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Patients receiving a diagnosis of MDS and prospectively enrolled in the FISiM registry.

Matteo Della Porta, MD

Maria Elena Bicchieri, PhD

Matteo Giovanni Della Porta, MD

Valeria Santini, MD

Emanuele Angelucci, MD

Enrico Balleari, MD

Elena Crisà, MD

Pellgrino Musto, MD

Antonella Poloni, MD

Renato Zambello, MD

Lorenza Borin, MD

Gastone Castellani, Physics

Pasquale Niscola, MD

Esther Oliva, MD

Paolo Giorgio Sergio Pasini, Presidente AIPaSiM

Francesco Passamonti, MD

Federica Pilo, MD

BACKGROUND Myelodysplastic syndromes (MDS) typically occur in elderly people and with time, a portion of the patients evolve into acute myeloid leukemia (AML). Therefore a risk-adapted treatment strategy is mandatory. Current prognostic scores present limitations, and in most cases fail to capture reliable prognostic information at individual level.

STATE OF THE ART Important steps forward have been made in defining the molecular architecture of MDS and gene mutations have been reported to influence survival and risk of disease progression in MDS. Evaluation of the mutation status may add significant information to currently used prognostic scores and a comprehensive analyses of large, prospective patient populations is warranted to correctly estimate the independent effect of each mutation on clinical outcome and response to treatments.

AIMS In this project, the investigators will develop a research platform by integrating genomic mutations, clinical variables and patient outcome derived from real-world data obtained from FISiM (Fondazione Italiana Sindromi Mielodisplastiche) clinical network, including 72 hematological centers.

This will allow the investigators to:

1. define the clinical utility of mutational screening in the diagnostic work-up and classification of MDS
2. assess the implementation of diagnostic and therapeutic guidelines (appropriateness) in the real-life
3. evaluate the impact of specific interventions (treatments) on clinical outcomes, long-term complications and costs
4. identify predictors of response to specific treatments, and develop precision medicine programs in hematology based on Real World Evidence RWD
5. measure patient-reported outcomes (PRO) and quality of life (QoL) in a real world MDS setting

Myelodysplastic syndromes (MDS) typically occur in elderly people. Patients present peripheral blood cytopenia, and with time a portion of these subjects evolve into acute myeloid leukemia (AML). MDS are heterogeneous ranging from conditions with a near-normal life expectancy to forms close to AML and therefore a risk-adapted treatment strategy is mandatory. Current prognostic scores present limitations, and in most cases fail to capture reliable prognostic information at individual level. Several therapeutic tools have been proposed for MDS but only few survived the evidence-based criteria of efficacy. Lenalidomide improves anemia in patients with 5q deletion. Allogeneic transplantation (HSCT) is the only potentially curative treatment for high risk patients; however, an accurate selection of candidate patients is needed. Hypomethylating agents (HMA) may improve survival in MDS not eligible HSCT, while predictive factors for clinical response remain to be defined.

Important steps forward have been made in defining the molecular architecture of MDS. The MDS associated with 5q deletion derives from the haploinsufficiency of RPS14 gene. The investigators and others identified genes encoding for spliceosome components in a high proportion of MDS. The investigators found a close relationship between ring sideroblasts and SF3B1 mutations, which is consistent with a causal relationship. In addition, an increasing number of genes have been found to carry recurrent mutations in MDS, involved in DNA methylation (DNMT3A, TET2, IDH1/2), chromatin modification (EZH2, ASXL1), transcriptional regulation (RUNX1), signal transduction. Gene mutations have been reported to influence survival and risk of disease progression in MDS, and the evaluation of the mutation status may add significant information to currently used prognostic scores. Moreover, mutation screening may affect clinical decision making : a) in MDS with 5q-, subjects carrying TP53 mutations have a higher risk of leukemic progression and a lower probability of response to lenalidomide; b) in patients receiving HSCT, TP53 mutations predict high probability of relapse; c) SF3B1 mutations are associated with increased probability of erythroid response to TGFb inhibitors

Despite these findings, caution is needed against immediately adopting such mutational testing in clinical practice. Most of scientific evidence derive from retrospective analyses of selected patient populations. In addition, in patients with MDS genetic abnormalities explain only a proportion of the total hazard for overall survival and outcome associated with specific treatments, meaning that a large percentage is still associated with clinical and non-mutational factors. Comprehensive analyses of large, prospective patient populations are warranted to correctly estimate the independent effect of each mutation on clinical outcome and response to treatments.

Real World Evidence (RWE) is information on health care that is derived from multiple sources outside typical clinical research settings, including electronic health records (EHRs), claims and billing data, product and disease registries, and data gathered through personal devices and health applications National healthcare systems of advanced countries, including Italy, widely agree on the approach whereby public healthcare decisions should be driven by available evidence on effectiveness and safety of therapeutics. It is equally accepted that randomized controlled clinical trials (RCTs), although universally recognized as the most robust "evidence generators", are insufficient for guiding the decision-making process since they are intrinsically unsuited to capture the impact of treatments in routine clinical practice. The complexity of treatments, as well as the demographic and clinical heterogeneity of patients receiving the treatments, and the long period of many treatments, explain the gap between the evidence generated in the controlled, but artificial, setting of RCTs and their current impact in the real world.

