Publications by authors named "John A Snowden"

142 Publications

One and a half million hematopoietic stem cell transplants: continuous and differential improvement in worldwide access with the use of non-identical family donors.

Haematologica 2021 Aug 12. Epub 2021 Aug 12.

CIBMTR (Center for International Blood and Marrow Transplant Research), National Marrow Donor Program/Be The Match, Minneapolis, MN; University of Minnesota, MMC 480, Minneapolis, MN 55455.

The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member societies, national registries and individual centers. In 2016, 82,718 first HCTs were reported from 1662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCTs had been performed by 2019 from 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCTs were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCTs are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated is plateauing and cord blood in decline.
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http://dx.doi.org/10.3324/haematol.279189DOI Listing
August 2021

Long-term survivors following autologous haematopoetic stem cell transplantation have significant defects in their humoral immunity against vaccine preventable diseases, years on from transplant.

Vaccine 2021 08 20;39(34):4778-4783. Epub 2021 Jul 20.

Department of Infection, Immunity and Cardiovascular Diseases and the Florey Institute for Host-Pathogen Interactions, University of Sheffield, UK; South Yorkshire Regional Department of Infection & Tropical Medicine, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Current international guidelines recommend routinely vaccinating haematopoetic stem cell transplant (HSCT) recipients. Despite significant infection-related mortality following autologous HSCT, routine vaccination programmes (RVP) completion is poor. For recovered HSCT recipients, it is uncertain whether catch-up vaccination remains worthwhile years later. To determine potential susceptibility to vaccine preventable infections, we measured antibody titres in 56 patients, a median of 7 years (range 0-29) following autologous HSCT, who had not completed RVP. We found that almost all participants had inadequate titres against diphtheria (98.2%) and pneumococcal infection (100%), and a significant proportion had inadequate titres against measles (34.5%). Of those subsequently vaccinated according to available guidelines, many mounted adequate serological responses. These data suggest a pragmatic catch-up approach for autologous HSCT recipients who have not completed RVP is advisable, with universal vaccination against some pathogens (e.g. Streptococcus pneumoniae and diphtheria) and serologically-guided approaches for others (e.g. measles and varicella zoster virus).
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http://dx.doi.org/10.1016/j.vaccine.2021.07.022DOI Listing
August 2021

Hematopoietic stem cell transplantation for autoimmune diseases in the time of COVID-19: EBMT guidelines and recommendations.

Bone Marrow Transplant 2021 07 24;56(7):1493-1508. Epub 2021 May 24.

Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Coronavirus disease-19 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), represents one of the biggest challenges of 21st century, threatening public health around the globe. Increasing age and presence of co-morbidities are reported risk factors for severe disease and mortality, along with autoimmune diseases (ADs) and immunosuppressive treatments such as haematopoietic stem cell transplantation (HSCT), which are also associated with adverse outcomes. We review the impact of the pandemic on specific groups of patients with neurological, rheumatological, and gastroenterological indications, along with the challenges delivering HSCT in adult and pediatric populations. Moving forward, we developed consensus-based guidelines and recommendations for best practice and quality of patient care in order to support clinicians, scientists, and their multidisciplinary teams, as well as patients and their carers. These guidelines aim to support national and international organizations related to autoimmune diseases and local clinical teams delivering HSCT. Areas of unmet need and future research questions are also highlighted. The waves of the COVID-19 pandemic are predicted to be followed by an "endemic" phase and therefore an ongoing risk within a "new normality". These recommendations reflect currently available evidence, coupled with expert opinion, and will be revised according to necessary modifications in practice.
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http://dx.doi.org/10.1038/s41409-021-01326-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143059PMC
July 2021

Autologous Hematopoietic Stem Cell Transplantation for Behçet's Disease: A Retrospective Survey of Patients Treated in Europe, on Behalf of the Autoimmune Diseases Working Party of the European Society for Blood and Marrow Transplantation.

Front Immunol 2021 6;12:638709. Epub 2021 May 6.

Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

Background: Behçet's Disease (BD) is an autoimmune disease mostly presenting with recurrent oral and genital aphthosis, and uveitis. Patients are rarely refractory to immunosuppressive treatments. Autologous hematopoietic stem cell transplantation (aHSCT) is a standard of care in other autoimmune diseases. Some patients with BD have been treated with aHSCT based on compassionate use.

