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Background: Glofitamab monotherapy induces durable remission in patients with relapsed or refractory diffuse large B-cell lymphoma after two or more previous therapies, but has not previously been assessed as a second-line therapy. We investigated the efficacy and safety of glofitamab plus gemcitabine-oxaliplatin (Glofit-GemOx) versus rituximab (R)-GemOx in patients with relapsed or refractory diffuse large B-cell lymphoma., Methods: The phase 3, randomised, open-label STARGLO trial was done at 62 centres in 13 countries in Asia and Australia, Europe, and North America. We recruited transplant-ineligible patients (aged ≥18 years) with histologically confirmed relapsed or refractory diffuse large B-cell lymphoma after one or more previous therapies. Patients were randomly assigned in permuted blocks (block size of six) via an interactive voice or web response system (2:1; stratified by 1 vs ≥2 previous lines of therapy and relapsed vs refractory status) to Glofit-GemOx (intravenous gemcitabine 1000 mg/m 2 and oxaliplatin 100 mg/m 2 plus glofitamab step-up dosing to 30 mg; for a total of eight cycles, plus four additional cycles of glofitamab monotherapy) or R-GemOx (intravenous gemcitabine 1000 mg/m 2 and oxaliplatin 100 mg/m 2 plus rituximab 375 mg/m 2 ; for a total of eight cycles). The trial independent review committee, which evaluated all response-based endpoints, was masked to treatment assignment. The primary endpoint was overall survival. Efficacy analyses were by intention to treat in all randomly assigned patients. We present results from both the primary analysis (cutoff: March 29, 2023) and updated analysis after all patients had completed study therapy (cutoff: Feb 16, 2024). Safety analyses included all patients who received any study treatment. This study is registered with ClinicalTrials.gov, NCT04408638, and is ongoing (closed to recruitment)., Findings: From Feb 23, 2021, to March 14, 2023, 274 patients were enrolled and randomly assigned to receive Glofit-GemOx (n=183) or R-GemOx (n=91). 158 (58%) patients were male and 116 (42%) were female; median age was 68 years (IQR 58-74). At the primary analysis after a median follow-up of 11·3 months (95% CI 9·6-12·7), overall survival was significantly improved with Glofit-GemOx versus R-GemOx (median not estimable [NE; 95% CI 13·8 months-NE] vs 9·0 months [7·3-14·4]; hazard ratio [HR] 0·59 [95% CI 0·40-0·89]; p=0·011). At the updated analysis after a median follow-up of 20·7 months (19·9-23·3), a consistent improvement in overall survival was observed with Glofit-GemOx versus R-GemOx (median 25·5 months [18·3-NE] vs 12·9 months [7·9-18·5]; HR 0·62 [0·43-0·88]). In the safety sets, 180 (100%) patients in the Glofit-GemOx group and 84 (96%) of 88 patients in the R-GemOx group had at least one adverse event during the study period. Cytokine release syndrome occurred in 76 (44%) of 172 glofitamab-exposed patients and was predominantly low grade. Deaths related to glofitamab or rituximab occurred in five (3%) patients in the Glofit-GemOx group and in one (1%) patient in the R-GemOx group., Interpretation: Glofit-GemOx had a significant overall survival benefit compared with R-GemOx, supporting its use in transplant-ineligible patients with relapsed or refractory diffuse large B-cell lymphoma after one or more previous lines of therapy., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests JSA has received grants or contracts from BMS, Cellectis, Merck, Mustang Bio, Regeneron, and Seagen; consulting fees from AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Celgene, Cellectar, Caribou Biosciences, Century Therapeutics, Celgene, Epizyme, Foresight Diagnostics, Genentech, Gilead, Interius, Lilly, F Hoffmann-La Roche, Seagen, and Takeda; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BMS, Incyte, Janssen, MorphoSys, Novartis, and Regeneron. MKu has received grants or contracts and consulting fees from and participated on a data safety monitoring board or advisory board for F Hoffmann-La Roche; a grant from BeiGene; and consulting fees from AbbVie. MH has received grants from Janssen and F Hoffmann-La Roche; consulting fees from Takeda, F Hoffmann-La Roche, Otsuka, AbbVie, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, F Hoffmann-La Roche, Otsuka, AbbVie, Gilead, and Pfizer; and participated on a data safety monitoring board or advisory board for Takeda, F Hoffmann-La Roche, Otsuka, AbbVie, and Gilead. CPF has received grants or contracts from BeiGene, F Hoffmann-La Roche, Genmab, and AbbVie; consulting fees from