This explains the growing interest in the development of methods able to produce evidence on the real-world impact of care pathways (i.e., real-world evidence). Among them, those based on the Electronic Healthcare Records (EHRs), are becoming established and receiving increasing attention from the scientific community and healthcare decision-makers. In addition, real world data (RWD) are currently used during drug development to examine aspects such as the natural history of a disease, delineating treatment pathways in clinical practice, and determining the costs and resource use associated with treatment interventions

In this project, the investigators will develop a research platform by integrating genomic mutations, clinical variables and patient outcome derived from real-world data obtained from FISiM (Fondazione Italiana Sindromi Mielodisplastiche) clinical network, including 72 hematological centers. In this context, there is clearly a need to develop effective solutions to analyze and integrate molecular and clinical data of large patient populations, in order to fully understand the relationship between genotype and the clinical expression of a disease. In this area, a solution of excellence has been developed by the research center i2b2 (Informatics for Integrating Biology and the Bedside, University of Harvard, Boston - www.i2b2.org). This center developed an open-source software based on a data-warehouse able to integrate and to exploit all data coming from clinical practice and hospital admissions, making them available and easily accessible by researchers. FISiM network is based on a platform to specifically support hematological research, called i2b2Hematology (www.biomeris.com/index.php/it/tasks/i2b2-hematology-pv-it), allowing researchers to explore and analyze three types of data: (i) the clinical data available in all hematological centers belonging to the clinical network, (ii) the information related to the samples stored in biobanks, and (iii) NGS sequencing data in terms of genomic variants. Relying on this national clinical network and on an innovative informatics infrastructure, in this project the investigators will analyze the interactions among driver mutations clinical variables and patient outcome of specific treatments. At the same time the investigators will render NGS analysis of somatic mutations available for the FISiM centers that need support for this technique.

The investigators will address strategical needs in MDS (i.e., standardization and improvement of diagnostic work-up, clinical relevance of mutational screening, adherence to evidence-based guidelines, drug safety and efficacy, clinical relevance of patient-reported outcomes, PRO and quality of life,QoL) in a real world MDS setting with the final objective to propose a personalized approach for the individual patient.

Personalized Medicine Program on Myelodysplastic Syndromes: Characterization of the Patient's Genome for Clinical Decision Making and Systematic Collection of Real World Data to Improve Quality of Health Care

Polymorphonuclear granulocytes (PMN)/mononucleated cells (MNC) will be isolated from peripheral blood (PB) and/or bone marrow (BM) samples. Separated cells will be frozen locally and sent to the central lab to perform DNA extraction and NGS screening every 4 months.In all cases, a NGS screening will be performed by targeted approach to sequence all coding exons of 60 candidate genes.

As a result of this approach, the investigators will describe type and frequency of recurrent gene mutations in MDS patients.

A research platform will be developped by combining FISiM data on genetic and molecular characterization of hematological malignancies together with the national platform (REDCAP database), where clinical data are kept in a protected environment .

The investigators will analyze the prognostic effect of gene mutations on MDS patients' outcome (overall survival) by multivariable analysis.

The investigators will use QOL-E questionnaire to measure QoL in MDS patients. QOL-E is a specific tool to evaluate patient reported outcomes in patients with Myelodysplastic Syndromes. It evaluates the impact of the disease and treatment on 4 general dimensions (physical, functional, social and sexual well-being) and on one specific MDS-related dimension and also fatigue (https://qol-e.it/). Each item is rescaled so that a better response corresponds to a higher numerical value and better QoL.Transformation of raw scores into a 0-100 scale will be carried out to generate the standardized scores for each domain.

Questionnaire will be completed by the patients upon study entry. Follow-up measurements will be performed every 6 months for patients receiving supportive care (including RBC transfusions), before and after disease modifying treatments (every 4 months) and at the time of disease progression.

The investigators will use HM-PRO questionnaire (Hematology specific patient-reported outocome measure) to measure PRO in MDS patients.

The HM-PRO is a composite measure consisting of two scales: Part A (mesures the impact of MDS and its treatment on a patient's quality of life; Part B (signs and symptoms, SS) captures the severity of different disease symptoms and treatment side effects (https://www.futuremedicine.com/doi/10.2217/cer-2018-0108?url_ver=Z39.88-2003\&rfr_id=ori%3Arid%3Acrossref.org\&rfr_dat=cr_pub%3Dwww.ncbi.nlm.nih.gov\&). Both scales have linear scoring system ranging from 0 to 100, with higher scores representing greater impact on QoL and symptom burden.

Questionnaire will be completed by the patients upon study entry. Follow-up measurements will be performed every 6 months for patients receiving supportive care (including RBC transfusions), before and after disease modifying treatments (every 4 months) and at the time of disease progression.

Fondazione Italiana Sindromi Mielodisplastiche-ETS

Leukemia

Cytopenia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Participants with myelodysplastic syndromes and associated malignancies

Participants (controls) without MDS or associated malignancies, contributing bone marrow

Rebecca Alexander

Kathy McGraw, Ph.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Myelodysplastic syndromes (MDS) occur when the cells that make blood cells are abnormal. There are limited treatment options for MDS. Researchers want to learn more through this natural history study so they can develop better treatments.