Objectives: Evaluate the outcome of aHSCT in adult patients with BD treated in member centers of the European Society for Blood and Marrow Transplantation (EBMT).

Methods: Adults who received aHSCT primarily for BD were identified retrospectively in the EBMT registry and/or in published literature. Data were extracted from either medical records of the patient or from publications.

Results: Eight out of 9 cases reported to the registry and extracted data of 2 further patients from literature were analyzed. Four were female, median age at onset of BD was 24y (range 9-50). Median age at aHSCT was 32y (27-51). Patients had received median 4 (2-11) previous lines of therapy (89% corticosteroids, 50% methotrexate, anti-TNFα therapy or cyclophosphamide). All patients had active disease before mobilization. Conditioning regimen was heterogeneous. Median follow-up was 48 months (range 6-240). No treatment-related mortality was reported. This procedure induced complete remission (CR) in 80%, partial remission in 10% and lack of response in 10% of the patients. Relapse rate was 30% (2 relapses in patients in CR and 1 relapse in the patient in PR) with panuveitis (n=1), aphthosis (n=2) and arthralgia (n=1). Six patients were in CR. No late complications were reported.

Conclusion: aHSCT has an acceptable safety profile and represents a feasible and relatively effective procedure in severe and conventional treatment-resistant cases of BD and has the potential to stabilize BD in patients with life-threatening involvements.
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http://dx.doi.org/10.3389/fimmu.2021.638709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136432PMC
May 2021

New autoimmune diseases after autologous hematopoietic stem cell transplantation for multiple sclerosis.

Bone Marrow Transplant 2021 07 28;56(7):1509-1517. Epub 2021 Apr 28.

Department of Neurology, Uppsala University, Uppsala, Sweden.

Secondary autoimmune diseases (2ndADs), most frequently autoimmune cytopenias (AICs), were first described after allogeneic hematopoietic stem cell transplantation (HSCT) undertaken for malignant and hematological indications, occurred at a prevalence of ~5-6.5%, and were attributed to allogeneic immune imbalances in the context of graft versus host disease, viral infections, and chronic immunosuppression. Subsequently, 2ndADs were reported to complicate roughly 2-14% of autologous HSCTs performed for an autoimmune disease. Alemtuzumab in the conditioning regimen has been identified as a risk for development of 2ndADs after either allogeneic or autologous HSCT and is consistent with the high rates of 2ndADs when using alemtuzumab as monotherapy. Due to the significant consequences but variable incidence, depending on conditioning regimen, of 2ndADs and similarity in known immune reconstitution kinetics after autologous HSCT for autoimmune diseases and after alemtuzumab monotherapy, we propose that an imbalance between B and T lineage regeneration early after HSCT may underlie the pathogenesis of 2ndADs.
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http://dx.doi.org/10.1038/s41409-021-01277-yDOI Listing
July 2021

The Cost Effectiveness of Immunoglobulin vs. Hematopoietic Stem Cell Transplantation for CIDP.

Front Neurol 2021 22;12:645263. Epub 2021 Mar 22.

Academic Department of Neuroscience and Sheffield, NIHR Translational Neuroscience BRC, Sheffield Teaching Hospitals NHS Foundation Trust, University of Sheffield, Sheffield, United Kingdom.

Intravenous immunoglobulin (IVIG) is effective as standard first line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but some patients remain dependent on its long-term use. Recently, we have reported that autologous non-myeloablative hematopoietic stem cell transplantation (HSCT) is an effective second line therapy for CIDP. To compare the cost of chronic IVIG vs. autologous HSCT (a one-time therapy), we collected data on patients with CIDP undergoing HSCT between 2017 and 2019. This was compared with published literature on the costs and efficacy defined by the Inflammatory Neuropathy Cause And Treatment (INCAT) disability score, Medical Research Council (MRC) sum score, hand grip strength, and SF-36 quality of life (QOL) for CIDP. Between 2017 and 2019, nineteen patients with chronic CIDP (mean disease treatment duration prior to HSCT of 6 years) underwent autologous HSCT with mean cost of $108,577 per patient (range $56,327-277,119, standard deviation $53,092). After HSCT, 80% of patients remain IVIG and immune treatment free for up to 5 years. In comparison, published cost of IVIG treatment in the USA for an average CIDP patient exceeds $136,000 per year. Despite remaining treatment free, HSCT demonstrated greater improvement in efficacy compared to immunoglobulins. Given the long-term treatment-free remission and better outcome measurements, autologous HSCT is more cost effective than long-term IVIG treatment in patients with chronic CIDP. However, costs will depend on patient selection, the HSCT regimen, and regional variations. Further analysis of the health economics, i.e., cost/outcome ratio, of HSCT as therapy for chronically IVIG dependent CIDP is warranted.
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http://dx.doi.org/10.3389/fneur.2021.645263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019941PMC
March 2021

