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Influence of invasive aspergillosis during acute leukaemia treatment on survival after allogeneic stem cell transplantation: a prospective study of the EBMT Infectious Diseases Working Party
Penack, O., Tridello, G., Salmenniemi, U., Martino, R., Khanna, N., Perruccio, K., Fagioli, F., Richert-Przygonska, M., Labussière-Wallet, H., Maertens, J., et al
EClinicalMedicine. 2024;67:102393
Abstract
BACKGROUND Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed. METHODS We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints. FINDINGS 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01). INTERPRETATION Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure. FUNDING There was no external funding source for this study.
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Low-dose fluconazole as a useful and safe prophylactic option in patients receiving allogeneic hematopoietic stem cell transplantation
Hirade, K., Kusumoto, S., Hashimoto, H., Shiraga, K., Hagiwara, S., Oiwa, K., Suzuki, T., Kinoshita, S., Ri, M., Komatsu, H., et al
Cancer medicine. 2024
Abstract
BACKGROUND Invasive fungal infections (IFIs) represent a potentially fatal complication in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) if the initiation of therapy is delayed. Some guidelines recommend antifungal prophylaxis or preemptive therapy for these patients depending on the risk of IFIs following allogeneic HSCT. This retrospective study aimed to identify the group of patients who safely undergo allogeneic HSCT with low-dose fluconazole (FLCZ) prophylaxis (100 mg/day). METHODS We retrospectively reviewed 107 patients who underwent their first allogeneic HSCT at Nagoya City University Hospital from January 1, 2010, to December 31, 2019. We analyzed the efficacy of low-dose FLCZ prophylaxis and investigated the relationship between major risk factors and antifungal prophylaxis failure (APF) within 100 days post-transplant. RESULTS Of the 107 patients, 70 received low-dose FLCZ prophylaxis, showing a cumulative incidence of APF of 37.1% and a proven/probable IFI rate of 4.3%. There were no fungal infection-related deaths, including Aspergillus infections, in the FLCZ prophylaxis group. In a multivariable analysis, cord blood transplantation (CBT) (subdistribution hazard ratio (SHR), 3.55; 95% confidence interval (CI), 1.44-8.77; p = 0.006) and abnormal findings on lung CT before transplantation (SHR, 2.24; 95% CI, 1.02-4.92; p = 0.044) were independent risk factors for APF in the FLCZ prophylaxis group. CONCLUSION Low-dose FLCZ prophylaxis is a useful and safe option for patients receiving allogeneic HSCT, except in those undergoing CBT or having any fungal risk features including history of fungal infections, positive fungal markers, and abnormal findings on lung CT before transplantation.
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Oral Candida carriage and resistance against common antifungal agents in hematopoietic stem cell transplantation recipients
Mauramo, M., Tonoz, N., Halter, J., Joseph, B., Waltimo, T.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2024;32(3):185
Abstract
PURPOSE Allogeneic hematopoietic stem cell transplant (HSCT) recipients receiving long-term and high-dose immunosuppressive medications suffer commonly from oral candida infections. This prospective cohort study examined oral fungal carriage in HSCT recipients and screened the susceptibility against commonly used antifungal agents. An increasing oral occurrence of Candida spp. and the development of resistance against clinically administered fluconazole were hypothesized. METHODS Two hundred HSCT recipients were included and followed up for 2 years post-HSCT. Oral microbiological specimens were analyzed with matrix-assisted laser desorption/ionization-time of flight mass spectrometry assays (MALDI-TOF). The colorimetric method was applied for the susceptibility testing by commercially available Sensititre YeastOne (SYO®, TREK Diagnostics Systems, Thermo-Fisher, UK). RESULTS The prevalence of oral Candida spp. carriage increased statistically significantly after a year post-HSCT being 30, 26, 35, 44, and 47%, pre-HSCT, 3, 6, 12, and 24 months post-HSCT, respectively. Altogether, 169 clinical oral Candida strains were isolated. Fourteen Candida spp. were identified, and C. albicans was predominant in 74% of the isolates pre-HSCT with a descending prevalence down to 44% 2 years post-HSCT. An increasing relative proportion of non-albicans species post-HSCT was evident. No development of resistance of C. albicans against fluconazole was found. Instead, a shift from C. albicans towards non-albicans species, especially C. dubliensis, C. glabrata, and relatively seldom found C. krusei, was observed. CONCLUSION Oral Candida carriage increases after HSCT. Instead of the expected development of resistance of C. albicans against fluconazole, the relative proportion of non-albicans strains with innate resistance against azole-group antifungals increased.
