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.

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 Empirical versus Preemptive Antifungal Therapy for High‐Risk, Febrile, Neutropenic Patients: A Randomized, Controlled Trial

2009 ◽  
Vol 48 (8) ◽  
pp. 1042-1051 ◽  
Author(s):  
Catherine Cordonnier ◽  
Cécile Pautas ◽  
Sébastien Maury ◽  
Anne Vekhoff ◽  
Hassan Farhat ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
High Risk ◽  
Antifungal Therapy ◽  
Controlled Trial ◽  
Randomized Controlled ◽  
Neutropenic Patients

scholarly journals A Randomized Placebo-Controlled Phase 2 Study of Metformin for the Prevention of Progression of Monoclonal Gammopathy of Undetermined Significance and Low Risk Smoldering Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1659-1659
Author(s):  
Catherine R. Marinac ◽  
Robert A. Redd ◽  
Julia Prescott ◽  
Alexandra Savell ◽  
Courtney Igne ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Monoclonal Gammopathy ◽  
Research Funding ◽  
Controlled Trial ◽  
Low Risk ◽  
M Protein ◽  
Advisory Committees ◽  
Randomized Controlled ◽  
Bone Marrow Plasma

Abstract Background: Multiple Myeloma (MM) is thought to evolve from the precursor conditions monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), which are common premalignant disorders that progress to overt MM in a subset of individuals for reasons that are poorly understood. Despite increasing interest in preventing disease progression in this patient population, the standard of care still consists of close surveillance until progression to MM; however, once MM develops it cannot be cured. Therefore, the identification of prevention and interception strategies for patients with MGUS and SMM is of considerable importance. A promising pharmacologic intervention to reduce the risk of progression of MGUS/SMM to MM is metformin, a drug commonly used to treat type 2 diabetes but that is also considered safe for use in non-diabetic populations. In vivo and in vitro studies have revealed that metformin has direct antitumor effects across a variety of cancers including MM, and recent epidemiological data suggests it may reduce the risk of MM in diabetic patients with MGUS. Here, we describe the first randomized controlled trial testing the efficacy of metformin in reducing clinical signs of disease progression in patients with MGUS and SMM (NCT04850846). Study Design and Methods: This is a phase II single center, randomized controlled trial of metformin vs. placebo in patients with high-risk MGUS and low-risk SMM. The primary objective of the study is to determine whether metformin can reduce or stabilize serum monoclonal (M-)protein concentrations from baseline to 6-months. Exploratory objectives include mass spectrometry quantification of M-protein, examination of molecular evolution of tumor cells in response to metformin, as well as changes in other clinical laboratory parameters in response to metformin. To be eligible, patients must have high-risk MGUS or low-risk SMM. High-risk MGUS is defined as bone marrow plasma cell concentration &lt;10% with one or more of the following higher-risk features: serum M-protein level ≥1.5 g/dL to &lt;3 g/dL or abnormal free light-chain (FLC) ratio (&lt;0.26 or&gt;1.65); a forthcoming amendment will include non-IgG subtype as an additional high-risk feature. Low-risk SMM is defined as bone marrow plasma cells ≥10%with the absence of any features of high-risk SMM. Metformin and its corresponding placebo are the pharmacological treatments. The metformin dose is 1500 milligrams/day, provided in 500 milligram pills. To minimize gastrointestinal symptoms, metformin is started at a low dose of 500 milligram (1 pill) per day and participants gradually increase the dosage over the course of the first month of treatment until the full 1500 milligram (3 pill) per day regimen is achieved. The study treatment period is 6 months, with primary outcomes assessed at the end of the 6-month treatment period. Conclusions and Future Directions: While the cornerstone of clinical management in MGUS and SMM is to delay therapy until progression to symptomatic MM, patients and oncologists continually seek new ways to prevent end organ damage and incurable malignancy. This trial is positioned to provide preliminary but robust mechanistic data to support the development of novel prevention strategies for MGUS and SMM patients. Disclosures Marinac: GRAIL Inc: Research Funding; JBF Legal: Consultancy. Sperling: Adaptive: Consultancy. Parnes: Sigilon: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; UniQure: Membership on an entity's Board of Directors or advisory committees; Sunovion: Consultancy; I-mAb: Consultancy; Aspa: Consultancy; Genentech/Hoffman LaRoche: Research Funding; Shire/Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson: Protocol Intelligence: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; AstraZeneca: Consultancy; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: metformin, which is an anti-diabetic medication

Prognostic Factors of Infections and Effect of Primary Anti-Infectious Prophylaxis in MDS Patients Treated with Azacitidine (AZA): A Prospective Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1917-1917
Author(s):  
Marie Sebert ◽  
Claire Aguilar ◽  
Sylvie Chevret ◽  
Lionel Ades ◽  
Olivier Lortholary ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Fungal Infection ◽  
Predictive Factors ◽  
Invasive Fungal Infection ◽  
Research Funding ◽  
Pulmonary Infection ◽  
Influenza B ◽  
Fatal Infection