Editorial: Novel Immunological Biomarkers for Allogeneic HSCT Outcome.

Front Immunol 2021 12;12:670822. Epub 2021 Mar 12.

Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.

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http://dx.doi.org/10.3389/fimmu.2021.670822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994590PMC
March 2021

Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years.

Bone Marrow Transplant 2021 07 23;56(7):1651-1664. Epub 2021 Feb 23.

Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany.

Numbers of Hematopoietic cell transplantation (HCT) in Europe and collaborating countries continues to rise with 48,512 HCT in 43,581 patients, comprising of 19,798 (41%) allogeneic and 28,714 (59%) autologous, reported by 700 centers in 51 countries during 2019. Main indications were myeloid malignancies 10,764 (25%), lymphoid malignancies 27,895 (64%), and nonmalignant disorders 3173 (7%). A marked growth in CAR-T cellular therapies from 151 in 2017 to 1134 patients in 2019 is observed. This year's analyses focus on changes over 30 years. Since the first survey in 1990 where 143 centers reported 4234 HCT, the number has increased to 700 centers and 48,512 HCT. Transplants were reported in 20 countries in 1990, and 51, 30 years later. More than 800,000 HCT in 715,000 patients were reported overall. Next to the massive expansion of HCT technology, most notable developments include the success of unrelated donor and haploidentical HCT, an increase followed by decrease in the number of cord blood transplants, use of reduced intensity HCT in older patients, and the phenomenal rise in cellular therapy. This annual report of the European Society for Blood and Marrow Transplantation (EBMT) reflects current activity and highlights important trends vital for health care planning.
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http://dx.doi.org/10.1038/s41409-021-01227-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263343PMC
July 2021

Conditioning intensity before allogeneic haematopoietic stem cell transplantation: a quality control audit.

Br J Haematol 2021 03 22;192(6):e151-e154. Epub 2021 Feb 22.

Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

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http://dx.doi.org/10.1111/bjh.17369DOI Listing
March 2021

Impact of early candidemia on the long-term outcome of allogeneic hematopoietic stem cell transplant in non-leukemic patients: an outcome analysis on behalf of IDWP-EBMT.

Bone Marrow Transplant 2021 07 29;56(7):1563-1572. Epub 2021 Jan 29.

Department of Pediatric Hematology and Oncology, Collegium Medicum UMK Torun, Bydgoszcz, Poland.

We assessed the incidence and outcome of early candidemia after hematopoietic stem cell transplant (HSCT). The analysis included all first HSCTs performed from 2000 to 2015 in adult and pediatric patients with a non-leukemic disease and recorded in the EBMT registry. Overall survival (OS), non-relapse mortality (NRM), and relapse mortality (RM) were evaluated. Candidemia was diagnosed in 420 of 49,852 patients at a median time of 17 days post HSCT (range 0-100), the cumulative incidence being 0.85%. In 65.5% of episodes, candidemia occurred by day 30 after HSCT. The mortality rate by day 7 was 6.2%, whereas 100-day NRM was higher (HR 3.47, p < 0.0001), and 100-day OS was lower (HR 3.22, p < 0.0001) than that of patients without candidemia. After a median follow-up of 4.3 years, 5-year OS, NRM, and RM for patients with and without candidemia were 50.5% vs. 60.8%, p < 0.0001, 28.2% vs.18.8%, p < 0.0001, and 25.3% vs. 27.2%, p = 0.4, respectively. In conclusion, in non-leukemic transplant patients, the occurrence of an early episode of candidemia is rare but it is still associated with a negative effect on the outcome.
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http://dx.doi.org/10.1038/s41409-021-01212-1DOI Listing
July 2021

The NICE COVID-19 rapid guideline on haematopoietic stem cell transplantation: development, implementation and impact.

