Population Pharmacokinetics and Pharmacodynamics of Ciprofloxacin Prophylaxis in Pediatric Acute Lymphoblastic Leukemia Patients.

BACKGROUND: Ciprofloxacin is used as antimicrobial prophylaxis in pediatric acute lymphoblastic leukemia (ALL) to decrease infections with gram-negative bacteria. However, there are no clear guidelines concerning prophylactic dose. AIMS: To determine the pharmacokinetics and pharmacodynamics (PKPD) of ciprofloxacin prophylaxis in a pediatric ALL population. The effect of patient characteristics and antileukemic treatment on ciprofloxacin exposure, the area under the concentration time curve over minimal inhibitory concentration (AUC24/MIC) ratios, and emergence of resistance were studied. METHODS: A total of 615 samples from 129 children (0-18 years) with ALL were collected in a multicenter prospective study. A population pharmacokinetic model was developed. Microbiological cultures were collected prior to and during prophylaxis. An AUC24/MIC of ≥125 was defined as target ratio. RESULTS: A 1-compartment model with zero-order absorption and allometric scaling best described the data. No significant (P < .01) covariates remained after backward elimination and no effect of asparaginase or azoles were found. Ciprofloxacin AUC24 was 16.9 mg*h/L in the prednisone prophase versus 29.3 mg*h/L with concomitant chemotherapy. Overall, 100%, 81%, and 18% of patients at, respectively, MIC of 0.063, 0.125, and 0.25 mg/L achieved AUC24/MIC ≥ 125. In 13% of the patients, resistant bacteria were found during prophylactic treatment. CONCLUSION: Ciprofloxacin exposure shows an almost 2-fold change throughout the treatment of pediatric ALL. Depending on the appropriateness of 125 as target ratio, therapeutic drug monitoring or dose adjustments might be indicated for less susceptible bacteria starting from ≥ 0.125 mg/L to prevent the emergence of resistance and reach required targets for efficacy.

Cost-effectiveness of a combined physical exercise and psychosocial training intervention for children with cancer: Results from the quality of life in motion study.

This study was performed to estimate the cost-effectiveness of a combined physical exercise and psychosocial intervention for children with cancer compared with usual care. Sixty-eight children, aged 8-18 years old, during or within the first year post-cancer treatment were randomised to the intervention (n = 30) and control group (n = 38). Health outcomes included fitness, muscle strength and quality adjusted life years; all administered at baseline, 4- and 12-month follow-up. Costs were gathered by 1 monthly cost questionnaires over 12 months, supplemented by medication data obtained from pharmacies. Results showed no significant differences in costs and effects between the intervention and control group at 12-month follow-up. On average, societal costs were €299 higher in the intervention group than in the control group, but this difference was not significant. Cost-effectiveness acceptability curves indicated that the intervention needs large societal investments to reach reasonable probabilities of cost-effectiveness for quality of life and lower body muscle strength. Based on the results of this study, the intervention is not cost-effective in comparison with usual care.

Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity.

Busulfan (Bu) is used as a myeloablative agent in conditioning regimens before allogeneic hematopoietic cell transplantation (allo-HCT). In line with strategies explored in adults, patient outcomes may be optimized by replacing cyclophosphamide (Cy) with or without melphalan (Mel) with fludarabine (Flu). We compared outcomes in 2 consecutive cohorts of HCT recipients with a nonmalignant HCT indication, a myeloid malignancy, or a lymphoid malignancy with a contraindication for total body irradiation (TBI). Between 2009 and 2012, 64 children received Flu + Bu at a target dose of 80-95 mg·h/L, and between 2005 and 2008, 50 children received Bu targeted to 74-80 mg·h/L + Cy. In the latter group, Mel was added for patients with myeloid malignancy (n = 12). Possible confounding effects of calendar time were studied in 69 patients receiving a myeloablative dose of TBI between 2005 and 2012. Estimated 2-year survival and event-free survival were 82% and 78%, respectively, in the FluBu arm and 78% and 72%, respectively, in the BuCy (Mel) arm (P = not significant). Compared with the BuCy (Mel) arm, less toxicity was noted in the FluBu arm, with lower rates of acute (noninfectious) lung injury (16% versus 36%; P = .007), veno-occlusive disease (3% versus 28%; P = .003), chronic graft-versus-host disease (9% versus 26%; P = .047), adenovirus infection (3% versus 32%; P = .001), and human herpesvirus 6 infection reactivation (21% versus 44%; P = .005). Furthermore, the median duration of neutropenia was shorter in the FluBu arm (11 days versus 22 days; P < .001), and the patients in this arm required fewer transfusions. Our data indicate that Flu (160 mg/m(2)) with targeted myeloablative Bu (90 mg·h/L) is less toxic than and equally effective as BuCy (Mel) in patients with similar indications for allo-HCT.

