JAK Inhibitor Prior to Allogeneic Stem Cell Transplant for Patients With Primary and Secondary Myelofibrosis: A Prospective Study
Phase: PHASE2
Conditions: Primary Myelofibrosis, Secondary Myelofibrosis
Sponsor: Fred Hutchinson Cancer Center

 
 
Official Title: 
JAK Inhibitor Prior to Allogeneic Stem Cell Transplant for 
Patients with Primary and Secondary Myelofibrosis: A 
Prospective Study 
NCT Number: 
NCT02251821 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
12/08/2022 
 
 

9033 
1 
FRED HUTCHINSON CANCER CENTER 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
Current version:  10/26/2022 
Previous version:  12/20/2021 
Title of Protocol: 
JAK Inhibitor Prior to Allogeneic Stem Cell Transplant for Patients with Primary and Secondary 
Myelofibrosis: A Prospective Study  
Investigators List: 
Rachel Salit, MD 
Principal Investigator 
Associate Professor, FHCC  
Assistant Professor, Dept of Medicine, UW 
206-667-1317
Bart Scott, MD 
Professor, FHCC 
Associate Professor, Dept of Medicine, UW 
206-667-1990
H. Joachim Deeg, MD
Professor, FHCC  
Professor of Medicine, Dept of Medicine, UW 
206-667-5985
Biostatistician: 
Ted Gooley, PhD  
Professor, FHCC 
206-667-6533
Research Staff: 
Megan Boullin 
Clinical Research Coordinator
206-667-7684
IRO REC'D 11/07/2022
FHCRC IRB Approval  
12/08/2022 
Document Released Date

9033 
2 
 
 
 
TABLE OF CONTENTS 
 
1.0 
INTRODUCTION 
 
2.0 
BACKGROUND 
2.1 
Prognostic factors in Myelofibrosis 
2.2 
Rationale for use of JAK inhibitors  
2.3 
Clinical Data to Date 
2.4 
Role of Surgical Splenectomy 
2.5 
Rationale for Pretransplant JAK Inhibitors Followed by Allogeneic Transplant in 
Myelofibrosis 
 
3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
 
4.0 
STUDY DESIGN 
4.1 
Description of Study 
4.2 
Endpoints 
 
5.0 
PATIENT SELECTION 
5.1 
Inclusion Criteria for Part 1: JAK inhibitor Administration 
5.2 
Exclusion Criteria for Part 1: JAK inhibitor Administration 
5.3  
Inclusion Criteria for Part 2: Allogeneic Stem Cell Transplant 
5.4  
Exclusion Criteria for Part 2: Allogeneic Stem Cell Transplant 
5.5 
Controls 
 
6.0 
Donor Selection  
 
7.0 
INFORMED CONSENT OF SUBJECT AND DONOR 
 
8.0 
SUBJECT REGISTRATION 
 
9.0 
PLAN OF TREATMENT 
 
10.0 
EVALUATION 
10.1 
Pre JAK Inhibitor Evaluation 
10.2 
Pre-transplant Evaluation 
10.3 
Patient Evaluations from Day 0 through day 28 
10.4 
Patient Evaluations from day 29 through Day 100, 6 Months, 1 Year and 2-5 Years 
10.5 
Residual/Recurrent Disease Evaluation 
 
10.6 
Study Evaluation Windows 
 
11.0 
DRUGS, IRRADIATION AND EXPANDED CORD BLOOD CELL ADMINISTRATION 
TOXICITIES AND COMPLICATIONS 
11.1 
Jak inhibitiors including Ruxolitinib, Momelotinib and Pacritinib. 
11.2  Busulfan 
11.3 
Cyclophosphamide 

9033 
3 
 
11.4 
Fludarabine 
11.5 
Methotrexate 
11.6 
Tacrolimus 
11.7 
MMF 
11.8  Melphalan 
11.9  GCSF 
11.10 TBI 
 
12.0 
GUIDELINES FOR ADVERSE EVENT REPORTING 
12.1 
Adverse Event Reporting/ Institutional Policy 
12.2 
Study-Specific Adverse Event Capture 
 
13.0 
DATA AND SAFETY MONITORING PLAN 
 
14.0 
DATA MANAGEMENT/CONFIDENTIALITY 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
16.0 
TERMINATION OF THE STUDY 
 
REFERENCES 
 
APPENDICES 
 
Appendix A: Disease Criteria and Staging  
Appendix B: Performance status criteria and Comorbidity Index 
Appendix C: GVHD Assessment 
Appendix D: Potential Adverse Events Associated or Expected with Hematopoietic Cell 
Transplantation 
Appendix E: FHCC IRB Policies and Cancer Consortium DSMP  
Appendix F: Schedule of Study Evaluations  
 
 
 
 
 

9033 
4 
 
1.0 
 INTRODUCTION 
  
Myelofibrosis (MF) can present as a de novo disorder (PMF) or evolve from polycythemia vera (PV) or essential 
thrombocythemia (ET). Regardless of the etiology, MF is characterized as a clonal stem cell disorder associated 
with elevated levels of pro-inflammatory and pro-angiogenic cytokines such as TNF alpha, IL-6 and IFN gamma 
resulting in a bone marrow stromal reaction that includes varying degrees of reticulin and collagen fibrosis and 
osteosclerosis. Clinically, MF is characterized by progressive anemia, leukopenia or leukocytosis, 
thrombocytopenia or thrombocythemia and multi-organ extramedullary hematopoiesis that frequently involves 
the spleen resulting in massive splenomegaly, severe constitutional symptoms, a hypermetabolic state and 
cachexia. The median age at diagnosis is 60 to 65 years. The clinical course is heterogeneous ranging from 
indolent disease in some patients who may survive for years or decades to aggressive disease in other cases with 
survival measured in months. The most common causes of death are progressive marrow failure leading to 
infection or hemorrhage, transformation to acute myelogenous leukemia and complications of portal 
hypertension.  
 
While in the past drug therapies including hydroxyurea, busulfan, 6-mercaptopurine, anagrelide, thalidomide, 
lenalidomide, interferon, corticosteroids, androgens, and erythropoiesis stimulating agents or other growth factors 
were used as the first line treatment of MF, none of these have been shown to improve survival. Ruxolitinib, a 
selective JAK-1/2 inhibitor, was recently FDA approved for treatment of primary and secondary MF. Impressive 
symptom control in MF patients on ruxolitinib treatment is predominantly mediated by profound suppression of 
inflammation, mirrored by a significant reduction in pro-inflammatory and pro-angiogenic cytokines. 1 Reduction 
of these cytokines is typically accompanied by a significant reduction in spleen size. To date, the only potentially 
curative therapy for MF is allogeneic hematopoietic stem cell transplantation (HCT). Whether JAK-2 inhibitor 
therapy prior to HCT by improving patient performance status and the degree of splenomegaly, can lead to more 
favorable post-transplant outcomes is an important area of investigation. However, no prospective studies have 
been performed to date. Herein, we aim to prospectively assess the effects of pre-transplant JAK-2 inhibitor 
therapy as an adjunct to HCT with the goal of improving post-transplant outcomes in patients with myelofibrosis. 
 
2.0  
BACKGROUND 
  
2.1 
Prognostic factors in myelofibrosis 
 
Prognosis of MF varies with the presence or absence of specific risk factors. In 2009, Cervantes et al published a 
multi-center analysis of risk factors and their impact on prognosis in patients with myelofibrosis.2  Age of greater 
than 65 years, presence of constitutional symptoms including weight loss, fever, or night sweats, anemia 
(hemoglobin < 10 g/dL), leukocytosis (white blood cells (WBC) > 25 x 109/L), and a circulating blast percentage 
≥ 1% were identified as most predictive of outcome. Patients with no risk factors (low-risk group) had a median 
survival of 135 months, patients with one risk factor (intermediate-1 risk) had a median survival of 95 months, 
patients with two risk factors (intermediate-2 risk) had a median survival of 48 months, and patients with 3 or 
more risk factors (high-risk) had a median survival of 27 months. 2 
 
This risk stratification is referred to as the international prognostic scoring system (IPSS). The Dynamic IPSS 
(DIPSS) uses the same 5 variables but can be used at any time in the disease course; Hb < 10 receives a score of 2 
points. The risk groups are scored as follows:  Low risk = (score) 0, Intermediate 1 = 1 or 2, Intermediate 2 = 3 or 
4, High risk = 5 or 6. The DIPSS plus scoring system includes, in addition, transfusion dependence, unfavorable 
and complex karyotype and platelet count.  
 
Current recommendations suggest that the potential risk of transplant related complications is justified in 
transplant-eligible patients with < 5 years expected survival if not transplanted.  Based on DIPSS data this would 
include patients in the intermediate 2 and high risk groups. Those are, indeed, the patients included in most 
clinical transplant trials; however, lower risk patients actually have better outcome following HCT, raising 
questions as to the selection of patients for HCT.  Published data from our center showed that the 6 year post-
HCT survival for Low, Intermediate 1, Intermediate 2 and High risk patients was 80%, 67%, 54% and 38%, 
respectively, validating the DIPSS as an accurate prognosticator for post-HCT outcome in MF.3  
  

9033 
5 
 
2.2 
Rationale for use of JAK inhibitors  
 
Myelofibrosis is a clonal hematopoietic stem cell disease characterized by molecular (JAK2V617F, 
MPLW515L/K) and cytogenetic (13q-, 20q-) markers. 4,5 The JAK2V617F mutation has been identified in over 
95% of patients with PV and approximately 50% of patients with ET and PMF. In clinical trials, treatment of MF 
patients with the JAK inhibitor ruxolitinib resulted in prompt resolution of constitutional symptoms concurrent 
with reduction in the plasma inflammatory cytokine profile. 6-8 In a phase 3 randomized trial of ruxolitinib, 42% 
of treated patients experienced a reduction in spleen size/volume of at least 35% compared with 0.7% in those 
receiving placebo. 8 This was true in both JAK-2 mutated and non-mutated patients.  Ruxolitinib also improved 
constitutional symptoms coincident with normalization of cytokine profiles.  
 
In a phase 1-2 study of ruxolitinib therapy at MD Anderson, OS was significantly superior in ruxolitinib treated 
patients as compared with the historical cohort in an analysis adjusted for IPSS. 7 Spleen volume reduction alone 
was associated with survival advantage in ruxolitinib treated patients; 63% of patients achieved >50% reduction 
in spleen volume with a median duration of approximately 2 years. Patients with >50% reduction in splenomegaly 
had superior survival when compared with patients with < 25% spleen size reduction (p < 0.0001). Furthermore, 
the finding of superimposable survival curves for high-risk and intermediate-2 risk patients treated with 
ruxolitinib suggests that ruxolitinib therapy may downgrade an individual’s prognostic score category and 
improve predicted survival. In fact, in the Comfort 1 trial, patients randomized to ruxolitinib versus placebo had a 
better median OS. 8  In the Comfort 2 study, 61% of patients on the best supportive care arm eventually received 
ruxolitinib. 6 Still, a modest survival advantage was seen among patients originally randomized to ruxolitinib. The 
reduction of an inflammatory state with improvement of performance status and cachexia may in itself represent a 
form of disease modification contributing to improved survival.6 
 
2.3  
Clinical to Date 
 
Myeloablative Conditioning Regimens 
 
While a broad range of conditioning regimens of different intensities has been developed, initial studies of 
allogeneic HCT for MF used high intensity regimens, which by most investigators would now be considered 
“myeloablative” (MAC). At that juncture, concern for graft failure/rejection due to fibrotic marrow was a concern, 
but subsequent experience showed that this was largely unfounded. In the largest retrospective analysis to date of 
289 patients reported to the CIBMTR, 229 of whom underwent MAC, day 100 treatment related mortality (TRM) 
was 22%-42% (dependent on performance status, URD donor, and peripheral blasts) and overall survival (OS) 
was 30%-40% at 5 years.9 Graft failure was more frequent in patients receiving cells from unrelated donors 
(URD). Among patients with favorable risk factors including a Karnofsky Performance Score (KPS) > 90%, no 
circulating blasts, and matched sibling donors, 1- and 3-year OS probabilities were 69% and 60%, respectively.  
For MAC regimens, graft failure rates of <5% 5 to 30% 10 have been reported reflecting the heterogeneity in 
patient population and specific conditioning regimens. Published TRM rates of 20% at 1 year to 34% at 5 years 
and OS from 39% at 3 years to 50% at 5 years have been reported (Table 1). 5,11-13 Data from our institution 
showed a 7 year survival of 61% in patients conditioned with targeted IV Busulfan and Cytoxan, which was 
significantly higher than among those not receiving this regimen 14. A more recent study demonstrated that 
administering Cytoxan 120mg/kg over 2 days followed by targeted Busulfan for 4 days conferred significantly 
less liver toxicity than Busulfan followed by Cytoxan in patients with MF. 15 This translated into decreased early 
TRM.  Based on the above data we have chosen to use the Cytoxan/targeted Busulfan combination as 
conditioning in patients with HLA-matched sibling and HLA-matched unrelated donors in the current study. 
 
Reduced Intensity Conditioning Regimens 
 
TRM has generally been high in older patients and those with comorbidities. To improve outcomes in those 
patient groups, several small studies of older patients transplanted after RIC have reported encouraging results 
with decreased TRM.  Kroger et al 2005 treated 21 patients with MF with fludarabine 180mg/m2 and busulfan 
10mg/kg and ATG followed by related donor or URD HCT and observed no graft failures and no 100-day 
TRM.16 One year TRM was 16%. At 3 years, the relapse free survival (RFS) was 84%; 78% of patients with JAK-

9033 
6 
 
2 mutations became  PCR negative. A follow-up report included 103 patients treated with 
fludarabine/busulfan/ATG, with a median age of 55 yrs; 33 had matched sibling donors, and among the 60 URD 
transplants, 30% were mismatched. 17 Relapse incidence was 22% at 3 yrs and 29% at 5 yrs. NRM was 16%.  
NRM was higher with HLA mismatched donors. 5-yr RFS was 51% and OS was 67%. RFS was inferior with 
HLA-mismatched transplants and advanced Lille score, and OS was lower with patient age > 55 years and HLA 
mismatched transplant. Rondelli et al reported on 21 patients most of whom were conditioned with fludarabine 
and melphalan or TBI or thiotepa-based RIC. 18 RFS was 74% and OS was 85% at 3 years. The CIBMTR series 
included 60 patients who underwent RIC. Among these, graft failure occurred in 7 patients, none of whom 
survived. TRM rate at 1 year was 15% for HLA matched sibling transplants, but 49% in those transplanted from 
URD. RFS at 3 years was 39% for matched sibling HCT but 17% with URD.  
 
On this background we have chosen to use fludarabine and melphalan for patients receiving matched sibling or 
URD grafts and require a RIC regimen.  
 
Selected  transplant  studies in patients with myelofibrosis (modified from Alchalby 2010)19 
Study 
Patients, n 
Conditioning 
regimen 
Median 
age, y 
Transplant-
related 
mortality 
Overall 
survival 
Myeloablative conditioning 
Ballen et al. 
2005 
170 sibling 
Various 
45 
22% at day 100 
39% at 5 y 
117 MUD 
47 
42% at day 100 
31% at 5 y 
33 
alternative 
40 
27% at day 100 
31% at 5 y 
Guardiola et 
al. 1999 
55 
TBI-based 
(n=35), 
various 
(n=20) 
42 
27% at 1 y 
47% at 5 y 
Deeg et al. 
2003 
56 
Busulfan-
based (n=44), 
TBI-based 
(n=12) 
43 
20% at 1 y 
58% at 3 y 
Kerbauy et 
al. 2007 
104 
TBI-based 
(n = 15), 
busulfan-
based (n=80), 
reduced-
intensity 
(n=9) 
49 
34% at 5 y 
61% at 7 y 
Reduced-intensity conditioning 
Hessling et 
al. 2002 
3 
Busulfan/flud
arabine 
51 
0% at 1 y 
100% at 1 y 
Devine et 
al. 2002 
4 
Melphalan/flu
darabine 
56 
0% at 1 y 
100% at 1 y 

9033 
7 
 
Study 
Patients, n 
Conditioning 
regimen 
Median 
age, y 
Transplant-
related 
mortality 
Overall 
survival 
Hertenstein 
et al. 2002 
20 
TBI or 
fludarabine 
50 
37% at 1 y 
54% at 1 y 
Rondelli et 
al. 2005 
21 
Various 
54 
10% at 1 y 
85% at 2.5 y 
Kröger et 
al. 2005 
21 
Busulfan/flud
arabine 
53 
16% at 1 y 
84% at 3 y 
Bacigalupo 
et al. 2007 
39 
Thiotepa-
based 
51 
 
50% at 5 y 
Bacigalupo 
et al. 2009 
46 
Thiotepa-
based 
51 
24% at 5 y 
45% at 5 y 
George et 
al. 2008 
6 
Busulfan/flud
arabine 
51 
0% at 16 mo 
100% at 
16 mo 
Kröger et 
al. 2009 
103 
Busulfan/flud
arabine 
55 
16% at 1 y 
67% at 5 y 
AHSCT allogeneic hematopoietic stem cell transplantation, mo months, MUD matched unrelated donor, NS not 
significant, pt patients, TBI total-body irradiation, y year(s) 
 
 
Umbilical Cord Blood Transplantation 
 
The incidence of delayed engraftment/graft failure associated with UCB transplants (UCBT) is of concern in this 
patient population due to the presence of a marrow fibrosis-induced “hostile” microenvironment. The Japanese 
UCBT program recently reported a case series of 14 patients who underwent RIC UCBT.20 Neutrophil 
engraftment occurred in more than 92% of patients (median 23 days,) and platelet engraftment in 43% of patients 
(median 56 days). Complete donor chimerism was achieved in all evaluable patients. Estimated 4-yr survival was 
28.6%.  The most prevalent regimen used in these patients consisted of fludarabine 125mg/m2, melphalan 
80mg/m2 and TBI 4Gy.  Based on these limited data, we are adopting this regimen for patients receiving UCB as 
their source of stem cells on this protocol.  
 
A second Japanese study focused on second transplants with UCB. Seven patients with various hematologic 
malignancies were treated with busulfan 16mg/kg, fludarabine 100mg/m2 and cyclophosphamide 120mg/kg. All 
but one patient achieved myeloid reconstitution, and four patients were alive at 4-40 months. Busulfan and 
Cytoxan alone as a cord blood conditioning regimen has not demonstrated high rates of successful engraftment. 21 
However, the addition of fludarabine to the busulfan/Cytoxan regimen was effective in securing successful 
engraftment of UCB.  Based on those data and the encouraging results with Cytoxan followed by busulfan 
presented by Rezvani et al15 we will use fludarabine + Cytoxan/busulfan as MAC for the respective patients 
receiving UCB transplants.  
 
2.4 
Role of Surgical Splenectomy 
 
Splenectomy was performed in approximately 10% of the patient cohort reported by Cervantes et al. 2 Data from 
Mayo Clinic on 314 MF patients undergoing splenectomy showed significant perioperative complications in 28% 
of patients and a mortality of 6.7%. 22 The report by Ballen et al 2010 did not suggest an effect of prior 
splenectomy on graft failure or disease free survival. 9 Ciurea 2008 noted that successful engraftment could still 

9033 
8 
 
occur despite even massive splenomegaly. 23 Finally, Michallet et al 2009 showed greater severity of GVHD in 
splenectomized patients. 24However, there are also proponents for pre-HCT splenectomy in myelofibrosis 
patients. Li et al 2001 showed that splenectomized patients had faster neutrophil recovery and decreased 
transfusion requirements.25 Robin et al 2011 in multivariate analysis of patients receiving peripheral blood stem 
cells, showed faster engraftment in patients who had had absence of splenomegaly or who had undergone 
splenectomy pre-transplant. 26 Kroger et al demonstrated a trend toward more rapid neutrophil engraftment in 
splenectomized vs non splenectomized RIC HCT patients.17 However, a higher rate of relapse at 3 years was seen 
in those who had undergone splenectomy. On the other hand, the retrospective analysis by Scott et al in 170 
patients transplanted at the FHCC, suggests that splenectomized patients have a superior post-HCT survival.  
Bacigalupo et al (2010), suggested that spleen size > 22 cm was an independent risk factor for survival. 
 
In the present study we propose, therefore, that patients whose spleen size does not decrease to 22 cm or less (as 
determined by the clinical provider) despite JAK inhibitor therapy, or are undergoing a UCBT, will be evaluated 
for surgical splenectomy.   
 
2.5 
Rationale for Pretransplant JAK Inhibitors Followed by Allogeneic Transplant in Myelofibrosis 
 
Presently ruxolitinib (Rux) is the only FDA approved therapy for MF, and the only non-HCT therapy to date 
associated with a survival benefit. Using Rux to reduce spleen size and improve performance status pre-HCT may 
be useful in improving engraftment, but no structured studies have to been performed to date. Rux also is known 
to decrease proinflammatory cytokines including IL-6 and has been shown to have benefit in treating acute 
GVHD. Whether Rux treatment prior to HCT can improve post-transplant outcomes is an important area of 
investigation.  
 
Diagrammatic representation of the postulated impact of JAK inhibitors on the myelofibrosis AHSCT pathway. 
(McLornan et al 2012) 
 
 

9033 
9 
 
 
3.0 
STUDY OBJECTIVES 
 
3.1 
Primary Objective  
 
The primary objective of this study is to optimize the role of allogeneic transplantation for primary and secondary MF 
in the JAK inhibitor era. 
 
4.0  STUDY DESIGN 
 
4.1 
Description of Study 
 
This Phase II trial is a single center study of JAK inhibitor therapy followed by myeloablative or reduced intensity 
HLA-matched related, unrelated or umbilical cord blood transplant for patients with primary and secondary 
myelofibrosis.  
 
Primary Endpoint 
 
Probability of 2-year survival in  63  patients with MF who receive treatment with a JAK inhibitor followed by an 
allogeneic transplant. 
 
4.2 
Secondary Endpoints 
A. To determine the overall incidence of primary and secondary graft failure/rejection 
B. Day 100 and 1 year NRM 
C. Incidence of relapse at 1 year 
D. Incidence and severity of acute and chronic GVHD. 
 
5.0 
  PATIENT SELECTION 
 
5.1       Inclusion Criteria for Part 1: JAK Inhibitor Administration 
A. Age > 18 years 
B. Disease Criteria 
1. Diagnosis of PMF as defined by the 2008 World Health Organization classification system or 
diagnosis of secondary MF as defined by the IWG for Myeloproliferative Neoplasms Research and 
Treatment criteria (Appendix A) 
2.  Patients meeting the criteria for intermediate-1, intermediate-2 or high-risk disease by the DIPSS 
or DIPSS-plus scoring system (Appendix A) 
C.  Ability to understand and the willingness to sign a written informed consent document 
D. Patient must be a potential hematopoietic stem cell transplant candidate 
 
5.2   
Exclusion Criteria for Part 1: JAK inhibitor administration 
A. Evidence of HIV infection or known HIV positive serology. 
B. Uncontrolled viral, bacterial, or fungal infections at the time of study enrollment. 
C. History of Prior Allogeneic Transplant 
D. Pregnant or breastfeeding (Only if patients have not been started on Rux by their primary oncologist 
prior to enrollment). 
 
5.3       Inclusion Criteria for Part 2: Allogeneic Stem Cell Transplant  
A. Meeting criteria for 1st phase as above, at time of initiation of JAK inhibitor,  including ability to 
understand and willingness to sign a written informed consent.  Patients arriving to our instition for 
transplant and not enrolled in Part 1 may still be enrolled in Part 2 if Part 1 criteria met.  These 
patients will have Part 1 endpoints transcribed from medical records 
B. Received Ruxolitinib for at least 8 weeks immediately prior to conditioning and be able to continue 
until Day -4 pre-transplant per Section 9.2. 

9033 
10 
 
C. Performance status score (Appendix B) 
Karnofsky ≥ 70  
D. Renal Function    
Calculated creatinine clearance using the Cockcroft-Gault formula or 24 hr urine creatinine 
clearance must be > 60 ml/min. .   
E. Hepatic Function 
Total serum bilirubin must be <3mg/dL unless the elevation is thought to be due to Gilbert’s 
disease or hemolysis.   
Transaminases must be < 3x the upper limit of normal 
Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of 
liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension. 
Patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging 
fibrosis, alcoholic hepatitis, hepatic encephalopathy, or correctable hepatic synthetic dysfunction 
evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, 
bacterial or fungal abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 
3mg/dL, and symptomatic biliary disease will be excluded. 
F. Pulmonary function 
DLCO corrected >60% normal. 
May not be on supplemental oxygen.  
G. Cardiac function 
Left ventricular ejection fraction >40% OR 
Shortening fraction > 26% 
H. Comorbidity Index < 5 at the time of pre-transplant evaluation (Appendix B) 
 
 
5.4   
Exclusion Criteria for Part 2: Allogeneic Stem Cell Transplant 
A. Uncontrolled viral or bacterial infection at the time of study enrollment 
B. Active or recent (prior 6 month) invasive fungal infection without ID consult and approval 
C. History of HIV infection 
D. Pregnant or breastfeeding 
E. Patients without an HLA-identical or 1-allele-mismatched related donor or unrelated donor or 
umbilical cord blood units that meet transplant criteria. 
5.5 Controls 
A. 15 de-identified samples will be requested from bioreporsitory protocol FH 1713 as controls for this 
protocol. The samples will be from patients who did not receive Ruxolitinib prior to transplant and 
will be used as control samples for the GVHD biomarker analysis. 
B. 20 de-identified samples will be requested from protocol IR7801 - FHCC Infectious Disease 
Sciences/Virology Specimen and Data Repository, to also be used as controls. The samples will be 
from patients who did not receive Ruxolitinib prior to transplant and will be used as control samples 
for the GVHD biomarker analysis. 
6.0  Donor Selection  
 
Allowable donors include the following: 
 
A.  HLA-matched or 1 antigen mismatched sibling donor  
B. 10 of 10 HLA-matched or 1 allele mismatched (9 of 10) unrelated donor 
C. Peripheral blood is preferred over bone marrow for non-umbilical cord blood recipients.  
D. Umbilical cord blood units will be selected according to the following umbilical cord blood graft 
selection criteria. One or 2 CB units may be used to achieve the required cell dose.  

