The MPN PROGRESSion Registry: A Retrospective and Prospective Observational Study Collecting Patient-Reported Outcomes, Electronic Health Records, and Claims Data to Track Symptoms, Treatments, and Disease Progression in Individuals Diagnosed With Myeloproliferative Neoplasms (MPNs).
Conditions: Polycythemia Vera, ET (Essential Thrombocythemia), Polycythemia Vera (PV), Essential Thrombocythemia (ET), Primary Myelofibrosis (MF), Primary Myelofibrosis (PMF), Myelofibrosis, Myelofibrosis (MF), Myelofibrosis, Primary, Myelofibrosis, Post ET, Myelofibrosis, Post PV, Myelofibrosis (PMF), Myelofibrosis，MF, Myelofibrosis; Primary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis, Myelofibrosis Due to and Following Polycythemia Vera, Myelofibrosis Transformation in Essential Thrombocythemia, Myelofibrosis With High Molecular Risk Mutations, MF, Secondary Myelofibrosis, Secondary Myelofibrosis in Myeloproliferative Disease, Secondary Myelofibrosis (Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis), Post-Polycythemia Vera Myelofibrosis, Post-polycythemia Vera Myelofibrosis (PPV-MF), Post-polycythemia Vera Myelofibrosis (Post-PV MF), Post-polycythemia Vera Myelofibrosis(Post-PV MF), Post-PV MF, Post-Essential Thrombocythemia Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis (PET-MF), Post-essential Thrombocythemia Myelofibrosis(Post-ET MF), Post-essential Thrombocythemia Myelofibrosis (Post-ET MF), Post-ET MF, Pre-fibrotic Myelofibrosis, Myeloproliferative Disorder, Myeloproliferative Disorders, Myeloproliferative Disorders (MPD), Myeloproliferative Neoplasms (MPNs), Myeloproliferative Neoplasm(MPN)-Associated Myelofibrosis, Myeloproliferative Neoplasm With 10% Blasts or Higher, Myeloproliferative Neoplasms, MPN, MPN (Myeloproliferative Neoplasms), MPN-associated Myelofibrosis, Myeloproliferative Neoplasm, Unclassifiable, Myeloproliferative Neoplasm, Not Otherwise Specified, Accelerated Phase MPN, Accelerated Phase Myeloproliferative Neoplasm, Blast Phase MPN, Blast Phase Myeloproliferative Neoplasm, Thrombocythemia Myelofibrosis (PET-MF), Thrombocythemia, Essential, Thrombocythemia, Hemorrhagic, Agnogenic Myeloid Metaplasia, Chronic Idiopathic Myelofibrosis, Idiopathic Myelofibrosis, MDS/MPN Crossover Syndromes
Sponsor: MPN Research Foundation

 
 
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MPN PROGRESSion Registry™ (PROGRESS-MPN): A U.S.-Based 
Observational Study Tracking Symptoms, Treatments, Clinical Outcomes, and 
Disease Progression in Myeloproliferative Neoplasms 
 
Protocol Reference Number: 
MPNRF-PROG-2025-001 
 
IRB Protocol Number: 
20251868 
 
Version Number: 
Version 1.1 
 
Version Date: 
Nov12, 2025 
 
Sponsor: 
MPN Research Foundation   
515 N State Street, 14th Floor   
Chicago, IL 60654 
 
Principal Investigator: 
Raajit Rampal, MD, PhD   
Memorial Sloan Kettering Cancer Center, New York, NY 
 
Sub-Investigators: 
Douglas Tremblay, MD — Icahn School of Medicine at Mount Sinai, New York, NY   
Jan Bewersdorf, MD — Yale School of Medicine, New Haven, CT 
 

 
 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ......................................................................................................... 4 
1. BACKGROUND ........................................................................................................................ 6 
1.1 Study Rationale ......................................................................................................................... 6 
2. PURPOSE ................................................................................................................................... 6 
3. OVERALL STUDY DESIGN .................................................................................................... 7 
4. OBJECTIVES ............................................................................................................................. 7 
4.1. Primary Objectives................................................................................................................... 7 
4.2. Secondary Objectives............................................................................................................... 9 
4.3. Exploratory Objectives ............................................................................................................ 9 
5. PARTICIPATION CRITERIA ................................................................................................... 9 
5.1 Inclusion Criteria ...................................................................................................................... 9 
5.2 Exclusion criteria .................................................................................................................... 10 
6. PARTICIPANT RECRUITMENT AND ENROLLMENT ..................................................... 10 
6.1. Duration of Observation and Participation ............................................................................ 10 
6.2. Informed Consent................................................................................................................... 11 
6.3. Visit Schedule ........................................................................................................................ 11 
6.3.1. Data Collection Intervals and Structured Follow-Up Schedule .......................................... 11 
6.3.2. Disease Progression and Post-Enrollment Markers ............................................................ 12 
6.3.3. Patient Retention and Engagement Strategies .................................................................... 12 
6.3.4. Data Quality Assurance and Compliance ........................................................................... 13 
6.4. Costs to the Participant and Payment for Participation ......................................................... 14 
6.4.1. No Direct Costs to Participants ........................................................................................... 14 
6.4.2. Participant Payment and Engagement Incentives ............................................................... 14 
6.4.3. Potential Indirect Costs ....................................................................................................... 14 
6.4.4. Payments from External Researchers for Data Access ....................................................... 14 
6.4.5. Ethical Considerations and Regulatory Compliance .......................................................... 14 
7. METHODS AND PROCEDURES........................................................................................... 15 
7.1. Data sources ........................................................................................................................... 15 
7.2. Data Storage and Sharing ....................................................................................................... 16 
7.3. Data Monitoring Plan ............................................................................................................. 17 
7.4. Research Methods .................................................................................................................. 17 
7.5. Withdrawal/Discontinuation .................................................................................................. 18 
7.6 Patient-Reported Outcomes Collection................................................................................... 18 

 
 
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7.6.1 Overview .............................................................................................................................. 18 
7.6.2 Selected Patient-Reported Outcomes Measures .................................................................. 18 
7.6.3 Data Collection Schedule ..................................................................................................... 19 
7.6.4 Data Integration and Analysis .............................................................................................. 20 
7.7 Study Sites and Coordinating Center ...................................................................................... 21 
8. RISK/BENEFIT ASSESSMENT ............................................................................................. 21 
8.1. Potential Risks ....................................................................................................................... 21 
8.2. Benefits .................................................................................................................................. 21 
8.3. Protection of Human Participants .......................................................................................... 22 
9. STATISTICAL CONSIDERATIONS ..................................................................................... 22 
9.1 Statistical Analysis Plan (SAP) ............................................................................................... 23 
9.2 Interim Analyses and Data Monitoring ................................................................................... 23 
9.3 Subgroup Analyses ................................................................................................................. 23 
9.4 Handling Multiple Testing ...................................................................................................... 23 
9.5 Competing Risks and Time-dependent Covariate Analyses ................................................... 24 
9.6 Missing Data and Sensitivity Analyses................................................................................... 24 
9.7 Propensity Score Methods ...................................................................................................... 24 
9.8 Statistical Software and Analysis Environment ...................................................................... 24 
9.9 Consideration for Potential Data Biases ................................................................................. 24 
9.10. Disseminating and Communicating Study Results .............................................................. 25 
10. APPENDIX ............................................................................................................................. 26 
10.1 WHO Criteria for Polycythemia Vera .................................................................................. 26 
10.2 WHO Diagnostic Criteria for Essential Thrombocythemia .................................................. 26 
10.3 WHO Diagnostic Criteria for Primary Myelofibrosis .......................................................... 27 
10.4. WHO Diagnostic Criteria for pre-PMF ............................................................................... 28 
10.5. IWG-MRT Criteria for Secondary Myelofibrosis ............................................................... 29 
10.6: Pre-Screening Questions for Participant Eligibility............................................................. 30 
10.7: Participant Notification Messages ....................................................................................... 34 
11. REFERENCES ....................................................................................................................... 36 

 
 
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LIST OF ABBREVIATIONS 
 
BMT 
bone marrow transplant 
CMML 
chronic myelomonocytic leukemia 
EMR 
electronic medical record 
ET 
essential thrombocythemia 
FHIR 
Fast Healthcare Interoperability Resources 
ICF 
informed consent form 
IRB 
institutional review board 
IWG-MRT 
International Working Group for Myelofibrosis Research and 
Treatment 
LAR 
legally authorized representative 
MDS 
myelodysplastic syndrome 
MDS/MPN-SF3B1-T 
MDS/MPN with SF3B1 and thrombocytosis 
MF 
Myelofibrosis 
MPN 
myeloproliferative neoplasm 
MPN-AP 
myeloproliferative neoplasm in accelerated phase 
MPN-BP 
myeloproliferative neoplasm in blast phase 
MPN-U 
myeloproliferative neoplasm, unclassifiable 
PI 
principal investigator 
PRO 
patient-reported outcomes 
pre-PMF 
pre-fibrotic primary myelofibrosis 
PV 
polycythemia vera 
QOL 
quality of life 
RWE 
real world evidence 
SCT 
stem cell transplant 
US 
United States 
WHO 
World Health Organization 
 
