Diagnosis and Phenotype Characterisation Using Genomics in Patients With Inherited Bone Marrow Failure (IBMDx Study)

Hematologic Diseases Clinical Trial

— IBMDx  

Official title:

Diagnosis, Discovery and Novel Phenotype Characterisation Using Multimodal Genomics in Patients With Inherited Bone Marrow Failure and Related Disorders (IBMDx Study)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05196789
• Other study ID #: 77923
• Status: Recruiting
• Start date: March 18, 2022
• Est. completion date: December 2025

Study information

• Verified date: March 2022
• Source: Peter MacCallum Cancer Centre, Australia
• Contact: Kelsey Man, PhD
• Phone: 61 3 8559 5000
• Email: kelsey.man[@]petermac.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This project seeks to perform whole genome sequence (WGS) and whole transcriptome sequence (WTS) analysis on 350 patients with suspected inherited bone marrow failure syndromes and related disorder (IBMFS-RD) in order to increase the genomic diagnostic rate in IBMFS.

Description:

IBMFS-RD are a heterogeneous group of rare diseases resulting in significant morbidity and early mortality. These syndromes are individually and collectively rare (affecting <1 per 10,000 people) and a significant proportion are unexplained by mutations in known genes. Whilst rare, these familial conditions are also likely underdiagnosed due to their relatively recent description and also due to lack of accessible genomic testing. For patients with clinically suspected IBMFS-RD, receiving a genomic diagnosis is critical to: - Establish a precise and reliable diagnosis (including distinguishing a monogenic aetiology from more common acquired or autoimmune causes of bone marrow failure which have dramatically different treatments (e.g. immunosuppression) - Inform prognosis, clinical course, optimal treatment choice and screening for non-haematological organ dysfunction - Optimise allogeneic haematopoietic stem cell transplant (HSCT) chemotherapy conditioning and minimise regimen-related toxicity - Inform risk-benefit analysis of performing allogeneic HSCT to potentially prioritise other therapies (including novel gene therapy strategies) - Avoiding the catastrophe of HSCT donation from occult genetically affected relatives - Provide counselling (including stem cell donor counselling) and offer genetic testing for potentially affected family members - Provide accurate reproductive counselling and reproductive options to affected individuals This study aims to provide WGS and WTS to a national cohort of patients with IBMFS-RD to determine diagnostic rate, health economic impact, health implementation challenges and other exploratory endpoints.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 350
• Est. completion date: December 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months and older

Eligibility

Inclusion Criteria:

1. age = 3 months

2. able to give informed consent (or parent/guardian able to give informed consent)

3. a clinicopathological diagnosis (or differential diagnosis) of inherited bone marrow failure syndrome or related disorder (IBMFS-RD) as per the study team

Exclusion Criteria:

1. A clinicopathological diagnosis of an acquired bone marrow failure syndrome (including acquired aplastic anaemia and hypoplastic myelodysplastic syndrome) as per the study team

2. Existing definitive genomic diagnosis for patient's haematological phenotype

Related Conditions & MeSH terms

• Blood Platelet Disorders
• Bone Marrow Failure Disorders
• Congenital Bone Marrow Failure Syndromes
• Hematologic Diseases
• Inherited Platelet Disorder
• Pancytopenia

Intervention

Diagnostic Test:
• whole genome and transcriptome sequencing
To perform whole genome/transcriptome analysis of patients in a cohort of up to 350 Australian patients with IBMFS-RD

Locations

Country	Name	City	State
Australia	Peter MacCallum Cancer Centre	Melbourne	Victoria

Sponsors (3)

Lead Sponsor	Collaborator
Peter MacCallum Cancer Centre, Australia	National Health and Medical Research Council, Australia, University of Melbourne

Country where clinical trial is conducted

Australia, 

References & Publications (1)

Blombery P, Fox L, Ryland GL, Thompson ER, Lickiss J, McBean M, Yerneni S, Hughes D, Greenway A, Mechinaud F, Wood EM, Lieschke GJ, Szer J, Barbaro P, Roy J, Wight J, Lynch E, Martyn M, Gaff C, Ritchie D. Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes. Haematologica. 2021 Jan 1;106(1):64-73. doi: 10.3324/haematol.2019.237693. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Definitive IBMFS-RD diagnosis	IBMFS-RD diagnosis - An initial analysis of a panel of ~100 genes of established relevance to IBMFS-RD phenotype will be performed on all patients. If no molecular diagnosis is made from the panel of genes, further analysis on the genomic data will be performed using the best practice analytical tools and techniques.; All results will be communicated to patients.	3-12 months post baseline
Secondary	Develop a whole transcriptome gene expression classifier	To develop a whole transcriptome gene expression classifier to aid diagnosis of IBMFS-RD.	4 years
Secondary	Cost-effectiveness of genomic testing in patients with suspected IBMFS-RD	The cost-effectiveness of genomic testing is assessed by the differences in costs and quality of life associated with genomic testings compared with standard of care. Costs being considered include direct medical costs incurred within the health system arising from utilisation of hospital services and drug dispensing. Quality of life is assessed by EORTC-QLQ-C30 version 3 and CHU9D questionnaires for adult and paediatric patients respectively.	4 years
Secondary	Budget-impact of genomic testing in patients with suspected IBMFS-RD	Evaluation of budget-impact of genomic testing includes examining the financial and operational sustainability as well as scalability of offering genomic testing beyond the trial period.	4 years
Secondary	Health implementation analyses regarding the acceptability of genomic testing	The acceptability of comprehensive and centralised genomic testing in IBMFS-RD to patients is measured by a patient acceptability questionnaire which assesses patients' view and understanding of genomic testing.	4 years
Secondary	Populate Registry	To populate the Aplastic Anaemia and Other Bone Marrow Failure Syndromes Registry (AAR, Monash University) with consenting patients with IBMFS-RD to facilitate long-term follow up.	4 years