Breakthrough Invasive Mold Infections in the Hematology Patient: Current Concepts and Future Directions

Abstract

Although the widespread use of mold-active agents (especially the new generation of triazoles) has resulted in reductions of documented invasive mold infections (IMIs) in patients with hematological malignancies and allogeneic hematopoietic stem cell transplantation (HSCT), a subset of such patients still develop breakthrough IMIs (bIMIs). There are no data from prospective randomized clinical trials to guide therapeutic decisions in the different scenarios of bIMIs. In this viewpoint, we present the current status of our understanding of the clinical, diagnostic, and treatment challenges of bIMIs in high-risk adult patients with hematological cancer and/or HSCT receiving mold-active antifungals and outline common clinical scenarios. As a rule, managing bIMIs demands an individualized treatment plan that takes into account the host, including comorbidities, certainty of diagnosis and site of bIMIs, local epidemiology, considerations for fungal resistance, and antifungal pharmacological properties. Finally, we highlight areas that require future investigation in this complex area of clinical mycology.

Invasive fusariosis masquerading as extramedullary disease in rapidly progressive acute lymphoblastic leukemia

“…In contrast, our patient's initial lesions developed despite normal ANC for 12 days prior, and the biopsy confirmed that these same lesions were due to IF. This case further highlights the complex epidemiology of breakthrough invasive mold infections occurring in immunosuppressed hematological patients …”

“…There are several reports of immunosuppressed patients developing severe fungal infections despite antifungal prophylaxis . Fluconazole and echinocandins are common well‐tolerated choices for antifungal prophylaxis in patients with ALL; echinocandins, as opposed to fluconazole, have some activity against Aspergillus .…”

“…Fluconazole and echinocandins are common well‐tolerated choices for antifungal prophylaxis in patients with ALL; echinocandins, as opposed to fluconazole, have some activity against Aspergillus . Despite antifungal prophylaxis and the anti‐ Aspergillus activity of echinocandins, breakthrough invasive fungal infections can still occur, and most echinocandin‐associated breakthrough mold infections are still due to aspergillosis, not IF . However, in patients with skin involvement, IF should be strongly considered, as cutaneous disease is uncommon with aspergillosis or mucormycosis .…”

Prospective CYP2C19‐Guided Voriconazole Prophylaxis in Patients With Neutropenic Acute Myeloid Leukemia Reduces the Incidence of Subtherapeutic Antifungal Plasma Concentrations

“…Breakthrough fungal infections in patients with neutropenia receiving prophylactic voriconazole are commonly observed, with trough concentrations < 1 μg/mL associated with progressive fungal disease. 6,8,16,21,22 Epidemiology studies have shown that drug-resistant Aspergillus and non-Aspergillus molds are commonly observed among those with breakthrough infections. 21,22 Prolonged exposure to suboptimal voriconazole concentrations may mechanistically promote acquired resistance and selection of subpopulations with primary resistance.…”

“…6,8,16,21,22 Epidemiology studies have shown that drug-resistant Aspergillus and non-Aspergillus molds are commonly observed among those with breakthrough infections. 21,22 Prolonged exposure to suboptimal voriconazole concentrations may mechanistically promote acquired resistance and selection of subpopulations with primary resistance. [23][24][25] The CYP2C19*17 allele is a risk factor for low voriconazole concentrations and can affect ~ 25% of patients.…”