Primary Antifungal Prophylaxis Research Articles

Invasive fungal infections are rare in pediatric and young adult autologous hematopoietic stem cell transplant patients.

Pediatric and young adult patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) face a crucial, yet understudied, risk of invasive fungal infections (IFI), especially compared to allogeneic transplants. This gap underscores the need for research in pediatric patients undergoing auto-HSCT. Our objective was to evaluate the incidence of IFI in pediatric and young adult patients during the first year after auto-HSCT. We conducted a single-center retrospective analysis of 150 pediatric and young adult auto-HSCT patients who underwent transplant from January 2013 to January 2023. We focused on IFI incidence within the first-year post transplant, using the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria for IFI identification. Among the 150 patients analyzed, with 240 unique transplant episodes, the primary indication was neuroblastoma (37.3%), and micafungin was extensively used for prophylaxis (82.7%). There was an absence of IFI from yeast and mold species, suggesting a low IFI risk in this cohort. The incidence of IFI in pediatric auto-HSCT recipients receiving micafungin primary antifungal prophylaxis is rare. The findings advocate for further research to refine prophylaxis guidelines and highlight the need for individualized risk assessment to optimize post-transplant care.

Primary antifungal prophylaxis after haematopoietic stem cell transplantation: will the search for perfection become the enemy of good?

Primary antifungal prophylaxis after haematopoietic stem cell transplantation: will the search for perfection become the enemy of good?

Impact of Inflammatory Burden on Voriconazole Exposure in Oncohematological Pediatric Patients Receiving Antifungal Prophylaxis after Allogeneic HCT.

(1) Background: The impact of inflammation on voriconazole exposure in oncohematological pediatric patients represents a debated issue. We aimed to investigate the impact of serum C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) levels on voriconazole exposure in oncohematological pediatric patients requiring allogeneic hematopoietic stem cell transplantation (HCT). (2) Methods: Pediatric patients undergoing allogeneic HCT and receiving therapeutic drug monitoring (TDM)-guided voriconazole as primary antifungal prophylaxis between January 2021 and December 2023 were included. The ratio between concentration and dose (C/D) of voriconazole was used as a surrogate marker of total clearance. A receiving operating characteristic curve analysis was performed by using CRP, PCT, or IL-6 values as the test variable and voriconazole C/D ratio > 0.188 or >0.375 (corresponding to a trough concentration value [Cmin] of 3 mg/L normalized to the maintenance dose of 16 mg/kg/day in patients of age < 12 years and of 8 mg/kg/day in those ≥12 years, respectively) as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated. (3) Results: Overall, 39 patients were included. The median (IQR) voriconazole Cmin was 1.7 (0.7-3.0) mg/L. A CRP value > 8.49 mg/dL (AUC = 0.72; 95%CI 0.68-0.76; p < 0.0001), a PCT value > 2.6 ng/mL (AUC = 0.71; 95%CI 0.63-0.77; p < 0.0001), and an IL-6 value > 27.9 pg/mL (AUC = 0.80; 95%CI 0.71-0.88; p < 0.0001) were significantly associated with voriconazole overexposure. Consistent results were found in patients aged <12 and ≥12 years. (4) Conclusions: A single specific threshold of inflammatory biomarkers may be linked to a significantly higher risk of voriconazole exposure in oncohematological pediatric patients after HCT, irrespective of age. Adopting a TDM-guided strategy could be useful for minimizing the risk of voriconazole overexposure.

Biomarker Driven Antifungal Stewardship (BioDriveAFS) in acute leukaemia—a multi-centre randomised controlled trial to assess clinical and cost effectiveness: a study protocol for a randomised controlled trial

