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

2020 ◽  
Vol 38 (8) ◽  
pp. 815-822 ◽  
Author(s):  
Yoshinobu Kanda ◽  
Shun-ichi Kimura ◽  
Masaki Iino ◽  
Takahiro Fukuda ◽  
Emiko Sakaida ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Fungal Infection ◽  
Antifungal Therapy ◽  
Invasive Fungal Infection ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Controlled Trial ◽  
Horizontal Line ◽  
Hematopoietic Stem ◽  
Randomized Controlled

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.

scholarly journals 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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 816-816
Author(s):  
Shun-Ichi Kimura ◽  
Yoshinobu Kanda ◽  
Masaki Iino ◽  
Takahiro Fukuda ◽  
Emiko Sakaida ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Fungal Infection ◽  
Antifungal Therapy ◽  
Invasive Fungal Infection ◽  
Research Funding ◽  
Controlled Trial ◽  
Pharmaceutical Research ◽  
Randomized Controlled ◽  
Neutropenic Patients

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.

Efficacy and Safety of Micafungin as An Empirical Antifungal Therapy for Suspected Fungal Infection in Patients with Hematological Disorders.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1939-1939
Author(s):  
Minoru Yoshida ◽  
Kazuo Tamura ◽  
Masahiro Imamura ◽  
Yoshiro Niitsu ◽  
Takeshi Sasaki ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Antifungal Therapy ◽  
Clinical Symptoms ◽  
Fungal Infections ◽  
Efficacy And Safety ◽  
Hematopoietic Stem ◽  
Persistent Fever ◽  
Hematological Disorders ◽  
Study Results ◽  
Empirical Antifungal Therapy

Abstract Background: Invasive fungal infections (IFIs) are of serious concern in the management of immunocompromised patients (pts) with hematological disorders. Empiric antifungal therapy is recommended for neutropenic pts with persistent fever, because treatment after confirmation of fungal infection often produces poor outcomes. Micafungin (MCFG), one of the echinocandin families, was launched first in Japan in 2002, and has now been approved in more than 11 countries and areas including the USA and the EU. Although the efficacy and safety of MCFG against both Candida and Aspergillus infections has been shown in many clinical trials, there are few clinical study reports on the empiric therapy of a suspected fungal infection. Here, we report the multi-center study results of MCFG for the empiric antifungal therapy, which were conducted from April 2005 to September 2006 in Japan. Objective: This prospective study was performed to clarify the efficacy and safety of MCFG for the empirical antifungal therapy on suspected fungal infection in pts with hematological disorders and neutropenia. Methods: Study design: A multiple-center, open, uncontrolled study. The investigator registered pts with neutropenia (&lt; 1,000/μl) who met the following criteria to the Subject Registration Center. Suspected fungal infections were divided into two categories: possible fungal infection defined by positive clinical symptoms/findings and serological testing (beta-D-glucan or galactomannan) or diagnostic imaging (chest X-ray or CT scan), refractory fever defined by unexplained persistent fever (an axillary temperature higher than 37.5 °C) after the antibacterial treatment over 2 days and by positive clinical symptoms/findings. IFIs categorized as proven or probable were not included in this study. Efficacy evaluation was performed using an algorithm based on each of the evaluation of clinical symptoms/findings, imaging study findings, and serological tests. Results: 388 pts (M:234, F:154, mean age:57.8 years old) were registered. The mean dosage and duration of treatment with MCFG were 154.6±55.3 mg/day and 14.0±6.9 days, respectively. The main underlying hematological disorders were acute leukemia (61.3%), non-Hodgkin’s lymphoma (18.3%) and myelodysplastic syndrome (10.8%). The number of pts with hematopoietic stem cell transplantation (HSCT) was 76 (19.6%). The clinical response rate (CRR), excluding 4 non-evaluable pts was 63.3% (243/384): 60.1% (89/148) for pts with possible fungal infection and 65.3% (154/236) for pts with refractory fever, respectively. Even in persistent neutropenic pts whose neutrophil counts were &lt; 500/μL throughout the treatment with MCFG, the CRR was high enough: 46.9% (61/130). No difference was observed in the CRR among the main underlying hematological disorders. The CRR in pts with HSCT and other conditions were 63.2% (48/76) and 63.3% (195/308), respectively. Drug-related adverse events (DAEs) were observed in 16.8% (65/388). Serious DAEs such as elevation of serum bilirubin and renal dysfunction was observed in 0.52% (2/388). Conclusion: MCFG was confirmed to have high clinical efficacy and be safe for the treatment of suspected fungal infection in pts with hematological disorders and neutropenia.