Objective:

To study the natural course of MDS and MDS/myeloproliferative neoplasms (MPN) and collect biological samples that can help researchers understand the disease.

Eligibility:

People with suspected or confirmed MDS or MDS/MPN. Healthy donors are also needed. They can be people who are scheduled to donate bone marrow at NIH for a relative, or they may be providing bone marrow in another study.

Design:

Participants will be screened with a medical history.

Participants will have a physical exam. They will give blood and urine samples. They will discuss their symptoms, medications, and ability to perform their normal activities. They will complete surveys about how they are feeling.

Participants will have a bone marrow biopsy. A needle will be inserted through a small cut. Bone marrow will be removed. A small piece of bone may be removed.

Participants may have an optional skin biopsy.

Participants may give optional saliva and stool samples. They may collect these samples at home and mail them to NIH.

Participants may undergo optional apheresis. One or two needles or intravenous (IV) lines will be placed in their arm, neck, or groin veins. Blood will be removed. A machine will separate out the white cells. The rest of the blood will be returned to the participant.

Participants will be contacted for follow-up once a year for up to 20 years.

Healthy donors will have marrow collected for this study during their scheduled procedure with no follow-up.

Background:

* Myelodysplastic syndromes (MDS) are heterogenous stem cell disorders characterized by ineffective hematopoiesis resulting in cellular dysplasia, peripheral cytopenias, and increased risk for transformation to acute myeloid leukemia (AML).
* There are limited treatments options, all of which have unimpressive response rates and limited response durations, with the only potential cure being hematopoietic stem cell transplant (HSCT). Unfortunately, as a disease of the elderly (average age of diagnosis \>65 years), most participants are not eligible for HSCT due to advanced age and other comorbidities.
* It is critical we further elucidate the processes that lead to disease manifestation in an effort to develop novel therapeutic strategies and to alter the natural history of the disease.
* Chronic inflammation is central to disease pathology, as evidenced by pro-inflammatory cytokines in the bone marrow milieu, transcriptional upregulation of inflammatory genes, and dysregulation of innate immune signaling pathways.
* We hypothesize the chronic inflammation drives MDS pathogenesis and may be exploited therapeutically. Further, we anticipate the correlatives proposed here to be used not only to uncover critical disease driving pathways, but also to potentially reveal disease and treatment response biomarkers, as well to better refine both diagnosis and prognosis.

Objectives:

- To characterize the natural history of myelodysplastic syndromes (MDS) and to assess overall and progression free survival

Eligibility:

Participants with MDS

* Any gender, any age
* Histologically or cytologically suspected or confirmed MDS, MDS/MPN, (MDS/MPN- RS-T, MDS/MPN-U, CMML, aCML) or sAML with antecedent MDS or MDS/MPN

OR

* diagnosis with a precursor condition that is associated with a risk of progression to MDS.
* Any amount of prior therapy and may be currently receiving MDS-directed therapy.
* Must have an identified primary oncologist, hematologist or generalist outside NIH who agrees to manage care and any diagnostic findings provided by this study.

Controls

* Any gender and must be eligible for marrow donation per clinical center requirements.
* No history of hematological malignancies listed as inclusion criteria for the group of participants with MDS or current autoimmune disease
* Control marrow volunteers must be scheduled for bone marrow harvest for clinical application, or if evaluated for malignancy, have a bone marrow aspirate scheduled to rule out bone marrow involvement at which time additional samples will be taken as controls for the research purposes of this study.

Design:

* This is a natural history and biospecimen acquisition protocol for participants with Myelodysplastic Syndromes (MDS).
* In addition, we will perform a comprehensive research analysis based on the hypothesis that chronic inflammation in MDS arising from a variety of contributors results in hematopoietic differentiation and maturation blocks leading to dysplasia, cytopenias, and disease progression, and that these may be exploited for novel therapeutic targeting strategies.
* This is a single site (Clinical Center) study that will accrue 1,000 MDS participants and 100 marrow controls (transplant donor or non-involved malignancy) volunteers over a 20-year study accrual duration.
* Diagnostic testing will be performed as is routine for these participants in addition to planned research correlative analyses. Follow-up will occur approximately annually to assess status and survival.

Comprehensive Molecular and Clinical Evaluation of Pediatric and Adult MDS

.All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@@@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

report the overall survival and progression status of participants

report the number of participants that have provided at least one of the biospecimens described in the protocol

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Personalized Medicine Program on Myelodysplastic Syndromes: Characterization of the Patient's Genome for Clinical Decision Making and Systematic Collection of Real World Data to Improve Quality of Health Care	NCT04212390	MDS (Myelodyspl...		18 Years - 100 Years	Fondazione Italiana Sindromi Mielodisplastiche-ETS
Comprehensive Molecular and Clinical Evaluation of Pediatric and Adult MDS	NCT05350748	Myelodysplastic...		1 Day - 120 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for gene mutations