Invasive Fungal Infections as a Complication of New Therapies.

Reduced Incidence of Early Invasive Fungal Infection in Allogeneic Transplant Patients Following Micafungin Prophylaxis

Multicenter, Randomized, Open-Label Study Comparing the Efficacy and Safety of Micafungin versus Itraconazole for Prophylaxis of Invasive Fungal Infections in Patients undergoing Hematopoietic Stem Cell Transplant

Background: Voriconazole is a second-generation triazole. It has excellent bioavailability and broad antifungal spectrum; thus, it is an attractive option for patients at high risk of invasive fungal infections (IFIs). Comparing efficacy and safety of voriconazole with other antifungals in prophylaxis or treatment of IFIs would be useful to draw conclusions regarding prevention and therapeutics of these infections.Aim: To assess efficacy and safety of voriconazole compared with other options as prophylaxis or treatment of IFIs in haematology-oncology patients.Materials and methods: A literature search was performed in MEDLINE database using the search term ‘voriconazole’ and completed with manual search.Study selection: Randomized controlled trials (RCTs) comparing voriconazole with other antifungal agents or placebo.Data extraction: Seven studies fulfilled the eligibility criteria.Results: Five studies compared voriconazole to another comparator as prophylaxis of IFIs and two as treatment. Pooled results showed that voriconazole was more effective than the comparator (RR = 1.17; 95%CI = 1.01–1.34), but heterogeneity was significant (Q test 32.7; p = .00001). Sub-analysis according to prophylaxis showed RR = 1.17; 95%CI = 1.00–1.37; while as treatment, RR = 1.23; 95%CI = 0.68–2.22. Risk of adverse events was not different from that observed for the comparator (RR = 1.06, 95%CI = 0.66–1.72) though significant heterogeneity was detected (p < .01).Conclusions: Voriconazole was as effective and safe as comparators, probably better as prophylaxis than as treatment, but limitations due to variability in the sample size of studies, differences in the age of patients, and heterogeneity between studies’ outcome measures indicate the need for further research.

Antifungal prophylaxis is an option to reduce the incidence of invasive fungal infection (IFI) in haematological patients. To date, no network meta-analysis (NMA) of high-quality evidence (double-blind randomized controlled trials) has been performed on this subject. This systematic review and NMA aimed to evaluate the safety and efficacy of different antifungal agents used for prophylaxis of IFI in patients with haematological disorders. A systematic review was performed according to PRISMA and Cochrane recommendations. The search for articles was conducted on PubMed, Scopus and the Web of Science. We searched for double-blind randomized clinical trials comparing antifungal agents for IFI prophylaxis head-to-head vs placebo in patients with any blood cancer. Network meta-analyses were conducted using Addis version 1.16.6. Evaluation of the quality of included RCTs was also performed. Twenty-five trials were included in the qualitative and quantitative analyses. Posaconazole stood out as the best IFI prophylaxis option and for avoiding IFI-related mortality. For the incidence of candidiasis outcome, the azoles were superior to placebo. Voriconazole and posaconazole were, respectively, the first and second best options. For the incidence of aspergillosis outcome, the probability rank suggested that voriconazole followed by liposomal amphotericin B is, possibly, the best choice. The quality of studies was considered good, with a mean Jadad score of 4.0. The results of our work support prophylaxis with antifungal agents as reducing the risk of IFI in haematological patients. Overall, the second-generation azoles were found to be the best option for preventing IFI in this population.

