Longitudinal Study of Individuals and Families With Aberrations in DDX41 or Similar Cancer Predisposition Variants
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 510
- 试验地点
- 1
- 主要终点
- To estimate the EFS in individuals with DEAD-box helicase 41 (DDX41) aberrations
研究概览
简要总结
Background:
Hereditary hematopoietic malignancy (HHM) syndromes are a group of inherited disorders that raises the risk of blood cancers. Many people with HHMs have changes in a gene (DDX41) that makes it more likely that they will develop myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or other cancers. This natural history study will explore the link between HHM syndromes and these diseases.
Objective:
To study the link between HHM and MDS/AML.
Eligibility:
People aged 1 month and older with HHM. Relatives with HHM are also needed.
Design:
Participants aged 3 years and older will have 1 initial clinic visit with the option to follow-up annually. They will undergo these procedures:
They will have a physical exam with blood and urine tests.
They may give samples of saliva, stool, nails, and skin.
Their ability to do normal activities will be reviewed.
Some may have a bone marrow biopsy: A tissue sample will be drawn from inside a bone.
They may answer questions about their health and family medical history.
Participants younger than 3 years, and those who cannot come to the clinic, will be contacted by phone or email. Their samples may be collected locally and sent to researchers.
For participants who have changes in their DDX41 gene: Researchers will contact them or their primary care provider once a year for 10 years. Researchers will check on participants health and collect any new test results. Some may be asked to send new samples.
Participants who do not have changes in their DDX41 gene may be contacted yearly, or less often, for 10 years.
Some participants may be asked to return to the clinic if needed.
详细描述
Background:
- Growing awareness of germline predisposition syndromes raises questions about how to best identify, test, and manage individuals carrying germline variants with 1.5%-6.1% of individuals with hematologic malignancies carrying an identified aberration.
- Germline mutations in DEAD-box helicase 41 (DDX41) were first identified as a susceptibility to myeloid neoplasms in 2015 and have been described in up to 6.1% in myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML) patients.
- Germline DDX41 variants are associated with a distinct subtype of myeloid neoplasms, marked by familial predisposition, male predominance, and several commonly commutated somatic genes such as AXL1, EZH2, SRSF2, CUX1 and TP53, and a few underrepresented mutations such as TET2, SF3B1 and NPM1.
- Somatic deleterious variants of the second allele in patients with DDX41 germline variants leads to the onset of multiple lineage cytopenias at a mean age of 66 years (range 50-85 years), followed by the development of a hematologic malignancy.
- The myeloid malignancy associated with DDX41 variants is generally responsive to standard upfront chemotherapy. However, relapses are common and the median survival for individuals with MDS/AML secondary to germline DDX41 variants is consistent with de novo AML at approximately 5.2 years.
- In cases of familial MDS/AML associated with DDX41, the family history may appear negative due to failure to recognize the disorder in family members, reduced penetrance, or late onset of disease.
- Other germline variants in genes such as, but not limited to, CEBPA, CHEK2, ETV6, Fanconi genes, GATA2, RUNX1, and short telomere syndrome associated genes also confer hereditary hematopoietic malignancy (HHM) risk and may induce downstream effects on DDX41. Combinations of variants may exhibit variable clinical presentations, phenotypic associations, therapy responses, and treatment outcomes.
- Currently there are no biomarkers or assays to predict which patients with known HHM variants will progress to a malignancy, and many patients present with a myeloid malignancy as their initial manifestation of a germline syndrome.
Objective:
-To estimate the event free survival (EFS) in individuals with DEAD-box helicase 41 (DDX41) aberrations
Eligibility:
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 1 Month 至 120 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Age > 1 month old.
- •Participants with history of aberrations that affect the DDX41 gene, DDX41 RNA, or DDX41 protein (Cohorts 1-2)
- •Participants with history of aberrations in another HHM variant (Cohort 3)
- •Participants with history of absence of HHM variants, who have first or second degree relative with history of confirmed or suspected HHM variant(s) per participant report (Cohort 4).
- •Participants must have an identified healthcare provider outside of NIH who manages participant care, and any diagnostic clinical findings provided by this study.
- •Ability of participant or parent/guardian to understand and the willingness to sign a written consent document.
排除标准
- 未提供
研究组 & 干预措施
Cohort 2
Participants with confirmed aberrations that affect the DDX41 gene, DDX41 RNA, or DDX41 protein and who do NOT have history of MDS/MPN/AML
Cohort 3
Participants with confirmed aberrations in another HHM variant
Cohort 1
Participants with confirmed aberrations that affect the DDX41 gene, DDX41 RNA, or DDX41 protein and who have a history of MDS/MPN/AML diagnosis
Cohort 4
Participants with confirmed absence of known HHM variants, and who have first or second degree relative with confirmed or suspected HHM variant(s) (control group)
结局指标
主要结局
To estimate the EFS in individuals with DEAD-box helicase 41 (DDX41) aberrations
时间窗: Up to 10 years
Describe the EFS separately for Cohort 1 and Cohort 2. Kaplan-Meier plots will be generated, five and 10-year EFS will be reported, along with 95% confidence intervals for each Cohort separately.
次要结局
- To define the OS in individuals with DDX41 aberrations(Up to 10 years)
- To identify secondary commonly co-mutated somatic or germline variants as well as underrepresented mutations that may impact clinical presentation, disease severity, progression to malignancies.(Up to 10 years)