Joint consensus statement on the vaccination of adult and paediatric haematopoietic stem cell transplant recipients: Prepared on behalf of the British society of blood and marrow transplantation and cellular therapy (BSBMTCT), the Children's cancer and Leukaemia Group (CCLG), and British Infection Association (BIA).

Haematopoietic stem cell transplant (HSCT) recipients have deficiencies in their adaptive immunity against vaccine preventable diseases. National and International guidance recommends that HSCT recipients are considered 'never vaccinated' and offered a comprehensive course of revaccination. This position statement aims to draw upon the current evidence base and existing guidelines, and align this with national vaccine availability and licensing considerations in order to recommend a pragmatic and standardised re-vaccination schedule for adult and paediatric HSCT recipients in the UK.

Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA).

BACKGROUND: Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. DESIGN: The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. RESULTS: Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues. CONCLUSIONS: We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic.

Metabolic syndrome and cardiovascular disease after haematopoietic cell transplantation (HCT) in adults: an EBMT cross-sectional non-interventional study.

Metabolic syndrome (MetS) is associated with cardiovascular disease in the general population and is also a potential cardiovascular risk factor in survivors of haematopoietic cell transplantation (HCT). We report an EBMT cross-sectional, multi-centre, non-interventional study of 453 adult HCT patients surviving a minimum of 2 years post-transplant attending routine follow-up HCT and/or late effects clinics in 9 centres. The overall prevalence of MetS was 37.5% rising to 53% in patients >50 years of age at follow-up. There were no differences in rates of MetS between autologous and allogeneic HCT survivors, nor any association with graft-versus-host disease (GvHD) or current immunosuppressant therapy. Notably, there was a significantly higher occurrence of cardiovascular events (CVE, defined as cerebrovascular accident, coronary heart disease or peripheral vascular disease) in those with MetS than in those without MetS (26.7% versus 9%, p < 0.001, OR 3.69, 95% CI 2.09-6.54, p < 0.001), and, as expected, MetS and CVE were age-related. Unexpectedly, CVE were associated with occurrence of second malignancy. Screening for and management of MetS should be integrated within routine HCT long-term follow-up care for both allogeneic and autologous HCT survivors. Further research is warranted, including randomised controlled trials of interventional strategies and mechanistic studies of cardiovascular risk in HCT survivors.

The promise and challenges of cell therapy for psoriasis.

The management of moderate-to-severe psoriasis has been transformed by the introduction of biological therapies. These medicines, particularly those targeting interleukin (IL)-17 and IL-23p19, can offer clear or nearly clear skin for the majority of patients with psoriasis, with good long-term drug survival. However, as currently used, none of these therapies is curative and disconcertingly there is a small but increasing number of patients with severe psoriasis who have failed all currently available therapeutic modalities. A similar scenario has occurred in other immune-mediated inflammatory diseases (IMIDs) where treatment options are limited in severely affected patients. In these cases, cell therapy, including haematopoietic stem cell transplantation (HSCT) and mesenchymal stromal cells (MSC), has been utilized. This review discusses the various forms of cell therapy currently available, their utility in the management of IMIDs and emerging evidence for efficacy in severe psoriasis that is unresponsive to biological therapy. Balancing the risks and benefits of treatment vs. the underlying disease is key; cell therapy carries significant risks, costs, regulation and other complexities, which must be justified by outcomes. Although HSCT has anecdotally been reported to benefit severe psoriasis, sometimes with apparent cure, this has mainly been in the setting of other coincidental 'routine' indications. In psoriasis, cell therapies, such as MSC and regulatory T cells, with a lower risk of complications are likely to be more appropriate. Well-designed controlled trials coupled with mechanistic studies are warranted if advanced cell therapies are to be developed and delivered as a realistic option for severe psoriasis.

Autologous haematopoietic stem cell transplantation as a first-line disease-modifying therapy in patients with 'aggressive' multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. OBJECTIVES: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. METHODS: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. RESULTS: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. CONCLUSION: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

[Autologous hematopoietic stem cell transplantation for autoimmune diseases : Current indications and mode of action, a review on behalf of the EBMT Autoimmune Diseases Working Party (ADWP)]. / Autologe hämatopoetische Stammzelltransplantation bei Autoimmunerkrankungen : Aktuelle Indikationen und Wirkungsweise, ein Review der EBMT Autoimmune Diseases Working Party (ADWP).