9033 
11 
 
1. The CB graft(s) must be matched at 4-6 HLA-A, B, DRB1 loci with the recipient and therefore may 
include 0-2 mismatches at the A or B or DRB1 loci. Unit selection will be based on cryopreserved 
nucleated cell dose and intermediate resolution A, B antigen and DRB1 allele typing for determination 
of HLA-match. While HLA-C antigen/allele level typing is not considered in the matching criteria, if 
available, it may be used to optimize unit selection. 
2. Selection of two CB units is allowed to provide sufficient cell dose (see below for algorithm to 
determine single versus double unit transplant). When multiple units are selected, the following rules 
apply: 
a. The CB unit with the least HLA disparity (with the patient) will be selected first (i.e., selection 
priority is 6/6 match >5/6 match>4/6 match). Additional CB units then may be selected to 
achieve the required cell dose, as outlined below. If a second unit is required, this unit will be the 
unit that most closely HLA matches the patient and meets minimum size criteria outlined below 
of at least 1.5 x 107 TNC/kg (i.e. a smaller, more closely matched unit will be selected over a 
larger, less well matched unit as long as minimum criteria are met). 
b. If two CB units are used: 
i. The total cell dose of the combined units must be at least 3.0 x 107 TNC per kilogram 
recipient weight. 
ii. Each CB unit MUST contain at least 1.5 x 107 TNC per kilogram recipient weight.  
c. Algorithm for determining single versus double unit cord blood transplant: 
 
Single Unit  
Allowed for: 
Match Grade TNC Dose 
6/6 
≥ 2.5 x 107/kg 
5/6, 4/6 
≥ 4.0 (± 0.5) x 107/kg 
 
3. General Comments: 
a. Units will be selected first based on the TNC dose and HLA matching.  
b. CD34+ cell dose will not be used for unit selection unless 2 units of equal HLA-match grade are 
available.  In this case, the unit with the larger CD34+ cell dose (if data available) should be selected. 
c. A CB unit that is 5/6 mismatched but homozygous at the locus of mismatch should be chosen over a 
5/6 unit with bidirectional mismatch even if the latter unit is larger (has more cells).  This also applies 
to 4/6 units.  This is only applicable to choosing units within a given match grade. 
d. Other factors to be considered:  
i. 
Within the same HLA match grade, matching at DR takes preference. 
ii. 
Cord blood banks located in the United States are preferred. 
e. Up to 5% of the cord blood product (s), when ready for infusion, may be withheld for research           
purposes as long as thresholds for infused TNC dose are met.  These products will be used to conduct 
studies involving the kinetics of engraftment and immunobiology of double cord transplantation. 
 
 
7.0  INFORMED CONSENT OF SUBJECT AND DONOR 
 
Patients  referred to the FHCC for consideration of a transplant may be consented for Part 1 of the study, JAK 
inhibitor administration, using forms approved by the Institutional Review Board.  
 
Part 2 of the study is the transplant.  The patient and related donor will be completely evaluated following the 
Center’s Standard Practice Guidelines. The PI, or his designee, will corroborate that eligibility criteria are met. 
Patients may be enrolled directly in Part 2 if they meet eligibility criteria for Part 1 and Part 2.  In this case, Part 1 
data will be extracted from the patient’s medical record. 
 
The patient and related donor will meet separately with an attending physician from the SCCA Transplant Team 
to discuss Part 2 of the study protocol, alternative treatment options and all known risks from participating in the 
study. Unrelated donors will meet with the evaluating physician at their respective institutions to discuss the 

9033 
12 
 
details of the collection procedure and give their informed consent, using forms specific for their institution. Cord 
blood donor units will be completely evaluated.  
 
Patients who have not started Jakafi within 6 months of signing Part 1 consent will be required to be reevaluted 
for Part 1 eligibility. If they do not meet Part 1 eligiblity, they will be taken off study.  
 
The protocol will be discussed thoroughly with the patient and family, including requirement for data collection 
and release of medical records and all known risks to the patient will be described. The procedure and alternative 
forms of therapy will be presented as objectively as possible and the risks and hazards of the procedure explained 
to the subject. Consent will be obtained using forms approved by the Institutional Review Board. A summary of 
the conference will be dictated for the medical record detailing what was covered. 
 
Subjects meeting the criteria set forth in the protocol will be offered the opportunity to participate in the study in a 
meeting in person or over the telephone.  
 
Patients who enroll on Part 1 of this protocol and meet eligibility criteria for Part 2, may continue on Part 2 of FH 
Protocol 9033, or enroll on Part 2 of either FH Protocol 10093 (continuing JAK inhibitor therapy through the 
transplant) or 10441 (using a haploidentical donor) if this is recommended by their treating clinician and agreed to 
by the PI. Part 1 of Protocol 10093 and Protocol 10441 are identical to the current protocol. Because the  data and 
samples gathered on Part 1 data greatly inform the results of Part 2, patients will be asked to consent for the use of 
their 9033 data and samples to be carried over to their new study if they switch. 
 
15 de-identified blood samples will be received from FH protocol 1713. The samples will be accompanied by a 
subject ID # issued for protocol 1713, but our team will not have access to the key to the code, nor have any other 
way to ascertain the identity of the patients. The patients consented under protocol 1713 for their leftover samples 
to be used for future research. The activities to be performed under this protocol align with what the subjects have 
consented to. No additional consent will be sought from these individuals.  
 
 
8.0  SUBJECT REGISTRATION 
 
Informed consent must be signed prior to the performance of any study related procedures or assessments. 
 
Subjects will be registered into the system by the Clinical Coordinators Office (CCO) (Intake Office) and 
assigned a UPN (Unique Patient Number). The CCO will register the subject on to the protocol through the Data 
Management Office. 
 
 
 
 

9033 
13 
 
9.0    TREATMENT PLAN 
 
9.1 
Treatment Schema 
This schema is a pictorial overview only; please see narrative Treatment and Evaluation sections of the protocol for 
specifics and allowable deviations from time frames shown.  
 
 
 
 
 
JAK Inhibitor x  8 
weeks or best 
response 
Meets transplant 
criteria 
Fails to meets 
transplant criteria 
Off Study  
HLA matched sib, 
or URD donor 
UCBT donor 
Spleen >22 cm 
consider 
splenectomy
MAC  
 
Cytoxan 
Busulfan + 
(Fludarabine 
for UCBT)
RIC 
 
Fludarabine
Melphalan 
RIC  
 
Fludarabine
Melphalan 
TBI 400 

9033 
14 
 
9.2    Ruxolitinib Therapy 
A.  Ruxolitinib will be started in all patients regardless of the presence of splenomegaly at least 8 weeks 
prior to the start of HCT conditioning and will be continued until best response through day -4 before 
transplantation. The starting dose will be determined by the patient’s treating clinician. Recommended 
taper schedule for Ruxolitinib: Start tapering by 5 mg BID every two to three days to be completed after 
their dose on day -4. 
B. Ruxolitinib will be dose adjusted or stopped for cytopenias as necessary per treating clinician. 
C. Ruxolitinib will be continued through  Day - 4 of transplantation with a taper schedule. 
D. Patients will have CBC performed as clinically indicated by their treating physician. 
E. Patients will be evaluated by physician visits with the physician of their choice at an interval deemed 
clinically appropriate by this physician.   
F. If patients had been receiving  Ruxolitinib therapy prior to arrival to the SCCA, we will use their pre-
therapy data from their medical records as their baseline. These patients may continue to follow with their 
home physicians until they arrive to a transplant team at the SCCA..  
G. If a patient’s spleen remains > 22 cm following at least 8 weeks of treatment with Ruxolitinib (or > 16 cm 
in patient’s undergoing cord blood transplant), they will be referred for consultation for surgical 
splenectomy to be performed at a local surgical center as deemed appropriate by the study PI. 
H. If the patient is on an alternate JAK inhibitor they will be required to change their therapy to Ruxolitinib      
for 8 weeks prior to the start of conditioning.  
 
9.3  
Conditioning Regimens  
MAC vs. RIC determination will be at the discretion of the clinical provider together with the CCO.  
 
A. Myeloablative Conditioning Regimen 
Day -8 
Fludarabine 25 mg/m2 IV * 
Day -7 
Fludarabine 25 mg/m2 IV * 
Cyclophosphamide 60 mg/kg IV  
Mesna 60mg/kg 
Day -6 
Fludarabine 25 mg/m2 IV * 
Cyclophosphamide 60 mg/kg IV  
Mesna 60mg/kg 
Dilantin starts 
Day -5 
Busulfan 4 mg/kg IV  
Day -4 
**Targeted Busulfan  
Stop JAK inhibitor 
Day -3 
**Targeted Busulfan  
Day -2 
**Targeted Busulfan 
Day -1 
Rest 
Day 0  
Stem Cell infusion  
 
*Umbilical cord blood recipients only 
** Dose to be adjusted as recommended by Busulfan Pharmacokinetics Lab to achieve plasma steady-
state BU concentrations of 800 - 900  ng/mL, per SPM. 
 
1. 
Cyclophosphamide will be given IV at doses of 60 mg/kg/day for 2 days, beginning on day -7 
before transplantation. Adjusted body weight should be used for calculating initial doses if 
patient’s actual weight is > 100% of ideal body weight.   
2. 
The initial dose of Busulfan will be administered IV at 4 mg/kg, infused over 3 hours. Adjusted 
body weight should be used for calculating initial doses if patient’s actual weight is > 100% of 
ideal body weight. The Busulfan Pharmacokinetic Laboratory (206-667-4572) must be notified of 
patient enrollment. Serial blood samples will be drawn after doses 1, 2, and 3 of intravenous 
Busulfan in accordance with standardized physicians’ orders to determine the steady-state 
concentration of Busulfan. Subsequent doses of Busulfan will be adjusted to achieve plasma 
steady-state BU concentrations of 800-900 ng/ml.  Prophylactic phenytoin (Dilantin) will be 

9033 
15 
 
started as per the Standard Practice Manual on day –6 after the second dose of cyclophosphamide 
has been administered. On day -1 phenytoin will be discontinued. 
 
3. 
For patients who have UCB as their donor source, Fludarabine will be administered at doses of 25 
mg/m2 IV over one hour once daily on each of 3 consecutive days starting on Day -8 for a total 
dose of 75 mg/m2.  Patients > 120% of ideal weight, BSA will be calculated using adjusted 
weight.   
 
B. Reduced Intensity Conditioning Regimen for patients with related or unrelated stem cell donors 
 
 
 
 
 
 
 
 
 
 
 
1. Fludarabine will be administered at doses of 30 mg/m2 IV over one hour once daily on each of 5 
consecutive days starting on Day -6 for a total dose of 150 mg/m2.  Patients > 120% of ideal weight, 
BSA will be calculated using adjusted weight.   
2. Melphalan will be administered at doses of 70mg/m2 IV over 15 to 30 minutes daily on 2 consecutive 
days starting on D-3 for a total dose of 140mg/m2.  Patients >120% of ideal weight, BSA will be 
calculated using adjusted weight (per Standard Practice) 
 
B. Reduced Intensity Conditioning Regimen for Umbilical cord blood recipients only 
 
 
 
 
 
 
 
 
 
 
 
 
1. Fludarabine will be administered at doses of  25 mg/m2 IV over one hour once daily on each of 5 
consecutive days starting on Day -6 for a total dose of 125 mg/m2.  Patients > 120% of ideal weight, 
BSA will be calculated using adjusted weight.   
2. Melphalan will be administered at doses of 40mg/m2 IV over 15 to 30 minutes daily on 2 consecutive 
days starting on D-3 for a total dose of 80mg/m2. Patients >120% of ideal weight, BSA will be 
calculated using adjusted weight (per Standard Practice) 
3. Total Body Irradiation (TBI) will be administered in two 2 Gy fractions to umbilical cord blood 
recipients only on Day -1.  
9.4  Immunosuppressive Therapies  
All patients will receive GVHD prophylaxis with 2 drugs as follows: 
A.  HLA-matched Related, Unrelated and Cord Blood Donor recipients:  
1.  Tacrolimus.   
Day -6 
Fludarabine 30 mg/m2 IV  
Day -5 
Fludarabine 30 mg/m2 IV  
Day -4 
Fludarabine 30 mg/m2 IV  
Stop JAK inhibitor 
Day -3 
Fludarabine 30 mg/m2 IV  
Melphalan 70 mg/m2 IV 
Day -2 
Fludarabine 30 mg/m2 IV  
Melphalan 70 mg/m2 IV 
Day 0  
Stem Cell infusion  
Day -6 
Fludarabine 25 mg/m2 IV  
Day -5 
Fludarabine 25 mg/m2 IV  
Day -4 
Fludarabine 25 mg/m2 IV  
Stop JAK inhibitor 
Day -3 
Fludarabine 25 mg/m2 IV  
Melphalan 40mg/m2 IV 
Day -2 
Fludarabine 25 mg/m2 IV  
Melphalan 40mg/m2 IV 
Day -1 
TBI 4 Gy * 
Day 0  
Stem Cell infusion  

9033 
16 
 
a. Tacrolimus will be given day –1 for patients receiving related or unrelated stem cells, and on day 
-3 for patients receiving umbilical cord blood. If a patient is inpatient, they will receive their 
initial dose of Tacrolimus as a continuous IV infusion at 0.03 mg/kg/day; if they are outpatient 
the initial dose should be 0.015 mg/kg/dose every 12 hours IV over 1 to 2 hours . Therapeutic 
monitoring should be done on day +2 and day +5, and the dose adjusted accordingly to achieve a 
steady-state level of 5-15 ng/ml of serum, with an optimal level of 10 ng/ml. Once the appropriate 
level is achieved, monitoring should be done at least weekly. Once the patient is therapeutic, 
administration of tacrolimus should be changed to the oral formulation at a dose conversion of 
1:4 (IV:oral) and given in divided doses twice daily (every 12 hours) as long as the patient is 
tolerating oral medications. If the patient vomits within one hour of administration of oral 
tacrolimus, repeat the dose. If vomiting persists, the drug should be given intravenously at the 
appropriate dose (PO:IV ratio 4:1). Dosing should be based on the patient’s ideal body weight. 
b. In the absence of GVHD, the tacrolimus taper will start on day +56 for related donors, and day 
100 for unrelated and umbilical cord blood donors.  The dose should be tapered by 20% per 
month or over 4 months per clinical judgement..  In the presence of GVHD, or if the patient is 
receiving corticosteroids or other therapy for GVHD, tacrolimus will not be tapered at day +56, 
and dosing will be maintained to target therapeutic levels. The attending physician and LTFU will 
determine the duration of therapy. Once tacrolimus taper is initiated, levels should be obtained 
only if toxicity is suspected. 
 
