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CD19 CAR-T have emerged as a new standard treatment for relapsed/refractory (r/r) large B-cell lymphoma (LBCL). CAR-T real-world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR-T in the UK. Consecutive patients with r/r LBCL approved for CAR-T by the National CAR-T Clinical Panel between December 2018 and November 2020 across all UK CAR-T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi-cel), 112 tisagenlecleucel (tisa-cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi-cel, 57% (44% CR) for tisa-cel. The 12-month progression-free survival was 41.8% (axi-cel) and 27.4% (tisa-cel). Median overall survival for the intention-to-treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi-cel and 7.9%/3.9% for tisa-cel. This prospective RW population of CAR-T eligible patients offers important insights into the clinical benefit of CD19 CAR-T in LBCL in daily practice. Our results confirm long-term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR-T failure.

Relapse following CD19-directed chimeric antigen receptor T-cells (CAR-T) for relapsed/refractory large B-cell lymphoma (r/r LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multi-antigen targeting and PD-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in r/r LBCL as inpatient or outpatient therapy (NCT03289455, https://clinicaltrials.gov/ct2/show/NCT03289455). Endpoints include toxicity (primary) and response rates (secondary). AUTO3 was manufactured for 62 patients using autologous leukapheresis, modified with a bicistronic transgene. 52 patients received AUTO3 (7/52,50x106; 45/52,150-450x106) and 48/52 received pembrolizumab. Median age was 59 years (range,27-83) and 46/52 had stage III/IV disease. Median follow-up was 21.6 months (range,15.1-51.3) at last data cut (Feb 28, 2022). AUTO3 was safe: grade 1-2 and grade 3 CRS affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), HLH affected 2 patients, and no Pembrolizumab-associated autoimmune sequalae were observed. On this basis, outpatient administration was tested in 20 patients, saving a median of 14 hospital days/patient. AUTO3 was effective: overall response rates were 66% (48.9%, CR; 17%, PR). For patients with CR, median DOR was not reached, with 54.4% (CI: 32.8, 71.7) projected to remain progression-free beyond 12 months after onset of remission. DOR for all responding patients was 8.3 months (95% CI: 3.0, NE) with 42.6% projected to remain progression-free beyond 12 months after onset of remission. Overall, AUTO3 +/- pembrolizumab for r/r LBCL was safe, lending itself to outpatient administration, and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion/persistence in vivo, and selection of CAR binders active at low antigen densities.

The impact of bridging therapy (BT) on CD19-directed chimeric antigen receptor T-cell (CD19CAR-T) outcomes in large B-cell lymphoma (LBCL) is poorly characterised. Current practice is guided by physician preference rather than established evidence. Identification of effective BT modalities and factors predictive of response could improve CAR-T intention to treat and clinical outcomes. We assessed BT modality and response in 375 adult LBCL patients in relation to outcomes following axicabtagene ciloleucel (Axi-cel) or tisagenlecleucel (Tisa-cel). The majority of patients received BT with chemotherapy (57%) or radiotherapy (17%). We observed that BT was safe for patients, with minimal morbidity/mortality. We showed that complete or partial response to BT conferred a 42% reduction in disease progression and death following CD19CAR-T therapy. Multivariate analysis identified several factors associated with likelihood of response to BT, including response to last line therapy, the absence of bulky disease, and the use of Polatuzumab-containing chemotherapy regimens. Our data suggested that complete/partial response to BT may be more important for Tisa-cel than Axi-cel, as all Tisa-cel patients with less than partial response to BT experienced frank relapse within 12 months of CD19CAR-T infusion. In summary, BT in LBCL should be carefully planned towards optimal response and disease debulking, to improve CD19CAR-T patient outcomes. Polatuzumab-containing regimens should be strongly considered for all suitable patients, and failure to achieve complete/partial response to BT pre-Tisa-cel may prompt consideration of further lines of BT where possible.

Perinatal palliative care (PNPC) is a holistic multidisciplinary model of care for both baby and family in the event of a perinatal diagnosis of a life-limiting condition. It aims to provide optimal symptom control and end-of-life care to the baby as well as specialized support to families from diagnosis through to birth, death, and bereavement. This chapter aims to address the challenging clinical, ethical, and practical issues specific to perinatal palliative care. It describes antenatal life-limiting diagnoses, the role of anticipatory bereavement care, a palliative care approach to pregnancy, and outlines the complex planning and models of care required to optimally provide for the baby, mother, and family throughout. This chapter ultimately aims to provide management strategies to guide multidisciplinary teams (MDT) to deliver high-quality PNPC to the family as a whole.