BackgroundAcute leukaemias (AL) are life-threatening blood cancers that can be potentially cured with treatment involving myelosuppressive, multiagent, intensive chemotherapy (IC). However, such treatment is associated with a risk of serious infection, in particular invasive fungal infection (IFI) associated with prolonged neutropenia. Current practice guidelines recommend primary antifungal (AF) prophylaxis to be administered to high-risk patients to reduce IFI incidence. AFs are also used empirically to manage prolonged neutropenic fever. Current strategies lead to substantial overuse of AFs. Galactomannan (GM) and β-D-glucan (BG) biomarkers are also used to diagnose IFI. Combining both biomarkers may enhance the predictability of IFI compared to administering each test alone. Currently, no large-scale randomised controlled trial (RCT) has directly compared a biomarker-based diagnostic screening strategy without AF prophylaxis to AF prophylaxis (without systematic biomarker testing).MethodsBioDriveAFS is a multicentre, parallel, two-arm RCT of 404 participants from UK NHS Haematology departments. Participants will be allocated on a 1:1 basis to receive either a biomarker-based antifungal stewardship (AFS) strategy, or a prophylactic AF strategy, which includes existing standard of care (SoC).The co-primary outcomes will be AF exposure in the 12-month post randomisation and the patient-reported EQ-5D-5L measured at 12-month post randomisation. Secondary outcomes will include total AF exposure, probable/proven IFI, survival (all-cause mortality and IFI mortality), IFI treatment outcome, AF-associated adverse effects/events/complications, resource use, episodes of neutropenic fever requiring hospital admission or outpatient management, AF resistance in fungi (non-invasive and invasive) and a Desirability of Outcome Ranking.The trial will have an internal pilot phase during the first 9 months. A mixed methods process evaluation will be integrated in parallel to the internal pilot phase and full trial, aiming to robustly assess how the intervention is delivered. Cost-effectiveness analysis will also be performed.DiscussionThe BioDriveAFS trial aims to further the knowledge of strategies that will safely optimise AF use through comparison of the clinical and cost-effectiveness of a biomarker-led diagnostic strategy versus prophylactic AF to prevent and manage IFI within acute leukaemia. The evidence generated from the study will help inform global clinical practice and approaches within antifungal stewardship.Trial registrationISRCTN11633399. Registered 24/06/2022.

Evaluation of the Effectiveness of Antifungal Prophylaxis in Adult Acute Lymphoblastic Leukemia during Induction Chemotherapy

Background and Objectives: Due to immune suppression, patients with hematological malignancies are at a high risk of invasive fungal disease (IFD) during chemotherapy. For patients with myeloid tumors, antifungal prophylaxis is generally recognized. However, there are evident interactions between agents used in acute lymphoblastic leukemia (ALL) remission-induction and antifungal agents, resulting in most clinical trials excluding ALL patients. The need for primary antifungal prophylaxis in ALL patients during chemotherapy is still under debate. This study analyzed the efficacy of primary antifungal prophylaxis (PAP) and the incidence of IFD during the first remission induction in the PDT-ALL-2016 cohort, as well as evaluated the impact of PAP on the outcomes of ALL patients. Methods: The PDT-ALL-2016 cohort consists of 408 newly diagnosed ALL patients aged ≥ 14 years, treated between January 2016 and December 2021. All patients were treated using the GRAALL-2003 backbone, a pediatric-like regimen. This study included 280 patients, with a total of 128 exclusions. Excluded patients consisted of 103 individuals who received initial induction treatment in other hospitals, 12 individuals who died without IFD during the induction period, 9 individuals who experienced fungal infection before induction treatment, 2 individuals who did not complete induction remission treatment and were discharged, and 2 individuals who had lost their cases. PAP was defined as the administration of any systemic antifungal agent for two or more consecutive days to a patient without any evidence or history of IFD during the neutropenic period. The diagnosis of IFD was based on the European Organization for Research and Treatment of Cancer/Mycosis Study Group criteria. Results: Among the 280 patients, 232 received PAP, with caspofungin (n=104), voriconazole (n=59), micafungin (n=44), and others being used as prophylaxis. The baseline characteristics of patients who did or did not receive PAP were similar, except for the age difference (prophylaxis group median age 28.7 versus without prophylaxis group 23.0, P&amp;lt;0.01). In the cohort, 11 proven/probable and 21 possible IFD cases were identified. The incidence of IFD in patients who did or did not receive PAP was 8.6% and 25.0%, respectively. The cumulative incidence of IFD was significantly lower in patients receiving PAP compared to those who did not (HR 0.3, 95% CI 0.1-0.6; P=0.001). In the cohort, the infections of IFD negatively affected overall survival (HR 1.6, 95% CI 0.9-2.7, P=0.093). Conclusions: Our study demonstrates, in a real-life setting, that IFD is a poor prognostic factor for adult ALL and that PAP significantly reduces the incidence of IFD during induction chemotherapy, thereby improving patient survival. Furthermore, compared to published studies (4.3%-18.3%), the incidence of IFD in the prophylaxis group within our cohort is relatively lower. This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).

