The rationale for antifungal prophylaxis is to prevent invasive fungal disease (IFD) caused by yeast and mould species in cancer patients with a solid organ tumour or a haematological malignancy. Patients with an intermediate to high risk of overall infection include those with:
- acute lymphoblastic leukaemia (ALL)
- acute myeloid leukaemia (AML)
- longer durations of profound neutropenia (> 10 days)
- significant graft versus host disease (GVHD) following allogeneic haematopoietic stem cell transplant (HSCT).
Antifungal prophylaxis should not be used routinely in all patients with neutropenia. Most of the available evidence for prophylaxis relates to haematological malignancies. For solid organ tumours, the need for prophylaxis remains undefined and is generally accepted to be lower than for a haematological malignancy. Expert advice should be sought on an individual case-by-case basis.r
As there can be variations in institutional practice, the choice of antifungal agent should be guided by advice from local infectious diseases or microbiology experts and based on local rates of IFD in specific patient populations. The recommendations in this document may also differ from those of specific institutions.
Factors for consideration include:
- haematology patient population (leukaemia, HSCT)
- degree of immunosuppression due to treatment / intensity of treatment
- use of targeted and immunomodulatory drug therapies (see below)
- previous treatments (higher risk in patients with relapsed or refractory disease)
- enrolment in clinical trials
- local epidemiology (incidence of invasive fungal disease, patterns of fungal infection, rates of fungal resistance)
- drug efficacy, cost, toxicity, drug-drug interactions and availability of therapeutic drug monitoring (TDM)
- requirement for prophylaxis against yeasts and moulds. Mould prophylaxis is generally only required for patients with a high risk of IFD.
Targeted and immunomodulatory drug therapies rrr
An increasing number of targeted agents are available as standard of care options for the treatment of both haematology and medical oncology patients. Due to their effects on immune function, the use of these agents may increase the risk of IFD. Reported rates of IFD vary according to the patient group being treated (i.e. treatment naive vs relapsed/refractory malignancy); previous treatments used, including number of lines of therapy; and whether these agents are used in combination with other therapies, especially conventional chemotherapy that induces mucositis or prolonged neutropenia.
However, there are currently very few prospective published studies available to guide decisions on the need and optimal choice of prophylaxis with the use of these agents, so care must be taken to appropriately assess the risk of developing an IFD with the use of clinical judgment, international guidelines and analysis of phase 3 studies.
Examples of targeted agents where higher IFD rates have been reported with their use include:
- FLT-3 inhibitors (e.g. midostaurin, gliteritinib)
- hypomethylating agents (e.g. azacitidine)
- tyrosine kinase inhibitors including BTK inhibitors (e.g. ibrutinib), JAK inhibitors (ruxolitinib) , PI3K inhibitors (e.g. idelalisib), BCL-2 inhibitors (e.g. venetoclax) and mTOR inhibitors (e.g. everolimus).
Adoptive T-cell therapies r
- Adoptive T-cell therapies such as chimeric antigen receptor (CAR) T-cell therapy and bi-specific constructs such as bi-specific T-cell engagers (BiTE) (e.g. blinatumomab) have now become standard of care in a range of haematological malignancies including relapsed, high-grade B-cell malignancies, diffuse large B-cell lymphoma and acute lymphoblastic leukaemia (ALL).
- Patients receiving these therapies have often had multiple prior lines of therapy, including HSCT, increasing their risk of fungal infection. Lympho-depleting chemotherapy administered prior to CAR T-cell infusion further increases this risk. Treatment for common toxicities of CAR T-cell therapy such as cytokine release syndrome (CRS) and immune effector-associated neurotoxicity syndrome also increases fungal risk, often involving treatment with corticosteroids and tocilizumab.
- Due to this risk, clinicians should have a low threshold for initiating investigations for suspected IFD in the setting of compatible symptoms such as persistent fever or pulmonary infiltrates.
- Recommended antifungal prophylaxis includes yeast prophylaxis with fluconazole or micafungin.
- Consider mould prophylaxis in the setting of prolonged neutropenia or additional treatments for high-grade cytokine release syndrome following CAR T-cell therapy.
- Previous therapies including recent allogeneic or autologous HSCT should also be taken into account.