Mold-active Prophylaxis Research Articles

Is there still a place for serum galactomannan in the diagnosis of invasive aspergillosis in children at high risk and under antifungal prophylaxis?

The performance of serum galactomannan (GM) for the diagnosis of invasive aspergillosis (IA) has been studied mainly in adults. Paediatric data are scarce and based on small and heterogeneous cohorts. To evaluate the performance of serum GM for the diagnosis of IA in a paediatric oncologic population at high risk of IA and to clarify the impact of antifungal prophylaxis on this test. We performed a retrospective study from January 2014 to December 2020 in the paediatric oncologic haematologic department of the University Hospital of Bordeaux. The diagnosis of IA was made using the recommendations of the EORTC and the MSGERC. Among the 329 periods at high risk of IA in 222 patients, the prevalence of IA was 1.8% (3 proven and 3 probable IA). In the total population, the sensitivity, and the positive predictive value (PPV) were respectively 50% and 17.6%. Under antifungal prophylaxis, the sensitivity and PPV dropped, respectively, to 33.3% and 14.3%. In this group, the post-test probability of IA was 2% for a negative serum GM and only 14%. In this large cohort of children at high risk of IA, the incidence of IA is low and the diagnostic performance of GM is poor, especially in the case of mould-active prophylaxis. Screening should be targeted rather than systematic and should be reserved for patients at highest risk for IA without mould-active prophylaxis. Combination with other tests such as Aspergillus PCR would increase the accuracy of GM in screening setting.

Coadministration of isavuconazole and sirolimus in allogeneic hematopoietic stem cell transplant recipients.

Invasive fungal infections (IFIs) represent a major cause of morbidity among allogeneic hematopoietic stem cell transplantation (allo-HSCT). Isavuconazole (ISA) is a broad-spectrum triazole with favorable safety profile. Herein, we evaluate the real life coadministration of ISA and sirolimus in allo-HSCT recipients in a single-center retrospective analysis, describing clinical efficacy, safety, and therapeutic drug monitoring (TDM) of both drugs. All consecutive allo-HSCT recipients who received the coadministration of ISA and sirolimus for at least 2 weeks between July 2017 and December 2022 were included in this retrospective analysis. TDM was longitudinally performed during treatment. IFIs were classified according to the revised European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus criteria. A total of 51 recipients were included in the analysis. A total of 17 patients received ISA as continuous antifungal treatment for IFI diagnosed before transplant: one patient experienced a probable invasive pulmonary aspergillosis, and one patient switched from ISA to liposomal amphotericin B for a possible IFI. A total of 34 patients started ISA as antifungal therapy for IFI diagnosed after transplant. Sixteen of 34 were treated for a proven/probable breakthrough IFI during mold-active prophylaxis: 6/16 patients died for IFI after a median of 51 days of ISA. Eighteen of 34 started ISA as empirical therapy for a possible IFI: 15/18 patients were alive with resolution of infection after 6 weeks, 1 died for disease progression, and 2 had empirically changed antifungal therapy due to pneumonia progression. Clinical and radiological response rate was 68% after 90 days from IFI diagnosis. No toxicities related to drug-drug interaction have been registered in patients reaching concomitant therapeutic levels of ISA and sirolimus. The coadministration of ISA and sirolimus was safe and feasible in this cohort, confirming favorable clinical efficacy in patients with multiple-drug coadministration.

Clinical presentation and outcome of invasive mould disease in paediatric patients with acute lymphoblastic leukaemia

BackgroundChildhood acute lymphoblastic leukaemia (ALL) cure rates have improved, but invasive mould disease (IMD) remains a life-threatening complication. Here, we evaluate the epidemiology, clinical presentation, treatment and outcome of IMD in paediatric patients with ALL. MethodsPatients (1–18 years) treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol from 2012–2021 were analysed for probable and proven IMD. Data was extracted from the Dutch national registry and the electronic health care system. ResultsAmong 643 patients with ALL, 47 (7.3%) were diagnosed with a probable (n = 29) or proven (n = 18) IMD. Aspergillosis was diagnosed in 42 (89%) patients. Forty-one episodes (87%) occurred during the induction (n = 20) and first consolidation (n = 21) course. The median age at ALL diagnosis was 5 years [IQR 3–10] in the overall group versus 14 years [IQR 7–16] in the IMD group. Two-third of the patients did not receive mould-active prophylaxis. The most prevalent clinical symptoms at presentation were persistent fever and respiratory symptoms. The lungs were the most common site of infection with involvement in 44 (94%) patients, followed by the CNS in 16 (34%) patients. The 6-week and 12-week mortality rate after IMD diagnosis was 10.6% and 14.9%, respectively. Discussion and conclusionIn our paediatric cohort a notable incidence of probable and proven IMD was observed during the early stages of treatment. Remarkable is the high frequency of CNS involvement. These findings highlight the importance of effective prophylactic strategies and warrant early brain imaging.