Comparative study of posaconazole and voriconazole for primary antifungal prophylaxis in patients with pediatric acute leukemia

Posaconazole and voriconazole are commonly used for preventing invasive fungal disease (IFD), but few studies compared posaconazole with voriconazole for primary antifungal prophylaxis (PAP) in pediatric acute leukemia. To compare posaconazole with voriconazole for PAP in pediatric acute leukemia. This retrospective observational study enrolled pediatric patients with non-M3 acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) between December 2017 and November 2019 in the Second Affiliated Hospital of Anhui Medical University. The patients received voriconazole or posaconazole for PAP. The primary outcome was the breakthrough of IFD. The secondary outcome was the overall survival (OS) and IFD-free survival of patients. A total of the 275 patients were enrolled, of which 120 patients taking voriconazole (43.6%) and 155 patients taking posaconazole (56.4%). The breakthrough of IFD occurred in 19 (15.8%) patients taking voriconazole and in 12 (7.7%) patients taking posaconazole (P = 0.035). There was no significant differences in IFD-free survival (P = 0.336) or OS (P = 0.069) between the patients taking voriconazole and posaconazole. In the subgroup of AML patients, the OS of patients taking posaconazole was better than those receiving voriconazole (P = 0.017). Posaconazole and voriconazole were comparable for PAP in patients with pediatric acute leukemia regarding the OS and IFD-free survival, but posaconazole might achieve a lower IFD breakthrough rate.

Primary Mold-Active Antifungal Prophylaxis Decreases the Need for Chest Computed Tomography Scans in Patients with Acute Lymphoblastic Leukemia.

Current guidelines recommend computed tomography (cCT) scans of the chest in children with leukemia following 96h of the onset of idiopathic neutropenia to eliminate pulmonary invasive fungal infections (IFIs). However, cCT exposes some children who are at a very high risk of developing secondary cancers to radiation. We aimed to determine the effect of antifungal prophylaxis (AFP) with voriconazole (VCZ) on the need for cCT scans in children with acute lymphoblastic leukemia (ALL) to eliminate pulmonary IFIs during chemotherapy. We retrospectively screened all patients' data from their electronic charts. Children who were diagnosed as having ALL before February 2013 and did (AFP group) or did not (NoP group) receive AFP were divided into two groups and compared regarding cCT scans and relapse-mortality rates. Ninety-six children were diagnosed before February 2013 and did not receive primary AFP and 146 children were administered VCZ following a diagnosis of ALL. There were no significant demographic differences between the groups. A total of 128 cCTs had been required in 62 children in the NoP group, compared with 64 cCTs in 52 children in the AFP group. The percentage of the patients who had required at least one chest CT scan and the mean number of cCT scans in the NoP group were significantly higher compared with the AFP group. Proven-probable IFIs and relapse-mortality rates were higher in the NoP group compared with the AFP group. Mold-active AFP revealed a significant decrease in the need for cCT scans in children with ALL.

Posaconazole and midostaurin in patients with FLT3-mutated acute myeloid leukemia: Pharmacokinetic interactions and clinical facts in a real life study.

Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real-life study to evaluate (i) how often concerns around PCZ-midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ-midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ-midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (Cmin ) was greater than three times higher than reported; moreover, midostaurin Cmin , maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient.

Antifungal Stewardship Programs in Children: Challenges and Opportunities.

Antifungal Stewardship Programs in Children: Challenges and Opportunities.

Epidemiology and Factors Associated with Treatment Success of Invasive Fungal Infections Among Newly Hematologic Malignancy Patients Receiving Chemotherapy or Hematopoietic Stem Cell Transplant in Thailand.

