SARS-CoV-2 Infection in the Pediatric Oncology Population: The Definitive Comprehensive Report of the Infectious Diseases Working Group of AIEOP.

OBJECTIVE: The objective of this study was to assess the clinical impact and outcome of the SARS-CoV-2 infection on children with cancer or those who received a hematopoietic stem cell transplantation. METHODS: AIEOP (Italian Association of Pediatric Hematology and Oncology) performed a nationwide multicenter observational cohort study, including consecutive patients between April 2020 and November 2022. RESULTS: Twenty-five Italian centers participated and 455 patients were enrolled. We reported a significant increasing trend of symptomatic cases over the years, while the number of nonmild infections remained stable. Early infection after oncologic diagnosis (<60 days) and severe neutropenia were identified as independent risk factors for developing moderate, severe, or critical infections. The percentage of patients who were asymptomatic and mildly symptomatic and who stopped chemotherapy reduced over the years of the pandemic. Nine patients died, but no death was attributed to SARS-CoV-2 infection. CONCLUSIONS: SARS-CoV-2 infection presented a self-limiting benign course in the Italian pediatric oncohematology population during the pandemic, and its main consequence has been the discontinuation of cancer-directed therapies. The rate of patients who were asymptomatic and stopped chemotherapy reduced over the years, suggesting that the continuation of chemotherapy is a feasible option.

Application of the Weighted-Incidence Syndromic Combination Antibiogram (WISCA) to guide the empiric antibiotic treatment of febrile neutropenia in oncological paediatric patients: experience from two paediatric hospitals in Northern Italy.

BACKGROUND: Guidelines about febrile neutropenia in paediatric patients are not homogeneous; the best empiric treatment of this condition should be driven by local epidemiology. The Weighted-Incidence Syndromic Combination Antibiogram (WISCA) addresses the need for disease-specific local susceptibility evidence that could guide empiric antibiotic prescriptions based on outcome estimates of treatment regimens obtained as a weighted average of pathogen susceptibilities. This study developed a WISCA model to inform empirical antibiotic regimen selection for febrile neutropenia (FN) episodes in onco-haematological paediatric patients treated at two Italian paediatric tertiary centres. METHODS: We included blood cultures from patients with a bloodstream infection and neutropenia admitted to the Paediatric Haematology-Oncology wards in Padua and Genoa Hospitals from 2016 to 2021. WISCAs were developed by estimating the coverage of 20 antibiotics as monotherapy and of 21 combined regimens with a Bayesian probability distribution. RESULTS: We collected 350 blood cultures, including 196 g-negative and 154 g-positive bacteria. Considering the most used antibiotic combinations, such as piperacillin-tazobactam plus amikacin, the median coverage for the pool of bacteria collected in the study was 78%. When adding a glycopeptide, the median coverage increased to 89%, while the replacement of piperacillin-tazobactam with meropenem did not provide benefits. The developed WISCAs showed that no monotherapy offered an adequate coverage rate for the identified pathogens. CONCLUSIONS: The application of WISCA offers the possibility of maximizing the clinical utility of microbiological surveillance data derived from large hospitals to inform the choice of the best empiric treatment while contributing to spare broad-spectrum antibiotics.

Vaccination practices in pediatric transplantation: A survey among member centers of the European reference network TransplantChild.

