Incidence and Risk Factors for Invasive Mold Infections in Children During First-Line Chemotherapy for Primary Acute Leukemia: A National Retrospective Cohort Study

BACKGROUND: Invasive mold infections (IMI) are life-threatening complications during treatment for pediatric acute leukemia. Population-based data on IMI incidence, timing, and outcomes during first-line therapy remain limited. We aimed to provide a nationwide epidemiological overview of IMI during first-line treatment of pediatric acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and explore potential treatment-related risk factors. METHODS: We conducted a retrospective nationwide cohort study of all children (<18 years) initiating first-line chemotherapy for AML or ALL in Denmark during 2008-2022. IMIs were classified as proven or probable according to 2020 EORTC/MSGERC criteria by review of microbiology, imaging, pathology, and chart data. Follow-up covered first-line chemotherapy. Competing risk-adjusted cumulative incidence of IMI was estimated, risk factors were evaluated using Cox regression, and survival after IMI was analyzed using the Kaplan-Meier method. RESULTS: Among 621 patients, 43 (6.9%) developed IMI: 14/90 (15.6%) with AML and 29/531 (5.5%) with ALL. In adjusted Cox regression, AML was associated with higher IMI hazard than ALL (HR 5.6, 95% CI 2.6 to 12.1), whereas no other prespecified risk factors were independently associated with IMI. Incidence rates were 38.6 per 100 patient-years in AML and 2.7 in ALL. Nearly half of IMIs occurred beyond 90 days after initiation of first-line chemotherapy. Four patients experienced a second distinct IMI episode; Aspergillus species accounted for 37/47 (79%) episodes and non-Aspergillus molds for 10/47 (21%). IMI-associated death occurred in 10 patients (1.6% of the cohort), yielding a case fatality rate of 23% among IMI cases; IMI was present in 43% of all deaths. CONCLUSIONS: In this nationwide cohort, IMI occurred more frequently than reported in many previous pediatric studies, particularly in AML. IMIs were observed throughout first-line therapy, despite antifungal prophylaxis, and were associated with substantial mortality, emphasizing the need for sustained clinical vigilance beyond induction.