Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening : an international, multicentre, retrospective cohort study

Background Children aged younger than 3 years were excluded from the ELIANA phase 2 trial of tisagenlecleucel in children with acute lymphoblastic leukaemia. The feasibility, safety, and activity of tisagenlecleucel have not been defined in this group, the majority of whom have high-risk (KMT2A-rearranged) infant acute lymphoblastic leukaemia and historically poor outcomes despite intensification of chemotherapy, and for whom novel therapies are urgently needed. We aimed to provide real-world outcome analysis of the feasibility, activity, and safety of tisagenlecleucel in younger children and infants with acute lymphoblastic leukaemia. Methods We did an international, multicentre, retrospective cohort study at 15 hospitals across ten countries in Europe. Eligible patients were children aged younger than 3 years at screening between Sept 1, 2018, and Sept 1, 2021, who were screened for tisagenlecleucel therapy for relapsed or refractory B-cell precursor acute lymphoblastic leukaemia according to licensed indications. Patients received a single intravenous infusion of tisagenlecleucel. We tracked chimeric antigen receptor T-cell therapy outcomes using a standardised data reporting form. Overall survival, event-free survival, stringent event-free survival, B-cell aplasia, and toxicity were assessed in all patients who received a tisagenlecleucel infusion. Findings 38 eligible patients were screened, of whom 35 (92%) received a tisagenlecleucel infusion. 29 (76%) of 38 patients had KMT2A-rearranged acute lymphoblastic leukaemia, and 25 (66%) had relapsed after previous allogeneic haematopoietic stem-cell transplantation (HSCT). Patients had previously received a median of 2 lines (IQR 2-3) of (non-HSCT) therapy. Seven (18%) of 38 patients had received inotuzumab and 14 (37%) had received blinatumomab. After a median of 14 months (IQR 9-21) of follow-up, overall survival at 12 months after tisagenlecleucel infusion was 84% (64-93; five patients had died), event-free survival was 69% (47-83; nine events), and stringent event-free survival was 41% (23-58; 18 events). The probability of ongoing B-cell aplasia was 70% (95% CI 46-84; seven events) at 12 months. Adverse events included cytokine release syndrome, which occurred at any grade in 21 (60%) of 35 patients and at grade 3 or worse in five (14%), and neurotoxicity at any grade in nine (26%), none of which were severe. Measurable residual disease-negative complete response with or without haematological recovery occurred in 24 (86%) of 28 patients who had measurable disease. Interpretation These data suggest that tisagenlecleucel has antitumour activity and has an acceptable safety profile for young children and infants with B-cell precursor acute lymphoblastic leukaemia. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd.Peer reviewe

Prospective cohort study of procalcitonin levels in children with cancer presenting with febrile neutropenia

BACKGROUND: Febrile neutropenia (FNP) causes significant morbidity and mortality in children undergoing treatment for cancer. The development of clinical decision rules to help stratify risks in paediatric FNP patients and the use of inflammatory biomarkers to identify high risk patients is an area of recent research. This study aimed to assess if procalcitonin (PCT) levels could be used to help diagnose or exclude severe infection in children with cancer who present with febrile neutropenia, both as a single measurement and in addition to previously developed clinical decision rules. METHODS: This prospective cohort study of a diagnostic test included patients between birth and 18 years old admitted with febrile neutropenia to the Paediatric Oncology and Haematology Ward in Leeds between 1(st) October 2012 and 30(th) September 2013. Each admission with FNP was treated as a separate episode. Blood was taken for a procalcitonin level at admission with routine investigations. 'R' was used for statistical analysis. Likelihood ratios were calculated and multivariable logistic regression. RESULTS: Forty-eight episodes from 27 patients were included. PCT >2 ng/dL was strongly associated with increased risk of severe infection (likelihood ratio of 26 [95% CI 3.5, 190]). The data suggests that the clinical decision rules are largely ineffective at risk stratification, frequently over-stating the risk of individual episodes. High procalcitonin levels on admission are correlated with a greatly increased risk of severe infection. CONCLUSIONS: This study does not show a definitive benefit in using PCT in FNP though it supports further research on its use. The benefit of novel biomarkers has not been proven and before introducing new tests for patients it is important their benefit above existing features is proven, particularly due to the increasing importance of health economics

Haematological cancers: improving outcomes. A summary of updated NICE service guidance in relation to Specialist Integrated Haematological Malignancy Diagnostic Services (SIHMDS).

