Benefits for children with suspected cancer from routine whole-genome sequencing

Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care.</p

Intention-to-treat outcomes utilising a stringent event definition in children and young people treated with tisagenlecleucel for r/r ALL through a national access scheme

Abstract CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2–74.2%) and 46.5% (95%CI 37.6–57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1–44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3–75.8) and 55.3% (95%CI 43.6–70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival

Intention-to-treat outcomes utilising a stringent event definition in children and young people treated with tisagenlecleucel for r/r ALL through a national access scheme

Acknowledgements: Although this project received no specific funding, MOE is funded by Children with Cancer UK (CPTSTSFA\100003) and would like to acknowledge their support. We would like to thank all staff who have contributed to patients’ care and especially acknowledge the late Amit Patel for his commitment to haematology and cell therapy. In addition, we would like to acknowledge all patients and their families.AbstractCAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2–74.2%) and 46.5% (95%CI 37.6–57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1–44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3–75.8) and 55.3% (95%CI 43.6–70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival.</jats:p

CD19/CD22 targeting with co-transduced CAR T-cells to prevent antigen negative relapse after CAR T-cell therapy of B-ALL

CD19-negative relapse is a leading cause of treatment failure after Chimeric antigen receptor (CAR) T-cell therapy for ALL. We investigated a CAR T-cell product targeting CD19 and CD22 generated by lentiviral co-transduction with vectors encoding our previously-described fast-off rate CD19CAR (AUTO1) combined with a novel CD22CAR capable of effective signalling at low antigen density. Twelve patients with advanced B-ALL were treated (CARPALL study, NCT02443831), a third of whom had failed prior licensed CAR therapy. Toxicity was similar to that of AUTO1 alone, with no cases of severe cytokine release syndrome. Ten of 12 patients (83%) achieved a Measurable Residual Disease (MRD) negative complete remission at 2 months post infusion. Of 10 responding patients, 5 had emergence of MRD (2) or relapse (3) with CD19 and CD22 expressing disease associated with loss of CAR T-cell persistence. With a median follow-up of 8.7 months there were no cases of relapse due to antigen-negative escape. Overall survival was 75% (95%CI: 41-91%) at 6 and 12 months. Six and 12-month event free survival (EFS) were 75% (95%CI: 41-91%) and 60% (95%CI: 23-84%). These data suggest dual targeting with co-transduction may prevent antigen negative relapse after CAR T-cell therapy

Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group

International audienceSurvivors of childhood, adolescent, and young adult cancer, previously treated with anthracycline chemotherapy (including mitoxantrone) or radiotherapy in which the heart was exposed, are at increased risk of cardiomyopathy. Symptomatic cardiomyopathy is typically preceded by a series of gradually progressive, asymptomatic changes in structure and function of the heart that can be ameliorated with treatment, prompting specialist organisations to endorse guidelines on cardiac surveillance in at-risk survivors of cancer. In 2015, the International Late Effects of Childhood Cancer Guideline Harmonization Group compiled these guidelines into a uniform set of recommendations applicable to a broad spectrum of clinical environments with varying resource availabilities. Since then, additional studies have provided insight into dose thresholds associated with a risk of asymptomatic and symptomatic cardiomyopathy, have characterised risk over time, and have established the cost-effectiveness of different surveillance strategies. This systematic Review and guideline provides updated recommendations based on the evidence published up to September, 2020

Benefits for children with suspected cancer from routine whole-genome sequencing.

Acknowledgements: We thank S. Wakeling (Alice’s Arc), J. Miles (East Genomics Laboratory Hub), A. Sosinsky (Genomics England), P. Moss (Genomics England), A. Maartens (science writer, Wellcome Sanger Institute), G. Collord (University College Hospitals, London) and T. Treger (Wellcome Sanger Institute) for the discussion regarding the paper. We thank the scientific, technical and administrative staff of the North Thames and East Genomic Laboratory Hubs for making WGS possible. We acknowledge funding from the Wellcome Trust (personal fellowship to S. Behjati, institutional grant to the Wellcome Sanger Institute; references 220540/Z/20/A and 223135/Z/21/Z), the Pessoa de Araujo family (personal fellowship to A.H.) and NIHR (academic clinical fellowship to S.M.L.). This research was supported by the NIHR GOSH Biomedical Research Centre and NIHR Cambridge Biomedical Research Centre (NIHR203312). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. We are indebted to the children and families who participated in this study.Funder: NIHR Cambridge Biomedical Research Centre (NIHR203312)Funder: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazilian Federal Agency for the Support and Evaluation of Graduate Education); doi: https://doi.org/10.13039/501100002322Funder: The Pessoa de Araujo family - Personal Fellowship to Dr Angus HodderFunder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272Funder: NIHR GOSH Biomedical Research CentreClinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care