Br J Haematol 2021 02 20;192(3):467-473. Epub 2021 Jan 20.

Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield, UK.

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http://dx.doi.org/10.1111/bjh.17280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898641PMC
February 2021

Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial.

PLoS Med 2021 01 11;18(1):e1003454. Epub 2021 Jan 11.

Perlmutter Cancer Center, NYU Langone Health, New York, New York, United States of America.

Background: Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy.

Methods And Findings: The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51-0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19-5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10-5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world.

Conclusions: The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy.

Trial Registration: ClinicalTrials.gov ISRCTN49407852.
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http://dx.doi.org/10.1371/journal.pmed.1003454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799846PMC
January 2021

Rehabilitation Before and After Autologous Haematopoietic Stem Cell Transplantation (AHSCT) for Patients With Multiple Sclerosis (MS): Consensus Guidelines and Recommendations for Best Clinical Practice on Behalf of the Autoimmune Diseases Working Party, Nurses Group, and Patient Advocacy Committee of the European Society for Blood and Marrow Transplantation (EBMT).

Front Neurol 2020 11;11:556141. Epub 2020 Dec 11.

Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used to treat people with multiple sclerosis (MS). Supported by an evolving evidence base, AHSCT can suppress active inflammation in the central nervous system and induce long-term changes in immune cell populations, thereby stabilizing, and, in some cases, reversing disability in carefully selected MS patients. However, AHSCT is an intensive chemotherapy-based procedure associated with intrinsic risks, including profound cytopenia, infection, and organ toxicity, accompanied by an on-going degree of immuno-compromise and general deconditioning, which can be associated with a transient increase in functional impairment in the early stages after transplantation. Although international guidelines and recommendations have been published for clinical and technical aspects of AHSCT in MS, there has been no detailed appraisal of the rehabilitation needed following treatment nor any specific guidelines as to how this is best delivered by hospital and community-based therapists and wider multidisciplinary teams in order to maximize functional recovery and quality of life. These expert consensus guidelines aim to address this unmet need by summarizing the evidence-base for AHSCT in MS and providing recommendations for current rehabilitation practice along with identifying areas for future research and development.
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http://dx.doi.org/10.3389/fneur.2020.556141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759663PMC
December 2020

Hematopoietic Stem Cell Transplantation for Autoimmune Disease.

Annu Rev Med 2021 01 26;72:215-228. Epub 2020 Oct 26.

Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, United Kingdom.

The introduction of targeted biologic therapies has changed the treatment landscape for autoimmune diseases (ADs) substantially, but although these therapies provide more specificity, they require continuous administration, rarely restore organ function or reverse disability, and are not curative. Over the last 25 years, hematopoietic stem cell transplantation (HSCT) has been increasingly used to treat patients in whom the risk:benefit ratio of HSCT is acceptable. In contrast to chronic suppression of immune function, this intensive one-off procedure aims to provide treatment-free remissions by the reinduction of self-tolerance. The European Society for Blood and Marrow Transplantation (EBMT) Autoimmune Diseases Working Party (ADWP) has been central to development of this approach, with over 3,300 HSCT registrations for ADs. Recent data have improved the evidence base to support autologous HSCT in multiple sclerosis, systemic sclerosis, and Crohn's disease, along with a wide range of rarer disease indications, and autologous HSCT has become an integral part of treatment algorithms in various ADs.
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http://dx.doi.org/10.1146/annurev-med-070119-115617DOI Listing
January 2021

Survivorship care for allogeneic transplant patients in the UK NHS: changes centre practice, impact of health service policy and JACIE accreditation over 5 years.

Bone Marrow Transplant 2021 03 20;56(3):673-678. Epub 2020 Oct 20.

Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Care of long-term survivors of allogeneic transplant is known to be variable despite international guidelines and accreditation standards. In 2014 a survey of UK NHS-based adult transplant centres identified significant barriers to delivery of long-term follow-up services. In 2019, we repeated the survey to assess changes over a 5-year period when health service policies had mandated JACIE accreditation incorporating standards for long-term care. Improvements were seen in the number of centres having a dedicated long-term follow-up clinic for allogeneic transplant recipients (52% versus 33%) and a standard operating procedure (88% versus 69%). Inclusion of psychological support in standard operating procedures remained low at both time points (32% versus 28%). There was ongoing variation in practice regarding vaccination programmes, access to cancer screening, and audit processes between centres. Perceived barriers to implementation of comprehensive long-term follow-up clinics were similar in 2019; mainly resourcing clinical staff and psychological support. Whilst the survey reflects the changing practice of transplant centres, best explained by increasing recognition of late effects and survivorship by clinicians, health service policy and JACIE accreditation standards, further developments are warranted to address unmet healthcare needs of long-term HSCT survivors, especially access to psychological support, cancer screening and vaccinations.
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http://dx.doi.org/10.1038/s41409-020-01067-yDOI Listing
March 2021

Autologous hematopoietic stem-cell transplantation in neurological disorders: current approach and future directions.

Expert Rev Neurother 2020 12 29;20(12):1299-1313. Epub 2020 Sep 29.

Department of Hematology, Sheffield Teaching Hospitals NHS Foundation Trust , Sheffield, UK.

Introduction: Autologous hematopoietic stem-cell transplantation (AHSCT) has become increasingly popular in recent years as an effective treatment of immune-mediated neurological diseases. Treatment-related mortality has significantly reduced primarily through better patient selection, optimization of transplant technique, and increased center experience.

Area Covered: Multiple sclerosis is the main indication, but people with neuromyelitis optica spectrum disorder, stiff-person spectrum disorder, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and other immune-mediated neurological disorders also have been treated. The review herein discusses the use of AHSCT in these neurological disorders, the importance of patient selection and transplant technique optimization and future directions.

Expert Opinion: Phase II and III clinical trials have confirmed the safety and efficacy of AHSCT in multiple sclerosis and recent phase II clinical trials have also suggested its safety and efficacy in chronic inflammatory demyelinating polyneuropathy and neuromyelitis optica spectrum disorder, with the evidence in other neurological disorders limited to individual case reports, small case series, and registry data. Therefore, further randomized controlled clinical trials are required to assess its safety and efficacy in other neurological conditions. However, in rare neurological conditions, pragmatic treatment trials or registry-based studies may be more realistic options for gathering efficacy and safety data.
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http://dx.doi.org/10.1080/14737175.2020.1820325DOI Listing
December 2020

UK national audit of extracorporeal photopheresis (ECP) in chronic graft versus host disease.

Leuk Lymphoma 2020 12 2;61(14):3511-3514. Epub 2020 Sep 2.

UK Photopheresis Society, Birmingham, Rotherham, Newcastle, Leeds, Sheffield, UK.

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http://dx.doi.org/10.1080/10428194.2020.1815015DOI Listing
December 2020

Autologous haematopoietic stem cell transplantation for refractory stiff-person syndrome: the UK experience.

J Neurol 2021 Jan 12;268(1):265-275. Epub 2020 Aug 12.

Academic Department of Neurosciences, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Stiff Person Syndrome (SPS) is a rare immune-mediated disabling neurological disorder characterised by muscle spasms and high GAD antibodies. There are only a few case reports of autologous haematopoietic stem cell transplantation (auto-HSCT) as a treatment for SPS.

Objective: To describe the UK experience of treating refractory SPS with auto-HSCT.

Methods: Between 2015 and 2019, 10 patients with SPS were referred to our institution for consideration of auto-HSCT. Eight patients were deemed suitable for autograft and four were treated. Of the treated patients, three had classical SPS and one had the progressive encephalomyelitis with rigidity and myoclonus variant. All patients were significantly disabled and had failed conventional immunosuppressive therapy. Patients were mobilised with Cyclophosphamide (Cy) 2 g/m + G-CSF and conditioned with Cy 200 mg/kg + ATG followed by auto-HSCT.