Optimizing antimicrobial prophylaxis strategies in acute leukemia patients: Assessing the efficacy of fluconazole

Background Acute myeloid (AML) and promyelocytic (APL) leukemia patients are at high risk for infection and mortality. While guidance for infection prevention is provided by the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO), each institution may vary in antimicrobial prophylaxis prescribing practices. The discrepancy may be explained by medication intolerance, cost, and low incidence of mold infections in leukemia patients. A recent meta-analysis demonstrated mortality benefits with the use of posaconazole, which was adopted by the NCCN. Despite known risks, it is unclear whether universal mold-active coverage is indicated for all AML and APL patients. Objective To assess the incidence of breakthrough infections in AML and APL patients. Methods This was a single-center, retrospective chart review of AML and APL patients receiving induction therapy at Baylor St Luke's Medical Center (BSLMC) between January 2019 and October 2021. The primary outcome assessed the incidence of breakthrough infections. Descriptive statistics were used to summarize the data. Results A total of 55 patients were included and 54 (98%) had prolonged neutropenia with a median duration of 30 days. Five patients (9.3%) experienced breakthrough infections during induction while 21 individuals (38.9%) during the follow-up period. Aspergillus infections occurred in three patients receiving nonmold coverage compared to none on mold-active agents (p = 1.0) with no statistical difference in mortality. Conclusion Despite the majority of patients not receiving mold-active prophylaxis, nonmold-active prophylaxis may be sufficient with consideration of low aspergillosis incidence.

Invasive Fungal Infections in Children With Acute Myeloid Leukemia: A Single-center Experience Over 19 Years.

Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality in children with acute myeloid leukemia (AML). This study aimed to evaluate the incidence, risk factors, etiology, and outcome of IFIs in children with AML and the effect of mold-active antifungal prophylaxis. We retrospectively reviewed pediatric patients treated for AML between January 2004 and December 2022. Proven, probable, or possible IFIs were defined using standardized definitions of the European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) classification published at 2008. A total of 298 febrile neutropenia episodes from 78 patients were evaluated. Proven, probable, and possible IFI rates were 3%, 2.6%, and 9.4%, respectively. Profound neutropenia was detected in 18 (58%) and prolonged neutropenia in 20 (64.5%) of the IFI episodes.. Invasive aspergillosis accounted for the majority of IFI episodes; however, non-albicans Candida spp. were the most isolated pathogens in the proven group. Patients with relapsed AML were particularly at risk for the development of IFI ( P =0.02). A significant decrease in IFI episodes was achieved with mold-active antifungal prophylaxis with voriconazole ( P =0.01, odds ratio: 0.288, %95 CI:0.104-0.797). The overall mortality was 35.8%, and the IFI-attributable mortality rate was 25%. In the multivariate analysis, relapsed disease was the most significant risk factor associated with mortality ( P =0.006, odds ratio:4.745; 95% CI: 1.573-14.316). Mold-active prophylaxis reduced the rate of IFIs in this cohort however IFI-related mortality was still high as 25% in pediatric AML patients. Relapsed AML was the most significant risk factor associated with mortality.

Invasive fungal infections after CLAG-M/CLAG chemotherapy for acute myeloid leukemia and high-grade myeloid neoplasms.

CLAG-M (cladribine, high-dose cytarabine [HiDAC], G-CSF, mitoxantrone)/CLAG are contemporary intensive chemotherapy regimens associated with higher and deeper complete remission rates than 7+3 (cytarabine, anthracycline)/HiDAC, but with greater myelosuppression and potential infection risks. Here, we compared the cumulative incidence (CI) and patterns of invasive fungal disease (IFD) between these regimens by identifying proven/probable and possible cases of IFD following CLAG-M (n=332) and 7+3 (n=115) chemotherapy and subsequent treatment cycles in adults ≥18 years old with newly diagnosed (ND) or relapsed/refractory (R/R) AML or other high-grade myeloid neoplasms between 2006 and 2018. By 90 days (D90) after initiating treatment, the CI of proven/probable IFD was 20% with CLAG-M and 12% with 7+3 (p=0.17). There was no significant difference in the CI of IFD between ND CLAG-M and R/R CLAG-M. Without mold-active prophylaxis, the D90 CI of proven/probable IFD was significantly higher in the CLAG-M than the 7+3 cohort (28% versus 11%; p=0.007), but this difference was mitigated with mold-active prophylaxis (CLAG-M, 7.5%; 7+3, 0%; p=0.65). After each chemotherapy treatment cycle, the CI of newly diagnosed IFD was similar, ranging from 15-20%. Use of mold-active prophylaxis was the only factor associated with reduced IFD risk in adjusted models (HR, 0.32; 95% confidence interval, 0.18-0.56). Together, these data indicate that the IFD risk with CLAG-M is higher than with 7+3 in the absence of mold-active prophylaxis; use of mold-active prophylaxis mitigates this risk.

Primary prophylaxis of invasive fungal diseases in patients with haematological malignancies: 2022 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).

