Antifungal Management in Patients with Hematologic Malignancies: From Primary Prophylaxis to Empirical and Diagnostic-Driven Treatment

Invasive fungal diseases (IFDs) remain a significant cause of morbidity and mortality among patients with hematologic malignancies, especially those undergoing intensive chemotherapy or hematopoietic stem cell transplantation (HSCT). This review provides a comprehensive, risk-adapted framework for antifungal prophylaxis, stratifying patients into high, intermediate, and low-risk categories. Mold-active prophylaxis, primarily with posaconazole, is recommended for high-risk patients such as those with acute myeloid leukemia (AML) during remission induction or those with grade III-IV graft-versus-host disease (GVHD) post-allogeneic HSCT. Fluconazole remains an option for yeast-active prophylaxis in intermediate-risk patients, while low-risk groups generally do not require prophylaxis. The evolving landscape of targeted therapies-such as venetoclax, fms-like tyrosine kinase 3 (FLT3) inhibitors, and CD19 chimeric antigen receptor T-cell (CAR-T) therapy-poses new challenges, particularly due to drug-drug interactions with triazole antifungals. In patients receiving venetoclax, azole co-administration necessitates significant dose adjustments. We also present algorithms for antifungal management in the context of CD19 CAR-T therapy and novel agents, emphasizing the role of individualized risk assessment. Beyond prophylaxis, timely diagnosis and early treatment of IFDs are critical. The role of thoracic computed tomography, serum and bronchoalveolar lavage galactomannan, and fungal biomarkers is discussed within diagnostic-driven strategies. We outline treatment pathways for suspected pulmonary or sinus fungal infections, including when to escalate antifungal therapy or consider surgical intervention. This review offers a practical and evidence-based guide for clinicians navigating antifungal strategies in a rapidly changing therapeutic landscape, aiming to reduce IFD-related mortality while balancing toxicity, resistance, and healthcare costs.