AbbVie, AstraZeneca, Atarabio, BMS, Genmab, Gilead, Kite, Incyte, Janssen, Lilly, Morphosys, Ono, F Hoffmann-La Roche, SERB, and SOBI; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, Atarabio, BMS, GenMab, Gilead, Kite, Incyte, Janssen, Lilly, Morphosys, Ono, F Hoffmann-La Roche, SERB, SOBI, and Takeda; and participated on a data safety monitoring board or advisory board for AbbVie, AstraZeneca, Atarabio, BMS, GenMab, Gilead, Kite, Incyte, Janssen, Lilly, Morphosys, Ono, F Hoffmann-La Roche, SERB, and SOBI. DHY has received grants or contracts from AbbVie, BeiGene, Boryung, Celltrion, Kyowa Kirin, Janssen, Samyang, and Sanofi; consulting fees from Abclon, BeiGene, BMS, GI Cell, GC Cell, Verismo, Janssen, Novartis, F Hoffmann-La Roche, and Pharos Bio; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Antengene, BMS, Boryung, GSK, Kyowa Kirin, Novartis, F Hoffmann-La Roche, Takeda, and Janssen; and participated on a data safety monitoring board or advisory board for Abclon, BeiGene, BMS, GI Cell, GC Cell, Verismo, Janssen, Novartis, F Hoffmann-La Roche, and Pharos Bio. HA has received grants or contracts from Morphosys, Genentech, Novartis, BMS, Epizyme, and Pfizer; consulting fees from Amgen, Genentech, Morphosys, Novartis, BMS, AstraZeneca, Acrotech, ADC Therapeutics, and AbbVie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Genentech; and participated on a data safety monitoring board or advisory board for Amgen, Genentech, Morphosys, Novartis, BMS, AstraZeneca, Acrotech, ADC Therapeutics, and AbbVie. WT has received grants or contracts and support for attending meetings or travel from F Hoffmann-La Roche; consulting fees from and participated on a data safety monitoring board or advisory board for F Hoffmann-La Roche, Takeda, AbbVie, Sobi, and Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F Hoffmann-La Roche, Takeda, Gilead, and AbbVie; and is grateful for and acknowledges funding and support from the University College London Hospitals NHS Foundation Trust Biomedical Research Centre. CH has received grants or contracts from Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F Hoffmann-La Roche, Janssen-Cilag, AbbVie, and Gilead; and support for attending meetings or travel from Janssen-Cilag, AbbVie, and F Hoffmann-La Roche. JMZ has received consulting fees from and participated on a data safety monitoring board or advisory board for Pierre Fabre, Takeda, BMS, Gilead, Novartis, Pfizer, Amgen, F Hoffmann-La Roche, AstraZeneca, and AbbVie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, F Hoffmann-La Roche, and AbbVie; and support for attending meetings or travel from F Hoffmann-La Roche and AbbVie. CYC has received grants or contracts from BMS, F Hoffmann-La Roche, AbbVie, MSD, and Lilly; consulting fees from F Hoffmann-La Roche, Janssen, Gilead, AstraZeneca, Lilly, BeiGene, Menarini, Dizal, AbbVie, Genmab, and BMS; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F Hoffmann-La Roche, Janssen, Gilead, AstraZeneca, Lilly, BeiGene, Menarini, Dizal, AbbVie, Genmab, and BMS; and participated on a data safety monitoring board or advisory board for F Hoffmann-La Roche, Janssen, Gilead, AstraZeneca, Lilly, BeiGene, Menarini, Dizal, AbbVie, Genmab, and BMS. HG has received consulting fees from F Hoffmann-La Roche, BMS, and Takeda; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead, F Hoffmann-La Roche, BMS, AbbVie, and Takeda. SS is an employee of and has received grants or contracts from Genentech; and has stock or stock options with F Hoffmann-La Roche. VO-N is an employee of Genentech and has provided all support for the present manuscript for Genentech and F Hoffmann-La Roche. RT is an employee of Genentech and has provided all support for the present manuscript for, has received support for attending meetings or travel from, and has stock or stock options with Genentech and F Hoffmann-La Roche. JR is an employee of and has received grants or contracts from F Hoffmann-La Roche, and has stock or stock options with F Hoffmann-La Roche. MD is an employee of, has provided all support for the present manuscript for, and has stock or stock options with F Hoffmann-La Roche. MKa is an employee of F Hoffmann-La Roche, and has received grants or contracts from Roche Diagnostics International and F Hoffmann-La Roche. EM is an employee of, has received grants or contracts from, has received support for attending meetings or travel from, and has stock or stock options with F Hoffmann-La Roche. HH is an employee of F Hoffmann-La Roche. LL is an employee of, has received grants or contracts from, has received royalties or licences from, has patents planned, issued or pending with, and has stock or stock options with F Hoffmann-La Roche. GPG has received grants or contracts from BeiGene and Merck; consulting fees from Merck, Gilead, Novartis, BMS, Clinigen, F Hoffmann-La Roche, and Prelude Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and F Hoffmann-La Roche; and participated on a data safety monitoring board or advisory board for Merck, Gilead, Novartis, BMS, Clinigen, F Hoffmann-La Roche and Prelude Therapeutics. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