The recent introduction of biologic and targeted synthetic disease-modifying drugs has led to more specificity in the treatment of autoimmune diseases; however, they require continuous or intermittent administration, are associated with cumulative risks for side effects, result in high costs and provide no cure. In contrast, high-dose chemotherapy followed by transplantation of autologous hematopoietic stem cells (AHSCT) has been demonstrated to induce clinical remission in various autoimmune diseases that can persist over many years without continued maintenance therapy. The principle behind AHSCT is an elimination of important components of the autoreactive immunological memory with subsequent regeneration of the complete immune system. Several studies have indicated that such an immune reset is associated with fundamental changes in the immune repertoire leading to an induction of tolerance against self-antigens. This article presents the current indications of AHSCT for autoimmune diseases based on the registry data of the European Society of Blood and Marrow Transplantation (EBMT) and discusses the results from mechanistic studies, which provide detailed insights into the mode of action of this treatment.

Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. A retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) who relapse/progress after first line chemoimmunotherapy. Long-term outcome of those who relapse after transplant is poor. We present the results of a retrospective study of 256 adult patients reported to the EBMT registry with DLBCL who relapsed after auto-HSCT performed between 2003 and 2013, and who received active salvage strategies. One hundred and fifty-four (60%) were male; median age was 53 years. Median time to relapse was 7 months, 65% relapsed during the first year. Overall response rate after salvage therapy was 46%. Median follow-up after first salvage therapy was 40 months (IQR 23-63 months). Overall survival (OS) at 3 years was 27% (95% CI 22-33). OS at 3 years of patients relapsing longer than 1 year after auto-HSCT was 41% (95% CI 31-53) compared with 20% (95% CI 14-24) in those who relapsed in less than 1 year. Eighty-two patients (32%) had a second HSCT, an allogeneic HSCT (allo-HSCT) in 69 cases, at a median time of 6.5 months after relapse. OS at 3 years after allo-HSCT was 36% (95% CI 25-51). In conclusion, the prognosis of patients with DLBCL that relapse after auto-HSCT is dismal. Patients who relapse in less than 1 year remain an unmet need, and should be considered for CAR T cell therapy or clinical trials. Patients who relapse after 1 year can be rescued with salvage therapies and a second HSCT. These results provide a benchmark to compare data of new prospective studies.

An international survey on the management of patients receiving CAR T-cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT.

PURPOSE OF THE STUDY: Two chimeric antigen receptor (CAR) T-cell therapies - Tisagenlecleucel (Kymriah™) and Axicabtagene ciloleucel (Yescarta™) - have been approved for commercial use. In order to inform forthcoming EBMT guidelines on the management of adults and children undergoing autologous CAR T-cell therapy, we undertook a survey of experienced clinicians. METHODS: An online survey with a dual focus on (1) 'real world' patient eligibility criteria and (2) models of care for patient follow-up was sent to experienced physicians. RESULTS: There were 41 respondents (10 countries) and 93% worked in FACT-JACIE-accredited transplant centres. Most felt that a history of malignancy (57%), prior allo-HCT for B-NHL (78%-81%) and prior treatment with anti-CD19/CD3 BiTE antibodies (76%-86%) do not constitute contra-indications to CAR T therapy. Clinicians were divided as to whether CNS involvement represented an exclusion criterion. There was agreement that patients with viral infections (HIV, Hepatitis B or Hepatitis C) are not eligible. There is no common model of care for long-term follow-up. Most respondents believed that patients should attend the hospital two (43%) to three (33%) times weekly during the first month following discharge. A majority (69%) of respondents work in centres where there is an MDT meeting with a specific focus on follow-up following CAR T Therapy. Follow-up care is currently delivered either in HCT or haematology-oncology outpatient clinics. CONCLUSION: The responses reveal wide variation in perceived patient eligibility criteria and highlight the need for consensus guidelines. The findings also illustrate the embryonic nature of current follow-up arrangements.

Current Practice in Vitamin D Management in Allogeneic Hematopoietic Stem Cell Transplantation: A Survey by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation.

Beyond its impact on bone health, numerous studies have investigated the immune-regulatory properties of vitamin D and shown how its deficiency can affect outcomes in allogeneic hematopoietic stem cell transplantation (HSCT), particularly in acute or chronic graft-versus-host disease. This survey, carried out by the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation (EBMT), describes the current clinical practice discrepancies across the EBMT HSCT programs. We therefore recommend the development of evidence-based guidelines to standardize evaluation criteria and to harmonize the management of vitamin D deficiency in patients undergoing allogeneic HSCT.