 
 
 
 
 
 

 
 
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1. BACKGROUND 
Patients diagnosed with myeloproliferative neoplasms (MPNs)—including primary 
myelofibrosis (MF), essential thrombocythemia (ET), and polycythemia vera (PV)—face 
progressive bone marrow diseases largely driven by JAK2, CALR, or MPL mutations.1-4 These 
conditions lead to overproduction of mature blood elements, marrow fibrosis, and heightened 
risks of thrombosis, cardiovascular events, and inflammatory complications.5-7 Although some 
patients live decades post-diagnosis, quality of life is often significantly reduced, and 
transformation to acute leukemia (MPN-BP) carries poor outcomes.8-9 
Despite affecting an estimated 300,000 individuals in the U.S.,10 much remains unknown about 
the biological drivers of disease progression, predictive biomarkers, and meaningful surrogate 
endpoints. Existing MPN registries have provided valuable but limited insights, often 
constrained to single-center, clinician-reported, or trial-based cohorts.11 This Registry addresses 
these gaps by integrating electronic medical records (EMRs), patient-reported outcomes (PROs), 
claims data, and genomic profiles across a broad patient spectrum—including pre-fibrotic MF 
(pre-PMF), MPN-AP, MPN-BP or post-MPN AML, and MDS/MPN overlap syndrome (defined 
as CMML, MDS/MPN-SF3B1-T, MDS/MPN with neutrophilia, or MDS/MPN not otherwise 
specified), including patients originally diagnosed with one of these conditions but who have 
received one or more SCTs and/or BMTs —supporting comprehensive longitudinal tracking of 
disease evolution, treatment response, and EMR. 
1.1 Study Rationale 
Historically, efforts to understand MPN disease progression have been siloed within individual 
research centers, leaving critical data gaps despite decades of published studies and a few 
approved therapies. This Registry aims to establish a robust, longitudinal observational research 
platform to address these unmet needs, benefiting the broader MPN community. 
Using a digital health platform, the Registry will collect multimodal data—centered on patient 
(EMRs) and enriched by self-reported outcomes. The cohort will include patients diagnosed with 
primary or secondary MF, ET, PV, pre-PMF, MPN-unclassifiable (MPN-U), MPN-AP, and 
MPN-BP or post-MPN AML, MDS/MPN overlap syndrome as defined above. This will also 
include patients originally diagnosed with one of these conditions but who have received one or 
more SCTs and/or BMTs. 
By integrating EMR data, PROs, claims data, and linked registries, this study enables 
comprehensive longitudinal analysis of disease trajectories, treatment patterns, and quality-of-
life outcomes. The Registry’s real-world evidence (RWE) will help identify early predictors of 
progression, validate surrogate endpoints, and support future clinical trials and drug 
development. 
Ultimately, this infrastructure will enhance regulatory decision-making, inform treatment 
guidelines, and improve prognostic modeling—advancing precision care and outcomes for 
patients with MPNs. 
2. PURPOSE 
The purposes of the MPN PROGRESSion Registry™ (“Registry”) are to: 

 
 
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• 
Facilitate high-quality observational research by collecting and analyzing EMRs, 
PROs, and linked external datasets — including mortality records, insurance claims, 
genetic testing results, and affiliated registries — to advance understanding of disease 
natural history, progression, real-world therapeutic effectiveness, and standards of care. 
• 
Improve clinical definitions of MPN disease progression by incorporating updated 
diagnostic criteria and emerging biomarkers, ensuring refined characterization of pre-
fibrotic myelofibrosis (pre-PMF), MPN in accelerated phase (MPN-AP), MPN in blast 
phase (MPN-BP) or post-MPN AML, and MDS/MPN overlap syndrome as defined 
above 
• 
Identify predictive biomarkers and surrogate endpoints to support drug development, 
regulatory decision-making, and improved understanding of disease progression. 
• 
Enhance standards of care and patient outcomes by leveraging RWE and longitudinal 
analytics to inform treatment sequencing, monitor therapeutic responses, and guide 
personalized care strategies. 
• 
Support participant identification for future research by enabling review of Registry 
data to identify and contact individuals eligible for future studies conducted by the MPN 
Research Foundation or approved collaborators. 
3. OVERALL STUDY DESIGN 
This is a prospective, non-interventional observational study, designed to evaluate patients with 
MPNs using both historical and prospective data. Participants will be enrolled over a minimum 
of three years during the initial run-in phase and followed longitudinally for disease progression, 
treatment response, clinical outcomes, and survival until withdrawal from the registry or death. 
Some participants may be followed for over ten years. 
The study uses a multimodal data collection strategy, integrating: 
• 
EMRs: Structured data extractions, including laboratory results, imaging, clinical notes, 
and treatment history. 
• 
PROs: Longitudinal assessments of symptoms, quality of life, and functional status. 
• 
Medical Claims and Insurance Data: Real-world healthcare utilization, treatment 
adherence, and cost metrics. 
• 
Mortality Data: Vital status and cause-specific mortality obtained through national 
mortality dataset linkages, ensuring accurate survival analyses and minimizing loss to 
follow-up. 
• 
Affiliated Registries: Select collaborations (e.g., CIBMTR, NCDB, SEER) may be used 
for external validation and cross-registry comparisons, though integration with 
international registries such as the European LeukemiaNet (ELN) will be considered only 
after addressing jurisdictional and data governance factors. 
In addition to evaluating disease and treatment outcomes, the Registry will systematically 
monitor enrollment feasibility, participant retention, and heterogeneity across demographic, 
clinical, and geographic dimensions. These metrics will support reporting obligations to federal 
registries (e.g., ClinicalTrials.gov) and inform future feasibility assessments for interventional 
trials. 
4. OBJECTIVES 
4.1. Primary Objectives 

 
 
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Stage 1: Feasibility Phase 
The study will begin with a 12- to 24-month feasibility phase focused on participant retention, 
data completeness, EMR integration, and engagement strategies. Results from this phase will 
help optimize study operations, guide participant engagement, and inform potential protocol 
amendments. 
• 
Evaluate enrollment feasibility and participant characteristics during the first 12–24 
months. 
• 
Characterize participant demographics, geographic distribution, and clinical settings. 
• 
Assess inclusion of underrepresented populations to enhance the generalizability and 
heterogeneity of RWD. 
• 
Assess representativeness of enrolled participants relative to the broader U.S. MPN 
population, ensuring alignment with clinical and demographic patterns. 
• 
Determine the proportion of participants providing a Minimal Viable Dataset (MVD) at 
enrollment. 
• 
Monitor consent rates for longitudinal EMR access and secondary data use. 
• 
Identify gaps in baseline data completeness and develop strategies to mitigate missing 
information. 
• 
Track participant retention at 12, 18, 24, and 36 months, and evaluate completion of at 
least three consecutive follow-ups. 
• 
Identify early indicators of dropout or disengagement to inform retention strategies. 
• 
Monitor response rates to quarterly PRO surveys (e.g., MPN-SAF TSS, PROMIS Short 
Form v1.0 – Fatigue 8a) and evaluate follow-up strategies (automated vs. manual). 
• 
Assess the proportion of participants using secondary contacts (caregivers, clinicians) for 
follow-up. 
• 
Measure success rates of EMR integration across sites using FHIR-based interoperability, 
compare self-reported and EMR-extracted data, and validate processing scalability. 
Stage 2: Surrogate Endpoint Phase 
• 
Establish composite surrogate endpoints integrating genetic markers (e.g., variant allele 
frequency shifts), clinical indicators (e.g., fibrosis progression, cytopenias), inflammatory 
markers (e.g., cytokine levels), and PROs (e.g., MPN-SAF TSS, PROMIS trends). 
• 
Ensure surrogate endpoints align with FDA and EMA regulatory standards for clinical 
trials. 
• 
Incorporate RWD (EMR, claims, PROs) to validate surrogate markers of disease 
progression. 
• 
Determine time from baseline to first progression event (e.g., ET → PV → MF, blast 
phase transformation) and assess median time to progression by subtype. 
• 
Measure progression rates per WHO 2022/IWG-MRT criteria using updated risk 
stratification models. 
• 
Develop surrogate endpoints predictive of disease progression and treatment response to 
support drug development. 
• 
Compare progression rates in treated vs. untreated cohorts and validate endpoints using 
external registries (e.g., SEER, NCDB, Mayo Clinic MPN Database, ELN). 
• 
Monitor overall survival (OS) and progression-free survival (PFS), evaluating prognostic 
significance of surrogate endpoints for future trials. 