BACKGROUND: There is considerable variation in vaccination practices between pediatric transplant centers. This study aims to evaluate active immunization attitudes and practices among ERN-TransplantChild centers and identify potential areas of improvement that could be addressed by shared evidence-based protocols. METHODS: A cross-sectional questionnaire of attitudes and practices toward immunization of pediatric SOT and HSCT candidates and recipients was sent to a representative member of multidisciplinary teams from 27 European centers belonging to the ERN-TransplantChild. RESULTS: A total of 28/62 SOT programs and 6/12 HSCT programs across 21 European centers participated. A quarter of centers did not have an on-site protocol for the immunizations. At the time of transplantation, pediatric candidates were fully immunized (80%-100%) in 57% and 33% of the SOT and HSCT programs. Variations in the time between vaccine administration and admission to the waiting list were reported between the centers, with 2 weeks for inactivated vaccines and variable time (2-4 weeks) for live-attenuated vaccines (LAVs). Almost all sites recommended immunization in the post-transplant period, with a time window of 4-8 months for the inactivated vaccines and 16-24 months for MMR and Varicella vaccines. Only five sites administer LAVs after transplantation, with seroconversion evaluated in 80% of cases. CONCLUSIONS: The immunization coverage of European pediatric transplant recipients is still inconsistent and far from adequate. This survey is a starting point for developing shared evidence-based immunization protocols for safe vaccination among pediatric transplant centers and generating new research studies.

Hypogammaglobulinemia in Children After Hematopoietic Stem Cell Transplantation and Rituximab Treatment: Relevance of B Cell Subsets.

Rituximab (RTX) is widely employed to treat Epstein-Barr virus reactivation in children undergoing Hematopoietic Cell Transplantation (HCT). The resulting loss of B cells may cause persistent hypogammaglobulinemia. This retrospective cross-sectional study aims to identify flow cytometry biomarkers associated with persistent hypogammaglobulinemia in patients receiving RTX after HCT. We analyzed 5 patients (cases group) requiring immunoglobulin substitution due to low level of IgG (IgG <5 g/L) detected after RTX treatment and 5 patients (controls group) not requiring long-term immunoglobulin (Ig) substitution. We investigated the B cell reconstitution, and in patients group we observed a significantly lower count in B total, IgD+CD27+ marginal B cells and IgD-CD27+ switched-memory B cells, after a median of 5 years from HCT, compared with the control group. Despite the importance limits of our study and the heterogeneity of our data (age of included patients, time of evaluation, interval between RTX dose and assessment) we conclude that RTX given early after HCT might cause a deranged B cell maturation, contributing to the delation in B cell recovery following HCT, and switched memory and marginal zone B cell counts could be a promising biomarker to identify patients requiring long-term Ig substitution.

Favorable outcome of SARS-CoV-2 infection in pediatric hematology oncology patients during the second and third pandemic waves in Italy: a multicenter analysis from the Infectious Diseases Working Group of the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP).

COVID-19 has a mild clinical course with low mortality rate in general pediatric population, while variable outcomes have been described in children with cancer. Infectious diseases working party of the AIEOP collected data on the clinical characteristics and outcomes of SARS-CoV-2 infections in pediatric oncology/hematology patients from April 2020 to May 2021, including the second and the third waves of the pandemic in Italy. Factors potentially associated with moderate, severe, or critical COVID-19 were analyzed. Of the 153 SARS-Cov2 infections recorded, 100 were asymptomatic and 53 symptomatic. The course of COVID-19 was mild in 41, moderate in 2, severe in 5, and critical in 5 children. A total of 40.5% of patients were hospitalized, ten requiring oxygen support and 5 admitted to the intensive care unit. Antibiotics and steroids were the most used therapies. No patient died due to SARS-CoV-2 infection. Infections occurring early (< 60 days) after the diagnosis of the underlying disease or after SCT were associated to moderate, severe, and critical disease compared to infections occurring late (> 60 days) or during maintenance therapy. In the patients on active chemotherapy, 59% withdrew the treatment for a median of 15 days. SARS-CoV-2 presented a favorable outcome in children with cancer in Italy during the pandemic. Modification of therapy represents a major concern in this population. Our findings suggest considering regular chemotherapy continuation, particularly in patients on maintenance therapy or infected late after the diagnosis.

Pediatric transplantation in Europe during the COVID-19 pandemic: Early impact on activity and healthcare.