Late treatment effects following bone marrow transplant: Efficacy of implementing international guidelines.

An increasing cohort of haematopoietic cell transplantation (HCT) survivors has raised awareness of long-term and late effects. Updated recommendations for HCT late effects screening were published in 2012 [Majhail et al. Biology of Blood and Marrow Transplantation, 18 (2012):348]. We aimed to assess the clinical efficacy of a dedicated screening clinic to identify problems in HCT survivors using the international guidelines. Clinic letters and test results of the first 59 consecutive patients attending the screening clinic were evaluated. 30 females and 29 males (mean age of 49 years, range 22-74) were included. The mean time since transplant was 6 years (0.5-18). 49/65 transplants were allogeneic. Primary indications for HCT were myeloid (56%), lymphoid (37%), solid tumour (5%) and auto-immune diseases (2%). 134 complications were reported (mean 2, range 0-8), with 114 documented further actions/referrals. The most commonly reported concerns were pain 18/59 (31%), fatigue 14/59 (24%), sexual function 14/59 (24%) and sleep disturbance 11/59 (19%). Second primary malignancies were recorded in five cases. Implementation and audit of the international late effect screening guidelines confirm the need for systematic long-term physical and psychological screening and care, thus ensuring timely and efficient identification of problems and the opportunity to minimise morbidity effects and optimise health.

Routine vaccination practice after adult and paediatric allogeneic haematopoietic stem cell transplant: a survey of UK NHS programmes.

This corrects the article DOI: 10.1038/bmt.2016.362.

Cardiopulmonary assessment of patients with systemic sclerosis for hematopoietic stem cell transplantation: recommendations from the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party and collaborating partners.

Systemic sclerosis (SSc) is a rare disabling autoimmune disease with a similar mortality to many cancers. Two randomized controlled trials of autologous hematopoietic stem cell transplantation (AHSCT) for SSc have shown significant improvement in organ function, quality of life and long-term survival compared to standard therapy. However, transplant-related mortality (TRM) ranged from 3-10% in patients undergoing HSCT. In SSc, the main cause of non-transplant and TRM is cardiac related. We therefore updated the previously published guidelines for cardiac evaluation, which should be performed in dedicated centers with expertize in HSCT for SSc. The current recommendations are based on pre-transplant cardiopulmonary evaluations combining pulmonary function tests, echocardiography, cardiac magnetic resonance imaging and invasive hemodynamic testing, initiated at Northwestern University (Chicago) and subsequently discussed and endorsed within the EBMT ADWP in 2016.

Provision of long-term monitoring and late effects services following adult allogeneic haematopoietic stem cell transplant: a survey of UK NHS-based programmes.

Despite international guidelines, optimal delivery models of late effects (LE) services for HSCT patients are unclear from the clinical, organizational and economic viewpoints. To scope current LE service delivery models within the UK NHS (National Health Service), in 2014, we surveyed the 27 adult allogeneic HSCT centres using a 30-question online tool, achieving a 100% response rate. Most LE services were led and delivered by senior physicians (>80% centres). Follow-up was usually provided in a dedicated allograft or LE clinic for the first year (>90% centres), but thereafter attrition meant that only ~50% of patients were followed after 5 years. Most centres (69%) had a standard operating procedure for long-term monitoring but access to a LE Multi-Disciplinary Team was rare (19% centres). Access to medical specialities necessary for LE management was good, but specialist interest in long-term HSCT complications was uncommon. Some screening (endocrinopathy, cardiovascular) was near universal, but other areas were more limited (mammography, cervical smears). Funding of extra staff and investigations were the most commonly perceived barriers to implementation of LE services. This survey shows variation in the long-term follow-up of allogeneic HSCT survivors within the UK NHS and further work is warranted to optimize effective, sustainable and affordable models of LE service delivery among this group.

Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report.