B. Related and unrelated donor recipients only 
1. Methotrexate.  Methotrexate will be given at doses of 10 mg/m2 IV on day +1 (at least 24 hours 
after PBSC infusion) and on days +3, +6, and +11. Indications for methotrexate dose adjustment 
include Grade 4 mucositis, severe renal impairment and significant third space fluid 
accumulation. Dose adjustments and leucovorin rescue, if necessary, will be performed per 
Standard Practice Guidelines.  
 
C. Umbilical cord blood donor recipients only 
1. MMF. All patients will receive MMF at the dose of 15 mg/kg every 8 hours with a maximum of 1 
gram/dose.  MMF should be started on day zero, 4 to 6 hours after cell infusion for patients 
receiving UCBT.   
a. MMF will be given every 8 hrs daily until day 40 post transplant and then, in the absence 
of GVHD, tapered by 12%/week with MMF discontinued after day + 96. 
b. MMF may be given IV or PO with preference that patients receive the IV form if and 
when they are admitted to the hospital.  
c. Markedly low (<40%) donor T cell chimerism after UCBT may indicate impending graft 
rejection. MMF should be continued at full dose or, if MMF taper has been initiated, 
reinstitution of full dose MMF should occur. If MMF has been discontinued, MMF should 
be reinstituted at full dose. 
d. If patient is diagnosed with GVHD and started on systemic steroids, and patient has stable 
chimerism, MMF may be tapered following discussion with PI.  
 
9.5  Growth Factor 
A. UCBT patients will receive G-CSF 5 mcg/kg/day SC (dose rounded to vial size) based on the actual 
body weight beginning on Day +1 after UCB infusion.  G-CSF will be administered daily until the 
ANC exceeds 2.5 x 109/L for three consecutive days and then discontinued.  If the ANC decreases to 
≤1.0 x 109/L, G-CSF will be reinstituted and titrated to maintain an ANC >1.0 x 109/L. 
 
9.6  Supportive Care 
A. Patients will receive transfusions, infection prophylaxis (bacterial, fungal, viral), and other therapy 
(including GVHD) according to Institutional Guidelines. 
 
9.7  Hematopoietic cell collection and Infusion (see also Protocol Specific Infusion Orders)   

9033 
17 
 
A. Bone marrow vs PBSC 
1.   PBSC mobilization is preferred over bone marrow harvest but either will be accepted per 
clinicians preference. 
B. HLA-matched related donors 
1. Related donors who consent to PBSC donation will receive 5 daily doses of G-CSF, 16 μg/kg/day 
by subcutaneous injection, commencing on day –5.  PBSCs will be collected in the afternoon of 
day -1, stored at 4ºC overnight, and infused as soon as possible on day 0.  
2. If the collection on day –1 contains less than 5.0 X 106 CD34+ cells per kg of recipient weight, a 
second collection will be performed the following morning and transfused on day 0. 
3. Bone marrow harvest 
C. Matched unrelated donors  
1. For unrelated donors, timing of PBSC collection is prearranged through the URD office, via  
NMDP or other donor centers.  
2. G-CSF will be administered at 10 μg/kg/day for 5 days by subcutaneous injection to unrelated 
donors per NMDP protocol.  
3. Collection centers will perform leukapheresis for 1 or 2 days and exchange up to a total of 24 
liters of blood, with a target to collect a minimum of 5.0 X 106 CD34+ cells per kg recipient 
weight.  
4. The Cellular Therapy Lab will perform quantitation of CD34 and CD3 cells. If possible, for 
unrelated donor products, cryopreservation of a portion of PBSC should take place for the 
purpose of possible donor lymphocyte infusion. 
5. Bone marrow harvest 
D. Umbilical Cord Blood donors 
1. Procedures for requesting, receiving and characterizing the cord blood unit(s) for infusion will be 
according to institutional protocol.    
2. The cord blood unit will be thawed and infused per  SCCA CTL SOPss. Cord blood products 
should be infused without delay as soon as the product arrives on the floor.   
a. 
The thawed product (either one or two units) will be delivered to the patient floor/bedside 
where the product is double-checked by a nurse with the technologist from the Cellular 
Therapy Laboratory. Visual inspection of the product is also made at this time. The 
unit(s) is verified according to 1) the infusion order sheets, 2) the patient’s identification 
number on the cell product, 3) the product (cell) identification number and 4) the patient 
wristband.  
b. 
If the cord blood unit(s) fail to pass inspection or if there is insufficient information to 
verify the cell product for the patient, notify the Director of the Cell Therapy Lab (Shelly 
Heimfeld, 667-4004) and the PI, Rachel  Salit (667-1317, pager 314-2845) immediately. 
c. 
The goal infusion time of each cord blood unit is 30 minutes, as clinically possible. Pre-
medications (if any) prior to cord blood infusion will be at the discretion of the attending. 
Under no circumstances is the cord blood to be irradiated. No medications or fluids 
should be given piggyback through the catheter lumen that is being used for cord blood 
infusion. 
d. 
The product is infused via IV drip directly into the central line according to standard 
practice with gravity-filtered tubing. 
e. 
Vital signs should be monitored before beginning the infusion and periodically during 
administration. Notify the attending physician, fellow or PA immediately if the patient 
exhibits signs or symptoms of a reaction.  
f. 
Benadryl, epinephrine, and hydrocortisone should be available at the bedside for 
emergency use if necessary. Oxygen with nasal prongs for standby use should be present 
in the room. 
g. 
If the patient is a double cord blood recipient, the two units may be given consecutively 
with no wait between infusion of the units. However, infusion of the second unit will not 
begin until any acute toxicities from the first unit have been controlled. The start and stop 
time of each unit should be recorded on the infusion record.  
 

9033 
18 
 
9.8  Management of Pre-Engraftment Immune Reactions in UCBT patients 
A. A well-recognized clinical entity consisting of skin rash, fever, and, often, loose stools and respiratory 
distress has been noted to occur prior to engraftment among cord blood patients, generally between 
Days +7 and +21.  This clinical syndrome likely involves cytokine activation, and though clinically 
similar to acute or hyperacute graft versus host disease, it appears to be a distinct entity, “pre-
engraftment syndrome.”   This syndrome is often controlled with brief steroid bursts, thus avoiding a 
commitment to extended steroid exposure. Patients should be monitored carefully for this syndrome. 
 
If patients have moderate to severe symptoms as described above and alternative etiologies (i.e., 
infection) have been excluded or are being appropriately evaluated, recommendations for management 
are: 
1. For patients not on steroid therapy when the syndrome occurs:  methylprednisolone should be 
given at 1 mg/kg IV q day for three days.  If symptoms have abated, steroids should be 
stopped.  If symptoms persist, 1 mg/kg methylprednisolone can be continued through six days 
then stopped if symptoms have abated.  If symptoms persist for more than six days, the 
patient should be considered to have acute/hyperacute GVHD and should be treated with 
prolonged steroids as deemed appropriate. 
 
2. For patients already on steroids for other reasons when the syndrome 
occurs:  methylprednisolone should be given at a dose of 3-5 mg/kg IV (max dose 500 mg) q 
12 hours x 48 hours, followed by a rapid taper to 1 mg/kg IV q 12 hours.  Patients should be 
weaned after response as tolerated. 
 
10.0  EVALUATION   
 
10.1 Pre JAK Inhibitor Evaluation for patients enrolled in Part 1 
A. 
All patients will have a complete history taken, including details of prior therapy for 
myelofibrosis such as cytotoxic treatment, growth factor administration, transfusion support and 
splenectomy (or splenic irradiation). Previous thrombotic or hemorrhagic complications will be 
noted. Constitutional symptoms such as weight loss, fever or night sweats will be recorded.  
 
B. 
The Dynamic International Prognostic Scoring System (DIPSS) (Appendix A) 
C. 
Karnofsky performance status (Appendix B).  
D. 
Physical examination including assessment by exam for splenomegaly and hepatomegaly.  
E. 
Complete blood and platelet count with leukocyte differential. 
F. 
Basic metabolic and hepatic function panels. 
G. 
Pregnancy test (blood or urine) in females of childbearing potential. 
H. 
Bone marrow: All patients should have diagnostic bone marrow biopsies and, if possible, 
aspirates taken for morphologic (microscopic) examination, cytogenetic analysis, and flow 
cytometric analysis within 6 months of enrollment .  
I.  
Peripheral blood: peripheral blood CD34+count (send to SCCA Cellular Therapy Lab), 
cytogenetic analysis (if not possible on marrow) 
J.  
Serum iron and TIBC, and ferritin levels will be obtained.  
K. 
Hotspot lab test (MF mutations).  
 
L.  
Bone marrow or peripheral blood (not both):  Should be sent fresh for JAK mutations (V617F, 
exon 12) , MPL1 and CALR. Send these only if patient’s  mutation status is unknown.  If patient 
is known to be positive for any of these mutations these tests do not need to be done.   
M. 
Research: Additional peripheral blood, up to 30 ml, to be used for research on the mechanism of 
responses to JAK inhibitors and biology of post-transplant disease progression and response. This 
will include but is not limited to analysis of cytokine levels and activity and genome sequencing. 
100mcl of plasma may also be collected from stored peripheral blood samples and sent 
deidentified to Incyte Corporation for GVHD biomarker analysis. Additional marrow up to 5ml to 
be used for future research on additional mutations and disease mechanisms will also be collected 
if possible.  

9033 
19 
 
N.  
Patients who present to the SCCA already on treatment with a JAK inhibitor, and not enrolled in 
Part 1 will have the pre JAK inhibitor evaluation information extrapolated from their medical 
records. 
O. 
Results of tests and/or procedures conducted as per standard of care may be used for eligibility 
determination. 
 
10.2  Pre-Transplant Evaluation 
 
Refer to FHCC Standard Practice Manual for Pre-Transplant Evaluation Guidelines for Allogeneic 
Transplant.   
 