Abstract Background: Hypomethylating agents, especially AZA, have become the reference first line treatment of high-risk MDS. Myelosupression, although less important than with chemotherapy, is however observed, leading to potentially life threatening infections. A retrospective study found unfavorable (unfav) cytogenetics and low platelet counts to be predictive factors of infections in high risk MDS and AML patients (pts) receiving AZA (Merkel and al, Am j Hemat 2012). However, prognostic factors of infections, and whether infection prophylaxis would be useful in this situation, has not been prospectively evaluated. Methods: Between June 2011 and March 2013, 120 high-risk MDS pts were included in a randomized phase II trial seeking the most promising drug association with AZA by comparison with AZA alone in higher risk MDS (including AML with 20 to 30% marrow blasts and CMML with > 10% marrow blasts) (NCT01342692). Pts received AZA (75mg/m²/dx7d every 4 weeks) alone (N=40), with Valproic acid (N=40) or with Lenalidomide (N=40) (10mg/dx14d every 4 weeks). G-CSF was not used. Infectious events (IE) (diagnosed as such by the treating physician), hospitalizations for sepsis and pts receiving antimicrobial prophylaxis were reported at each cycle. Predictive factors of the occurrence of IE were analyzed. Results: 75 (62.5%) pts developed 259 IE, including 61 requiring hospitalization in 46 pts (61.3% of infected patients). The number of IE and of infected patients were similar in the 3 study arms. 39 pts died during the study, 12 of them because of infection, none of whom had responded to AZA (4 progressions, 4 failures and 4 deaths before evaluation). IE were more common during the first two cycles of therapy, with 86 (31.3%), 52 (23.5%) 45 (18.9%), 26 (15%), 15(19.2%) and 24 (19.7%) IE during cycles 1, 2, 3, 4, 5, and 6, respectively. Fever of unknown origin (FUO) (39.6%) and pneumonia (28.8%) were the most common type of infections followed by ENT (9.9%), urinary tract (8.1%), skin (5.4%), dental (4.5%) and intra-abdominal (3.6%). 6,3% were bacteriemia. Among the 26 microbiologically documented IE, 13 were CG+ (4 staph aureus, 4 enteroccus species, 4 coag neg staph and 1 other), 9 were BG- (6 E Coli, 1 pseudomonas and 2 others) and 3 were viral (HSV1, influenza B, Hepatitis E) and only one patient had documented invasive fungal infection (asp fumigatus). Overall, 23 (19%), 22 (18%), 10(8%) pts received bacterial (Levofloxacine), fungal (posaconazole) and viral (Valaciclovir) prophylaxis resp. Predictive factors of IE were unfav karyotype (79.5% infections vs. 50.8% in pts with fav or int karyotype; p=0.005) and platelets (PLT) < 20 G/L (92.3% infections vs. 58.9% for platelets > 20 G/L; p=0.03). In multivariate analysis, only unfav karyotype was predictive of IE (p=0.01). Other baseline parameters (including ANC, IPSS, age, sex, Hb level, and BM blast %) and bacterial, fungal or viral prophylaxis had no significant predictive value on the occurrence of IE. In multivariate analysis, predictive factors of pulmonary infection were anemia at baseline (p=0.04) and unfav karyotype (p<0.001), while prophylaxis had no significant impact. Infected pts had significantly more hospitalizations and deaths than non-infected pts (p<0.0001 and p=0.028 resp.). In multivariate analysis, unfav karyotype (p<0.001) and PLT <20 G/L (p=0.05) were significantly predictive of hospitalization for infection, while baseline Hb <10g/dL (p=0.02), and unfav karyotype (p=0.03) were predictors of fatal infection. Conclusion: 62.5% of the 120 pts developed infections during AZA treatment, mainly during the first 2 cycles, and 10% of the pts died from infection. Only one invasive fungal infection was documented. Unfav karyotype was strongly predictive of IE, hospitalization for infection and fatal infections. Other significant predictive factors were baseline anemia for pulmonary infection and fatal infection, and thrombocytopenia for hospitalization for infection, while ANC was not a significant factor. Moreover, prophylaxis was not associated with a decrease of IE in our study, but the small number of pts who received it precludes any conclusion. Disclosures Ades: celgene: Research Funding; Novartis: Research Funding. Fenaux:Novartis: Research Funding; celgene: Research Funding; Janssen: Research Funding.

Evidence-based approach to treatment of febrile neutropenia in hematologic malignancies

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 414-422 ◽  
Author(s):  
Juan Gea-Banacloche
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Fungal Infection ◽  
Antifungal Therapy ◽  
Antibacterial Prophylaxis ◽  
Evidence Based ◽  
Beta Lactam ◽  
Health Care Environment ◽  
Serological Tests ◽  
Persistent Fever

Abstract Applying the principles of evidence-based medicine to febrile neutropenia (FN) results in a more limited set of practices than expected. Hundreds of studies over the last 4 decades have produced evidence to support the following: (1) risk stratification allows the identification of a subset of patients who may be safely managed as outpatients given the right health care environment; (2) antibacterial prophylaxis for high-risk patients who remain neutropenic for ≥ 7 days prevents infections and decreases mortality; (3) the empirical management of febrile neutropenia with a single antipseudomonal beta-lactam results in the same outcome and less toxicity than combination therapy using aminoglycosides; (4) vancomycin should not be used routinely empirically either as part of the initial regimen or for persistent fever, but rather should be added when a pathogen that requires its use is isolated; (5) empirical antifungal therapy should be added after 4 days of persistent fever in patients at high risk for invasive fungal infection (IFI); the details of the characterization as high risk and the choice of agent remain debatable; and (6) preemptive antifungal therapy in which the initiation of antifungals is postponed and triggered by the presence, in addition to fever, of other clinical findings, computed tomography (CT) results, and serological tests for fungal infection is an acceptable strategy in a subset of patients. Many practical management questions remain unaddressed.

Sign in / Sign up

Export Citation Format

Share Document