Classical Empiric Antifungal Therapy Vs. D-Index Guided Early Therapy Using Micafungin for Persistent Febrile Neutropenia (CEDMIC trial): A Randomized Controlled Trial from Japan FN Study Group

Shun-Ichi Kimura 1, Yoshinobu Kanda 1,2, Masaki Iino 3, Takahiro Fukuda 4, Emiko Sakaida 5, Tatsuo Oyake 6, Hiroki Yamaguchi 7, Shin-ichiro Fujiwara 2, Junji Suzumiya 8, Akinao Okamoto 9, Hiroyuki Fujita 10, Yasushi Takamatsu 11, Yoshio Saburi 12, Jun Yamanouchi 13, Itaru Matsumura 14, Souichi Shiratori 15, Moritaka Gotoh 16, Shingen Nakamura 17 and Kazuo Tamura 18

Author address: 

1Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan 1Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan 2Division of Hematology, Jichi Medical University, Shimotsuke, Japan 3Department of Medical Oncology, Yamanashi Prefectural Central Hospital, Kofu, Japan 4Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan 5Department of Hematology, Chiba University Hospital, Chiba, Japan 6Division of Hematology and Oncology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan 7Department of Hematology, Nippon Medical School, Tokyo, JPN 8Department of Oncology and Hematology, Shimane University Hospital, Izumo, JPN 9Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan 10Department of Hematology and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan 11Division of Medical Oncology, Hematology and Infectious Diseases, Department of Internal Medicine, Fukuoka University Hospital, Fukuoka, Japan 12Department of Hematology, Oita Prefectural Hospital, Oita, Japan 13Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan 14Division of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka, Japan 15Department of Hematology, Faculty of Medicine, Hokkaido University, Sapporo, Japan 16Department of Hematology, Tokyo Medical University, Tokyo, Japan 17Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, JPN 18General Medical Research Center, Fukuoka University, Fukuoka, Japan


ntroduction: Empiric antifungal therapy (EAT) is recommended for persistent or recurrent febrile neutropenia based on an old randomized controlled trial, but such treatment is apparently overtreatment for the majority of patients. On the other hand, preemptive therapy triggered by positive blood tests for fungal antigens and/or imaging study findings was shown to increase the incidence of invasive fungal infection, and thus, a risk-based approach is important. The D-index, which is defined as the area over the neutrophil curve during neutropenia and hence reflects both the duration and depth of neutropenia (Figure 1A), enables real-time monitoring of the risk of invasive fungal infection. Previous studies showed that the cumulative D-index (c-D-index), which was calculated as cumulative D-index from the onset of neutropenia (Figure 1B), had high negative predictive values for invasive mold infection or pulmonary infection with cutoff values of 5,800 or 5,500 in high-risk neutropenic patients [J Clin Oncol 2009; 27: 3849-54. Biol Blood Marrow Transplant 2010; 16: 1355-61].

Methods: We investigated a novel approach, called D-index-guided early antifungal therapy (DET) and compared it to EAT in high-risk neutropenic patients. In the EAT group, empiric antifungal therapy was started for persistent (>=4 days) or recurrent febrile neutropenia. For patients with persistent or recurrent febrile neutropenia in the DET group, preemptive antifungal therapy was applied until c-D-index reached 5,500, but antifungal agent was initiated after c-D-index exceeded 5,500, even if there was no significant finding in serum fungal makers or imaging studies, to prevent excessive invasive fungal infection. Micafungin at 150 mg/day was administered as EAT or DET in this study. We randomized 423 patients who underwent chemotherapy or hematopoietic stem cell transplantation for hematological malignancies, in which predicted period of neutropenia exceeded 7 days, into the EAT group or the DET group, and 413 were eligible for intent-to-treat analyses (201 patients in the EAT group, 212 patients in the DET group). The prophylactic use of fluconazole or itraconazole was allowed. Primary endpoint was the development of proven/probable invasive fungal infection.

Results: Backgrounds of the patients were similar between the 2 groups (Table 1). Invasive fungal infection (proven/probable/possible) was observed in 12 patients (6.0%) of the EAT group and 5 patients (2.4%) of DET group, respectively. Proven/probable invasive fungal infection was identified in 5 patients (2.5%) of the EAT group and 1 patient (0.5%) of DET group, which fulfilled the predetermined criteria of non-inferiority of the DET group. Regarding the pathogens, the EAT group included 1 case of candidemia and 4 cases of invasive pulmonary aspergillosis, and the DET group included one fusariosis. The survival rate of the EAT and DET group was 98.0% vs. 98.6% at day 42 and 96.4% vs. 96.2% at day 84, respectively. During the observation period, 31 patients died due to disease progression (n=19), infection (n=5) or other causes (n=7). Causes of infection related mortality included Pseudomonas aerginosa infection (n=2), fusariosis (n=1), toxoplasmosis (n=1) and septic shock by unknown pathogen (n=1). The frequency of micafungin use was significantly lower in the DET group than the EAT group (32.5% vs. 60.2%, P<0.001). Similar results were obtained in per-protocol set analyses.

Conclusions: DET successfully reduced the use of antifungal agents without increasing invasive fungal infection or mortality compared to EAT. This randomized controlled study revealed the feasibility of DET in high-risk neutropenic patients.



abstract No: 


Full conference title: 

60th American Society of Hematology Annual Meeting 2018
    • ASH 60th (2018)