 
 
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4.2. Secondary Objectives 
• 
Characterize Disease Burden and Risk Stratification 
Develop a composite risk model distinguishing high- and low-risk patients by integrating 
genetic, inflammatory, and clinical markers. Assess how cytokine levels and 
inflammatory pathways influence disease trajectory and symptom burden. 
• 
Evaluate Treatment Response as a Surrogate for Disease Progression 
Compare progression rates in patients treated with JAK inhibitors, interferons,  
investigational agents, and other drugs. Determine whether therapy-induced molecular or 
clinical changes correlate with improved outcomes. 
• 
Analyze Genetic and Morphological Disease Evolution 
Monitor available variant allele frequency (VAF) changes in high-risk mutations and 
evaluate bone marrow fibrosis progression, where data is available, to understand clinical 
implications. 
• 
Assess Quality of Life and Symptom Burden at Disease Progression 
Track longitudinal changes using validated PROs, including MPN-SAF TSS, EORTC 
QLQ-C30, modified PHQ-9, PGI-S, and PROMIS Short Form v1.0 – Fatigue 8a, to 
evaluate how symptom burden correlates with disease progression 
4.3. Exploratory Objectives 
• 
Develop Predictive Models for MPN Progression 
Train and validate artificial intelligence (AI) and machine learning (ML) models to 
predict time to disease progression, likelihood of transformation to accelerated or blast 
phase, and overall survival using early clinical and molecular indicators. 
• 
Validate Findings Across External Data Sources 
Compare registry data against European MPN registries, Mayo Clinic datasets, and 
claims-based registries to assess consistency, generalizability, and cross-cohort 
validation. 
• 
Assess Healthcare Utilization and Economic Impact 
Track hospitalization rates, transfusion needs, major interventions, and conduct cost-
effectiveness analyses to inform early intervention strategies and support health policy 
development 
• 
Assess Early Patterns of Care and Treatment Setting Influence 
Evaluate how early patterns in healthcare utilization—including differences between 
academic centers, community hospitals, and rural clinics—impact disease monitoring, 
treatment choices, referral patterns, and long-term outcomes. Identify disparities in access 
to specialized care and examine how practice setting influences adherence to evidence-
based guidelines and clinical outcomes. 
5. PARTICIPATION CRITERIA 
5.1 Inclusion Criteria 
• 
Confirmed diagnosis of pre-PMF, primary MF, secondary MF, PV, ET, MPN-U, MPN-
AP,   MPN-BP or post-MPN AML, and MDS/MPN overlap syndrome as defined above 
per WHO 2022 criteria, including patients originally diagnosed with one of these 
conditions but who have received one or more SCTs and/or BMTs 
• 
Willingness and ability to provide written informed consent. 

 
 
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• 
Willingness and ability to complete patient assessments, independently or with minimal 
assistance. 
• 
Accessible EMR data from a participating healthcare institution to enable longitudinal 
data collection. 
• 
U.S. residency, where the Registry has regulatory approvals and data-sharing agreements. 
• 
Reasonable expectation of ongoing medical care and follow-up data availability for 
longitudinal objectives. 
5.2 Exclusion criteria 
Participants will be excluded if they meet any of the following: 
1. Lack of EMR data access due to technical limitations, non-participating institutions, or 
missing patient authorization (self-reported or claims-only data is insufficient for 
inclusion). 
2. Missing compulsory data elements: WHO 2022 MPN diagnosis, date of initial diagnosis, 
or baseline demographics. 
3. Lack of capacity to provide informed consent and absence of a legally authorized 
representative. 
4. Significant gaps in clinical history, lab data, treatment records, or follow-up availability 
that limit longitudinal analysis. 
5. Revised diagnosis to a non-MPN hematologic malignancy or other condition outside 
WHO 2022 criteria (other than post-MPN AML, and MDS/MPN overlap syndrome as 
defined above); such participants will be removed from future analyses. 
6. Enrollment in external studies that restrict medical data access or impose data-sharing 
limitations incompatible with this Registry. 
6. PARTICIPANT RECRUITMENT AND ENROLLMENT 
The MPN Research Foundation aims to enroll a representative cohort that reflects the 
heterogeneity of MPN biology across varied ancestral, socioeconomic, geographic, and clinical 
backgrounds. Recruitment strategies will include: 
• 
Establishing partnerships with community health centers, primary care providers, and 
hematology/oncology clinics to broaden outreach. 
• 
Utilizing targeted online advertising through search engines and social media platforms, 
patient advocacy networks, and Search Engine Optimization (SEO) to enhance visibility. 
• 
Providing standardized educational toolkits to healthcare providers to promote referrals. 
• 
Deploying patient navigators to engage potential participants via phone, email, or online 
platforms to address barriers. 
• 
Offering multilingual, plain-language materials to improve accessibility and health 
literacy. 
• 
Monitoring demographic heterogeneity in real time and adjusting strategies to improve 
representation of underrepresented populations. 
6.1. Duration of Observation and Participation 
Participants will be followed for a minimum of five years, with the potential for extended 
participation beyond ten years to support long-term observational analyses. 

 
 
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Standardized data collection will occur at baseline, six months, and every six months thereafter. 
Collected data will include: 
• 
EMR extractions (clinical history, labs, imaging, treatments) 
• 
Insurance claims and pharmacy records (healthcare utilization, medication use) 
• 
PROs, including MPN-SAF TSS, PROMIS Short Form v1.0 – Fatigue 8a, and quality-of-
life assessments 
Data integration will prioritize FHIR-based EMR retrieval, supplemented by validated 
participant surveys and secondary data sources. 
Ongoing monitoring and planned assessments include: 
• 
Year 1: Baseline validation, data completeness review, and participant engagement 
check 
• 
Year 3: Disease trajectory modeling, retention analysis, and interim outcome assessment 
• 
Year 5 and beyond: Predictive analytics on disease progression, long-term outcomes, 
and composite endpoint evaluation 
To promote retention, the Registry will deploy automated reminders, provide quarterly study 
updates, and offer virtual engagement opportunities (e.g., newsletters, webinars). Participants 
may withdraw at any time, as outlined in Section 6.2. 
6.2. Informed Consent 
All participants (or their legally authorized representatives) will provide written informed 
consent using an IRB-approved form detailing the study’s purpose, duration, procedures, risks, 
benefits, and privacy protections. Informed consent allows the study team to access participant 
medical records, collect survey and PRO data, and link external datasets (e.g., claims, mortality, 
genetic testing) for approved research purposes. Participants will have the opportunity to ask 
questions prior to signing and will receive a copy of the signed consent for their records. Consent 
can be withdrawn at any time without penalty. Consent materials will be available electronically, 
with printable copies provided via the MPN Research Foundation website. A secure, encrypted 
system will capture and store electronic signatures. 
6.3. Visit Schedule 
The Registry is designed for extended longitudinal follow-up, with no required in-person study 
visits due to its non-interventional, observational nature. Data will be collected continuously 
through EMRs, PROs, insurance claims, mortality data, and linkages to affiliated registries. 
 
The visit schedule aligns with structured follow-up intervals to ensure consistent longitudinal 
tracking of disease progression, treatment response, and post-enrollment clinical markers. 
Retention and engagement strategies will be employed to maintain data completeness and 
minimize loss to follow-up. 
6.3.1. Data Collection Intervals and Structured Follow-Up Schedule 
Participants will be followed for a minimum of five years, with many continuing beyond ten 
years. 
Follow-Up 
Data Collected 
Collection Method 

 
 
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Timepoint 
Baseline 
(Enrollment) 
Demographics, medical history, WHO 2022 MPN 
subtype, other hematologic disease information 
(e.g., post-MPN AML, MDS/MPN overlap 
syndrome as defined above, history of SCT and/or 
BMT) baseline labs, molecular testing (if 
available), treatment history, and PROs (MPN-
SAF TSS, EORTC QLQ-C30, modified PHQ-9, 
PGI-S, PROMIS Short Form v1.0 – Fatigue 8a) 
Initial EMR 
extraction, PROs, 
insurance claims 
Every 3 Months 
(0-10+ yrs) 
Symptom burden updates (MPN-SAF TSS + PGI-
S) 
PROs 
Every 6 Months 
(0-10+ yrs) 
Updates on disease status, treatment changes, 
adverse events, healthcare utilization, 
molecular/genetics results (if available), mortality 
status, progression milestones, and PROs (MPN-
SAF TSS, EORTC QLQ-C30, modified PHQ-9, 
PROMIS Short Form v1.0 – Fatigue 8a) 
EMR reauthorization, 
PROs, claims 
retrieval, mortality 
data linkage 
 
6.3.2. Disease Progression and Post-Enrollment Markers 
The Registry will monitor disease evolution, therapeutic response, and emerging clinical risks 
through ongoing data collection from EMRs, laboratory results, imaging reports, mortality 
linkages, healthcare utilization data, and PROs. 
Key post-enrollment markers include: 
• 
Molecular and Genetic Changes: Emergence of high-risk mutations and shifts in VAF 
over time. 
• 
Bone Marrow and Imaging Biomarkers: Assessments of fibrosis and splenomegaly 
progression, based on clinically indicated bone marrow biopsies or imaging. 
• 
Symptom Burden and Quality of Life: Trends captured through validated PROs, 
including MPN-SAF TSS, EORTC QLQ-C30, modified PHQ-9, PGI-S, and PROMIS 
Fatigue Short Form. 
• 
Cardiovascular and Thrombotic Events: Documentation of new complications such as 
deep vein thrombosis, pulmonary embolism, stroke, or myocardial infarction. 
• 
Mortality Status: Vital status and cause of death, obtained through national mortality 
data linkages. 
To maintain complete and up-to-date records, participants will be asked every six months to 
refresh their EMR data access permissions. 
6.3.3. Patient Retention and Engagement Strategies 
To support long-term participant retention, the Registry will implement a multi-faceted 
engagement approach that includes: 

 
 
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• 
Automated Communications: 
Email and SMS reminders will notify participants about upcoming surveys, EMR data 
refreshes, and study milestones. 
• 
Aggregate Study Updates: 
Participants will periodically receive summaries of registry progress, including 
enrollment trends, geographic representation, heterogeneity metrics, and de-identified 
PRO findings (MPN-SAF TSS, EORTC QLQ-C30, modified PHQ-9, PGI-S, PROMIS 
Fatigue Short Form), delivered via secure channels. 
• 
Educational Materials: 
Plain-language resources will explain how participant contributions advance MPN 
research and improve understanding of disease progression. 
• 
Interactive Opportunities: 
Invitations to webinars, virtual town halls, or Q&A sessions will allow participants to 
hear updates directly from investigators. 
• 
Non-Monetary Incentives: 
Digital badges, certificates,  or eligibility for future research opportunities will help 
sustain engagement. 
• 
Patient Support Access: 
A dedicated patient navigator will assist with survey completion, consent renewals, and 
EMR data access questions. 
As PRO surveys and EMR refreshes occur approximately every six months, communications 
will reflect cumulative study updates. All outreach will use de-identified data, and participants 
will have secure access to their own summaries through the registry dashboard. 
6.3.4. Data Quality Assurance and Compliance 
To ensure the highest quality of data capture across all sources, the Registry will implement the 
following quality assurance measures: 
• 
Automated Data Validation Checks 
Incoming data will be systematically screened for missing values, inconsistencies, and 
outliers at the point of entry using predefined validation rules aligned with international 
standards (ICD-10, SNOMED CT, LOINC). 
• 
Cross-Source Data Verification 
Clinical data extracted from EMRs will be compared against PROs to confirm 
consistency, with discrepancies flagged for review. 
• 
Audit Trails and Data Security 
All data modifications, including additions, corrections, or deletions, will be tracked 
through secure, HIPAA-compliant audit trails to ensure full traceability. 
• 
Regulatory Compliance 
All procedures will adhere to U.S. FDA and EMA guidelines for the use of RWE in 
regulatory decision-making, ensuring compliance with relevant national and international 
standards. 
• 
Periodic Reviews and Oversight 
The PI and designated data management personnel will perform regular reviews to assess 
adherence to protocol-defined quality benchmarks. The Registry’s scientific steering 

 
 
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committee will also receive summary reports detailing data completeness, validation 
outcomes, and unresolved issues. 
These layered measures will ensure the Registry produces accurate, reliable, and high-quality 
datasets suitable for robust observational research and regulatory submission. 
6.4. Costs to the Participant and Payment for Participation 
Participation in the Registry is voluntary, and participants will not incur direct costs for 
enrollment, data submission, or study-related activities. To acknowledge the time and effort 
required, the Registry will offer non-monetary engagement incentives, including entry into 
periodic randomized incentive distributions, designed to support retention without exerting 
undue influence or coercion. 
 
6.4.1. No Direct Costs to Participants 
Participants will not be charged for completing electronic surveys, EMR data retrieval, or other 
study-related activities. All Registry tasks, including PRO completion, EMR refreshes, and 
communications, are provided at no financial burden. 
6.4.2. Participant Payment and Engagement Incentives 
• 
Participation-Based Incentives: 
Participants who complete biannual PRO surveys and remain actively enrolled will be 
automatically entered into periodic incentive drawings. Specifically, gift card drawings 
will be conducted periodically for survey completion and active retention. Winners will 
be selected at random, and no additional steps are required beyond completing the 
associated activities. 
• 
Non-Monetary Engagement Opportunities: 
Participants will have access to educational materials, aggregate study progress updates, 
invitations to webinars or virtual events, and optional certificates or badges recognizing 
their contributions to MPN research. 
 
6.4.3. Potential Indirect Costs 
Participants may require internet, smartphone, or computer access to complete study activities. 
While the Registry will minimize any institutional or medical record retrieval fees, these costs 
are not typically covered. 
 
6.4.4. Payments from External Researchers for Data Access 
The MPN Research Foundation may receive payments from approved external investigators who 
access de-identified data for secondary research. These funds will support Registry operations, 
improve data quality, and advance MPN research; they will not affect individual participant 
incentives. 
 
6.4.5. Ethical Considerations and Regulatory Compliance 
All compensation and incentive approaches comply with IRB, FDA, and EMA regulations. 
Participants will receive IRB-approved disclosures detailing drawing eligibility, prize 
distribution, data use, and external funding. Compensation is structured to ensure fair 
acknowledgment of participant contributions without coercion or undue influence. 

 
 
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7. METHODS AND PROCEDURES 
Participation in the Registry consists of collection of the participants’ information in a research 
database and the use of this information for observational research studies and for identification 
and recruitment of potential eligible participants for future research studies. 
 
7.1. Data sources 
Data collection for the registry will be done in non-interventional settings. This is not a clinical 
trial. 
 
1. Registry participants may use a mobile and/or web-based application to add their 
participant-reported data (“Participant-Reported Data”).  
 
2. Registry participants will be asked to provide their written informed consent for their 
health care providers to disclose relevant EMRs to MPN Research Foundation for 
inclusion in the Registry and for MPN Research Foundation to access EMRs directly 
using a medical records technology interface (“EMR Data” and together with PROs and 
Survey Data, “Registry Data”). 
 
3. Registry participants will also provide information in response to surveys periodically 
administered by MPN Research Foundation (“Survey Data”).  
 
4. Additional data may be generated from:  
a. Medical claims and insurance data. 
b. Mortality Data: Vital status and cause-specific mortality outcomes will be 
captured through linkage to national mortality datasets. This linkage will 
strengthen the accuracy of survival analyses, enhance longitudinal outcome 
assessments, and minimize loss to follow-up. 
c. Data from affiliated disease registries. 
 
5. The registry will collect a wide range of data variables, ensuring a holistic understanding 
of disease progression and treatment effects. These variables include: 
a. Demographics: Age, sex, race, ancestral background, socioeconomic indicators, 
geographic location, history of military service, and insurance status. 
b. Clinical Data: WHO-defined MPN subtype, disease stage, duration of disease, 
history of thrombotic events, splenomegaly, and systemic symptoms. 
c. Treatment Data: Medication history, treatment response, adverse events, dose 
adjustments, and reason for therapy discontinuation. 
d. Genetic and Molecular Data: JAK2, CALR, and MPL mutation status, variant 
allele frequencies, and other emerging genomic biomarkers. 
e. PROs: Symptom burden assessment using MPN-SAF TSS, fatigue severity, 
psychological well-being, and functional status. 
f. Healthcare Utilization: Frequency of hospitalizations, emergency department 
visits, specialist consultations, and treatment adherence. 
g. Environmental and Lifestyle Factors: Tobacco use, alcohol consumption, 
dietary habits, physical activity, and occupational exposures. 
 

 
 
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6. PROs will be captured through structured survey instruments designed to measure 
symptom burden, quality of life, and treatment satisfaction. These surveys will include: 
a. MPN-SAF Total Symptom Score (TSS): Assesses key MPN symptoms, 
including fatigue, pruritus, night sweats, bone pain, and early satiety. 
b. PGI-S: Captures patient-perceived overall change in health status. 
c. EORTC QLQ-C30: Evaluates overall health-related quality of life, including 
functional status and symptom burden. 
d. Modified PHQ-9: Screens for depressive symptoms commonly observed in MPN 
patients. 
e. PROMIS Short Form v1.0 – Fatigue 8a: Assesses fatigue in MPN patients, 
specifically targeting the experience of fatigue and its impact on daily life. 
f. Data from patient surveys will be integrated with clinical and genomic data to 
create a robust dataset that allows for multidimensional analyses of disease 
progression, therapeutic impact, and patient experience. 
In the future, participants may be invited to provide optional blood or tissue samples to support 
additional research on genetic, molecular, or biomarker analyses. Any biospecimen collection 
will require a separate IRB-approved protocol and additional informed consent. Participation in 
biospecimen sub-studies will be entirely voluntary and will not affect participation in the main 
registry. 
 
