To our knowledge, this is the first study to evaluate objective and Aspergillus-specific criteria to determine the quality of and time to response of IA and to compare these criteria with the current standard for response assessment. More importantly, these findings were examined in a high-risk homogeneous patient population (90% with myeloma) cared for at a single institution, undergoing standardized antineoplastic therapies and infectious disease management, including diagnostic workup and therapy.
Our results indicate that the GMI-based response criteria compare favorably to the EORTC/MSG definition, as shown by the excellent KCC. In addition, the GMI-based criteria allow a much earlier assessment of response in the vast majority of patients and segregate patients into rapid and slow responders. In addition, the characteristics of the 10 discordant cases (success according to GMI and failure according to EORTC/MSG criteria) suggest that they indeed responded to treatment, as discussed earlier, and that the GMI-based criteria may be more precise than the current response definition.
Our findings are supported by several experimental models [6
], clinical reports [7
], and autopsy studies of IA [19
], all of which revealed a 95%–100% correlation between GMI-determined infection burden and outcome. That relapse was not observed among the 44 responders who were not treated or received ≤14 days of antifungal therapy is further validation of the good performance of the GMI-based response criteria.
The EORTC/MSG response criteria are currently the accepted standard for assessing IA response in clinical trials. However, these criteria rely on “attributable” clinical and radiologic findings. For example, success requires resolution of (or improvement in) all attributable symptoms and signs of disease. This requirement complicates response assessment, because the clinical manifestations of IA are nonspecific, and persistence or recurrence of such symptoms as fever and cough may be due to several other causes [20
]. Likewise, positive fungal culture results may represent colonization; repeated sampling is not always feasible; false-negative results are common; and concordance between culture results and survival has not been shown [2
The other major component of the EROTC/MSG response criteria is radiologic findings. However, radiologic images are not specific for aspergillosis [22
] and may even be misleading, because lesions may increase in patients whose condition is responding to treatment, as a result of an inflammatory immune reconstitution syndrome (IRIS) [21
In contrast, Aspergillus
-specific GMI serodiagnosis fulfills all criteria as a surrogate endpoint for outcome evaluation [2
], including (1) biological plausibility—galactomannan is released by Aspergillus
species during growth [24
], and GMI values correlate with fungal burden in experimental models [11
]; (2) prediction of outcome—a strong concordance exists between serum GMI test result and outcome [7
]; (3) excellent attributes—the GMI test is standardized, reproducible, easy to perform, noninvasive, relatively inexpensive, quantitative, and its results rapidly available [2
]; and (4) applicability—results are applicable to infections caused by various Aspergillus
species and at various anatomical sites [2
In the present study, all patients with persistently positive GMI test results (ie, classification as failure according to the Aspergillus
-specific GMI–based criteria) were also considered nonresponders according to the EORTC/MSG criteria, albeit it at a much later time point. This is important, because an appropriate and earlier classification of failure may lead to timely changes in treatment strategies. This early classification of response would probably not be possible on the basis of clinical and radiologic criteria only, because worsening clinical and radiologic findings may represent IRIS [21
Our study shares the limitations of all retrospective studies and is hampered by a low rate of autopsy examination, a trend noted worldwide [30
]. In addition, some CT scans were not performed precisely at 6 weeks, hampering a precise assessment of the EORTC/MSG response criteria. Finally, our results should be confirmed in other clinical settings (other underlying diseases, allogeneic transplantation, and so forth).
Our findings that GMI kinetics may be used as endpoint for clinical trials have implications for trial methodology in IA. Determining the sample size for clinical trials using the EORTC/MSG response criteria relies on the difference in proportions of response at a given time point (eg, 70% vs 50% response rate at 6 weeks). This typically requires a large sample size [31
]. Relying on serial GMI testing provides an objective and Aspergillus
-specific endpoint [2
], offers the advantage of a smaller sample size for clinical trials (because of the large number of serial GMI endpoints), [31
] and further enables us to determine the exact time to response. Although 2 regimens may have similar response rates, one may achieve response faster and would therefore be the treatment of choice, particularly in cancer patients in whom delay of antineoplastic therapy is detrimental. Because of the smaller sample size required with a GMI-based strategy, trials of IA therapies can be conducted more efficiently. In turn, this provides patients with earlier access to potentially life-saving therapies. A randomized controlled trial of combination antifungal therapy in IA using time to normalization of GMI as endpoint is currently underway. The clinical implications of our findings include the opportunity to change therapy in a timely fashion if response is deemed unlikely on the basis of GMI kinetics and to individualize the duration of antifungal therapy.
In conclusion, we show that the Aspergillus-specific GMI–based response criteria compare favorably to those of the EORTC/MSG, provide a much earlier time to response assessment, and rely on a quantifiable test that is simple to perform, widely available, reproducible, objective, and Aspergillus specific. Therefore, we recommend the adoption of this response definition as a primary endpoint in clinical trials of IA.