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Summary: The success of CD19 Chimeric antigen receptor (CAR) T‐cell therapy in large B‐cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off‐the‐shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the ʽstandard‐of‐care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020–2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression‐free survival (1‐year PFS 50% vs. 32%, p < 0.001) and overall survival (1‐year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high‐grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up‐to‐date clinical data when comparing CAR T against new treatment options for r/r LBCL. [ABSTRACT FROM AUTHOR]

High-precision, individualised RT protocols allowed successful tumour de-bulking with limited toxicity, providing the basis to develop specific RT bridging protocols in lymphoma. RADIOTHERAPY BRIDGING IN LARGE B-CELL LYMPHOMA PATIENTS RECEIVING CD19 CAR-T - THE UK EXPERIENCE B Background: b Radiotherapy (RT) has potential synergistic effects with CAR T but is not widely used as bridging therapy for lymphoma patients due to logistical challenges, uncertainty about patient selection and lack of standardised protocols. [Extracted from the article]

Brexucabtagene autoleucel (brexu-cel) is an autologous CD19 CAR T-cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA-2, brexu-cel demonstrated impressive responses in patients failing ≥2 lines, including a bruton's tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real-world intention-to-treat (ITT) outcomes for brexu-cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu-cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow-up of 13.3 months, median progression-free survival (PFS) for infused patients was 21 months (10.1-NA) with a 6- and 12-month PFS of 82% (95% confidence interval [CI], 71-89) and 62% (95% CI, 49-73), respectively. ≥Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS > 1 and previous MF. Cumulative incidence of non-relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA-2 and other real-world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention., Competing Interests: Maeve A. O'Reilly: honoraria from Kite Gilead, Novartis, and Janssen. Advisory boards Kite Gilead and Autolus. Conference/travel support Kite Gilead. William Wilson: No COI. David Burns: Kite Gilead consultancy fees and support for educational meetings. Andrea Kuhnl: Kite Gilead conference support, honoraria, advisory board, Novartis: honoraria, research funding, Advisory board: Roche, Abbvie, BMS. Frances Seymour: No COI. Ben Uttenthal: No COI. Caroline Besley: Honoraria: Kite, Janssen, Novartis and Takeda. Rajesh Alajangi: No COI. Thomas Creasey: No COI. Shankara Paneesha: No COI. Johnathon Elliot: No COI. Carlos Gonzalez Arias: Kite Gilead conference support, honoraria, advisory board, research funding; Novartis conference support, honoraria, advisory board; BMS advisory board. Sunil Iyengar: conference support Beigene, BMS, Takeda. Speaker fees Kite Gilead, Takeda. Advisory boards Kite, MSD. Matthew R. Wilson: Honoraria/speaker fees: Kite/Gilead, Janssen, Sobi, Takeda, Veriton Pharma, AstraZeneca, Roche. Conference/travel support: Gilead, Janssen, Kite, Takeda, AstraZeneca. Alison Delaney: Kite Gilead conference support. Lourdes Rubio: No COI. Jonathan Lambert: advisory boards: Kite‐Gilead and Blueprint Pharmaceuticals; BMS, Takeda and Novartis: conference support. Khalil Begg: No COI. Stephen Boyle: Honoraria Kite Gilead. Kathleen P. L. Cheok: No COI. Graham P. Collins: Kite Gilead speaker fees, advisory board. Claire Roddie: Advisory boards and speakers fees Novartis, Kite Gilead, BMS, Amgen, Autolus. Rod Johnson: Kite Gilead consultancy fees, support for educational meetings. Robin Sanderson: Kite Gilead speakers bureau, honoraria, conference travel, Novartis speakers bureau, honoraria, conference travel., (© 2024 The Authors. HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

