Next Generation Sequencing (NGS) in Familial Acute Myeloid Leukemia and Myelodisplastic Syndromes

Next Generation Sequencing (NGS) Approach to Study Known and New Germline Mutations in Familial Acute Myeloid Leukemia and Myelodisplastic Syndromes

The aim of this study is to look for predisposing mutations in patients and relatives affected by AML and MDS with familial history of myeloid or, less frequently, lymphoid malignancies. Taking advantage of a next generation sequencing (NGS) platform, screening for known and unknown mutations potentially associated with the disease will be done. The screening will be performed on affected and unaffected family members, in order to outline new pedigrees that either validate previous findings or constitute novel discoveries.

Study Overview

• Status: Recruiting
• Conditions: Leukemia
• Intervention / Treatment: Genetic: Analysis with molecular biology

Detailed Description

Patients with a diagnosis of AML or MDS with at least one relative affected by AL/MDS or, secondly, lymphoproliferative disorders, will be enrolled into the study, and will be referred to as the index case. The analysis will be performed both retrospectively and prospectively. A gene panel deep sequencing (GPDS) of the tumor DNA from peripheral blood of the index case at diagnosis will be performed in order to identify mutations in a number of genes known to be associated to myeloid malignancies, mainly: ASXL1, BCOR, NRAS, TP53, RUNX1, CEBPA, FLT3, EZH2, IDH1, IDH2, NPM1, DNMT3A, TET2, CBL, KRAS, ETV6, SF3B1, SRSF2, U2AF1, ZRSR2, GATA2, TERT, TERC, SRP72, and ANKRD26.

In case none of the known mutations is found by the GPDS, whole exome sequencing (WES) will be performed as second step on the tumor cells of the index case.

When one or multiple somatic mutations are found, a Sanger Sequencing (SS) on germline DNA from epithelial buccal cells of the index cases and affected relatives will be performed for the screening of the same somatic leukemic mutations on germline DNA. If the index case and affected relatives share the same mutations on the germline, the same germline mutations will be checked by SS in the unaffected family members.

• Study Type: Observational
• Enrollment (Estimated): 20

Contacts and Locations

• Study Contact: Name: Domenico Russo, MD; Phone Number: 0039303996811; Email: domenico.russo@unibs.it
• Study Contact Backup: Name: Francesca Schieppati, MD; Phone Number: 0039303996811; Email: fschieppati@gmail.com

Study Locations

• Italy
  • Brescia, Italy, 25123
    • Recruiting
    • Chair of Hematology and Bone marrow Transplant Unit
    • Contact: Domenico Russo, MD; Email: domenico.russo@unibs.it
    • Contact: Francesca Schieppati, MD; Email: fschieppati@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Detailed personal and family history from every patient affected by myeloid malignancy will be obtained, in order to identify patients with at least one relative affected by myeloid malignancy or lymphoproliferative disorders or with the features that increase the likelihood of one of the aforementioned familial myeloid malignancy predisposition syndromes

Description

Inclusion criteria:

Any patient with acute myeloid leukemia (AML) or Myelodisplastic Syndrome (MDS) with:

1. a first- or second-degree relative with Acute leukemia or MDS or other myeloid malignancies
2. a first- or second-degree relative with Lymphoproliferative neoplasms

3. or with clinical features that resemble one of the familial MDS/AML predisposition syndromes:

   • History of thrombocytopenia and/or a clinical bleeding propensity (as in RUNX1, ANKRD26 or ETV6 germline mutations)
   • Abnormal nails or skin pigmentation, oral leukoplakia, idiopathic pulmonary fibrosis, unexplained liver disease (as in TERT and TERC germline mutations)
   • Lymphedema, atypical infections, immune deficiencies (as in GATA2 germline mutations)

Exclusion Criteria:

1. any diagnosis other than acute myeloid leukemia (AML) or Myelodisplastic Syndrome (MDS);
2. acute myeloid leukemia (AML) or Myelodisplastic Syndrome (MDS) without a first- or second-degree relative with Acute leukemia or MDS or other myeloid malignancies or without a first- or second-degree relative with Lymphoproliferative neoplasms or with clinical features that resemble one of the familial MDS/AML predisposition syndromes;
3. unability to sign the informed consent

Study Plan

How is the study designed?

Design Details

• Observational Models: Family-Based
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Analysis with molecular biology; Any patient with acute leukemia or other myeloid malignancy AND; a first- or second-degree relative with acute leukemia or other myeloid malignancies; a first- or second-degree relative with lymphoproliferative neoplasms; or with clinical features that resemble one of the familial myeloid malignancies predisposition syndromes	Genetic: Analysis with molecular biology; Molecular screening by next generation sequencing (NGS) platform, for known and unknown mutations potentially associated with the disease

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Discovery of predisposing mutations	Screening of tumor and germline DNA for predisposing mutations	After enrollment of the first 10 cases (an avarage of 2 years)

Collaborators and Investigators

• Sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
• Investigators: Principal Investigator: Domenico Russo, MD, Chair of Hematology

Study record dates

Study Major Dates

• Study Start (Actual): February 9, 2017
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: February 9, 2017
• First Submitted That Met QC Criteria: February 16, 2017
• First Posted (Actual): February 23, 2017

Study Record Updates

• Last Update Posted (Actual): April 30, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia
• Other Study ID Numbers: NEXT-FAMLY 1016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No