7.2. Data Storage and Sharing 
Data will be stored electronically within the MPN Research Foundation Service Database. 
Identifiable details, including names, email addresses, dates other than year, photographic 
images, and free-text notes, will be removed and replaced with a linkage code. 
A designated Honest Broker for this study has been established with a third-party through a 
specific contractual agreement. Serving independently from the study analysis team and outside 
MPN Research Foundation, the Honest Broker will assign linkage codes, maintain the secure 
linkage file, and ensure the separation of identifiable data from research datasets. The linkage file 
will be stored in an encrypted system accessible only to the Honest Broker, with all access 
documented through audit trails. The Honest Broker will also serve as a resource to the MPN 
PROGRESSion Registry governance committees, including the Data Access, Use & Publications 
(DAUP) Committee. 
Coded research data will be retained indefinitely by the MPN Research Foundation to support 
ongoing and future observational research, in accordance with organizational data retention 
policies and applicable regulatory requirements. 
Investigator access to Registry data requires approval by the DAUP Committee, based on 
scientific quality, validity, and ethical compliance, with all approvals documented in writing. De-
identified data may be shared with external researchers for approved secondary studies, subject 
to appropriate IRB approvals. Investigator access to Registry information for recruitment or 
eligibility screening will only occur with documented IRB approval. 
While participants may receive insights from aggregate analyses, they will not necessarily be 
informed of all results from every observational study using their data.  

 
 
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7.3. Data Monitoring Plan 
The monitoring plan for the Registry will involve routine (i.e., quarterly) monitoring by the PI 
and/or designees to ensure 1) direct participant identifiers are not contained within the Registry; 
2) MPN Research Foundation investigator exports from the Registry are documented; 3) 
information linking the Registry linkage codes with participant identifiers is stored securely and 
access to the linkage code key is audited; and 4) any conditions that may negatively impact the 
confidentiality of information contained within the Registry are reported to the appropriate MPN 
Research Foundation personnel.  
 
As specified previously, the DAUP Committee must provide approval for an MPN Research 
Foundation investigator to access the Registry for research studies involving the use of study 
Data. Access by MPN Research Foundation investigators to the Data for the purpose of 
identifying potential participants for participation in a research study shall be granted only upon 
the provision of documentation that an IRB has approved the research study. At the time of 
annual IRB continuing review, a list of studies conducted using the Registry will be submitted to 
the IRB. In addition, any unauthorized access to information contained within the Registry or to 
the information linking the Registry information linkage codes to participant direct identifiers 
shall be reported to the IRB. 
 
7.4. Research Methods 
This study will implement a structured methodology encompassing data acquisition, curation, 
validation, and governance. Data will be sourced from: 
• EMRs: Retrospective and prospective clinical data, including laboratory results, imaging 
studies, physician notes, and treatment history. 
• PROs: Longitudinal symptom assessments, quality of life metrics, and functional status 
evaluations. 
• Genomic and Molecular Data: Mutation profiles, variant allele frequencies, and 
emerging biomarkers relevant to disease evolution. 
• Administrative Claims Data: Healthcare utilization patterns, insurance claims, and 
medication adherence metrics. 
To ensure data consistency and quality, all collected data will be standardized using 
internationally recognized coding systems, such as ICD-10, SNOMED CT, LOINC, and the 
United States Core Data for Interoperability (USCDI). Rigorous data validation processes will be 
implemented, including: 
• Automated and manual data quality checks. 
• Cross-validation between EMRs and PROs. 
• Real-time monitoring of data completeness and accuracy. 
• Periodic external audits to ensure compliance with best practices. 
A governance framework will be established to oversee ethical compliance, data security, and 
appropriate use of registry data for research and regulatory purposes. Adaptive protocols will be 

 
 
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incorporated, allowing for modifications based on emerging scientific discoveries, technological 
advancements, and stakeholder feedback. 
The study team anticipates that the protocol may be amended over time based on findings from 
the feasibility phase, input from one or more of the governance committees, stakeholder 
feedback, or evolving scientific and operational priorities. Potential amendments may include the 
addition of sub-studies, optional biospecimen collection, adjustments to PRO schedules, or 
updates to data collection methods. All amendments will be submitted for IRB review and 
approval prior to implementation 
 
7.5. Withdrawal/Discontinuation 
Participants may withdraw consent at any time by submitting a written request (such as a signed 
form, email, or letter) to the study team. A record of the withdrawal will be maintained for 
regulatory compliance. Data collected prior to withdrawal will remain in the Registry for 
approved research; no additional data will be collected unless the participant re-consents. 
 
7.6 Patient-Reported Outcomes Collection 
7.6.1 Overview 
The Registry will incorporate PROs to assess disease burden, symptom severity, quality of life, 
mental health, fatigue, and healthcare access. PROs will complement clinical and molecular data 
collected through EMRs to provide a comprehensive analysis of disease progression and 
treatment impact from the patient perspective. 
PRO collection will provide valuable RWE to: 
• Assess the impact of disease and therapy on quality of life. 
• Support clinical decision-making and future research. 
Identify early indicators of disease progression and treatment response. 
The estimated time to complete the full PRO battery is 8–10 minutes per assessment. Efforts will 
be made to streamline survey administration and minimize participant burden while ensuring 
comprehensive data collection. 
7.6.2 Selected Patient-Reported Outcomes Measures 
Validated instruments have been selected based on their established use in major MPN clinical 
trials, including COMFORT-I & II, JAKARTA, PERSIST-1 & 2, RESPONSE, and SIMPLIFY 
trials. These measures align with recommendations for RWE collection in chronic hematologic 
diseases. 
Category 
Measure 
Purpose 
Estimated 
Completion 
Time 
Symptom 
Burden 
MPN-SAF Total 
Symptom Score 
(MPN-SAF TSS) 
Assesses key MPN symptoms, including 
fatigue, pruritus, night sweats, bone pain, 
and early satiety 
5–7 minutes 

 
 
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Category 
Measure 
Purpose 
Estimated 
Completion 
Time 
Global 
Change 
PGI-S (Patient 
Global Impression 
of Severity) 
Captures patient-perceived overall change in 
health status 
<1 minute 
Quality of 
Life 
EORTC QLQ-C30 
Evaluates overall health-related quality of 
life, including functional status and 
symptom burden 
7–10 minutes 
Mental 
Health 
Modified PHQ-9 
Screens for depressive symptoms commonly 
observed in MPN patients. Modified version 
excludes Question 9, which asks about 
suicidal ideation. 
2–3 minutes 
Fatigue 
PROMIS Short 
Form v1.0 – Fatigue 
8a 
Assesses fatigue in MPN patients, 
specifically targeting the experience of 
fatigue and its impact on daily life 
5-10 minutes 
Special Procedures for modified PHQ-9 Monitoring 
The Registry collects patient-reported depressive symptoms using the modified PHQ-9 
instrument.. While the registry is a non-interventional, observational study and does not provide 
clinical care or psychiatric services, the following safeguards are in place to responsibly manage 
participant well-being: 
• 
All participants will see a message alerting them to the potentially sensitive nature of the 
questions included in the modified PHQ-9 and reminding them that they may choose to 
skip any question and may choose to forego completion of the modified PHQ-9 at any 
time.  
• 
All participants, regardless of modified PHQ-9 score, will immediately see a resource 
referral pop-up in the online portal upon survey completion. This pop-up provides 
national mental health and crisis support resources, including the 988 Suicide & Crisis 
Lifeline, Crisis Text Line, and other relevant support services. 
• 
The informed consent form will clearly communicate these boundaries to participants, 
including that the registry team does not provide medical or mental health services and 
that participants are responsible for seeking professional care if they have concerns about 
their well-being. 
7.6.3 Data Collection Schedule 
Data collection will follow a structured schedule to balance scientific objectives with participant 
burden. PROs will be collected on a tiered schedule. MPN-SAF TSS and PGI-S will be collected 
every 3 months (quarterly) to track changes in symptom burden. EORTC QLQ-C30, modified 
PHQ-9, and PROMIS Short Form v1.0 – Fatigue 8a will be collected every 6 months 
(biannually) to assess quality of life, mood, overall health, and fatigue. 

