Managing the use of antifungal drugs for blood cancer patients by using blood tests to identify fungal infection

INTERVENTION: Trial design: The trial is designed as a multicentre, 500‐patient, randomised controlled trial with parallel groups, of a biomarker‐based antifungal stewardship (AFS) strategy versus a prophylactic antifungal (AF) strategy, including existing standard of care (SoC), in reducing AF therapy use in patients with acute leukaemia undergoing intensive chemotherapy (IC). The cost‐effectiveness of these two strategies will also be compared. Blinding is not possible given the nature of the intervention. Randomisation: Randomisation will be implemented using the secure web‐based data collection/management interface ‘REDCap’. This system will be accessed by clinical research staff involved in patient recruitment at recruiting sites (as detailed in the site delegation log) and will be accessible 24 hours a day and 7 days a week. The allocation sequences (using block randomisation stratified by site, with randomly permuted block sizes) will be designed by the trial statistician. The actual sequences embedded in the randomisation system will be generated by a separate YTU statistician independent of the Trial Management Group, using a random number seed that will be concealed from all members of the trial team for the duration of the trial. Intervention arm: Participants allocated to the biomarker based AFS strategy will be monitored for invasive fungal infections (IFIs) with regular blood biomarker tests, combined with, when necessary (e.g. prolonged Neutropenic Fever (NF) and/or symptoms or signs), further responsive tests to identify patients likely to have IFI prior to directed AF therapy. Control (SoC) arm: Participants in the control arm must receive prophylactic AF therapy with a recognised anti‐Aspergillus agent (posaconazole, itraconazole [only when one of the other a CONDITION: Fungal infection following treatment for acute myeloid leukaemia (AML), high risk myelodysplasia (HRMDS), and acute lymphoblastic leukaemia (ALL) ; Infections and Infestations PRIMARY OUTCOME: 1. Antifungal (AF) exposure in the 12 months from recruitment, defined as receipt of =72 hours of therapeutic systemic AF, measured as a dichotomous variable (Yes/No) at 12 months; 2. Health‐related quality of life at 12 months post‐randomisation measured using EuroQol 5 Dimensions (5L) Score (EQ‐5D‐5L) collected at 12 months SECONDARY OUTCOME: 1. Total antifungal (AF) exposure in the 12 months from recruitment measured using the total Defined Daily Doses (DDD) and whole days of therapy of prophylactic and therapeutic AF use at 12 months; 2. Probable/proven invasive fungal infection (IFI) measured using clinical assessment of probable and proven IFIs as per the consensus definitions of the Infectious Diseases Group of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group at 12 months; 3. Survival, all‐cause mortality, and invasive fungal infection (IFI) mortality measured using patient status data collected at 12 months; 4. Invasive fungal infection (IFI) treatment outcomes measured using data on the outcome of IFI treatment (treatment given and completed with no relapse; treatment given and completed, but with relapse; ongoing treatment; and IFI related mortality) collected at 12 months; 5. Antifungal associated adverse effects/events/complications, measured using the adverse event reporting procedure records, and/or from relevant follow‐up case report forms as appropriate, between baseline and 12 months; 6. Resource use measured using hospital care health service use (e.g. length of hospital inpatient stay, readmissions, and outpatient visits) and product cost data collected from hospital records and through patient questionnaires at 3, 6, and 12 months; 7. Episodes of neutropenic fever requiring hospital admission or outpatient management, measured using the standard ESMO Clinical Practice Guidelines definition at 12 months; 8. Antifungal resistance in fungi (non‐invasive and invasive) measured using fungi isolated from clinical specimens taken as part of routine care (additional samples will not be taken unless the patient has consented and the site is participating in additional sampling for storage/research) between baseline and 12 months. This will be reported to YTU for the 12 months from study recruitment.; 9. Desirability of Outcome Ranking (DOOR) measured using data that will be collected throughout the 12‐month follow‐up period and ranked based on defined hierarchical levels that will be developed and confirmed following discussion with stakeholders, using Delphi methodology, and the Patient Advisory Group. It is anticipated that the hierarchical levels will take into account elements such as survival, presence of proven/probable IFI, and antifungals adverse effects/events. INCLUSION CRITERIA: Current inclusion criteria as of 26/05/2023: 1. Aged =16 years 2. Diagnosis of new, or relapsed, acute leukaemia or haematological disorder judged to need intensive chemotherapy by the patient’s clinical care team. Eligible conditions include acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), high‐risk myelodysplastic syndrome (HRMDS), or AML transformation of a myeloproliferative neoplasm (tMPN). 3. The patient is expected to have prolonged neutropenia related to intensive chemotherapy which would mandate either antifungal prophylaxis and/or systematic invasive fungal infection biomarker monitoring (at least weekly). 4. Patient is willing and able to give informed consent for participation in the study _____ Previous INCLUSION CRITERIA: 1. Aged =16 years 2. New diagnosis of, or relapsed, acute myeloid leukaemia (AML; according to WHO classification), acute lymphoblastic leukaemia (ALL), or high‐risk myelody