In addition to Standard Practice Guidelines complete the following protocol specific requirements: 
A. The Dynamic International Prognostic Scoring System (DIPSS) (Appendix A) 
B. Comorbidity Index Score (Appendix B) 
C. Physical examination including assessment by exam for splenomegaly and hepatomegaly. 
D. Peripheral blood: peripheral blood CD34+count (send to SCCA Cellular Therapy Lab), cytogenetic 
analysis (if not possible on marrow). 
E. Serum iron and TIBC, and ferritin levels will be obtained. 
F. Heme Gene Panel if not performed at the time of enrollment on Part 1, or if > 6 months since last 
evaluation.   
G. Bone marrow or peripheral blood:  Should be sent fresh for JAK-2 mutations (V617F, exon 12), or 
MPL1 or CALR  if positive pre JAK inhibitor.  If mutational status is known, only test for the 
mutation that was positive pre JAK inhibitor. If mutational status was unknown pre JAK inhibitor 
therapy test marrow or peripheral blood (not both) for JAK-2 mutations V617F, exon 12), MPL1 and 
CALR.   
H. Research:  Additional peripheral blood, up to 30 ml,to be used for research on the biology of post-
transplant disease progression and response. This will include but is not limited to analysis of 
cytokine levels and activity and genome sequencing. 100mcl of plasma may also be collected from 
stored peripheral blood samples and sent deidentified to Incyte Corporation for GVHD biomarker 
analysis. Additional marrow up to 5ml to be used for future research on additional mutations and 
disease mechanisms will also be collected if possible.  
1. Blood samples from patients who did not receive Ruxolitinib prior to transplant will be taken 
from previously collected pre-transplant samples on Fred Hutch 1713 or 7801 biorepository 
protocols and sent to Incyte Corporation to be used as control samples for the GVHD biomarker 
analysis. 
I. MRI (bone marrow and STIR) of pelvis, femoral heads and shafts and lumbar spine will be obtained 
(these films will also provide additional information on spleen size). If patient is unable to have an 
MRI performed, CT chest, abdomen and pelvis,  or ultra sound abdomen/pelvis, may be substituted to 
assess spleen volume as well as extramedullary sites of disease. 
J. Echocardiography with measurement of the left ventricular ejection fraction (LVEF) or left 
ventricular shortening fraction.  MUGA is not preferred but can be used in the event 
echocardiography is unable to be obtained in a timely manner. 
K. Chest CT without contrast to exclude occult infection prior to transplant within 30 days of start of 
conditioning.   
L. Pulmonary function tests. 
M. Viral screening including CMV PCR 
N. DNA specimen from cord blood unit(s) for chimerism studies (FHCC patients: submitted to CIL) 
O. Panel Reactive Antibody (PRA) per Institutional Guidelines 
P. Pregnancy test per Institutional Guidelines in females of childbearing potential. 
Q. Results of tests and/or procedures conducted as per standard of care for pre transplant work-up may 
be used for eligibility determination.  
 
10.3  Patient Evaluations from Day 0 through day 28.    
 

9033 
20 
 
Refer to FHCC Standard Practice Manual for Post-Transplant Evaluation Guidelines for Allogeneic 
Transplant.   
In addition to Standard Practice Guidelines complete the following protocol specific requirements: 
  
A. Peripheral blood donor chimerism cell sorted for CD3+, CD33+ cells (and CD56+ if clinically 
indicated) will be evaluated at Day 28 for patients receiving UCBT and  patients receiving reduced 
intensity  conditioning only, unless clinically indicated   
B. Bone marrow biopsy and aspirate if possible on Day 28 for disease restaging (morphology, 
immunophenotyping, cytogenetics and molecular studies as indicated). 
C. GVHD evaluation (Appendix C) weekly or as clinically indicated 
D. Research: Additional peripheral blood, on Days 0, 7 and 28, not to exceed 30 ml,to be used for 
research on the mechanism of responses to Ruxolitinib  and biology of post-transplant disease 
progression, and response. 100mcl of plasma may also be collected from stored peripheral blood 
samples and sent deidentified to Incyte Corporation for GVHD biomarker analysis. This will include 
but is not limited to analysis of cytokine levels and activity and genome sequencing. 
 
10.4 
Patient Evaluations  through Day 100, 6 Months, 1 Year and 2-5 Years 
 
Refer to FHCC Standard Practice Manual for Post-Transplant Evaluation Guidelines for Allogeneic 
Transplant.  
  
In addition to Standard Practice Guidelines complete the following protocol specific requirements: 
 
A. Karnofsky/ECOGperformance status (Appendix B) once between Day 80 and Day 100, and at 1 
year. 
B. MRI (bone marrow and STIR) of pelvis, femoral heads and shafts and lumbar spine will be 
obtained (these films will also provide additional information on spleen size), between day 80 and 
100, and also at the 1 year Long Term Follow-up.  If patient is unable to have an MRI performed, 
CT chest, abdomen and pelvis,  or ultra sound abdomen/pelvis, may be substituted to assess spleen 
volume as well as extramedullary sites of disease.  If the patient had one of these assessments at 
baseline, it is acceptable to repeat the same modality for comparison. 
C. Peripheral blood for the molecular mutation (JAK-2, CALR, MPL) that was previously positive to 
be done between day 80 – 100 with work-up for discharge from transplant service, at 6 months 
(only if mutation was positive at day 80-100 evaluation), and yearly until 5 years post transplant.  
D. Bone marrow aspirate and biopsy between Day 80 and 100 and 1 year for assessment of donor 
engraftment, disease restaging, and chimerism analysis. BM should be performed at Day 180 if 
Day 80-100 marrow demonstrates residual disease, mixed chimerism or molecular  mutation  is 
still positive. At the 2-5 year time points BM biopsy will only be done if residual disease in 
marrow, mixed chimerism or the patient has molecular mutation that is still positive in the marrow 
at the 1 year evaluation. If chimerism is less than 50% donor, patient should be considered for 
DLI. 
E. Peripheral blood for chimerism studies cell sorted for CD3+ and CD33+ , (and if clinically 
indicated CD56+)  between days 80-100, and 1 year. At Day 180 and years 2-5 PB chimerism 
should be performed as clinically indicated (ie in patients with unresolved or new cytopenia or 
mixed chimerism).  If chimerism is less than 50% donor, patient should be considered for DLI. 
F. Peripheral blood for chimerisms at day 56 if CD3 or CD33 is less than 50% donor, at day 28 or if 
clinically indicated. 
G. The Dynamic International Prognostic Scoring System (DIPSS) (Appendix A) at 1 year and yearly 
until 5 years. 
H. GVHD evaluation (Appendix C) weekly and/or as clinically indicated through Day 100 (or longer 
if clinically indicated), then at 6 months, 1 year and 2-5 years  
I. Autopsy report, if available, if death occurs before the 5 year follow-up 

9033 
21 
 
J. Research: Additional peripheral blood, up to 30 ml,to be used for research on the biology of post-
transplant disease progression and response will be done between days 80 and 100 and at 1 year. 
This will include but is not limited to analysis of cytokine levels and activity and genome 
sequencing. Additional marrow up to 5ml at the one year time point only to be used for future 
research on additional mutations and disease mechanisms will also be collected if possible.  
 
 
 
10.5   Residual/Recurrent Disease Evaluation 
A. Patients will be evaluated routinely for evidence of recurrent malignancy as per Institutional 
Guidelines on Day 28 and Day 80-100.  If at any time the attending physician suspects recurrent 
disease, additional analyses will be performed as clinically indicated. 
B. Research: Additional peripheral blood, up to 30 ml,to be used for research on the biology of disease 
progression and response. 100mcl of plasma may also be collected from stored peripheral blood 
samples and sent deidentified to Incyte Corporation for GVHD biomarker analysis This will include 
but is not limited to analysis of cytokine levels and activity and genome sequencing. Additional 
marrow up to 5ml to be used for future research on additional mutations and disease mechanisms of 
recurrence will also be collected if possible.  
 
10.6 
Study Evaluation Windows 
The target dates for post-transplant study evaluations are outlined in the table below. In certain clinical 
circumstances (e.g., relapse, clinical status or terminal illness) study tests may be omitted at the 
physician’s or PI’s discretion.  
 
 
Evaluation Timepoint Post 
Transplant 
Window** 
Day 0 
- 2 days 
Day +10 
+/- 3 days 
Day +28 
± 7 days 
Day +56 
 ± 7 days 
Day +80 to +100 
± 7 days 
Day +180 
± 30 days 
1 year 
± 90 days 
2-5 years 
* 
* Every effort will be made to complete the 1 year and 2-5 year 
evaluations as close to these dates as possible, taking into 
consideration patient’s circumstances at these time points. 
** These timepoints may be delayed beyond window due to a 
patient’s unstable clinical condition as determined by the 
provider. 
 
11.0  DRUGS, IRRADIATION AND CORD BLOOD INFUSION: TOXICITIES AND  
 COMPLICATIONS 
 
11.1 Ruxolitinib 
Ruxolitinib has been studied in over 650 patients with MF and over 40 patients with rheumatoid arthritis and 
the following risks have been observed: 
Likely Side Effects (over  10%) 
Less Likely Side Effects (3-9%) 
Rare Side Effects (under 2%) 
 
Diarrhea  
 
Vomiting 
 
Low white blood cell count 
 
Increased risk of infection 
 
Low to moderate grade 
fever 
 
Pneumonia 
 
Urinary tract infection 
 
Inflammation of the bowel 
 
Gastrointestinal bleeding 
 
Gas 
 
High potassium count 
 
Low levels of sodium 

9033 
22 
 
 
Nausea 
 
Mild to moderately low blood 
cell counts (red blood cells 
(anemia) and platelets) 
 
Shortness of breath 
 
Swelling of the hands or feet 
 
Feeling hot 
 
Headache 
 
Increased risk of bruising and 
bleeding 
 
Weight gain 
 
Heart murmur 
 
Changes in blood pressure 
 
 
Bronchitis 
 
Fatigue 
 
Sleep disturbances 
 
Pain in the arms or legs 
 
Itchiness 
 
Rash (viral skin infections, 
herpes zoster or singles) 
 
 
High cholesterol 
 
Abdominal pain 
 
Fainting 
 
Neck ache 
 
Infection or pain in joints 
 
Severe and life-threatening 
form of inflammation of the 
pancreas 
 
Bone marrow suppression 
 
Significantly low red blood 
cells, platelets, and ANC (a 
type of white blood cell) 
 
Intracerebral hemorrhage 
(bleeding) 
 
Upper respiratory infection 
 
High-grade fever 
 
Sore throat 
 
Low oxygen level 
 
Inflammation of the lungs 
 
Weakness 
 
Anxiety 
 
Acute response to drug 
withdrawal 
 
Depression 
 
Cardiomyopathy (weakening 
and enlargement of the heart 
muscle) 
 
Heart failure 
 
Acute myocardial infarction 
 
Liver toxicity 
 
Necrotizing fasciitis (rare 
infection of the deeper layers 
of skin and tissues underneath 
the skin) 
 
Blurred vision/vision loss 
 
Necrosis of talus bone (located 
in the top of the foot joining 
ankle) 
 
As the purpose of this study is to find out if JAK inhibitors, when given intentionally as part of a treatment plan 
prior to transplant, will improve transplant outcomes in patients with MF, patients enrolled in clinical trials for 
pacritinib and momelotinib will be allowed to also enroll in this study. 
 
11.2 Busulfan 
Busulfan can increase your chance of having seizures. Treatment with Dilantin an antiseizure medication both 
prior to and during busulfan treatment can decrease your chance of having seizures 

9033 
23 
 
Likely Side Effects (over 10%) 
Less Likely Side Effects (3-9%) 
Rare Side Effects (under 2%) 
 
Lower white blood cell count 
with increased risk of infection 
 
Diarrhea  
 
Vomiting and nausea  
 
Liver damage 
 
Lower sperm production in 
men 
 
Hair loss 
 
Loss of appetite 
 
Missing or stopping menstrual 
cycle in women 
 
Sores in mouth or on lips 
 
Blood in urine 
 
Fatigue 
 
Lower platelet count (mild) 
with increased risk of 
bleeding, especially with an 
injury like falling 
 
Darkening of nail beds 
 
Lung fibrosis with cough and 
shortness of breath 
 
Heart failure with high doses 
 
Decrease in sodium level in the 
blood with high doses 
 
Secondary cancers 
.  
11.3 Cyclophosphamide (Cytoxan) 
Cyclophosphamide can cause bleeding in your bladder. Getting more fluid through a vein or your catheter and drinking 
extra liquids may prevent this.  
Likely Side Effects (over 10%) 
Less Likely Side Effects (3-9%) 
Rare Side Effects (under 2%) 
 
Nausea and vomiting  
 
Diarrhea  
 
Loss of appetite  
 
Low white blood cell count with 
increased risk of infection 
 
Lower sperm production in 
men 
 
Hair loss  
 
Liver problems 
 
Missing or stopping of 
menstrual periods in women 
 
Anemia  
 
Low platelet count with 
increased risk of bleeding 
 
Sores in mouth or on lips  
 
Blood in urine 
 
Fatigue  
 
Darkening of nail beds 
 
Fetal damage if pregnancy 
occurs while taking 
cyclophosphamide 
 
Lung fibrosis with cough and 
shortness of breath 
 
Heart failure with high doses 
 
Decrease in sodium level in the 
blood with high doses 
 
Secondary cancers 
 
11.4 Fludarabine 
Likely Side Effects (over 10%) 
Less Likely Side Effects (3-9%) 
Rare Side Effects (under 2%) 
 
Low white blood cell count with 
increased risk of infection  
 
Low platelet count with 
increased risk of bleeding 
 
Anemia 
 
 
Nausea and vomiting 
 
Diarrhea 
 
Fatigue 
  
 
 
Rash 
 
Visual changes 
 
Numbness and tingling in hands 
or feet 
 
Severe problems with brain 
(coma at high-dose, confusion) 
 
Pneumonia 
 
Irregular heart beats 
 
Renal failure 
11.5 Methotrexate  
Likely Side Effects (over 10%) 
Less Likely Side Effects (3-9%) 
Rare Side Effects (under 2%) 
 
Nausea and/or vomiting 
 
Loss of appetite 
 
Mouth sores that are painful 
 
 
Low white blood cell 
count and increased risk 
of infection 
 
Lower platelet count with 
increased risk of bleeding 
 
Diarrhea or loose stools 
 
Damage to the liver (may be 
permanent or cause death) 
 