High-dose methotrexate (HDMTX) is used in the treatment of a range of adult and childhood cancers. Although HDMTX can provide effective anti-tumor activity with an acceptable safety profile for most patients, delayed methotrexate elimination (DME) develops in a minority of patients receiving HDMTX and may be accompanied by renal dysfunction and potentially life-threatening toxicity. A panel of European physicians with experience in the use of HDMTX as well as of glucarpidase convened to develop a series of consensus statements to provide practical guidance on the prevention and treatment of DME, including the use of glucarpidase. Robust implementation of supportive measures including hyperhydration and urine alkalinization emerged as critical in order to reduce the risk of DME with HDMTX treatment, with leucovorin rescue critical in reducing the risk of DME complications. Early recognition of DME is important to promptly implement appropriate treatment including, intensified hydration, high-dose leucovorin and, when appropriate, glucarpidase., (© 2024. The Author(s).)

This Good Practice Paper provides recommendations for the baseline investigation, risk stratification and use of prophylactic interventions for patients with large B-cell lymphoma at risk of central nervous system relapse. Recent evidence which has questioned the role of high-dose methotrexate in this clinical scenario is discussed in detail., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Autologous stem-cell transplantation (ASCT) is standard therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), but many patients are either ineligible or unable to receive it. This retrospective study characterized outcomes in R/R LBCL, delineated by eligibility for, and receipt of, ASCT. Median progression-free survival (PFS) and event-free survival (EFS) for patients undergoing ASCT were 35.2 and 31.6 months (overall survival [OS] not reached). Median PFS, EFS, and OS were 4.3, 4.3, and 6.9 months for ineligible patients, and 2.7, 2.6, and 9.4 months for those eligible for but unable to receive ASCT. This highlights an unmet need for alternative therapies in patients unable to receive ASCT., Competing Interests: Farah Toron and Paula Williams are employees of Bristol Myers Squibb. Emma Tyas is an employee of Lumanity, which received fees from Bristol Meyers Squibb in relation to this study. Miranda Cooper and Joshua Rickards were employees of Lumanity at the time of this study. Christopher P. Fox has received remuneration for consultancy and/or participation in advisory boards from Abbvie, AstraZeneca, Atarabio, BMS/Celgene, GenMab, Gilead/Kite, Incyte, Janssen, Lilly, Morphosys, Ono, Roche, SERB, SOBI, and Takeda. Christopher P. Fox also received research funding from BeiGene. William Townsend has received remuneration for consulting from Roche and Gilead and has received remuneration for speaking at educational events from Roche, and for participating in advisory boards from BMS and Takeda. John G. Gribben has received honoraria from Abbvie, Amgen, AstraZeneca, BMS, Gilead/Kite, and Janssen. John G. Gribben also received gratin fusing from AstraZeneca, Celgene, and Janssen. Tobias Menne has received travel grants from Amgen, Jazz, Pfizer, Bayer, Kyowa Kirin, BMS/Celgene, Gilead/Kite, Janssen, and Takeda and also received honoraria for advisory board meetings from Gilead/Kite, Amgen, Novartis, Pfizer, BMS/Celgene, Daiichi Sankyo, Atara, Roche, and Janssen. Tobias Menne has received honoraria for lectures from Gilead/Kite, Takeda, Janssen, Roche, Servier, Novartis, BMS/Celgene, Pfizer, and Incyte, and received research funding from Janssen, AstraZeneca, and Novartis Nagesh Kalakonda received remuneration for lectures. presentations, manuscript writing, and/or educational events from BMS/Celgene, Takeda, Morphosys, Incyte, Janssen, Karyopharm, Roche, and Gilead, and received support for attending meetings from Janssen, Morphosys, and Takeda. John Radford has received remuneration for consultancy from Takeda and ADC Therapeutics. JR's