Invasive fungal infection (IFI) causes disability/death in patients with hematologic malignancy (HM) receiving chemotherapy or hematopoietic stem cell transplant (HSCT). There is limited epidemiological data, treatment outcomes, and factors associated with IFI treatment success in Thailand. This study aimed to identify factors associated with IFI treatment success among new HM patients receiving chemotherapy or HSCT, determine IFI incidence among HM patients receiving chemotherapy or HSCT, and the IFI incidence of a breakthrough in patients receiving primary antifungal prophylaxis, and identify antifungal drugs susceptibility. This study reviewed the charts of patients aged ≥ 15 years with newly HM who received chemotherapy or HSCT between January 2016 and June 2021 at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. The 2020 EORTC/MSG criteria were used to diagnose IFI. IFI treatment success factors were evaluated using logistic regression. Ninety-two patients with 107 episodes of IFI met the inclusion criteria. IFI incidence on proven and probable cases among newly HM patients receiving chemotherapy or HSCT was 7%. Most infections (38.3%) occurred during the induction-phase chemotherapy. Aspergillosis (35.5%) was the commonest IFI, followed by candidiasis (11.2%), Pneumocystis jirovecii pneumonia (8.4%), mucormycosis (3.7%), and others, respectively. The 12-week IFI treatment success rate was 67.3%. It was associated with age < 60 years, absence of coinfection, and the receipt of appropriate empirical therapy on the first day of IFI diagnosis. The incidence of breakthrough IFI from proven and probable cases in patients receiving primary antifungal prophylaxis was 6.1%. Most fungal pathogen isolates were still highly susceptible to antifungal drugs. The IFI treatment success in patients with HM or HSCT in our study was high. Close monitoring of coinfected patients aged ≥ 60 is recommended. Appropriate antifungal drugs are essential for clinical outcomes.

New Perspectives on Primary Prophylaxis of Invasive Fungal Infection in Children Undergoing Hematopoietic Stem Cell Transplantation: A 10-Year Retrospective Cohort Study

Allogenic hematopoietic stem cell transplantation (a-HCT) remains a therapeutic treatment for many pediatric hematological diseases. The occurrence of invasive fungal infections (IFIs) is a complication for which ECIL-8 recommends primary antifungal prophylaxis. In this study, we evaluated the impact of our local strategy of not systematically administering primary antifungal prophylaxis in children undergoing a-HCT on the occurrence and mortality of IFIs. We performed a retrospective monocentric study from 2010 to 2020. We retained all proven and probable IFIs diagnosed during the first year post a-HCT. 308 patients were included. Eighteen patients developed twenty IFIs (thirteen proven, seven probable) (6.5%) among which aspergillosis (n = 10, 50%) and candidosis (n = 7, 35%) were the most frequently diagnosed infections. Only 2% of children died because of an IFI, which represents 14% of all deaths. Multivariate analysis found that age > 10 years (OR: 0.29), the use of a therapeutic antiviral treatment (OR: 2.71) and a low neutrophil count reconstitution (OR: 0.93) were significantly associated with the risk of IFI occurrence. There was also a trend of malignant underlying disease and status ≥ CR2 but it was not retained in multivariate analysis. IFI occurrence was not higher in our cohort than what is reported in the literature with the use of systematic antifungal prophylaxis, with a good survival rate nonetheless. Thus, a prophylaxis could be considered for children with a high risk of IFI such as those aged over 10 years.

Real-life comparison of posaconazole versus fluconazole for primary antifungal prophylaxis during remission-induction chemotherapy for acute leukemia

Patients undergoing remission-induction intensive chemotherapy for acute leukemia are at high risk for life-threatening invasive fungal infections (IFIs). Primary antifungal prophylaxis with posaconazole has been shown to reduce the incidence of IFI compared to fluconazole, but real-life data are limited and the effect on mortality remains unclear. This retrospective cohort study compared fluconazole and posaconazole as primary prophylaxis in real-life practice over a 10-year period, in a Canadian hospital. A total of 299 episodes were included (fluconazole, n = 98; posaconazole, n = 201), of which 68% were first inductions. The underlying hematologic malignancy was acute myeloid leukemia or myelodysplastic syndrome in 88% of episodes and acute lymphoblastic leukemia in 9%. Overall, 20 cases of IFI occurred (aspergillosis, n = 17; candidiasis, n = 3) and 14 were considered as breakthrough IFI. IFI incidence was significantly lower in the posaconazole group (3.5% versus 13.2%; p = 0.001). Empirical or targeted antifungal therapy was also reduced in the posaconazole cohort. Mortality was similar in both groups. In a real-life setting in Canada, primary posaconazole prophylaxis reduces the incidence of IFI during remission-induction chemotherapy, compared to fluconazole.

