Clinical trial NCT05196789: Diagnosis and Phenotype Characterisation Using Genomics in Patients With Inherited Bone Marrow Failure (IBMDx Study)
Official title: Diagnosis, Discovery and Novel Phenotype Characterisation Using Multimodal Genomics in Patients With Inherited Bone Marrow Failure and Related Disorders (IBMDx Study)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Inherited BMF Syndrome
Inherited Platelet Disorder
Hematologic Diseases
Keywords: bone marrow failure syndrome
whole genome sequencing
hematological diseases
pancytopenia
Lead sponsor: Peter MacCallum Cancer Centre, Australia
Sponsor class: OTHER
Collaborators: name: National Health and Medical Research Council, Australia
name: University of Melbourne
First posted: 2022-01-19
Enrollment: 350
Sex: ALL
Minimum age (years): 3
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with suspected IBMFS-RD

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Definitive IBMFS-RD diagnosis
timeFrame: 3-12 months post baseline
Secondary outcomes:
measure: Develop a whole transcriptome gene expression classifier
timeFrame: 4 years
measure: Cost-effectiveness of genomic testing in patients with suspected IBMFS-RD
timeFrame: 4 years
measure: Budget-impact of genomic testing in patients with suspected IBMFS-RD
timeFrame: 4 years
measure: Health implementation analyses regarding the acceptability of genomic testing
timeFrame: 4 years
measure: Populate Registry
timeFrame: 4 years
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
Study officials:
affiliation: Peter MacCallum Cancer Centre, Australia
name: Piers Blombery, MBBS(Hons)
role: PRINCIPAL_INVESTIGATOR
References:
citation: Blombery P, Fox L, Ryland GL, Thompson ER, Lickiss J, McBean M, Yerneni S, Trainer A, 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.