 
 
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Participants will have up to 7 days to complete each survey after it is sent, supported by 
automated reminders. This approach is designed to maximize data completeness while 
minimizing burden. 
Clinical and EMR data will be updated at the same biannual timepoints and as available through 
data linkages. Table 2 provides an overview of the assessment schedule, and the recommended 
completion windows are summarized below. 
Timepoint 
Recommended Completion 
Window 
Baseline Assessments 
7 days 
3-Monthy and Quarterly Follow-Ups (MPN-SAF TSS + 
PGI-S) 
7 days 
6-Month and Biannual Follow-ups (All PROs + EMR) 
7 days 
Note: MPN-SAF TSS and PGI-S are assessed every 3 months (quarterly); EORTC QLQ-C30, 
modified PHQ-9, PROMIS Short Form v1.0 – Fatigue 8a, and EMR data are assessed every 6 
months (biannually). All assessments have a 7-day completion window supported by automated 
reminders. 
7.6.4 Data Integration and Analysis 
Integration of PROs with clinical and molecular datasets follows established methodologies for 
multi-source data validation in observational hematology studies⁷⁻⁹. 
Handling of Partial or Incomplete Responses 
• 
If participants complete only a partial assessment, data from completed sections will be 
retained. 
• 
Participants with consistently incomplete responses will be flagged for additional follow-
up. 
• 
A threshold (e.g., ≥50% completion) may be used to determine whether a submission is 
valid for analysis. 
• 
Participants who submit incomplete assessments will be encouraged to complete the 
missing sections within the established grace period. 
• 
If the assessment remains incomplete after the grace period, responses will be retained as 
submitted, and trends will be monitored for persistent gaps in reporting. 
Non-Digital Data Entry and Quality Control 
• 
Non-digital submissions (phone-based or paper forms) will be transcribed into the 
registry’s electronic database by designated study personnel. 
• 
A quality control process will be implemented to minimize transcription errors. 
Providing PROs to Participants and Clinicians 
• 
Participants may request summary reports of their individual PRO trends, which will be 
available through the registry portal. 
• 
Where applicable, these reports may also be integrated into EMRs for treating physicians 
to support shared decision-making. 
PROs will be integrated with clinical and molecular data collected through EMRs to create a 
comprehensive real-world dataset. This will allow for the evaluation of: 

 
 
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• 
Longitudinal changes in symptom burden and quality of life. 
• 
Associations between trends and disease progression markers. 
• 
Treatment effectiveness and tolerability from the patient perspective. 
• 
Barriers to accessing care and medication adherence. 
In the future, an optional online dashboard may be developed to allow participants to view their 
own reported data alongside general, de-identified study summaries. This dashboard will be 
intended solely for informational purposes and will not provide medical advice, treatment 
recommendations, or individualized clinical interpretations. Participation in dashboard access 
will be entirely optional and will not affect participation in the main registry. 
7.7 Study Sites and Coordinating Center 
The Principal Investigator, Dr. Raajit Rampal, is based at Memorial Sloan Kettering Cancer 
Center (MSKCC), which serves as the IRB site of record. All study operations, including 
participant recruitment, informed consent management, data collection, data storage, and 
participant communications, are centrally coordinated and administered by the MPN Research 
Foundation, located in Chicago, Illinois. The MPN Research Foundation functions as the study 
coordinating center and administrative office. No other clinical sites or healthcare institutions are 
engaged in participant enrollment, study management, or data operations. 
8. RISK/BENEFIT ASSESSMENT 
8.1. Potential Risks 
Participation in this Registry involves minimal risk. The primary risk is potential loss of 
confidentiality or unauthorized access to personal information. To minimize this risk, all 
personally identifiable information (PII) will be separated from clinical and survey data and 
securely managed by the Honest Broker. Each participant’s data will be linked using a unique 
study identifier, stored separately from the research database. 
Although all data will be de-identified and coded, there is a minimal risk of re-identification, 
particularly when linking with external registries. Only authorized investigators operating under 
approved data use agreements will have access to de-identified datasets. 
Survey responses will be stored in a secure, HIPAA-compliant system, with access restricted to 
authorized study personnel. As a non-interventional, observational study, there are no 
foreseeable physical or psychological risks, and no investigational treatments or procedures are 
involved. 
Because the study does not involve clinical interventions or investigational products, no 
compensation for injury is provided. Participants will not incur any direct costs. In the event of a 
data breach, institutional policies and applicable laws will be followed, including prompt 
notification to affected participants and IRB reporting. 
8.2. Benefits 
As this is a non-interventional, observational study, there are no direct benefits to participants in 
this registry. However, their contributions will advance understanding of MPNs, disease 
progression, treatment patterns, and patient-reported experiences. The data collected may inform 

 
 
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clinical decision-making, improve care standards, support therapeutic development, and 
contribute to public health and regulatory efforts. 
As part of the engagement strategy, participants will be eligible for periodic drawings for $50 
gift cards, held twice per year for completing PROs and once per year for maintaining active 
enrollment. Winners will be randomly selected, and no additional steps are required beyond 
completing the associated activities. These drawings are intended to acknowledge participant 
time and effort without exerting undue influence or coercion, as described in the ICF. 
Participants may also benefit indirectly through access to educational materials, aggregate study 
updates, and invitations to optional webinars or virtual events related to MPN research. 
8.3. Protection of Human Participants 
Coded participant data will be retained for at least 10 years after study closure or as required by 
institutional policy and applicable regulations. 
All data collection, storage, and sharing procedures will comply with IRB, HIPAA, FDA, EMA, 
and national research guidelines. Access to de-identified data for secondary research will require 
approval from the Registry Steering Committee, DAUP Committee and the IRB, and all requests 
will be reviewed for ethical use and scientific merit. 
This protocol has been reviewed and approved by a central IRB. Ongoing oversight will include 
annual continuing review and prompt reporting of any unanticipated problems or breaches. 
Participation in the Registry is voluntary, and participants may withdraw at any time without 
penalty. Data collected prior to withdrawal will be retained in coded form and may continue to 
be used for approved research unless otherwise requested by the participant. 
To protect privacy, all electronic data will be stored on encrypted, access-restricted servers. 
Physical records will be secured in locked facilities. All study staff will be trained in Good 
Clinical Practice (GCP), human subjects protections, and institutional data privacy procedures. 
9. STATISTICAL CONSIDERATIONS 
Patient data will come from multi-modal data sources, including academic and non-academic 
health centers, patient-consented access to medical records, validated survey instruments, and 
patient self-reports. A durable and sizeable cohort over several years will generate longitudinal 
data that can be used in studies to allow researchers to analyze data potentially pertinent to 
disease progression. This cohort will capture a sufficient number of relatively rare events, such 
as disease progression to blast-phase MPN. At the development stage, the cohort composition 
and subsequent estimates of the risk of progression are uncertain. The registry aims to enroll 
approximately 1500 patients within 3 years. Under this sample size assumption, we estimate 
statistical power to detect an association between various risk factors and progression, as detailed 
in Table 1 
 
Table 1: Minimum Hazard Ratio (HR) needed for the risk marker with power of 80%, type-1 
error 5%, and the assumption of progression of 50% during the follow-up period 

 
 
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Sample Size\Prevalence of marker 
10% 
20% 
30% 
50% 
1000 
1.53 
1.37 
1.32 
1.3 
2000 
1.35 
1.25 
1.22 
1.2 
3000 
1.27 
1.2 
1.17 
1.16 
5000 
1.2 
1.15 
1.13 
1.12 
 
We estimate that the initial run-in part of a study duration will be at least 3 years. After 3 years, a 
statistical team will review the data and define a statistical analysis plan (SAP) based on the 
composition and completeness of the data.  
 
Based on experience from similar projects in the past, we estimate an annual drop-out rate of 10-
20%. As patients will enroll in this study on an ongoing basis, patients lost to follow up will be 
replaced over time to maintain adequate statistical power as illustrated in Table 1.  
 
9.1 Statistical Analysis Plan (SAP) 
An initial SAP will be developed prior to data collection, outlining intended descriptive and 
inferential statistical methods, including Kaplan-Meier survival analysis26, Cox proportional 
hazards modeling27 for progression events, and multivariate analyses. Primary endpoints include 
time to documented MPN progression events and overall survival. Secondary endpoints include 
PROs, quality-of-life measures (e.g., EORTC QLQ-C30), and healthcare utilization patterns. 
Overall survival and cause-specific mortality endpoints will be determined using EMR  data and 
validated through linkage with national mortality datasets, ensuring robust and comprehensive 
survival analyses. The SAP will undergo formal annual reviews and be updated based on interim 
analysis results, changes in data availability, or emerging scientific questions. Significant 
amendments will be documented, scientifically justified, and communicated to the IRB. Data 
will be securely retained for a minimum of 10 years following study completion, in accordance 
with institutional policies and regulatory requirements. 
 
9.2 Interim Analyses and Data Monitoring 
Interim analyses will be conducted annually to evaluate data completeness, quality, and 
preliminary outcomes. These analyses will be reviewed by the Steering Committee and DAUP 
Committee, who will advise on data integrity, patient safety, and protocol compliance. Criteria 
triggering protocol amendments or corrective actions, such as enrollment targets or data quality 
thresholds, will be generally defined in the SAP. Corrective actions may include targeted data 
validation audits, protocol amendments, re-training of staff, or adjustments to participant follow-
up procedures. Protocol deviations or violations identified during interim analyses will be 
documented, categorized, and reported to the IRB. Systematic issues leading to protocol 
deviations will trigger corrective actions. 
 
9.3 Subgroup Analyses 
Planned subgroup analyses will examine outcomes based on demographic factors (e.g., age, sex, 
ancestral background), MPN subtype, treatment modalities, and genetic markers. Subgroup 
analysis methodology will be explicitly defined in the SAP, including interaction tests in 
regression models to ensure scientific rigor. 
 
9.4 Handling Multiple Testing 

 
 
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Appropriate statistical methods (e.g., Bonferroni, Holm-Bonferroni, False Discovery Rate28) will 
be employed to adjust for multiple comparisons, ensuring control of Type I error rates. Details of 
the selected adjustment method will be clearly specified in the SAP. 
 