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Effects of Extracorporeal Photopheresis on Quality of Life and the Course of Diseases in Patients With Mycosis Fungoides and Graft-Versus-Host Disease: A Single-Center Analysis
Vogiatzis, R., Krüger, W., Jünger, M., Arnold, A.
Cureus. 2023;15(5):e38929
Abstract
INTRODUCTION The aim of the study was to systematically analyze the influence of extracorporeal photopheresis (ECP) on the quality of life (LQ) and the course of the disease in patients with Mycosis Fungoides (MF), as well as with Graft-versus-Host Disease (GvHD). METHODS LQ was monitored retrospectively by using the dermatology life quality index (DLQI) and Skindex-29 test before ECP onset and after the last ECP. Disease parameters were assessed by objective criteria i.e. number of associated medical drugs taken, intervals between therapeutic cycles, gradual change of the disease, and eventual side-effects and complications of ECP therapy. RESULTS Fifty-one patients were treated with ECP during 2008-19; 19 out of 51 died, and follow-up was not completed in 13 patients. Finally, treatment protocols of 671 ECP procedures were evaluated in 19 patients (10 MF; 9 GvHD). MF and GvHD subpopulations did not differ in the individual scores of LQ questions, either before the outset or after the last ECP. DLQI and Skindex-29 scores were ameliorated by the ECP therapy (p= 0.001 and p< 0.001, respectively) due to improvement of individual scores of feelings, daily/social activities (p< 0.05), and functionality (p≤ 0.05). The median interval between ECP cycles was extended from two to eight weeks (p= 0.001). Needs of GvHD patients for drugs being received for the underlying disease were reduced (p= 0.035). Two of the 10 MF patients worsened from stage IIA to IIIA. Severe or minor side effects leading to a therapy interruption were not recorded. CONCLUSION Patients with GvHD experienced a notable decrease in the administration of drugs for their underlying condition, and there were no instances of severe side effects that resulted in the discontinuation of treatment. ECP is safe and effective for the treatment of MF and GvHD.
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Invasive Pulmonary Aspergillosis in Hospitalized Hematopoietic Stem Cell Transplantation Recipients: Outcomes Based on the United States National Readmission Database
Khalil, A., Singh, P., Mir, T., Uddin, M., Soubani, A. O.
Hematology/oncology and stem cell therapy. 2023;17(1):43-50
Abstract
BACKGROUND AND OBJECTIVE Hematopoietic stem cell transplant (HSCT) is a well-established treatment for hematologic malignancies and certain autoimmune and congenital conditions. HSCT is associated with immunocompromise and increased risk of infections. This study assessed whether invasive pulmonary aspergillosis (IPA) affects in-hospital mortality and 30-day readmission among HSCT patients. A secondary objective was to examine potential differences in complications between HSCT with and without IPA. MATERIALS AND METHODS A retrospective study of a nationally representative cohort of hospital admissions was conducted, with data collected from the Agency for Healthcare Research and Quality's Healthcare Cost and Utilization Project Nationwide Readmissions Database between 2013 and 2019. The International Classification of Diseases, 10th revision (ICD-10), and 9th revision (ICD-9) diagnostic codes were used to identify patients with IPA and HSCT. All adult patients ≥18 years were included in the study. RESULTS There were 90,451 hospitalizations for HSCT from 2013 to 2019; 89,331 (98.8%) had HSCT without IPA, while 1092 (1.2%) hospitalizations had HSCT with IPA. The in-hospital mortality for HSCT-IPA was higher compared to HSCT without IPA (18.3% vs. 4.2%; p < 0.001). HSCT-IPA had a significantly higher 30-day readmission rate (36.2%) than that of HSCT without IPA (24.0%). HSCT-IPA also had a higher mean cost of admission ($303,437) than that of HSCT without IPA ($57,587).The HSCT-IPA group had higher multi-organ complications, including respiratory failure (51.3% vs. 13.5%, p < 0.001), sepsis (38.2% vs. 18.5%, p < 0.001), septic shock (16.1% vs. 5.1%, p < 0.001), need for mechanical ventilation (21.1% vs. 5.1% p < 0.001), non-invasive positive pressure ventilation (4.9% vs. 2.5%, p < 0.001), and intensive-care unit admission (21.8% vs. 6.1% p < 0.001). CONCLUSION IPA is a rare but severe complication associated with HSCT, with higher in-hospital mortality, complications due to multi-organ failure, readmission rates, and cost of hospitalization when compared to HSCT without IPA.