Background Oxycodone/naloxone has a reported equivalent analgesic effect to oxycodone due to insufficient naloxone reaching systemic circulation to affect analgesia. Naloxone plasma concentrations can increase in some, e.g. patients with hepatic or renal impairment. Case presentation A 75 year-old male with prostate and lung carcinoma was admitted for palliative radiotherapy. Admission analgesia included oxycodone/naloxone 70/35 mg bd, pregabalin 100 mg bd and oxynorm 20 mg prn. Management Day 3: Multiple breakthroughs required for severe pain. Oxycodone/naloxone changed to oxycodone 90 mg bd (maximum licensed dose of oxycodone/naloxone exceeded). Pregabalin increased to 150 mg bd. Day 4: Respiratory infection diagnosed and treated with intravenous antibiotics. Mild myoclonus but no other signs of toxicity. Pain ongoing. Day 5: Sudden deterioration with respiratory depression (respiratory rate - 6, oxygen saturations -60%). Rapid response to naloxone 40micrograms intravenously. Opioids and pregabalin discontinued. Multiple further naloxone doses required for recurrent respiratory depression. Continuous subcutaneous infusion (CSCI) of 1.5 mg naloxone commenced. Day 6: Naloxone infusion discontinued when pain recurred. CSCI of oxycodone 30mg/24hours commenced and subsequently rotated to hydromorphone 4mg/24hours due to mild opioid toxicity. Radiotherapy completed and patient discharged home on hydromorphone and gabapentin. Discussion Given the timing, and despite normal renal and liver function, we believe the oxycodone/naloxone to oxycodone switch contributed to the severity of opioid toxicity in this case. Other possible factors include infection and titration of pregabalin. When repeated naloxone doses are required for toxicity, a continuous intravenous infusion often necessitates transfer to an acute hospital and may be avoided by administering a CSCI of naloxone. To the best of the authors’ knowledge, this is the first case report of naloxone administered via CSCI for opioid toxicity. Conclusion When switching preparations of oxycodone, specific patient factors and intra- and inter-patient variability should be considered and patients monitored carefully. CSCIs of naloxone for opioid toxicity should be considered if intravenous administration is not feasible.

BACKGROUND: Adoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBV-associated lymphomas (EBV-PTLD) after transplantation of hematopoietic cell (HCT) or solid organ (SOT) but is unavailable for most patients. METHODS: We developed a third-party, allogeneic, off-the-shelf bank of 330 GMP-grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (n = 33) or SOT (n = 13) with established EBV-PTLD, who had failed rituximab therapy, with third-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation. RESULTS: EBV-CTLs did not induce significant toxicities. One patient developed grade I skin graft-versus-host disease. Complete remission (CR) or sustained partial remission (PR) was achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, one year overall survival was 88.9% and 81.8%, respectively. In addition, 3 of 5 recipients with POD after a first cycle who received EBV-CTLs from a different donor achieved CR or durable PR (60%) and survived longer than 1 year. Maximal responses were achieved after a median of 2 cycles. CONCLUSION: Third-party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV-PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab-refractory EBV-associated lymphoma after transplantation. TRIAL REGISTRATION: Phase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, the FDA, and the National Marrow Donor Program. FUNDING: This work was supported by NIH grants CA23766 and R21CA162002, the Aubrey Fund, the Claire Tow Foundation, the Major Family Foundation, the Max Cure Foundation, the Richard “Rick” J. Eisemann Pediatric Research Fund, the Banbury Foundation, the Edith Robertson Foundation, and the Larry Smead Foundation. Atara Biotherapeutics licensed the bank of third-party EBV-CTLs from Memorial Sloan Kettering Cancer Center in June 2015.

This paper reports the findings from a Delphi Study undertaken to identify the research priorities in children's palliative care in Ireland. Palliative care for children is a small and highly specialised field of healthcare that focuses on improving the quality of life of children living with, or dying from, a life-limiting condition. Ideally, support for children requiring palliative care begins at the time of diagnosis, which for many children with life-limiting conditions can be from birth. There is a notable overlap between the needs of children requiring palliative care and those with disabilities and other complex care needs, resulting in care being provided by a range of voluntary and statutory agencies. As a new specialty, there is a need to develop an evidence-based approach to providing children's palliative care. In order to do this in a systematic way, identification of the research priorities in children's palliative care within Ireland is required.