The current pandemic SARS-CoV-2 has required an unusual allocation of resources that can negatively impact chronically ill patients and high-complexity procedures. Across the European Reference Network on Pediatric Transplantation (ERN TransplantChild), we conducted a survey to investigate the impact of the COVID-19 outbreak on pediatric transplant activity and healthcare practices in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The replies of 30 professionals from 18 centers in Europe were collected. Twelve of 18 centers (67%) showed a reduction in their usual transplant activity. Additionally, outpatient visits have been modified and restricted to selected ones, and the use of telemedicine tools has increased. Additionally, a total of 14 COVID-19 pediatric transplanted patients were identified at the time of the survey, including eight transplant recipients and six candidates for transplantation. Only two moderate-severe cases were reported, both in HSCT setting. These survey results demonstrate the limitations in healthcare resources for pediatric transplantation patients during early stages of this pandemic. COVID-19 disease is a major worldwide challenge for the field of pediatric transplantation, where there will be a need for systematic data collection, encouraging regular discussions to address the long-term consequences for pediatric transplantation candidates, recipients, and their families.

Successful Treatment of an EBV-positive Diffuse Large B-Cell Lymphoma in a Patient With Trisomy 21.

Diffuse large B-cell Lymphoma (DLBCL) secondary to a chronic severe Epstein-Barr virus (EBV) infection has not been previously described in a patient with trisomy 21. Here we report the case of a 14-year-old girl with trisomy 21 with impaired control of EBV and DLBCL. She was cured with dose-adapted chemotherapy and hematopoietic stem cell transplantation without severe treatment-related toxicity. We describe the first case of EBV-positive DLBCL in a patient with trisomy 21 and we propose a treatment modality for this rare entity.

Posaconazole delayed-release tablets in paediatric haematology-oncology patients.

BACKGROUND: To date, there are few studies that describe pharmacokinetics, safety and efficacy of posaconazole delayed-release tablet (DRT) formulation in the paediatric population. OBJECTIVES: We evaluated retrospectively posaconazole plasma concentrations and safety of posaconazole DRT in paediatric haematology-oncology patients. PATIENTS AND METHODS: Posaconazole DRT was assessed in 28 haematological paediatric patients with a median age 15 of years (range 5-18) and a median body weight of 50 kg (range 22-83 kg). Twenty-one patients received posaconazole DRT as prophylaxis and 7 patients as therapy. RESULTS: As prophylaxis, the median daily dose was 5.5 mg/kg/day (range 2.2-22.2) with posaconazole trough level ≥ 0.7 µg/mL in 80% by first week, 62.5% by second week and 87.5% by fourth week. As therapy, the median daily dose was 4 mg/kg/day (range 3.3-4.5) with trough level ≥ 1 µg/mL 100% by first week, 80% by second week and 33.4% by fourth week. CONCLUSIONS: Posaconazole DRT is feasible in paediatric patients capable to swallow tablets. Specific pharmacokinetic studies are needed.

A mixed-methods study of the disease experience in hematopoietic stem cell transplantation survivors: the contribution of text analysis.

OBJECTIVES: Few studies have detected qualitative and quantitative aspects of patients who underwent HSCT during childhood. The aims of this study are to explore the most recurrent narrative themes of HSCT experience in families five years after the procedure, and to observe statistical correlations between meaning attributed to the experience and defined variables. METHODS: Thirty-five families of pediatric HSCT survivors participated in the research. Both survivors and their families were asked to write a brief composition about their disease experiences. Qualitative analysis of the texts was performed using the T-LAB software. Information about medical aspects and psychological problems in HSCT survivors were collected with interviews and administering the Child Behavior Checklist 6-18. RESULTS: HSCT survivor families that reported the presence of externalizing and internalizing symptoms focused on thematic areas concerning broken families with separation between parents and the affected child versus healthy children. CONCLUSIONS: Long term psychological problems seem to be connected to the perception of family disruption. Specifically, family relationships seem to be the factor that protects from or enhances the risk of psychopathology in HSCT survivors. Moreover, the use of metaphoric terms to refer to HSCT presents higher associations with psychopathology. On the contrary, the possibility of referring directly to the transplantation is associated with psychological well-being. It is important to consider the family as a group in order to improve care.

Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease after Autologous or Allogeneic Hematopoietic Stem Cell Transplantation in Children: a retrospective study of the Italian Hematology-Oncology Association-Hematopoietic Stem Cell Transplantation Group.

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a potentially life-threatening complication that may develop after hematopoietic stem cell transplantation (HSCT). The aims of this retrospective multicenter study were to evaluate the incidence of SOS/VOD in a large cohort of children transplanted in centers across Italy by applying the new European Society for Blood and Marrow Transplantation (EBMT) criteria and to analyze the risk factors underlying this complication. We retrospectively reviewed data of pediatric HSCTs performed in 13 AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica)-affiliated centers between January 2000 and April 2016. The new pediatric EBMT criteria were retrospectively applied for diagnoses of SOS/VOD and severity grading. Among 5072 transplants considered at risk for SOS/VOD during the study period, 103 children (2%) developed SOS/VOD, and the grade was severe or very severe in all patients. The median time of SOS/VOD occurrence was 17 days after HSCT (range, 1 to 104). Sixty-nine patients (67%) were treated with defibrotide for a median time of 16 days (range, 4 to 104). In multivariable analysis age < 2 years, use of busulfan during the conditioning regimen, female gender, and hemophagocytic lymphohistiocytosis were risk factors statistically associated with the development of SOS/VOD. The overall mortality directly related to SOS/VOD was 15.5%. Overall survival at 1 year was worse in patients with SOS/VOD (P = .0033), and this difference disappeared 5 years after HSCT. Nonrelapse mortality was significantly higher 1 and 5 years after transplantation in patients who developed SOS/VOD (P < .001). Based on the application of new EBMT criteria, the overall incidence of SOS/VOD recorded in this large Italian pediatric retrospective study was 2%. Nonrelapse mortality was significantly higher in patients who developed SOS/VOD. Identifying the risk factors associated with SOS/VOD can lead to more effective early treatment strategies of this potentially fatal HSCT complication in childhood.

Invasive mucormycosis in children with cancer: A retrospective study from the Infection Working Group of Italian Pediatric Hematology Oncology Association.

BACKGROUND: Invasive mucormycosis is a rare but frequently fatal fungal disease. The acute and rapidly progressive evolution causes unfavourable outcome in 22%-59% of patients and its treatment represents a clinical challenge, especially in immunocompromised patients. Current data in paediatric oncological patients are limited. OBJECTIVES: The infection Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) analysed the episodes of invasive mucormycosis occurred between 2009 and 2016. PATIENTS: Fifteen cases of proven mucormycosis (male/female 8/7; median age 14.1 years, range 7.7-18.6) were reported after chemotherapy for acute leukaemia and lymphoma (12) and allogeneic stem cell transplantation (3). The aetiology was Rhizopus oryzae 4, Lichtheimia corymbifera 3 and Mucor spp. 8. RESULTS: Paranasal sinus was the primary site of infection in 14/15 patients combined with orbital involvement (9), central nervous system (8), lung (4), thyroid gland and kidney (1). All patients received liposomal Amphotericin B (L-AmB) (3-10 mg/kg), with surgical debridement in 14/15 cases. Eleven patients received maintenance treatment with posaconazole (9) or isavuconazole (2). Eight out of fifteen patients (53.3%) died, after 3-6 months. CONCLUSIONS: Mucormycosis involved mainly the sinu-orbital site and affected children >10 years. Despite aggressive treatment with high-dose L-AmB and timely surgical debridement, the mortality rate remains still high.

Posaconazole oral dose and plasma levels in pediatric hematology-oncology patients.

BACKGROUND: Posaconazole is a triazole with limited pharmacokinetic information in children. This study assessed the correlation between posaconazole oral solution daily dosage/kg/body weight and trough plasma level. METHODS: A total of 97 hematology-oncology pediatric patients with ≥1 posaconazole plasma concentration level (PPC) assessment in the first 6 weeks after the start of posaconazole treatment were included. RESULTS: Posaconazole was used as prophylaxis in 84 of 97 (87%) patients and as therapy in 13 of 97 (13%). The median daily dose/kg/bw ranged from 10 to 12 mg in the prophylaxis group and 12.5 to 16.5 mg in the therapy group. The median value of PPC for the prophylaxis group was 0.9 and 0.8 µg/mL at the first and second/third determinations, respectively. Posaconazole prophylaxis failed in 4 of 84 patients (5%). The median value of PPC for the therapy group was 1.5 and 1.4 µg/mL at the first/second and the third determination, respectively. Posaconazole-related side effects were reported in 6 patients and all regressed with the suspension of the drug. In the prophylaxis group, the use of proton-pump inhibitors was significantly associated with a lower PPC, P = 0.04. CONCLUSIONS: Posaconazole may be a valuable antifungal agent in children despite the incomplete knowledge of its pharmacokinetic characteristics.

Risk Factors and Outcomes Related to Pediatric Intensive Care Unit Admission after Hematopoietic Stem Cell Transplantation: A Single-Center Experience.

To describe incidence, causes, and outcomes related to pediatric intensive care unit (PICU) admission for patients undergoing hematopoietic stem cell transplantation (HSCT), we investigated the risk factors predisposing to PICU admission and prognostic factors in terms of patient survival. From October 1998 to April 2015, 496 children and young adults (0 to 23 years) underwent transplantation in the HSCT unit. Among them, 70 (14.1%) were admitted to PICU. The 3-year cumulative incidence of PICU admission was 14.3%. The main causes of PICU admission were respiratory failure (36%), multiple organ failure (16%), and septic shock (13%). The overall 90-day cumulative probability of survival after PICU admission was 34.3% (95% confidence interval, 24.8% to 47.4%). In multivariate analysis, risk factors predisposing to PICU admission were allogeneic HSCT (versus autologous HSCT, P = .030) and second or third HSCT (P = .018). Characteristics significantly associated with mortality were mismatched HSCT (P = .011), relapse of underlying disease before PICU admission (P < .001), acute respiratory distress syndrome at admission (P = .012), hepatic failure at admission (P = .021), and need for invasive ventilation during PICU course (P < .001). Our data indicate which patients have a high risk for PICU admission after HSCT and for dismal outcomes after PICU stay. These findings may provide support for the clinical decision-making process on the opportunity of PICU admission for severely compromised patients after HSCT.

Retrospective study on the incidence and outcome of proven and probable invasive fungal infections in high-risk pediatric onco-hematological patients.

BACKGROUND: Invasive fungal infection (IFI) is a cause of morbidity, mortality and increased health costs in children undergoing chemotherapy or hematopoietic stem cell transplant (HSCT). METHODS: Multicenter, retrospective study to assess the incidence, outcome of proven and probable IFI (PP-IFI) in children treated for acute leukemia, non-Hodgkin lymphoma or who underwent HSCT from 2006 to 2012. RESULTS: Over the 7-year period, 127 PP-IFI were diagnosed in 123 patients, median age of 9.7 years. The 1-year cumulative incidence was 2.5% (CI 1.8-3.7) after frontline chemotherapy, 9.4% (CI 5.8-15.0) after relapse, and 5.3% (CI 3.9-7.1) after HSCT. Severe neutropenia was present in 98 (77%) patients. Culture-proven agents were Candida spp., mostly non-albicans, 28, mold 23, whereas three proven IFI were identified by histopathology. Favorable response to treatment within 3 months from diagnosis was observed in 77 (89%). The overall ninety-day probability of survival was 68% (CI 59-76). CONCLUSIONS: About two-thirds of pediatric patients with PP-IFI survived, regardless of whether the infection occurred after frontline chemotherapy, reinduction chemotherapy for disease relapse, or after HSCT. Further prospective studies are needed to define the impact of antifungal prophylaxis and early combination therapy on short-term overall survival.

Treatment of Acute Graft-versus-Host Disease in Childhood with Extracorporeal Photochemotherapy/Photopheresis: The Padova Experience.

Acute graft-versus-host disease (aGVHD) is the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Systemic steroid treatment represents the first-line therapy for aGVHD and is associated with a response rate of 30% to 60%. Steroid-resistant patients have a poor prognosis with high transplantation-related mortality (TRM). Several second-line therapies have been proposed for the management of unresponsive aGVHD, without proven beneficial effects on patients' outcome or overall long-term survival. For these reasons, extracorporeal photochemotherapy/photopheresis (ECP), a cell-based approach to control GVHD that spares generalized immunosuppression, seems to be promising. In this study, we report the outcome of 72 consecutive pediatric patients treated with ECP between 1997 and 2013 for aGVHD. Among them, 21 patients had steroid-resistant aGVHD, 42 had steroid-dependent aGVHD, and 9 did not receive steroid as first-line therapy because of clinical contraindications. A complete response was obtained in 72% of patients, a partial response was observed in 11%, and there was no response in 17% of patients. At day +180, TRM was 4% in the whole cohort; TRM was 3% and 20% among responders and nonresponders to ECP, respectively (P < .0001). The 5-year overall survival was 71%, showing a difference between responders and nonresponders of 78% and 30%, respectively (P = .0004). The 5-year time to progression of primary disease was 81%, without any significant difference between the 2 groups. Moreover, the 5-year progression-free survival of primary disease was 72%, with a significant difference (P = .0007) between responders (79%) and nonresponders (30%) to ECP. In conclusion, this study demonstrates that ECP is highly effective in aGVHD without a negative impact on primary disease.

Long-Term Complications after Allogeneic Hematopoietic Stem Cell Transplantation with Treosulfan- or Busulfan-Based Conditioning in Pediatric Patients with Acute Leukemia or Myelodysplastic Syndrome: Results of an Associazione Italiana Ematologia Oncologia Pediatrica Retrospective Study.

Patients undergoing hematopoietic stem cell transplantation (HSCT) for hematologic malignancies during childhood have an increased risk of developing long-term sequelae that are in part attributable to the conditioning regimen. The present study aimed to assess the occurrence of long-term toxicities in a population of children who underwent HSCT for hematologic malignancies using either treosulfan or busulfan in the conditioning regimen. The cumulative incidences of growth impairment, altered gonadal function, altered thyroid function, cataracts, secondary malignant neoplasia, and altered pulmonary function were evaluated retrospectively by univariable and multivariable analyses in a population of 521 pediatric patients with acute leukemias or myelodysplastic syndromes treated in 20 Italian transplant centers affiliated with the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP). The median duration of follow-up for the entire study population was 7.1 years (range, 1 to 16 years). Overall, a larger proportion of patients given busulfan developed long-term toxicities compared to patients treated with treosulfan (34% versus 20%; P = .01). In univariable analysis, gonadal toxicity developed in 10% of patients who received treosulfan (95% confidence interval [CI], 3% to 15%), compared with 38% (95% CI, 24% to 39%) of busulfan-treated patients (P = .02), and this finding was confirmed by multivariable analysis (relative risk, .51; 95% CI, .34 to .76; P = .0009). We did not find any statistically significant associations between the occurrence of other long-term toxicities and the use of either busulfan or treosulfan. This study provides evidence that the use of treosulfan is correlated with a reduced incidence of gonadal toxicity in children undergoing HSCT for hematologic malignancies.

Phase II Study of Allogeneic Hematopoietic Stem Cell Transplantation for Children with High-Risk Neuroblastoma Using a Reduced-Intensity Conditioning Regimen: Results from the AIEOP Trial.

Despite aggressive multimodal treatment, the outcomes of pediatric patients with high-risk (HR) neuroblastoma (NB) remain poor. The rationale for allogeneic hematopoietic stem cell transplantation (allo-HCT) to treat NB was based on the possible graft-versus-tumor effect; however, toxicity limits its efficacy. We sought to prospectively assess the feasibility and efficacy of allo-HCT using a reduced-intensity conditioning regimen in pediatric patients with HR NB in a multicenter phase II trial. Primary endpoints were the rate of neutrophil and platelet engraftment, 5-year transplantation-related mortality (TRM), and disease-free survival (DFS). Secondary endpoint measures included the incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD. Fifty-one patients were enrolled in the study. The 5-year cumulative incidence (CuI) of TRM was 29.4 ± 6.4%, and that of DFS was 11.8 ± 4.5%. Patients undergoing allo-HCT within 1 year of diagnosis or with bone marrow as their stem cell source had a higher DFS probability. The CuI of neutrophil engraftment, platelet engraftment, and grade II-IV aGVHD was 97.9 ± 2.1%, 93.8 ± 3.5%, and 47.1 ± 7.0%, respectively. The development of new therapeutic strategies could further improve disease control.

Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP).

Letermovir prophylaxis revolutionized the approach to Cytomegalovirus infection in adult hematopoietic stem cell transplant (HCT), while data in pediatric setting are still lacking. We retrospectively analyzed 87 HCT children transplanted in 11 AIEOP centers receiving letermovir as off-label indication between January 2020 and November 2022. Letermovir was used as primary, secondary prophylaxis or CMV treatment in 39, 26 and 22 cases, respectively; no discontinuation due to toxicity was reported. Median duration was 100 days (14-256) for primary and 96 days (8-271) for secondary prophylaxis, respectively. None of the patients experienced CMV-clinically significant reactivation during Letermovir primary prophylaxis; one patient developed breakthrough infection during secondary prophylaxis, and 10 and 1 patient experienced asymptomatic CMV-reactivation and CMV-primary infection after drug discontinuation, respectively. Median duration of letermovir in CMV treatment was 40 days (7-134), with 4/22 patients suffering CMV-pneumonia, with an overall response rate of 86.4%. With a median follow-up of 10.7 months (8.2-11.8), estimated 1-year overall survival was 86%; no CMV-related deaths were reported in prophylaxis groups. This is the largest report on Letermovir use in pediatric HCT; real-life data confirm an excellent toxicity profile, with high efficacy as CMV prophylaxis; results in CMV-infection treatment should be investigated in larger, prospective trials.

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.

Pneumocystis pneumonia (PCP) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). However, allo-HCT procedures have evolved toward older patients, unrelated donors, and reduced-intensity conditioning, possibly modifying the risks. Polymerase chain reaction (PCR), widely used nowadays, is more sensitive than microscopy diagnostic methods. This study aimed to assess the factors associated with PCP in allo-HCT recipients within 2 years of HCT and managed according to current procedures. This multicenter, nested case-control study included PCP cases diagnosed by PCR, cytology, or immunofluorescence on bronchoalveolar lavage fluid between 2016 and 2018. Two controls per case were selected from the ProMISe registry and matched for the center, transplant date, and underlying disease. Fifty-two cases and 104 controls were included among the 5452 patients who underwent allo-HCT in the participating centers. PCP occurred at a median of 11.5 months after transplantation. The mortality rate was 24% on day 30 after the PCP diagnosis and 37% on day 90. The clinical presentation and mortality rates of the 24 patients diagnosed using only PCR were not different from those diagnosed with microscopy methods. Our study demonstrates a substantial incidence of, and mortality from, PCP, after allogeneic HCT despite well-established prophylactic approaches. In our experience, PCP nowadays occurs later after transplant than previously reported, justifying the prolongation of prophylaxis after six months in many cases. Allo-HCT recipients diagnosed with PCR as the only PCP marker should benefit from specific treatment as for other patients.