Outcome Analysis of Breakthrough Invasive Aspergillosis on Anti-Mold Azole Prophylaxis and Treatment: 30-Year Experience in Hematologic Malignancy Patients

Background: Anti-mold azoles have improved the outcomes of invasive aspergillosis (IA) when used therapeutically, but they are extensively used as prophylaxis. There are limited data regarding the outcomes of patients with hematologic malignancy who develop breakthrough IA on anti-mold azoles. We aimed to determine whether breakthrough IA on azole prophylaxis shows worse outcomes compared to no prophylaxis. Methods: We compared outcomes including therapy response and mortality between antifungal regimens in hematologic malignancy patients with IA between July 1993 and July 2023. Results: Compared to an amphotericin B-containing regimen (AMB), an anti-mold azole as the primary therapy was independently associated with successful response at the end of therapy (OR = 4.38, p < 0.0001), protective against 42-day IA-associated mortality (OR = 0.51, p = 0.024) or all cause mortality (OR = 0.35, p < 0.0001), and protective against 84-day mortality, both IA-associated (OR = 0.50, p = 0.01) and all-cause mortality (OR = 0.27, p < 0.0001). Azole prophylaxis was independently associated with higher IA-associated mortality at 42 days (OR = 1.91, p = 0.012) and 84 days (OR = 2.03, p = 0.004), compared to fluconazole or no prophylaxis. Conclusions: Patients with breakthrough IA on anti-mold azole prophylaxis show a worse prognosis than those on other or no prophylaxis, possibly related to the emergence of azole resistance due to their widespread use as prophylaxis agents. On the other hand, anti-mold azole primary therapy is superior to AMB therapy in the treatment of IA.