Background:Invasive fungal infections (IFIs), particularly due to Aspergillus species, are an important cause of morbidity and mortality in patients with haematological malignancies. In 2017 and 2018 the European Conference on Infections in Leukaemia (ECIL) published guidelines for both prophylaxis and treatment of IFIs in haematology patients. A previous survey of UK practice undertaken in 2010 demonstrated marked variability in practice in relation to the prevention and treatment of IFIs in this patient group, similar to what had been reported in earlier Europe‐wide surveys.Aims:The aim of the current study was to investigate whether variability in practice still exists in the UK or whether recently published guidelines have helped to standardise practice.Methods:A questionnaire was sent electronically to all members of the UKBMT pharmacists’ group. The majority of questions focused on prophylaxis and treatment of fungal infection in four clinical areas – AML induction, ALL induction, autologous stem cell transplantation (SCT) and allogeneic SCT. Further questions related to uptake of the newer azole, isavuconazole, and the use of therapeutic drug monitoring (TDM) for azoles.Results:Responses were received from 29 centres. All centres treated autologous SCT and AML/ALL patients and 25 treated allogeneic SCT patients. Seventeen centres treated adult patients only, seven were paediatric centres and five treated both adults and children. The most commonly recommended prophylactic antifungals for the four indications were:Autograft – fluconazole (59% of centres); Allograft – posaconazole (44%); AML induction – posaconazole (45%); ALL induction – lipid amphotericin (69%). There was marked variability in dosing schedules for fluconazole (50mg‐400 mg/day) and lipid amphotericin (12 different schedules ranging from 50 mg thrice weekly (TTW) to 3 mg/kg TTW) and only 69% of centres gave prophylaxis routinely to all 4 patient groups. Compared with the previous survey, itraconazole use had fallen sharply and was only used prophylactically by 38% of centres (previously 76%). Empirical therapy was recommended by 79% of centres. The criteria for starting an antifungal empirically (i.e. duration of fever unresponsive to broad spectrum antibiotics) varied from 48–120 hours. As in the previous survey, Ambisome® (at doses ranging from 1–3 mg/kg/day) was the most common empirical antifungal agent, followed by caspofungin. However, voriconazole had replaced Ambisome® as the most widely recommended first line drug for the management of invasive aspergillosis. Caspofungin, micafungin, posaconazole and IV itraconazole were only recommended in a minority of policies. Ambisome® was the most popular second line agent, being recommended in 62% of policies, followed by caspofungin (24%) and isavuconazole (17%). Twenty one centres (72%) would consider giving dual therapy. In terms of uptake of new agents, Isavuconazole was included in the antifungal policy in 34% of centres, had been used on an adhoc basis in a further 28% but had not yet been used in 38% of centres. For those centres that included the following azoles in their antifungal policies, the use of TDM was inconsistent – 76% of centres undertook TDM for voriconazole, 71% for itraconazole and 55% for posaconazole.Summary/Conclusion:Similar to the previous 2010 survey, this study showed significant variations in practice between UK haematology centres with respect to both preventing and treating invasive fungal infections. Recent guidelines in this area do not appear to have resulted in a noticeable standardisation of practice.

To evaluate the efficacy and safety of itraconazole for secondary prophylaxis of previous proven or probable invasive fungal infection (IFI) in patients undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) in agranulocytosis state. A phase IV prospective, open-label, multicenter trial was conducted to evaluate itraconazole (200 mg q12h intravenously d1-2, 200 mg/d) as secondary antifungal prophylaxis in patients (18-65 years old) undergoing chemotherapy or HSCT with previous proven or probable IFI. Itraconazole was started when patients' neutrophils＜1.5 × 10⁹/L, and stopped when chemotherapy patients' neutrophils ＞0.5 × 10⁹/L and stem cell transplant recipients' neutrophils＞1.0 × 10⁹/L. The primary end-point of the study was the incidence of proven, probable or possible IFI. Seventy one patients from November 2008 to September 2010 were enrolled in the trial. The median duration of itraconazole prophylaxis was 14 (4-35) days. No patients died of drug-related toxicity within trial. Five cases occurred IFI during the trial. The cumulative incidence of invasive fungal disease was 7.0%. One patient was withdrawn from the study due to treatment-related adverse events (liver malfunction and severe phlebitis). Itraconazole appears to be safe and effective for secondary prophylaxis of systemic fungal infection after chemotherapy and allogeneic HSCT. The observed incidence of 7.0% is considerably lower than the relapse rate reported in historical controls, suggesting that itraconazole is a promising prophylactic agent in this population.

