Title: Biomarker Driven Antifungal Stewardship (BioDriveAFS) in Acute Leukaemia – a Multi-Centre Randomised Controlled Trial to Assess Clinical and Cost Effectiveness
Funder: Department of Health and Social Care

Abstract: Acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) and high risk myelodysplasia (HRMDS) are blood cancers treated by intensive chemotherapy. Prolonged fever is common during chemotherapy and can be due to fungal infection. This may be life-threatening and is difficult to diagnose. Different ways have been used to prevent fungal infection in these patients. Drugs called antifungals are often given as a preventive (prophylaxis). This is the usual way to prevent fungal infection in AML/ALL/HRMDS. Doctors often treat patients as if they have fungal infection when they get ill, even if a preventive has been used. This approach means that all patients take a drug to prevent a small total number of fungal infections. Antifungals have side-effects and overuse may lead to infections that are resistant to them. Another way, used in some hospitals, is not to give patients a preventive antifungal, but to monitor them closely and treat fungal infection early if suspected. Blood tests (biomarkers) can be used to detect fungal infection before symptoms start. _x000D_ _x000D_ We discussed this way with patients with experience of blood cancers and fungal infection, organised with charity Leukaemia Care. Patients told us the number of drugs they have to take is a burden. More blood tests were not seen as an issue. Some patients worry fungal infections will become resistant if antifungals are overused. It is important therefore to identify the best approach to fungal infections in AML/ALL/HRMDS. We want to assess if monitoring the risk of fungal infection by regular blood tests is safe and reduces antifungal use, but does not reduce patients’ quality of life or increase fungal infections._x000D_ _x000D_ We will do a study comparing these approaches in about 500 patients. In half we will do blood tests for fungal infections twice a week. We will recommend further tests if these are positive or if the patient becomes ill in a way suggesting fungal infection. Antifungals will be recommended if tests suggest a fungal infection is likely. In the other half we will give patients preventive antifungals. Patients will have tests and receive antifungal therapy based on the opinion of the doctor in charge. Patients will go into one group or another by chance. This will allow for an objective assessment of the main aim, which is to see if less antifungals are used in those having regular blood tests without decreasing quality of life._x000D_ _x000D_ We will also look at side-effects, the number of fungal infections and deaths in each group. This will allow us to assess which is the best way, while considering value for money. We will ask healthcare staff what they think about the two approaches and measure whether they find them easy or difficult to use and why. We can use what everyone tells us to suggest how the blood tests are best used. _x000D_ _x000D_ The research team has a lot of experience in creating positive change in the use of medicines, in research, and in the care of AML/ALL/HRMDS patients. We will continue to talk with Leukaemia Care and patients as we progress, ensuring patients’ priorities are always considered. _x000D_ _x000D_ If we show the blood test way is best, we will build on existing experience in the safe use of antifungals, called antifungal stewardship, and what we find in this study, to help increase the use of these tests in the NHS. Based on the results, we will encourage hospitals to review the way they use antifungals. We will also share our results in medical journals, via social media and a study website, and at open meetings.

Lay abstract: RESEARCH QUESTION _x000D_ 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?_x000D_ _x000D_ BACKGROUND _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ 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._x000D_ _x000D_ AIM _x000D_ 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_x000D_ _x000D_ OBJECTIVES _x000D_ To conduct:_x000D_ 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)_x000D_ 2. An internal pilot to optimise trial processes (WP1/3)_x000D_ 3. An economic analysis to establish cost-effectiveness (WP2)_x000D_ 4. A process evaluation to understand context, assess fidelity, and inform implementation (WP3)_x000D_ _x000D_ METHODS_x000D_ 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:_x000D_ • A cost effectiveness analysis based on resource use data_x000D_ • A mixed methods process evaluation concentrating on fidelity and implementation assessment via qualitative interviewing and clinical data collection_x000D_ _x000D_ TIMELINES_x000D_ Start of grant: 1st September 2021_x000D_ Start of RCT / pilot: 1st March 2022_x000D_ End of pilot: 30th Nov. 2022_x000D_ End of recruitment: 30th August 2024_x000D_ End of follow-up: 30th August 2025_x000D_ Completion: 28th February 2026_x000D_ _x000D_ ANTICIPATED IMPACT and DISSEMINATION_x000D_ • Practice changing/informing results that optimise AF use across the NHS_x000D_ • Bespoke clinical dissemination via an engagement and training legacy_x000D_ • Cost-effectiveness data to inform policy making_x000D_ • Post-trial implementation strategy developed from process evaluation to embed findings into NHS practice

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;INFECTION