Allergic inflammation of the 
lung with fever, cough, and 
feeling short of breath 
 
Hair loss 
 
Skin reactions (rash, itching) 

9033 
24 
 
 
Kidney damage (may be 
permanent) 
 
Greater risk of sunburn  
 
Skin changes in areas 
where previous radiation 
was given  
 
Feeling dizzy 
 
Blurred vision 
 
Hard to think 
 
Headaches 
 
Redness of eyes and maybe 
itching but not serious 
conjunctivitis 
11.6 Tacrolimus 
Likely Side Effects (over 10%) 
Less Likely Side Effects (3-9%) 
Rare Side Effects (under 2%) 
 
Hypertension (high blood 
pressure) 
 
Tremor (shaking of the 
hands)  
 
Nausea and/or vomiting 
 
Altered levels of 
magnesium, calcium, 
potassium, and sugars in 
the blood 
 
 
Headache 
 
Pain in the hands and/or 
feet  
 
Increases in cholesterol and 
triglyceride 
 
Changes in how clearly 
one can think  
 
Trouble sleeping 
 
Increased hair growth 
 
Destruction of red blood 
cells (hemolysis) 
 
Seizures 
 
Renal failure from damage to 
the blood vessel walls and 
destruction of red blood cells by 
a condition called hemolytic 
uremic syndrome (HUS) 
 
11.7 Mycophenolate Mofetil (MMF) 
Likely Side Effects (over 10%) 
Less Likely Side Effects (3-9%) 
Rare Side Effects (under 2%) 
 
Nausea  
 
Miscarriage or birth defects if 
become pregnant while taking 
and within 6 weeks after 
stopping MMF 
 
 
Vomiting   
 
Diarrhea (loose stools) 
and abdominal discomfort 
 
Lower red blood cell 
count that is reversible 
 
Lower white blood cell count 
with increased risk of 
infection 
 
Stomach and bowel bleeding 
(blood in stools) 
 
Secondary cancers 
 
Progressive multifocal 
leukoencephalopathy (a serious 
brain infection that can cause 
weakness, clumsiness and 
confusion and can lead to death) 
 
11.8 Melphalan 
Likely Side Effects (over 10%) 
Less Likely Side Effects (3-9%) 
Rare Side Effects (under 2%) 
 
Vomiting  
 
Nausea 
 
Mouth ulcers 
 
Diarrhea 
 
Skin redness 
 
Hair loss 
 
Loss of appetite 
 
Fatigue 
 
Change in taste of food 
 
Nail discoloration 
 
Pulmonary scar tissues to 
form 
 
Confusion and coma 
 
Lowers the white blood cell 
count, which, in turn, 
increases the risk of 
infection, which can be life 
threatening 
 
Lowers the platelet count 
(necessary for blood 
clotting) which may lead to 
serious or life-threatening 
bleeding complications. 
 
 
11.9 Granulocyte Colony Stimulating Factor (G-CSF) 
Likely Side Effects (over 10%) 
Less Likely (1-10%) 

9033 
25 
 
 
Muscle aches or pain 
 
Bone pain 
 
Itching 
 
Skin rashes 
 
Headache 
 
Blood vessel inflammation  
 
Ruptured spleen 
 
 
11.10 Total body irradiation (TBI) 
Likely Side Effects (over 10%) 
Less Likely Side Effects (3-9%) 
 
Nausea  
 
Fatigue  
 
The irradiation dose used may result in 
sterility, and there is a risk of major genetic 
damage to any children conceived after 
transplantation 
 
Temporary hair loss    
 
Vomiting  
 
Cataracts (an opacity or whitening of the lens) may 
develop in the eye 
 
Inflammation of the salivary gland 
 
Diarrhea  
 
Painful swelling of the parotid gland (a gland 
under the chin) for a few days   
 
Secondary cancers 
 
Mucositis (temporary damage to the lining of the 
mouth) 
 
 
12.0  GUIDELINES FOR ADVERSE EVENT REPORTING 
 
12.1  Adverse Event Reporting/Institutional Policy 
The following guidelines are the minimum Cancer Consortium IRB adverse event (AE) reporting guidelines.  
 
In accordance with institutional policy, all adverse events which in the opinion of the principal investigator are 
unexpected and related or possibly related to the research and serious or suggest that the research places research 
participants or others at greater risk of physical or psychological harm than was previously known or recognized 
are to be reported to the IRB within 10 calendar days of learning of the problem. 
 
Definitions: 
 
Adverse Event - Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product, medical treatment or procedure and which does not necessarily have to have a causal 
relationship with this treatment. An adverse event 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, medical treatment or procedure whether or not considered related to the medicinal 
product.  
 
Life-threatening Adverse Event – Any adverse event that places the patient or subject, in view of the 
investigator, at immediate risk of death from the reaction.  
 
Unexpected Adverse Event – An adverse event is “unexpected” when its nature (specificity), severity, or 
frequency are not consistent with (a) the known or foreseeable risk of adverse events associated with the research 
procedures described in the Protocol-related documents, such as the IRB-approved research protocol, informed 
consent document and other relevant sources of information such as product labeling and package inserts; and are 
also not consistent with (b) the characteristics of the subject population being studied including the expected 
natural progression of any underlying disease, disorder or condition any predisposing risk factor profile for the 
adverse event. 
Serious Adverse Event (SAE) – Any adverse event occurring that results in any of the following outcomes: 
 
death  

9033 
26 
 
 
a life-threatening adverse event (real risk of dying) 
 
inpatient hospitalization or prolongation of existing hospitalization  
 
a persistent or significant disability/incapacity 
 
a congenital anomaly 
 
requires intervention to prevent permanent impairment of damage 
 
Attribution - The following are definitions for determining whether an adverse event is related to a medical 
product, treatment or procedure: 
 
 
An adverse event is “related or possibly related to the research procedures” if in the opinion of the 
principal investigator, it was more likely than not caused by the research procedures. 
 
Adverse events that are solely caused by an underlying disease, disorder or condition of the subject or by 
other circumstances unrelated to either the research or any underlying disease, disorder or condition of the 
subject are not “related or possibly related.”  
 
If there is any question whether or not an adverse event is related or possibly related, the adverse event 
should be reported. 
 
12.2 Protocol –Specific Collection, Grading and Reporting of Adverse Events   
Patients enrolled in this study are receiving pre-transplant treatments and other transplant-related procedures that 
are generally associated with high rates of “expected” adverse events. Refer to Appendix D for a list of potential 
adverse events associated or expected with hematopoietic cell transplantation. Toxicities will be graded using the 
NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. The scale in its entirety can be 
found at: http://www.acrin.org/Portals/0/Administration/Regulatory/CTCAE_4.02_2009-09-
15_QuickReference_5x7.pdf 
 
The following events occurring from the start of the conditioning regimen through day 100 (or through discharge 
prior to that date) will be captured in protocol-specific case report forms:  
 
 
Non-hematologic adverse events of ≥ grade 3  
 
Grade ≥4 blood and lymphatic system disorder-related adverse events occurring between Day 43 and 
Day 100  
 
Serious adverse events as defined above   
 
The following events are not identified as AEs in this study: 
 
Disease progression or relapse. However, clinical events associated with progression/relapse may be 
reportable as AEs. 
 
Hospitalization for the purpose of facilitating stem cell transplant, for protocol-scheduled procedures, 
blood product transfusions, or for social reasons (i.e., awaiting transport home) will not be considered 
a serious adverse event. Hospitalization occurring at any time pre- or post-transplant will be 
considered a SAE only if it is unexpected or the duration of the hospital stay is unexpected. 
 
Medical or surgical procedures in and of themselves, including those that require hospitalization (e.g., 
surgery, endoscopy, biopsy procedures) are not considered AEs. However, an event or condition 
requiring such procedures may be an AE. 
 
All patients undergoing hematopoietic stem cell transplant are expected to have ≤ Grade 4 
pancytopenia as an intended therapeutic effect. These hematologic AEs will therefore be tracked and 
recorded between day 0 and 43 only as time to recovery of blood counts/engraftment. 
 
Abnormal laboratory values will be identified and recorded as AEs only if clinical intervention is 
required as a result. 
 
When a grade 3 adverse event increases in severity to grade 4 or above, the event will be captured at its highest 
grade. If a patient experiences relapse or graft failure and goes on to further treatment off protocol, adverse events 
will no longer be collected with the exception of death. 

9033 
27 
 
In accordance with FHCC institutional policy, all AEs which in the opinion of the FHCC principal investigator 
meet all three of the following criteria will be reported to the Coordinating Center IRB within 10 calendar days of 
learning of the problem:  
A. unexpected  
B. related or possibly related to the research  
C. serious or suggests that the research places research participants or others at greater risk of physical or 
psychological harm than was previously known or recognized 
Graft versus Host Disease assessment, performed by the clinical team as part of routine care, will be reviewed 
once weekly through Day +100.  After Day +100, GVHD data will be captured at Day +180, 1 year, then once 
yearly through 2 years after Day 0. GVHD data is captured in a GVHD-specific CRF.  
Relapse, graft failure and death data will be captured as they occur in CRFs specific to those events. If a patient 
experiences relapse or graft failure and goes on to further treatment off protocol, adverse events will no longer be 
collected with the exception of death.. 
 
13.0 DATA AND SAFETY MONITORING PLAN 
 
This is single institution Phase 2 clinical trial that is monitored by the principal investigator (PI) and a Data and 
Safety and Monitoring Board (DSMB). The PI of the study will have primary responsibility for ensuring that the 
protocol is conducted as approved by the FHCC Scientific Review Committee and Institutional Review Board. 
The PI will ensure that the monitoring plan is followed, that all data required for oversight of monitoring are 
accurately reported to the DSMB and FHCC/UW Cancer Consortium Data and Safety  Monitoring Committee 
(DSMC), that all adverse events are reported according to the protocol guidelines, and that any adverse reactions 
reflecting patient safety concerns are appropriately reported. The PI will personally review with the Research 
Nurse the clinical course of all the enrolled patients at least twice monthly. 
 
Under the provisions of the FHCC/UW Cancer Consortium Data and Safety Monitoring Plan (DSMP), the Cancer 
Consortium Clinical Research Support Office provides monitoring for quality process and compliance by 
qualified monitors unaffiliated with the conduct of the study. Monitoring visits occur at specified intervals 
determined by the assessed risk level of the study and the findings of the previous visit. The scope of monitoring 
is specified in the Cancer Consortium DSMP: 
http://www.cancerconsortium.org/content/dam/consortium/Resource-Documents/Data-Safety-
Monitoring/DSMPlan.pdf 
 
This protocol will be monitored by the MDS/Aplastic Anemia DSMB. This committee meets at six-month 
intervals and all outcome data is reviewed including all adverse events. The DSMB determines whether the trial 
has met any stopping rules and reviews any patient safety problems potentially necessitating discontinuation of 
the trial. A report from the DSMB is submitted to the FHCC IRB and to the study coordinators/PI of this protocol. 
The DSMB will discontinue the review of outcomes when this protocol is closed to accrual. 
 
An annual review of the progress of the study with respect to the monitoring plan will be performed by the 
DSMC. The DSMC reviews accrual, serious adverse events, stopping rules and adherence to the protocol-specific 
data and safety monitoring plan.  
 
14.0 DATA MANAGEMENT/CONFIDENTIALITY 
 
Study data will be recorded in a password-protected research database.  Case report forms are generated from the 
database for review by the principal investigator and study monitors. Clinical Statistics maintains a subject 
database at FHCC to allow storage and retrieval of subject data collected from a wide variety of sources. The 
investigator will ensure that data collected conform to all established guidelines for coding, collection, key entry 
and verification. Each subject is assigned a unique patient number to assure subject confidentiality. Subjects will 
not be referred to by this number, by name, or by any other individual identifier in any publication or external 
presentation. The licensed medical records department, affiliated with the institution where the subject receives 
medical care, maintains all original inpatient and outpatient chart documents. Subject research files are scanned 

9033 
28 
 
and stored in a secure database (OWL). OWL records are maintained by the FHCC data abstraction staff. Access 
is restricted to personnel authorized by the Division of Clinical Research. 
 
Control samples will be received with no associated identifiying information. They would be sent to Incyte 
Corporation to be used as control samples for the GVHD biomarker analysis.   
 
