Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 22nd European Congress on Clinical Microbiology and Infectious Diseases (ECCMID)

London, UK / March 31- April 3, 2012

London - The first randomized study of combination therapy in the treatment of invasive aspergillosis (IA) has provided new evidence-based guidance for hematological malignancy patients, including allograft hematopoietic stem cell transplant recipients. Although many clinicians report empirical use of combination therapy in challenging infections, the newly completed study allows this approach to be considered on the basis of objective data. The need for more aggressive therapy is supported by the frequency with which IA outcomes remain suboptimal even when employing the most effective therapies. The controlled trial evaluating a combination of an azole plus an echinocandin was presented as a latebreaker at this year’s ECCMID. The trends for benefit observed in this study do not circumvent the need for individualized care, but it is the first major multicentre study to measure the impact of moving to a combination regimen when there is concern about the potential for cure from a single agent.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

The need for alternative strategies in invasive aspergillosis (IA), despite the development of new and more potent antifungal agents, is based on substantial mortality rates in vulnerable patients, such as those with hematological malignancies, particularly those who undergo hematopoietic stem cell transplant (HSCT). Combination therapy is a logical step in the effort to provide more aggressive control of proven or probable IA in patients with a high risk of poor outcome. 

The first randomized, double-blind, multicentre study was conducted with voriconazole, a third-generation agent, and anidulafungin, an echinocandin. In the study, all patients received voriconazole; the randomization was to anidulafungin or placebo.

Despite substantial signs of benefit, the study produced mixed results, according to Dr. Johan A. Maertens, Universitair Ziekenhuizen Leuven, Katholieke Universiteit Leuven, Belgium, who headed the investigating team at one of the participating European centres.  Mortality at 6 weeks, which was the primary outcome, was lower in the group that received 2 active drugs relative to those who received voriconazole plus placebo (19.3% vs. 27.5%). Although not statistically significant (P<0.09), the difference trended in favour of combination therapy. There was also support for greater activity from the combination in subgroup analyses. In particular, a reduction in mortality at 6 weeks for the combination among those with probable IA based on galactomannan did reach statistical significance (15.7% vs. 27.3%; (P=0.037) in a post-hoc analysis. 

Controlled Trial Considered an Achievement

The trial is considered an achievement because of the challenges inherent to collecting controlled data in this setting of IA. According to Dr. Maertens, “One of the most important problems in analyzing and designing combination studies is that, like the monotherapy studies, there are many host factors confounding the true efficacy of the antifungal combinations and comorbidities that may have a high impact on overall mortality in the study.” This includes the fact that many patients have concomitant bacterial/viral infections or mixed fungal infections and are recovering from immunosuppression. The lack of a reliable laboratory marker for monitoring efficacy is another obstacle. Large studies are needed to eliminate the impact of these variables.

In this study, which was led by Dr. Kieren A. Marr, Johns Hopkins University School of Medicine, Baltimore, Maryland, 454 patients were enrolled into the trial from 93 sites in 24 countries. Of these, 277 patients were included in the primary analysis with proven or probable IA based on adjudication by a review committee. Although almost all patients had an underlying hematological malignancy, only one-third of the patients received HSCT.  All patients received 6 mg/kg open-label voriconazole intravenously (IV) every 12 hours on day 1 followed by 4 mg/kg IV voriconazole every 12 hours subsequently. They were randomized to receive 200 mg IV anidulafungin on day 1 followed by 100 mg/kg IV every 24 hours subsequently or to receive a matched placebo. Investigators were allowed to switch patients to oral voriconazole (300 mg every 12 hours) after at least 7 days of IV treatment, but all patients had to remain on the combination for at least 2 weeks and all patients were maintained on antifungal therapy for at least 6 weeks.

The global response rate, which includes complete response, was measured at 6 weeks. While the global response (32.6% vs. 43%) and complete response (5.9% vs. 12%) rates were lower on the combination, these outcomes did not differ significantly. Moreover, the relevance of this difference was complicated by the large proportion of patients categorized by the data review committee as “not evaluable.” Conversely, death due to IA (17.3% vs. 23.9%) and mortality at 12 weeks (29.3% vs. 39.4%) were lower on voriconazole plus anidulafungin. Again, these differences were non-significant although there was a trend for benefit from voriconazole plus anidulafungin for the latter outcome (P=0.077). 

Adverse events (AEs) were common in both treatment arms, but the addition of anidulafungin did not appear to provide a substantial increase in risk of these events when evaluated globally or across specific organ systems. For example, the AEs considered to be related to voriconazole treatment occurred in 43.8% of patients in the placebo group and 46.5% of those also receiving anidulafungin. The rate of all-causality serious AEs was 46% on voriconazole plus placebo and 50.4% of those on the active combination. Serious AEs attributed to voriconazole climbed from 5.3% in the placebo group to 8.8% in those also receiving anidulafungin.

Rationale for Combination Therapy

The design for the study of combination therapy for IA was a logical extension in the effort to build on existing data. Although antifungal agents used in the treatment of IA include azoles, echinocandins and amphotericin B (AmB), voriconazole was a reasonable choice for the anchor treatment due to randomized trials that have led this agent to be recommended first-line by several organizations, including the Infectious Diseases Society of America (IDSA). The most frequently cited of these studies, conducted almost a decade ago, associated voriconazole with greater response rates and survival at 12 weeks relative to the previous standard, AmB deoxycholate (Herbrecht et al. N Engl J Med 2002;347: 408-15). More recent data, such as those derived from the US Transplant Associated Infection Network (TRANSNET) database (Baddley et al. Clin Infect Dis 2010;50:1559-67), have reinforced this efficacy.

Combination therapy for IA is supported by animal studies, but it has not been listed as an option in most guidelines because of the limited human data, according to Dr. Maertens. The need for such data has been acute because of advantages which include the potential for an increased rate and extent of fungal killing (synergy) and enhanced spectrum of activity. Greater fungicidal activity is particularly sought for immunocompromised patients and others who experience poor outcomes with IA. Two agents with different mechanisms of activity also offer the potential for increasing fungicidal effects without increasing rates of AEs.

Previous efforts to evaluate the impact of combination therapy in IA have had various limitations, particularly ambiguous findings. For example, a retrospective evaluation of the combination of voriconazole and caspofungin did show a survival advantage at 3 months relative to voriconazole alone, but the advantage was lost at one year (Marr et al. Clin Infect Dis 2004;39:797-802). In the only previous randomized trial, which was a pilot study with only 30 patients, standard-dose liposomal AmB plus caspofungin provided both a greater overall response (67% vs. 27%) and a 20% reduction in mortality at 12 weeks (Caillot et al. Cancer 2007;110:2740-6), but a confirmatory trial of sufficient size to evaluate the clinical significance has not followed.

The current study combining a first-line agent with a drug with a different antifungal mechanism is the most ambitious study to date to provide controlled data on the efficacy and safety of combination therapy for IA. The relative advantage of the combination in patients with probable IA based on galactomannan is encouraging but does not negate the importance of efforts to accelerate the diagnosis of IA in order to rapidly introduce the most effective therapy.

Summary

Combination antifungal therapy remains a conceptually appealing treatment strategy. Even though the results of the first large, multicentre controlled trial of combination antifungal therapy in IA failed to show a significant mortality benefit according to predefined criteria, there was substantial evidence of a clinically meaningful increase in IA control on several outcomes. The data suggest that patients should be considered for combination antifungal therapy on a case-by-case basis.  

Mednet reports which have been accredited by McGill University under the MedPoint Accredited Conference Report Series are eligible for Mainpro-M1 and MOC Program credits.