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Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL., Bicistronic CAR T cells targeting CD19 and CD22 exhibit clinical activity and low toxicity in pediatric and young adult patients with B cell acute lymphoblastic leukemia, with relapses associated with limited CAR T cell persistence.

Outcomes for adolescents and young adults (AYAs) with leukemia differ from other age groups and are still under-represented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYAs with acute leukemia reported to Eurocord/European Society for Blood and Marrow Transplantation. Patients (N = 504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15 to 25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. The primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIFs) of nonrelapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute graft-versus-host disease (GVHD) grades II to IV at day 100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (hazard ratio [HR], 2.74; P.001) and more recent UCBT (HR, 1.43; P = .01) were associated with increased OS, and a similar effect of these factors was observed on LFS. Contrastingly, the use of antithymocyte globulin had a negative effect in LFS. The risk of acute GVHD grades II to IV increased with the use of double UCBT (HR, 1.65; P = .02) and decreased with more recent transplant period (HR, .65; P = .02) and antithymocyte globulin use (HR, .55; P = .01). Outcomes of AYA UCBT improved in more recent years, becoming comparable with pediatric results. Demonstrating the feasibility of UCBT in AYAs facilitates stem cell source selection and provides the basis for future prospective studies.

Lymphoblastic lymphoma (LBL) is a rare, malignant disorder of precursor T- or B- cells, which forms the lymphoma variant of acute lymphoblastic leukemia (ALL). Whilst morphologically and immunophen...

Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

Young people with cancer are at increased risk of psychological difficulty; yet there is little research on their experiences of low mood or depressive symptoms to help inform treatment interventions. This qualitative study explored experiences and opinions of low mood or depression in young people with cancer, how their mood related to developmental challenges, strategies used to cope, and how services could improve support. Nineteen young people diagnosed and treated for cancer completed semistructured interviews. Transcripts were thematically analyzed using the framework approach, and analysis produced eight themes, organized into three domains: “A Harder Time of Life,” “Interpersonal Impact of Cancer,” and “Learning to Understand and Describe Low Mood,” Participants interviewed experienced low mood during cancer and predominantly felt “low mood” was a helpful term to describe their emotions. There were similarities and variations in their reported mood compared with clinical depression. The developmental challenges of being a young person with cancer negatively affected their mood. Participants used a variety of different coping strategies to manage these challenges. Young people were clear that they would like others to help them understand negative emotions experienced through cancer are normal to feel and support for low mood to be accessible and available.

Purpose The primary aim of this study was to investigate the health behaviour status of teenage and young adult (TYA) cancer patients and survivors; the secondary aim was to determine if TYA cancer patients and survivors health behaviour differs to general population controls. Methods Two hundred sixty-seven young people with cancer (n =83 cancer patients receiving active treatment: n =174 cancer survivors, 57.1% >1 year since treatment completion) and 321 controls completed a health and lifestyle questionnaire which included validated measures of physical activity (PA) (Godin Leisure Time Exercise Questionnaire), diet (Dietary Instrument for Nutrition Education, DINE), smoking status, and alcohol consumption (AUDIT-C). Results General population controls and cancer survivors were more likely to meet current (PA) recommendations (p

Young people with cancer are at increased risk of depression, yet evidence-based psychological interventions that are tailored to the specific needs of young people with cancer are scarce, and depression in this group may be particularly challenging to recognize and treat. The aims of this study were to (1) explore the views of health professionals in recognizing and treating low mood in young people with cancer and (2) identify the key components of an effective online treatment package for depression in this population.Eighteen NHS health professionals with a range of professional backgrounds working directly with young people with cancer were interviewed using a semi-structured interview schedule. Responses were analyzed using thematic analysis.Five themes emerged: (1) one size doesn't fit all-the nature of depression is complex and varied, and symptoms fluctuate greatly in relation to physical health; (2) distress is completely understandable-it is important not to pathologize a normal reaction; (3) a stepping stone intervention-online interventions may promote engagement with face-to-face therapy; (4) connecting with others-the intervention should promote sharing experiences with others to reduce isolation; and (5) ownership and empowerment-lack of independence may be a cause of distress, and young people should have control of the intervention.The nature of depression in young people with cancer is complex and multifaceted. Online guided self-help may be useful when added as a component or first step of a treatment package including face-to-face talking therapies.

Introduction Parkinson’s disease (PD) a complex neurodegenerative disorder mainly affecting the dopaminergic neurones of the substantia nigra. Numerous studies have examined the role of α-synuclein within PD pathogenesis, although as yet a causal factor has not been established. The hibernating spore hypothesis was a theory originally delineated in 2002. It hypothesised the ability of an infectious agent, possibly fungal in origin to act as the casual factor in PD development .1 Recent literature has described varying levels of bacterial dysbiosis between individuals afflicted by PD, thus paving the way for research into the role of the mycobiome in PD pathogenesis.2 Methods Stool samples were obtained from 35 PD patients and 20 healthy controls. The samples were aliquoted and underwent DNA extraction utilising PSP and Qiagen kit protocols. Qubit analysis was performed with samples being diluted to 10 ng/µl to then undergo 18srRNA gene quantification for the PCR process. Once appropriate reagents had been added the PCR tube the constituents were entered into a Roche thermo-cycler 480 to undergo DNA replication. The amplified samples were then seeded at 5µl into a 1.6% agarose gel to undergo electrophoresis. The trialled samples were refined to a total of 24 that proceeded to be inputted into the University of Liverpool CGR for sequencing. Generated data was analysed using MicrobiomeAnalyst. The data set was refined using a prevalence of 10% and variance filters employing inter-quartile ranges to remove fungal organisms with very low prevalence and reduce the number of sequencing errors. Data was then normalised using total sum scaling. Results Comparison of the mycobiome of individuals with PD relative to healthy controls have presented an altered fungal composition of the gastro-intestinal tract. 8 OTU-level and 3 order-level specific fungal species have been identified to be differentially abundant by varying statistical tests (figure 1, depicts the relative species abundance change of fungal organisms between PD VS healthy controls) Conclusion Overall this study provides evidence of alteration to the mycobiome of patients afflicted with PD relative to that of healthy controls. It reinforces data previously presented by the hibernating spore hypothesis on how a fungal organism may be involved in PD pathogenesis, and now paves the way for future studies examining specific fungal species and their possible pathological interaction with both the gastrointestinal system and the CNS. References Broxmeyer L. ( 2002) Parkinson’s: another look. Medical Hypotheses. 59, 373–377 Scheperjans F, Aho V, Pereira PAB, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K and Auvinen P. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Movement Disorders 2015;30:350–358.

Metabolomics studies have the potential to discover biomarkers. Fecal volatile organic compounds (VOCs) have been found to differ in patients with inflammatory bowel disease and irritable bowel syndrome. Murine models of colitis offer an alternative to human studies in which diet can be controlled. We aimed to investigate fecal VOCs from mice in which acute and chronic colitis was induced. Groups of adult C57BL/6 mice underwent treatment with oral dextran sulfate sodium to induce colitis. Control mice received no treatment or had acute osmotic diarrhea induced with magnesium sulfate. Colitis was assessed clinically and by histology. Samples of feces and/or colon contents were collected and volatile compounds determined by solid phase microextraction-GC-MS. Statistics were performed using metabolomics tools. Acute colitis was associated with an increase in aldehydes and chronic colitis with one specific ketone. Osmotic diarrhea was associated with a significant reduction in VOCs, especially alcohols. We provide evidence that the identification of disease-associated VOC concentration ranges, combined with specific marker compounds, would potentially increase the likelihood of finding an inflammatory bowel disease-specific fecal VOC marker profile.-Reade, S., Williams, J. M., Aggio, R., Duckworth, C. A., Mahalhal, A., Hough, R., Pritchard, D. M., Probert, C. S., Potential role of fecal volatile organic compounds as biomarkers of chemically induced intestinal inflammation in mice.

Paediatric therapy-related acute myeloid leukaemia (t-AML) is rare and the outcome is poor. While allogeneic haematopoietic stem cell transplantation (HSCT) is generally the accepted modality of treatment, data regarding salvage chemotherapy, remission induction, conditioning regimens, transplant-related mortality and outcome is scarce. Between 2000 and2016, 36 children with t-AML were treated in seven UK paediatric HSCT centres. The most common salvage protocol for remission induction was FLAG with or without idarubicin and 28 patients were in complete morphological remission prior to BMT. Only 12 patients survived (33%). Transplant-related mortality (TRM) was the leading cause of death.

The improvement in overall survival in children with acute lymphoblastic leukemia (ALL) over the last 5 decades has been considerable, with around 90% now surviving long term. The risk of relapse has been reduced to such an extent that the risk of treatment-related mortality is now approaching that of mortality caused by relapse. Toxicities may also lead to the suboptimal delivery of chemotherapy (treatment delays, dose reductions, dose omissions), potentially increasing relapse risk, and short- and long-term morbidity, adding to the “burden of therapy” in an increasing number of survivors. Thus, the need to reduce toxicity in pediatric ALL is becoming increasingly important. This work focuses on the risk factors, pathogenesis, clinical features, and emergency management of the life-threatening complications of ALL at presentation and during subsequent chemotherapy, including leucostasis, tumor lysis syndrome, infection, methotrexate encephalopathy, thrombosis, and pancreatitis. Potential strategies to abrogate these toxicities in the future are also discussed.

