scholarly journals The Efficacy of CT-Diagnostic-Driven Antifungal Strategy with Voriconazole for Invasive Aspergillosis in Patients with Hematological Diseases: A Multicenter, Prospective Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2370-2370
Author(s):  
Yu Ji ◽  
Yuqian Sun ◽  
Chenhua Yan ◽  
Xiaojun Huang ◽  
Daihong Liu ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Antifungal Therapy ◽  
Conflicts Of Interest ◽  
Financial Burden ◽  
Antifungal Treatment ◽  
Successful Outcome ◽  
Intensive Chemotherapy ◽  
Hematopoietic Stem ◽  
Halo Sign ◽  
Neutropenic Patients

Abstract Background The frequency of invasive fungal disease (IFD) has increased in recent two decades and has emerged as an important cause of life-threatening infections in immunocompromised patients, especially in those who have undergone allogeneic hematopoietic stem cell transplantation (HSCT). Empirical antifungal therapy has been the standard of care used to decrease the number of deaths due to IFD among neutropenic patients who have persistent or recurrent fever despite broad-spectrum antibacterial treatment. However, about two thirds of these patients may be potentially exposed to unnecessary empirical antifungal treatment with associated potential toxicity and considerable financial burden. It was demonstrated that high-resolution computerized tomography (HRCT) had early predictive value for fungal infection, and the major signs on chest CT scans generally precede the positive outcome of serum galactomannan test. It was also shown that the diagnosis-based treatment strategy only based on HRCT results could reduce more than a half use of antifungal agents in HSCT patients who had persistent febrile neutropenia. Thus, we would like to explore the feasibility of this new strategy for hematological patients with IA in China. Method This was a prospective and single-arm study. Up to now, 24 neutropenic patients after intensive chemotherapy or HSCT with high risk factors for IFD from three hospitals were enrolled. After recruitment, HRCT of thorax will be conducted within 24h. If HRCT shows any new changes suspicious of fungal infection, including halo sign, cavity, air-crescent sign, or other non-specific signs, voriconazole would be given intravenously for two weeks, followed by oral voriconazole. Six weeks after initiation of antifungal therapy, the outcome was evaluated by clinicians according to the patients' imagining and microbiological evidences and clinical conditions, and complete or partial responses were defined as successful outcome of antifungal therapy. Result The median age of this population was 38.5 years (range from 19 to 78). Four of 24 patients were the recipients of HSCT, and the others received intensive chemotherapy. There were four patients had history of IFD, and 7 take fluconazole orally for antifungal prophylaxis. At the beginning of antifungal therapy with voriconazole, 12 had non-specific infiltrates on pulmonary HRCT, 8 had dense lesions with halo sign, and 4 had cavity. At the end of six-week follow-up, 5 patients were diagnosed with possible IA, 6 with probable IA and 1 with proven IA. The total successful rate of antifungal therapy with CT-diagnostic-driven strategy was 50.0% (12/24). Notably, efficacies of the antifungal treatment in patients with specific IA signs on pulmonary HRCT were significant higher than that in patients with non-specific signs (75.0% vs. 25.0%, P=0.043). Conclusion The CT-diagnostic-driven antifungal strategy was effective and suitable for patients with hematological malignancies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Diagnostic-driven management of invasive fungal disease in hematology in the era of prophylaxis and resistance emergence: Dutch courage?

2019 ◽  
Vol 57 (Supplement_3) ◽  
pp. S267-S273
Author(s):  
E A de Kort ◽  
J Maertens ◽  
P E Verweij ◽  
B J A Rijnders ◽  
N M A Blijlevens
Keyword(s):  
Antifungal Therapy ◽  
Standard Of Care ◽  
Diagnostic Procedures ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Antifungal Treatment ◽  
Clinical Implementation ◽  
Hematopoietic Stem ◽  
Haematological Patient ◽  
Emergence Of Resistance