CAR T-cell therapy has transformed relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukaemia (B-ALL) management and outcomes, but following CAR T infusion, interventions are often needed. In a UK multicentre study, we retrospectively evaluated tisagenlecleucel outcomes in all eligible patients, analysing overall survival (OS) and event-free survival (EFS) with standard and stringent definitions, the latter including measurable residual disease (MRD) emergence and further anti-leukaemic therapy. Both intention-to-treat and infused cohorts were considered. We collected data on feasibility of delivery, manufacture, toxicity, cause of therapy failure and followed patients until death from any cause. Of 142 eligible patients, 125 received tisagenlecleucel, 115/125 (92%) achieved complete remission (CR/CRi). Severe cytokine release syndrome and neurotoxicity occurred in 16/123 (13%) and 10/123 (8.1%), procedural mortality was 3/126 (2.4%). The 2-year intent to treat OS and EFS were 65.2% (95%CI 57.2-74.2%) and 46.5% (95%CI 37.6-57.6%), 2-year intent to treat stringent EFS was 35.6% (95%CI 28.1-44.9%). Median OS was not reached. Sixty-two responding patients experienced CAR T failure by the stringent event definition. Post failure, 1-year OS and standard EFS were 61.2% (95%CI 49.3-75.8) and 55.3% (95%CI 43.6-70.2). Investigation of CAR T-cell therapy for B-ALL delivered on a country-wide basis, including following patients beyond therapy failure, provides clinicians with robust outcome measures. Previously, outcomes post CAR T-cell therapy failure were under-reported. Our data show that patients can be successfully salvaged in this context with good short-term survival., (© 2024. The Author(s).)