Background: Tisagenlecleucel was approved in Europe for relapsed/refractory acute lymphoblastic leukemia (ALL) in young patients in 2018. In England, a national CAR T cell panel (NCCP ALL) ensures equity of access and assesses eligibility using inclusion and exclusion criteria based on the ELIANA study. All UK cases are discussed. Eligible cases are allocated to one of 9 JACIE-FACT IEC-approved centres based on age-appropriate service, capacity, distance and patient preference. We systematically reviewed all cases from panel inception providing an opportunity to analyse complete real-world ALL outcomes from this national access programme for tisagenlecleucel on an intention-to-treat (ITT) basis. Methods: We included all patients discussed in the NCCP ALL from Nov 2018 up to July 16th 2020. Clinical data were retrospectively reported in a standardised dataset to allow central analysis of disease and toxicity-related outcomes. Survival outcomes were assessed as for other CAR studies, using Kaplan-Meier estimates of survival from infusion. These included overall survival (interval to death from any cause) and event-free survival as defined in the ELIANA study (interval to death, disease relapse, or treatment failure defined in turn as failure to respond by day 30, with patients receiving further therapy being censored). In order to report outcomes on an ITT basis, survival outcomes were also assessed from time of treatment allocation for all patients considered eligible for tisagenlecleucel. Further, a more comprehensive event-free survival measure encompassing interval to molecular or frank relapse, further therapy, B cell recovery, death or treatment failure was analysed. Median follow up was calculated using a reverse Kaplan-Meier method. Results: Figure 1 demonstrates all patients: 66 patients were screened, 60 patients were deemed eligible for therapy (the ITT cohort), 57 patients were harvested and 49 infused. A total of 3 patients were not harvested and 2 not infused because of progressive disease (n=4) and 1 manufacturing failure. Patient and disease characteristics are summarised in Table 1. The cohort comprised patients with advanced ALL, having been treated with a median of 2.5 therapy lines not including HSCT (range 1-6), and with 47.5% of the cohort having had a prior HSCT. The median follow-up from infusion was 9.9 months and from treatment allocation for the ITT cohort was 11.9 months. The median lead time from allocation to infusion was 2 months. The CR/CRi rate was 95% in the first 90 days, 78.9% were MRD-. On an ITT basis, CR/CRi rate was 84.8%. Median OS and EFS as defined in the ELIANA study were not reached. Overall survival at 6 and 12 months for infused patients was 97.6% and 86.1%, and for the ITT cohort was 90.4% and 78.3%. EFS for infused patients at 6 and 12 months were 74.8% and 68.2%, and for the ITT cohort were 78.5% and 60.9%. Of 49 patients infused, 14 (28.5%) received further therapy including 6 (8.2%) who received allogeneic SCT for relapse or B cell recovery. For patients relapsing following CR (n=10 infused) there were 4/10 CD19- relapses. A composite EFS including molecular or frank relapse, further therapy, B cell recovery, death or treatment failure was analysed. Using this more stringent definition from infusion, the 6, 12 month EFS were 47.6%, and 33.6% and from treatment allocation for the ITT cohort were 63% and 34.3% Toxicity outcomes are summarised in Table 2. Severe (grade ≥3) CRS, neurotoxicity, infection or cytopenia after day 30 post infusion occurred in 20.4%, 10.2% 27.1% and 54.2% respectively. 71.4% of the cohort developed hypogammaglobulinaemia, (Figure 3A). The 6 and 12 month probabilities of B cell depletion were 67.1% and 51.3% respectively. Conclusions: Whilst registry data provide outcomes of large cohorts receiving Tisagenlecleucel, standardised data collection on complete populations are lacking. The framework of a national access scheme provides a unique opportunity to study outcomes on an ITT basis. The CR and MRD negative CR rates, as well as conventional EFS and OS and severe toxicities noted in our cohort compare favourably to published registry reports (Grupp et al., 2019). We found a greater proportion of CD19+ compared to CD19- relapses than noted in the ELIANA study. Consideration of OS and EFS on an ITT basis are informative for clinicians when screening patients for eligibility. If selected for presentation at ASH 2020, updated data will be presented Disclosures Ghorashian: Amgen: Honoraria; Novartis: Honoraria; UCLB: Patents & Royalties. O'Reilly:Gilead: Honoraria; Novartis: Honoraria, Other: Travel support. Roddie:Celgene: Honoraria; Gilead: Honoraria; Novartis: Honoraria. Neill:Novartis: Other: Funded attendance at academic conferences; Celgene: Other: Funded attendance at academic conferences. Pagliuca:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Patel:Novartis: Honoraria, Other: travel support. Hough:Novartis: Other: Travel support.

The heterogeneous nature of inflammatory bowel disease (IBD) presents challenges, particularly when choosing therapy. Activation of the NF-κB transcription factor is a highly-regulated, dynamic event in IBD pathogenesis. We expressed the human NF-κB/p65 subunit in blood-derived macrophages, using lentivirus. Confocal imaging of p65 activation revealed that a higher proportion of macrophages from Crohn’s patients responded to lipid-A compared to controls. In contrast, cells from ulcerative colitis (UC) patients exhibited a shorter duration of p65 nuclear localisation compared to healthy controls and Crohn’s donors. Using a similar lentivirus approach, NF-κB-regulated luciferase was expressed in patient macrophages, isolated from frozen peripheral blood mononuclear cell samples. Following activation, samples could be segregated into three clusters based on the NF-κB-regulated luciferase response. The majority of UC samples appeared in hypo-responsive cluster 1, with Crohn’s patients representing the majority of hyper-responsive cluster 3. A positive correlation was seen between NF-κB-induced luciferase activity and cytokine levels released to medium from stimulated macrophages, but not in serum or biopsy. Analysis of macrophage cytokine responses and patient metadata revealed a strong correlation between Crohn’s patients who smoked and hyper-activation of p65. Thesein vitrodynamic assays of NF-κB activation in blood-derived macrophages segregate IBD patients into groups with different phenotypes and therefore may help determine response to therapy.Significance statementThis manuscript describes two dynamic assays of NF-κB activation in blood-derived macrophages that can segregate IBD patients into groups with different phenotypes. For the first time we introduce the use of dynamic measurements of a transcription factor activation as a method to stratify patients and we are confident that our approach will lead in future to early patient stratification and prediction of treatment outcome.

Introduction Accumulating evidence implicates the brain gut axis in the pathogenesis of Parkinson’s disease (PD). Altered gut permeability may result in afferent vagal transport of an unknown antigen or toxin to the central nervous system, leading to the characteristic dopaminergic neurodegeneration. A study in fruit flies identified the possible role for fungal metabolites, for example 1-octen-3-ol, in a loss of dopamine activity. We investigated the hypothesis that such fungal metabolites might arise from the faeces. We present the results of an evaluation of the faecal metabolome by assessing volatile organic compounds (VOCs) in PD patients. Methods Using solid phase micro-extraction and gas chromatography and mass spectrometry VOCs were extracted from faecal samples from 35 PD patients (69% male; age 67±8 years; disease duration 11±5 years) and 35 healthy controls (37% male; age 65±8 years). VOCs were identified using automated mass-spectral deconvolution and identification system software and the national institute of standards and technology library. Distinguishing compounds were identified using fold change and t-test and corrected for multiple comparisons; group associations were determined using principal components analysis (PCA) and dendrograms. Findings were compared among groups and correlated with main variables. Results A mean of 63 VOCs were found from PD samples and 74 from controls (p Conclusions Metabolomic characterisation in PD patients demonstrates a distinct profile to healthy controls and an increased abundance of fungal metabolites, suggesting a potential role of fungal dysbiosis in PD pathogenesis.

Introduction Oral iron supplementation treats iron deficiency anaemia, but it may cause GI side effects. Iron influences the growth of specific gut bacteria and may lead to dysbiosis, which may contribute to the side effects. Previously, we have shown that oral iron worsens colitis in mice and causes a dysbiosis. Here we report the effect of ferrous sulphate supplementation on the human metabolome by quantifying changes in faecal volatile organic compounds (VOCs), for the first time. VOCs are part of the metabolome and reflect gut bacterial metabolism. We aimed to compare the faecal metabolome before and after ferrous sulphate supplementation. Methods 77 faecal samples were collected from patients with iron deficiency anaemia, before treatment and after two months of therapy. Faecal headspace gases were analysed using gas chromatography–mass spectrometry: VOC identification involved matching mass spectra against the NIST Library. Univariate and multivariate analysis was performed on the VOCs found, including partial least squares regression (PLS-DA). Results A significant change in abundance of 17 VOCs was found. Adjustment was made for the number of comparisons: one VOC was then shown to increase significantly. The median abundance of 2-pentylfuran changed four-fold (FDR adjusted P = 0.006) in patients taking ferrous sulphate for two months (figure 1A). Overall, a plot to illustrate the PLS-DA shows how the pre- and post-treatment samples differ (figure 1B). Though the abundance changed in 16 other VOCs–which included aldehydes, esters and ketones–their significance was lost after correction for multiple testing, which indicates that the study may be underpowered. Conclusions The abundance of faecal 2-pentylfuran increases significantly during ferrous sulphate therapy. 2-pentylfuran is a metabolite of fungi. It remains to be seen whether ferrous sulphate directly acts on fungi or whether there is an interaction between iron and bacteria, and then between bacteria and fungi. It is very clear that faecal metabolites are influenced by ferrous sulphate supplementation.

