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Summary: 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.

Invasive fungal infections (IFI) cause morbidity and mortality in children with acute leukemia (AL). We retrospectively collected data on febrile neutropenic episodes (FNE) in AL children (2016–2021) and assessed factors associated with proven/probable IFI. Ninety-three children developed 339 FNE. Seventeen (18.3%) children developed 19 proven/probable IFI (11 yeast; eight molds). The proven/probable yeast IFI rate was 6/52 (11.5%) in children who belong to the high risk for IFI category (HR-IFI-AL: high-risk acute lymphocytic leukemia (ALL), acute myeloid leukemia, relapse); and 5/41 (12.2%) in the non-HR-IFI-AL category (standard/intermediate risk ALL). The proven/probable mold IFI rate was 7/52 (13.5%) in HR-IFI-AL children and 1/41 (2.4%) in the non-HR-IFI-AL category. In the multivariable analysis, underlying genetic syndrome, oral mucositis, and older age were significantly associated with proven/probable IFI, while a longer time since AL diagnosis was protective. Two of 13 (15.4%) HR-IFI-AL children died because of IFI. The elevated risks of proven/probable mold IFI and the associated mortality in HR-IFI-AL children, and high risk of invasive candidiasis in the non-HR-IFI-AL group, emphasize the need for the close monitoring of local epidemiology and the adjustment of practices accordingly.

Candida spp. can cause bloodstream infection and is associated with significant mortality. The proportion of fluconazole-resistant Candida non-albicans has increased over the years, and empirical fluconazole maybe inappropriate. In this retrospective study, we analyzed clinical characteristics, antifungal resistance patterns, and mortality in children with candidemia treated at a tertiary medical center in Jerusalem between 2009 and 2022. A total of 122 children developed 127 candidemia episodes with 132 Candida isolates. Half the episodes occurred in immunocompromised children. Septic shock was present in 27 (21.3%). Candida non-albicans was responsible for 71/132 (56.5%) episodes; 16/132 (12.1%) of isolates were fluconazole-resistant. The rate of Candida non-albicans was significantly higher in fluconazole-resistant episodes (90 vs. 50.5%, p = 0.02). Prolonged severe neutropenia and previous fluconazole exposure were more frequent in fluconazole-resistant episodes. Thirty-day mortality was 25 (19.7%). Greater mortality, as shown by multivariate analysis, was associated with candidemia contracted in the pediatric intensive care unit (PICU), previous use of azoles or carbapenems, and in the presence of shock. In conclusion, mortality rates in our study were higher than those previously reported. In suspected infection associated with factors which we found to increase the probability of mortality—PICU admission, shock, and earlier azole or carbapenems exposure—empirical antifungals should be considered.

BackgroundHematopoietic stem cell transplantation (HSCT) is the only curative option for many nonmalignant hematopoietic-derived diseases in pediatric patients. Survival after HSCT has improved in recent years and resulted in a 90% survival rate and cure in some nonmalignant diseases. Graft-vs.-host disease (GVHD) remains a frequent and major complication of HSCT, and a leading cause of morbidity and mortality. Prognosis of patients with high-grade GVHD is dismal, with survival rates varying from 25% in the adult population to 55% in pediatric patients.MethodsThe main aim of this study is to evaluate the incidence, risk factors, and outcome of severe acute GVHD (AGVHD) in pediatric patients with nonmalignant diseases, following allogeneic HSCT. Clinical and transplant data were retrospectively collected for all pediatric patients who underwent allogeneic HSCT for nonmalignant diseases at the Hadassah Medical Center between 2008 and 2019. Patients who developed severe AGVHD were compared with those who did not.ResultsA total of 247 children with nonmalignant diseases underwent 266 allogeneic HSCTs at Hadassah University Hospital over an 11-year period. Seventy-two patients (29.1%) developed AGVHD, 35 of them (14.1%) severe AGVHD (grade 3–4). Significant risk factors for developing severe AGVHD were unrelated donor (p