Optimal Use of Granulocyte Colony Stimulating Factor (G-CSF) after Autologous Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2519-2519
Author(s):  
Firas Al Sabty ◽  
Martin Mistrik ◽  
Mikuláš Hrubiško ◽  
Eva Bojtárová ◽  
Ján Martinka ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Febrile Neutropenia ◽  
Stem Cell Transplantation ◽  
Fungal Infection ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Fungal Infections ◽  
Hematopoietic Stem ◽  
Lymphoid Malignancies

Abstract Introduction:high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHSCT) is widely used in the treatment of patients with haematological and non-haematological malignancies. One of the most common causes of mortality after HSCT is infection during the time of prolonged neutropenia. Prolonged neutropenia more than 7 days increase the risk of fungal infections and it is an indication for the use of antifungal prophylaxis. After hematopoietic SCT, G-CSF is commonly used to enhance stem cell engraftment to minimize the morbidity and mortality associated with prolonged neutropenia. However, there is no consensus on the optimal use of G-CSF after autoHSCT, most studies have been conducted on small numbers of patients and have varied significantly in patient’s demographics, G-CSF dosage regimen and other factors affecting outcomes. Objective:restrospective study to evaluate the efficacy of early vs. delayed initiation of G-CSF after autoHSCT in patients with lymphoid malignancies. Methods: between January 2009 and July 2014, 117 patients with lymphoid malignancies who underwent autoHSCT in the Department of Hematology and Transfusion medicine in Bratislava were included. The patients were divided into two groups; in the first group (43 patients), G-CSF (filgrastim, 5μg/kg s.c.) was applied late (on day 6.-8.) after autoHSCT. In the second group (74 patients), G-CSF (filgrastim, 5μg/kg s.c.) was applied early (on day 3.-4.) after autoHSCT. All patients received standard conditioning regimen for the underlying disease, and standard supportive treatment, including treatment of febrile neutropenia. Patient’s demographics are shown in table 1. Statistical analysis was performed using SPSS statistical software v. 20, with significant Pvalue of 0.05 (two-tailed). Results: sever neutropenia (ANC < 0.5 x 109) and very severe neutropenia (ANC < 0.1 x 109) for more than 7 days were recorded as following: in the first group (delayed G-CSF), 34/42 (81%) and 25/41 (61%) patients respectively. In the second group (early G-CSF), 11/66 (17%) and 2/52 (4%) patients respectively (RR = 4.8, 95% CI = 2.7 to 8.4 and RR = 15, 95% CI = 3.9 to 63). Median time to engraftment of leukocytes above 1, granulocytes above 0.5, and 0.1 x 109/l was 6, 5, and 4 days for patients who received G-CSF early and 7, 7 and 5 days for patients who received G-CSF late (P <0001). The median duration of hospitalization was 19 (15-28) days in the first group and 16 (11-23) days in the second group (P = 0.001, 95% CI =2.02-4.17). There was no significant difference in the rate of febrile neutropenia in both groups (P = 0.53), but the rate of fungal infection and the use of HRCT scan of the lung was higher in the group of patients who received delayed G-CSF than early G-CSF (19% vs. 3%, P=0.005) and (23% vs. 6%, P=0.007) respectively. Conclusion:early application of G-CSF (3rd-4th day) after autologous HSCT accelerates engraftment, shorten the duration of neutropenia, reduce the risk of infectious complications (especially fungal infections), reduce the use of antimicrobial drugs, shorten the hospital stay and overall costs. Table.1 Delayed application of G-CSF Early application of G-CSF Patient N. 43 74 Age, m edian(range) 60 (39-67) years 59 (33-68) years P = 0.694 Sex P = 0.079 Male, N (%) 16 (37%) 40 (54%) Female, N (%) 27 (63%) 34 (46%) CD34+cells x106/kg, m edian(range) 2.5 (1.3-5.6) 2.3 (1.3-4.5) P = 0.138 Diagnosis P = 0.855 Multiple myeloma, N (%) 41 (95%) 72 (97%) NHL, N (%) 2 (5%) 2 (3%) ECOG performance status P = 0.221 0 35 (82%) 53 (72%) 1 7 (16%) 18 (24%) 2 1 (2%) 2 (3%) 3 0 0 4 0 1 (1%) Engraftment , median(range) Leu. > 1 x 109/l 7 (4-12) days 6 (3-9) days P ≤ 0,0001 Neut.> 0.5 x 109/l 7 (5-9) days 5 (3-7) days P ≤ 0,0001 Neut. > 0.1 x 109/l 5 (3-6) days 4 (2-6) days P ≤ 0,0001 Hospitalization, median(range) 19 (15-28) days 16 (11-23) days P= 0,001 Sever neutropenia ≥ 7 days, N (%) 34/42 (81%) 11/66 (17%) RR = 4.8, 95% CI = 2.7 to 8.4 Very sever neutropenia ≥ 7 days, N (%) 25/41 (61%) 2/52(4%) RR = 15, 95% CI = 3.9 to 63 Febrile neutropenia, N (%) 40 (93%) 64 (88%) P = 0.531 Invasive fungal infection, N (%) 8/43 (19%) 2/73 (3%) P = 0,005 HRCT scan use, N (%) 10 (23%) 4 (6%) P = 0.007 Cost 3582 (787-18187) Eur. 1408 (263-2143) Eur. P=0,041 Disclosures No relevant conflicts of interest to declare.