Introduction Anti-tumour necrosis factor (TNF) agents are used to treat UC but response is variable. Apart from concurrent immunomodulatory therapy and there are no clear predictors of efficacy. Analysis of transcriptome from peripheral blood CD4 and CD8 T-cells has been shown to predict disease outcome in inflammatory bowel diseases (IBD) but this strategy has not been tested to predict response to biological therapy. We investigated the utility of baseline CD4 and CD8 transcriptome in predicting response to anti-TNF agents in UC. Methods Patients who were commenced on any anti-TNF therapy for ambulant UC were included in this single centre cohort study. Clinical response and remission was defined using full or partial Mayo score at week 14. RNA was extracted from peripheral blood CD-4 and CD-8 populations and subjected to transcriptome analysis using human Clariom D analysis. Transcriptome Analysis Console (TAC) 4.0 from ThermoFisher Scientific was used to analyse Expression Array feature intensity (CEL) files. The analysis was carried out with the Clariom_D_Human NetAffx Library. Statistical analysis to detect differential expressed genes was carried out with default settings of TAC, except that the use of FDR p-values was set from false to true. Results Ten patients with UC with a median age of 35 (range 19–69) and median Mayo score of 8 (range 2–12) were included. Three (30%) had pancolitis and 6 (60%) of patients were on concomitant immunomodulators. At week 14, six (60%) and 4 (40%) patients achieved clinical response and remission respectively. Of the 135,750 genes tested, differential expression was noted in over 900 genes between responders and non-responders at a P value of 95% sensitivity and specificity (P Conclusions CD4 transcriptome analysis at baseline identified differentially expressed genes in patients with lack of clinical remission. This has potential utility as a novel non-invasive biomarker of resposne to anti-TNF therapy in UC. Our findings require further validation in a larger cohort.

BACKGROUND: Teenagers and young adults (TYAs) with cancer are known to suffer poor sleep quality and sleep disturbances; understanding the level of burden is essential to improving patient outcomes via supportive care interventions. OBJECTIVES: To compare sleep quality and the prevalence of sleep disturbances among TYA cancer patients, TYA survivors, and general population TYAs with no history of cancer. METHODS: Teenager and young adult patients receiving active cancer treatment (n = 70), TYA cancer survivors (n = 151), and general population TYAs (n = 324) aged between 13 and 24 years completed the Pittsburgh Sleep Quality Index. Analyses of covariance were used to investigate potential group differences. Age at survey diagnosis, gender, ethnicity, and health status were included as covariates. RESULTS: 84.29% of TYA patients, 62.91% of TYA cancer survivors, and 65.12% of general population TYAs reported Pittsburgh Sleep Quality Index scores greater than 5, suggesting clinically significant sleep disorders. Teenager and young adult patients reported significantly poorer global sleep quality compared with TYA survivors (mean difference, 0.99; 95% confidence interval, 0.03-1.96; P = .044) and general population TYAs (mean difference, 1.34; 95% confidence interval, 0.26-2.41; P = .009). Teenager and young adult patients and survivors reported significantly poorer sleep latency (P = .003 for TYA patients, P = .035 for TYA survivors off treatment) and habitual sleep efficiency (P < .001 for TYA patients, P = .014 for TYA survivors) than general population controls. CONCLUSIONS: The significant differences observed suggest young people with cancer, particularly those on treatment, may benefit from specialized sleep interventions. IMPLICATIONS FOR PRACTICE: Efforts to ensure health professionals have the knowledge and skills to provide advice about sleep to young people with cancer are needed.

ObjectivesTo understand the experiences of young adults with cancer for whom cure is not likely, in particular what may be specific for people aged 16–40 years and how this might affect care.DesignWe used data from multiple sources (semi-structured interviews with people with cancer, nominated family members and healthcare professionals, and workshops) informed by a preliminary programme theory: realist analysis of data within these themes enabled revision of our theory. A realist logic of analysis explored contexts and mechanisms affecting outcomes of care.SettingThree cancer centres and associated palliative care services across England.ParticipantsWe aimed for a purposive sample of 45 people with cancer from two groups: those aged 16–24 years for whom there may be specialist cancer centres and those 16–40 years cared for through general adult services; each could nominate for interview one family member and one healthcare professional. We interviewed three people aged 16–24 years and 30 people 25–40 years diagnosed with cancer (carcinomas; blood cancers; sarcoma; central nervous system tumours) with a clinician-estimated prognosis of ResultsData were available from 69 interviews (33 people with cancer, 14 family carers, 22 healthcare professionals) and six workshops. Qualitative analysis revealed seven key themes: loss of control; maintenance of normal life; continuity of care; support for professionals; support for families; importance of language chosen by professionals; and financial concerns.ConclusionsCurrent care towards end of life for young adults with cancer and their families does not meet needs and expectations. We identified challenges specific to those aged 16–40 years. The burden that care delivery imposes on healthcare professionals must be recognised. These findings can inform recommendations for measures to be incorporated into services.

PURPOSE: The diagnosis of cancer is often prolonged in teenagers and young adults (TYA). There may be lessons in improving this from international comparisons. However, international studies are complex and so we conducted a pilot study to examine the key barriers to large-scale research in this field.METHODS: We provided translated questionnaires covering key aspects of presentation and clinical management within 60 days of a confirmed cancer diagnosis, to patients 13-29 years of age inclusive, to their primary care physicians and to the cancer specialists managing their cancer. We conducted descriptive analyses of the data and also the process of study implementation.RESULTS: For our pilot, collecting triangulated data was feasible, but varying regulatory requirements and professional willingness to contribute data were key barriers. The time of data collection and the method for collecting symptom reports were important for timely and accurate data synthesis. Patients reported more symptoms than professionals recorded. We observed substantial variation in pathways to cancer diagnosis to explore definitively in future studies.CONCLUSION: Focused research upon the mechanisms underpinning complex cancer pathways, and focusing that research upon specific cancer types within TYA may be the next key areas of study.

Introduction Prebiotic β-galactooligosaccharides (B-GOS) may counteract the microbiome modifying effect of the low FODMAP diet (LFD) in patients with irritable bowel syndrome (IBS). Faecal metabolites may predict why only some patients respond to the LFD paving the way towards more personalised treatment. The aim of this randomised controlled trial (RCT) was to investigate: a) the impact of the LFD and LFD+1.4 g/d B-GOS compared to Control on the gut microbiome in IBS, and b) if differences in faecal or urinary metabolites predict response to the LFD. Methods A 3-arm RCT was performed in 69 IBS patients randomised to: Sham diet +Placebo (Control), LFD +Placebo (LFD) or LFD +B GOS. This study investigated global symptom response (adequate relief), gut microbiome (16S rRNA sequencing), short-chain fatty acids (SCFA, gas liquid chromatography), volatile organic compounds (VOC) (gas chromatography/mass spectrometry) and urine metabolomics (NMR spectroscopy) at baseline (BL) and 4 weeks. Data were analysed by Chi2 for dichotomous outcomes and Kruskal-WallisMann-Whitney U tests for continuous variables. Predictive analysis was tested using receiver operator curves (ROC) and orthoganol partial least squared discriminant analysis (OPLS-DA). Results Response rate (adequate relief) at 4 weeks was greater in the LFD+GOS (67%) and LFD (50%) than the Control group (30%) (p=0.046). The phylum Actinobacteria was lower (p Conclusions The LFD +B GOS improves symptoms in IBS compared to Control but the LFD significantly reduces Actinobacteria and addition of 1.4 g/d of prebiotic B-GOS does not overcome this effect. Faecal VOCs and SCFAs and urine metabolomes may predict clinical response to the LFD, and specific bacterial groups correlate with predictive metabolites. Larger studies are required to validate these algorithms to develop personalised nutrition in IBS.

Skin cancers are a common form of second malignant neoplasm among teenage and young adult cancer survivors (TYACS). The Children's Oncology Group specifies that TYACS should adhere to safe sun practices and be screened for skin cancer annually. Cross-sectional self-report data collected by our group indicate over a third of TYACS (n = 229; mean age: 19.8 years) intentionally sunbathe, with many reporting sunburn. TYACS sunbathing, sunburn, and sunbed use are similar to the general population (P > 0.05). These data suggest TYACS require intervention to limit sun exposure and improve their sun safety habits.

Purpose: Teenage and young adult (TYA) cancer survivors experience a range of health-related problems during and beyond the active treatment period. This study examined associations between fatigue, sleep quality, and health-related quality of life (HRQOL) among TYA survivors.Methods: Self-reported data on sleep quality (Pittsburgh Sleep Quality Index), fatigue (Functional Assessment of Chronic Illness Therapy Fatigue), and HRQOL (EuroQoL-5) were gathered from United Kingdom TYA survivors between 13 and 24 years of age. TYA survivors were stratified into those on (n = 67) and off (n = 135) treatment. Linear regression analyses were used with HRQOL as the dependent variable to investigate potential associations. Fatigue and sleep were entered separately and together in the same model. Age at survey and diagnosis, gender, and ethnicity were included as covariates.Results: 85.07% of TYAs on and 62.69% of TYAs off treatment had sleep quality scores suggestive of clinically significant sleep disorders. 56.72% of TYAs on and 26.67% of TYAs off treatment reported clinically significant levels of fatigue. Strong independent associations between sleep (B = 0.05, 95% confidence intervals [CI] = 0.03–0.07, p

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.