spouse is a shareholder in AstraZeneca., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Abstract: Posttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, and patients with low-risk disease after initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly diagnosed CD20+ B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560 mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline International Prognostic Index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] immunochemotherapy, with ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11 of 38 patients (29%; 95% confidence interval [CI], 15-46). This did not reach the prespecified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%; 95% CI, 44-76), and 2-year overall survival (76%; 95% CI, 63-91). Adverse events were mostly hematological, gastrointestinal, and infective. Although TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered at www.clinicaltrials.gov as #ISRCTN32667607., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

This EHA-ESMO Clinical Practice Guideline provides key recommendations for managing primary DLBCL of the CNS.The guideline covers clinical, imaging and pathological diagnosis, staging and risk assessment, treatment and follow-up.Algorithms for first-line and salvage treatments are provided.The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.Recommendations are based on available scientific data and the authors' collective expert opinion., Competing Interests: AJMF reports personal financial interests for advisory board membership for AbbVie, AstraZeneca, Bristol Myers Squibb (BMS), Genmab, Gilead, Incyte, Juno, Novartis, PletixaPharm and Roche; institutional financial interests as local Principal Investigator (PI) for ADC Therapeutics, Amgen, BeiGene, BMS, Genmab, Gilead, Hutchison Medipharma, Incyte, Janssen, Novartis, Pfizer, Pharmacyclics and Takeda; institution research grants from BTG Therapeutics; institutional funding from Roche; non‐financial interests as a member of the Global Outreach Committee of the EHA and as a member of the Board of Directors (President) of Fondazione Italiana Linfomi. GI reports personal financial interests as an advisory board member for Gilead, Incyte, Roche and as an invited speaker for Riemser; non‐financial interests as a member of Deutsche Gesellschaft für Hämatologie und Onkologie (DGHO) and a leadership role for the German Lymphoma Alliance (Mitglied des Vorstandes). JKD reports personal financial interests as an advisory board member for Eli Lilly. DPA reports non‐financial interests as a member of an academic subcommittee for the British Society of Neuroradiologists. JECB reports personal financial interests as an advisory board member for Gilead and lecture honorarium from Novartis; institutional financial interests for funding of educational symposia from Roche and TEVA. TC reports personal financial interests for advisory board membership and consultancy for Janssen‐Cilag S.p.A; speaking honoraria from Takeda; participation in the Hema for the Future project for Sandoz. KC reports personal financial interests as an advisory board member for AbbVie, Atara, Celgene, Incyte, Janssen, Kite, Roche and Takeda; personal financial interests as an invited speaker for Incyte, Kite, Roche and Takeda; non‐financial interests as a member of the American Society of Clinical Oncology (ASCO) and the EHA, and leadership roles with the National Cancer Research Institute (NCRI; chair of UK NCRI T‐cell lymphoma study group). CPF reports personal financial interests as an advisory board member for AbbVie, AstraZeneca, Atarabio, BMS, Genmab, Gilead/Kite, Incyte, Janssen, Lilly, MorphoSys, Ono, Roche, SERB and Sobi; personal financial interests as an invited speaker for AbbVie, Gilead/Kite, Incyte, Janssen, Roche and Takeda; institutional financial interests as coordinating PI for BeiGene and Roche; institutional financial interests as a steering committee member for Genmab and MorphoSys; non‐financial interests for an advisory role for Blood Cancer UK (clinical trials funding committee member) and Lymphoma Action (medical advisory panel member); non‐financial interests for leadership roles with Cure Leukaemia (clinical trials steering committee member) and the NCRI (chair of UK NCRI aggressive lymphoma study group). KHX reports personal financial interests as an invited speaker for BTG. MP reports personal financial interests as an invited speaker for BeiGene and Novartis; personal financial interests for expert testimony for Ventana Roche. ES reports personal financial interests as an invited speaker