Myelodysplastic Syndrome Clinical Trial
Natural History of Acquired and Inherited Bone Marrow Failure Syndromes
Summary
Background:
Bone marrow failure diseases are rare. Much is known about the diseases at the time of diagnosis, but long-term data about the effects of the diseases and treatments are lacking. Researchers want to better understand long-term outcomes in people with these diseases.
Objective:
To follow people diagnosed with acquired or inherited bone marrow failure disease and study the long-term effects of the disease and its treatments on organ function.
Eligibility:
People aged 2 years and older who have been diagnosed with acquired or inherited bone marrow failure or Telomere Biology Disorder. First degree family members may also be able to take part in the study.
Design:
Participants will be screened with a medical history, physical exam, and blood tests. They may have a bone marrow biopsy and aspiration. For this, a large needle will be inserted in the hip through a small cut. Marrow will be drawn from the bone. A small piece of bone may be removed.
Participants may also be screened with some of the following:
Cheek swab or hair follicle sample
Skin biopsy
Urine or saliva sample
Evaluation by disease specialists (e.g., lung, liver, heart)
Imaging scan of the chest
Liver ultrasounds
Six-Minute Walk Test
Lung function test
Participants will be put into groups based on their disease. They will have visits every 1 to 3 years. At visits, they may repeat some screening tests. They may fill out yearly surveys about their medicines, transfusions, pregnancy, bleeding, and so on. They may have other specialized procedures, such as imaging scans and ultrasounds.
Participation will last for up to 20 years.
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Full Description
Study Description: This study will allow for the long term follow up of patients with acquired and inherited bone marrow failure, both treated and untreated.
Objectives:
Primary Objective
The primary objective is to characterize disease and treatment related long-term outcomes in subjects with inherited or acquired marrow failure.
Secondary Objectives
Rates of disease progression requiring intervention
Determine overall survival
Determine event free survival in subjects who receive treatment
Genetic or molecular biomarker to predict the long-term outcomes/early diagnosis in SAA and disease progression in other marrow failures.
Determine effects of pregnancy, viral infections, and vaccinations on disease course
Determine rates of both hematologic and solid organ malignancies
For Telomere Biology Disorders (TBD) cohort, assess the systemic impact of the disease including lung function, liver function, immunodeficiency, endocrine disorders, vascular disorders, and cardiovascular disease
For diseases with a genetic cause, determine the differences in clinical phenotype between different mutations causing the syndrome (example within TBD)
Family genetic studies to determine the incidence and penetrance of specific gene mutations within one family
Tertiary/Exploratory Objectives
Genomic analysis (including whole exome or whole genome sequencing) to seek a potentially disease-causing mutations in subjects who meet the clinical phenotype for inherited disease but do not harbor a known mutation using sequencing
Serial assessment of hematopoiesis and immune activity as it relates to clinical course
Endpoints:
Primary Endpoints:
Cohort 1 (SAA): Rate of relapse and clonal evolution in previously treated subjects.
Cohort 2 (Other marrow failure): Rate of progression (cytopenias or clonal evolution) requiring therapeutic intervention.
Cohort 3 Telomere Biology Disorders (TBD): Development of cytopenias, lung disease or liver disease, or (if present at baseline)
characterization, and rate of progression of cytopenias, lung disease or liver disease in TBD subjects and looking at their overall contribution to morbidity and mortality.
Cohort 4 Inherited Bone Marrow Failure (IBMF): Rate of progression to transfusion dependent marrow failure, marrow failure requiring therapeutic intervention (such as medical therapy or HSCT) or the progression to hematological or solid malignancy.