9.5 Competing Risks and Time-dependent Covariate Analyses 
Competing risk analyses, such as Fine and Gray's subdistribution hazard models29, will be 
utilized to appropriately account for events that might prevent or alter the probability of the 
primary outcomes, ensuring unbiased estimates of progression risk. Additionally, time-dependent 
covariate analyses will evaluate how changes in treatment regimens, symptom severity, or other 
relevant covariates over time influence disease progression or outcomes. 
 
9.6 Missing Data and Sensitivity Analyses 
Patients or their legal representatives lost to follow-up will be contacted via phone or 
electronically (e.g., email). Missing data will be clearly identified and handled in line with the 
principles detailed in the SAP. While primary analyses will rely on complete-case data, 
sensitivity analyses will evaluate the impact of missing data assumptions using multiple 
imputation methods30 and other appropriate strategies to ensure robustness of study findings. 
Additional sensitivity analyses will include assessments of the robustness of results across 
varying assumptions for distributional assumptions, model specifications, and subgroup effects. 
Patients not meeting the minimum data requirements will be excluded from analyses. 
 
9.7 Propensity Score Methods 
Propensity score matching or adjustment methods31 will be utilized to minimize confounding and 
selection bias when analyzing comparative effectiveness among treatment groups or exposure 
categories. Methodologies and matching criteria will be explicitly described in the SAP. 
 
9.8 Statistical Software and Analysis Environment 
Statistical analyses will be conducted using validated statistical software, including SAS (version 
9.4 or later), R (version 4.2 or later), or STATA. Analytical scripts and procedures will be 
documented and version-controlled to facilitate reproducibility and audits by IRB and regulatory 
authorities. 
 
9.9 Consideration for Potential Data Biases 
This study is an observational, non-interventional registry that relies on data collected from 
multiple sources, including EMRs, PROs, validated survey instruments, and claims data. Such a 
study design is inherently associated with data biases, including misclassification, recall bias, 
and missing data, which cannot always be independently verified by investigators. 
However, the large sample size, objective disease assessments, and multi-source data validation 
minimize these limitations. To further enhance data reliability, the Registry will implement a 
structured quality control framework in collaboration with the data vendor. This framework 
includes: 
• 
Automated Data Validation Checks – Incoming data will be systematically screened for 
missing values, internal inconsistencies, and entry errors using predefined validation rules 
aligned with ICD-10, SNOMED CT, and LOINC terminologies. 

 
 
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• 
Cross-Source Data Verification – Self-reported patient data will be cross-checked with 
EMR-derived records, laboratory values, and claims data to ensure consistency and flag 
discrepancies requiring manual review. 
• 
Longitudinal Data Quality Monitoring – The completeness and accuracy of collected data 
will be reviewed at predefined study milestones (e.g., 6 months, 12 months, 18 months, 
annually) to detect unexpected deviations that may indicate systematic errors or reporting 
inconsistencies. 
• 
Audit Trails and Data Traceability – All modifications to the dataset, including data 
corrections, updates, and deletions, will be logged through an automated audit trail 
system to ensure full traceability and compliance with research standards. 
• 
Outlier Detection and Resolution – Advanced statistical methods and machine learning 
algorithms will be used to flag outlier data points that significantly deviate from expected 
clinical patterns. Flagged data will undergo secondary review before inclusion in 
analyses. 
• 
Investigator-Led Quality Assurance Reviews – The PI and designated data management 
personnel will conduct periodic reviews to assess adherence to protocol-defined data 
quality standards, document findings, and implement corrective actions. 
• 
Regulatory & Stakeholder Oversight – The data vendor will provide quarterly reports 
detailing data completeness, validation performance, and unresolved discrepancies. These 
reports will be reviewed in collaboration with the Registry’s scientific steering 
committee, aligning with regulatory best practices for RWE studies. 
By integrating these multi-tiered quality control measures, the Registry ensures that collected 
data is accurate, complete, and reliable, enabling robust observational research while minimizing 
bias in study findings. 
9.10. Disseminating and Communicating Study Results 
Study results will be disseminated through multiple channels, ensuring broad access to findings. 
Peer-reviewed journal articles will be submitted to peer-reviewed medical and scientific journals. 
Findings will be presented at relevant hematology and oncology conferences. Lay summaries 
and newsletters will be distributed to study participants and patient advocacy organizations. 
Interactive webinars and educational materials will be developed to engage the broader 
community. Policy briefs will be prepared to inform healthcare decision-makers, regulatory 
agencies, and industry stakeholders. Real-time access to aggregated, de-identified data insights 
will be provided to key stakeholders through a secure online platform. 

 
 
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10. APPENDIX 
10.1 WHO Criteria for Polycythemia Vera 
Major criteria  
1. Hemoglobin >16.5 g/dL in men, Hemoglobin >16.0 g/dL in women  
or,  
Hematocrit >49% in men, Hematocrit >48% in women  
or,  
increased red cell mass (RCM), more than 25% above mean normal predicted value. 
2. BM biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including 
prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature 
megakaryocytes (differences in size)  
3. Presence of JAK2V617F or JAK2 exon 12 mutation  
Minor criterion  
Subnormal serum erythropoietin level  
Diagnosis of PV requires meeting either all 3 major criteria, or the first 2 major criteria and the 
minor criterion†  
Criterion number 2 (BM biopsy) may not be required in cases with sustained absolute 
erythrocytosis: hemoglobin levels >18.5 g/dL in men (hematocrit, 55.5%) or >16.5 g/dL in 
women (hematocrit, 49.5%) if major criterion 3 and the minor criterion are present. However, 
initial myelofibrosis (present in up to 20% of patients) can only be detected by performing a 
BM biopsy; this finding may predict a more rapid progression to overt myelofibrosis (post-PV 
MF). 
 
10.2 WHO Diagnostic Criteria for Essential Thrombocythemia 
Major criteria  
1. Platelet count ≥450 × 109/L  
2. BM biopsy showing proliferation mainly of the megakaryocyte lineage with increased 
numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant 
increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 
1) increase in reticulin fibers  
3. Not meeting WHO criteria for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or 
other myeloid neoplasms  
4. Presence of JAK2, CALR, or MPL mutation  
Minor criterion  
Presence of a clonal marker or absence of evidence for reactive thrombocytosis  
Diagnosis of ET requires meeting all 4 major criteria or the first 3 major criteria and the minor 
criterion  
 
 
 

 
 
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10.3 WHO Diagnostic Criteria for Primary Myelofibrosis 
Major criteria  
1. Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or 
collagen fibrosis grades 2 or 3*  
2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndromes, or 
other myeloid neoplasms  
3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence 
of another clonal marker, † or absence of reactive myelofibrosis‡  
Minor criteria  
Presence of at least 1 of the following, confirmed in 2 consecutive determinations:  
a. Anemia not attributed to a comorbid condition  
b. Leukocytosis ≥11 × 109/L  
c. Palpable splenomegaly  
d. LDH increased to above upper normal limit of institutional reference range  
e. Leukoerythroblastosis  
Diagnosis of overt PMF requires meeting all 3 major criteria, and at least 1 minor criterion  
†In the absence of any of the 3 major clonal mutations, the search for the most frequent 
accompanying mutations (eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in 
determining the clonal nature of the disease. 
‡BM fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory 
conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic 
(chronic) myelopathies. 
 
 
 

 
 
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10.4. WHO Diagnostic Criteria for pre-PMF 
Major criteria  
1. Megakaryocytic proliferation and atypia, without reticulin fibrosis >grade 1*, accompanied 
by increased age-adjusted BM cellularity, granulocytic proliferation, and often decreased 
erythropoiesis  
2. Not meeting the WHO criteria for BCR-ABL1+ CML, PV, ET, myelodysplastic syndromes, 
or other myeloid neoplasms  
3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence 
of another clonal marker, † or absence of minor reactive BM reticulin fibrosis‡  
Minor criteria  
Presence of at least 1 of the following, confirmed in 2 consecutive determinations:  
a. Anemia not attributed to a comorbid condition  
b. Leukocytosis ≥11 × 109/L  
c. Palpable splenomegaly  
d. LDH increased to above upper normal limit of institutional reference range  
Diagnosis of prePMF requires meeting all 3 major criteria, and at least 1 minor criterion  
†In the absence of any of the 3 major clonal mutations, the search for the most frequent 
accompanying mutations (e.g., ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in 
determining the clonal nature of the disease. 
‡Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic 
inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic 
malignancy, or toxic (chronic) myelopathies 
 
 
 

 
 