The primary immunodeficiencies (PIDs), rare inherited diseases characterized by severe dysfunction of immunity, have been successfully treated by allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in childhood. Controversy exists regarding optimal timing and use of Allo-HSCT in adults, due to lack of experience and previous poor outcomes. Twenty-nine consecutive adult patients, with a mean age at transplant of 24 years (range, 17-50 years), underwent Allo-HSCT. Reduced-intensity conditioning (RIC) included fludarabine (Flu)/melphalan/alemtuzumab (n = 20), Flu/busulfan (Bu)/alemtuzumab (n = 8), and Flu/Bu/antithymocyte globulin (n = 1). Stem cell donors were matched unrelated donors or mismatched unrelated donors (n = 18) and matched related donors (n = 11). Overall survival (OS), event-free survival, transplant-related mortality (TRM), acute and chronic graft-versus-host disease incidence and severity, time to engraftment, lineage-specific chimerism, immune reconstitution, and discontinuation of immunoglobulin replacement therapy were recorded. OS at 3 years for the whole cohort was 85.2%. The rarer PID patients without chronic granulomatous disease (CGD) achieved an OS at 3 years of 88.9% (n = 18), compared with 81.8% for CGD patients (n = 11). TRM was low with only 4 deaths observed at a median follow-up of 3.5 years. There were no cases of early or late rejection. In all surviving patients, either stable mixed chimerism or full donor chimerism were observed. At last follow-up, 87% of the surviving patients had no evidence of persistent or recurrent infections. Allo-HSCT is safe and effective in young adult patients with severe PID and should be considered the treatment of choice where an appropriate donor is available.

Improving outcomes for teenagers and young adults (TYA) with cancer is a key element of the national cancer strategy in England. Recognition of the unique needs of this group has led to the development of recommendations for specific models of care and delivery of this care through the provision of dedicated clinical units in principal treatment centers (PTCs) across the United Kingdom. The aim of this study was to understand the current cancer patient experience for this patient group. We aimed to determine whether treatment experience is influenced by place of treatment and whether it has changed over time using patient-reported data from national cancer patient experience surveys. This study highlights that a prolonged pathway to diagnosis remains an issue for the TYA group and identifies areas on which quality improvement measures for TYA services should focus, including communication and involvement of the patient in treatment decisions. Positive experiences for the TYA group such as involvement in research were also highlighted. Treatment within a TYA PTC was associated with positive patient perception in a number of key areas highlighting the need for future studies to fully elucidate the impact of the full range of TYA services now available in the United Kingdom on both patient experience and outcome.

Trials with second generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but are associated with risk of cytokine release syndrome (CRS). Instead, we studied the use of donor Epstein–Barr virus-specific T-cells (EBV CTL) transduced with a first generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi-center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric acute lymphoblastic leukaemia (ALL). Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10-4) post first stem cell transplant (SCT), or prophylactically post second SCT. An initial cohort showed poor expansion/persistence. We therefore investigated EBV-directed vaccination to enhance expansion/persistence. Eleven patients were treated. No CRS, neurotoxicity or graft versus host disease (GVHD) was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de novo), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Although CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range: 0–28) days without vaccination compared to 56 (range: 0–221) days with vaccination (P=0.06). This study demonstrates the feasibility of multi-center studies of CAR T cell therapy and the potential for enhancing persistence with vaccination.Leukemia advance online publication, 10 March 2017; doi:10.1038/leu.2017.39

Aim:To explore the utility of [18F] Fluoro-2-deoxyglucose (18-FDG) positron emission tomography computed tomography (PET/CT) in lymphoblastic lymphoma (LBL). Background: LBL is a rare, malignant disorder of precursor T- or B- cells, which forms the lymphoma variant of acute lymphoblastic leukaemia (ALL). Whilst morphologically and immunophenotypically similar to ALL, distinction is made on degree of bone marrow infiltration (typically less than 25% in LBL). Due to the rarity of the condition, investigations at diagnosis, treatment approach and methods to evaluate disease response are not standardised. Bone marrow examination with MRD determination is the gold standard modality for disease monitoring in ALL yet the utility of this investigation is limited in LBL due to the low levels of marrow involvement at presentation. Computed tomography (CT) scanning is widely used in the diagnosis and assessment of lymphomas, however the criteria for disease are based purely on size of a lesion. Difficulties in distinguishing inflammatory from malignant lesions on CT have been widely reported (Elstrom et al. Blood. 2003;101(10):3875-6). 18-FDG PET/CT has been shown to be sensitive for staging high grade non-Hodgkin's lymphoma and is better at differentiating inflammatory from malignant lesions compared to CT alone (Ngeow et al, Ann Oncol. 2009;20(9):1543-7). Normalisation of the SUV to a suitable reference region such as the tumor-to-liver ratio (TLR), has reduced issues with inter-scanner variability. Retrospective data on the use of PET/CT in LBL is limited. In most series, few patients underwent PET/CT at diagnosis making interpretation of subsequent scans difficult thus PET/CT is currently only used at physician discretion in LBL. Methods: Patients with a diagnosis of T- or B-cell LBL managed at University College London Hospital, a large tertiary haematology unit in the UK since 2011 were identified. Data on timing of PET/CT scans in patients with a diagnosis of LBL were collected retrospectively and correlated with clinical outcome data. SUVmax values within the lesion(s) and within the liver, spleen and mediastinal (aortic) blood pool were collected and the TLR calculated. Results:20 patients were identified (14 T-LBL, 6 B-LBL), median age 24.5 years (range 13-66). Ten patients aged 13-24 years were treated using the UKALL 2011 protocol and 10 patients aged >24, years were treated using the UKALL 14 protocol. Sixteen of 20 (80%) of patients had a PET/CT scan at diagnosis before commencing treatment. The remaining 4 patients presented in extremis, requiring intensive care support and immediate empirical treatment. Of the 16 patients who had a PET/CT at diagnosis, all but one had significant FDG avid disease (mean SUVmax 8.6, range 2.7-17.1, TLR >1). Overall survival (OS) for the whole cohort was 70% (median follow up 31 months, range 6-91 months). Consistent with previous published data, OS was superior in the younger patients (90% in the 13-24 year age group vs 50% in those aged >24 years) although due to different patient characteristics and therapy these groups are not comparable. Regardless of age, all patients with a negative PET/CT scan after cycle 1 of chemotherapy survived, disease free (see table 1). Patients with a positive PET/CT after course 2 of treatment or at the end of treatment had a much poorer OS (60% and 0% respectively). In keeping with data from other high-grade lymphomas, SUVmax>10 at presentation may predict an aggressive clinical course, with average SUVmax of 11.9 (TLR4.23) in the patients who died of their disease compared to 6.225 (TLR2.33) in patients who survived. PET/CT had 100% sensitivity and specificity for detecting relapsed disease in this small series. In 8 patients who presented with symptoms suggestive of disease progression or relapse PET/CT detected all 6 patients with true positive disease and excluded relapse in 2 patients with inflammatory lesions. Conclusions: Our data suggests that PET/CT is useful in the diagnosis and response assessment of LBL particularly if the clinical scenario permits a scan at diagnosis. Although patient numbers are small, these data suggest that a high lesion SUVmax at diagnosis correlates with an aggressive subtype and patients with a negative scan after their first cycle of chemotherapy appear to have an excellent prognosis. Further investigation of the utility of PET/CT in risk stratification in LBL is warranted. Disclosures Fielding: Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Consultancy.

Introduction As survival rates for acute lymphoblastic leukaemia (ALL) in children and young people improve, the need to understand and mitigate toxicity becomes increasingly important. The contribution of toxicity to mortality or significant morbidity is well described. However, the impact of dose reductions, drug omissions or delays in treatment which result from toxicity is poorly understood, other than the established association between effective count suppression during maintenance chemotherapy and a reduction in relapse rate. We report the significance of treatment delays and dose reductions in induction chemotherapy in the UKALL2003 trial. Methods UKALL2003 was a prospective multicenter phase 3 study recruiting patients aged 1-24 years with newly diagnosed Philadelphia chromosome negative ALL in the UK. Data regarding 4 different protocol deviations were prospectively collected at the end of each block of therapy; a) not given allocated regimen, b) 1 week in commencing the next treatment block. Univariable (UVA) and Multivariable (MVA) Cox regression was used to assess the association of each deviation with risk of relapse. To control for immortality bias, this was assessed at the end of each therapy block with only patients alive and relapse free at the end of the block included in the analysis. Patients with Down Syndrome were excluded from all analyses. Results Of 2991 patients without Down Syndrome completing induction chemotherapy, 9 patients did not receive the allocated regimen, 1558 patients received 90% of one or more drugs and delay of greater than 1 week was significantly associated with an increased risk of relapse with hazard ratios of 1.70 (95% CI 1.11 - 2.60, p=0.014) and 1.99 (95% CI 1.14 - 3.48, p=0.013) respectively. On MVA (complete cases, n=2464), including other factors of established prognostic significance, both deviations remained significantly associated with an increased risk of relapse (Table 1). The impact of a major deviation (defined here as dose reduction of >90% of one or more drugs or treatment delay of >1week) was seen in both the paediatric (90% of one or more drugs in induction were also more likely to have major deviations in subsequent blocks of therapy (p Conclusion Major deviations in the delivery of induction chemotherapy on UKALL2003 were significantly associated with a greater risk of further deviations in subsequent blocks of therapy and a higher risk of relapse. Further improvement in efficacy of ALL therapy in children and young people will require a greater understanding of which toxicities lead to major deviations in therapy and strategies developed to mitigate these risks. Disclosures Rowntree: Novartis: Consultancy.