Patients with haematological malignancies (HM) are at high risk of developing invasive fungal disease (IFD) with high morbidity and attributable mortality. We reviewed data published until September 2021 to update the 2017 antifungal prophylaxis recommendations of the German Society of Haematology and Medical Oncology (DGHO). The strong recommendation to administer antifungal prophylaxis in patients with HM with long-lasting neutropenia, i.e. <500 cells/μL for >7 days remains unchanged. Posaconazole remains the drug of choice for mould-active prophylaxis in these patients. Novel treatment options in HM, such as CAR-T-cell treatment or novel targeted therapies for acute myeloid leukaemia (AML) were considered, however, data are insufficient to give general recommendations for routine antifungal prophylaxis in these patients. Major changes regarding specific recommendations compared to the 2017 edition are the now moderate instead of mild support for the recommendations of isavuconazole and voriconazole. Furthermore, published evidence on micafungin allows recommending it at moderate strength for its use in HM. For the first time we included recommendations for non-pharmaceutical measures regarding IFD, comprising the use of high-efficiency particulate air (HEPA) filters, smoking, measures during construction work and neutropenic diets. We reviewed the impact of antifungal prophylaxis with triazoles on drug-drug interactions with novel targeted therapies that are metabolized via cytochrome p450 where triazoles inhibit CYP3A4/5. The working group recommends reducing the dose of venetoclax when used concomitantly with strong CYP3A4 inhibiting antifungals. Furthermore, we reviewed data on the prophylactic use of novel antifungal agents. Currently there is no evidence to support their use in a prophylactic setting in clinical practice.

2100. Epidemiology and Risk Factors for Invasive Fungal Infections Among Patients with Hematological Malignancies In Colombia

Abstract Background Invasive fungal infection (IFI) is a potentially lethal complication in patients with hematological malignancies (HM). However, studies are scarce in this population, especially in developing countries. The aim of this study was to investigate the prevalence, epidemiology, predictive factors, and outcomes of IFI in patients with HM hospitalized in non-HEPA-filtered rooms (resource-limited settings) in a reference center in Colombia. Methods A cross-sectional, retrospective study was conducted on the clinical data of HM patients and pulmonary infection hospitalized in a tertiary university hospital in Bucaramanga, Colombia, between 2015 and 2020. The primary outcome was proven/probable IFI according to the EORTC/MSGERC criteria. A descriptive and group comparison analysis were performed between patients with IFI and patients with non-fungal infections. The main risk factors for the development of IFI were identified by multivariate stepwise logistic regression analysis. Table 1Statistically significant variables in the univariate analysis of patient characteristics compared between patients with invasive fungal infection and patients with non-fungal infection.Image 1Associated factors to develop invasive fungal infections (IFIs) in patients with HM. The graph shows the variables showed statistically significant difference in the multivariate analysis. Results In 201 patients, the prevalence of proven/probable IFI was 21.39% (43 cases). The most common IFI was caused by Aspergillus spp. (41.8%), followed by Candida spp. (34.8%), Mucor spp. (6.9%), Penicillium spp. (4.6%) and Cryptococcus neoformans (4.6%). The lung was the most commonly affected site (n=34; 81.3%); four patients (9.3%) developed fungal sinusitis and disseminated IFI, respectively. In-hospital mortality was 86% (37/43). Multivariate logistic regression analysis (area under the ROC curve=0.90) showed that antibiotic use ≥3 weeks (OR, 4.11; 95% CI, 1.26-13.31; p&amp;lt; .001), history of pulmonary infection (OR, 5.75; 95% CI, 1.41-23.39; p&amp;lt; .001) and neutropenia duration ≥21 days (OR, 5.88; 95% CI, 1.26-19.86; p &amp;lt; .001) were independent risk factors for the development of IFI and mould-active prophylaxis (OR: 0.20; 95% CI: 0.060–0.705; p=0.012) was significantly associated with a lower occurrence of IFI. Conclusion HM patients in resource-limited settings have a high prevalence of IFI with an elevated mortality. The use of mould-active prophylaxis is associated with a significantly lower occurrence of IFI. Cost-effective strategies for prevention and early diagnosis of IFI are required to improve survival in patients with HM. Disclosures All Authors: No reported disclosures.

Management of Invasive Fungal Infections in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: The Turin Experience.

BackgroundAllogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are exposed to an increased risk of invasive fungal infections (IFIs) due to neutropenia, immunosuppressive treatments, graft-versus-host disease (GvHD) and incomplete immune reconstitution. Although clinical benefit from antifungal prophylaxis has been demonstrated, IFIs remain a leading cause of morbidity and mortality in these patients. In the last decades, attention has also been focused on potential risk factors for IFI to tailor an antifungal prevention strategy based on risk stratification.Aim of the StudyThis retrospective single-center study aimed to assess the epidemiology and the prognostic factors of IFI in a large cohort of allo-HSCT patients.MethodsBetween January 2004 and December 2020, 563 patients with hematological malignancies received an allo-HSCT at the Stem Cell Transplant Unit in Turin: 191 patients (34%) received grafts from a matched sibling donor, 284 (50.5%) from a matched unrelated donor, and 87 (15.5%) from an haploidentical family member. The graft source was peripheral blood in 81.5% of the patients. Our policy for antifungal prophylaxis included fluconazole in matched related and unrelated donors, while micafungin was administered in patients receiving haploidentical transplant. According to this practice, fluconazole was administered in 441 patients (79.6%) and micafungin in 62 (11.2%), while only 9 patients received mold-active prophylaxis. Galactomannan testing was routinely performed twice a week; patients with persisting fever unresponsive to broad spectrum antibiotics were evaluated with lung high-resolution computed tomography (HRCT) scan. In case of imaging suggestive of IFI, bronchoalveolar lavage (BAL) was performed whenever feasible.Statistical AnalysisOnly probable/proven IFI (PP-IFI) occurring during the first 12 months after transplant have been evaluated. IFIs were classified as probable or proven according to the new revised European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG) consensus criteria. Multivariate competing risk regression, binary logistic, and proportional hazard models were performed to identify risk factors for PP-IFI.ResultsA total of 58 PP-IFIs (n = 47 probable; n = 11 proven) occurred in our patients resulting in a cumulative incidence of 4.1%, 8.1%, and 9.6% at 30, 180, and 365 days, respectively. Molds were the predominant agents (n = 50 Aspergillus; n = 1 Mucor), followed by invasive candidemia (n = 5 non-albicans Candida; n = 1 Candida albicans; n = 1 Trichosporon). Lung was the most frequent site involved in patients with mold infections (47/51, 92.2%). Median time from HSCT to IFI was 98.44 days (0–365 days). Only 34.5% of patients with IFI were neutropenic at the time of infection. The presence of IFI had a significant impact on overall survival at 1 year (IFI, 32.8% vs. non-IFI, 54.6%; p < 0.001). IFI-related mortality rate was 20.7% in the overall population, 17% in patients with probable IFI, and 36% in patients with proven IFI. Multivariate competing risk regression revealed that donor type was the factor significantly associated to the risk of IFI [subdistribution hazard ratio (SDHR), 1.91, IC 1.13–3.20; p = 0.015]. BAL was informative in a consistent number of cases (36/57, 63.2%) leading to the identification of fungal (21), bacterial (4), viral (3), and polymicrobial (8) infections. Overall, 79 patients (14%) received a diagnostic-driven treatment, and 63 patients (11.2%) received a fever-driven treatment. Liposomal amphoteric B was the drug used in the majority of patients receiving diagnostic-driven therapy (30/79, 38%), while caspofungin was administered more frequently in patients who received a fever-driven strategy (27/63, 42.9%).ConclusionAccording to our experience, a non-mold active prophylaxis in patients undergoing allo-HSCT is feasible when combined with an intensive diagnostic work-up including CT scan and BAL. BAL performed at the onset of the disease may provide informative results in most patients. A diagnostic-driven treatment strategy may contribute to limit the use of costly antifungal therapies.

710. Comparison of Initial CXR to CT in Patients (pts) with Hematologic Malignancy (HEM) and Documented Symptomatic Pulmonary Mucormycosis (PM)

BackgroundThere is a spectrum of pulmonary disease burden in pts with HEM and PM. There have not been any data comparing the sensitivity and findings of initial Chest X-Ray (CXR) and chest CT in these pts.MethodsWe compared the findings of the initial CXR and CT in all pts with proven or probable PM via EORTC/MSG criteria. We included only pts who had pulmonary symptoms and who had both CXR and CT within 5 days of each other and within seven days of symptom onset or date of culture at MD Anderson Cancer Center from April 2000 and April 2020. We collected data regarding demographics, status of HEM, clinical presentation, frequency and findings of BAL and imaging findings, mold-active prophylaxis and treatment regimens, and mortality. CXR findings were classified as normal or abnormal, and if abnormal sub-classified as mass-like/consolidative, nodular, cavitary or heterogenous/non-specific. CT findings were classified in a similar manner. ResultsWe Identified such 39 pts with PM who had both CXR and CT within 5 d. All pts had positive CT. Five pts (13%) had a negative CXR. The majority of pts 28 (72%) were neutropenic (neutrophil count < 500). The most common CXR findings were consolidation or mass-like lesions (56%), followed by patchy, heterogenous or non-specific findings (33%) and nodules (13%). Only 3% had cavitary lesions. Similarly, consolidation or mass-like lesions were the most common finding on CT (69%), followed by nodular lesions with or without ground glass halos (56%). Cavitary lesions and/or reverse halo sign (RHS) were common (31%) on CT. Patients with normal CXR vs those with abnormal CXR were comparable in all clinical parameters we collected. The median survival from time of symptoms onset for all pts was 45 days. There was a trend for lower 42 day mortality in pts with normal CXR (20% vs 47%, P=.253). ConclusionA negative CXR does not preclude PM, especially in neutropenic pts. A CT is recommended for better sensitivity and although there was concordance in CXR with CT findings in some chest abnormalities (mass, consolidation), CT more commonly revealed nodules and signs highly suggestive of PM such as RHS. Although small numbers precluded a robust comparison, it is possible that HEM pts with PM and negative initial CXR have better prognosis, perhaps reflecting a lower burden of pulmonary involvement Disclosures Dimitrios P. Kontoyiannis, MD, Astellas (Consultant)Cidara Therapeutics (Advisor or Review Panel member)Gilead Sciences (Consultant, Grant/Research Support, Other Financial or Material Support, Honoraria)

Infectious Complications after Intensive Chemotherapy with CLAG-M or '7+3' for Adults with Acute Myeloid Leukemia and Other High-Grade Myeloid Neoplasms

