Medicine (RMH) - Theses
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ItemIntegrating genomics into diagnostic and management strategies for patients with Bone Marrow Failure Syndromes( 2023-03)The bone marrow failure syndromes (BMFS) are a heterogeneous group of diseases with differing underlying pathogenic processes and treatment approaches. Diagnosis remains challenging as these conditions can mimic each other, both in clinical presentation, on morphological examination of the bone marrow and their shared potential to transform to haematological malignancy. The BMFS are associated with poor outcomes and there remain many gains to be made in improving both diagnostic and treatment strategies. Both comprehensive clinical data interrogation and genomic analysis by next generation sequencing (NGS) were employed in an effort to examine the clinical, genomic and molecular determinants of outcome in patients with BMFS. The focus of this thesis was to integrate genomics into diagnostic and management strategies to improve outcomes for patients with BMFS. Initially, the utility of comprehensive genomic sequencing to attain accurate diagnosis in patients presenting with bone marrow failure (BMF) was analysed. This work was a prospective demonstration evaluation study. The observed utility of germline and somatic genetic testing in patients presenting with hypocellular BMF and hereditary predisposition to haematological malignancy (HPHM) led to availability of clinical accredited BMF testing, the uptake and outcomes of which were then analysed in the real world setting. The comprehensive dataset of the Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (the AAR) was interrogated to examine the treatments applied in and outcomes of patients with immune aplastic anaemia (iAA). The AAR was modernised to facilitate enrolment of patients with both traditional inherited BMF (IBMF) and also novel germline conditions, including those recently discovered and described as conferring a HPHM. Consideration of whether a HPHM exists is now considered to represent a crucial component of new leukaemia diagnostic work up. The AAR provides an opportunity to document the Australian experience and natural history of patients with BMFS/HPHM and permit further research including facilitating offering clinical trials and novel therapies to patients with these individually rare conditions. Recognising the poor outcomes of patients with BMFS and HPHM, interview and survey of key stakeholders (patients, patient advocates and clinicians caring for patients with BMFS/HPHM) was performed to formally identify issues faced and barriers experienced by this diverse patient group and their families and care providers. A comprehensive model of care (MoC) for patients with BMFS/HPHM was developed which incorporates the results of stakeholder assessment and also the observations determined during earlier studies detailed above. The MoC is undergoing evaluation with a hybrid implementation-effectiveness study to determine both patient and clinician acceptability and satisfaction with this approach. Overall, the work presented in this thesis demonstrates strategies to improve diagnosis, management and outcomes of Australian patients with BMFS/HPHM and their families.