Radiation exposure and mortality risk from CT and PET imaging of patients with malignant lymphoma.

OBJECTIVE: To quantify radiation exposure and mortality risk from computed tomography (CT) and positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)F-FDG) in patients with malignant lymphoma (Hodgkin's disease [HD] or non-Hodgkin's lymphoma [NHL]). METHODS: First, organ doses were assessed for a typical diagnostic work-up in children with HD and adults with NHL. Subsequently, life tables were constructed for assessment of radiation risks, also taking into account the disease-related mortality. RESULTS: In children with HD, cumulative effective dose from medical imaging ranged from 66 mSv (newborn) to 113 mSv (15 years old). In adults with NHL the cumulative effective dose from medical imaging was 97 mSv. Average fractions of radiation-induced deaths for children with HD [without correction for disease-related mortality in brackets] were 0.4% [0.6%] for boys and 0.7% [1.1%] for girls, and for adults with NHL 0.07% [0.28%] for men and 0.09% [0.37%] for women. CONCLUSION: Taking into account the disease-related reduction in life expectancy of patients with malignant lymphoma results in a higher overall mortality but substantial lower incidence of radiation induced deaths. The modest radiation risk that results from imaging with CT and (18)F-FDG PET can be considered as justified, but imaging should be performed with care, especially in children.

B-cell depletion abrogates immune mediated cytopenia and rejection of cord blood transplantation in Hurler syndrome.

Umbilical cord blood is the preferred donor cell source for children with Inherited Metabolic disorders undergoing Hematopoietic Cell Transplant (HCT), and its use has been associated with improved "engrafted survival" and higher donor chimerism compared to other cell sources. However, as in other pediatric cord blood transplants for non-malignant disease, immune-mediated cytopenia and primary graft failure limit its use, and the latter remains the commonest cause of death following cord blood transplant for non-malignant disease. We have previously shown an association between immune-mediated cytopenia and graft failure in inherited metabolic diseases suggesting that both immune-mediated cytopenia and graft failure could be mediated by antibodies from the residual recipient B cells. Since rituximab is effective in depletion of B cells and management of refractory immune-mediated cytopenia following HCT, we have added rituximab to the conditioning regimen. We studied 57 patients in 2 centers who received myeloablative conditioning for cord blood transplant in Hurler syndrome, and report a significant improvement in event-free survival with reduced incidence of graft failure and without any evidence of immune-mediated cytopenia in those patients that had received rituximab.

Refined characterization and reference values of the pediatric T- and B-cell compartments.

Work in the past years has led to a refined phenotypical description of functionally distinct T- and B-cell subsets. Since both lymphocyte compartments are established and undergo dramatic changes during childhood, redefined pediatric reference values of both compartments are needed. In a cohort of 145 healthy children, aged 0-18 years, the relative and absolute numbers of the various T- and B-cell subsets were determined. In addition, we found that besides thymic output, naive (CD27(+)CD45RO(-)) T-cell proliferation contributed significantly to the establishment of the naive T-cell compartment. At birth, regulatory (CD25(+)CD127(-)CD4(+)) T cells (Tregs) mainly had a naive (CD27(+)CD45RO(-)) phenotype whereas 'memory or effector-like' (CD45RO(+)) Tregs accumulated slowly during childhood. Besides the CD27(+)IgM(+)IgD(+) memory B-cell population, the recently identified CD27(-)IgG(+) and CD27(-)IgA(+) memory B-cell populations were already present at birth. These data provide reference values of the T- and B-cell compartments during childhood for studies of immunological disorders or immune reconstitution in children.

Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes.

Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area-based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conducted with data from patients undergoing HCT with fludarabine (160 mg/m2) as part of a myeloablative conditioning (busulfan targeted to an area under the plasma-concentration-time curve [AUC] of 90 mg*h/L) and rabbit antithymocyte globulin (6-10 mg/kg; from day -9/-12) between 2010 and 2016. Fludarabine exposure as AUC was calculated for each patient using a previously published population pharmacokinetic model and related to 2-year event-free survival (EFS) by means of (parametric) time-to-event models. Relapse, nonrelapse mortality (NRM), and graft failure were considered events. One hundred ninety-two patients were included (68 benign and 124 malignant disorders). The optimal fludarabine exposure was determined as an AUC of 20 mg*h/L. In the overexposed group, EFS was lower (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.5; P = .02), due to higher NRM (HR, 3.4; 95% CI, 1.6-6.9; P <001) associated with impaired immune reconstitution (HR, 0.43; 95% CI, 0.26-0.70; P <001). The risks of NRM and graft failure were increased in the underexposed group (HR, 3.3; 95% CI, 1.2-9.4; P = .02; HR, 4.8; 95% CI, 1.2-19; P = .02, respectively). No relationship with relapse was found. Fludarabine exposure is a strong predictor of survival after HCT, stressing the importance of optimum fludarabine dosing. Individualized dosing, based on weight and "renal function" or "therapeutic drug monitoring," to achieve optimal fludarabine exposure might improve survival.

Characteristics and quality of oral anticoagulation treatment in pediatric patients in the Netherlands based on the CAPS cohort.

Essentials The knowledge of quality and safety of acenocoumarol and phenprocoumon use in children is limited. We used data from a multicenter retrospective follow-up study in children in the Netherlands. The quality of anticoagulation control in the first month of use was low, but improved thereafter. No thromboembolic events occurred, however bleeding events occurred in 1-3 out of 10 patients. SUMMARY: Background The use of vitamin-K antagonists in pediatric patients is rare and information on the quality and safety of treatment with acenocoumarol and phenprocoumon is limited. Objectives To assess the quality, safety and effectiveness during the first year of acenocoumarol and phenprocoumon treatment in pediatric patients in the Netherlands. Methods The Children Anticoagulation and Pharmacogenetics Study (CAPS) was designed as a multicenter retrospective follow-up study. Patients who used acenocoumarol or phenprocoumon at an age of ≤ 18 years, were selected from four pediatric hospitals and one anticoagulation clinic in the Netherlands. The quality of treatment was assessed by calculating the percentage of time in therapeutic INR range (TTR) for the first month and for every 3 months of use during the first year of treatment. Effectiveness and safety were assessed by the number of thromboembolic and bleeding events. Results In total, 213 patients participated, of whom 187 (155 acenocoumarol; 32 phenprocoumon) were included in this analysis. The mean TTR was 47.0% and 51.4% in the first month of use for acenocoumarol and phenprocoumon, respectively. After the first 3 months the mean TTR for both VKAs was above 64%. In 14.6% (acenocoumarol) and 31.3% (phenprocoumon) of the patients a bleeding event occurred during the first year of treatment; no thromboembolic events were reported. Conclusions The quality of anticoagulation treatment was low during the first month of use and leaves room for improvement. After the first month it increased to an acceptable level. However, bleeding events occurred frequently during the first year.

The pediatric acenocoumarol dosing algorithm: the Children Anticoagulation and Pharmacogenetics Study.