IntroductionInfections cause substantial morbidity and mortality in patients with acute myeloid leukemia (AML) and other high-grade myeloid neoplasms. The contemporary regimen of CLAG-M (cladribine, high-dose cytarabine, G-CSF, mitoxantrone) has favorable hematologic outcomes compared to '7+3' (standard-dose cytarabine, anthracycline) in some studies but may be more myelosuppressive. The aim of this investigation was to determine and compare the incidence and spectrum of infections after CLAG-M and 7+3.MethodsFor this retrospective cohort study, we identified microbiologically documented moderate to severe infections (grade ≥2 infections; Blood and Marrow Transplant Clinical Trials Network Technical Manual of Procedures (BMT CTN MOP) guideline) after the first cycle of CLAG-M for newly-diagnosed (ND) or relapsed/refractory (R/R) AML or other high-grade myeloid neoplasms (≥10% blasts in marrow or peripheral blood) and compared these findings to adults receiving 7+3 for ND disease. We recorded infections for up to 90 days from the start of chemotherapy or until the start of a second cycle or death, whichever occurred first. We compared the cumulative incidence probability of time-to-first infection between cohorts using Gray's test with start of additional therapy and death as competing risk events. Infection rates, defined as average number of infections per 1000 patient days-at-risk, were compared between cohorts using Poisson regression.ResultsThe study included 442 individuals consisting of 196 with ND disease and 131 with R/R disease receiving CLAG-M, and 115 with ND disease receiving 7+3 (Table 1). Fifty-four (28%), 65 (50%), and 19 (17%) individuals per cohort had one or more moderate to severe microbiologically documented infection, respectively. The absolute neutrophil count was <500 cells/mm 3 at the time of each infection in 67 of 71 (94%), 82 of 86 (95%), and 27 of 27 (100%) infection events per cohort, respectively. Time to neutrophil recovery, defined as the first of three consecutive days with a neutrophil count ≥500 cells/mm 3, was shortest among individuals treated with CLAG-M for ND disease (Fig. 1). Among individuals with ND disease, overall infection rates tended to be higher in those receiving CLAG-M versus 7+3 but this trend did not reach statistical significance (Fig. 2). Individuals with R/R disease treated with CLAG-M had a significantly higher overall infection rate compared to those with ND disease, primarily driven by bacterial infections (Fig. 2). Similar patterns were observed in cumulative incidence curves of time-to-first infection (Fig. 3). First infections occurred a median of 11-13 days after start of treatment. The most frequent infections were bloodstream infections consisting of 37 (52%), 56 (65%), and 11 (41%) infection events per cohort, respectively, followed by respiratory tract infections (31 [44%], 27 [31%], and 10 [37%] infection events per cohort, respectively). Fungal infections were relatively frequent and similar between groups (Fig. 4), although mold-active prophylaxis was used more frequently in CLAG-M cohorts (44-53%) compared to the 7+3 cohort (7%). Individuals receiving mold-active prophylaxis had a lower incidence of proven and probable invasive fungal infections. Among individuals with ND disease not receiving mold-active prophylaxis, invasive fungal infections tended to be more common in the CLAG-M cohort than in the 7+3 cohort. Viral infections were uncommon. Among 29 patients (7%) who died during the study period, infection was a primary or contributing cause of death in 17 (59%).ConclusionsModerate to severe microbiologically documented infections are common after the first cycle of chemotherapy for ND or R/R AML or other high-grade myeloid neoplasms. CLAG-M may be associated with more moderate to severe microbiologically documented infections than 7+3 for ND disease. Individuals with R/R disease are at the highest risk. Invasive fungal infections were relatively frequent but may be significantly reduced by mold-active azole prophylaxis. New approaches to improve neutrophil recovery and function may reduce infection risk. [Display omitted] DisclosuresHalpern: Abbvie: Consultancy; Tolero Pharmaceuticals: Research Funding; Agios: Consultancy; Gilead: Research Funding; Agios Pharmaceuticals: Research Funding; Bayer: Research Funding; Novartis: Research Funding; Imago Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Nohla Therapeutics: Research Funding; Pfizer: Research Funding. Delaney: Deverra Therapeutics: Current Employment, Other: Founder, CSO. Pergam: Chimerix, Inc: Research Funding; Global Life Technologies, Inc: Research Funding; Merck & Co.: Research Funding; Sanofi Aventis: Research Funding. Boeckh: Merck: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; AlloVir: Consultancy; SymBio Pharmaceuticals: Consultancy; Helocyte: Consultancy; Evrys Bio: Consultancy; Moderna: Consultancy; GSK: Consultancy. Walter: BMS: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amphivena: Consultancy, Other: ownership interests; Selvita: Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Research Funding; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Hill: Gilead: Consultancy, Research Funding; Karius: Research Funding; Octapharma: Consultancy; Allovir: Consultancy, Research Funding; Amplyx: Consultancy; Takeda: Consultancy, Research Funding; Allogene therapeutics: Consultancy; CRISPR therapeutics: Consultancy; CLS Behring: Consultancy; OptumHealth: Consultancy.

