Validation of Serum Aspergillus Galactomannan Index as a Surrogate Endpoint for Outcome of Invasive Aspergillosis: Clinical and Research Implications.

Background: Assessing clinical outcome of aspergillosis with conventional clinical and laboratory criteria is difficult. A composite “global outcome response” (clinical, radiologic, pathologic and microbiologic criteria) is frequently used but suffers from poor sensitivity and specificity, and has not been standardized or validated. A reliable, quantitative, non-invasive, and easy to measure laboratory test than can substitute for this composite endpoint, i.e. serve as a surrogate endpoint for aspergillosis outcome is highly desirable. Galactomannan (GM) is an Aspergillus-specific polysaccharide released during aspergillosis and detected by the serum GM test. The test which is reported as an index of optical density (OD) is an accepted diagnostic marker for aspergillosis and preliminary data suggest a correlation between GM index (GMI) and outcome.

Purpose: To evaluate serum GMI as a surrogate endpoint for outcome of invasive aspergillosis in patients with hematological cancer.

Patients and Methods: patients at risk for aspergillosis (11/03-2/06) underwent GMI screening during periods at risk. The clinical and laboratory findings of patients with ≥ 2 (+) GMI (OD ≥ 0.5) were reviewed. To validate GMI as a surrogate endpoint for aspergillosis, a k correlation concordance coefficient test between GMI and an objective clinical outcome of aspergillosis (death) was applied. The correlation is considered perfect when k is 1.0; excellent when ≥ 0.75.

Results: 30 patients had GMI (+) aspergillosis of the respiratory tract [myeloma 92%; median age: 59 years (27–75); 15 males]. Aspergillosis developed following stem cell transplantation [autologous (11), allogeneic (1)], or after conventional chemotherapy (18). Among 25 neutropenic patients (<1000/ml), persistent GMI elevation was associated with death (5/5 patients) while return to negative values predicted survival (20/20 patients). Among 5 non-neutropenic patients, 1 with persistently elevated GMI died compared to no death among the remaining 4 whose GMI became negative. Overall, the GMI correlated with clinical outcome in all 30 patients with a perfect 1.0 k correlation concordance coefficient.

Conclusion: we have validated GMI as an excellent surrogate endpoint for the outcome of invasive aspergillosis among patients with hematological cancer. This FDA-approved test is reproducible, quantitative, non-invasive, easy to measure and widely available. These findings have important implications for patient care and for the design of clinical trials of mould-active antifungal agents.