Biomarker Driven Antifungal Stewardship (BioDriveAFS) in Acute Leukaemia – a Multi-Centre Randomised Controlled Trial to Assess Clinical and Cost Effectiveness

RESEARCH QUESTION Is biomarker-based antifungal stewardship (AFS) superior to prophylactic antifungal (AF) and standard of care (SoC) in reducing AF therapy use in patients with acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or high risk myelodysplasia (HRMDS) having intensive chemotherapy (IC), without adverse impact on health-related quality of life (HRQoL) or invasive fungal infection (IFI) incidence? BACKGROUND AML, ALL and HRMDS are common blood cancers; HRMDS often progresses to AML. All are curable with IC. Neutropenic fever (NF) is common during IC and can be due to IFI with high mortality. AML/HRMDS account for 80% of first-line AF therapy in the Dept. of Haematology at the sponsor’s site. Prophylactic AF is the SoC in preventing IFI in AML/ALL/HRMDS; in our preparatory survey, 80% use it. Despite this, during NF doctors over-diagnose IFI resulting in many patients also having AF therapy. This requires all patients to take an AF to prevent a small number of IFI (~6%), but commonly results in unnecessary AF therapy exposure (=>27%), resulting in side-effects, drug resistance and costs. An alternative is monitoring of biomarkers with responsive tests/therapy if IFI is suspected. Galactomannan (GM) and beta-D-glucan (BG) are the most used IFI biomarkers in the NHS and can detect IFI before symptoms. SoC has not been compared to a combined GM/BG strategy in a large trial. Our patient, public and clinical engagement has informed us that HRQoL is important to patients; AF therapy use and proven/probable IFI are the key endpoints for clinical staff. We propose a randomised controlled trial (RCT) in the context of current NHS practice. AIM To establish clinical and cost-effectiveness of biomarker-driven care for IFI using GM/BG versus prophylactic AF/SoC in those with AML/ALL/HRMDS having IC OBJECTIVES To conduct: 1. A multicentre RCT to assess if biomarker based AFS is superior to prophylactic AF/SoC, and non-inferior with respect to HRQoL and IFI (WP1) 2. An internal pilot to optimise trial processes (WP1/3) 3. An economic analysis to establish cost-effectiveness (WP2) 4. A process evaluation to understand context, assess fidelity, and inform implementation (WP3) METHODS A multicentre RCT comparing biomarker-based care for IFI in AML/ALL/HRMDS versus prophylactic AF/SoC for AF use, HRQoL and proven/probable IFI. Trial processes will be optimised by an internal pilot ensuring we recruit, randomise, and retain participants with clear progress criteria. Additionally: • A cost effectiveness analysis based on resource use data • A mixed methods process evaluation concentrating on fidelity and implementation assessment via qualitative interviewing and clinical data collection TIMELINES Start of grant: 1st September 2021 Start of RCT / pilot: 1st March 2022 End of pilot: 30th Nov. 2022 End of recruitment: 30th August 2024 End of follow-up: 30th August 2025 Completion: 28th February 2026 ANTICIPATED IMPACT and DISSEMINATION • Practice changing/informing results that optimise AF use across the NHS • Bespoke clinical dissemination via an engagement and training legacy • Cost-effectiveness data to inform policy making • Post-trial implementation strategy developed from process evaluation to embed findings into NHS practice