Risk factors for invasive fungal infection in 5-azacytidine treated patients with acute myeloid leukemia and myelodysplastic syndrome.

The rate of invasive fungal infection (IFI) in patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) receiving 5-azacytidine is incompletely defined and published recommendations for mold-active fungal prophylaxis in such patients vary according to source. We performed a retrospective cohort study in order to identify contemporary IFI rates and infection-related mortality in relation to known risk factors and the use of antifungal prophylaxis. One hundred and seventeen patients receiving 5-azacytidine for MDS and low blast count AML were identified, of whom 71 (61%) received antifungal prophylaxis. The IFI rate was 7.7% across the entire cohort: 5.6% in those receiving prophylaxis vs 10.9% in the subgroup who did not (P=.30). The presence of neutropenia at three months of treatment was associated with increased IFI risk (hazard ratio [HR] 8.29; (95% confidence interval [CI)] 1.61-42.6; P=.01), and on multivariate analysis, IFI was independently associated with increased all-cause mortality risk (HR 8.37; 95% CI 3.67 - 19.11; P<.0001). These data further highlight the risk of IFI in this population and support the use of mold-active prophylaxis in neutropenic patients receiving 5-azacytidine for MDS and AML.

Cost-Effectiveness of Serum Galactomannan Surveillance during Mould-Active Antifungal Prophylaxis

Serial galactomannan (GM) monitoring can aid the diagnosis of invasive aspergillosis (IA) and optimise treatment decisions. However, widespread adoption of mould-active prophylaxis has reduced the incidence of IA and challenged its use. We evaluated the cost-effectiveness of prophylaxis-biomarker strategies. A Markov model simulating high-risk patients undergoing routine GM surveillance with mould-active versus non-mould-active prophylaxis was constructed. The incremental cost for each additional quality-adjusted life-year (QALY) gained over a lifetime horizon was calculated. In 40- and 60-year-old patients receiving mould-active prophylaxis coupled with routine GM surveillance, the total cost accrued was the lowest at SGD 11,227 (USD 8255) and SGD 9234 (USD 6790), respectively, along with higher QALYs gained (5.3272 and 1.1693). This strategy, being less costly and more effective, dominated mould-active prophylaxis with no GM monitoring or GM surveillance during non-mould-active prophylaxis. The prescription of empiric antifungal treatment was influential in the cost-effectiveness. When the GM test sensitivity was reduced from 80% to 30%, as might be anticipated with the use of mould-active prophylactic agents, the conclusion remained unchanged. The likelihood of GM surveillance with concurrent mould-active prophylaxis being cost-effective was 77%. Routine GM surveillance remained cost-effective during mould-active prophylaxis despite lower IA breakthroughs. Cost-saving from reduced empirical antifungal treatment was an important contributing factor.

Choice and duration of antifungal prophylaxis and treatment in high-risk haematology patients.

This review aims to summarize available guidelines as well as the emerging evidence for the prevention and treatment of invasive fungal diseases in high-risk haematology patients. Primary mould-active prophylaxis is the strategy used in many centres to manage the risk of invasive fungal disease in high-risk haematology patients, and posaconazole remains the antifungal of choice for most of these patients. Data on the use of other antifungals for primary prophylaxis, including isavuconazole, are limited. There is considerable interest in identifying a strategy that would limit the use of mould-active agents to the patients who are the most likely to benefit from them. In this regard, a recent trial demonstrated that the preemptive strategy is noninferior to the empiric strategy. For primary treatment of invasive aspergillosis, two randomized trials found isavuconazole and posaconazole to be noninferior to voriconazole. Isavuconazole does not appear to require therapeutic drug monitoring. Prophylaxis and treatment of invasive fungal diseases in high-risk haematology patients is a rapidly evolving field. Critical clinical questions remain unanswered, especially regarding the management of suspected invasive fungal diseases breaking through mould-active prophylaxis, and the duration of antifungal therapy for invasive mould infections.

Validation of the EQUAL Aspergillosis Score by analysing guideline-adherent management of invasive pulmonary aspergillosis.

To investigate the diagnosis and treatment standards at the University Hospital of Cologne, Germany, by applying the EQUAL Aspergillosis Score to invasive pulmonary aspergillosis (IPA) patients. The charts of 103 patients with probable or proven IPA at the University Hospital of Cologne were reviewed and the score retrospectively applied to all patients. Patients were stratified into two groups according to the underlying disease: a haematology group (n = 76, 73.8%) and a non-haematology group (n = 27, 26.2%). While the haematology group attained 67.8% of achievable score points (median: 15; IQR: 13-18; range: 8-25), the non-haematology group reached 48.4% (median: 12 points; IQR: 9-14; range: 4-18) (P < 0.001). Regarding diagnostics, haematological patients achieved 81.3% of achievable points (median: 7; IQR: 8-10; range: 3-13) and non-haematological 56.3% (median: 7; IQR: 5-9; range: 3-11). Concerning treatment, haematological patients gained 86.3% (median: 5; IQR: 5-5; range: 0-5) and non-haematological 68.1% (median: 5; IQR: 0-5; range: 0-5) of achievable points. Among the haematological patients with versus those without mould-active prophylaxis, 90 day mortality was 46.0% and 59.3% (P = 0.004), respectively. Guideline adherent management of IPA was observed in 31.1% of cases (39.5% in haematological patients and 7.4% in non-haematological). The EQUAL Aspergillosis Score is more suitable for evaluation of management of haematological patients compared with those without such underlying disease. In both groups there was no correlation between score points and survival. Larger prospective studies may be suitable to correlate outcome and score. A revision of the score should be considered based on the data presented.

