Research trial aims to revolutionise antifungal treatment for patients with acute leukaemia

A new research programme will seek to identify the most effective way to prevent and detect fungal infection in patients with acute leukaemia.

Candida fungi - human pathogenic yeasts
“It’s cutting down the amount of medication. Your system's been through a lot. So, reducing the amount of medication, I see this as a positive thing.” 

This is the sentiment from a patient who, after going through difficult chemotherapy for acute leukaemia, was then treated for a fungal infection on top of that ‘just in case’. 

Now, a groundbreaking trial which aims to revolutionise infection management and improve the outcomes of patients with acute leukaemia has been launched at Hull York Medical School. 

Acute leukaemia patients undergoing intensive chemotherapy face a high risk of infections, particularly invasive fungal infections, which can be fatal. 

Currently, all patients are typically given antifungal medication throughout the course of chemotherapy. However, only a minority of them will actually develop a fungal infection, leading to overuse of antifungals, potential adverse effects, and fuelling the emergence of antifungal resistance. 

This trial, called BioDriveAFS, seeks to optimise antifungal use and identify patients who truly need treatment. 

Professor Gavin Barlow, Professor of Infection at Hull York Medical School and Consultant in Infection at Hull University Teaching Hospitals NHS Trust, is co-lead for the trial, alongside his colleague at the Trust Dr David Allsup, Senior Lecturer in Haematology at Hull York Medical School and Consultant Haematologist. 

Professor Barlow is a prominent figure in the field of infectious diseases. An NHS consultant in infection at Hull University Teaching Hospitals NHS Trust, he played a critical role during the early days of the COVID-19 pandemic. He was the first healthcare professional in the country to receive and respond to a positive COVID-19 result for a patient, and also supported the setup of the Oxford vaccine trial and local research responses to the pandemic with colleagues. 

He has been actively involved in national and international projects, including a MOOC about antimicrobial stewardship in collaboration with the British Society for Antimicrobial Chemotherapy and a published e-book which has garnered international recognition. 

In collaboration with the York Trials Unit at the University of York, the trial has received funding of almost £2.5million from the NIHR. 

The problem 

Patients with acute leukaemia, including acute myeloid leukaemia, myelodysplasia, and acute lymphoblastic leukaemia, are treated by intensive chemotherapy. Patients with this condition who receive intensive chemotherapy are at risk of developing a potentially serious fungal infection. These infections have a high mortality of about 25%.1 

Prolonged fever is common during chemotherapy, and this may or may not be caused by a fungal infection. Diagnosing the underlying cause of an infection is difficult; as such, all patients are given antifungal medication as a preventative measure (prophylaxis). 

This means that all patients take a drug to prevent a small number of fungal infections. 

“acute leukaemia patients account for about 75% of NHS antifungal use; Yet only 1 in 10 to 1 in 20 of these patients actually develop a serious fungal infection that needs to be treated”2 
Professor Gavin Barlow

The most common invasive fungal infection is called invasive aspergillosis, that is found naturally all around us and does not normally make us ill. However, in people with weakened immune systems aspergillus can cause severe lung and other infections. 

Candida is another very common fungus that can cause non-serious infections in people with healthy levels of immunity, but in people with lowered immune systems more serious infections can occur. 

Professor Barlow said, “The drugs used to treat fungal infections can have side effects and may interact with other drugs, including chemotherapy. So we want to find better ways of deciding which patients do have a fungal infection, so we can target treatment at these patients.” 

Antifungal resistance and antifungal stewardship 

This pioneering research not only holds the promise of transforming antifungal stewardship for acute leukaemia patients but also contributes to the broader efforts to combat antimicrobial resistance (AMR). 

Overuse of antifungal drugs may also have serious consequences for the NHS and wider society in general. The ‘AFS’ in the BioDriveAFS trial title stands for ‘antifungal stewardship’, which is a sub-section of antimicrobial stewardship, an area of medicine within which Professor Barlow has considerable expertise.

Antimicrobial stewardship aims to optimise antimicrobial use in the fight against AMR, which has been identified as one of the most pressing global challenges the NHS faces; The World Health Organisation (WHO) has declared AMR as one of the top 10 global public health threats, and AMR is listed on the UK Government’s National Risk Register. 

AMR happens when disease-causing microorganisms (like bacteria, viruses, fungi, and parasites) become resistant to the effects of antimicrobial medicines such as antibiotics, antivirals, antifungals, and antiparasitics. This resistance means that the drugs we normally use to kill, prevent, or treat these microorganisms no longer work effectively. This resistance is accelerated by use of antimicrobial drugs. 

The UK Government has developed an AMR 5 year National Action Plan (NAP), to contain and control AMR by 2040. 

The BioDriveAFS trial aims to support this national plan and transform antifungal stewardship in acute leukaemia patients, by actively and safely identifying patients who truly need treatment. 

By optimising antifungal use, the study aligns with the national and global push for more precise and targeted treatments, mitigating the emergence of drug-resistant infections. 

Acute myelocytic leukaemia

About the trial 

In collaboration with the York Trials Unit, the trial involves randomising patients into two groups: the diagnostics approach and the standard care approach. 