Dosage, Safety and Efficacy of Posaconazole As Primary Antifungal Prophylaxis in High-Risk Recipients of Allogeneic Stem Cell Transplantation

Introduction: The use of anti-mold prophylaxis with anti-aspergillus activity is recommended for patients (pts) undergoing allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with high risk of fungal infection (Maertens, J Antimicrob Chemother 2018). Yet, few data are available regarding the use of posaconazole. Methods: This retrospective study included all Allo-HSCT adult recipients having benefited from posaconazole therapy in our center as a primary anti-fungal prophylaxis for high-risk of fungal infection. The latter was defined as use of i)an alternative donor, ii)sequential conditioning regimen, iii)a regimen associated with severe mucositis, iv) post-transplant cyclophosphamide (PT-Cy) or v) previous allo-HSCT. Posaconazole was programmed to be initiated at day (D) 0 or D5/6 (in case of PT-Cy) and administered up to day 100. We report here on the residual concentration of posaconazole during the neutropenic phase then on the tolerance and efficacy of such prophylaxis in this cohort. Results: Seventy high-risk pts (males 63.3%, median age 54 years old, range 20-73) received Allo-HSCT between April 2020 and December 2021 for a myeloid (n=51), lymphoid (n=17) or non-malignant hematological (n=2) disease and received posaconazole as a primary prophylaxis. The Sorror score at transplant time was ≥ 3 for 24 pts (33.8%). Twenty-two patients had already received posaconazole as a primary prophylaxis before Allo-SCT including 26 during the neutropenic phase of their induction for AML or MDS, 3 for prolonged neutropenia, 2 during treatment with alemtuzumab for T-cell leukemia/lymphoma, and 1 during a previous AlloHCST. Four patients had also received other antifungal agentsbefore Allo-SCT (caspofongine (n=1), voriconazole (n=1) or liposomal amphotericin B (n=2)) because of a suspected mold infection which has been finally excluded. All pts had at least one high-risk criterion of fungal infection. These included the use of an alternative donor in 42 pts (haplo-identical donor n= 41, umbilical cord blood n=1), sequential conditioning regimen in 9, with PT-Cy in 57, second or third allo-HSCT in 8 and conditioning regimen associated with severe mucositis in 11 (TBI 8-12gy n=3, thiotepa-based n=8). All but one pts received posaconazole using the gastroresistant tablet form at a dose of 300mg/day. One patient received the drinkable suspension form at a dose of 200mg 3 times a day. Following prophylaxis initiation, serum posaconazole concentrations were available in 51 and 16 patients at medians of 9 and 39 days, respectively. A protective residual level of posaconazole (> 0.5mg/L) was achieved in 57% of the patients (n=29) at first assessment and 87.5% (n=12) at second evaluation. Posaconazole was stopped early due to related-toxicity in 9 cases (12.6%), including liver toxicity in 7 pts, QT prolongation in 1 and skin hyperesthesia in 1. Treatment was restarted without recurrence of toxicity in 2 cases. Posaconazole was stopped early in 2 patients due to non-related toxicity, including one veno-occlusive disease and one hepatic acute GVHD. Posaconazole was temporary discontinued in 4 patients due to a suspected fungal infection before being restarted. Most patients (n=59/70, 84.2%) did not present fungal infections while being under posaconazole therapy. Only 11 cases were documented with this complication (Table 1), including 8 invasive pulmonary aspergillosis (IPA; possible n=3; probable n=5), one possible invasive fungal infection and 2 mucormycoses (1 with possible IPA). Fungal infections occurred despite documentation of a protective residual level of posaconazole (> 0.5mg/L) in 5 of 6 evaluable patients. Of note, 9/11 patients had received PTCY as GVHD prophylaxis. Posaconazole was stopped (before D7 in 3) and other antifungal drugs started (voriconazole or liposomal amphotericin B) allowing to fungal infection cure in 5 pts. However, 7 pts died including 2 of an uncontrolled fungal infection. Conclusion: Posaconazole is a well-tolerated and efficient primary prophylaxis in recipients of Allo-HSCT at high-risk of fungal infection. As some fungal infections occured very early after D0 while prophylaxis started only a D5/6 after PTCY, our results suggests to propose posaconazole as early as the beginning of the conditionning together with dose monitoring. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-World Comparison of Isavuconazole and Voriconazole in Terms of the Need for Dosage Adjustments Guided by Clinical Pharmacological Advice During Primary Prophylaxis of Invasive Fungal Infections in Pediatric Patients with Hemato-Oncological Malignancies.