Secondary Endpoints:
Cohort 1 (SAA):
Response to treatment at 3 and 6 months and rates of relapse
Overall survival
Type and severity of additional medical diagnoses
Rates of clinically significant paroxysmal nocturnal hemoglobinuria (PNH)
Rates, timing, and treatment of abnormal iron status (iron overload or deficiency)
Rates and outcomes of pregnancy, and rate and treatment of abnormal menses
Rates of drug induced complications
Incidence of vaccination and rates of relapse following administration
Cohort 2 (Other marrow failure):
Treatment response
Development of PNH and occurrence of symptoms, or need for therapy
Overall survival
Cohort 3 (TBD):
Overall survival
Response to treatment in terms of improvement of cytopenias, or slower progression of lung or liver disease or fibrosis
Development of hematological or solid organ malignancy
Presence of an immunodeficiency or abnormal lab values (immunoglobulin or lymphocyte profile)
Presence of an endocrine disorder or abnormal hormonal levels
Presence of a vascular abnormality
Presence of an abnormal ECG or ECHO. Incidence of IHD over time
Presence, development of or rate of progression of cytopenias,lung disease, and liver disease compared between TBD causing mutations
Presence of TBD mutation in a family member and its association with cytopenias, short telomeres, and evidence of lung or liver involvement. Presence, development of or rate of progression of cytopenias, lung disease, and liver disease compared between family members with the same mutation
Genomic analysis using whole exome sequencing or whole genome sequencing to look for potentially disease causing variants in subjects who meet the clinical phenotype for TBD but do not have a known mutation
Cohort 4 (IBMF):
Overall survival
Treatment response
Development of hematological or solid organ malignancy
New medical diagnosis and its relationship to any treatment received
Record PNH incidence in IBMF as defined by a clone size of >1% in granulocytes
Determine the incidence of iron overload, its course with any IBMF treatments, and its response to chelation therapy
Record the outcomes of pregnant subjects
The presence of viral and bacterial infections and correlation to worsening cytopenias. Presence of worsening cytopenias after vaccination
Presence of IBMF mutation in a family member and its association with cytopenias, and other clinical phenotypes
Genomic analysis using whole exome sequencing or whole genome sequencing to look for potentially disease causing variants in subjects who meet the clinical phenotype for TBD but do not have a known mutation
Eligibility Criteria
INCLUSION CRITERIA:
To be eligible to participate in this study, an individual must meet all of the following criteria. Subjects and their family members who undergo screening but ultimately do not meet criteria for cohorts 1-5 will be removed from the study. Subjects may forgo screening and sign directly onto cohorts 1-5 if they meet criteria based on either prior NIH testing or external examinations. Family members will only be asked to be screened for participation onto this study after confirmation of eligibility by an affected participant.
Cohorts 1-4
Age >=2 years
Diagnosis of acquired or inherited bone marrow failure or ineffective hematopoiesis or TBD (see below for cohort 3 specific criteria)
Ability and willingness to come to the NIH CC for consultation and testing
Ability of subject or Legally Authorized Representative (LAR) to understand the investigational nature of the protocol and their willingness to sign a written informed consent document.
For cohort 3 - TBD:
Presence of a pathogenic, likely pathogenic, or known family mutation in a telomere maintenance gene
OR
If mutation negative or VUS, telomere length <10^th percentile in lymphocytes with at least two clinical features: 1) cytopenia (Hb <10g/dL or ANC <1.5x10^9 or platelets<100), 2) documented liver fibrosis by histology OR abnormal liver US / fibro scan consistent with fatty liver or fibrosis), 3) documented pulmonary fibrosis by histology /
Cohort 5
Age >= 2 years
First degree family member with a known or suspected inherited bone marrow failure syndrome from a patient enrolled on this or another NIH protocol as determined by a PI
or AI
Ability and willingness to safely provide blood, buccal swab, or fibroblasts for testing as stated by subject
Ability of subject or Legally Authorized Representative (LAR) to understand the investigational nature of the protocol and the willingness to sign a written informed consent document.
EXCLUSION CRITERIA:
Post HSCT (except if cohort 3 - TBD)
MDS/AML on chemotherapy (patients with hypoplastic MDS who have received or are on erythropoietin stimulating agent (ESA), granulocyte colony-stimulating factor (GCSF), or immunosuppressive treatment will not be excluded). Subjects in Cohort 3 with TBD can be seen if they have received chemotherapy for MDS/AML.
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There is 1 Location for this study
Bethesda Maryland, 20892, United States More Info
Contact
800-411-1222
[email protected]
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