Aims Prompt communication with all professionals involved in the care of a child who has died is essential. To aid this, Our Lady’s Children’s Hospital Crumlin (OLCHC), has developed a pan departmental algorithm to provide guidance. The ‘When a Child Dies (WACD) Algorithm’ provides a guided checklist for staff to ensure all stakeholders are informed of the death, and that tasks related to the care of the child and family following a death are completed. This research aimed to audit the activation and completion of the WACD algorithms. Methods A retrospective study was conducted in a 324-bed in OLCHC. The deaths of 251 children from 2015–2016 were included. Demographic information, diagnoses, disease status, end of life care, place of death and algorithm completion was investigated. The audit was conducted against standards from current institutional guidelines. Results Of the 251 paediatric deaths audited, 43% died in OLCHC, 11% died in another hospital or hospice, 3% were unaccounted for, and 42% died at home. The most common departments were Cardiology and Haematology/Oncology, accounting for 26.3% and 21.5% of deaths respectively. 17% (43) had the appropriate WACD fully completed, 48% (120) were partially completed and 35% (88) of cases had no WACD forms completed. Conclusions Departments that more commonly encounter paediatric deaths were more consistent in completion of the WACD algorithm. There is a need to disseminate information and knowledge of the algorithms, especially in departments with a low frequency of childhood deaths. This would ensure that primary care teams, GPs, referring hospitals and any other relevant healthcare professionals are informed on the death of their patient. It also ensures that families are met by the on-call team, the chaplain, and that follow-up with their primary consultant is arranged for the family.

Background and aim Palliative Care for Children is defined as ‘an active and total approach to care, from the point of diagnosis or recognition throughout the child’s life, death and beyond’. It is recognised that the prevalence of children with life-limiting conditions (LLC) is increasing. In Ireland the majority of children with LLC are cared for by paediatricians working in hospitals with no direct access to specialist paediatric palliative care(PPC) services. This study was part of a learning needs assessment of paediatrician’s training and experience in PPC. Methods Consultants and Specialist Registrars in Paediatrics were approached by email and asked to complete a questionnaire regarding their learning needs in PPC. The Quality of Care Collaborative for Australia in PPC Project Research Study Group Learning Needs Assessment template was used with permission. The questionnaire included both multiple choice and free-text questions. Quantitative data from the study has been reported elsewhere. Thematic analysis based on the approach of Braun and Clarke (2006) was used to analyse data provided in the free-text answers. Results 114 paediatricians responded to the survey, 72 respondents (63%) provided free-text answers to the question ‘Reflecting on your most recent clinical interactions with children requiring palliative care support. What were the challenges?’ On analysis, three overarching themes emerged, ‘Best interests of the child’, ‘Inadequate training and confidence’ and ‘Co-ordinating care’. ‘Best interests of the child’ referred to the challenges experienced in ensuring that best interests of the child remain at the core of all decisions made when providing palliative care. This overarching theme included two sub-themes ‘Complex communication’ which referred to the challenges in managing parental expectations in increasingly technologically advanced healthcare systems and ‘First do no harm’ referring to the frequent ethical dilemmas that arise in PPC. ‘Inadequate adequate training and confidence’ referred to lack of specific education in complex symptom management and also to lack of familiarity with community based healthcare services. The theme of ‘coordinating care’ encompassed the need to liaise with community services but also the need to provide holistic care to the whole family which may be unfamiliar paediatricians working in an acute hospital setting. Conclusion This study explores the challenges experienced by paediatricians providing palliative care to children with LLCs. The themes provide insight into those experiences and provides valuable direction to support the development of future educational programmes in this important and rapidly evolving paediatric sub-speciality.

ObjectiveTo analyse the referral patterns of perinatal patients referred to a specialist palliative care service (SPCS), their demographics, diagnoses, duration of illness, place of death and symptom profile.DesignA retrospective chart review of all perinatal referrals over a 4-year period to the end of 2015.SettingA consultant-led paediatric SPCS at Our Lady’s Children’s Hospital, Crumlin, Dublin, and the Coombe Women & Infants University Hospital, Dublin.Results83 perinatal referrals were received in a 4-year period. Chromosomal abnormalities accounted for 35% of diagnoses, congenital heart disease 25%, complex neurological abnormalities 11% and renal agenesis 4%. 22 referrals (26.5%) were made antenatally, with 61 (73.5%) postnatally. Of the postnatal referrals, 27 (44%) were asymptomatic on referral. An opioid medication was recommended (regularly or as required) in 46 cases. Symptom control was achieved without dose titration in 43 of these cases (93%). Of 47 deaths in this group referred postnatally, 22 of these (47%) died at home with support from community teams. Discharge home for best supportive care required complex interagency communication and cooperation.ConclusionsPerinatal palliative care requires effective multidisciplinary work, whether delivered in the inpatient setting or in the community. With appropriate support, end-of-life care can be delivered in the community.