Introduction CAR T-cell therapies directed against CD19 or CD22 have shown remarkable activity in r/r B-ALL but relapse due to target antigen down-regulation/loss has been the major cause of treatment failure. To address this, we developed AUTO3, a CAR T-cell therapy designed to target CD19 and CD22 simultaneously. Preliminary results of this study showed an acceptable safety profile and encouraging efficacy in pediatric r/r B-ALL (all 6 patients treated in active doses ≥3 x 106 CAR T-cells/ Kg achieved complete remission (CR) with negative minimal residual disease (MRD) (Amrolia et al, Blood 2018 132:279). Here we present the updated results of CAR naïve patients treated at the active doses. Methods & Patients We constructed a bicistronic retroviral vector encoding both an anti-CD19 CAR and an anti-CD22 CAR. This second-generation CAR incorporated an OX40 co-stimulatory domain for the CD19 CAR and a 41BB for the CD22 CAR. The cell product was manufactured on a semi-automated/closed process. Patients (aged 1‒24 years) with high risk relapsed (IBFM criteria) or refractory B-ALL, adequate performance score/organ function, an absolute lymphocyte count ≥0.5 x 109/L are eligible. Patients with CNS Grade 3 disease, active graft versus host disease are excluded. Patients receive lymphodepletion with 30 mg/m2/day fludarabine x 4 days and 500 mg/m2/day cyclophosphamide x 2 days prior to AUTO3 infusion. Three dose levels were explored (1 x 106, 3 x 106, and 5 x 106 cells/kg), CAR T cells are infused as a single (for Results As of the data cut-off date (June 17, 2019), 10 patients received AUTO3 at 3 x 106 cells/Kg (n= 5, of whom 1 received split dose) or 5 x 106 CAR T-cells/Kg (n= 5, all of them received single infusion). The median transduction efficiency was 15.5% (range 8.6‒39.3%). Median age was 8.5 years (range 5‒16 years) and 5 (50%) patients had prior haemopoietic stem cell transplant (HSCT). One patient (10%) had prior anti-CD19 CAR-T cells. The disease burden at Day ‒7 ranged from 0 to 38% (median 7.5%) blasts. Among the 10 treated patients, 2 have not completed the 30 days post-infusion DLT observation period as of the cut-off date. No deaths or DLTs were observed. MTD has not yet been reached. The most common grade (Gr) ≥3 adverse events were neutropenia (60%), anaemia (50%), pyrexia (40%), febrile neutropenia (40%) and thrombocytopenia (30%). Eight patients (80%) had Gr 1 cytokine release syndrome (CRS), one (10%) had Gr 2 CRS; no ≥Gr 3 CRS was observed. Only one patient was treated with tocilizumab and none required admission to ICU due to CRS. One patient (10%) experienced Gr 1 neurotoxicity; no ≥ Gr 2 neurotoxicity was reported. Among the 9 CAR naïve patients, 7 (4 in the 3 x 106 cells/Kg dose cohort, 3 in the 5 x 106 cells/Kg dose cohort) had a minimum of 8 weeks' follow up and were evaluable for efficacy analysis. All 7 patients achieved CR/CRi (100%) following AUTO3 infusion as well as molecular negative remission (100%). After a median follow-up of 8 months (range 2-12), emergence of MRD by PCR occurred in four patients, lack of persistence of circulating CAR T-cells was observed in 3 of the 4 patients. Three relapses were reported including one with CD19 negative/CD22 low expression at 1 year after treatment. One patient in ongoing molecular remission proceeded to HSCT. All the remaining 4 patients in ongoing CR/CRi maintain B-cell aplasia. The median CAR T-cell expansion (expressed as vector copy number per microgram of DNA) at peak was 102K (range 56-128). The median persistence of CAR-T cells in blood was 180 days (range 21-330). Updated data with longer follow up and additional patient data will be presented. Conclusion This interim data analysis demonstrates that AUTO3 at ≥3 x 106 cells dose achieved 100% molecular remission rate with a favourable safety profile, no ≥ Gr 3 CRS or ≥ Gr 2 neurotoxicity was reported. The most common cause of relapse was antigen positive relapse due to lack of CAR T cell persistence. Evaluation of patients with a modified manufacturing process is planned. Disclosures Amrolia: UCLB: Patents & Royalties. Clark:Autolus Ltd: Employment, Equity Ownership. Al-Hajj:Autolus Therapeutics: Employment, Equity Ownership. Cordoba:Autolus: Employment, Equity Ownership. Kotsopoulou:Autolus Therapeutics: Employment, Equity Ownership. Khokhar:Autolus Therapeutics: Employment, Equity Ownership. Pule:Autolus: Employment, Equity Ownership, Patents & Royalties. Peddareddigari:Autolus Therapeutics: Employment, Equity Ownership.

We report the outcome for children and young people with Down syndrome-associated acute lymphoblastic leukaemia (DS-ALL) treated on a contemporary protocol. Compared with non-DS ALL, patients with DS-ALL had an inferior event-free survival (65·6% vs. 87·7% at 5 years; P < 0·00005) and overall survival (70·0% vs. 92·2%; P < 0·00005). Excess treatment-related mortality - was primarily responsible for the worse outcomes for DS-ALL (21·6% at 5 years, vs. 3·3%, P < 0·00005). Minimal residual disease (MRD) risk status was highly discriminant for relapse in DS patients with 0/28 relapses in the MRD low risk group. © 2014 John Wiley and Sons Ltd.

Purpose Reduced-intensity conditioning has minimized nonrelapse-related mortality rates after allogeneic transplantation in patients with Hodgkin's lymphoma, and relapse has now become the major cause for treatment failure. We aimed to assess the impact of donor lymphocyte infusions (DLIs) on relapse incidence when administered for mixed chimerism and their utility as salvage therapy when given for relapse. Patients and Methods This study reports the outcomes of 76 consecutive patients with multiply relapsed or refractory Hodgkin's lymphoma who underwent allogeneic transplantation that incorporated in vivo T-cell depletion. Forty-two patients had related donors and 34 had unrelated donors. DLIs were administered in a dose-escalating fashion to 22 patients for mixed chimerism (median time of first dose, 9 months post-transplantation) and to 24 patients for relapse. Results Three-year donor lymphocyte–related mortality was 7%, relating mainly to the induction of graft-versus-host disease. Nineteen (86%) of 22 patients receiving donor lymphocytes for mixed chimerism converted to full donor status. Four-year relapse incidence was 5% in these 22 patients compared with 43% in patients who remained relapse free but full donor chimeras at 9 months post-transplantation (P = .0071). Nineteen (79%) of 24 patients receiving donor lymphocytes for relapse responded (14 complete responses, five partial responses). Four-year overall survival from relapse was 59% in recipients of donor lymphocytes, contributing to a 4-year overall survival from transplantation of 64% and a 4-year current progression-free survival of 59% in all 76 patients. Conclusion These data demonstrate the potential for allogeneic immunotherapy with donor lymphocytes both to reduce relapse risk and to induce durable antitumor responses in patients with Hodgkin's lymphoma after hematopoietic stem-cell transplantation that incorporates in vivo T-cell depletion.

Introduction Reported outcomes for children with Downs syndrome (DS) and acute lymphoblastic leukaemia (ALL) treated on our previous national study, UKALL 2003, were inferior compared to non-DS children. 5 year event free survival (EFS) for DS children was 65.6% vs. 87.7% for non-DS children and 5 year overall survival (OS) was 70.0% vs. 92.2% (British Journal of Haematology 2014; 165: 552-555). Excess treatment related mortality (TRM, 21.6% vs. 3.3% at 5 years) in children with DS-ALL was primarily due to infection. Similar results have been reported by other study groups. In our successor study, UKALL 2011, we employed several steps of de-escalation for DS-ALL patients compared to standard therapy. Here, we report that de-escalated therapy has resulted in a dramatic reduction in TRM for children with DS-ALL treated in the UK. Methods DS-ALL patients treated on UKALL 2011 had their treatment modified in the following respects: 1)NCI high risk patients did not receive anthracycline in induction unless they had a slow early response at day 15; 2) two years maintenance was given for both boys and girls; 3) no pulses were given in maintenance for MRD low risk patients. In addition, we recommended use of prophylactic antibiotics during induction and intensive phases of treatment. Fisher's exact test was used to compare induction mortality in the DS and non-DS pts. OS was defined as time from registration to death. EFS was defined as time from registration to first event (induction failure, relapse, second malignancy or death from any cause). The Kaplan-Meier method was used for survival estimation. Results The UKALL 2011 trial opened to recruitment on 26th April 2012 and has recruited 2362 patients, of whom 50 have Down syndrome, in the period up to 22nd February 2018. The study is open in 41 centres in UK and Ireland and included patients with both ALL and lymphoblastic lymphoma (LBL). The baseline characteristics of the patients recruited up to this date are shown in the table below. For DS-ALL, Day 29 MRD was available for 48 patients and was low risk in 25 cases (50%), risk in 19 (38 %) and no result was obtained in 4 (8 %). The therapy was generally well-tolerated, there have been no cases of therapy curtailment due to toxicity and only one patient due to receive intensified therapy per MRD risk assessment was unable to escalate due to toxicity. At a median follow-up of 32.7 months, there have been 4 events. These include two relapses (relapse rate: 4.1% (1.1-15.5) at 3 years) and two TRMs (one TRM in induction and the other in consolidation; both due to infection). Three year EFS is: 92.9% (95% CI: 79.1 - 97.7) with a three year OS of 95.9% (84.5 - 99.0). The remarkably low induction TRM for DS children on UKALL 2011 (1 death out of 50 patients, 2%), is comparable to that of non-DS children treated on the same protocol with a 3 drug induction (12 out of 1174 children, 1% induction TRM; induction TRM in DS-ALL vs non-DS-ALL p=0.42). It is also comparable to the induction TRM in DS-ALL noted in the latter half of the UKALL 2003 study (1/40, 2.5%) when the aforementioned treatment modifications were first implemented in the UK. Importantly, this TRM is a quarter of that when an historic cohort of DS-ALL children were treated with a 4-drug induction on our previous study (UKALL 2003, DS-ALL TRM 4/46 patients i.e. 8 %, p=0.19). Conclusion These preliminary results suggest that de-escalation of treatment is successful in reducing treatment related mortality for children with DS-ALL without increasing the risk of early relapse, however longer term follow-up is needed. Disclosures Ghorashian: Celgene: Other: travel support; Novartis: Honoraria. Hough:University College London Hospital's NHS Foundation Trust: Employment. Kearns:Pfizer: Consultancy, Research Funding; Galen: Research Funding. Vora:Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board; Amgen: Other: Advisory board; Novartis: Other: Advisory board.