Background: A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population., Methods: This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m 2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 10 6 CD34 + cells per kg), before conditioning (fludarabine 125 mg/m 2 , cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440., Findings: Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure., Interpretation: Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease., Funding: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership., Competing Interests: Declaration of interests JOL reports grants for investigator-initiated research from the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation research grant for the current project, AbbVie, Gilead Sciences, Takeda UK, and Shire; honoraria for consulting or advisory boards from AbbVie, Allergan, Atlantic Healthcare, Bristol Meyers Squibb, Celgene, Celltrion, Lilly, Ferring Pharmaceuticals, Galapagos NV, Gilead Sciences, GlaxoSmithKline, Janssen, MSD, Napp Pharmaceuticals, Norgine BV, Pfizer, Shire, Takeda UK, and Vifor Pharma Management; honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Meyers Squibb, Ferring Pharmaceuticals, Galapagos NV, Janssen, Norgine BV, Pfizer, Shire, Takeda UK, and Cornerstone Healthcare Group; and support for attending meetings, travel, or both from AbbVie, Takeda UK, MSD, Ferring Pharmaceuticals, and Janssen, outside the submitted work. DH reports part funding for salary through the NIHR Efficacy and Mechanism Evaluation research grant for this project. RE reports participation in the NIHR Clinical Trials Unit Standing Advisory Committee (2020 to present), and the Health Technology Assessment Clinical Evaluation and Trials Committee (2017–21). LD reports various NIHR grants, none of which relate to Crohn's disease or investigate treatments similar to those in ASTIClite. SD reports salary funding from NHS Research Scotland via NHS Lothian to support clinical trial work; grants from the Edinburgh & Lothian Health Foundations Award, the Pathological Society of Great Britain & Northern Ireland, Helmsley Charitable Trust–Gut Cell Atlas Normal and Crohn's Disease, and Helmsley Charitable Trust CDTREAT and BIOPIC studies; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Jannsen, Ferring, Takeda, and AbbVie; and support for attending meetings, travel, or both from Janssen, Dr Falk Symposium, and AbbVie. SD also reports participation on a data safety monitoring board or advisory board for AbbVie and MHRA; and leadership or fiduciary role on other board, society, committee, or advocacy groups for the British Society of Gastroenterology, the Royal College of Physicians of Edinburgh, and the Scottish Government. JG reports consulting fees from AbbVie, AstraZeneca, Bristol Meyers Squibb, Gilead Sciences, Janssen, MorphoSys AG, and Novartis AG; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Meyers Squibb, Gilead Sciences, and Janssen; and participation on a data safety monitoring board or advisory board for AstraZeneca, outside the submitted work. PI reports grants or contracts from MSD, Takeda UK, Celltrion, and Pfizer; consulting fees from Bristol Meyers Squibb, AbbVie, Arena, Boehringer-Ingelheim, Celgene, Celltrion, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Bristol Meyers Squibb, Celgene, Celltrion, Dr Falk Pharma GmbH, Ferring Pharmaceuticals, Galapagos NV, Gilead Sciences, MSD, Janssen, Pfizer, Takeda UK, Tillotts Pharma AG, Sapphire Medical, Sandoz, Shire, and Warner Chilcott UK, outside the submitted work. EL reports various other NIHR grants, none of which relate to Crohn's disease or investigate treatments similar to those in ASTIClite; and participation in two data monitoring and ethics committees and two trial steering committees for NIHR trials outside the submitted work, none of which relate to Crohn's disease. MP reports grants or contracts from Pfizer, Gilead Sciences, and Crohn's & Colitis UK, outside the submitted work; and a leadership role as Director of Cambridge Biomedical Research Centre, outside the submitted work (2020 to present). AL reports consulting fees from Takeda UK, Vifor Pharma Management, Janssen, and PredictImmune; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda UK, Janssen, and Celltrion; support for attending meetings, travel, or both from Janssen, Tillotts Pharma AG, Takeda UK, and Vifor Pharma Management; and is Director of the non-executive IBD Registry Board. AGP reports being the Chief Executive Officer of multimmune GmbH, Chief Scientific Officer of Alphageneron Pharmaceuticals, and a member of the scientific advisory board of Cytomos, none of which relate to Crohn's disease and all are outside the submitted work. SS reports grants or contracts from Crohn's & Colitis UK and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda UK, Janssen, AbbVie, Celltrion, Boehringer Ingelheim International GmbH, and Bristol Meyers Squibb, outside the submitted work; and participation on a data safety monitoring board or advisory board for Takeda UK, Janssen, AbbVie, Celltrion, Boehringer Ingelheim International GmbH, Bristol Meyers Squibb, and Vifor Pharma Management, outside the submitted work. JS reports grant funding for IBD research from the European Crohn's & Colitis Organization (ECCO), The Leona M and Harry B Helmsley Charitable Trust, Crohn's & Colitis UK, Crohn's & Colitis Foundation, Action Medical Research, the NIHR Efficacy and Mechanism Evaluation, European Commission FP-7, and Horizon 2020 programmes, outside the submitted work; and payment or honoraria for a lecture for the Falk Foundation, and a leadership role on the UK IBD Registry Management Board. ST reports grants or contracts from ECCO, the Leona M and Harry B Helmsley Charitable Trust, Ferring Pharmaceuticals, Janssen, Lilly, Pfizer, Takeda UK, and the Norman Collisson Charitable Trust; and consulting fees from ai4gi Joint Venture, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim International GmbH, Bristol Meyers Squibb, Bühlmann Laboratories AG, Celgene, ChemoCentryx, Cosmo Pharmaceuticals NV, Enterome, Equillium, Ferring Pharmaceuticals, Genentech–Roche, Gilead Sciences, Glenmark Pharmaceuticals, Grünenthal, GlaxoSmithKline, Immunometabolism, Indigo Diabetes, Janssen, Lilly, Merck KGaA, Mestag Therapeutics, Novartis AG, Pfizer, PharmaVentures, Phesi, Satisfai Health, Sensyne Health, Sorriso, SynDermix, Synthon, Takeda UK, Topivert, UCB SA, Vertex Pharmaceuticals, VHsquared, and Vifor Pharma Management, outside the submitted work. ST also reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, Amgen, Biogen, Dr Falk Pharma GmbH, Ferring Pharmaceuticals, Janssen, Pfizer, Shire, Takeda UK, and UCB SA; payment for expert testimony from Cosmo; support for attending meetings, travel, or both from AbbVie, Amgen, Biogen, Dr Falk Pharma GmbH, Ferring Pharmaceuticals, Janssen, Pfizer, Shire, Takeda UK, and UCB SA; and participation on a data safety monitoring board or advisory board for Amgen, outside the submitted work. SR reports research funding from MacroGenics and Kura Oncology, outside the submitted work. BU reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Gilead and Novartis; and support for attending meetings, travel, or both from Takeda and Gilead. JS reports support for the current work through a NIHR Efficacy and Mechanism Evaluation grant; consulting fees from Medac (not directly related to Crohn's disease); and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Jazz Pharmaceuticals, Mallinckrodt Pharmaceuticals, Janssen, Gilead Sciences, Vertex, and Actelion, none of which directly relate to Crohn's disease, outside the submitted work. JS also reports participation on the Kiadis Pharma trial Independent Data Monitoring Committee, which does not directly relate to Crohn's disease, outside the submitted work. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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 characterized. Current practice is guided through physician preference rather than established evidence. Identification of effective BT modalities and factors predictive of response could improve both CAR-T intention to treat and clinical outcomes. We assessed BT modality and response in 375 adult patients with LBCL in relation to outcomes after axicabtagene ciloleucel (Axi-cel) or tisagenlecleucel (Tisa-cel) administration. The majority of patients received BT with chemotherapy (57%) or radiotherapy (17%). We observed that BT was safe for patients, with minimal morbidity or mortality. We showed that complete or partial response to BT conferred a 42% reduction in disease progression and death after 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 or partial response to BT may be more important for Tisa-cel than for Axi-cel, because all patients receiving Tisa-cel 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 toward optimal response and disease debulking, to improve patient outcomes associated with CD19CAR-T. Polatuzumab-containing regimens should be strongly considered for all suitable patients, and failure to achieve complete or partial response to BT before Tisa-cel administration may prompt consideration of further lines of BT where possible., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