Real World Outcomes of Liposomal Daunorubicin and Cytarabine Versus 7+3 in Patients with Secondary Acute Myeloid Leukemia

Introduction: Liposomal daunorubicin and cytarabine (CPX-351) was approved based on data which showed improved overall survival (9.56 v 5.95 months; p = .003) and remission rates (47.7% v 33.3%; p = .016) compared to conventional cytarabine and daunorubicin (7+3) chemotherapy in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients receiving CPX-351 had prolonged time to neutrophil and platelet count recovery compared to 7+3, which was not associated with adverse outcomes (Lancet et al, JCO 2018). Based on these data, our center adopted CPX-351 as a first-line agent in this patient population. Considering the significant cost differences and delays in count recovery, we conducted a comparison of outcomes in patients who received CPX-351 versus 7+3 at our center. Methods: The objective of this study was to compare efficacy and safety of CPX-351 versus 7+3 in patients with sAML. Primary outcome was response rate as defined by CR or CRi. Secondary outcomes included duration of neutropenia, incidence of invasive fungal infections (IFIs), and number of patients proceeding to allogeneic hematopoietic cell transplant (HCT). Patients with sAML receiving induction with 7+3 (daunorubicin dosed at 60 or 90 mg/m2 per treating physician's discretion) or CPX-351 from July 2014 to April 2020 were reviewed. Secondary AML was defined as: AML with a history of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), AML with myelodysplasia-related changes, or therapy-related AML. Patients with prior myeloproliferative neoplasms, myelofibrosis, or FLT3 mutations were excluded. Patient characteristics were summarized using descriptive statistics (TABLE 1) including mean for continuous measures and proportions and frequencies for categorical measures. The association between continuous variables and patient groups were assessed using ANOVA or Student's t-test. The associations between categorical variables and patient groups were evaluated using Chi-square test. Results: Over the study period, 65 patients with sAML received induction therapy with either CPX-351 (n = 31) or 7+3 (n = 34). Of these, 61 patients had an evaluable bone marrow biopsy at count recovery. The data is summarized in Table 2. The response rates (CR or CRi) were no different (36% 7+3 vs 36% CPX-351, p = 0.958) among the study population. Longer duration of neutropenia was observed with CPX-351 (33 days 7+3 vs 47 days CPX-351, p = 0.026). More patients in the 7+3 arm proceeded to allogeneic HCT; however, this was not statistically significant (59% 7+3 vs 39% CPX-351, p = 0.105). In an efficacy subgroup analysis of patients with TP53 mutation, there was no difference in response rates (33% 7+3 vs 11% CPX-351, p = 0.224). There was no difference in IFI between the groups (38% 7+3 vs 42% CPX-351, p = 0.761). Upon further analysis of IFI characteristics, there was no difference in choice of mold-active vs non mold-active prophylaxis (ppx) and the incidence of IFIs (40% mold ppx vs 39% non-mold ppx, p = 0.91). Patients with baseline neutropenia prior to induction did not have increased risk of IFIs (65% 7+3 vs 74% CPX-351, p = 0.626). Additionally, there were no between group differences in incidence of IFIs in patients who were neutropenic prior to induction. Conclusions: In the evaluable dataset of patients receiving 7+3 or CPX-351, there was no difference in CR/CRi rate between the two subgroups. There was a longer duration of neutropenia in the CPX-351 group without increased incidence of IFI. However, we report a higher incidence of IFI compared to the study population in Lancet et al (18% Lancet vs 40% Miami) despite appropriate anti-fungal prophylaxis, which may be due to patient selection on the clinical trial, demographic differences (e.g., age, ethnicity), or locoregional environmental factors. In our population, a greater percentage of patients who received 7+3 proceeded to allogeneic HCT. While this study was not powered to detect a significant difference between the two regimens and these findings require validation in larger cohorts, they do not support superior outcomes in patients who receive CPX-351. Data on differences in hospital costs will also be presented. Future directions include a larger multi-center real-world analysis to evaluate patient outcomes, safety, and the financial implications of these two regimens. Disclosures Watts: Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptevo Therapeutics: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees.