Limited evidence concerning optimal azole dosing regimens currently exists for antifungal prophylaxis in hemato-oncological pediatric patients. Hemato-oncological children receiving intravenous or oral isavuconazole or voriconazole for primary antifungal prophylaxis at IRCCS Azienda Ospedaliero-Universitaria of Bologna during November 2020 to October 2021 and undergoing CPA programs based on real-time therapeutic drug monitoring (TDM) were retrospectively analyzed. CPAs for isavuconazole and voriconazole and the number of dosage adjustments were collected. Normalized trough concentrations [(C min )/dose/kg] were calculated for both drugs at each TDM assessment, and the coefficient of variation was determined. The efficacy and safety of the drugs were evaluated. Sixteen hemato-oncological pediatric patients received azole prophylaxis (mean age and weight: 9.1 ± 4.9 years and 32.6 ± 16.0 kg; 6 isavuconazole and 10 voriconazole). Sixty and 89 CPAs were delivered as isavuconazole and voriconazole, respectively. Dosage adjustments were needed in 3.3% of cases for isavuconazole and 53.9% of cases for voriconazole ( P < 0.001). At first TDM, achievement of the desired target during standard dosing regimens was higher for isavuconazole (83.3%) than for voriconazole (10.0%; P = 0.008). Dispersion of normalized concentrations was higher for voriconazole (CV = 139.1% vs. CV = 79.4%). Elevation of ALT and aspartate aminotransferase levels between baseline and the third month was higher in patients receiving voriconazole (median, 28 vs. 90 U/L; P = 0.038, and 19 vs. 65.5 U/L; P = 0.002). Our findings suggest that there is limited variability in isavuconazole exposure in hemato-oncological pediatric patients receiving azole prophylaxis , resulting in a low need for CPA-guided dosage adjustments.

Invasive Fungal Disease in Patients with Myeloid Malignancies: A Retrospective Cohort Study of a Diagnostic-Driven Care Pathway Withholding Mould-Active Prophylaxis

Objectives: Patients receiving remission induction therapy for acute myeloid leukaemia (AML) are at high risk of developing invasive fungal disease (IFD). Newer therapies with targeted antileukemic agents and the emergence of azole resistance pose a challenge to the strategy of primary antifungal prophylaxis. We report the experience of a diagnostic-driven care pathway (DCP) for the management of IFD in these patients, using only culture-directed mould inactive prophylaxis. Methods: Retrospectively, we used a single-centre study of consecutive patients receiving intensive chemotherapy for myeloid malignancies between 2014 and 2021. DCP consisted of serial cultures and serum galactomannan (sGM) screening, CT imaging, and bronchoscopy to direct targeted antifungal treatment. IFD was classified according to the 2020 EORTC/MSGERC criteria. Results: A total of 192 patients with myeloid malignancies received 300 courses of intensive chemotherapy. There were 14 cases of invasive yeast infections and 18 of probable/proven invasive mould disease (IMD). The incidence of probable/proven IMD during the first cycle of remission-induction chemotherapy was 4.6% (n = 9). sGM remained negative in all cases of invasive aspergillosis (IA), with positive mycology findings in bronchoalveolar lavage. All-cause mortality was 9.4% (n = 18) 100 days after starting chemotherapy and was comparable between patients with or without IFD. The fungal-related mortality was 1% (n = 2). Conclusion: Diagnostic-driven based management without universal mould active prophylaxis is a feasible strategy in the management of IFD and limits unnecessary antimould treatment during intensive chemotherapy. The poor performance of serial serum galactomannan screening in detecting IA warrants further investigation.

Comparison of Mold Active Triazoles as Primary Antifungal Prophylaxis in Patients With Newly Diagnosed Acute Myeloid Leukemia in the Era of Molecularly Targeted Therapies.

Multiple factors influence the choice of primary antifungal prophylaxis (PAP) in patients with acute myeloid leukemia (AML) undergoing remission induction chemotherapy (RIC) given the recent incorporation of targeted leukemia therapies into these regimens. We evaluated the incidence and characteristics of breakthrough invasive fungal infections (bIFI) in 277 adult patients with newly diagnosed AML undergoing RIC with high-intensity, or low-intensity venetoclax-containing therapy. Patients receiving posaconazole (PCZ), voriconazole (VCZ), or isavuconazole (ISA) for > 5 days as PAP during RIC were included. Echinocandin use prior to, but not concomitantly with, the PAP azole was allowed. IFI (modified EORTC/MSG criteria) occurring after > 5 days of continuous azole exposure or within 14 days of discontinuation were considered bIFI. Proven or probable bIFI were observed in 11 patients (4%). The incidence of bIFI was 2.9% for PCZ, 4.8% for VCZ, and 5.7% for ISA (P = .55). In total, 161 patients (58%) received echinocandin prophylaxis prior to azole initiation. Neither echinocandin exposure nor chemotherapy intensity impacted bIFI rate. Patients with bIFI had a lower rate of absolute neutrophil count recovery > 1000 cells/µL (64% vs 90%, P = .021) or complete remission (CR; 18% vs 66%, P = .002) after RIC. Thirty-eight patients (14%) discontinued PAP due to toxicity, most often hepatotoxicity. Discontinuation due to hepatotoxicity was similar among azoles (PCZ: 13%; VCZ: 15%; ISA: 13%). The rate of bIFI is low during RIC in patients with newly diagnosed AML receiving any of the mold-active triazoles as PAP. Neutrophil recovery and achievement of CR are important for bIFI risk.