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., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Hypothesis/Gap Statement. The impacts of increased biomarker testing on antifungal prescribing have not yet been fully examined in a real-life setting. Objectives. Biomarkers for invasive fungal disease (IFD) have been shown to reduce antifungal prescriptions in neutropaenic haemato-oncology patients. Our study aimed to assess the real-life impacts of introducing a novel biomarker-based pathway, incorporating serum galactomannan and Aspergillus PCR, for pyrexial haemato-oncology admissions. Methods. Patients with neutropaenic fever were identified prospectively after introduction of the new pathway from 2013-2015. A historical group of neutropaenic patients who had blood cultures taken from 2009-2012 was generated for comparison. Clinical details, including demographics, underlying diagnosis, investigations, radiology and antimicrobial treatment were obtained. Results. Prospective data from 308 patients were compared to retrospective data from 302 patients. The proportion of patients prescribed an antifungal medication was unchanged by the pathway ( P =0.79), but the pattern was different, with more patients receiving targeted antifungals ( P =0.04). A negative serum galactomannan test was not sufficient evidence to withhold therapy, with 17.2% of these episodes felt to have possible or probable IFD using the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. There was no difference in 30-day mortality ( P =0.21) or 1-year mortality ( P =0.57) following introduction of the pathway. Conclusions. Biomarkers can be used safely as part of a multidisciplinary approach to the diagnosis of IFD in neutropaenic haemato-oncology patients. Whilst they do not necessarily result in antifungal therapy being withheld, they can allow more confident diagnosis of IFD and more specific antifungal therapy in selected cases.

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., (© 2018 by The American Society of Hematology.)

Viral infection is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplant (HSCT), with up to one in four deaths directly linked to viral disease. Whilst awaiting lymphocyte reconstitution post-HSCT, the innate antiviral immune response is the first line of defense against invading viruses. Several novel innate viral-sensing pathways have recently been characterized, but their physiological importance in humans is poorly understood. We analyzed a panel of innate viral-sensor genes in HSCT patients, and assessed whether differences in innate antiviral responses could account for variation in susceptibility to viral infections. Expression levels of innate viral sensors in HSCT patients with active viral infections, HSCT patients without active infections and healthy volunteers were highly homogenous. Although IFN-α expression was up-regulated in actively infected patients relative to controls, a corresponding up-regulation of innate viral sensor expression was not observed. IFN-α stimulation of patient PBMCs in vitro showed intact IFN-α signaling, but actively infected patients' PBMCs had reduced up-regulation of innate viral sensors. We show that the aberrant IFN-α responses in HSCT patients were not due to calcineurin inhibition. Our data therefore raises the possibility of an intrinsic defect in innate viral sensor up-regulation in HSCT patients following viral infection.

Wilms' Tumour 1 (WT1) is a zinc finger transcription factor that is over-expressed in acute myeloid leukaemia (AML). Its restricted expression in normal tissues makes it a promising target for novel immunotherapies aiming to accentuate the cytotoxic T lymphocyte (CTL) response against AML. Here we report a phase I/II clinical trial of subcutaneous peptide vaccination with two separate HLA-A2-binding peptide epitopes derived from WT1, together with a pan-DR binding peptide epitope (PADRE), in Montanide adjuvant. Eight HLA-A2-positive patients with poor risk AML received five vaccination cycles at 3-weekly intervals. The three cohorts received 0·3, 0·6 and 1 mg of each peptide, respectively. In six patients, WT1-specific CTL responses were detected using enzyme-linked immunosorbent spot assays and pWT126/HLA-A*0201 tetramer staining, after ex vivo stimulation with the relevant WT1 peptides. However, re-stimulation of these WT1-specific T cells failed to elicit secondary expansion in all four patients tested, suggesting that the WT1-specific CD8(+) T cells generated following vaccination may be functionally impaired. No correlation was observed between peptide dose, cellular immune response, reduction in WT1 mRNA expression and clinical response. Larger studies are indicated to confirm these findings., (© 2013 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)