Haematological malignancies are a diverse group of cancers that affect the blood, bone marrow and lymphatic systems. Laboratory diagnosis of haematological malignancies is dependent on combining several technologies, including morphology, immunophenotyping, cytogenetics and molecular genetics correlated clinical details and classification according to the current WHO guidelines. The concept of the Specialised Integrated Haematological Malignancy Diagnostic Services (SIHMDS) has evolved since the UK National Institute for Health and Care Excellence (NICE) Improving Outcomes Guidance (IOG) in 2003 and subsequently various models of delivery have been established. As part of the 2016 update to the NICE IOG, these models were systematically evaluated and recommendations produced to form the basis for quality standards for future development of SIHMDS. We provide a summary of the systematic review and recommendations. Although the recommendations pertain to the UK National Health Service (NHS), they have relevance to the modern delivery of diagnostic services internationally

Information discernment, mis-information and pro-active scepticism

A participatory action research approach was employed to investigate school students’ information discernment capabilities. Placing school student participants at the centre of the research process enabled them to define the problem in their own words and begin to find solutions to the issue of how to choose good quality information. Findings confirmed the results of many studies - that school students adopt a cognitive default position of trust and are relatively unquestioning when using information sources for their work (in this case the Extended Project Qualification or EPQ). Results also showed that with an appropriate embedded learning and teaching intervention, which includes aspects of information and digital literacy, school students adopt a cognitive questioning state, which leads to pro-active scepticism, enhancing their information discernment and in turn enables them to make better information choices. This has implications not only for school teachers and librarians but for educational policy makers also

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Additional file 1: of Prospective cohort study of procalcitonin levels in children with cancer presenting with febrile neutropenia

Procalcitonin study data. (XLSX 65 kb

Selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex):study protocol for an international, parallel-group, dose-finding with expansion phase I/II trial

INTRODUCTION: Event-free survival rates at 15 years for paediatric patients with relapsed/refractory acute lymphoblastic leukaemia (ALL) are 30%–50%, with 5-year survival for adult patients only 20%. Many patients with newly diagnosed and relapsed ALL harbour somatic RAS-signalling activation mutations. Induction therapy for ALL involves steroids, with preclinical data suggesting the combination of dexamethasone with the MEK1/2 inhibitor, selumetinib (ARRY-142886) has a synergistic anticancer effect. METHODS AND ANALYSIS: The SeluDex trial is an international, parallel-group, dose-finding with expansion, phase I/II trial to assess the selumetinib/dexamethasone combination in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALL. The Cancer Research UK Clinical Trials Unit at University of Birmingham is the UK Coordinating Centre, with national hubs in Copenhagen, Denmark; Monza, Italy; Münster, Germany; Paris, France; and Utrecht, Netherlands. Patients with morphologically proven relapsed/refractory or progressive B-cell precursor or T-cell ALL, with demonstrated RAS pathway activating mutations are eligible. Adult patients are >18 years old, ECOG <2 and paediatric <18 years old, Lansky play scale ≥60% or Karnofsky score ≥60%. Phase I primary objective is the recommended phase II dose of selumetinib as defined by occurrence/non-occurrence of dose limiting toxicities using the continual reassessment method; phase II will evaluate preliminary antileukaemic activity of the combination, as defined by morphological response 28 days post-treatment using a Bayesian approach. Target recruitment is between 26 and 42 patients (minimum 13 and maximum 21 per group), depending the number of phase I patients included in phase II. ETHICS AND DISSEMINATION: Medical ethical committees of all the participating countries have approved the study protocol; initial (UK) ethics approval (17/YH/0123) was granted by Yorkshire & The Humber—Leeds West Research Ethics Committee. Participants are required to provide written informed consent/assent. Results will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN92323261