Blastemia portrays a poor prognosis in acute leukemia patients with invasive pulmonary aspergillosis

Objectives: Severe and prolonged neutropenia is associated with poor outcomes of invasive pulmonary aspergillosis (IPA) in leukemia patients. Given the high frequency of IPA in patients with relapsed/refractory leukemia, we studied the association of peripheral blood blast burden (blastemia), IPA outcomes, and antifungal immune failure, even without neutropenia. Methods: We retrospectively reviewed adult patients with acute leukemia (AL) or myelodysplastic syndrome and culture-positive proven/probable IPA (2011-2022). Blast and neutropenia indices were calculated and incorporated into multi-variable prognostic models. The impact of blasts on immune cell-mediated fungal clearance was studied in vitro. Results: Among 74 patients, 69% had neutropenia and 57% had blastemia at IPA diagnosis. Blast index ≥90 at IPA diagnosis and ≥3 lines of prior chemotherapies were independent predictors of 42-day mortality and early antifungal treatment failure. Leukemic blasts had minimal immune activity against Aspergillus fumigatus and impaired fungal inhibition by peripheral blood mononuclear cells. Conclusion: Blastemia is common in contemporary leukemia patients with IPA and is a significant risk factor for poor IPA outcomes, possibly due to interference with fungal clearance by immune cells. Therefore, blastemia should be considered as a risk stratification parameter in future mycology trials and as an experimental variable in preclinical IPA models.