Introduction CAR T-cell therapies directed against CD19 or CD22 antigens have shown significant activity in pediatric patients with r/r B-ALL. Whilst complete response (CR) rates of 70‒90% have been observed, relapse due to target antigen downregulation or loss is the major cause of treatment failure. This Phase I/II study evaluates the safety and efficacy of AUTO3, a CAR T-cell therapy designed to target CD19 and CD22 simultaneously in order to reduce the likelihood of relapse due to antigen loss. Methods & Patients We constructed a novel bicistronic retroviral vector encoding both an anti-CD19 CAR and an anti-CD22 CAR. Antigen binding domains were humanized and both CARs are in "2nd generation" format (incorporating an OX40 co-stimulatory domain for the CD19 CAR and a 41BB for the CD22 CAR). The performance of the CD22 CAR was optimized by incorporating a novel pentameric spacer. The cell product was manufactured on a semi-automated and closed process using CliniMACS® Prodigy (Miltenyi Biotec). Patients (1‒24 years of age) with high risk relapse (IBFM criteria) or relapse post-allogeneic stem cell transplant (SCT), adequate performance score/organ function, and an absolute lymphocyte count ≥0.5 x 109/L are eligible. Patients with CNS 3 disease, active graft versus host disease, and clinically significant infection or serious toxicity from prior CAR T-cell are excluded. Patients receive lymphodepletion with 30 mg/m2/day fludarabine x 4 days and 500 mg/m2/day cyclophosphamide x 2 days prior to AUTO3 infusion. Three dose levels are being explored (1 x 106, 3 x 106, and 5 x 106 transduced CAR+ T cells/kg) and CAR T cells are infused as a single (for 25% blasts) dose based on leukemia burden. Bridging therapy is allowed during the manufacturing period. The primary endpoint of Phase I is the frequency of dose-limiting toxicities (DLTs) and key secondary endpoints include proportion of patients achieving a morphological/minimal residual disease (MRD) negative CR, disease-free survival, overall survival, as well as biomarker endpoints including AUTO3 levels and persistence in blood and bone marrow. Results As of the data cut-off date (July 16, 2018), 9 patients have been enrolled and 8 have received AUTO3. It was possible to generate a product in all patients and the median transduction efficiency was 16% (range 9‒34%). Median age was 7.5 years (range 4‒16 years) and 5 (63%) patients had prior SCT. One patient (13%) had prior anti-CD19 CAR-T cells and blinatumomab. The disease burden at Day ‒7 ranged from 0% to 90% leukemic blasts. Eight patients had a minimum of 4 weeks' follow up and were evaluable for safety and efficacy analysis. Three patients received ≤1 × 106 CAR T cells/kg as single dose, 1 patient received 2 × 106/kg as split dose, and 4 received 3 × 106 CAR cells/kg (3 single infusions, 1 split). No AUTO3 related deaths and no DLTs were observed. The most common grade (Gr) ≥3 adverse events were neutropenia (63%), febrile neutropenia (50%), pyrexia (25%), and anemia (25%). Five patients (63%) had Gr 1 cytokine release syndrome (CRS); no Gr 2 or higher CRS was seen. Five patients (63%) experienced neurotoxicity: 4 had Gr 1 and 1 patient (13%) had Gr 3 encephalopathy that was considered likely related to prior intrathecal methotrexate. No patients required ICU admission. Six of 8 patients achieved MRD negative CR, giving an objective response rate of 75% (95% CI 34.9‒96.8%) at 1 month. In patients treated at doses copies/µg DNA in blood at peak) compared to those receiving lower doses (median 10,243 copies/µg DNA). Conclusion This interim data analysis demonstrates for the first time the feasibility and safety of simultaneous targeting of CD19 and CD22 with AUTO3. Promising efficacy was demonstrated at a dose level of 3 × 106 CAR T cells/kg, as 4/4 patients achieved MRD complete remission with no antigen negative escape at this early stage. The study continues to enrol and updated follow up and additional patient data at higher dose levels, as well as cellular kinetics and additional biomarker analysis, will be presented. Disclosures Wynn: Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Hough:University College London Hospital's NHS Foundation Trust: Employment. Vora:Amgen: Other: Advisory board; Medac: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board; Jazz: Other: Advisory board. Veys:Servier: Research Funding; Pfizer: Honoraria; Novartis: Honoraria. Chiesa:Gilead: Consultancy; Bluebird Bio: Consultancy. Al-Hajj:Autolus Ltd: Employment; Autolus Ltd: Equity Ownership. Cordoba:Autolus Ltd: Employment; Autolus Ltd: Equity Ownership; Autolus Ltd: Patents & Royalties. Onuoha:Autolus Ltd: Employment, Equity Ownership, Patents & Royalties. Kotsopoulou:Autolus Ltd: Equity Ownership; Autolus Ltd: Employment. Khokhar:Autolus Ltd: Employment; Autolus Ltd: Equity Ownership. Pule:Autolus Ltd: Employment, Equity Ownership, Other: Salary contribution paid for by Autolus, Research Funding; University College London: Patents & Royalties: Patent with rights to Royalty share through UCL. Peddareddigari:Autolus Therapeutics plc: Equity Ownership; Autolus Therapeutics plc: Patents & Royalties; Autolus Therapeutics plc: Employment.

Outcomes for adolescents and young adults (AYA) might be considerably different from children and older adults with acute leukemia (AL). Patients in this transitory period tend to be considered at higher risk for poorer outcomes. However, AYA is still underrepresented in most hematopoietic stem cell transplant (HSCT) studies. Recent evidence shows superior outcomes for AYA with acute lymphoblastic leukemia (ALL) using pediatric rather than adult first line chemotherapy regimens. The aim of this study is to analyze outcomes of umbilical cord blood transplant (UCBT) in AYA patients with ALL or acute myeloid leukemia (AML) after myeloablative conditioning regimen (MAC). Eligibility criteria included patients with AL aged 15-25 (median 19) years, transplanted between 2004 and 2016 in EBMT centers, with single or double UCBT as first allogenic transplantation after MAC regimen and reported to Eurocord. A total of 504 patients were included. Primary endpoint was overall survival (OS). Median follow-up for survivors was 38 months (1 month-11 years). Median time from diagnosis to UCBT was 11 months (1 month-17 years) (interquartile range 5-29 months). Diagnosis was ALL in 59% (n=297) and AML in 41% (n=207); 64% of patients were male. Disease status at UCBT were 42% in 1st complete remission (CR) (n=203), 2nd CR in 38% (n=183), and advanced disease in 20% (n=96). Fifty eight percent of patients (n=293) received single and 42% (n=211) double UCBT. Cyclophosphamide + TBI ± fludarabine (45%) was the most frequently used conditioning regimen. Anti-thymoglobulin (ATG) was used in 54% and GVHD prophylaxis was cyclosporine A + mycophenolate mofetil in 44% of patients. Median nucleated cell dose at collection was 3.63 (range 0.9-9.0) X107/Kg for single and 5.25 (range 2.3-10.6) X107/Kg for double UCBT. The 3-year OS was 45±2%; 3-year leukemia free survival (LFS) was 41±2% and refined GVHD free/relapse free survival (rGRFS) was 32±2%. OS was similar in ALL and AML (45±3% vs 45±4%, p-value=0.69). According to disease status at UCBT, 3-year OS was 54±4% for patients in CR1, 48±4% for CR2 and 20±4% for advanced disease (p-value Cumulative incidence function (CIF) for neutrophil engraftment at day-60 was 88% [95% confidential interval (CI) 85-90] in a median time of 24 days. CIF of acute GVHD grade II-IV at day-100 was 28% (95%CI 24-32) and out of the 233 patients with aGVHD, 73 (21%) had grade III-IV. The 1-year CIF of chronic GVHD was also 28% (95%CI 24-33) and out of the 124 patients with cGVHD, 52 (42%) had the extensive form. The 3-year CIF of transplant related mortality (TRM) was 31% (95%CI 24-33). The 3-year CIF of relapse was 28% (95%CI 24-32), and according to disease status at UCBT, relapse was 28% (95%CI 21-34) for patients in CR1, 24% (95%CI 18-31) for those in CR2 and 37% (95%CI 27-47) for advanced disease. Main causes of death were relapse (41%) and TRM (57%, mainly infections and GVHD). In multivariate analysis, disease remission at UCBT (HR 0.46, 95%CI 0.32-0.66, p-value This large series of AYA patients with AL provides detailed information on UCBT for this particular cohort with results comparable with other sources of HSCT. Due to the lack of information on pre-transplant chemotherapy (pediatric versus adult protocols), we were unable to evaluate its effect on outcomes. Nevertheless, this study contributes to a better understanding of HSCT for an age group that is not thoroughly described in most publications. Demonstrating the feasibility of UCBT in AYA patients is important to facilitate the decision of stem cell source selection when a more standard donor is not available. Disclosures Hough: University College London Hospital's NHS Foundation Trust: Employment. Angelucci:Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Roche Italy: Other: Local (national) advisory board. Bader:Medac: Patents & Royalties, Research Funding; Neovii: Research Funding; Riemser: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau.