Essentials A pediatric pharmacogenetic dosing algorithm for acenocoumarol has not yet been developed. We conducted a multicenter retrospective follow-up study in children in the Netherlands. Body surface area and indication explained 45.0% of the variability in dose requirement. Adding the genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased this to 61.8%. SUMMARY: Background The large variability in dose requirement of vitamin K antagonists is well known. For warfarin, pediatric dosing algorithms have been developed to predict the correct dose for a patient; however, this is not the case for acenocoumarol. Objectives To develop dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information. Methods The Children Anticoagulation and Pharmacogenetics Study was designed as a multicenter retrospective follow-up study in Dutch anticoagulation clinics and children's hospitals. Pediatric patients who used acenocoumarol between 1995 and 2014 were selected for inclusion. Clinical information and saliva samples for genotyping of the genes encoding cytochrome P450 (CYP) 2C9, vitamin K epoxide reductase complex subunit 1 (VKORC1), CYP4F2, CYP2C18 and CYP3A4 were collected. Linear regression was used to analyze their association with the log mean stable dose. A stable period was defined as three or more consecutive International Normalized Ratio measurements within the therapeutic range over a period of ≥ 3 weeks. Results In total, 175 patients were included in the study, of whom 86 had a stable period and no missing clinical information (clinical cohort; median age 8.9 years, and 49% female). For 80 of these 86 patients, genetic information was also available (genetic cohort). The clinical algorithm, containing body surface area and indication, explained 45.0% of the variability in dose requirement of acenocoumarol. After addition of the VKORC1, CYP2C9, and CYP2C18 genotypes to the algorithm, this increased to 61.8%. Conclusions These findings show that clinical factors had the largest impact on the required dose of acenocoumarol in pediatric patients. Nevertheless, genetic factors, and especially VKORC1, also explained a significant part of the variability.

Loss of antibodies and response to (re-)vaccination in children after treatment for acute lymphocytic leukemia: a systematic review.

Intensified chemotherapy regimens resulting in improved survival of children with acute lymphocytic leukemia (ALL) lead to concerns about therapy-induced immune damage reflected by the loss of protection of previous immunizations and the efficacy of (re-)vaccination. The severity of secondary immunodeficiency, however, is not clear and knowledge is based on a limited number of studies. We performed a systematic review on literature concerning vaccination data of children with ALL published since 1980. Eight studies fulfilled the inclusion criteria. Regarding antibody titers after treatment, the number of children who had preserved the defined protection level for antibodies differed widely, ranging from 17 to 98% for diphtheria, 27 to 82% for Bordetella pertussis, 20 to 98% for tetanus, 62 to 100% for poliomyelitis, 35 to 100% for Haemophilus influenzae type B (HiB), 29 to 92% for mumps, 29 to 60% for measles and 72 to 92% for rubella. Most patients however responded to revaccination, demonstrating immunological recovery. Although the designs and results of the included studies varied widely, it can be concluded that cytostatic therapy for ALL in children results in a temporarily reduction of specific antibody levels. Memory is preserved but revaccination may be warranted. This is the first systematic review and the best possible current approximation of chemotherapy-induced immune damage in children after ALL treatment.

Extramedullary infiltrates at diagnosis have no prognostic significance in children with acute myeloid leukaemia.

This retrospective study was designed to review the relative frequency and prognostic significance of extramedullary infiltrates in children with acute myeloid leukaemia (AML). The registration data and initial discharge summaries were reviewed for all children diagnosed with AML, and registered by the Dutch Childhood Leukaemia Study Group (DCLSG). Between 1972 and 1998, 477 children were diagnosed with AML. Of these patients, 120 (25.1%) had extramedullary leukaemia (EML) at diagnosis. Four categories of EML were found: skin, soft tissue or bone, gingival infiltration and central nervous system (CNS) involvement. Patients who presented with gingival infiltrates, were older than those without EML or those in the other EML subgroups, had a high initial WBC count and a high proportion of M4/M5 morphological variants. This type of presentation could indicate a special biological entity. Univariate analysis of prognostic factors in patients treated after 1985 with intensive protocols showed that initial WBC count and the presence of favourable cytogenetic findings were significant. The presence of EML at diagnosis had no significant effect on event-free survival. In a stepwise multiple regression analysis only favourable cytogenetic findings remained significant.

Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes.

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential to cure patients with an inherited bone marrow failure syndrome (IBMFS). However, the procedure involves the risk of treatment-related mortality and may be associated with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks. IBMFS are rare, whereas case reports and small series in the literature illustrate highly heterogeneous practices in terms of indications for HSCT, timing, stem cell source and conditioning regimens. A consensus meeting was therefore held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation to discuss HSCT in the setting of IBMFS. This report summarizes the recommendations from this expert panel, including indications for HSCT, timing, stem cell source and conditioning regimen.

