complex karyotype  
 Single or two abnormalities including +8, −7/7q-, i(17q), −5/5q-, 12p-, inv(3) or 11q23 
rearrangement 
 


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Appendix 4 
IWG-MRT criteria for response assessment 
 
IWG-MRT criteria for response assessment (from Tefferi et al., 2006) 
Response Criterion Parameter 
Complete remission (CR) 
i. 
Complete resolution of disease-related symptoms and signs including palpable 
hepatosplenomegaly.  
ii. 
Peripheral blood count remission defined as hemoglobin level at least 110 g/L, 
platelet count at least 100 x 109/L, and absolute neutrophil count at least 1.0 x 109/L. 
In addition, all 3 blood counts should be no higher than the upper normal limit. 
iii. 
Normal leukocyte differential including disappearance of nucleated red blood cells, 
blasts, and immature myeloid cells in the peripheral smear, in the absence of 
splenectomy.  
iv. 
Bone marrow histologic remission defined as the presence of age-adjusted 
normocellularity, no more than 5% myeloblasts, and an osteomyelofibrosis grade no 
higher than 1. 
 
Partial remission (PR) 
Requires all of the above criteria for CR except the requirement for bone marrow histologic 
remission. However, a repeat bone marrow biopsy is required in the assessment of PR and may 
or may not show favorable changes that do not however fulfill criteria for CR. 
 
Clinical improvement (CI) 
Requires one of the following in the absence of both disease progression (as outlined below) and 
CR/PR assignment (CI response is validated only if it lasts for no fewer than 8 weeks): 
i. 
A minimum 20 g/L increase in hemoglobin level or becoming transfusion 
independent (applicable only for subjects with baseline hemoglobin level of less than 
100 g/L). 
ii. 
Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 
10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes 
not palpable. 
iii. 
A minimum 100% increase in platelet count and an absolute platelet count of at least 
50 000 x 109/L (applicable only for subjects with baseline platelet count below 50 x 
109/L). 
iv. 
A minimum 100% increase in ANC and an ANC of at least 0.5 x 109/L 
(applicableonly for subjects with baseline absolute neutrophil count below 1 x 109/L). 


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Progressive disease (PD) 
Requires one of the following: 
i. 
Progressive splenomegaly that is defined by the appearance of a previously absent 
splenomegaly that is palpable at greater than 5 cm below the left costal margin or a 
minimum 100% increase in palpable distance for baseline splenomegaly of 5-10 cm 
or a minimum 50% increase in palpable distance for baseline splenomegaly of greater 
than 10 cm. 
ii. 
Leukemic transformation confirmed by a bone marrow blast count of at least 20%. 
iii.  
 An increase in peripheral blood blast percentage of at least 20% that lasts for at least 
8 weeks. 
 
Stable disease (SD)  
None of the above. 
 
Relapse  
Loss of CR, PR, or CI. 
In other words, a subject with CR or PR is considered to have undergone relapse when he or she 
no longer fulfills the criteria for even CI. However, changes from either CR to PR or CR/PR to 
CI should be documented and reported. 


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Appendix 5 
Myeloproliferative Neoplasm symptom assessment form (MPN-SAF) and 
Brief Fatigue Inventory (BFI) 
Instructions: Please fill out all questions, as best able, reflecting how these symptoms 
affected you over the LAST WEEK unless directed otherwise. Complete forms until the 
STOP instruction toward the end of the packet.  
 
Symptom  
1 to 10  (0 if absent) ranking* 
1 is most favorable and 10 least favorable 
Please rate your fatigue (weariness, 
tiredness) by circling the one 
number that best describes your 
fatigue right NOW 
(No Fatigue)    0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Please rate your fatigue (weariness, 
tiredness) by circling the one 
number that best describes your 
USUAL level of fatigue during past 
24 hours 
(No Fatigue)    0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Please rate your fatigue (weariness, 
tiredness) by circling the one 
number that best describes your 
WORST level of fatigue during past 
24 hours 
(No Fatigue)    0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
 
Circle the one number that describes how, during the past 24 hours, fatigue has 
interfered with your 
 
General activity 
(Does not Interfere)   0  1  2  3  4  5  6  7  8  9  10   (Completely Interferes) 
Mood 
(Does not Interfere)   0  1  2  3  4  5  6  7  8  9  10   (Completely Interferes) 
Walking ability 
(Does not Interfere)   0  1  2  3  4  5  6  7  8  9  10   (Completely Interferes) 
Normal work (includes work both 
outside the home and daily chores) 
(Does not Interfere)   0  1  2  3  4  5  6  7  8  9  10   (Completely Interferes) 
Relations with other people 
(Does not Interfere)   0  1  2  3  4  5  6  7  8  9  10   (Completely Interferes) 
Enjoyment of life 
(Does not Interfere)   0  1  2  3  4  5  6  7  8  9  10   (Completely Interferes) 
 
 