Introduction: Graft failure (GF) is an infrequent but serious complication of following matched related or unrelated donor peripheral blood stem cell transplantation. Although infusion of CD34+-selected stem cells without additional conditioning is currently one strategy to treat this complication, few studies have reported predictors of response. Methods: We report the outcome of consecutive patients identified at two UK transplant centres between 1999 and 2017 who had primary or secondary GF after an allogeneic peripheral blood stem cell transplant and who underwent a CD34+ selected stem cell infusion without further conditioning. GF was confirmed by chimerism, bone marrow examination and exclusion of relapsed disease. Primary GF was defined by failure to ever achieve count recovery in one or more lineages (neutrophils >0.5x109/L, untransfused platelets >20 x109/L and untransfused Hb >8 g/L) post transplantation. Secondary GF was defined by loss of counts after the initial achievement of engraftment. A complete response (CR) was defined as haematological improvement (HI) in all cell lines (Hb>8g/L, platelets > 30x109/L and neutrophils > 1.5x109/L). A partial response (PR) was defined as HI within the first 30 days but not in all cell lineages. Responses were categorized as early (30 days); in the latter case, the role of the CD34+ infusion in count recovery was not known. Results: We identified 62 patients with GF, male:female 35:27, with a median age of 43 years (range, 10-66). Fifty-six patients (90%) had had reduced intensity conditioning. Median follow up was 6.4 years. Diagnoses included acute leukemia (n=18), non-Hodgkin's lymphoma (n=18), Hodgkin's Lymphoma (n=7), MDS (n= 6), multiple myeloma (n=3), myelofibrosis (n=2), CLL (n=2), severe aplastic anaemia (n=2), primary immunodeficiency (n=2), CML (n=1) and sickle cell disease (n=1). The original graft source was peripheral blood stem cells from a matched related donor (n=29), matched unrelated donor (n=18) and mismatched unrelated donor (n=15). Twenty-one (34%) patients had primary GF and 41 (66%) had secondary GF. Forty-three patients (69%) had GF in all 3 lineages and 19 patients (31%) had GF in 1 or 2 lineages. The median CD34+ cell dose/kg recipient weight was 3.2 x 106/kg (range, 0.47-14.2 x 106/kg) at a median of 181 days (range, 21-2718 days) following transplant. No response to CD34+ infusion was seen in 15 (24%) patients. Of the remaining 47 patients who responded (76%), 19 patients achieved a CR 30 days, 5 had a PR 30 days. Of those who responded, the median number of days required for neutrophil recovery was 29 days (6-1182), platelets recovery was 18 days (5-600) and haemoglobin recovery was 25 days (6-511). In a multivariate analysis, parameters significantly associated with response were CMV serostatus negative for both patient and donor (OR: 20.12, CI 95%= 1.6 - 248) and matched patient/donor sex (OR: 73, CI 95%= 3.3- 1605). Other factors including CD34+ dose, unrelated/related donor, underlying disease, disease risk score, timing of infusion, recipient/donor age, primary or secondary GF and presence or absence of GVHD did not predict for response. Overall survival (OS) for all patients at 1 and 5 years was 70% (95% CI 58-82) and 54% (95% CI 41-68) respectively. OS at 1 and 5 years was 86.4% (95% CI 75-98) and 73.6% (95% CI 54-92) in patients showing a CR versus 66.7% (95% CI 35-98) and 27.8% (95% CI 3-60) in patients with PR (Figure 1). Patients showing no response had poor outcomes with OS of 33.3% (95% CI 9-58) and 22.2% (CI 95% 5-47) at 1 and 5 years. In responding patients, those who initially had GF in 1-2 lineages had 5-year OS of 93.8% (95% CI 82-99) versus GF in 3 lineages who had a 5-year OS of 53% (95% CI 34-88) (Figure 2). Conclusions: This analysis represents the largest report of outcomes in patients who have received a CD34+ selected stem cell infusion without conditioning for GF. Negative donor/recipient CMV serostatus and sex matching predicted response. In responding patients, GF initially affecting Disclosures Hough: University College London Hospital's NHS Foundation Trust: Employment.

Background: Neurotoxicity during treatment for childhood acute lymphoblastic leukaemia (ALL) remains a significant problem. It can be acute as in methotrexate stroke-like syndrome, posterior reversible encephalopathy syndrome, or seizures, or may be subacute resulting in chronic neurocognitive defects. Symptomatic and asymptomatic neurotoxicity can affect long-term neurocognitive outcomes (e.g. attention, executive function). Worryingly, studies in patients 20-30 years post treatment suggest accelerated CNS ageing and the burden of neurological late effects may worsen over the next few decades. Thus, there is an urgent need to better understand the pathophysiology of neurotoxicity and develop ways of identifying children at risk. Previous reports suggest that treatment intensity, (particularly methotrexate exposure), age greater than 10 years and number of intrathecals may predispose to neurotoxicity but none of the studies have been sufficiently large to identify independent risk factors in multivariable analysis. In order to investigate clinical risk factors for neurotoxicity and its effect on outcomes in a large cohort of patients, we carried out a review of all neurotoxic serious adverse events (SAEs) reported for UKALL2003. Methods: Between Oct 2003 and June 2011, the UKALL2003 trial enrolled 3113 patients aged 1-24 years with ALL. The trial SAE database was interrogated for reports of seizures, encephalopathy or arachnoiditis. Cerebral venous sinus thrombosis, cerebral haemorrhage, miscellaneous encephalopathy secondary to systemic disorders and steroid psychosis (n=22) were excluded from this analysis due to their distinct aetiologies. Survival rates were calculated and compared using Kaplan Meier methods and log-rank tests. The association between neurotoxicity event and risk factors was investigated using χ2 test, univariate and multivariate logistic regression. All tests were conducted at the 5% significance level and the analyses were performed using Intercooled Stata. Results: There were 300 SAE reports of neurotoxicity in 254 patients (8.2% of all trial participants), 159 with encephalopathy, 86 with seizures and 9 other. These patients were compared to 2837 controls without any reported neurotoxicity. There was no significant difference in 5-year event-free survival, overall survival and relapse risk between the two groups. We observed a significant association between the neurotoxicity events and each of; treatment intensity, age, female sex, CNS status, T-cell immunophenotype and white cell count (Table 1). Multivariate analysis revealed that treatment allocation (regimen B/C v A, odds ratio (OR) 2.61 (95% CI 1.86-3.65), female sex (OR 1.42 (1.10-1.85), CNS status (CNS2/3/TLP v CNS1, OR 1.60 (1.14-2.24)) and age (OR 1.04 (1.01-1.07) per year) remained significant independent predictors of neurotoxicity. In order, to examine further the effect of age, we performed a stratified analysis by treatment group (regimen A v regimen B/C). Age remained significant in both groups: OR 1.15 (1.03-1.29) and 1.03 (1.01-1.06) per year, both p=0.01. Therefore, age was still a risk factor among patients receiving regimen A who were, by definition, under 10 years; despite lower methotrexate exposure. Discussion: This large study identifies treatment intensity as the main risk factor for developing acute neurotoxicity with female sex, age and CNS status having a significant modifying effect. CNS status may reflect increased intrathecal therapy given to non-CNS-1 patients. Females are more vulnerable to cranial radiotherapy induced neurotoxicity but this is the first report of female sex as a risk factor on contemporary chemotherapy treatment protocols. Reassuringly, the occurrence of acute neurotoxicity did not influence survival rates. These data provide an important benchmark for ongoing international deep phenotyping studies of chemotherapy-associated neurotoxicity. Disclosures Hough: University College London Hospital's NHS Foundation Trust: Employment. Vora:Amgen: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board; Jazz: Other: Advisory board; Medac: Other: Advisory board. Halsey:Jazz Pharmaceuticals: Honoraria, Other: Support for conference attendance.

There is an ever-increasing number of cancer survivors entering adult life. Health-care professionals in this field must ensure that there is seamless transition through paediatric, teenage and young adult and adult services such that an individual patient is able to achieve his/her maximum potential and enjoy a quality, ‘cancer-free’ future.