Hematopoietic stem cell transplantation (HSCT) is an established procedure for many acquired and congenital disorders of the hematopoietic system. A record number of 42 171 HSCT in 37 626 patients (16 030 allogeneic (43%), 21 596 autologous (57%)) were reported by 655 centers in 48 countries in 2015. Trends include continued growth in transplant activity over the last decade, with the highest percentage increase seen in middle-income countries but the highest absolute growth in the very-high-income countries in Europe. Main indications for HSCT were myeloid malignancies 9413 (25%; 96% allogeneic), lymphoid malignancies 24 304 (67%; 20% allogeneic), solid tumors 1516 (4%; 3% allogeneic) and non-malignant disorders 2208 (6%; 90% allogeneic). Remarkable is the decreasing use of allogeneic HSCT for CLL from 504 patients in 2011 to 255 in 2015, most likely to be due to new drugs. Use of haploidentical donors for allogeneic HSCT continues to grow: 2012 in 2015, a 291% increase since 2005. Growth is seen for all diseases. In AML, haploidentical HSCT increases similarly for patients with advanced disease and for those in CR1. Both marrow and peripheral blood are used as the stem cell source for haploidentical HSCT with higher numbers reported for the latter.

Observational study of the development and evaluation of a fertility preservation patient decision aid for teenage and adult women diagnosed with cancer: the Cancer, Fertility and Me research protocol.

INTRODUCTION: Women diagnosed with cancer and facing potentially sterilising cancer treatment have to make time-pressured decisions regarding fertility preservation with specialist fertility services while undergoing treatment of their cancer with oncology services. Oncologists identify a need for resources enabling them to support women's fertility preservation decisions more effectively; women report wanting more specialist information to make these decisions. The overall aim of the 'Cancer, Fertility and Me' study is to develop and evaluate a new evidence-based patient decision aid (PtDA) for women with any cancer considering fertility preservation to address this unmet need. METHODS AND ANALYSIS: This is a prospective mixed-method observational study including women of reproductive age (16 years +) with a new diagnosis of any cancer across two regional cancer and fertility centres in Yorkshire, UK. The research involves three stages. In stage 1, the aim is to develop the PtDA using a systematic method of evidence synthesis and multidisciplinary expert review of current clinical practice and patient information. In stage 2, the aim is to assess the face validity of the PtDA. Feedback on its content and format will be ascertained using questionnaires and interviews with patients, user groups and key stakeholders. Finally, in stage 3 the acceptability of using this resource when integrated into usual cancer care pathways at the point of cancer diagnosis and treatment planning will be evaluated. This will involve a quantitative and qualitative evaluation of the PtDA in clinical practice. Measures chosen include using count data of the PtDAs administered in clinics and accessed online, decisional and patient-reported outcome measures and qualitative feedback. Quantitative data will be analysed using descriptive statistics, paired sample t-tests and CIs; interviews will be analysed using thematic analysis. ETHICS AND DISSEMINATION: Research Ethics Committee approval (Ref: 16/EM/0122) and Health Research Authority approval (Ref: 194751) has been granted. Findings will be published in open access peer-reviewed journals, presented at conferences for academic and health professional audiences, with feedback to health professionals and program managers. The Cancer, Fertility and Me patient decision aid (PtDA) will be disseminated via a diverse range of open-access media, study and charity websites, professional organisations and academic sources. External endorsement will be sought from the International Patient Decision Aid Standards (IPDAS) Collaboration inventory of PtDAs and other relevant professional organisations, for example, the British Fertility Society. TRIAL REGISTRATION NUMBER: NCT02753296; pre-results.

JACIE accreditation for blood and marrow transplantation: past, present and future directions of an international model for healthcare quality improvement.

Blood and marrow transplantation (BMT) is a complex and evolving medical speciality that makes substantial demands on healthcare resources. To meet a professional responsibility to both patients and public health services, the European Society for Blood and Marrow Transplantation (EBMT) initiated and developed the Joint Accreditation Committee of the International Society for Cellular Therapy and EBMT-better known by the acronym, JACIE. Since its inception, JACIE has performed over 530 voluntary accreditation inspections (62% first time; 38% reaccreditation) in 25 countries, representing 40% of transplant centres in Europe. As well as widespread professional acceptance, JACIE has become incorporated into the regulatory framework for delivery of BMT and other haematopoietic cellular therapies in several countries. In recent years, JACIE has been validated using the EBMT registry as an effective means of quality improvement with a substantial positive impact on survival outcomes. Future directions include development of Europe-wide risk-adjusted outcome benchmarking through the EBMT registry and further extension beyond Europe, including goals to faciliate access for BMT programmes in in low- and middle-income economies (LMIEs) via a 'first-step' process.