Invasive aspergillosis (IA) is a serious infection that usually occurs in patients with compromised immune systems. Those with hematologic malignancies and hematopoietic cell transplants have a particularly high risk for developing IA. A number of antifungal drugs are available to treat IA, and monotherapy with voriconazole is currently the most often prescribed. Previous studies have suggested that combination antifungal therapy may lead to better outcomes. Marr and colleagues sought to determine whether combination therapy with voriconazole and anidulafungin would improve overall mortality compared to voriconazole monotherapy.
The study was a randomized, double-blind, placebo-controlled, multi-center investigation funded by the manufacturer of voriconazole and anidulafungin. It included patients aged 16 years or older with an underlying hematologic malignancy or hematopoietic cell transplant diagnosed with possible, probable, or proven IA based on consensus criteria. Those with a possible diagnosis had to be upgraded on the basis of microbiology data within the first week in order to continue in the study. Subjects were randomly assigned in a 1:1 ratio to receive voriconazole with anidulafungin or a placebo for a minimum of two weeks; those given voriconazole monotherapy received it for at least six weeks. The primary end point was all cause mortality at six weeks. Secondary end points included all-cause mortality at 12 weeks and six-week mortality in the following subgroups: HCT recipients, HAL match and relatedness of donor among allogeneic HCT recipients, conditioning intensity for allogeneic HCT, receipt of high-dose corticosteroids for graft-vs-host disease, neutropenia at diagnosis (absolute neutrophils count < 0.5 x 109 cells/L), and geographic region. An external data review committee (DRC) that was blinded to the study drug assignments decided on the global response to therapy, which was defined as complete response, partial response, stable disease, or failure.
A total of 459 patients were enrolled in the study from 93 sites in 24 countries. Of these, the DRC confirmed probable or proven IA in 277 patients (the modified intention-to-treat population [mITT]); 135 received combination therapy and 142 received monotherapy. Acute myelogenous leukemia was the most common underlying condition, 30% had a HCT, and 60% were neutropenic when they entered the study. The median duration of combination therapy was 14 days (range, 1 to 29); the median duration of voriconazole alone was 42 days (range, 1 to 48). In the primary analysis, mortality at six weeks in the mITT group was 19.5% (26 of 135) for combination therapy and 27.8% (39 of 142) for monotherapy (P = 0.087). Mortality at 12 weeks was 29.3% (39 of 135) for combination therapy and 39.4% (55 of 142) for monotherapy (P = 0.077). In the ITT population, which included patients who did not have a confirmed diagnosis of IA, the mortality at six weeks did not differ between combination and monotherapy (20.6% and 23.5%, respectively). Multivariate analysis identified low Karnofsky score (a commonly used performance score in oncology that ranges from 100-normal to 0-dead), low platelet count, and high serum galactomannan antigen at baseline as independent predictors of mortality at six weeks. A post-hoc analysis of mortality on patients with probable IA based on radiographic abnormalities and galactomannan positivity found all-cause mortality to be 15.7% (17 of 108) in the combination therapy group compared to 27.3% in the monotherapy group (30 of 110, P = 0.037). Adverse events were similar with combination and monotherapy, with more patients in the combination therapy group developing hepatobiliary adverse events than in the monotherapy group (12.7% vs. 8.4%, respectively.)
This was a large study that involved an impressive number of clinical sites (93) and countries (24). The investigators are to be commended for using all-cause mortality at six weeks as their primary endpoint instead of global response, which is the traditional endpoint used in most studies on IA. However, the present study found no significant difference in mortality between monotherapy and combination therapy for IA. Although a significant reduction in mortality was seen with combination therapy in patients with probable IA, this was determined by post-hoc analysis. Thus, the data do not provide conclusive evidence of superiority for combination therapy. The safety of the two regimens was very similar, which is not surprising since echinocandins are a relatively safe class of antimicrobials with few drug interactions and side effects. The additional cost of anidulafungin (approximately $2,550 for a two-week course per www.goodrx.com, accessed 2/1/15) is an important concern, especially in the present health care environment in which cost-containment is paramount.
The major limitation of the study was that the outcomes for patients with IA were worse than the investigators anticipated, thus making the power to detect a treatment difference lower than expected. The inclusion criteria were designed to measure treatment in patients with low risk of death. It seems possible that had these criteria been less stringent and included a more heterogeneous mix of patients, the outcomes may have favored combination therapy. This hypothesis could be evaluated in future trials. Also, the study by Marr and colleagues lends further support to use of galactomannan antigen testing to diagnose IA earlier in its course when therapy would presumably be more efficacious.
In conclusion, combination therapy cannot yet be recommended for IA. Additional studies are needed to determine which patients with IA would most benefit from combination therapy. I strongly agree with the investigator’s contention that future trials include mortality as the primary endpoint and not the more nebulous concept of global response.