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Association Between Candidemia and Noninfectious Interstitial Pneumonia After Allogeneic Hematopoietic Cell Transplantation: JSTCT Transplant Complications Working Group
Kimura, S. I., Akahoshi, Y., Shiratori, S., Okinaka, K., Harada, K., Uchida, N., Doki, N., Ikegame, K., Nakamae, H., Tanaka, M., et al
Open forum infectious diseases. 2023;10(4):ofad163
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Abstract
BACKGROUND α-mannan from Candida albicans reportedly induces Th17-mediated pulmonary graft-versus-host disease (GVHD) in mouse models. This study aimed to evaluate the association between candidemia and noninfectious interstitial pneumonia (IP) in allogeneic hematopoietic cell transplantation (HCT) recipients. METHODS Using a Japanese transplant registry database, we analyzed 9143 pediatric and adult patients with hematological malignancies who underwent their first (n = 7531) or second (n = 1612) allogeneic HCT between 2009 and 2019. RESULTS Noninfectious IP was observed in 694 patients at a median (range) of 63 (0-1292) days after HCT. Candidemia occurred in 358 patients at a median (range) of 31 (0-903) days after HCT. Candidemia treated as a time-dependent covariate was significantly associated with an increased incidence of noninfectious IP (hazard ratio [HR], 2.51; 95% CI, 1.48-4.25), along with total body irradiation (>8 Gy; HR, 1.57; 95% CI, 1.18-2.10) and malignant lymphoma (vs acute myeloid leukemia; HR, 1.30; 95% CI, 1.004-1.69). On the other hand, prompt platelet recovery (HR, 0.58; 95% CI, 0.45-0.75) and acute lymphoblastic leukemia (vs acute myeloid leukemia; HR, 0.68; 95% CI, 0.49-0.94) were associated with reduced incidence of noninfectious IP. The median survival after the development of noninfectious IP in patients with prior candidemia was significantly shorter than that in those without it (22 days vs 59 days; P < .001). CONCLUSIONS Candidemia was associated with an increased incidence of noninfectious IP. The prognosis of noninfectious IP after candidemia was extremely poor.
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Pneumocystis pneumonia after allogeneic hematopoietic cell transplantation: A case-control study on epidemiology and risk factors on behalf of the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation
Robin, C., Cordonnier, C., Tridello, G., Knelange, N., Xhaard, A., Chantepie, S., Tanguy-Schmidt, A., Schouten, H. C., Yesherun, M., Rocha, V., et al
Transplantation and cellular therapy. 2023
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Pharmacogenetic and clinical predictors of voriconazole concentration in hematopoietic stem cell transplant recipients receiving CYP2C19-guided dosing
Patel, J. N., Robinson, M., Morris, S. A., Jandrisevits, E., Lopes, K. E., Hamilton, A., Steuerwald, N., Druhan, L. J., Avalos, B., Copelan, E., et al
The pharmacogenomics journal. 2023
Abstract
CYP2C19-guided voriconazole dosing reduces pharmacokinetic variability, but many patients remain subtherapeutic. The aim of this study was to evaluate the effect of candidate genes and a novel CYP2C haplotype on voriconazole trough concentrations in patients receiving CYP2C19-guided dosing. This is a retrospective candidate gene study in allogeneic hematopoietic cell transplant (HCT) patients receiving CYP2C19-guided voriconazole dosing. Patients were genotyped for ABCB1, ABCG2, CYP2C9, CYP3A4, CYP3A5, and the CYP2C haplotype. Of 185 patients, 36% were subtherapeutic (of which 79% were normal or intermediate metabolizers). In all patients, CYP2C19 (p < 0.001), age (p = 0.018), and letermovir use (p = 0.001) were associated with voriconazole concentrations. In the subset receiving 200 mg daily (non-RM/UMs), CYP2C19 (p = 0.004) and ABCG2 (p = 0.015) were associated with voriconazole concentrations; CYP2C19 (p = 0.028) and letermovir use (p = 0.001) were associated with subtherapeutic status. CYP2C19 phenotype and letermovir use were significantly associated with subtherapeutic voriconazole concentrations and may be used to improve voriconazole precision dosing, while further research is needed to clarify the role of ABCG2 in voriconazole dosing.
