What Is the Prognostic Significance of Culture-Documented Breakthrough Invasive Pulmonary Aspergillosis in Patients with Hematological Malignancies? A Propensity Score-Adjusted Analysis

Mold-active prophylaxis has reduced the incidence of invasive pulmonary aspergillosis (IPA) in patients with hematological malignancies (HMs), but breakthrough IPA (Bt-IPA) is increasingly encountered. Therefore, we studied determinants of Bt-IPA risk and its prognostic significance. We retrospectively reviewed culture-positive proven/probable IPA cases in HM patients at MD Anderson Cancer Center (2016-2021). Bt-IPA and non-Bt-IPA cases were compared to characterize risk factors, clinical presentation, and outcomes. Independent predictors of 42-day all-cause mortality were assessed using propensity score-adjusted Cox regression. Among 118 IPA cases, 50 (42.4%) were Bt-IPA. Bt-IPA was associated with acute leukemia/myelodysplastic syndrome, active HM, severe neutropenia (<100/mm³), and graft-versus-host diseases. Uncommon <i>Aspergillus</i> species (non-<i>fumigatus</i>, <i>flavus</i>, <i>terreus</i>, or <i>niger</i>) were more frequent in Bt-IPA than non-Bt-IPA (20.4% vs. 4.8%, <i>p</i> = 0.010). Forty-two-day mortality was higher in Bt-IPA (65.3% vs. 37.3%, <i>p</i> = 0.003), but Bt-IPA itself was not an independent predictor or mortality (<i>p</i> = 0.064), which was instead driven by neutropenia (<i>p</i> = 0.020) and hypoalbuminemia (<i>p</i> = 0.002). In conclusion, Bt-IPA accounted for nearly half of contemporary IPA cases and was linked to host-related risk factors and the recovery of uncommon <i>Aspergillus</i> species. Although not an independent prognostic predictor, Bt-IPA reflected poor host status. Thus, early diagnosis, immune enhancement strategies, and effective first-in-class antifungals may improve outcomes.