Results: Despite their significantly reduced performance status, all patients tolerated the procedure with no unexpected toxicities. Following autograft, all patients improved symptomatically and stopped all forms of immunosuppressive therapies. Two patients were able to ambulate independently from being wheelchair dependent. One patient's walking distance improved from 300 meters to 5 miles and one patient's ambulation improved from being confined to a wheelchair to be able to walk with a frame. Two patients became seronegative for anti-GAD antibodies and normalised their neurophysiological abnormalities.

Conclusions: Auto-HSCT is an intensive but well tolerated and effective treatment option for patients with SPS refractory to conventional immunotherapy. Further work is warranted to optimise patient selection and establish the efficacy, long-term safety, and cost-effectiveness of this treatment.
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http://dx.doi.org/10.1007/s00415-020-10054-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815605PMC
January 2021

Health economics and patient outcomes of hematopoietic stem cell transplantation versus disease-modifying therapies for relapsing remitting multiple sclerosis in the United States of America.

Mult Scler Relat Disord 2020 Oct 17;45:102404. Epub 2020 Jul 17.

College of Pharmacy, Oregon State University/Oregon Health & Science University, Portland, United States.

Objective: To estimate differences in treatment costs and health outcomes between non-myeloablative hematopoietic stem cell transplantation (HSCT) and disease-modifying therapies (DMTs) for the treatment of relapsing-remitting multiple sclerosis (RRMS).

Methods: We collected data on costs and reimbursements for patients who underwent HSCT for RRMS at Northwestern Memorial Hospital in Chicago (USA) between January 2017 and January 2019. The costs of HSCT were compared against those for DMTs in the United States, obtained from the literature. We also conducted a literature review to interpret the cost comparisons in terms of disease control and patients' wellbeing defined as no evidence of disease activity (NEDA), neurologic disability by the Expanded Disability Status Scale (EDSS), and quality of life by the short form SF-36, respectively.

Results: Outside of the data, herein, no other studies on cost of HSCT for RRMS were found in the literature. HSCT mean total costs, based on our own hospital, were $85,184 (range $70,635 to $120,260). Mean revenue collected was $95,268 (range $16,544 to $173,204). In comparison, according to the literature, 2019 DMT costs in the USA ranged from $80,000 to $100,000 per year per patient. Compared to DMTs, studies of HSCT reported greater improvement in no evidence of disease activity, disability, and quality of life.

Limitations: Costs of HSCT would be expected to vary by conditioning regimen utilized, patient selection, center experience, and regional variation. No cost data on other HSCT regimens or on the three most recently licensed DMTs, alemtuzumab, ocrelizumab, and cladribine, are available. Randomized trials for cost comparisons are missing and variations in HSCT designs, populations, and methodology preclude more precise cost estimates.

Conclusion: Costs of non-myeloablative HSCT after which DMTs are indefinitely discontinued, are approximately the same cost as those for one year of prescription DMTs. Since DMTs assessed in this analysis are given on an ongoing basis, whilst HSCT is not, HSCT is expected to produce long-term cost-savings. When considered alongside the available clinical evidence, which suggests that HSCT may generate more health gains than DMTs, HSCT is likely to represent a cost-effective use of resources. Model-based health economic analyses are required to substantiate this conclusion.
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http://dx.doi.org/10.1016/j.msard.2020.102404DOI Listing
October 2020

Insights Into the Role of Vitamin D as a Biomarker in Stem Cell Transplantation.

Front Immunol 2020 8;11:966. Epub 2020 Jun 8.

Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

Vitamin D was discovered 100 years ago and since then multiple studies have consistently proved its effect on bone health and mineral metabolism. Further research has also explored its so-called "non-classical" biological effects, encompassing immune regulation and control of cell proliferation and differentiation. Vitamin D downregulates pro-inflammatory immune cells and subsequently their cytokine production, while enhancing the anti-inflammatory subsets, thus mediating inflammation and fostering a more tolerogenic environment. Its biological action is exerted through the vitamin D receptor, a nuclear receptor that mediates gene transcription and is expressed in most cells from the innate and adaptive immunity. Owing to its immune-modulatory properties, its role in cancer pathophysiology, hematology disorders and stem cell transplantation has also been investigated. Vitamin D deficiency causes immune imbalance and cytokine dysregulation, contributing to some autoimmune diseases. In the hematopoietic stem cell transplant setting this could lead to complications such as acute and chronic graft-versus-host disease, ultimately impacting transplant outcomes. Other factors have also been linked to this, including specific polymorphisms of the vitamin D receptor in both stem cell donors and recipients. Nevertheless, studies thus far have shown conflicting results and the use of vitamin D or its receptor as biomarkers has not been validated yet, therefore there are no evidence-based consensus guidelines to guide clinicians in their day-to-day practice. To gain more insight in this topic, we have reviewed the existent literature and gathered the current evidence. This is an overview of the role of serum vitamin D and its receptor as biomarkers for clinical outcomes in patients undergoing hematopoietic stem cell transplantation. Further prospective studies with larger cohorts are warranted to validate the viability of using serum vitamin D, and its receptor, as biomarkers in potential stem cell donors and patients, to identify those at risk of post-transplant complications and enable early therapeutic interventions.
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http://dx.doi.org/10.3389/fimmu.2020.00966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295104PMC
March 2021

Gender gaps in transplantation.

Br J Haematol 2020 07 25;190(2):e123-e125. Epub 2020 May 25.

Department of Biomedical Data Sciences, Section Medical Statistics, Leiden University Medical Centre, Leiden, the Netherlands.

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http://dx.doi.org/10.1111/bjh.16765DOI Listing
July 2020

A Case of Multiple Sclerosis-Like Relapsing Remitting Encephalomyelitis Following Allogeneic Hematopoietic Stem Cell Transplantation and a Review of the Published Literature.

Front Immunol 2020 5;11:668. Epub 2020 May 5.

Department of Haematology, Royal Hallamshire Hospital, Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.

Complications involving the central nervous system (CNS) occur in 9-14% of patients following allogeneic hematopoietic stem cell transplantation (HSCT), including stroke-like episodes, demyelination, encephalitis, and nonspecific neurological symptoms. Here we report a case of multiple sclerosis (MS) like relapsing remitting encephalomyelitis following allogeneic HSCT, which did not respond to disease modifying therapies (DMTs) and "domino" autologous HSCT. A 53-year-old male was treated with allogeneic HSCT for lymphoid blast transformation of chronic myeloid leukemia. Ten months later he presented with confusion, slurred speech, left sided facial weakness and ataxia. A magnetic resonance imaging brain scan showed multiple enhancing tumefactive lesions. Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. After extensive investigations for infections, autoimmune disorders and recurrence of malignancy, he underwent brain biopsy, which showed a macrophage rich lesion with severe myelin loss but axonal preservation indicating a demyelinating pathology. Although his symptoms improved with corticosteroids, he relapsed five months later. In the absence of any systemic features suggesting graft versus host disease (GvHD), his presentation was thought to be compatible with MS. The illness followed an aggressive course that did not respond to glatiramer acetate and natalizumab. He was therefore treated with "domino" autologous HSCT, which also failed to induce long-term remission. Despite further treatment with ocrelizumab, he died of progressive disease. An autopsy limited to the examination of brain revealed multifocal destructive leukoencephalopathy with severe myelin and axonal loss. Immunohistochemistry showed macrophage located in the perivascular area, with no T or B lymphocytes. The appearance was unusual and not typical for chronic MS plaques. Reported cases of CNS demyelination following allogeneic HSCT are very limited in the literature, especially in relation to histopathological examination. Although the clinical disease course of our patient following allogeneic HSCT resembled an "MS-like" relapsing remitting encephalomyelitis, the autopsy examination did not show any evidence of active inflammation. The impact of DMTs and HSCT on the histological appearance of "MS-like" CNS pathologies is unknown. Therefore, reporting this and similar cases will improve our awareness and understanding of underlying disease mechanisms.
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http://dx.doi.org/10.3389/fimmu.2020.00668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214636PMC
March 2021

The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy.

Bone Marrow Transplant 2020 11 13;55(11):2071-2076. Epub 2020 May 13.

Pediatric Hematology and Oncology, University Hospital, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland.