Physiochemical disparity of mismatched HLA class I alloantigens and risk of acute GVHD following HSCT.

We determined whether assessment of the immunogenicity of individual donor-recipient HLA mismatches based on differences in their amino-acid sequence and physiochemical properties predicts clinical outcome following haematopoietic SCT (HSCT). We examined patients transplanted with 9/10 single HLA class I-mismatched grafts (n=171) and 10/10 HLA-A-, -B-, -C-, -DRB1- and -DQB1-matched grafts (n=168). A computer algorithm was used to determine the physiochemical disparity (electrostatic mismatch score (EMS) and hydrophobic mismatch score (HMS)) of mismatched HLA class I specificities in the graft-versus-host direction. Patients transplanted with HLA-mismatched grafts with high EMS/HMS had increased incidence of ⩾grade II acute GVHD (aGVHD) compared with patients transplanted with low EMS/HMS grafts; patients transplanted with low and medium EMS/HMS grafts had similar incidence of aGVHD to patients transplanted with 10/10 HLA-matched grafts. Mortality was higher following single HLA-mismatched HSCT but was not correlated with HLA physiochemical disparity. Assessment of donor-recipient HLA incompatibility based on physiochemical HLA disparity may enable better selection of HLA-mismatched donors in HSCT.

Biomarker profiling of steroid-resistant acute GVHD in patients after infusion of mesenchymal stromal cells.

We performed a prospective phase II study to evaluate clinical safety and outcome in 48 patients with steroid-refractory grade II-IV acute graft-versus-host disease (aGVHD) treated with mesenchymal stromal cells (MSCs). Clinical outcomes were correlated to comprehensive analyses of soluble and cellular biomarkers. Complete resolution (CR) of aGVHD at day 28 (CR-28) occurred in 12 (25%) patients, CR lasting >1 month (CR-B) occurred in 24 (50%) patients. One-year overall survival was significantly improved in CR-28 (75 versus 33%, P=0.020) and CR-B (79 versus 8%, P<0.001) versus non-CR patients. A six soluble biomarker-panel was predictive for mortality (HR 2.924; CI 1.485-5.758) when measured before MSC-administration. Suppression of tumorigenicity 2 (ST2) was only predictive for mortality 2 weeks after but not before MSC-administration (HR 2.389; CI 1.144-4.989). In addition, an increase in immature myeloid dendritic cells associated with decreased mortality (HR 0.554, CI 0.389-0.790). Patients had persisting T-cell responses against defined virus- and leukemia-associated antigens. In conclusion, our data emphasize the need to carefully assess biomarkers in cohorts with homogeneous GVHD treatments. Biomarkers might become an additional valuable component of composite end points for the rapid and efficient testing of novel compounds to decrease lifecycle of clinical testing and improve the success rate of phase II/III trials.

The appearance of transferrin receptors on cultured human cytotrophoblast and in vitro-formed syncytiotrophoblast.

Using trypsinization and Percoll gradient centrifugation, mononuclear cell populations were prepared from human term placentae. These populations consist mainly of cytotrophoblast, which probably lacks transferrin receptors. In vitro, transferrin receptors appear on these mononuclear cells and on syncytiotrophoblast formed in vitro, independently, of cellular fusion and proliferative state.

Cidofovir for adenovirus infections after allogeneic hematopoietic stem cell transplantation: a survey by the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.

Adenovirus is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation and there is no established therapy. Cidofovir has in vitro efficacy against adenovirus. We performed a retrospective analysis of 45 patients treated with cidofovir for adenovirus from 10 centers. In total, 16 patients had definite adenovirus disease, 13 probable disease, and 16 asymptomatic infections. A total of 31 (69%) patients were successfully treated with cidofovir, 10 failed, and four were not evaluable owing to early death from other causes. Cidofovir therapy was successful in 10 patients with adenovirus disease, 10 patients with probable disease, and in 10 patients with asymptomatic infections. The overall survival at 28 days and 6 months after initiation of cidofovir therapy was 76 and 46%, respectively. Of the patients, 18 developed toxicity associated with cidofovir: 14 developed renal toxicity and four other types of toxicities. We conclude that cidofovir may be useful against adenovirus after allogeneic hematopoietic stem cell transplantation but additional studies are needed.

