Invasive Fungal Infections in Patients Following Stem Cell Transplant

Invasive fungal infections (IFIs) remain a leading cause of mortality and morbidity in immunosuppressed patients who undergo allogenic haematopoiectic stem cell transplant (aHSCT). Both yeast and moulds cause serious IFIs in this cohort of patients, especially during the pre-engraftment neutropenic phase, and post-engraftment period when patients need to be on prolonged course of corticosteroids for severe graft-versus-host-disease (GVHD). Other risk factors for IFIs include environmental factors, genetic factors, and co-viral infections. Candida spp accounts for most of the invasive yeast infections whereas Aspergillus spp is the most common mould in aHSCT recipients. The estimated incidence of proven and probable invasive Candida infections without antifungal prophylaxis ranged from 8% to 24%; on the other hand the incidence of invasive aspergillosis was reported to be in between 3% to 14%. IFIs are often associated with mortality rate as high as 60%, and have been identified as one of the independent predictors of death in multivariate analysis. Other complications include extended hospital stay from invasive fungal infections, intensive care admissions, huge treatment cost and significant morbidity and reduced quality of life in patients.

Antifungal prophylaxis with fluconazole in aHSCT recipient has become a routine in the 1990s after several studies demonstrated fits efficacy in reducing morbidity and mortality in this group of patients. In 2007 two multi-centres, double-blinded trials, involving either aHSCT patients with GVHD or non-transplantation patients with haematologic malignancy and prolonged neutropenia, proved superiority of the mould-active agent with posaconazole to fluconazole in preventing invasive aspergillosis and death from IFI. This finding was further confirmed by a systemic review and meta-analysis in 2012 that included 20 randomised trials, comparing mould-active prophylaxis with fluconazole prophylaxis in aHSCT recipients or patients with haematologic malignancy receiving chemotherapy. Consequently, current Australian guideline proposed that all patients at high risk of IFIs (>10%) be administered mould-active antifungal prophylaxis, and these patients include aHSCT recipients with expected neutropenia of >14 days, extensive chronic GVHD, severe steroid refractory or dependent GVHD and patients with acute leukaemia or myelodysplasia who are undergoing induction or re-induction chemotherapy. Broad-spectrum triazole posaconazole is the recommended first-line therapy, with other triazoles such as voriconazole, itraconazole or echinocandin as alternative therapy.

In Australia, until 2015 posaconazole was only available in liquid form. Posaconazole suspension needs to be taken with high-fat meal or supplements to enhance its absorption. The unpredictable absorption of the suspension, especially in patients with mucositis or neutropenic colitis from chemotherapy prompted the recommendation of monitoring the trough posaconazole level. However in Victoria, this assay was not widely available and the turnaround time was often long, hence it could not be performed in real-time fashion for optimal management. A delayed-release tablet formulation of posaconazole was approved by TGA in 2013 and it was added to the Pharmaceutical Benefits Scheme (PBS) in Australia in mid-2015. At the same time an intravenous formulation was also approved by TGA. The tablet formulation has improved bioavailability as its absorption was not dependent upon high fat or supplement content like its liquid counterpart, and it is anticipated that its administration will likely result in therapeutic drug levels. As a result routine therapeutic drug monitoring is not required during prophylaxis with posaconazole tablets. The availability of the intravenous and tablet formulation may have a positive impact on the rates of IFIs, however this has not been formally reviewed in Australia. Patients on posaconazole prophylaxis with the Bone Marrow Transplant Clinical Service are currently on either tablets or the intravenous formulation (if patients have factors that impaired oral intake).

Although the introduction of mould-active antifungal prophylaxis has reduced the incidence of IFIs significantly, there have been numerous studies reporting on the changing epidemiology of these infections and concerns raised over the rates of breakthrough IFIs and emergence of azole-resistant strains, including non-albicans species of invasive candidiasis. Winston et al reported of a breakthrough IFI rate 7.5% while on posaconazole liquid formulation, and this finding was consistent with some European studies, which found incidence of 3-14% of breakthrough invasive mould disease. On the other hand, Tverdek et al reported a much improved rate of breakthrough IFI of 2% in 343 patients who received intravenous or delay-released tablet formulation of posaconazole, suggesting that these new formulations resulted in better absorption of the medication with direct implication on rates of IFI.

Most of the studies mentioned above, that reported incidence of IFIs in the era of mold-active antifungal prophylaxis, were conducted in the United States or Europe. Specifically there has not been a study done locally in Australia looking at this question, including breakthrough IFIs. The epidemiology of fungal isolates in Australia may be very different compared to that of European or American continents. For example there have been reports of higher incidence of systemic infection due to Lomentospora prolificans in Australia and Spain, involving patients with acute leukemia or with aHSCT.

The introduction of the posaconazole tablets may have improved IFI breakthrough rates in our local Bone Marrow Transplant Centre, although this has not yet been examined. Anecdotal evidence suggests that the rates of posaconazole therapeutic drug monitoring at our institution are low, but again this has not been formally documented.

It is imperative to evaluate the epidemiology of these infections in this cohort in the new era of posaconazole prophylaxis, to monitor the rates of breakthrough IFIs and if there is emergence of azole-resistance fungal isolates in the Australian context. This study aims to establish an overview of IFIs in patients receiving stem cell transplant. Not only will it provide invaluable information on local epidemiology and microbiology of invasive fungal infections, it will also enable more appropriate planning of antifungal prophylaxis strategies in these high-risk patients.

Study's hypothesis:

• Invasive fungal infections remain an ongoing challenge and one of leading sources of morbidity and mortality post allogeneic haematopoietic stem cell transplant (aHSCT) despite the widespread use of anti-mould prophylaxis.
• Improvements could be made in the prophylaxis, treatment and monitoring of fungal infections.
• Knowledge of local epidemiology could inform efforts to improve current practice.

Aims of the study:

1. To describe the epidemiology of invasive fungal infections (IFIs) in patients undergoing allogeneic haematopoiectic stem cell transplant (aHSCT) in the era of antifungal prophylaxis with posaconazole delay-released tablets.
2. To report the incidence of IFIs, and in particular breakthrough IFIs in this cohort of high-risk patients.
3. To identify the risk factors of acquiring IFIs in this cohort of patients.
4. To evaluate the current practice and use of antifungal agents as prophylaxis, the reasons for selection, the frequency of therapeutic drug monitoring, adverse effects and appropriateness of antifungal prescription.
5. To determine the all-cause mortality rate and fungal infections related death following aHSCT at 3, 6 and 12 months post aHSCT.
6. To identify areas of current divergence from best practice in the prevention and treatment of invasive fungal infections in patients receiving allogeneic HCT.