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.

• Authors: Yoshinobu Kanda, Shun-Ichi Kimura, Masaki Iino, Takahiro Fukuda, Emiko Sakaida, Tatsuo Oyake, Hiroki Yamaguchi, Shin-Ichiro Fujiwara, Yumi Jo, Akinao Okamoto, Hiroyuki Fujita, Yasushi Takamatsu, Yoshio Saburi, Itaru Matsumura, Jun Yamanouchi, Souichi Shiratori, Moritaka Gotoh, Shingen Nakamura, Kazuo Tamura, Japan Febrile Neutropenia Study Group
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 38 Issue 8 Pg. 815-822 (03 10 2020) ISSN: 1527-7755 [Electronic] United States
• PMID: 31977270 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antifungal Agents
• Itraconazole
• Fluconazole
• Micafungin

Topics

• Adult
• Aged
• Antifungal Agents (administration & dosage)
• Febrile Neutropenia (blood, drug therapy, microbiology)
• Female
• Fluconazole (administration & dosage)
• Hematologic Neoplasms (blood, drug therapy, microbiology, therapy)
• Hematopoietic Stem Cell Transplantation (adverse effects, methods)
• Humans
• Itraconazole (administration & dosage)
• Leukocyte Count
• Male
• Micafungin (administration & dosage)
• Middle Aged
• Mycoses (blood, etiology, prevention & control)
• Neutrophils (pathology)
• Young Adult