Abstract: Background: During chemotherapy for hematological malignancies, febrile neutropenia (FN) is a frequent and serious complication. The causative organisms of FN vary from era to era and depending on bacterial resistance in each country. Therefore, epidemiological data are required for each era and country from prospective large clinical trials. We previously reported a prospective clinical trial indicating the importance of the D-index, a measure of neutropenia severity (CEDMIC trial, J Clin Oncol. 2020 10; 38: 815). We hypothesized that analyzing these data would provide accurate contemporary epidemiological data for hematological malignancies. Furthermore, as encountered in practice, we suspected that gram-negative (GN) bloodstream infections (BSIs) are more common at high body temperatures (BTs) than at low BTs and examined the relationship between causative bacteria and BT. Patients and Methods: Between June 2013 and April 2017, we enrolled patients with hematological malignancies aged 16-79 years post-chemotherapy or -stem cell transplantation (SCT) with expected neutropenia durations & gt;7 days. Neutrophil counts & lt;500/mL reflected neutropenia, and all fevers had axillary temperatures ≥37.5°C. Prophylactic antibiotics (Abx) were drugs administered post-chemotherapy and pre-FN onset. The FN incidence and blood culture (BC) positivity rate were examined in 4 treatment groups: allogeneic SCT (Allo-SCT), autologous SCT (Auto-SCT), induction chemotherapy for acute leukemia, and other treatments. Results: In total, 423 patients were enrolled, and 413 (median age: 56 years) were included in the intention-to-treat analyses (Table 1). The treatments included induction chemotherapy (n=67), Allo-SCT (n=106), Auto-SCT (n=158), and others (n=82). Prophylactic Abx were administered in 281 (68.5%) patients (only quinolone, n=222; with β-lactam, n=59). Prophylaxis rates were significantly higher in the Allo-SCT (n=94, 88.7%, p & lt;0.001) and induction chemotherapy (n=49, 73.1%, p & lt;0.017) groups. FN occurred in 356/413 patients (86.4%, Table 1). The Allo-SCT group had a higher FN incidence than that in the other treatments group (93.4% vs. 72%, p & lt;0.001). D-indices ≥5500 and & lt;5500 were associated with FN incidences of 100% and 81.8%, respectively (p & lt;0.001). Prophylaxis did not reduce the FN incidence. In total, 1272 BC sets were collected from 356 patients with FN. At FN onset, BCs were collected from 346 patients; 72 (20.8%) were positive (Table 2). Among initial BCs, 46 (63.9%) harbored gram-positive (GP) and 28 (38.9%) harbored GN bacteria. Three patients had multiple bacterial infections. The 2 most frequent GP bacteria were coagulase-negative Staphylococcus (n=21, 44.7%) and viridans streptococci (n=14, 29.8%). The 3 most frequent GN bacteria were Escherichia coli (n=13, 44.9%), Klebsiella pneumoniae (n=4, 13.8%), and Pseudomonas aeruginosa (n=4, 13.8%). Among initial BCs, prophylactic Abx use did not reduce BC positivity. However, the GN BSI incidence was significantly lower in the prevention group vs. non-prevention group (23.8% vs. 56.7%, p=0.007). Among patients who received prophylactic β-lactam, GN BSIs did not occur. Maximum BTs (maxBTs) were significantly higher in patients with positive BCs than negative BCs (38.4°C vs. 38.0°C, p & lt;0.001). The BTs associated with GN BSIs were significantly higher than those associated with negative BCs and GP BSIs (38.7°C vs. 38.0°C vs. 38.2°C, p & lt;0.001, Figure 1). The maxBTs and BC positivity rates were strongly related (Table 3). The BC positivity rates were significantly higher in patients with BTs ≥38°C vs. & lt;38°C (26.5% vs. 14.5%, p=0.008), 38.5°C vs. & gt;38.5°C/ & lt;38.5°C (39.7% vs. 15.3%, p & lt;0.001), and ≥39°C vs. & lt;39°C (52.6% vs. 16.9%, p & lt;0.001). Among patients who did not receive prophylactic Abx (n=106), the GN BSI positivity rate was significantly lower in patients with maxBTs & lt;38°C vs. ≥38°C (14.3% vs. 76.2%, p=0.007). Conclusion: In FN patients with high-risk hematological malignancies in Japan, the frequency of GP BSIs is high. Prophylactic Abx use reduces the GN BSI risk but not the FN or BSI risk. Fever severity and BC positivity at FN onset are strongly associated. The BTs of patients with GN BSIs are high. Disclosures Kanda: Astellas Pharma: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Merck Sharp & Dohme: Honoraria; Pfizer: Honoraria, Research Funding; Shionogi: Research Funding; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Otsuka: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria; Mundipharma: Honoraria. Kimura:Takeda Pharmaceuticals: Honoraria; Astellas Pharma: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Merck Sharp & Dohme: Honoraria; Nippon Kayaku: Honoraria; Kyowa Hakko Kirin: Honoraria; Ono Pharmaceutical: Honoraria; Celgene: Honoraria; Asahi Kasei: Honoraria. Oyake:Astellas Pharma: Honoraria; Bayer: Research Funding; Chugai Pharma: Honoraria, Research Funding; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Bristol-Myers Squibb Japan: Honoraria; Pfizer: Honoraria; Sionogi: Research Funding. Tamura:Asahi Kasei: Honoraria; Ono Pharmaceutical: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria.

Abstract: Introduction: 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. Disclosures Kimura: Astellas: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Other: Investigator in the institute; Nippon Kayaku: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria. Kanda:Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Tanabe-Mitsubishi: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Taisho-Toyama: Research Funding; Taiho: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria. Fujiwara:Shire: Consultancy; Pfizer: Consultancy; Chugai: Consultancy; Kirin: Consultancy; Kyowa-Hakko: Consultancy; Astellas: Consultancy. Suzumiya:Celltrion: Research Funding; Taiho: Research Funding, Speakers Bureau; SymBio: Research Funding; Toyama Chemical: Research Funding; Takeda: Research Funding, Speakers Bureau; Eisai: Research Funding, Speakers Bureau; Chugai-Roche: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Zenyaku Kogyo: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Research Funding; Sumitomo Dainioppon: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Ono: Speakers Bureau; Ohtsuka: Speakers Bureau; Shire Japan: Speakers Bureau. Takamatsu:Taisho Toyama Pharmaceutical: Research Funding; TAIHO Pharmaceutical: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Chugai Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Celgene: Honoraria. Tamura:Astellas Phrma: Research Funding; Eisai: Speakers Bureau; Kyowa Hakko Kirin: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau.

Abstract: 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.