Posaconazole at Standard Dose Is Safe and More Effective Than Echinocandins As IFD Prophylaxis in Patients with FLT3 Mutated AML Treated with Midostaurin

Introduction. The potential drug-drug interactions of midostaurin (M), particularly with CYP450 inhibitors, may impact the choice of antifungal (AF) prophylaxis and treatment in FLT3-positive (FLT3+) acute myeloid leukemia (AML) patients (pts). However, there are no supportive data to guide the choice of AF drugs in this subset of pts. Aim. To evaluate the incidence of invasive fungal diseases (IFD) during induction and consolidation treatment of FLT3+ AML pts and to correlate it to the different AF prophylaxis strategies adopted. Patients and Methods. Within the SEIFEM (Sorveglianza Epidemiologica Infezioni nelle Emopatie) Group, we planned a restrospective/prospective multicenter observational study enrolling all FLT3+ AML pts treated with chemotherapy (CHT)+M. IFD were classified as possible, probable and proven according to EORTC/MSG revised definitions (Donnelly JP et al, Clin Infect Dis 2020). Relationships between the type of AF prophylaxis, IFD development and AML outcome were evaluated. Results. As of 30 th June, 90 pts treated with CHT+M as induction/reinduction, consolidation or both, have been enrolled. M/F ratio was 35/55, median age 56y (range 18-78). FLT-ITD and FLT3-TKD mutations were detected in 73 and 17 pts, respectively, NPM-1 mutation in 51 (57%) pts. AML risk stratification according to ELN classification was available in 80 pts (24 low risk). A total of 216 CHT+M courses have been delivered (85 inductions, 8 reinductions and 135 consolidations). Overall, 25 IFD were reported: 19 during induction (22%), 2 during reinduction (25%) and 4 during consolidation (3%) given without AF prophylaxis in all the four. Sixty-five (72%) pts achieved complete remission (CR) after the induction. During induction, 11 pts did not receive mold-active AF prophylaxis and developed 4 (36%) IFD (3 possible and 1 probable aspergillosis), while 74 pts received mold-active AF prophylaxis and developed 15 (20%) IFD (8 possible and 4 probable aspergillosis, 3 candidemia). Incidence according to mold-active AF prophylaxis strategy was: 7/40 (17%) with posaconazole 300 mg/d, 5/13 (38%) with echinocandins (micafungin 50 mg/d or caspofungin 70>50 mg/d), 2/17 (12%) with posaconazole given for 7 days followed by micafungin or caspofungin, 1/2 with isavuconazole 200 mg/d, and 0/2 with L-AmB 50 mg every other day). A posaconazole-containing AF prophylaxis regimen was protective against IFD (9/57, 16%, vs 10/28, 36%, p=0.05), while a trend toward a higher incidence of IFD was observed in pts receiving echinocandins alone as AF prophylaxis (5/13, 38%, vs 14/72, 19%, p=0.15). IFD were more frequent in pts aged 60y or older (11/31, 35%, vs 8/54, 15%, p=0.034), while no correlations between IFD and gender, ELN classification, failure to achieve CR were observed. At multivariate analysis, age≥60y was confirmed as a risk factor for IFD (OR 3.021, CI 1.028-8.849), while receiving AF prophylaxis without posaconazole was of borderline significance (OR 2.817, CI 0.955-8.306). Three pts out of 40 on posaconazole prophylaxis received reduced dose of M (50 mg/d). M was discontinued in 12 pts during induction; of these, 6 (50%) did not achieve a CR. IFD was the main reason for M discontinuation in 6 pts; in the other 6, toxicity was responsible (QTc prolongation in 3, 1 during caspofungin, 1 during posaconazole and 1 out of AF prophylaxis; gastrointestinal toxicity in 2, 1 during posaconazole and 1 during caspofungin prophylaxis; liver toxicity in 1, during posaconazole prophylaxis). After a median follow-up of 5 months, overall survival (OS) was similar in pts with or without IFD (p=0.294), while in those not achieving CR after first induction it was significantly lower in pts developing IFD (p=0.03) (Fig. 1A and 1B). Conclusions. IFD is still a frequent complication during AML induction treatment, also in patients receiving AF prophylaxis; it is associated with a frequent discontinuation of M and to a worsening of OS in patients not in CR after the first induction, probably contributing to a delay in the appropriate timing of the AML treatment. A posaconazole-containing prophylaxis was a better strategy against IFD occurrence, compared to echinocandins alone. M discontinuation for toxicity was a relatively rare event and no specific relationship with the type of AF prophylaxis ongoing was observed. A study evaluating plasma M levels during different prophylaxis strategies adopted is ongoing within the SEIFEM group. Figure 1 Figure 1. Disclosures Fracchiolla: Gilead: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rossi: Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Pagano: Gilead Sciences, MSD, Pfizer Pharmaceuticals, Astellas Pharma: Speakers Bureau; Gilead Science, MSD, Pfizer, Basilea, Janssen, Novartis, Jazz Pharmaceutical, Cidara: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy.