Clinical Characteristics and Risk Factors of Invasive Fungal Infections in Acute Leukemia Patients in Tropical Regions

To analyze the clinical characteristics and risk factors of invasive fungal infection (IFI) occurenced in patients with acute leukemia (AL) during treatment in tropical regions. The clinical data of 68 AL patients admitted to the Hainan Hospital of PLA General Hospital from April 2012 to April 2019 was retrospectively analyzed. Logistic regression analysis was used to analyze the factors affecting the occurrence of IFI in AL patients. Among the 68 patients, 44 were acute myeloid leukemia, 24 were acute lymphoblastic leukemia, 39 were male, 29 were female and the median age was 41(13-75) years old. The 68 patients received 242 times of chemotherapy or hematopoietic stem cell transplantation(HSCT), including 73 times of initial chemotherapy or inducting chemotherapy after recurrence, 14 times of HSCT, 155 times of consolidating chemotherapy. Patients received 152 times of anti-fungal prophylaxis, including 77 times of primary anti-fungal prophylaxis and 75 times of secondary anti-fungal prophylaxis. Finally, the incidence of IFI was 31 times, including 24 times of probable diagnosis, 7 times of proven diagnosis, and the total incidence of IFI was 12.8%(31/242), the incidence of IFI in inducting chemotherapy was 24.66%(18/73), the incidence of IFI in HSCT patients was 28.57% (4/14), the incidence of IFI in consolidating chemotherapy was 5.80% (9/155). Multivariate analysis showed that inducting chemotherapy or HSCT, the time of agranulocytosis ≥7 days, risk stratification of high risk were the independent risk factors for IFI in AL patients during treatment in tropical regions. The incidence of IFI in patients with AL in the tropics regions is significantly higher than that in other regions at homeland and abroad. Anti-fungal prophylaxis should be given to the patients with AL who have the high risk factors of inducting chemotherapy or HSCT, time of agranulocytosis ≥7 days and risk stratification of high risk.

Fluconazole as primary antifungal prophylaxis for pediatric hematopoietic stem cell transplant in antifungal NA ÆVE patients

Fluconazole as primary antifungal prophylaxis for pediatric hematopoietic stem cell transplant in antifungal NA ÆVE patients

941. Isavuconazole Prophylaxis Against Invasive Fungal Infection: A Pooled Analysis with a Comparison of Posaconazole Delayed-release Tablet Prophylaxis

BackgroundThere are limited data regarding the use of isavuconazole as primary antifungal prophylaxis against invasive fungal infection (IFI) among immunocompromised patients. Therefore, the purpose of this study was to assess efficacy and breakthrough IFIs of isavuconazole prophylaxis by a pooled analysis of the reported cases of isavuconazole prophylaxis with a comparison of cases of posaconazole delayed-release tablet prophylaxis.MethodsPubmed was searched for English-written articles published up to April 2021. Studies that reported cases of primary antifungal prophylaxis with isavuconazole or posaconazole delayed-release tablet in adults ≥ 18 years were reviewed. Breakthrough IFI was defined as the occurrence of proven or probable IFI while on prophylaxis.ResultsFor overall isavuconazole prophylaxis, a total of 818 courses of prophylaxis was identified from 12 studies. Breakthrough IFIs were noted in 41 patients. The median duration of isavuconazole prophylaxis of these patients before the diagnosis of IFI was 17 days. The most common breakthrough IFI was candidiasis (34.1%), followed by aspergillosis (24.4%) and mucormycosis (12.2%). Sixteen patients died (39.0%). Among patients with hematologic malignancies or hematopoietic stem cell transplantation, isavuconazole prophylaxis (404 courses) was compared with posaconazole delayed-release tablet prophylaxis (1952 courses). The incidence rate of breakthrough IFIs was higher in the cohort of isavuconazole prophylaxis (24 patients of 404 courses) than in the cohort of posaconazole delayed-release tablet prophylaxis (44 patients of 1952 courses). Aspergillosis (40.9%) was the most common breakthrough IFI in the cohort of isavuconazole prophylaxis among patients with hematologic malignancies or hematopoietic stem cell transplantation, followed by candidiasis (27.3%) and mucormycosis (18.2%).ConclusionAlthough isavuconazole is licensed to treat aspergillosis and mucormycosis, breakthrough IFIs including aspergillosis, mucormycosis, and candidiasis may occur while on isavuconazole prophylaxis. Therefore, further studies are needed to define the benefits and risks of isavuconazole prophylaxis.Disclosures All Authors: No reported disclosures

