Clinical trial NCT07019155: Study of Individuals and Families With Aberrations in DDX41 or Similar Cancer Predisposition Variants
Official title: Longitudinal Study of Individuals and Families With Aberrations in DDX41 or Similar Cancer Predisposition Variants
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Germline Mutation
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Keywords: DEAD-box helicase 41 (DDX41)
germline mutations
MDS
AML
Germline Predisposition Syndromes
Hereditary Hematopoietic Malignancy
Cancer Predisposition
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2025-06-13
Enrollment: 510
Sex: ALL
Minimum age (years): 1
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Participants with aberrations in DDX41 or other HHMs and relatives of individuals with aberrations in DDX41 or other HHMs.

Brief summary: 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.

Detailed description: 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:

* Age \> 1 month old
* Must have confirmed aberrations that affect the DDX41 gene, DDX41 RNA, or DDX41 protein or confirmed aberrations in another HHM variant

or

must have confirmed absence of HHM variants and have first or second degree relative with confirmed or suspected HHM variant(s)

-Must have an identified medical provider outside NIH who manages care, and any diagnostic findings provided by this study.

Design:

* This is a natural history and biospecimen analysis protocol for participants with aberrations in DDX41 or other HHMs and relatives of individuals with aberrations in DDX41 or other HHMs.
* We will perform comprehensive research analysis to understand the biology of HHM variants that contributes to dysregulation in hematopoietic differentiation and maturation blocks leading to dysplasia, cytopenia, and disease progression, so that these may be exploited for novel therapeutic targeting strategies.
* 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.

Eligibility criteria: * INCLUSION CRITERIA:
* Age \> 1 month old.
* Participants with history of aberrations that affect the DDX41 gene, DDX41 RNA, or DDX41 protein (Cohorts 1-2)

OR

Participants with history of aberrations in another HHM variant (Cohort 3)

OR

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.

EXCLUSION CRITERIA:

None

Primary outcomes:
measure: To estimate the EFS in individuals with DEAD-box helicase 41 (DDX41) aberrations
timeFrame: Up to 10 years
Secondary outcomes:
measure: To define the OS in individuals with DDX41 aberrations
timeFrame: Up to 10 years
measure: 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.
timeFrame: Up to 10 years
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Sung-Yun Pai, M.D.
role: PRINCIPAL_INVESTIGATOR
References: