Maria Caterina Putti

Central and peripheral neurotoxicity after methotrexate is a rare but challenging complication of therapy for pediatric lymphoid malignancies. In this Ponte‐di‐Legno Toxicity Working Group and international Berlin‐Frankfurt‐Münster Group study, we describe nine children and adolescents with transverse myelitis ( n = 6) or Guillain–Barré syndrome ( n = 3) after chemotherapy that included methotrexate. All transverse myelitis cases but one occurred in lymphoma patients with central nervous system status 3‐disease, and early imaging and cerebrospinal fluid findings frequently failed to distinguish the two entities. Three patients died from the toxicity, and all survivors of transverse myelitis had permanent deficits. Re‐exposure to intrathecal chemotherapy produced more severe recurrences and should therefore be avoided.

PAX5-altered acute lymphoblastic leukemia (PAX5-alt ALL) is a recently recognized molecular subtype of B-ALL characterized by a distinct transcriptional signature and frequent PAX5 fusions (PAX5-r). While PAX5-alt ALL has been associated with intermediate outcomes, clinical data specifically investigating pediatric PAX5-r ALL remain limited. We collected and analyzed 159 pediatric cases of PAX5-r ALL treated between 2001-2024 within AIEOP-BFM ALL studies across Italy, Germany and Austria, revealing high-risk clinical features. Comparative analyses of patients consecutively enrolled in the AIEOP-BFM ALL 2017 study (PAX5-r, n=96 vs. non-PAX5-r, n=1948) confirmed higher rates of hyperleukocytosis at diagnosis (22.9% vs. 8%, p<0.001) and enrichment of IKZF1plus profile (14.7% vs. 7.8%, p=0.0015) in PAX5-r patients. No relevant differences in terms of minimal/measurable residual disease (MRD)-based treatment response and risk-group stratification were observed. PAX5-r patients had a 4-year EFS and OS of 72.6±5.7% and 95.4±2.3%, respectively. Four-year EFS were 100%, 63.4±9.7% and 63.3±10% for standard-risk, medium-risk (MR) and high-risk (HR) groups, respectively, indicating that the poor prognostic impact of PAX5-r applies only when end-of-induction MRD is positive (MR/HR). Whole transcriptome sequencing revealed high FLT3 median expression in PAX5-r ALL and high-throughput drug screening of patient-derived xenografts (PDXs) showed marked sensitivity to several FLT3 inhibitors. Gilteritinib showed potent ex vivo cytotoxicity and synergism with dexamethasone in PAX5-r PDX models. Collectively, this study investigated clinical and biological features of pediatric PAX5-r ALL highlighting its MRD-dependent unfavorable prognosis and identifying FLT3 overexpression as a novel, potential therapeutic target.

Background: Invasive fungal disease (IFD) is typically aggressive and related with high mortality in children with a hematological malignancy. The association of medical and surgical treatment may ameliorate the outcome. The aim of this study was to analyze the surgical treatment of fungal infections in pediatric oncological populations.Methods: Retrospective study (2000–2022) of a single‐center experience. We reviewed the medical record of all patients with hematologic malignancies and IFD, analyzing the outcome.Results: From the 70 pediatric cases of hematologic malignancies with the diagnosis IFD over 22 years, we included in the present study 44 cases who required surgical approaches for either diagnosis or treatment. Twenty‐one patients were males and the mean age was 11 (range 1–23) years. The main indications for surgery were lack of improvement following medical treatment and/or progression of fungal infection (80%) and diagnosis confirmation (20%). Only five patients needed an emergency operation for rapid worsening of symptoms. The most common site of infection was the lung (80%) and the most frequently identified pathogen was Aspergillus (75%). The most common surgical procedures were lobectomy (performed in 17 patients) and atypical lung resection (10). Complications of surgery were mostly treated by medical approach. The mean time of resumption of oncological treatment was 40 (range 0–150) days.Conclusions: Surgery is an important step in the multimodal treatment of invasive fungal infection with excellent resolution rate. Overall mortality depends on the underlying malignancy.

Malignant histiocytoses (MHs) are a group of accessory cell-derived neoplasms, traditionally sub-classified into histiocytic sarcoma, interdigitating cell sarcoma, Langerhans cell (LC) sarcoma and ...

Background: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which patients typically develop fever, splenomegaly, cytopenias and coagulopathy. In patients with primary HLH, interferon gamma (IFNy) is considered to be the key player driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation in order to bring patients to allogeneic hematopoietic stem cell transplantation (HSCT), the only potentially curative therapy. Current conventional therapy for HLH is based on the combined use of dexamethasone and etoposide, and, although effective in many patients, these drugs may promote the development of opportunistic infections and tissue toxicity, and are associated with high morbidity and mortality. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. It is approved by the FDA for the treatment of adult and pediatric patients with primary HLH with refractory, recurrent or progressive disease, or intolerance with conventional HLH therapy. Herein, we report on the safety of emapalumab in primary HLH seen in the pivotal phase 2/3 study (Locatelli et al. NEJM 2020) and investigate the relationship of adverse events (AE) to dose and duration of treatment. Methods: Due to the rare and life-threatening nature of the disease, the efficacy and safety of emapalumab was assessed in an open-label pivotal study (NCT01818492) which included patients aged ≤18 years with a diagnosis of primary HLH and active disease (Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 3, 6 and 10 mg/kg if required, based on predefined laboratory and clinical response parameters. Treatment duration was 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to the time of HSCT if needed. Analysis was performed on 34 patients at a database cut-off date of July 2017 (Locatelli et al NEJM 2020). The relationship of AE to emapalumab treatment was reported by the study investigator. The impact of treatment duration on AE or infection occurrence was measured by the number of events with onset in a predefined time interval from emapalumab initiation. The impact of the dosing scheme on AE and infection occurrence was assessed by the number of AEs or infections in a predefined dose range. Results: Overall, 29% of patients had at least one AE deemed related to emapalumab use. Most (90%) of these events were infusion-related reactions, all of which were mild to moderate and resolved. No severe or serious hypersensitivity reactions were reported. Infections caused by pathogens potentially favored by IFNy neutralization occurred in 1 patient during emapalumab treatment (disseminated histoplasmosis) and resolved with appropriate treatment. There was no increase in AE frequency or the number of viral, bacterial, or fungal infections with increased dose or duration of emapalumab treatment. Conclusion: Neutralization of IFNy with emapalumab in this very fragile population of patients with active primary HLH was associated with a favorable and manageable safety profile across all doses and treatment durations assessed, allowing for flexible and tailored use based on patient clinical response. In addition, 102 patients have been treated in the US following FDA approval, and post-marketing surveillance has not revealed any additional safety concerns with the use of emapalumab in primary HLH (cutoff date 19 May 2020). Taken together, these safety results suggest that emapalumab may offer an additional advantage over conventional HLH therapies.

Among fungal infection, mucormycosis is a rare but severe etiology in immunocompromised patients. Lung and sinus are the usual sites; the involvement of blood vessels is also described. The diagnosis is a real challenge, because blood tests (galactomannan, beta-D-glucan) are negative and the only diagnostic tool is usually the biopsy of the affected zone. Aortitis is rare and usually caused by bacterial infection, fungal etiology is unusual and only episodic cases are reported in literature. Medical therapy alone is usually not sufficient and debilitating surgical intervention is required. We report the case of a child affected by B precursor acute lymphoblastic leukemia, presenting a systemic fungal infection complicated by aortitis, probably due to Mucor. The patient developed fever and pneumonia during the Induction phase of chemotherapy. At the beginning, the infection was treated as bacterial and the diagnosis of Mucor infection was possible only after surgical intervention with histological analysis. Medical therapy (antifungal) was not sufficient alone to cure the infection and an urgent surgical intervention was required. This case underlines the challenge in the diagnosis of mucomycosis, that should be suspected in case of prolonged fever during aplasia, not responding to standard antibiotic and antifungal therapies. Mucor infection often require a combined intervention, both medical and surgical to cure the infection.

Summary: Data from large case series of children with cerebral thrombotic events are pivotal to improve prevention, early recognition and treatment of these conditions. The Italian Registry of Pediatric Thrombosis (R. I. T. I.) was established in 2007 by a multidisciplinary team, aiming for a better understanding of neonatal and paediatric thrombotic events in Italy and providing a preliminary source of data for the future development of specific clinical trials and diagnostic-therapeutic protocols. We analysed data relative to the paediatric cerebral thrombotic events of the R. I. T. I. which occurred between January 2007 and June 2012. In the study period, 79 arterial ischaemic stroke (AIS) events (49 in males) and 91 cerebral sinovenous thrombosis (CSVT) events (65 in males) were enrolled in the R. I. T. I. Mean age at onset was 4.5 years in AIS, and 7.1 years in CSVT. Most common modes of presentation were hemiparesis, seizures and speech disturbances in AIS, and headache, seizures and lethargy in CSVT. Most common etiologies were underlying chronic diseases, vasculopathy and cardiopathy in AIS, and underlying chronic diseases and infection in CSVT. Time to diagnosis exceeded 24 hours in 46 % AIS and 59 % CSVT. Overall data from the Italian Registry are in substantial agreement with those from the literature, despite small differences. Among these, a longer time to diagnosis compared to other registries and case series poses the accent to the need of an earlier recognition of paediatric cerebrovascular events in Italy, in order to enable prompt and effective treatment strategies.

Essential thrombocythemia (ET) is extremely rare in the pediatric population. In most patients no molecular abnormality can be found, with about 40% of pediatric patients harboring a JAK2 V617F mutation. Another recurrent mutation, involving a W to L or K transversion at MPL codon 515, has been reported in about 3–8% of adult ET patients. Herein we describe this mutation in a pediatric patient. Pediatr Blood Cancer 2013;60E52‐E54.