scholarly journals 591. Comparison of Fluconazole to Other Antifungal Agents in Allogeneic Hematopoietic Cell Transplant Recipients: A Meta-Analysis of Randomized Clinical Trials

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S398-S399
Author(s):  
Ce Cheng ◽  
Iloabueke Chineke ◽  
Ali McBride ◽  
Alejandro Recio-Boiles ◽  
Lakshmi Saritha Ainapurapu ◽  
...  
Keyword(s):  
Randomized Controlled Trials ◽  
Subgroup Analysis ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Meta Analysis ◽  
Controlled Trials ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Randomized Controlled ◽  
Anti Fungal

Abstract Background Invasive fungal infections (IFI) are adverse complications of allogeneic and autologous hematopoietic stem cell transplantation (HSCT) with significant mortality and morbidity. Randomized Controlled Trials (RCT) have addressed the optimal anti-fungal prophylaxis regimen. However, the consensus for an anti-fungal prophylaxis regimen has remained elusive. Hence, we performed a meta-analysis of currently available RCTs comparing the efficacy of fluconazole vs. other antifungal agents including voriconazole, micafungin, and itraconazole in the endpoint of preventing IFI. Methods Randomized controlled trials were retrieved from PubMed, according to our inclusion criteria. The relative risk (RR), hazard risk (HR), and 95% confidence intervals (CI) were calculated. A random effect or fixed-effect model was used to calculate the pooled HR, based on heterogeneity. All statistical analyses were performed using RevMan software and R Core Team, and all p-values were two-tailed, and the significance level was 0.05. Results Ten RCTs were selected involving 2654 pts. Our results showed fluconazole is statistically inferior to other agents that include voriconazole, micafungin, and itraconazole with regards to the endpoint of a lower incidence of IFI (RR: 1.05; 95%CI: 1.02, 1.08; p=0.0002, I2=5%). However, subgroup analysis showed no statistical difference between fluconazole vs. other agents to prevent breakthrough proven IFI (HR: 0.76; 95%CI: 0.47, 1.23; p=0.27, I2=0%). Our subgroup analysis further showed that other agent’s group might have a superior role in preventing aspergillus compared with fluconazole (HR: 0.64; 95%CI: 0.44, 0.94; p=0.02, I2=0%), but no significant advantages over fluconazole for candidiasis (HR: 0.96; 95%CI: 0.45, 2.07; p=0.92, I2=0%). Successful Rate Without Incidence of IFI Figure 1. Successful Rate Without Incidence of IFI Proven IFI vs. Suspected IFI Figure 2. Proven IFI vs. Suspected IFI Candidiasis vs. Aspergillus Figure 3. Candidiasis vs. Aspergillus Conclusion This meta-analysis yield data that suggests fluconazole might be inferior to other agents in preventing IFI in all intent to treat patients undergoing HSCT. However, fluconazole is non-inferior in preventing proven IFI and candidiasis IFI based on our results. Thus, we continue to recommend fluconazole in selected patients who require anti-fungal prophylaxis. More RCTs are needed in the future to demonstrate the drug of choice for anti-fungal prophylaxis and address patient selection characteristics. Disclosures All Authors: No reported disclosures

Of Yeasts and Hyphae: A Hematologist’s Approach to Antifungal Therapy

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 361-367 ◽  
Author(s):  
Eric J. Bow
Keyword(s):  
Fungal Infection ◽  
Antifungal Therapy ◽  
Invasive Fungal Infection ◽  
Dose Intensity ◽  
Empirical Therapy ◽  
Diagnostic Techniques ◽  
Careful Study ◽  
Hematopoietic Stem ◽  
Established Disease ◽  
Combination Regimens

Abstract Improvements in anticancer treatments, the ability to modify myelosuppression profiles, greater duration and intensity of immunosuppression, and the variety of available antimicrobial therapies have influenced the spectrum of pathogens associated with invasive fungal infection complicating treatment of hematological malignancies and hematopoietic stem cell transplantation. The approaches to the management of these infections encompass strategies of prevention for all those at risk, pre-emptive therapy based upon surrogates of infection before the onset of clinical disease, empirical therapy for patients with clinical evidence of early disease, and directed or targeted therapy for infected patients with established disease. Chemoprophylaxis is effective if applied to the highest risk patients over the duration of the risk. Pre-emptive strategies, while promising, have yet to be validated and linked to reliably predictive nonmicrobiological diagnostic techniques. Empirical antifungal therapy, as it is currently applied, now seems questionable. Patients with probable or proven invasive fungal infection still have suboptimal outcomes despite the availability of promising anti-fungal agents. Strategies examining the concept of dose-intensity and combination regimens require careful study and cannot yet be regarded as an acceptable standard of practice.

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