We investigated the incidence and outcome of anti-CD19 chimeric antigen receptor (CAR) T-cells-associated Common Terminology Criteria for Adverse Events (CTCAE) ≥grade 3 cytopenia. In the EBMT CAR-T registry, we identified 398 adult patients with large B-cell lymphoma who had been treated with CAR-T-cells with axicel (62%) or tisacel (38%) before August 2021 and had cytopenia status documented for the first 100 days. Most patients had received two or three previous lines of therapy, however, 22.3% had received four or more. Disease status was progressive in 80.4%, stable in 5.0% and partial/complete remission in 14.6%. 25.9% of the patients had received a transplantation before. Median age was 61.4 years (min–max; IQR=18.7–81; (52.9–69.5)).The cumulative incidence of ≥grade 3 cytopenia was 9.0% at 30 days (95% CI (6.5 to 12.1)) and 12.1% at 100 days after CAR T-cell infusion (95% CI (9.1 to 15.5)). The median time from CAR-T infusion to cytopenia onset was 16.5 days (min–max; IQR=1–90; (4–29.8)). Grade 3 and grade 4 CTCAE cytopenia occurred in 15.2% and 84.8%, respectively. In 47.6% there was no resolution.Severe cytopenia had no significant impact on overall survival (OS) (HR 1.13 (95% CI 0.74 to 1.73), p=0.57). However, patients with severe cytopenia had a poorer progression-free survival (PFS) (HR 1.54 (95% CI 1.07 to 2.22), p=0.02) and a higher relapse incidence (HR 1.52 (95% CI 1.04 to 2.23), p=0.03). In those patients who developed severe cytopenia during the first 100 days (n=47), OS, PFS, relapse incidence and non-relapse mortality at 12 months after diagnosis of severe cytopenia were 53.6% (95% CI (40.3 to 71.2)), 20% (95% CI (10.4 to 38.6)), 73.5% (95% CI (55.2 to 85.2)) and 6.5% (95% CI (1.7 to 16.2)), respectively.In multivariate analysis of severe cytopenia risk factors, only year of CAR-T infusion (HR=0.61, 95% CI (0.39 to 0.95), p=0.028) and total number of treatment lines before CAR-T infusion (one or two lines vs three or more, HR=0.41, 95% CI (0.21 to 0.83), p=0.013) had a significant positive association with the incidence of cytopenia. Other factors, such as previous transplantation, disease status at time of CAR-T, patient age and patient sex, had no significant association.Our data provide insight on frequency and clinical relevance of severe cytopenia after CAR T-cell therapy in the European real-world setting.

IntroductionCOVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients.MethodsThis study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic.ResultsThe median age was 50.3 years (min – max; 1.0 – 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min – max; 0.0 – 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 – 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is an efficient treatment for numerous malignant and nonmalignant conditions affecting children. This procedure can result in infectious and noninfectious neurological complications (NCs).ObjectiveThe objective of the study is to examine the incidence, risk factors, and outcomes of NCs in pediatric patients following allogeneic HSCT.MethodsWe performed a retrospective study of 746 children who underwent 943 allogeneic HSCTs in two large pediatric hospitals in Israel from January 2000 to December 2019.ResultsOf the pediatric patients 107 (14.3%) experienced 150 NCs. The median follow-up was 55 months. Noninfectious NCs were more common than infectious NCs (81.3% vs. 18.7%). Factors significantly associated with type of NC (infectious vs. noninfectious) were underlying disease (immunodeficiency vs. malignant and metabolic/hematologic disease) (p-value = 0.000), and use of immunosuppressive agent, either Campath or ATG (p-value = 0.041). Factors with a significant impact on developing neurological sequelae post-NC were number of HSCT >1 (p-value = 0.028), the use of alemtuzumab as an immunosuppressive agent (p-value = 0.003), and infectious type of NC (p-value = 0.046). The overall survival rate of whole NC-cohort was 44%; one-third of all mortality cases were attributed to the NC. The strongest prognostic factors associated with mortality were older age at HSCT (p-value = 0.000), the use of alemtuzumab as an immunosuppressive agent (p-value = 0.004), and the existence of neurological sequelae (p-value = 0.000). Abnormal central nervous system imaging (p-value = 0.013), the use of alemtuzumab as an immunosuppressive agent (p-value = 0.019), and neurological sequelae (p-value = 0.000) had statistically significant effects on neurological cause of death.ConclusionInfectious and noninfectious NCs are a significant cause of morbidity and mortality following allogeneic HSCT in children. Further research is required to better understand the risk factors for different NCs and their outcomes regarding sequelae and survival.