Infection is associated with great morbidity and mortality in patients with multiple myeloma (MM), but evidence for invasive fungal infections (IFIs) is lacking. We aimed to investigate risk factors for IFI in MM patients and to determine its impact on patients' survival. We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 2002 and October 2018. MM was diagnosed according to the International Myeloma Working Group criteria. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. All risk factors of IFI in MM patients were estimated using Cox regression models in the univariate and multivariate analyses. Of the 623 patients recruited, 22 (3.5%) were diagnosed with proven or probable IFI. Light chain disease (adjusted hazard ratio [HR] 6.74, 95% confidence interval [CI] 2.10-21.66), hemoglobin less than 8g/dl (adjusted HR 3.34, 95% CI 1.32-8.42), serum albumin < 3.5g/dl (adjusted HR 3.24, 95% CI 1.09-9.68), and having received allogeneic stem cell transplantation (allo-SCT) (adjusted HR 5.98, 95% CI 1.62-22.03) were significantly associated with IFI in the multivariate analysis. Contracting IFI was in turn associated with early mortality (adjusted HR 11.60, 95% CI 1.26-106.74). Light chain disease, anemia, hypoalbuminemia, and receiving allo-SCT were independent predictors of IFI in MM patients. The early mortality risk is much higher in those encountering IFI. Physicians must be aware of the rare but potentially lethal infections.

Invasive Aspergillosis in Solid Organ Transplant Recipients

Posaconazole: An extended-spectrum triazole antifungal agent

Background Controversy surrounds the true incidence of invasive fungal infections (IFIs) in patients on Bruton tyrosine kinase inhibitors (BTKIs) due to incomplete epidemiological data. This systematic review and meta-analysis evaluated the prevalence and risk factors of IFIs in BTKI-treated patients.Figure 1.Forest plot for the prevalence of invasive fungal infections in patients treated with Bruton tyrosine kinase inhibitors This study was registered under PROSPERO (CRD42024523198). The prevalence was calculated using a generalized linear mixed model random-effects meta-analysis and presented as effect sizes with 95% confidence intervals (CIs). IFIs were defined according to The European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) consensus definitions. Methods Studies up to April 17, 2024, from Pubmed, Scopus, and Embase, including observational studies reporting prevalence and/or associated risk factors of IFIs with at least 30 BTKI-treated patients, were searched and analyzed. IFIs were defined according to standard definitions. The prevalence of IFIs and odds ratio (ORs) for the risk factors associated with IFIs were reported alongside 95% confidence intervals (CIs).Figure 2.Forest plot for the prevalence of proven/probable invasive fungal infections in patients treated with Bruton tyrosine kinase inhibitors according to the World Health Organization regions Results This study included 14,679 patients across 24 studies (13,981 with hematologic malignancies and 67 with chronic graft-versus-host disease). Of these, 15 studies specifically included only proven/probable IFIs (ppIFIs) (Figure 1 and Table 1). The overall IFI prevalence was 2.23% (95% CI 1.73-2.88%), and for ppIFIs, was 2.64% (95% CI 1.87-3.70%). The median durations from BTKI initiation to ppIFI onset ranged from 24-186 days. The highest prevalence of ppIFIs was in patients with mantle cell lymphoma (7.60%, 95% CI 3.14-17.26%), followed by chronic lymphocytic leukemia (3.01%, 95% CI 1.93-4.66%), and Waldenström's macroglobulinemia (2.18%, 95% CI 0.33-12.96%). Regional ppIFI prevalence was the highest in Western Pacific (7.58%, 95% CI 3.19-16.94%), followed by Europe (2.60%, 95% CI 1.49-4.49%) and America (2.37%, 95% CI 1.59-3.52%) (Figure 2). The most common ppIFIs were invasive aspergillosis (1.78%, 95% CI 1.24-2.57%), followed by pneumocystosis (0.80%, 95% CI 0.16-3.81%), invasive candidiasis (0.40%, 95% CI 0.14-1.16%), and cryptococcosis (0.33%, 95% CI 0.19-0.56%). Corticosteroid use was significantly associated with ppIFIs (OR 5.03, 95% CI 2.31-10.92) (Figure 3).Figure 3.Forest plot for risk factors associated with proven/probable invasive fungal infections in patients treated with Bruton tyrosine kinase inhibitorsGRADE = Grading of Recommendations Assessment, Development and Evaluation certainty of evidence; OR = odds ratio. Odds ratios were directly extracted from regression analysis or manually calculated by comparing associated factors between patients with and without invasive fungal infections. Conclusion In conclusion, the prevalence of IFIs in patients treated with BTKIs (mostly ibrutinib) reaches 2%, and up to 7.6% in those with mantle cell lymphoma, indicating a significant risk. Antifungal prophylaxis should be customized based on individual underlying diseases and steroid use.Table 1.Characteristics of included studies BTKI = Bruton tyrosine kinase inhibitor; cGVHD = chronic graft-versus-host disease; CLL = chronic lymphocytic leukemia; DLBCL = diffuse large B-cell lymphoma; EORTC/MSGERC = the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium; FL = follicular lymphoma; HCL = hairy cell leukemia; HM = hematologic malignancies; LPL = lymphoplasmacytic lymphoma; MCL = mantle cell lymphoma; MZL = marginal zone lymphoma; NA = not available; NHL = non-Hodgkin’s lymphoma; PCNSL = primary central nervous system lymphoma; PLL = prolymphocytic leukemia; RS = Richter’s syndrome; SCNSL = secondary central nervous system lymphoma; SLL = small lymphocytic lymphoma; USA = United States of America; WM = Waldenström's macroglobulinemia Disclosures Shmuel Shoham, MD, F2G: Grant/Research Support Veronica Dioverti, MD, AlloVir: Grant/Research Support|Regeneron: Advisor/Consultant|Regeneron: Grant/Research Support Nitipong Permpalung, MD, MPH, CareDx: Grant/Research Support|Cidara Therapeutics: Grant/Research Support|ClearView: Advisor/Consultant|IMMY Diagnostics: Grant/Research Support|Merck: Grant/Research Support|Pearl Diagnostics: Grant/Research Support|Pulmicide: Advisor/Consultant|Scynexis: Grant/Research Support