Free circulating mircoRNAs support the diagnosis of invasive aspergillosis in patients with hematologic malignancies and neutropenia

Fungal infections represent a worrisome complication in hematologic cancer patients and in the absence of disease specific symptoms, it is important to establish new biological indicators, which can be used during mould-active prophylaxis. Recently, miRNAs have appeared as candidate diagnostic and prognostic markers of several diseases. A pilot clinical study was performed to evaluate the diagnostic utility of 14 microRNAs which can be related to invasive fungal infections. Based on our data miR-142-3p, miR-142-5p, miR-26b-5p and miR-21-5p showed significant overexpression (p < 0.005) due to invasive aspergillosis in hemato-oncology patients with profound neutropenia. A tetramiR assay was designed to monitor peripheral blood specimens. Optimal cut-off was estimated by using the median value (fold change 1.1) of the log10 transformed gene expressions. The biomarker panel was evaluated on two independent sample cohorts implementing different antimicrobial prophylactic strategies. The receiver operating characteristic analysis with area under the curve proved to be 0.97. Three miRNAs (miR-142-5p, miR-142-3p, miR-16-5p) showed significant expression alterations in episodes with sepsis. In summary, the tetramiR assay proved to be a promising diagnostic adjunct with sufficient accuracy and sensitivity to trace invasive aspergillosis in hemato-oncology patients.

Future challenges and chances in the diagnosis and management of invasive mould infections in cancer patients

Diagnosis, treatment, and management of invasive mould infections (IMI) are challenged by several risk factors, including local epidemiological characteristics, the emergence of fungal resistance and the innate resistance of emerging pathogens, the use of new immunosuppressants, as well as off-target effects of new oncological drugs. The presence of specific host genetic variants and the patient's immune system status may also influence the establishment of an IMI and the outcome of its therapy. Immunological components can thus be expected to play a pivotal role not only in the risk assessment and diagnosis, but also in the treatment of IMI. Cytokines could improve the reliability of an invasive aspergillosis diagnosis by serving as biomarkers as do serological and molecular assays, since they can be easily measured, and the turnaround time is short. The use of immunological markers in the assessment of treatment response could be helpful to reduce overtreatment in high risk patients and allow prompt escalation of antifungal treatment. Mould-active prophylaxis could be better targeted to individual host needs, leading to a targeted prophylaxis in patients with known immunological profiles associated with high susceptibility for IMI, in particular invasive aspergillosis. The alteration of cellular antifungal immune response through oncological drugs and immunosuppressants heavily influences the outcome and may be even more important than the choice of the antifungal treatment. There is a need for the development of new antifungal strategies, including individualized approaches for prevention and treatment of IMI that consider genetic traits of the patients.Lay Anticancer and immunosuppressive drugs may alter the ability of the immune system to fight invasive mould infections and may be more important than the choice of the antifungal treatment. Individualized approaches for prevention and treatment of invasive mold infections are needed.

Risk factors for the development of invasive aspergillosis after kidney transplantation: Systematic review and meta-analysis.

To investigate risk factors for invasive aspergillosis (IA) after kidney transplantation (KT), we conducted a systematic search in PubMed and EMBASE to identify studies published until June 2020. We included case-control or cohort design studies comprising KT recipients with a diagnosis of IA, defined according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group criteria, and assessed risk factors for the development of IA. Random-effect models meta-analysis served to pool data. We identified eleven case-control studies (319 IA cases and 835 controls). There was an increased risk of IA among recipients with underlying chronic lung diseases (odds ratio [OR]=7.26; 95% confidence interval [CI]=1.05-50.06) and among those with diabetic nephropathy (OR=1.65; 95% CI=1.10-2.48). Requiring posttransplant hemodialysis (OR=3.69; 95% CI=2.13-6.37) or surgical reintervention (OR=6.28; 95% CI=1.67-23.66) were also associated with an increased risk. Moreover, a positive link was identified between IA and posttransplant bacterial infection (OR=7.51; 95% CI=4.37-12.91), respiratory tract viral infection (OR=7.75; 95% CI=1.60-37.57), cytomegalovirus infection or disease (OR=2.67; 95% CI=1.12-6.32), and acute graft rejection (OR=3.01; 95% CI=1.78-5.09). In contrast, receiving a kidney from a living donor was associated with a reduced risk (OR=0.65; 95% CI=0.46-0.93). KT recipients that accumulate several of these conditions should be closely monitored and a low threshold of suspicion for IA should be maintained. Future studies should explore the benefit of mold-active prophylaxis to this subgroup of KT recipients at highest risk.

Risk of invasive fungal infections in patients with high-risk MDS and AML receiving hypomethylating agents.

Invasive fungal infections (IFI) are a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Given the heterogeneity of the population receiving hypomethylating agents (HMA), it is difficult for clinicians to accurately assess their patients' risk of infection. Literature on the incidence of IFI following HMA is limited to several studies of azacitidine. The primary objective of this retrospective study was to establish the incidence of IFI in HMA treated AML/MDS patients at a large U.S. comprehensive cancer center. Secondary objectives included comparing incidence of IFI among pre-specified subgroups to identify potential risk factors for IFI. Two hundred three patients with AML, intermediate to very high risk MDS or chronic myelomonocytic leukemia who received at least two cycles of HMA were included. The incidence of IFI, as defined by the European Organization for Research and Treatment of Cancer / Invasive Fungal Infections Cooperative Group criteria, was 9.6%, with 20 IFI diagnosed following HMA (three proven, four probable, 13 possible). Among the proven cases of IFI, molds included Scedosporium and Fusarium spp. Eleven patients who developed IFIs were neutropenic upon initiating HMA. The majority (17/20) of infections occurred during the first four cycles. Given this incidence, mold-active prophylaxis can be considered in patients who are neutropenic at the start of therapy.