Abstract Patients receiving intensive anti-leukemic treatment or recipients of allogeneic hematopoietic stem cell transplantation (HSCT) are prone to develop invasive fungal disease caused by both Aspergillus and non-Aspergillus moulds. Overall mortality following invasive mould disease (IMD) is high; adequate and timely antifungal treatment seems to ameliorate the outcome, yet early diagnosis in the haematological patient remains a challenge for most clinicians. Prophylaxis and the empiric addition of antifungal therapy to neutropaenic patients with fever persisting or recurring during broad-spectrum antibiotic treatment is therefore standard of care in many institutions. However, aside from the potential for overtreatment and important side effects, the emergence of resistance to medical triazoles in Aspergillus fumigatus poses a risk for inadequate initial treatment. Initial voriconazole therapy in patients with azole-resistant invasive aspergillosis was recently shown to be associated with a 23% increased mortality rate compared to the patients with azole-susceptible infection, despite changing to appropriate antifungal therapy once resistance was detected. Moreover, fever is not always present with IMD; therefore, cases may be missed when relying solely on this symptom for starting diagnostic procedures and antifungal treatment. At our institution, a diagnostic-driven treatment approach for IMD was implemented relying on clinical but also laboratory markers to start antifungal treatment. We describe the basis and clinical implementation of our diagnostic-driven approach in this review.

Efficacy and Safety of Micafungin as An Empirical Antifungal Agent for Febrile Neutropenic Patients with Hematological Diseases.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4661-4661
Author(s):  
Joon Seong Park ◽  
Dong Hwan Kim ◽  
Chul Won Choi ◽  
Seong Hyun Jeong ◽  
Jin-Hyuk Choi ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Success Rate ◽  
Antifungal Agent ◽  
Conflicts Of Interest ◽  
Multicenter Trial ◽  
Base Line ◽  
Efficacy And Safety ◽  
Hematological Disorders ◽  
Neutropenic Patients ◽  
Grade 3

Abstract Abstract 4661 Introduction Invasive or possible fungal infection is often fatal and its incidence is increasing in febrile neutropenic patients with hematological malignancies. Thus, empirical antifungal agent should be carefully selected for those patients. Patients and Methods The study was conducted as a prospective multicenter trial to document the efficacy and safety of micafungin (Mycamine®), a class of echinocandin, as an empirical antifungal agent in febrile neutropenic patients. Micafungin was administrated for sustained fever (>38.4°C) on day 3 - 5 after initiation of empirical antibiotic therapy. The overall success rate according to the composite score (no breakthrough fungal infection, survival for seven days beyond the end of therapy, did not discontinue therapy prematurely, had resolution of fever during the period of neutropenia, and successfully treated a documented base-line fungal infection) and side effects were evaluated. Results A total of 47 patients with AML, ALL, MDS or lymphomas were enrolled. The overall success rate was 61.7% (29/47). Three patients (6.4 %) experienced grade 3/4 elevated aspartate aminotransferase and ten patients (21 %) showed grade 3/4 hyperbilirubinemia and nine of which resolved, and four patients died of septic shock. Patients with young age (< 50 yr) and ALL rather than AML showed a better response to micafungin. Less profoundly neutropenic (≥50 /mm3) patients revealed a better response, as did the patients who recovered from fever or neutropenia. Conclusions Micafungin has been reported to have an excellent efficacy (61.7 %) and safety profile when used as an empirical antifungal agent to treat febrile neutropenic patients with hematological disorders. Disclosures: No relevant conflicts of interest to declare.

Micafungin Versus Voriconazole for Empirical Antifungal Therapy In Febrile Neutropenic Patients with Acute Myeloid Leukemia: A Randomized, Controlled Trial.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1062-1062
Author(s):  
Tatsuo Oyake ◽  
Shugo Kowata ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Antifungal Therapy ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Fungal Infections ◽  
Controlled Trial ◽  
End Point ◽  
Empirical Antifungal Therapy ◽  
Neutropenic Patients ◽  
Acute Myeloid