In the diagnostics approach, patients do not receive any antifungal prophylaxis but undergo weekly blood tests to detect biomarkers of invasive fungal infection, galactomannan and beta D glucan. 

If these biomarkers show signs of infection, additional tests and assessments are conducted, leading to an early diagnosis and prompt treatment. The goal is to reduce overall antifungal use while providing early and effective treatment to those who need it. 

Professor Barlow explained, “We want to find out if by utilising biomarkers to guide antifungal therapy, we can minimise unnecessary medication exposure and potential side effects for patients. 

"Our goal is to achieve better outcomes while enhancing the patients' overall quality of life during their treatment journey” 
Professor Gavin Barlow

Professor Barlow explained that their engaged Patient Advisory Group have provided critical insight into their experience of taking antifungal medications while undergoing their chemotherapy treatment for acute leukaemia. 

He explained, "As doctors, sometimes we think that just taking one extra tablet a day is not a big deal, or one extra drip a week. But actually, patients have told us they don't like taking it when they're feeling sick already. They don't want to swallow another pill in the morning. 

“If they have to come to hospital for a drip for the antifungals that means they may have to make an additional trip, and they're already in and out because of the chemotherapy. And of course, they're feeling lousy." 

The collaboration between various institutions is essential to the success of the BioDriveAFS trial. In addition to Prof Barlow, Dr Allsup and the York Trials Unit, Andrea Hilton, an academic pharmacist at the University of Hull, and Dr Patrick Lillie, who led the successful Oxford-Astra-Zeneca COVID-19 vaccine trial at Hull University Teaching Hospitals NHS Trust, are key contributors to this innovative research. 

The BioDriveAFS trial is currently recruiting centres and patients to the trial, with the study aiming to recruit 404 patients. The results are expected to be published in 2027, offering a potential paradigm shift in antifungal therapy and opening new avenues for personalised medicine in the field of infectious diseases. 

Investigating microbiomes and personalised medicine 

A parallel study, led by Research Fellow Dr Tom Taynton, under the supervision of Professor Matthew Hardman, Chair in Wound Care at Hull York Medical School, is investigating the oral and skin microbiome as part of the BioDriveAFS trial. 

Through his doctoral research, he is analysing sequential samples from patients undergoing intensive chemotherapy for acute leukaemia. By studying how the oral and skin microbiomes evolve during treatment, Dr Taynton aims to identify patterns and characteristics that may help predict infection risk. The research could inform the future of infectious disease management, where patients receive tailored treatment plans based on their unique microbiome profiles. 

In addition, Professors Barlow and Hardman were recently successful in gaining funding from the Medical Research Council for state-of-the-art equipment, a PromethION 24, an advanced technology that enables comprehensive and high-throughput analysis of the patients' microbiome.

A researcher using the PromethION

The integration of the PromethION 24 into skin research is noteworthy, as Hull University Teaching Hospitals NHS Trust is one of the few NHS trusts in possession of this cutting-edge technology

The integration of the PromethION 24 into skin research is noteworthy, as Hull University Teaching Hospitals NHS Trust is one of the few NHS trusts in possession of this cutting-edge technology

The equipment has the potential to advance omics research locally - biological research that focuses on the comprehensive study of biological molecules and their interactions within biological systems - and contribute to the fight against antimicrobial resistance. 

“The integration of the PromethION 24 into our research is especially noteworthy, as Hull University Teaching Hospitals NHS Trust is one of the few NHS trusts in possession of this cutting-edge technology” 
Professor Gavin Barlow

Professor Barlow and Professor Hardman aim to leverage this opportunity to expand omics research not only at the hospital but also throughout the wider health research community. 

This rare piece of equipment allows for sophisticated analyses of microbial and genetic data, offering a deeper understanding of antimicrobial resistance and enabling novel approaches to combating infectious diseases; an incredibly powerful tool in personalised medicine. 

Collectively, these initiatives underscore Professor Barlow’s and the team’s commitment to advancing healthcare and contributing to the fight against antimicrobial resistance on a national and international scale.

For more information about the BioDriveAFS trial, please contact Professor Gavin Barlow or visit the BioDriveAFS website. Professor Barlow is a member of the Experimental Medicine and Biomedicine research group. This study/project is funded by the NIHR HTA programme (NIHR132674). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. 

References

(1) Lestrade PP, Bentvelsen RG, Schauwvlieghe AFAD, Schalekamp S, van der Velden WJFM, Kuiper EJ, van Paassen J, van der Hoven B, van der Lee HA, Melchers WJG, de Haan AF, van der Hoeven HL, Rijnders BJA, van der Beek MT, Verweij PE. Voriconazole Resistance and Mortality in Invasive Aspergillosis: A Multicenter Retrospective Cohort Study. Clin Infect Dis. 2019 Apr 24;68(9):1463-1471. doi: 10.1093/cid/ciy859. PMID: 30307492.

(2) Van De Peppel R, Visser L, Dekkers O, De Boer M. The burden of invasive aspergillosis in patients with haematological malignancy: a meta-analysis and systematic review. Journal of Infection. 2018;76(6):550-62.

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