Invasive Aspergillosis in Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Large Cohort Single-Center Study

Background. Invasive aspergillosis (IA) is dominant among invasive fungal infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The emergence of new immunosuppressive drugs, the expanding use of antifungal agents with activity against Aspergillus spp. on the one hand, and the improvement of the diagnostics and therapy on the other hand affect epidemiology of IA.Methods. We analyzed 663 patients who underwent allo-HSCT from 2016 to 2020 years in CIC 725. During the observation period, 43 patients with proven and probable IA were included into analysis. According to EORTC/MSG 2019 criteria, 2 proven and 41 probable cases were diagnosed in adults with hematological malignances and non-malignant hematological diseases during 1 year after allo-HSCT. We characterized the IA after allo-HSCT and conducted the comparative analysis of patients and transplant characteristics who developed IA after allo-HSCT and did not. The median follow up time was 13,9 months.Results. Cumulative incidence of IA during 1-year period after allo-HSCT was 8%. Among all cases of IA most common underlying diagnoses were acute leukemia - 32% and lymphomas - 30%. The main sites of infection were lungs 93%, sinuses - 2%, disseminated lesions - 5%. The IA was diagnosed by bronchoalveolar (BAL) or sinuses liquid culture in 54% cases, and the etiology were Aspergillus fumigatus - 8 (42%), Aspergillus niger - 5 (26%), Aspergillus flavus - 2 (11%), Aspergillus terreus - 1 (5%), Aspergillus spp. - 3 (16%). The median day of IA onset was day +59 (range, 2 to 282) after allo-HSCT. First line therapy of IA was predominantly with voriconazole (vori) monotherapy - 35 (81%), combination based on vori - 5 (12%). Salvage combination therapy were prescribed in two patients: vori + echinocandins (echino) and L amph B + echino. Overall survival at 12 weeks in patients with IA was 76%. Comparative analysis showed that in patients with IA statistically significant more frequent were patients with AML, HL, NHL, Ph(-) MPNs, second or more allo-HSCT, CMV-reactivation, aGVHD, aGVHD grade 3-4, severe chGVHD (Table 1). To identify the risk factors including primary antifungal prophylaxis planning to conduct the multivariate subgroup analysis. Patients with IA had lower level of lymphocytes on day +60 (p=0.006) and 100 (p=0.009) compared to patients without IA (pic.1).Conclusions. Incidence of IA after allo-HSCT was 8% with the median day +59. The main site of infection was lungs, etiology - Aspergillus fumigatus. Overall survival at 12 weeks in patients with IA was 76%. In the era of primary and secondary prophylaxis we identified risk groups for developing IA after allo-HSCT among the previously undescribed, worthy of further study: subsequent allo-HSCT, underlying disease: HL, NHL, Ph (-) MPNs. [Display omitted] DisclosuresKlimko: Gilead Sciences, MSD, Pfizer Pharmaceuticals, and Astellas Pharma: Speakers Bureau; Gilead Science, MSD, Pfizer: Membership on an entity's Board of Directors or advisory committees. Kulagin: Pfizer: Speakers Bureau; Johnson & Johnson: Speakers Bureau; Roche: Speakers Bureau; Sanofi: Speakers Bureau; Generium: Speakers Bureau; Biocad: Research Funding; Apellis: Research Funding; Alexion: Research Funding; X4 Pharmaceuticals: Research Funding; Novartis: Speakers Bureau.