Abstract Abstract 1062 Background: Invasive fungal infections (IFIs) incur significant morbidity and mortality among neutropenic patients after chemotherapy. The risk for these infections is related to the intensity and duration of neutropenia, and varies from 2% to 40%. Mortality rates associated with documented IFIs are considerable, reportedly ranging from 30% to 60%. Empirical antifungal therapy is the standard care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. Several antifungal agents including voriconazole (VRCZ) or liposomal amphotericin B (L-AMB) have been studied as empirical therapy for febrile neutropenia (FN). However, limited data are available concerning the efficacy of micafungin (MCFG) in FN patients with acute myeloid leukemia (AML). Methods: We conducted a randomized, cooperative group, open-label trial comparing MCFG (150 mg once daily) with VRCZ (6 mg/kg twice on day 1 followed by 4 mg/kg twice daily) as first-line empirical antifungal treatment for 95 hospitalized FN patients with AML during induction or consolidation chemotherapy (MCFG, 49; VRCZ, 46). The efficacy end point was a favorable overall response, as determined by a five-component end point according to the criteria of Walsh et al (N Engl J Med 2004; 351: 1391). Results: At the time of enrolment, there were no significant differences in the demographics or baseline characteristics between the two groups. The mean treatment duration for MCFG and VRCZ was 10 and 9 days, respectively. The efficacy rates of MCFG and VRCZ were not significantly different (37.8% vs. 32.4%). The rates of breakthrough fungal infections (proven, probable and possible IFIs), successful treatment of baseline fungal infections, survival 7 days after end of therapy, and resolution of fever during neutropenia were similar in the two groups. However, premature discontinuation of therapy occurred less often in the MCFG group than in the VRCZ group (32.4% vs. 55.9%, P=0.0457*). In safety evaluation, there were fewer adverse events in the MCFG group than in the VRCZ group (27.0% vs. 64.7%, P=0.0013*). *: Chi square test Conclusions: MCFG was as effective as VRCZ, and better tolerated than VRCZ as empirical antifungal therapy in FN patients with AML. Disclosures: No relevant conflicts of interest to declare.

Thoax CT Scan as Invasive Fungal Infection (IFI) Screening In Neutropenic Patients, a Prospective-Retrospective Experience of It Impact on Therapeutic Intervention.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4554-4554
Author(s):  
Sebastian Sevilla ◽  
Gustavo Daniel Kusminsky ◽  
Mario Atilio Damiano ◽  
Miguel Rizzo ◽  
Jose Trucco
Keyword(s):  
Ct Scan ◽  
Conflicts Of Interest ◽  
Antimicrobial Treatment ◽  
Antifungal Treatment ◽  
Ct Scans ◽  
Diagnostic Tools ◽  
Persistent Fever ◽  
Pulmonary Infiltrates ◽  
Neutropenic Patients ◽  
Thorax Ct

Abstract Abstract 4554 Introduction: Persistent fever in high risk neutropenic patients (HRNF) after day 5 of empiric treatment is a sign of high susceptibility for IFI with elevated morbidity and mortality. Diagnostic tools in this setting are inaccurate to determine the occurrence of IFI and most patients start with empiric antifungal agents. Drugs are usually associated with increasing costs and toxicity. It is challenging to establish the population of patients in whom in spite of persistent fever and neutropenia, avoidance of antifungal treatment is a reasonable strategy. Methods: We have prospectively allocated 229 HRNF patients in different empiric antimicrobial regimens over a 4.5 year period. In a retrospective revision, there were 33 patients with persistent fever on day 5 of empirical antimicrobial treatment and no evident new infection episode or clinical impairment. In 28 patients, a thorax CT scan was performed as part of the evaluation of persistent fever. The clinical outcome was evaluated regarding the presence or absence of pulmonary infiltrates in the CT scans. Initial empiric antifungal treatment, transfusions, days in hospital, days with neutropenia, antimicrobial treatment, and days with fever were evaluated. Results: Nineteen patients (68%) of 28 presented with pulmonary infiltrates. All of them received antifungal treatment. In 9 patients with normal CT scan antifungal treatment was deferred. The difference of the decision in not giving antifungals according CT scans was highly significant (p <0,0001). Transfusions of red blood cells and platelets were significantly less in the group of normal scans (p 0,0004 and 0,005 respectively). Antimicrobial treatment, days in hospital and days with fever were not significantly different in both groups. There was one death in the normal scan group due to relapse. Mortality was not significantly different in both groups. Conclusion: In HRNP, normal thorax CT scan changed the clinical decision in not starting antifungal treatment in spite of persistent fever. There was no difference in mortality with patients under antifungal treatment, allowing continuing with this strategy in more patients in the future. Disclosures: No relevant conflicts of interest to declare.

