D-Index–Guided Early Antifungal Therapy Versus Empiric Antifungal Therapy for Persistent Febrile Neutropenia: A Randomized Controlled Noninferiority Trial

Abstract

PURPOSE Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/μL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index–guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial. PATIENTS AND METHODS We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET. RESULTS In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (−2.0%; 90% CI, −4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2% v 32.5%; P < .001). CONCLUSION A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.

Impact of neutropenia evaluated in terms of the D‐index on invasive fungal disease while on empiric or preemptive antifungal treatment strategy in the early phase after allogeneic hematopoietic stem cell transplantation

“…However, the incidence of early IFD (4.82%) is comparable to those in previous clinical trials and is considered to be acceptable as a real-world value, particularly under strict management. 6,34,35 Third, although the D-index and c-D-index were more accurate than days of neutropenia for predicting IFD with a statis-…”

“…The CEDMIC trial confirmed the non-inferiority of D-indexguided early antifungal therapy to empiric antifungal therapy among hematological patients receiving intensive chemotherapies or HSCT. 6 The CO value of the c-D-index for triggering empiric antifungal therapy was set at 5500 based on our previous retrospective study. 5 The incidence of IFD in the CEDMIC trial was as low as 2.…”

“…Febrile neutropenia was treated with broad‐spectrum antibiotics after blood and other cultures, if applicable, were obtained in accordance with published guidelines 14 . For persistent or recurrent febrile neutropenia during the administration of broad‐spectrum antibiotics, an empiric or preemptive antifungal treatment strategy was performed at the discretion of the attending physician 6,14,15 . Chest X‐ray was performed every week in the early period of allogeneic HSCT.…”

“…14 For persistent or recurrent febrile neutropenia during the administration of broad-spectrum antibiotics, an empiric or preemptive antifungal treatment strategy was performed at the discretion of the attending physician. 6,14,15 Chest X-ray was performed every week in the early period of allogeneic HSCT. Chest and nasal sinus computed tomography (CT) was per-…”

“…5 Based on this result, a multicenter prospective study in Japan (CEDMIC trial) confirmed the non-inferiority of D-index-guided early antifungal therapy to empiric antifungal therapy in hematological patients receiving intensive chemotherapies or HSCT. 6 In brief, empiric antifungal therapy could be successfully postponed until the c-D-index exceeded 5500 without increasing mortality or the incidence of IFD compared to classical empiric antifungal therapy.…”