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Circle the one number that describes how, during the past Week how much 
difficulty you have had with each of the following symptoms 
Filling up quickly when you eat 
(Early satiety) 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Abdominal pain  
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Abdominal discomfort 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Inactivity 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Problems with headaches  
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Problems 
with 
concentration 
Compared to prior to my MPD 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Dizziness/ Vertigo/ Lightheadedness 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Numbness/ Tingling (in my hands 
and feet) 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Difficulty sleeping 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Depression or sad mood 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Problems with sexual desire or 
Function  
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Cough 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Night sweats 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Itching (pruritus) 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Bone pain (diffuse not joint pain or 
arthritis) 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
Fever (>100° F) 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Daily) 
Unintentional weight loss last 6 
months 
(Absent)   0   1   2   3   4   5   6   7   8   9   10    (Worst Imaginable) 
What is your overall quality of life?  
(As good as it can be)   0 1 2 3 4 5 6 7 8 9 10  (As bad as it can be) 
 


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Appendix 6 
EORTC QLQ-C30 (VERSION 3) 
 


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Appendix 7 
FACT-BMT (VERSION 4) 
 


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Appendix 8 
Patient Global Impression of change (PGIC) 
 
 Since starting treatment, my overall quality of life is:  (please circle one) 
-3 
-2 
-1 
0 
1 
2 
3 
Very much 
worse 
Moderately 
worse 
A little 
worse 
About the 
same 
A little 
better 
Moderately 
better 
Very much 
better 
 
 
 Since starting treatment, my physical condition is:  (please circle one) 
-3 
-2 
-1 
0 
1 
2 
3 
Very much 
worse 
Moderately 
worse 
A little 
worse 
About the 
same 
A little 
better 
Moderately 
better 
Very much 
better 
 
 
 Since starting treatment, my emotional state is:  (please circle one) 
-3 
-2 
-1 
0 
1 
2 
3 
Very much 
worse 
Moderately 
worse 
A little 
worse 
About the 
same 
A little 
better 
Moderately 
better 
Very much 
better 
 


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Version #5, 12/21/2015 
Page 131 of 134 
 
Appendix 9 
Regimen Related Toxicity: Bearman Toxicity Criteria 
 
Grade I 
Grade II 
Grade III 
Cardiac toxicity 
*Dysrhythmias 
- 
recurrent 
or 
persistent, no therapy required.  
*EF/CHF - asymptomatic decline of 
resting ejection fraction by more 
than 20% of baseline value 
*Ischemia - asymptomatic ST and T 
wave changes suggesting ischemia 
*Pericardial - pericarditis (rub, chest 
pain, ECG changes) 
*Dysrhythmias - requires monitoring 
or treatment 
*EF/CHF - mild CHF, responsive to 
therapy 
*Ischemia - angina without evidence 
for infarction 
*Pericardial - symptomatic effusion, 
drainage required 
*Dysrhythmias 
with 
hypotension 
or 
ventricular tachycardia or fibrillation 
*EF/CHF - severe or refractory CHF 
*Ischemia - acute myocardial infarction 
*Pericardial 
- 
tamponade; 
drainage 
urgently required.  
Pulmonary toxicity 
*Dyspnea 
-no CXR changes 
-no infection 
-no congestive heart failure 
*CXR showing isolated infiltrate or 
mild interstitial changes 
-no infection 
-no congestive heart failure 
-asymptomatic 
*CXR 
with 
extensive 
localized 
infiltrate 
or 
moderate 
interstitial 
change combined with dyspnea and 
not caused by infection or CHF. 
*Decrease 
of 
PO2 
(>10% 
from 
baseline) 
but 
not 
requiring 
mechanical ventilation or >50% O2 
on mask and not caused by infection 
or CHF. 
*Interstitial changes requiring mechanical 
ventilatory support or >50% oxygen on 
mask and not caused by infection or CHF. 
 
Stomatitis toxicity 
*Pain and/or ulceration not requiring 
a continuous IV narcotic drug. 
 
*Pain and/or ulceration requiring a 
continuous 
IV 
narcotic 
drug 
(morphine drip). 
 
*Severe 
ulceration 
and/or 
mucositis 
requiring preventive intubation. 
*severe ulceration resulting in documented 
aspiration pneumonia with or without 
intubation.  
GI toxicity 
*Watery stools >500ml but <2000ml 
every day not related to infection. 
*Watery stools >2000ml every day 
not related to infection. 
*Macroscopic 
hemorrhagic 
stools 
with no effect on cardiovascular 
status not caused by infection 
*subileus not related to infection.  
*Ileus requiring nasogastric suction and/or 
surgery and not related to infection. 
*Hemorrhagic 
enterocolitis 
affecting 
cardiovascular 
status 
and 
requiring 
transfusion.  