Secondary Antifungal Prophylaxis in Allogeneic Hematopoietic Stem Cell Recipients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4140-4140
Author(s):  
Qifa Liu ◽  
Ren Lin ◽  
Jing Sun ◽  
Yu Zhang ◽  
Fen Huang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Fungal Infection ◽  
Treatment Response ◽  
Hematopoietic Stem Cell ◽  
Antifungal Therapy ◽  
Stable State ◽  
Active State ◽  
Hematopoietic Stem ◽  
Related Mortality

Abstract Abstract 4140 Background Invasive fungal infection (IFI) is a serious complication in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is widely accepted that the patients with stable fungal infection is not a contraindication for allo-HSCT, but whether transplantation can be done in the patients with active fungal infections is still a matter of discussion. In addition, the optimal agent for SAP is not well defined. In this study, we investigated the efficacy of SPA for recipients in stable state or active state of prior invasive pulmonary aspergillosis (IPA). The choice of prophylaxis agent was based on treatment response of initial antifungal therapy. Methods A total of 63 patients with prior IPA undergoing allo-HSCT were enrolled in this prospective study. Forty-one patients with IPA were in stable and 22 patients were in active state at the time of transplant. SAP was given from the start of the conditioning until 90 days after transplantation for patients in stable state or until eradication of residual foci for patients in active state. The same agent was given for SAP if patients developed acute GVHD and treated with corticosteroids. The agents of SAP included Itraconazole in 16, Vorinazole in 30, Caspofungin in 12 and Amphotericin B in 5 cases. In addition, surgery was performed in 3 patients who had the cavity lesion of more than 2cm diameter in lung before HSCT. Results The median time of SAP was 96 days (range, 13 to 183). None of the patients was interrupted prophylaxis due to event of intolerance. At a median follow-up period of 260 days (range, 13–2010), 22 patients (34.9%) occurred the relapse of IPA, including 11 (17.5%) occurred SAP failure. Two-year cumulative incidence of IPA relapse was 42.8%±7.3%. The incidence of SAP failure was similar between the patients with active IPA and stable IPA (26.9% vs. 12.4%; P=0.174). The rates of SAP failure were not different between the different antifungal agents. Multivariate analyses showed II to IV aGVHD was the risk factor of SAP failure (RR= 14.4, 95%CI 3.011–68.864, P=0.001). None of the 3 patients underwent surgery occurred IPA relapse. And 3 patients with the cavity lesion of more than 2cm diameter in lung not received surgery all occurred IPA after HSCT including one died of hemoptysis. All the patients occurred IPA relapse received the salvage therapy for IFI. Seven patients achieved CR, 11 achieved PR and 4 patients had no response to the treatment. Six patients occurred IFI-related mortality including 3 cases in active state and 3 in stable state. At the end of follow-up, 26 patients were alive, 20 patients die of leukemia relapse and 17 died of transplant-related mortality. Five-year overall survival (OS) and disease-free survival (DFS) were 38.0% and 34.0%, respectively. OS and DFS were similar between active patients and stable patients. Conclusions The results suggest that active fungal infection is not a contraindication for allo-HSCT. It appears to be safe and effective to choose the antifungal agent for second prophylaxis based on treatment response of initial antifungal therapy. Disclosures: No relevant conflicts of interest to declare.