The use of complementary and alternative medicine (CAM) in the Irish pediatric cancer setting has not previously been established.To investigate the prevalence and predictors of CAM use in this group of patients, an anonymous cross-sectional survey was offered to all carers of patients either on or off treatment for malignancy at a single pediatric cancer center over an 8-week period.Of a total of 220 questionnaires distributed, 98 (43%) were returned. Six were excluded because of inadequate data. A total of 58% of children were male and the mean age was 9 years. The most common cancer diagnosis was leukemia (45%). Fifty-two respondents (57%) said their child had used or was using CAM, and 55% of whom had started since their cancer diagnosis. The most common types of CAM used were vitamins and minerals (18%), reflexology (11%), dietary supplements (11%), faith healers (9%), and energy therapies (9%). The most common reason for CAM use was to improve physical well-being (31%). A total of 65% of CAM users had not told their doctor that they were doing so. Of the 52 CAM users, 30 (58%) were using oral CAM medication. A total of 86% of CAM users reported benefit from the treatment, and no respondent reported side effects.There was no significant relationship between sex, tumor type, age, income, previous treatment, and CAM use. Where parents had a higher level of education, children were more likely to use CAM (P=0.035.) There was a statistically significant relationship between respondents rating of conventional therapy and CAM use (P=0.007). Interestingly, parents who were satisfied with conventional therapy were more likely to use CAM.The high prevalence of CAM use demonstrated in this study and particularly the high use of CAM medication therapies underlines the importance of physicians asking routinely about CAM use in this population.

Central venous access devices (CVADs) play an essential role in the care of critically ill children. Significant challenges exist for teams in managing CVADs particularly in a community setting. The authors aimed to assess the experience of general practitioners (GPs) caring for children with CVADs. From 200 CVADs inserted in a pediatric hospital in 2009, 50 patients were randomly selected and 44 GPs were forwarded a questionnaire. Twenty (46%) GPs responded. The main reasons (n = 22) for using CVADs were medication administration (n = 11), nutrition (n = 6), and blood sampling (n = 5). Thirteen (65%) GPs had no education in CVAD management and 14 (70%) were unaware of existing guidelines. Those identified by GPs as having primary responsibility for care of CVADs in the community included hospital/pediatric teams (n = 9), parents (n = 3), GPs (n = 2), public health nurses (n = 1), and palliative care ("home care") teams (n = 1). The main challenges (n = 15) identified by GPs were lack of education (n = 4), line management difficulties (n = 3), infection risk (n = 3), infrequent exposure to CVADs (n = 3), and poor communication (n = 1). GPs felt that these challenges could be addressed through: education (n = 8), increased manpower and community support (n = 1), and improved communication (n = 1). This study highlights the inconsistency and challenges for GPs surrounding CVAD use in children. Further education and support is necessary to assist GPs in their use particularly when providing end-of-life care for children in the community.

Background: Seizures are a common complication in patients with central nervous system (CNS) tumors. Optimal management is unclear with no defined guidelines and pharmacological management poses many controversies. Due to a hypothesized lack of consistency, we aimed to retrospectively review seizure management in patients with high-grade CNS tumors in our institution. Methods: The medical records of patients with high-grade CNS tumors referred to the specialist palliative medicine service in our institution from January-June 2008 were retrospectively reviewed. Seizure incidence, antiepileptic drug (AED) choice, neurology input, medication interactions, and appropriate drug level monitoring were assessed. Results: Twenty-seven patients were included for analysis. Fifteen (56%) were female. The mean age was 58.8 years (range 31-82 years). Three (11%) patients presented with seizures and 8 (30%) developed seizures subsequently. Eight (73% of those with seizures) were on monotherapy AED. Six different agents were used as first-line agents. Phenytoin was the most common AED used (n = 4). Three (27%) patients were on combination AEDs. Five (45.5%) patients had been seen by neurology and 6 (54.5%) had appropriate drug level monitoring performed. Six (55%) patients had potential AED-non-AED interactions. None of the patients had instructions documented in the clinical notes against driving. Conclusion: Seizure management in patients with CNS tumors is not consistent and remains very much a neglected area. Appropriate choice of AED is crucial. Physicians should be aware of potential drug interactions. Ownership and regular follow-up of this group is required to ensure optimum patient management.