Real-world use of isavuconazole in adult oncohematology patients.

We analyzed administrative data to determine the 1-year incidence of invasive fungal infections (IFIs) in patients beginning small molecule kinase inhibitor (SMKI) therapy. The incidence of IFIs by small molecule kinase inhibitor ranged from 0.0% to 10.6%, with patients taking midostaurin having the highest incidence. An IFI developed in 38 of 1286 patients taking ibrutinib (3.0%).

Posaconazole is widely recommended for preventing and treating invasive fungal infections (IFIs) in immunocompromised patients, especially those with prolonged neutropenia. However, the concentration of the oral suspension formulation can be affected by factors such as co-administration with acid-suppressing medications, influencing its efficacy and safety. This study examined the impact of proton pump inhibitors (PPIs) and other factors on posaconazole concentrations and the concentration-to-dose ratio (C/D) while also evaluating adverse drug reactions in patients with hematologic malignancies. We conducted a retrospective analysis of patients who received posaconazole for IFI prophylaxis or treatment, assessing demographic and clinical data, adverse reactions, treatment outcomes, and drug concentration assays. The study focused on the effects of PPIs on Cmin and C/D. Data from 283 posaconazole Cmin measurements in 86 patients were analyzed. The incidence of probable or proven IFIs was 6.4% (5/78). PPI use reduced posaconazole Cmin levels but did not significantly impact prophylactic efficacy. Esomeprazole and rabeprazole were explicitly associated with decreased Cmin. Hepatotoxicity was linked to the co-administration of hepatotoxic drugs, indicating that posaconazole was not the sole contributor. Co-administration of esomeprazole or rabeprazole lowers posaconazole plasma concentrations without compromising prophylactic efficacy against IFIs. Nonetheless, caution is advised when combining these drugs in high-risk immunocompromised patients.

Invasive fungal infections in paediatric patients

Despite recent advances in the last decade, invasive fungal infections are still associated with a high morbidity and mortality. Invasive fungal infections constitute severe infectious complications in patients with hematological malignancies receiving myelosuppressive chemotherapy or sustained immunosuppression after allogeneic transplant regimens. Following a long period of stagnation, considerable progress has been made during the last 5 years in non-culture-based diagnostics and in the treatment of invasive fungal infections. This review highlights recent developments in the epidemiology, diagnosis, and treatment in the context of state-of-the-art management of invasive fungal infections in cancer patients.