Antifungal Therapy in Neutropenic Oncohemopatic Patients. A Single Centre Retrospective Analysis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5334-5334
Author(s):  
Alessandro Bonini ◽  
Alessia Tieghi ◽  
Simona Bulgarelli ◽  
Luigi Gugliotta
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Renal Insufficiency ◽  
Acute Leukemia ◽  
Fungal Infection ◽  
Amphotericin B ◽  
Antifungal Therapy ◽  
Secondary Prophylaxis ◽  
Antifungal Treatment ◽  
Empiric Treatment

Abstract Infections are the most frequent complication during chemotherapy-induced neutropenia and fungal infections are a cause of morbility and mortality. We have retrospectively analysed our patients who received an antifungal treatment for a possible, probable or proven fungal infection. Between April 1998 and July 2005 we analysed 750 consecutive phases of treatment for 309 patients admitted at our Institution. The treatment phases were for: acute leukemia 253, lymphoma 168, multiple myeloma 215, chronic leukemia 19, severe aplastic anemia 12, solid tumors (breast, renal, testis cancer) 44, multiple sclerosis 5, others 34. Among them 474 (63.2%) were at high risk for infections (the risk was considered high for lenght of neutropenia, diagnosis of acute leukemia, allogeneic BMT). There were 31 allo-BMT and 145 autologous BMT. The antifungal therapy was for a first short period (until mid-1999) an empirical treatment (when fever persisted more than 4 days despite antibiotic therapy during neutropenia); after, only when another sign (clinical or radiological or microbiological) of fungal infection was present, the patients received an antifungal treatment. We treated also a small cohort of patients with a secondary prophylactic regimen (they were patients who developed a fungal infection during a previous treatment). Seventy-four patients received an antifungal treatment (10% of all phases and 15.6% of high-risk phases). The infection was possible (empiric treatment) in 4 cases, probable (presumptive therapy) in 37 cases, proven in 16 cases; 17 cases of secondary prophylaxis. The first administered drug was Amphotericin B deoxycholate (AMB) in 31/74 cases (41.9%), Abelcet (ABCT) in 6/74 (8%), Liposomal Amphotericin B (LAMB) in 18/74 cases (24.4%), Voriconazole (VCZ) in 3/74 cases (4%) and Caspofungin (Caspo) in 16/74 cases (21.7%). The schedule of treatment was: AMB 0.7–1 mg/Kg in 6 hours, ABCT 5 mg/Kg in 3 hours, LAMB 3 mg/Kg in 1 hour, VCZ 6 mg/Kg bid iv in 2 hours for 3 days then 4 mg/Kg bid orally, Caspo 70 mg iv on the first day and then 50 mg in 1 hour. For the empiric treatment the first drug was AMB 3 and Caspo 1; for presumptive therapy AMB 18, ABCT 4, LAMB 4, VCZ 1 and Caspo 10. For proven infections AMB 8, ABCT 1, LAMB 5, VCZ 1, Caspo 1; for secondary prophylaxis AMB 2, ABCT 1, LAMB 9, VCZ 1 and Caspo 4. The isolated fungi were Candida albicans 4, Aspergillus spp 4, Scedosporium 2, Fusarium solani 1, others (only histological isolation) 5. The days of treatment were 7.64 for AMB, 6.88 for ABCT, 14.22 for l-AMB, 14.1 for Caspo and 30 for VCZ. Adverse events with AMB and ABCT were similar: mild to moderate renal insufficiency (50%), fever (50%), ipokalemia (75%), chills (30%); with VCZ visual disturbances (80%) and mild hepatic insufficiency (20%); with LAMB mild renal insufficiency (10%) and low back pain (5%); no adverse events with Caspo were noted. AMB was discontinued 9/31 times (29%), ABCT 1/6 (17%) for adverse events. Our conclusions are that AMB and ABCT are problematic drugs for their poor tolerability, they need an important premedication, a hyperhydration regimen and a long-time administration; moreover for a great cohort of patients we have had to discontinue the drug. The other drugs seems to be better tolerated; no organ failures were seen and the treatment duration was longer for Caspo and LAMB. Even if the cost of these two drugs is major than others the lack of adverse events and the new mechanism of action of Caspo make these drugs probably better than ABCT, AMB and VCZ.

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.

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.

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