Introduction: Published studies of CD19 CAR T cells have shown unprecedented response rates in ALL but with a 23-27% incidence of severe Cytokine Release Syndrome (CRS) and 27-50% incidence of severe neurotoxicity which may limit broader application. We developed a novel second generation CD19CAR (CAT-41BBz CAR) with a lower affinity and faster off-rate but equivalent on-rate than the FMC63-41BBz CAR (Kd 116 nM vs 0.9 nM, T1/2 10s vs 1260s) utilised in CTL019 currently under consideration by the FDA. Pre-clinical studies indicated T-cells transduced with CAT-41BBz mediate enhanced tumor clearance and show increased expansion in an NSG-NALM6 stress test model (Kramer et al., submitted). We here report interim results from a multi-centre, Phase I clinical study of autologous CAT-41BBz CAR T cells as therapy for high risk/relapsed paediatric ALL, CARPALL (NCT02443831) demonstrating efficacy with an excellent safety profile. Methods: Autologous T cells were activated with anti-CD3/CD28 beads, transduced with a SIN lentiviral vector encoding CAT-41BBz CAR and expanded for 4 days prior to magnetic bead removal and cryopreservation. Transduction efficiency was assessed using an anti-idiotype antibody. Serum levels of cytokines associated with CRS were measured using cytometric bead array. All patients received lymphodepletion with fludarabine 150 mg/m2 + cyclophosphamide 1.5g/m2 followed by a single infusion of CAR T cells at a dose of 1x106 CAR+ T cells. Patients were monitored for the presence of CAR T cells in the blood by flow cytometry and by qPCR for the 41BBz junctional region, as well as circulating B cell count monthly for 6 months and then 6 weekly to 1 year. Disease status was assessed in the bone marrow morphologically, by IgH qPCR, as well as by flow cytometric assessment of MRD at the same time-points to establish durability of responses as a stand-alone therapy. The primary end-points were incidence of grade 3-5 toxicity related to CAR T cells within 30 days and the proportion of patients achieving molecular remission. Results: We have enrolled 10 patients and treated 8 to date. Six of 8 had relapsed post myeloablative SCT. The median disease burden prior to lymphodepletion was 9% blasts (ranging from molecular CR to 74% blasts, Table 1). It was possible to generate a product meeting release criteria in all but 1 patient (90% feasibility). Median transduction efficiency was 18.1% (range 6.7 to 76.3%). All treated patients received the anticipated dose of 1x106 CAR T cells/kg. Cytokine release syndrome occurred in all patients (grade 1 n=4, grade 2 n=4), but to date none have developed ≥ grade 3 CRS, required ICU admission or therapy with Tocilizumab. CRS was associated with modest elevations of IL-6, IFN-γ and IL-10 and resolved spontaneously in all. Grade 2 neurotoxicity was observed in 3 patients and resolved spontaneously, but no severe (≥grade 3) neurotoxicity was seen. Five patients had prolonged grade 4 neutropenia lasting > 30 days but this resolved in all by 2 months. Only 1 patient experienced significant infective complications in the context of pre-existing poor marrow reserve following allogeneic SCT. 6/7 (86%) evaluable patients achieved molecular remission at a median of 30 days post infusion (range 30-60 days, Table 1). One patient did not respond and died of CD19+ disease progression. At a median follow-up of 5.9 months (range 28-328 days), 4/7 evaluable patients remain in flow MRD negative remission of whom 3 show no evidence of molecular MRD at 1, 7.5 and 9 months. Two patients relapsed with CD19- disease at 3 and 4 months post infusion: 1 of these remains alive with disease at 11 months and the other died of disease progression. Reflecting our pre-clinical data with CAT-41BBz CAR, we have seen excellent CAR T cell expansion (median 65459 copies/µg DNA at 1 month, range 609 to 230112) and persistence at up to 11 months post-infusion (Figure 1). All 7 evaluable patients have ongoing CAR T cell persistence detectable by both flow and qPCR as well as ongoing B cell aplasia at last follow-up. Conclusions: These interim results with a novel low affinity CD19 CAR show similar remission rates to those reported by US studies in paediatric ALL with an improved safety profile. No severe (grade ≥3) CRS or neurotoxicity has occurred to date despite high tumour burden in 4 patients. Excellent CAR T cell expansion has been documented, as well as long duration of CAR T cell persistence and associated B cell aplasia. Disclosures Ghorashian: UCL: Patents & Royalties: UCL Business. Kramer: UCL: Patents & Royalties: UCL Business. Lucchini: Alexion: Membership on an entity's Board of Directors or advisory committees. Pule: Autolus Ltd: Employment, Equity Ownership, Research Funding; UCL: Patents & Royalties: UCL Business.

Allogeneic haematopoietic cell transplantation is an established curative treatment modality for patients with malignant and non-malignant haematological disorders. Since the first related umbilical cord blood transplant (UCBT) in 1988, the use of UCB as a stem cell source for transplantation has become a standard practice in many countries, with approximately 8000 such transplants having been performed worldwide to date.

Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment.

Fulminant hepatitis is a rare complication of adenoviral infection that has not previously been reported in children receiving standard chemotherapy for acute leukemia. The authors have observed fatal adenovirus hepatitis in three children receiving first-line chemotherapy for acute lymphoblastic leukemia (ALL). The patients presented 10, 17, and 8 months into therapy according to the UKALL XI (third intensification), UKALL 97/99 (maintenance), and pilot UKALL 2003 (delayed intensification II) protocols, respectively. All patients received aggressive supportive care and intravenous immunoglobulins. The second and third patients were also treated with intravenous cidofovir. Despite these measures, all three children deteriorated rapidly and died of fulminant liver failure. Although rare, adenovirus infection should be considered in the differential diagnosis of acute hepatitis in children receiving standard chemotherapy for ALL.

‘Stroke-like syndrome’ caused by intrathecal methotrexate in patients treated during the UKALL 2003 trial

Summary. We have carried out comparative genomic hybridization (CGH) analysis on archival biopsy material from a series of 30 UK mantle cell lymphomas. The most frequent aberrations were gains of 3q (21 cases), 6p (19 cases), 7q (8 cases), 12p (8 cases), 12q (9 cases) and 17q11q21 (8 cases), and losses of 1p13p32 (10 cases), 5p13p15.3 (9 cases), 6q14q27 (11 cases), 8p (7 cases), 11q13q23 (8 cases) and 13q (18 cases). Nineteen cases (63%) had a common region of amplification at 3q28q29, which was highly amplified in three cases, suggesting the presence of a mantle cell lymphoma (MCL)-related oncogene in this region. There was a minimal common region of deletion at 6q25q26 in nine cases (30%). No MCL-specific locus has previously been identified on chromosome 6 and this region may contain a tumour suppressor gene specifically implicated in the development of this subtype of lymphoma. An increased number of chromosome aberrations, gain of Xq and loss of 17p were all significantly associated with a worse prognosis. A greater understanding of the genetics of mantle cell lymphoma may allow the identification of prognostic factors which will aid the identification of appropriate treatment regimens.

Background: No randomised study has shown whether stratification of treatment by minimal residual disease (MRD) response improves outcome in children and young people with acute lymphoblastic leukaemia (ALL). We assessed whether children and young people with clinical standard and intermediate-risk ALL who have persistent MRD at the end of induction therapy benefit from augmented post-remission therapy. Methods: Between Oct 1, 2003, and June 30, 2011, we enrolled eligible patients aged 1-24 years and initially categorised them into clinical standard-risk, intermediate-risk, and high-risk groups on the basis of a combination of National Cancer Institute criteria, cytogenetics, and early morphological response to induction therapy. Clinical standard-risk and intermediate-risk patients with MRD of 0·01% or higher at day 29 of induction (MRD high risk) were randomly assigned (1:1) to standard therapy (treatment regimens A and B) or augmented post-remission therapy (regimen C). Compared with standard therapy, the augmented treatment regimen (regimen C) included an additional eight doses of pegylated asparaginase, 18 doses of vincristine, and escalated-dose intravenous methotrexate without folinic acid rescue during interim maintenance courses. Computer randomisation was used for treatment allocation and was balanced for sex, age (

Although infection is the major cause of treatment-related mortality (TRM) in childhood acute lymphoblastic leukemia, factors associated with infection-related mortality (IRM) are poorly understood. To address this, we report an analysis of all 75 cases of IRM in the United Kingdom Childhood Acute Lymphoblastic Leukaemia Randomised Trial 2003 (UKALL 2003). The 5-year cumulative incidence of IRM was 2.4% (95% confidence interval [CI], 1.9%-3.0%), accounting for 75 (30%) of 249 trial deaths and 75 (64%) of 117 TRM deaths. Risk for IRM as a proportion of TRM was greater in induction than other phases (77% vs 56%; P = .02). Sixty-eight percent of cases were associated with bacterial infection (64% Gram-negative) and 20% with fungal infection. Down syndrome was the most significant risk factor for IRM (odds ratio [OR], 12.08; 95% CI, 6.54-22.32; P < .0001). In addition, there was a trend toward increased IRM in girls (OR, 1.63; 95% CI, 1.02-2.61; P = .04), as well as increasing treatment intensity (regimen B vs A: OR, 2.11 [95% CI, 1.24-3.60]; regimen C vs A: OR, 1.41 [95% CI, 0.76-2.62]; P = .02). Importantly, patients with Down syndrome were at significantly higher risk for IRM during maintenance (P = .048). Our results confirm Down syndrome as a major risk factor for IRM. Enhanced supportive care and prophylactic antibiotics should be considered in high-risk patient groups and during periods of increased risk. This study was registered at http://www.controlled-trials.com/ as #ISRCTN07355119.