The new coronavirus SARS-CoV-2 has rapidly spread over the world causing the disease by WHO called COVID-19. This pandemic poses unprecedented stress on the health care system including programs performing allogeneic and autologous hematopoietic cell transplantation (HCT) and cellular therapy such as with CAR T cells. Risk factors for severe disease include age and predisposing conditions such as cancer. The true impact on stem cell transplant and CAR T-cell recipients in unknown. The European Society for Blood and Marrow Transplantation (EBMT) has therefore developed recommendations for transplant programs and physicians caring for these patients. These guidelines were developed by experts from the Infectious Diseases Working Party and have been endorsed by EBMT's scientific council and board. This work intends to provide guidelines for transplant centers, management of transplant candidates and recipients, and donor issues until the COVID-19 pandemic has passed.
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http://dx.doi.org/10.1038/s41409-020-0919-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220575PMC
November 2020

Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning regimens in refractory Takayasu arteritis: a retrospective multicenter case-series from the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT).

Bone Marrow Transplant 2020 11 22;55(11):2109-2113. Epub 2020 Apr 22.

Sorbonne Université, Service de Médecine Interne and Inflammation-Immunopathology-Biotherapy Department (DMU i3), Hôpital Saint-Antoine, APHP, F-75012, Paris, France.

Autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a promising treatment option in severely affected and refractory patients with autoimmune diseases. This is a retrospective survey of patients reported to the EBMT registry between 1998 and 2019, who received AHSCT for TAK. Data from six patients treated with AHSCT for refractory TAK have been identified, five were female (83%), median age 25 (9-39) years. All patients were pretreated with a median of 6 (4-8) lines of therapy, including steroids (six patients), methotrexate (five patients), cyclophosphamide, mycophenolate mofetil or infliximab (four patients), tocilizumab or etanercept (two patients). Conditioning included cyclophosphamide and rabbit anti-thymocyte globulin in all patients. At 6 months post transplantation, remission was obtained in all cases, which persisted at 12 months in five cases. Four patients reactivated TAK at a median time of 27 (7-52) months after AHSCT, and three resumed disease-modifying therapy. At last follow-up, all patients were alive, two patients were in remission (off-therapy), two patients improved compared with baseline, and two patients were in complete and partial remission, respectively, under immunosuppressive treatment. This retrospective case-series demonstrates that AHSCT has the potential to provide significant clinical responses in TAK patients, but large prospective trials are necessary to confirm these preliminary data.
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http://dx.doi.org/10.1038/s41409-020-0907-4DOI Listing
November 2020

Clinical phenotype and mortality in patients with idiopathic small bowel villous atrophy: a dual-centre international study.

Eur J Gastroenterol Hepatol 2020 08;32(8):938-949

Istituti Clinici Scientifici Maugeri, IRCCS, Gastroenterology Unit of Pavia Institute, University of Pavia, Pavia, Italy.

Objective: Causes of small-bowel villous atrophy (VA) include coeliac disease (CD), its complications and other rare non-coeliac enteropathies. However, forms of VA of unknown aetiology may also exist. We defined them as idiopathic VA (IVA). To retrospectively classify the largest cohort of IVA patients and compare their natural history with CD.

Methods: Notes of 76 IVA patients attending two tertiary centres between January 2000 and March 2019 were retrospectively reviewed. CD, its complications and all the known causes of VA were excluded in all of them. Persistence of VA during follow-up and lymphoproliferative features were used to retrospectively classify IVA, as follows. Group 1: IVA with spontaneous histological recovery (50 patients). Group 2: persistent IVA without lymphoproliferative features (14 patients). Group 3: persistent IVA with lymphoproliferative features (12 patients). Survival was compared between IVA groups and 1114 coeliac patients. HLA was compared between IVA patients, coeliac patients and appropriate controls.

Results: Five-year survival was 96% in IVA group 1, 100% in IVA group 2, 27% in IVA group 3 and 97% in CD. On a multivariate analysis hypoalbuminemia (P = 0.002) and age at diagnosis (P = 0.04) predicted mortality in IVA. Group 2 showed association with HLA DQB1*0301 and DQB1*06.

Conclusion: IVA consists of three groups of enteropathies with distinct clinical phenotypes and prognoses. Mortality in IVA is higher than in CD and mainly due to lymphoproliferative conditions necessitating more aggressive therapies.
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http://dx.doi.org/10.1097/MEG.0000000000001726DOI Listing
August 2020
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