Private and Confidential 
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Ruxolitinib  + RIC 
Version #5, 12/21/2015 
Page 132 of 134 
 
 
Grade I 
Grade II 
Grade III 
Hepatic toxicity 
*Mild 
hepatic 
dysfunction 
with 
bilirubin >34.2 micromoles/litre and 
bilirubin <102.6 micromoles/litre 
*Weight gain >2.5% and < 5% from 
baseline, of noncardiac origin.  
*SGOT increase more than 2-fold 
but less than 5-fold from lowest 
preconditioning. 
*Moderate hepatic dysfunction with 
bilirubin >102.6 micromoles/litre and 
<342 micromoles/litre. 
*SGOT 
increase 
>5 
-fold 
from 
preconditioning/ 
*Clinical 
ascites 
or 
image 
documented ascites >100ml. 
*Weight gain >5% from baseline of 
noncardiac origin. 
*Severe hepatic dysfunction with bilirubin 
>342 micromoles/litre. 
*Hepatic encephalopathy. 
*Ascites 
compromising 
respiratory 
function.  
CNS toxicity 
*Somnolence, 
patient 
is 
easily 
arousable 
and 
oriented 
after 
arousal.  
*Somnolence with confusion after 
arousal 
*Other new objective CNS symptoms 
with no loss of consciousness not 
more easily explained by other 
medication, 
bleeding, 
or 
CNS 
infection.  
*Seizures 
or 
coma 
not 
explained 
(documented) by other medication, CNS 
infection, or bleeding.  
Bladder toxicity 
*Macroscopic hematuria after 2 
days from last chemotherapy dose. 
-no subjective symptoms of cystitis 
-no infection 
*Macroscopic hematuria after 7 days 
from last chemotherapy dose 
-no infection 
*Hematuria 
after 
2 
days 
with 
subjective symptoms of cystitis 
-no infection. 
*Hemorrhagic cystitis with frank blood 
necessitating invasive local intervention 
with instillation of sclerosing agents, 
nephrostomy or other surgical procedure.  
Renal 
*Increase in creatinine up to twice 
the baseline value (usually the last 
recorded 
before 
start 
of 
conditioning). 
*Increase in creatinine above twice 
baseline 
-no dialysis. 
*Requirements of dialysis.  
 


Private and Confidential 
MPD-RC Protocol 114 
Ruxolitinib + RIC 
Version #5, 12/21/2015 
Page 133 of 134 
Appendix 10 
Assesment of Acute and Chronic GvHD 
The staging and grading of acute GvHD should be done according to consensus criteria as 
defined by Przepiorka et al, BMT, 1994.  
Extent of organ involvement 
Skin 
Liver 
Gut 
Stage 
1 
Rash on <25% of skin 
Total bilirubin 2-3 mg/dl or 
35-50 μmol/L 
Diarrhea >500 ml/day 
or persistent nausea 
2 
Rash 25-50% of skin 
Total bilirubin 3-6 mg/dl or 
51-102 μmol/L 
Diarrhea >1000 ml/day  
3 
Rash >50% of skin 
Total bilirubin 6-15 mg/dl 
or 103-225 μmol/L 
Diarrhea >1500 ml/day  
4 
Generalized erythroderma 
with bullous formation 
Total bilirubin >15 mg/dl 
or >225 μmol/L 
Severe abdominal pain 
with or without ileus 
Grading 
I 
Stage 1-2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
- 
Stage 2-3 or 
Stage 2-4 
IV 
Stage 4 
Stage 4 
- 
Grading of chronic GVHD 
Chronic GVHD should be graded as mild, moderate or severe according to NIH consensus 
criteria (Filipovich et al, 2005, BBMT). The scoring for each organ involved is done as  
Score 0 
=  
no involvement 
Score 1 
=  
Mild involvement (no significant impairment of daily living) 
Score 2 
=  
moderate involvement (significant impairment of daily living) 
Score 3 
= 
severe impairment (major disability) 
Global scoring of severity of chronic GvHD is done as follows:  
Global scoring of severity of chronic GvHD 
Number of organs 
Mild cGvHD 
Moderate cGvHD 
Severe cGvHD 
1 
Score 1 
Score 2 
Score 3 
2 
Score 1 
Score 2 
Score 3 
3 
 
Score 1 
Score 3 
Lung involvement 
 
Score 1 
Score 2 
 
Mild cGVHD = 1 or 2 organs involved (except for lung) with maximum score of 1 
Moderate cGvHD= lung score of 1 or 3 organs with score of 1 or at least 1 organ with score of 2 
Severe cGvHD= lung score of 2 or score of 3 in any organ 


Private and Confidential 
MPD-RC Protocol 114 
Ruxolitinib + RIC 
Version #5, 12/21/2015 
Page 134 of 134 
Appendix 11 
Request for Release of Nonconforming HCT/Ps 
 
I certify that patient_____________________________________________________ 
 
MRN#________________________________________________________________ 
 
Has a medical emergency________________________________________________ that requires that he/she 
receives nonconforming HCT/Ps  
 
Products to be released for infusion: 
Product UPN 
 
 
 
Nature of Nonconformance  
 
 
1. 
____________ 
 
 
____________________________________ 
 
2. 
____________ 
 
 
____________________________________ 
 
3. 
____________ 
 
 
____________________________________ 
 
4. 
____________ 
 
 
____________________________________ 
 
 
Comments:______________________________________________________________ 
 
Signature:    ________________________ Date: ________________