15.0 STATISTICAL CONSIDERATIONS 
 
ANTICIPATED/PLANNED LOCAL ENROLLMENT: 
Number of Participants (must provide exact numbers. i.e., no range) 
Ethnic Categories 
Sex/Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
3 
3 
6 
Not Hispanic or Latino 
20 
22 
42 
Ethnic Categories: Total of All Participants* 
23 
25 
48 
Racial Categories 
American Indian/Alaska Native 
2 
2 
4 
Asian 
3 
2 
4 
Native Hawaiian or Other Pacific Islander 
2 
2 
3 
Black or African American 
2 
2 
3 
White 
15 
15 
19 
More Than One Race 
0 
1 
0 
Racial Categories: Total of All Participants * 
24 
24 
48 
 
 
15.1 Statistical Analysis.  The primary objective of this single-arm Phase II trial is to assess the potential efficacy 
of the administration of a JAK inhibitor among patients transplanted for MF.  The primary endpoint for these 
purposes is two-year overall survival.  In a previous report, it was shown that DIPSS correlated with mortality 
following HCT.  We hypothesize that the use of a JAK inhibitor will lower the DIPSS risk category, and as a 
result will lead to improved survival relative to that seen historically for a similar group of patients.  We expect to 
see an absolute improvement in two-year overall survival of 20%.  Our previous data show an estimated two-year 
survival of 50% among 51 patients transplanted for high-risk MF, 64% among 50 patients treated for 
intermediate-2-risk MF, and 77% among patients treated for intermediate-1-risk MF3; patients with various donor 
sources were included in this study.  If the true one-year overall survival is 80%, then 33 patients will provide 
90% power to observe a statistically significantly improved probability relative to the fixed value of 60% (at the 
one-sided significance level of .10).  The exact benchmark that we will use for comparison will be determined 
from the mix of DIPSS categories among those enrolled and treated with JAK on the current trial.  From this mix, 
we will create an expected two-year survival as a weighted average of the data cited above.  This weighted 
average will be used as the benchmark to which the data from the current trial will be compared. 
 
15.2 Stopping Rules. If sufficient evidence exists to suggest that the true probability of treatment-related death by 
day 100 exceeds 30%, we will reevaluate the prescribed conditioning regimens in combination with JAK inhibitor 
therapy and consider stopping the protocol.  
   
16.0 TERMINATION OF STUDY 
 
The PI may terminate the study at any time. The IRB also has the authority to terminate the study should it be 
deemed necessary. 

9033 
29 
 
REFERENCES 
 
1. 
Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 
inhibitor, in myelofibrosis. The New England journal of medicine 2010;363:1117-27. 
2. 
Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based 
on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009;113:2895-
901. 
3. 
Scott BL, Gooley TA, Sorror ML, et al. The Dynamic International Prognostic Scoring System for 
myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood 2012;119:2657-64. 
4. 
Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis 
with myeloid metaplasia. PLoS medicine 2006;3:e270. 
5. 
Kerbauy DM, Gooley TA, Sale GE, et al. Hematopoietic cell transplantation as curative therapy for 
idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia. Biology of blood and 
marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2007;13:355-65. 
6. 
Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from 
COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood 
2013;122:4047-53. 
7. 
Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis 
receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. 
Blood 2012;120:1202-9. 
8. 
Verstovsek S, Mesa RA, Gotlib J, et al. The clinical benefit of ruxolitinib across patient subgroups: 
analysis of a placebo-controlled, Phase III study in patients with myelofibrosis. British journal of haematology 
2013;161:508-16. 
9. 
Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibrosis. Biology of 
blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 
2010;16:358-67. 
10. 
Gupta V, Kroger N, Aschan J, et al. A retrospective comparison of conventional intensity conditioning 
and reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in myelofibrosis. Bone 
marrow transplantation 2009;44:317-20. 
11. 
Guardiola P, Anderson JE, Bandini G, et al. Allogeneic stem cell transplantation for agnogenic myeloid 
metaplasia: a European Group for Blood and Marrow Transplantation, Societe Francaise de Greffe de Moelle, 
Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative 
Study. Blood 1999;93:2831-8. 
12. 
Ditschkowski M, Beelen DW, Trenschel R, Koldehoff M, Elmaagacli AH. Outcome of allogeneic stem 
cell transplantation in patients with myelofibrosis. Bone marrow transplantation 2004;34:807-13. 
13. 
Ditschkowski M, Elmaagacli AH, Trenschel R, et al. Dynamic International Prognostic Scoring System 
scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic 
hematopoietic stem cell transplantation for myelofibrosis. Haematologica 2012;97:1574-81. 
14. 
Deeg HJ, Gooley TA, Flowers ME, et al. Allogeneic hematopoietic stem cell transplantation for 
myelofibrosis. Blood 2003;102:3912-8. 
15. 
Rezvani AR, McCune JS, Storer BE, et al. Cyclophosphamide followed by intravenous targeted busulfan 
for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical outcomes. Biology of blood and 
marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2013;19:1033-9. 
16. 
Kroger N, Zabelina T, Schieder H, et al. Pilot study of reduced-intensity conditioning followed by 
allogeneic stem cell transplantation from related and unrelated donors in patients with myelofibrosis. British 
journal of haematology 2005;128:690-7. 
17. 
Kroger N, Holler E, Kobbe G, et al. Allogeneic stem cell transplantation after reduced-intensity 
conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working 
Party of the European Group for Blood and Marrow Transplantation. Blood 2009;114:5264-70. 
18. 
Rondelli D, Barosi G, Bacigalupo A, et al. Allogeneic hematopoietic stem-cell transplantation with 
reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia. 
Blood 2005;105:4115-9. 
19. 
Alchalby H, Kroger N. Reduced-intensity conditioning followed by allogeneic hematopoietic stem cell 
transplantation in myelofibrosis. Current hematologic malignancy reports 2010;5:53-61. 

9033 
30 
 
20. 
Takagi S, Ota Y, Uchida N, et al. Successful engraftment after reduced-intensity umbilical cord blood 
transplantation for myelofibrosis. Blood 2010;116:649-52. 
21. 
Konuma T, Ooi J, Takahashi S, et al. Second myeloablative allogeneic stem cell transplantation (SCT) 
using cord blood for leukemia relapsed after initial allogeneic SCT. Leukemia research 2009;33:840-2. 
22. 
Mesa RA, Nagorney DS, Schwager S, Allred J, Tefferi A. Palliative goals, patient selection, and 
perioperative platelet management: outcomes and lessons from 3 decades of splenectomy for myelofibrosis with 
myeloid metaplasia at the Mayo Clinic. Cancer 2006;107:361-70. 
23. 
Ciurea SO, Sadegi B, Wilbur A, et al. Effects of extensive splenomegaly in patients with myelofibrosis 
undergoing a reduced intensity allogeneic stem cell transplantation. British journal of haematology 2008;141:80-
3. 
24. 
Michallet M, Corront B, Bosson JL, et al. Role of splenectomy in incidence and severity of acute graft-
versus-host disease: a multicenter study of 157 patients. Bone marrow transplantation 1991;8:13-7. 
25. 
Li Z, Gooley T, Applebaum FR, Deeg HJ. Splenectomy and hemopoietic stem cell transplantation for 
myelofibrosis. Blood 2001;97:2180-1. 
26. 
Robin M, Tabrizi R, Mohty M, et al. Allogeneic haematopoietic stem cell transplantation for 
myelofibrosis: a report of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (SFGM-TC). 
British journal of haematology 2011;152:331-9. 
27. 
Devine, S.M., Koen van Besien.  Allogeneic blood cell transplantation following reduced-intensity 
conditioning is effective therapy for older patients with myelofibrosis with myeloid metaplasia. Blood 2003; 
99.6.2255 
 
 
 

9033 
31 
 
Appendix A-Disease Criteria and Staging 
 
2008 WHO Classification System 
 
Requires A1 - A3 and any two B criteria 
A1 
Megakaryocyte atypia and fibrosis or megakaryocyte atypia, increased granulcytic and  
            decreased erythroid cellularity without fibrosis 
A2 
Not meeting WHO criteria for PV, CML, MDS or other myeloid neoplasm 
A3 
Acquired mutation or clonal marker or no reactive cause for fibrosis 
 
B1 
Leukoerythroblastic blood film 
B2 
Increased lactate dehydrogenase1 
B3 
Anemia2 
B4 
Palpable splenomegaly3 
 
1Degree of abnormality may be mild or marked;  
2Hemoglobin < 11.5g/dL for men, < 10 g/dL for women 
3Weight loss >10% over 6 months, drenching night sweats or diffuse bone pain 
 
Tefferi A, Vardiman  JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization 
criteria and point-of-care diagnostic algorithms. Leukemia. 2008;22:14-22.  
 
 
 
IWG for myeloproliferative neoplasms research and treatment criteria 
 
 
 
 
Barosi G, Mesa RA, Thiele J, et al; International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). 
Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus 
statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia. 2008;22:437-438. 
 
 

9033 
32 
 
 
 
 
 
  DIPSS Scoring System 
 
 
 
 
 
 
 
 
 

9033 
33 
 
Appendix B - Performance Status Criteria and Comorbidity Index 
 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 

9033 
34 
 
The Hematopoietic Cell Transplant-Comorbidity Index (HCT-CI) 
Instructions: Circle applicable scores and provide actual value or cause of' co-morbidity. 
Comorbidities  
Definitions 
 
HCT-CI 
weighted 
scores  
Actual Lab 
Values/Comments 
Arrhythmia 
Atrial fibrillation or flutter, sick sinus  syndrome, 
and ventricular arrhythmias 
1 
 
Cardiac 
Coronary artery disease, congestive heart failure, 
myocardial infarction, or EF<50% 
1 
 
Inflammatory bowel 
disease 
Crohn's disease or ulcerative colitis 
1 
 
Diabetes* 
Requiring treatment with insulin or oral 
hypoglycemics, but not diet alone 
1 
 
Cerebro-vascular 
disease 
Transient ischemic attack or cerebro-vascular 
Accident 
1 
 
 
 
Psychiatric 
Disturbance 
Depression anxiety requiring psychiatric consult 
or treatment 
1 
 
Hepatic -mild* 
Chronic hepatitis, Bilirubin >ULN- 1.5 X ULN, 
or AST/ALT >ULN-2.5XULN 
1 
 
 
Obesity* 
Patients with a body mass index > 35kg/ m2 
1 
 
 
 
Infection* 
Requiring continuation of anti-microbial 
Treatment after day 0 
1 
 
 
 
Rheumatologic 
SLE, RA, polymyositis, mixed CTD 
Polymyalgia rheumatic 
2 
 
 
Peptic ulcer* 
Requiring treatment 
2 
 
Moderate/severe 
renal* 
serum creatinine>2mg/dl, on dialysis, or prior 
renal transplantation 
2 
 
 
Moderate 
pulmonary* 
DLCO and/or FEV, >65%-80% or 
Dispend on slight activity 
2 
 
 
Prior solid tumor 
Treated at any time point in the patient's past 
history, excluding non-melanoma skin cancer 
3 
 
 
 
Heart valve disease* 
Except mitral valve prolapse 
3 
 
 
Severe pulmonary* 
DLCO and/or FEV1 <65% or 
dyspnea at rest requiring oxygen 
3 
 
Moderate/severe 
Hepatic 
Liver cirrhosis, Bilirubin>1.5XULN or 
AST/ALT>2.5XULN 
3 
 
 
 
 
Please provide                       Karnofksy performance 
Score=______________% 
     (KPS):  
Total 
Score 
=________
__ 
 
 
Completed by (print):______________________________________________ Date completed:_______________ 
 
Signature:______________________________________________ 
*Comorbidity is currently active or patient requires medical treatment + 
One or more vessel-coronary artery stenosis, requiring medical treatment, stent, or bypass graft  
EF indicates ejection fraction; ULN, upper limit of normal; SLE, systemic lupus erythematosus;  RA, rheumatoid arthritis; 
CTD, connective tissue disease; 
DLCO, diffusion capacity of carbon monoxide; FEV1, forced expiratory volume in one second; AST, aspartate 
aminotransfcrase; ALT, alanine aminotransferase 
 

9033 
35 
 
Appendix C - GVHD Assessment 
 
 
ACUTE GVHD ASSESSMENT 
 
Staging by Individual Organ Involvement 
 
SKIN: 
measured by rash first appearing generally between 10 and 70 days after transplant. (excludes 
rashes of known viral or other origin) 
 
Stage 
Description 
1 
Maculopapular rash <25% BSA 
2 
Maculopapular rash 25 – 50% BSA 
3 
Generalized erythroderma  
4 
Generalized erythroderma with 
bullous formation and desquamation 
 
LIVER*: measured by total serum bilirubin 
 
Stage 
Description 
1 
2.0 – 2.9 mg/dL 
2 
3.0 – 5.9 mg/dL 
3 
6.0 – 14.9 mg/dL 
4 
> 15.0 mg/dL 
 
GUT**: includes only diarrhea occurring after Day +21 
 
Score 
Adult 
Pediatric*** 
1 
upper GI (anorexia, nausea, 
vomiting) with diarrhea of <1000 
mL/day 
upper GI (anorexia, nausea, 
vomiting) with diarrhea of <555 
mL/m2/day 
2 
1000 – 1499 mL/day diarrhea 
556-833 mL/m2/day diarrhea 
3 
> 1500 mL/day diarrhea 
>833 mL/m2/day diarrhea 
4 
severe abdominal cramping, bleeding or ileus caused by GVHD 
 
* In cases where another cause of hyperbilirubinemia antedated the onset of rash, the liver score 
should be decreased by one stage. 
** In cases where peak GI symptoms are exacerbated by a cause other than GVHD, the gut score 
should be decreased by one stage. 
*** Pediatric patients <17 years of age 
 
 

9033 
36 
 
 
ACUTE GVHD ASSESSMENT 
 
Overall Grade 
 
The determination of an overall GVHD grade should be based on the organ stage, response to treatment 
and whether GVHD was a major cause of death. 
 