The Impact of Revised Definitions for TACO and TRALI on Hemovigilance Reporting

Introduction Transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) are serious adverse transfusion reactions. Standardized surveillance definitions are important to ensure consistent and accurate reporting of cases. Recently, revised definitions have been developed for both TACO and TRALI, the latter which have not yet been widely implemented. The primary aim of this study is to assess the impact of the new TACO and TRALI definitions on hemovigilance reporting. The secondary aim is to collate a TRALI case series to describe the epidemiological and laboratory features of this uncommon condition. Methods The Australian Red Cross Lifeblood Adverse Transfusion Reaction database, a passive reporting system, was accessed to identify all cases of suspected or confirmed TACO and TRALI referred from 1 July 2015 to 30 June 2019. Cases were assessed against both the former and new definitions of TACO and TRALI and results compared. For confirmed cases of TRALI the following information was collected: patient demographics, antibody investigation results, type and age of products implicated, donor gender and donor outcomes. Statistical analysis was performed using Fisher's exact test. Results In total 99 cases were identified, of which 12 cases were excluded from analysis due to insufficient clinical details. A further 14 cases were excluded as they were deemed not to be transfusion related. The final number of cases assessed was 73. There were 48 TACO cases identified. Only 26 cases strictly met the former 2011 International Society of Blood Transfusion (ISBT) definition of TACO; 6 cases did not meet the definition and 16 cases lacked sufficient clinical details due to the passive nature of the reporting system. In comparison, 46 cases met the revised 2018 ISBT definition, with only 2 cases having insufficient details. There were 24 cases of TRALI according to the 2004 Canadian Consensus Conference (CCC) definition compared with 25 cases according to the proposed 2019 revised definition. Of the 24 cases of TRALI, 15 were classified as TRALI and 9 as possible TRALI. One case was excluded from having TRALI or possible TRALI under the 2004 CCC definition as the patient had pre-existing acute respiratory distress syndrome from influenza A pneumonia, but could be diagnosed as a TRALI Type II under the revised definition as their respiratory status had been stable for more than 12 hours. A total of 62 components from 81 donors were associated with the 24 TRALI cases. Forty-nine (60%) of these donors were male, 31 (38%) female and 1 (1%) unknown (cadaveric liver). Thirty-three (41%) of these donors were deferred due to the presence of HLA antibodies or being the only donor associated with a case. Sixteen cases (67%) were associated with donor antibodies, most commonly HLA class I and HLA class II antibodies that were non-recipient specific. HNA antibodies were present in 3 cases. There were 8 cases in which an HLA or HNA antibody was not implicated. There was no difference in antibody detection rates between low plasma volume components (red cells, pooled platelets and cryoprecipitate) and high plasma volume components (fresh frozen plasma and apheresis platelets) (45% versus 34%, p=0.44). There was a trend towards higher antibody detection rates in female donors (46%) compared with male donors (29%), however this was not statistically significant (p=0.10). Conclusions The revised TACO definition appears to capture more cases than the former definition. There appears to be no significant difference in the number of TRALI cases under the proposed new definition compared to the definition currently in use. This is the first study to provide validation data for the revised TRALI definition. TRALI is a rare condition and further studies such as these are required to improve our understanding of its pathophysiology and laboratory findings. Disclosures No relevant conflicts of interest to declare.

Threat Intelligence Quality Dimensions for Research and Practice

As the adoption and diversity of cyber threat intelligence solutions continue to grow, questions about their effectiveness, particularly in regards to the quality of the data they provide, remain unanswered. Several studies have highlighted data quality issues as one of the most common barriers to effective threat intelligence sharing. Nevertheless, research and practice lack a common understanding of the expected quality of threat intelligence. To investigate these issues, our research utilised a systematic literature review followed by a modified Delphi study that involved 30 threat intelligence experts in Europe. We identify a set of threat intelligence quality dimensions along with revised definitions for threat data, information and intelligence.

Impact of Changes of the 2020 Consensus Definitions of Invasive Aspergillosis on Clinical Trial Design: Unintended Consequences for Prevention Trials?

Background Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials. Methods In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria. Results Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1–105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially. Conclusions The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies.

Redefining outcomes in immune TTP: an international working group consensus report

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission, and relapse were initially proposed in 2003 and modified by the International Working Group for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects on the platelet count of caplacizumab, a novel anti–von Willebrand factor (VWF) nanobody. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy, by using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE but also that of anti-VWF therapy. Retrospective validation of the revised definitions is described, although they have yet to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided to highlight their clinical relevance.

EORTC/MSGERC Definitions of Invasive Fungal Diseases: Summary of Activities of the Intensive Care Unit Working Group

The EORTC/MSGERC recently revised and updated the consensus definitions of invasive fungal disease (IFD). These definitions primarily focus on patients with cancer and stem cell or solid-organ transplant patients. They may therefore not be suitable for intensive care unit (ICU) patients. More in detail, while the definition of proven IFD applies to a broad range of hosts, the categories of probable and possible IFD were primarily designed for classical immunocompromised hosts and may therefore not be ideal for other populations. Moreover, the scope of the possible category of IFD has been diminished in the recently revised definitions for classically immunocompromised hosts. Diagnosis of IFD in the ICU presents many challenges, which are different for invasive candidiasis and for invasive aspergillosis. The aim of this article is to review progresses made in recent years and difficulties remaining in the development of definitions applicable in the ICU setting.