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10.5. IWG-MRT Criteria for Secondary Myelofibrosis 
Criteria for post-polycythemia vera myelofibrosis 
 Required criteria: 
1 Documentation of a previous diagnosis of polycythemia vera as defined by the WHO 
criteria 
2 Bone marrow fibrosis grade 2–3 (on 0–3 scale) or grade 3–4 (on 0–4 scale),a 
 Additional criteria (two are required): 
1 Anemiab or sustained loss of requirement of either phlebotomy (in the absence of 
cytoreductive therapy) or cytoreductive treatment for erythrocytosis 
2 A leukoerythroblastic peripheral blood picture 
3 Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm 
(distance of the tip of the spleen from the left costal margin) or the appearance of a newly 
palpable splenomegaly 
4 Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night 
sweats, unexplained fever (>37.5°C) 
Criteria for post-essential thrombocythemia myelofibrosis 
 Required criteria: 
1 Documentation of a previous diagnosis of essential thrombocythemia as defined by the 
WHO criteria 
2 Bone marrow fibrosis grade 2–3 (on 0–3 scale) or grade 3–4 (on 0–4 scale),a 
 Additional criteria (two are required): 
1 Anemiab and a ≥2 mg ml−1 decrease from baseline hemoglobin level 
2 A leukoerythroblastic peripheral blood picture 
3 Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm 
(distance of the tip of the spleen from the left costal margin) or the appearance of a newly 
palpable splenomegaly 
4 Increased LDH (above reference level) 
5 Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night 
sweats, unexplained fever (>37.5°C) 
Abbreviations: IWG-MRT, International Working Group for Myelofibrosis Research and 
Treatment; LDH, lactate dehydrogenase; post-ET MF, post-essential thrombocythemia 
myelofibrosis; post-PV MF, post-polycythemia vera myelofibrosis. 
aGrade 2–3 according to the European classification: 3 diffuse, often coarse fiber network with 
no evidence of collagenization (negative trichrome stain) or diffuse, coarse fiber network with 
areas of collagenization (positive trichrome stain). Grade 3–4 according to the standard 
classification:4 diffuse and dense increase in reticulin with extensive intersections, occasionally 
with only focal bundles of collagen and/or focal osteosclerosis or diffuse and dense increase in 
reticulin with extensive intersections with coarse bundles of collagen, often associated with 
significant osteosclerosis. 
bBelow the reference range for appropriate age, sex, gender and altitude considerations. 
 
 

 
 
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10.6: Pre-Screening Questions for Participant Eligibility 
The following questions will be presented through the Registry online portal to assess participant 
eligibility prior to consent. Participants who do not meet the inclusion criteria will be 
automatically disqualified and will not proceed to the informed consent stage.  Participants 
providing responses to these pre-screening questions will be asked to provide their permission to 
utilize and retain this basic information by MPN Research Foundation for the sole purpose of 
understanding the basic characteristics of those interested participants who are eligible versus 
those who are ineligible. The MPN Research Foundation store data collected as part of this pre-
screening process in a secure, HIPAA-compliant system, with access restricted to authorized 
study personnel. 
1. Are you at least 18 years old? 
Options: 
• 
Yes, I am 18 or older 
• 
No 
→ If No → participant is ineligible 
2. Do you currently live in the United States? 
Options: 
• 
Yes 
• 
No 
→ If No → participant is ineligible 
3. Have you ever been diagnosed with a myeloproliferative neoplasm (MPN) by a 
healthcare provider? 
Options: 
• 
Yes, confirmed by hematologist/oncologist 
• 
No, still undergoing testing or unsure 
→ If No → participant is ineligible 
• Have you ever had a hematopoietic stem cell transplant (HSCT) — either a bone 
marrow transplant (BMT), peripheral or umbilical stem cell transplant (SCT) — 
after an MPN diagnosis? 
• Yes 
• No 
• When were you diagnosed with your MPN? 
Options: 
• 
Enter date (MM/YYYY) 
• 
If only year known, enter “07/YYYY” 
• 
If unsure, write “Unsure” 
→ No exclusion applied 

 
 
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5. Which type of MPN have you been diagnosed with? (Select all that apply) 
Options: 
• 
Polycythemia Vera (PV) 
• 
Essential Thrombocythemia (ET) 
• 
Primary Myelofibrosis (PMF) 
• 
Post–PV Myelofibrosis (Post-PV MF) 
• 
Post–ET Myelofibrosis (Post-ET MF) 
• 
Pre-fibrotic Primary Myelofibrosis (pre-PMF) 
• 
MPN-Unclassifiable (MPN-U) 
• 
MPN in Accelerated Phase (MPN-AP) 
• 
MPN in Blast Phase (MPN-BP) or post-MPN AML 
• 
Myelodysplatic Syndrome/Myeloproliferative Neoplasm (MDS/MPN) Overlap 
Syndrome 
• 
Chronic Myelomonocytic Leukemia (CMML) 
• 
Other (please specify) 
→ No exclusion applied 
6. Has your MPN diagnosis ever been revised to a different condition? 
Options: 
• 
No, diagnosis is the same 
• 
Yes, changed to another condition 
→ If Yes → proceed to Question 7 
7. If yes, what is your new diagnosis? 
Options: 
• 
Myelodysplastic Syndromes (MDS) not including MDS/MPN overlap syndrome 
• 
Acute Myeloid Leukemia (AML) 
• 
Chronic Myeloid Leukemia (CML) 
• 
Other blood cancer or hematologic malignancy 
• 
Other non-cancer blood disorder 
• 
Unsure 
• 
Other (please specify) 
→ If revised to non-MPN malignancy → participant is ineligible 
8. When was your diagnosis revised? 
Options: 
• 
Enter date (MM/YYYY) 
• 
Approximate year or “Unsure” 
→ No exclusion applied 
Commented [DS1]: Note: we need to specify that sAML 
is eligible (MPN-BP) to avoid any confusion 
Commented [DT2R1]: Agree 

 
 
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9. Do you currently receive medical care for your MPN and have access to past 
medical records (e.g., online portal)? 
Options: 
• 
Yes 
• 
No 
→ If No → participant is ineligible 
10. Do you have access to your electronic medical records (EMR) from one or more 
participating healthcare institutions? 
Options: 
• 
Yes 
• 
No 
→ If No → participant is ineligible 
11. Has a healthcare provider ever told you that your condition may be reactive (not an 
MPN)? 
Options: 
• 
No, I have an MPN 
• 
Yes, I have been told it may be reactive 
→ If Yes → participant is ineligible 
12. Have you been diagnosed with any of the following blood disorders? (Select all that 
apply) 
Options: 
• 
Chronic Myeloid Leukemia (CML) 
• 
Myelodysplastic Syndromes (MDS) not including MDS/MPN overlap syndrome 
• 
None of the above 
→ If any except “None of the above” → participant is ineligible 
13. Are you currently enrolled in a clinical trial that does not allow your medical 
records to be shared with external research studies? 
Options: 
• 
No 
• 
Yes 
→ If Yes → participant is ineligible 
14. Are you able to provide informed consent, or do you have a legally authorized 
representative (LAR) who can provide consent? 
Options: 
• 
Yes, I can consent for myself 

 
 
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• 
Yes, my LAR can consent 
• 
No, I cannot consent and have no LAR 
→ If No → participant is ineligible 
15. This registry requires long-term participation, including data sharing, surveys, and 
follow-up over multiple years. Do you understand and agree to these terms? 
Options: 
• 
Yes 
• 
No 
→ If No → participant is ineligible 
 

 
 
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10.7: Participant Notification Messages 
The following participant notifications are used within the Registry portal to guide participants 
through the screening, consent, enrollment, and withdrawal process. These messages are 
designed to ensure respectful, clear, and ethically appropriate communication at each decision 
point. No personally identifiable information is retained for individuals who are screened as 
ineligible. All content aligns with IRB-approved consent language and complies with applicable 
legal and regulatory standards. 
1. Disqualified Notification 
Displayed when a participant does not meet eligibility criteria after pre-screening. 
 
Thank you for your interest. 
Based on your responses, you are not eligible to participate in the MPN PROGRESSion 
Registry at this time. 
 
We appreciate your time and your interest in helping advance MPN research. 
 
2. Eligible Notification 
Displayed when a participant meets all eligibility criteria and is cleared to review the 
informed consent form. 
 
Thank you for completing the eligibility questions. 
You are eligible to participate in the MPN PROGRESSion Registry. 
 
Please proceed to the informed consent form (ICF) to learn more about the study and provide 
consent. 
 
3. Consent Completion / Enrollment Confirmation Notification 
Displayed after a participant successfully completes electronic informed consent. 
 
Thank you for enrolling in the MPN PROGRESSion Registry. 
We appreciate your participation and look forward to working with you. 
 
Please check your registry dashboard for surveys, updates, and study communications. 
 
4. Withdrawal or Opt-Out Confirmation Notification 
Displayed when a participant withdraws or opts out of the registry. 
 
You have successfully withdrawn from the MPN PROGRESSion Registry. 
Thank you for your contributions to MPN research. 
 
If you have any questions, please contact the registry team at [insert contact email or phone 
number]. 
 
5. Welcome / Onboarding Message (Optional) 
Displayed after enrollment to welcome the participant and guide them to the next steps. 

 
 
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Welcome to the MPN PROGRESSion Registry! 
You are now enrolled. Please check your dashboard for upcoming surveys and study updates. 
 
Thank you for helping advance research and improve care for people living with MPNs. 
 
 
 

 
 
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