Overall 
Grade 
 Organ Stage 
Qualifying Conditions 
Additional Qualifying Conditions 
I 
Stage 1 -2 skin  
No liver or gut 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD. 
II 
Stage 3 skin  
 
or  
Stage 1 liver  
 
or  
Stage 1 gut 
N/A 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD, but glucocorticoid treatment 
after the onset of GVHD was generally 
sufficient to control the disease. 
III 
Stage 4 skin  
 
or  
Stage 2-4 liver  
 
or  
Stage 2-4 gut  
 
without GVHD as a 
major contributing cause 
of death 
 
 
Indicates that the prophylactic 
immunosuppressive regimen was not 
sufficient to prevent all manifestations of 
aGVHD and that additional treatment 
after the onset of GVHD did not readily 
control the disease. 
IV 
Stage 4 skin  
 
or  
Stage 2-4 liver  
 
or  
Stage 2-4 gut  
 
with GVHD as a major 
contributing cause of 
death 
 
 
GVHD was resistant to both the 
prophylactic immunosuppressive 
regimen and any additional treatment 
after the onset of the disease. 
 
References:  
 
1. Leisenring, WM, Martin, PJ, Petersdorf, EW, et al. An acute graft-versus-host-disease activity 
index to predict survival after hematopoietic cell transplantation with myeloablative conditioning 
regimens, Blood, 2006:108: 749-755. 
2. Przepiorka D, Weisdorf D, Martin PJ, et al. 1994 Consensus Conference on Acute GVHD 
Grading. Bone Marrow Transplant. 1995:15: 825-828. 
 
 
 
 

9033 
37 
 
Chronic graft-versus-host disease grading* 
 
In all cases, concomitant processes (i.e. infections or drug reactions) must be ruled out. Karnofsky or 
Lansky Clinical Performance scores, 60%, > 15% weight loss, and recurrent infections are usually signs 
of clinical extensive chronic GVHD. Abnormalities that could indicate chronic GVHD are categorized 
by organ systems as listed below. 
 
Skin 
Erythema, dryness, pruritus, pigmentary changes (i.e. hyperpigmentation, vitiligo), 
mottling, papulosquamous plaques, nodules, exfoliation, macular-papular or 
urticarial rash, scleroderma, morphea (one or several circumscribed, indurated and 
shiny lesions) 
Nails 
Ridging, onychodystrophy, onycholysis 
Hair 
Premature graying, (scalp hair, eyelashes, eyebrows), thinning scalp hair, alopecia, 
decreased body hair 
Mouth 
Dryness, burning, gingivitis, mucositis, striae, atrophy, erythema, lichenoid 
changes, ulcers, labial atrophy or pigmentary changes, tooth decay, tightness 
around the mouth 
Eyes 
Dryness, burning, blurring, gritty eyes, photophobia, pain 
Vagina/vulva 
Dryness, dyspareunia, stricture or stenosis, erythema, atrophy or lichenoid changes 
not included 
Liver 
Elevated liver function tests not due to other causes (alkaline phosphatase  3x 
upper limit of normal, AST or ALT 4x upper limit of normal or total serum 
bilirubin  2.5; in the absence of chronic GVHD involving other organs, liver 
biopsy is required to confirm diagnosis) 
Lung 
Bronchiolitis obliterans (see diagnostic indicators), cough, wheezing, dyspnea on 
exertion, history of recurrent bronchitis or sinusitis 
GI 
Anorexia, nausea, vomiting, weight loss, dysphasia, odynophagia, malabsorption 
Fasciitis 
Stiffness and tightness with restriction of movement, occasionally with swelling 
pain, cramping, erythema and induration, most commonly affecting forearms, 
wrists and hands, ankles, legs, and feet, inability to extend wrists without flexing 
the fingers or the elbows, contractures 
Serositis 
Chest pain or cardiopulmonary comprise due to pericarditis or pleuritis 
Muscle 
Proximal muscle weakness, cramping 
Skeletal 
Arthralgia of large proximal girdle joints and sometimes smaller joints 
 
________________ 
* From Standard Practice Guidelines for “Chronic Graft-versus-Host Disease Classification at the time 
of presentation” developed by Long Term Follow-Up at the FHCC 
 
 
 
 
 
 

9033 
38 
 
 
 
Laboratory testing and diagnostic indicators of chronic GVHD* 
Eye 
Schirmer’s test with a mean value  5mm at 5 minutes, or symptomatic with 
values of 6-10mm or keratitis detected by slit lamp examination 
Liver 
Elevated liver function tests not due to other causes (see definition of clinical 
limited and extensive chronic GVHD) 
Lung 
New obstructive lung defect defined as FEV1 < 80% of predicted with either an 
FEF 25-75 <65% of predicted or RV >120% of predicted, or a decrease of 
FEV1/FVC by > 12% within a period of less than 1 year. A diagnosis of 
bronchiolitis obliterans requires negative microbiological tests from 
bronchoalveolar lavage and evidence of air trapping by high resolution end-
expiratory and end-inspiratory CAT scans o the chest. A thoracoscopic lung 
biopsy may be necessary in order to confirm the diagnosis of bronchiolitis 
obliterans in patients who have obstructive lung disease without air trapping 
when chronic GVHD involving other organs is absent 
Esophagus 
Esophageal web formation, stricture or dysmotility demonstrated by barium 
swallow, endoscopy or manometry 
Muscle 
Elevated CPK or aldolase, EMG findings consistent with myositis 
Blood 
Thrombocytopenia (usually 20,000-100,000/l), eosinophilia, 
hypogammaglobulinemia, hypergammaglobulinemia, and autoantibodies occur 
in some cases 
________________ 
* From Standard Practice Guidelines for “Chronic Graft-versus-Host Disease Classification at the time 
of presentation” developed by Long Term Follow-Up at the FHCC 
 
 
 

9033 
39 
 
 
Appendix D  
Potential Adverse Events Associated or Expected with Hematopoietic Cell Transplantation 
 
1. Graft versus host disease:  GVHD is a major toxicity associated with the infusion of allogeneic donor stem 
cells.  GVHD may be acute or chronic and may affect multiple organ systems, including the skin, liver, and GI 
tract. 
 
2. Opportunistic infections, including viral and fungal infections, can result in severe pulmonary, neurologic, 
hepatic and other organ dysfunction, and possible death. 
 
3. Gastrointestinal toxicity. Nausea and vomiting can be anticipated during the entire course of ablative therapy. 
Mucositis and diarrhea should be expected. Prednisone can cause GI bleeding. 
 
4. Cardiac toxicity. Cardiotoxicity (congestive heart failure, pericardial effusion, EKG changes) is uncommonly 
associated with the chemotherapy agents and TBI used in the regimen and these sequelae may prove lethal. 
 
5. Pulmonary toxicity. Diffuse interstitial pneumonitis of unknown etiology and diffuse alveolar hemorrhage 
occurs with some regularity after BMT and interstitial fibrosis occurs much more rarely. Both are well-described 
complications of intensive chemotherapy and TBI regimens and may prove lethal. 
 
6. Hepatic toxicity. Veno-occlusive disease of the liver is a common toxicity of high-dose chemoradiotherapy and 
may result in death. Cyclosporine may cause elevation of ALT/AST. 
 
7. Renal dysfunction. Chemoradiotherapy may uncommonly cause renal dysfunction. More commonly, 
nephrotoxicity results from cyclosporine and generally responds to dose reduction. Rarely, idiopathic or 
calcineurin inhibitor-associated hemolytic-uremic syndrome may occur and may be progressive and fatal. A 
syndrome of moderate renal insufficiency and hemolysis has been seen 5-7 months post HSCT after intensive 
multi-agent conditioning plus TBI. 
 
8. Hemorrhagic cystitis, manifested either as gross or microscopic hematuria, is a common toxicity after high-
dose chemoradiotherapy, but usually associated with regimens that include cyclophosphamide. Hemorrhagic 
cystitis may predispose to a long-term increased risk of bladder cancer. 
 
9. Central nervous system toxicity. Radiation and chemotherapy can cause CNS toxicity, including seizures, 
depressed mental status, or leukoencephalopathy. Calcineurin inhibitors can cause seizures or other CNS toxicity. 
 
10. Marrow aplasia. Severe neutropenia, thrombocytopenia, and anemia, is expected to occur for a period of 7 to 
42 days following infusion of marrow. Transfusion of platelets and red blood cells is expected as supportive care. 
Transfusion of blood products may be associated with acquisition of HIV or a hepatitis virus. Neutropenia may 
increase the risk for acquiring serious infection. Thrombocytopenia may increase the risk of life-threatening 
hemorrhage. Hemorrhagic or infectious complications during the expected period of aplasia may result in death. 
 
11. Miscellaneous. Alopecia and sterility are expected complications of the program as a whole. Cataract 
development is possible after TBI and/or steroids. Deficiencies of growth hormone, thyroid hormone, and sex 
hormones are possible after TBI. Calcineurin inhibitors can cause transient gingival hyperplasia, tremor, seizure, 
hypertension, headache, dysesthesia and hirsutism. Steroid therapy can also contribute to fluid retention, easy 
bruising, hypertension, aseptic necrosis of bone and increased susceptibility to infection. MMF can cause 
spontaneous abortions and birth defects. Hospitalization during conditioning and recovery period is expected to be 
5-9 weeks in duration. 
 
 

9033 
40 
 
 
Appendix E - FHCC IRB Policies   
 
 
IRB Policy Web Page: http://extranet.fhcrc.org/EN/sections/iro/irb/policy/index.html 
 
Adverse Events and Noncompliance are addressed in the following policies: 
 
Policy 1.9: “Noncompliance” 
 
Policy 1.11: “Reporting Obligations for Principal Investigators” 
 
Policy 2.6:  “Unanticipated Problems Involving Risks to Subjects or Others” 
 
 
 
 

9033 
41 
 
Appendix F Schedule of Study Evaluations see section 10.8 for evaluation windows 
Study Evaluations 
Prior to 
JAK 
inhibitor  
Prior to 
Conditioning 
 
 
Long Term Follow-up 
Daily to 
engraftment  
Weekly to 
Day 100 
Day 0 
Day +10  
Day+28 
Day+56 
Day+80-
100 
6 months 
1 year 
2-5 years 
Informed Consent 
X9 
X 
 
 
 
 
 
 
 
 
 
 
H & P Exam 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
X 
DIPPS status 
X 
X 
 
 
 
 
 
 
 
 
X 
X 
Karnofsky 
X9 
X 
 
 
 
 
 
 
X 
 
X 
 
MRIMUGA/Echo, 
EKG, Chest CT  
 
X 
 
 
 
 
 
 
 
PRN 
PRN 
PRN 
CBC w/differential 
X 
X 
X 
X 
 
 
X 
 
X 
X 
X 
X 
Blood Chemistry 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Hepatic Panel 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Serum Iron, TIBC, 
ferritin 
X9 
X  
 
 
 
 
 
 
 
 
 
 
PB CD34 
X9 
X  
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X9 
X 
 
 
 
 
 
 
 
 
 
 
Viral screening 
 
X 
 
 
 
 
 
 
 
 
 
 
CMV Surveillance 
by PCR  
 
X 
 
X6 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
Disease Restaging: 
BM 
aspirate/biopsy 
X9 
X 
 
 
 
 
X 
 
X 
X1 
X 
X1 
Comorbidity 
 
X 
 
 
 
 
 
 
 
 
 
 
Spleen assessment5 
 
X 
 
 
 
 
 
 
X 
 
X 
 
Chimerism – Bone 
Marrow 
 
 
 
 
 
 
 
 
X 
X2 
X 
X2 
Chimerism – 
Peripheral Blood 
 
 
 
 
 
 
X8 
X7 
X 
X3 
X 
X3 
Research blood 
X9 
 X 
 
 
X 
      X 
X 
 
X 
 
X 
 
Research  marrow11 
X9 
 X 
 
 
 
 
 
 
 
 
X 
 
Sample Collection 
for V617F , 
CAL1R, MPL 
X9 
X 
 
 
 
 
 
 
X 
X10 
X 
X 
GVHD Evaluation 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Hot spot lab test 
X 
X10 
 
 
 
 
 
 
 
 
 
 
Notes: 1 Day 180 will only be done if residual disease in marrow or JAK mutation still positive  at day 80 and 2-5 year BM biopsy will only be done if residual disease in marrow or JAK mutation still positive at 1year or  
prior yearly check. 2 Day 180,  and 2-5 year chimerisms will only be done only if previous chimerism did not show greater than 95% engraftment. 3 Chimerisms should be performed as clinically indicated ( in patients with 
unresolved or new cytopenia or mixed chimerism.  5 If patient is unable to have an MRI performed, CT chest, abdomen and pelvis, or ultra sound,  may be substituted to assess spleen volume as well as extramedullary sites 
of disease.  6Twice weekly for UCBT.   7If clinically indicated. 8UCBT and non-myeloablative only. 9 If enrolled in Part 1. 10If positive at day80-100 evaluation. 10If not enrolled in part 1 or not done when enrolled in part 1. 
11Collect research bone marrow if possible