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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Hematologic Diseases; Inherited Platelet Disorder; Inherited BMF Syndrome
• Intervention / Treatment: Diagnostic test: whole genome and transcriptome sequencing

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.

• Study Type: Observational
• Enrollment (Anticipated): 350

Contacts and Locations

• Study Contact: Name: Kelsey Man, PhD; Phone Number: 61 3 8559 5000; Email: kelsey.man@petermac.org
• Study Contact Backup: Name: Piers Blombery, MBBS(Hons); Email: piers.blombery@petermac.org

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia
      • Recruiting
      • Peter Maccallum Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with suspected IBMFS-RD

Description

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

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Develop a whole transcriptome gene expression classifier	To develop a whole transcriptome gene expression classifier to aid diagnosis of IBMFS-RD.	4 years
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
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
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
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

Collaborators and Investigators

• Sponsor: Peter MacCallum Cancer Centre, Australia
• Collaborators: National Health and Medical Research Council, Australia; University of Melbourne
• Investigators: Principal Investigator: Piers Blombery, MBBS(Hons), Peter MacCallum Cancer Centre, Australia

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2022
• Primary Completion (Anticipated): June 1, 2025
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: December 15, 2021
• First Submitted That Met QC Criteria: January 4, 2022
• First Posted (Actual): January 19, 2022

Study Record Updates

• Last Update Posted (Actual): April 6, 2022
• Last Update Submitted That Met QC Criteria: March 28, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: hematological diseases; whole genome sequencing; bone marrow failure syndrome; pancytopenia
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Infant, Newborn, Diseases; Hematologic Diseases; Bone Marrow Failure Disorders; Pancytopenia; Blood Platelet Disorders; Congenital Bone Marrow Failure Syndromes
• Other Study ID Numbers: 77923 (Other Identifier: Stanford University Alternate IRB Approval Number)

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