Pregnancy and guinea-pig isotransferrins--isolation and characterization of both isotransferrins.

Microheterogeneity patterns of pregnant and non-pregnant guinea-pig serum transferrin differ significantly. Using preparative isoelectric-focusing 'slow' and 'fast' isotransferrins were separated. Amino-acid and carbohydrate composition of these two fractions are presented.

[Congenital amegakaryocytic thrombocytopenia: indication for allogeneic stem cell transplantation]. / Congenitale amegakaryocytaire trombocytopenie: indicatie voor allogene stamceltransplantatie.

In two neonates, girls, persistent thrombocytopenia was found, which afterwards proved to be caused by a megakaryocytosis. Congenital amegakaryocytic thrombocytopenia is a rare bone marrow failure in young children that is defined as thrombocytopenia with absent or markedly decreased megakaryocytes in the bone marrow. Untreated, amegakaryocytic thrombocytopenia progresses to marrow failure with pancytopenia. Allogeneic stem cell transplantation offers the only possibility for cure, and is successful in approximately half of the patients. Both patients were treated by stem cell transplantation, the one with a matched unrelated donor, the second with stem cells from her HLA-identical sister. The first patient died, the second recovered with a normal number of circulating thrombocytes of donor origin.

Outcome of invasive mechanical ventilation after pediatric allogeneic hematopoietic SCT: results from a prospective, multicenter registry.

Exact data on prognosis of children receiving invasive mechanical ventilation (IMV) after allogeneic hematopoietic SCT (HSCT) is lacking. We therefore started a prospective registry in four European university HSCT centers (Leiden, Paris, Prague and Utrecht) and their pediatric intensive care units (PICUs). The registry started in January 2009. In January 2013, the four centers together had treated a total of 83 admissions with IMV. The case fatality rate in these patients was 52%. Mortality 6 months after PICU discharge was 45%. There were significant differences between centers in the proportion of children who received IMV after HSCT (6-23%, P<0.01), in severity of disease on admission to PICU (predicted mortality 14-37%, P<0.01), in applying noninvasive ventilation before IMV (3-75% of admissions, P<0.01) and in the use of renal replacement therapy (RRT) (8-58% of admissions, P<0.01). Severe impairment in oxygenation, use of RRT and CMV viremia were independent predictors of mortality. Our study shows that mortality in children receiving IMV after HSCT remains high, but has clearly improved compared with older studies. Patient selection and treatment in PICU differed significantly between centers, which underscores the need to standardize and optimize the PICU admission criteria, ventilatory strategies and therapies applied in PICU.

Predictors of invasive fungal infection in pediatric allogeneic hematopoietic SCT recipients.

This study was aimed at finding predictors of invasive fungal infection (IFI) after pediatric allogeneic hematopoietic SCT (HSCT). All children who received allogeneic HSCT in the Wilhelmina Children's Hospital Utrecht between 2004 and 2012 were included. HSCT data were prospectively collected. Patients were retrospectively classified into high- or low-risk groups for developing IFI using criteria based on available literature. Predictors for the occurrence of IFI were analyzed using Cox regression models. We used logistic regression models to analyze the association between other HSCT-related complications and IFI. Secondary outcomes were overall survival and treatment-related mortality (TRM). Two-hundred nine patients were included in the analysis; median age was 6.6 years. The cumulative incidence of IFI was 12%. In patients classified as 'low risk' (n=75), only 5.3% developed IFI (odds ratio (OR): 0.325; P=0.047). In multivariate analysis, a predictor for the occurrence of IFI was an a priori determined HSCT TRM risk >20% (based on EBMT-risk score). Post-HSCT, the administration of high-dose steroids was associated with IFI (OR: 4.458; P=0.010). Patients who developed IFI showed an increased risk of TRM (OR: 3.773; P=0.004). These results confirm that risk group stratification should guide intensity of monitoring for IFI and use of antifungal prophylaxis.