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Prophylaxis for invasive fungal infection in pediatric patients with allogeneic hematopoietic stem cell transplantation
Perez, P., Patiño, J., Franco, A. A., Rosso, F., Beltran, E., Manzi, E., Castro, A., Estacio, M., Valencia, D. M.
Blood research. 2022
Abstract
BACKGROUND Antifungal prophylaxis is recommended for hematopoietic stem cell transplantation (HSCT) to decrease the incidence of invasive fungal infections (IFI). This study aimed to compare the two groups of antifungal prophylaxis in pediatric patients undergoing allogeneic HSCT. METHODS This observational, analytic, retrospective cohort study compared the incidence of IFI with antifungal prophylaxis with voriconazole vs. other antifungals in the first 100 days after allogeneic HSCT in patients aged <18 years between 2012 and 2018. The statistical analysis included univariate and multivariate analyses and determination of the cumulative incidence of invasive fungal infection by the Kaplan-Meier method using STATA 14 statistical software. RESULTS A total of 139 allogeneic HSCT were performed. The principal diagnosis was acute leukemia (63%). The 75% had haploidentical donors, and 50% used an antifungal in the month before transplantation. Voriconazole (69%) was the most frequently administered antifungal prophylaxis. The cumulative incidence of IFI was 5% (7 cases). Of the patients with IFIs, four began prophylaxis with voriconazole, one with caspofungin, and one with fluconazole. Additionally, six were possible cases, one was proven (Candida parapsilosis), and 1/7 died. CONCLUSION There were no differences in the incidence of IFI between patients who received prophylaxis with voriconazole and other antifungal agents.
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Sequential low-dose CT thorax scans to determine invasive pulmonary fungal infection incidence after allogeneic hematopoietic cell transplantation
Enger, K., Tonnar, X., Kotter, E., Bertz, H.
Annals of hematology. 2022
Abstract
Invasive fungal disease (IFD) during neutropenia goes along with a high mortality for patients after allogeneic hematopoietic cell transplantation (alloHCT). Low-dose computed tomography (CT) thorax shows good sensitivity for the diagnosis of IFD with low radiation exposure. The aim of our study was to evaluate sequential CT thorax scans at two time points as a new reliable method to detect IFD during neutropenia after alloHCT. We performed a retrospective single-center observational study in 265/354 screened patients admitted for alloHCT from June 2015 to August 2019. All were examined by a low-dose CT thorax scan at admission (CT t(0)) and after stable neutrophil recovery (CT t(1)) to determine the incidences of IFD. Furthermore, antifungal prophylaxis medications were recorded and cohorts were analyzed for statistical differences in IFD incidence using the sequential CT scans. In addition, IFD cases were classified according to EORTC 2008. At CT t(0) in 9.6% of the patients, an IFD was detected and antifungal therapy initiated. The cumulative incidence of IFD in CT t(1) in our department was 14%. The use of Aspergillus-effective prophylaxis through voriconazole or posaconazole decreased CT thorax t(1) suggesting IFD is statistically significant compared to prophylaxis with fluconazole (5.6% asp-azol group vs 16.3% fluconazole group, p = 0.048). In 86%, CT t(1) was negative for IFD. Low-dose sequential CT thorax scans are a valuable tool to detect pulmonary IFDs and guide antifungal prophylaxis and therapies. Furthermore, a negative CT t(1) scan shows a benefit by allowing discontinuation of antifungal medication sparing patients from drug interactions and side effects.