Combination antifungal therapy for breakthrough invasive mould disease in patients with haematological malignancies: when management reasoning eclipses evidence-based medicine

Abstract

Management reasoning is a term used to define the cognitive process required to develop an optimal plan of action to care for a patient. Sound management reasoning is situational, complex, dynamic and depends on the preferences, values and resources of the patient, clinician, institution and healthcare system.¹ Because there are often multiple paths to a successful outcome, effective management of life-threatening infections such as invasive mould disease involves contrasting, prioritizing and selecting among several possible care plans.

A frequently debated question in the management of invasive mould disease is when should combination antifungal therapy be used? Many review articles and pro–con debates have attempted to answer this question by summarizing conflicting evidence of synergy or antagonism from in vitro studies, preclinical animal models, case–control studies, cohort studies and only one randomized study.² While this body of work has contributed to our knowledge concerning antifungal interactions, it often cannot be directly applied to patient care decisions, especially for patients who develop breakthrough infections while on antifungal prophylaxis. Therefore, it is worthwhile to consider what reasoning drives clinicians to prescribe combination antifungal therapy outside typical ‘evidence’ of synergy or antagonism.

Effective mould-active antifungal prophylaxis has been a significant advance in the supportive care of patients undergoing treatment or transplantation for haematological malignancies.³ However, the downside is that breakthrough infections still occur and are often caused by a broader range of sometimes difficult-to-diagnose yeasts and moulds with greater resistance to antifungals. These breakthrough infections also disproportionately afflict the most severely immunosuppressed and frail.⁴

Unfortunately, there is very little evidence to guide decisions on how to manage breakthrough mould infections.⁵ Major prospective randomized controlled trials in the field of invasive aspergillosis that established the efficacy of voriconazole and isavuconazole monotherapy⁶ were performed in patients with haematological malignancies who did not receive mould-active prophylaxis before treatment and mostly excluded patients with a poor prognosis of their underlying malignancy or severe comorbidities such as acute liver or renal dysfunction.⁷

Taking these factors into consideration, we assert that randomized controlled trials published to date, which form the basis of current treatment guidelines, do not accurately reflect the growing majority of breakthrough invasive moulds encountered by clinicians after antifungal prophylaxis. In these patients, many patient- and disease-related factors could favour the initial use of a combination antifungal regimen while awaiting diagnostic results (Figure 1). Specifically, clinicians should be concerned, in severely immunocompromised patients, about the potential of breakthrough infections caused by resistant moulds, mixed infections or undetected dissemination to anatomically privileged sites. All these scenarios favour the initial use of combination therapy to achieve the broadest spectrum of antifungal activity possible in likely sites of infection or dissemination.

Figure 1.

Evidence versus management reasoning in decisions to use combination therapy for invasive mould disease. The fulcrum of the scale represents evidence of scientific studies exploring combination antifungal therapy for invasive mould disease. The largest number of publications are animal and laboratory reports. The smallest number of studies are randomized controlled trials, represented at the peak. The clinical relevance of evidence increases as one moves from the base to the peak of the fulcrum. PK/PD, pharmacokinetics/pharmacodynamics; RCTs, randomized controlled trials.

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No study has shown that combination therapy is beneficial for culture-documented aspergillosis⁸ and mucormycosis,⁹ possibly because positive cultures are more common in patients with a higher fungal burden and advanced disease.¹⁰ In contrast, early treatment with voriconazole and anidulafungin in patients with invasive aspergillosis diagnosed by positive biomarkers and CT findings was associated with an 11.5% reduction in 60 day mortality.² Yet it is unknown whether there is a similar mortality benefit in patients with breakthrough invasive aspergillosis diagnosed using biomarkers on mould-active prophylaxis.

Confirming the efficacy of early, pre-emptive biomarker-driven combination therapy in a randomized controlled trial for breakthrough invasive mould disease would be challenging, as there are relatively few patients who could be enrolled and multiple confounders that impact treatment outcomes such as survival. Specifically, the activity of the underlying disease, coinfections (e.g. pneumonia or bacteraemia caused by MDR Gram-negative bacteria) and comorbidities are competing causes of death.

Future studies of combination therapy will likely rely on combining screening tools with a high negative predictive value (e.g. broad-range mould PCR or lateral flow device for detection of a broad spectrum of relevant antigens) and individualized prognostic risk models composed of clinical and genetic risk factors to identify a population with sufficient (i.e. >30%) baseline probability of breakthrough invasive mould disease. At the first onset of signs of infection, confirmed by low-radiation dose CT, these patients could be randomized to a combination versus monotherapy approach while they undergo testing with more invasive diagnostic assays that have a higher positive predictive value (i.e. fibre-optic bronchoscopy ± biopsy) combined with imaging approaches that have enhanced sensitivity [CT pulmonary angiography, fungal antigen-directed immuno-positron emission tomography (immuno-PET) imaging]. Once the pathogen is identified or infection clinically stabilizes, patients could then be transitioned to an appropriate monotherapy if they were previously receiving a combination regimen.

Such trials would ideally incorporate new antifungals with novel mechanisms of action to allow clinicians to switch patients from failing regimens or toxicity to a combination regimen with two unique mechanisms of action against the most likely breakthrough mould pathogens. These trials should also better reflect the populations where combination therapy is most likely to be considered; i.e. enrolling patients with comorbidities typically excluded from randomized trials used for drug registration (e.g. patients with pre-existing liver dysfunction) even if these comorbidities may complicate the analysis of treatment endpoints. Finally, given the problems of suboptimal ante-mortem diagnosis for many of these pathogens, greater efforts should be focused on autopsy examination for patients who do not survive, to understand better the spectrum of pathogens involved and the cause of death in populations who develop mould infection as part of a terminal process in their underlying disease. Some key considerations in the clinical investigation of combination therapy for opportunistic invasive mould disease are given in Table 1.

We currently have no high-quality clinical data to guide evidence-based decisions for managing breakthrough invasive mould disease in severely immunocompromised patients. Although in vitro studies and preclinical animal models provide some possible indications of how antifungals may interact, the results of these studies, which are highly method dependent, should not be over-interpreted¹¹ and should not outweigh clinical considerations that largely determine how these patients are managed. Pre-emptive use of antifungal combination therapy with frequent re-evaluation with an aim of de-escalation to monotherapy is a well-reasoned management strategy until diagnostic results are available or the invasive mould disease has stabilized.

Transparency declarations

C.G.-V. has received honoraria for talks on behalf of Gilead Sciences, MSD, Novartis, Pfizer and Janssen, as well as a grant from Gilead Sciences, and is a recipient of an INTENSIFICACIÓ Grant from the Project PI18/01061. R.E.L. has received honoraria for talks sponsored by Gilead, Cidara Therapeutics and Merck, and has received research support from Merck. D.P.K. has received research support from Merck, Pfizer, Astellas and T2 Biosystems, has received honoraria from Merck, Astellas, Gilead, Amplyx, Scynexis and Mayne Pharmaceuticals, and acknowledges the Texas 4000 Distinguished Professorship for Cancer Research.

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