for Riemser Pharma; personal financial interests for a writing engagement for Riemser Pharma; personal financial interests as an advisory board member for SERB Pharmaceuticals; institutional financial interests as a coordinating PI for Riemser Pharma and as a local PI for AbbVie, Riemser Pharma and Roche; non‐financial interests as a PI for AbbVie and Roche; non‐financial interests as a member of the DGHO and German Lymphoma Alliance. CS reports institutional funding from AstraZeneca. LS reports personal financial interests as an advisory board member for Kyowa Kirin and Takeda; personal financial interests as author royalties from Munksgaard Publishing and Springer Verlag; institutional financial interests as a steering committee member for Varian and ViewRay; non‐financial interests for leadership roles with the International Lymphoma Radiation Oncology Group (Vice Chair) and the Danish Lymphoma Radiation Oncology Group (Chair); non‐financial interests as a PI for the European Organisation for Research and Treatment of Cancer (EORTC); non‐financial interests as a member of ASCO, American Society for Therapeutic Radiology and Oncology (ASTRO) and European Society for Therapeutic Radiology and Oncology (ESTRO). EZ reports personal financial interests as an advisory board member for AbbVie, BeiGene, BMS, Curis, Eli Lilly, Incyte, Ipsen, Janssen, Merck, Miltenyi Biomedicine and Roche; institutional financial interests for travel grants from BeiGene, Gilead, Janssen and Roche; institutional financial interests for trial sponsorship from AstraZeneca, BeiGene, Celgene/BMS, Incyte, Janssen and Roche. CB reports personal financial interests as an invited speaker for AbbVie, Pfizer and Sobi; personal financial interests as an advisory board member for BeiGene, Celltrion, Gilead Sciences, Incyte, Janssen, MorphoSys, Novartis, Regeneron and Roche; institutional funding from AbbVie, Amgen, Celltrion, Janssen, MSD, Pfizer and Roche. MJ reports personal financial interests as an advisory board member for BMS, Genmab, Gilead, Janssen and Novartis; personal financial interests as an invited speaker for Incyte; institutional financial interests as an invited speaker for Roche; institutional funding from AbbVie, AstraZeneca, Celgene, Gilead, Janssen and Roche; institutional financial interests as coordinating PI for BioInvent. MD reports personal financial interests as an invited speaker for AstraZeneca, Gilead/Kite, Janssen, Novartis and Roche; personal financial interests as an advisory board member for AstraZeneca, BeiGene, BMS/Celgene, Genmab, Gilead, Janssen, Lilly/Loxo, Novartis and Roche; institutional research grants from AbbVie, Bayer, Celgene, Janssen and Roche; institutional funding from Gilead/Kite; non‐financial interests as a member of ASCO, American Society of Hematology (ASH; subcommittee member), DGHO (prior Board member), EHA (Executive Board member), ESMO (Faculty member) and Lymphoma Research Foundation [LRF; Mantle Cell Lymphoma (MCL) Consortium member]. DM has declared no conflicts of interest., (© 2024 The Authors. HemaSphere Published by John Wiley & Sons on behalf of European Hematology Association and by Elsevier Ltd on behalf of European Society for Medical Oncology.)

Background: Follicular helper T-cell lymphomas (TFHL) harbour frequent alterations in genes that regulate DNA methylation. Preliminary reports suggest that treatment with 5-azacitidine has clinical activity in patients with relapsed or refractory TFHL. We aimed to compare the oral form of azacitidine with investigator's choice standard therapy (ICT; ie, gemcitabine, bendamustine, or romidepsin) in patients with relapsed or refractory TFHL., Methods: Patients older than 18 years with relapsed or refractory TFHL (angioimmunoblastic T-cell lymphoma, follicular lymphoma, or nodal T-cell lymphoma with phenotype, ie, positive with two or more markers among CD10, BCL6, CXCL13, PD1, or ICOS) based on the 2017 WHO classification of haematological neoplasms, with an Eastern Cooperative Oncology Group performance status score of 0-3, were recruited in university hospitals from five European countries and from Japan. Patients were randomly assigned 1:1 to treatment with either azacitidine given at a dose of 300 mg once a day (200 mg in Japanese patients) for 14 days in a 28-day cycle or gemcitabine, bendamustine, or romidepsin according to the investigator's choice. Random assignment was stratified by the number of previous lines of therapy and by the presence of previous or concomitant myeloid malignancy. The primary endpoint was investigator-assessed progression-free survival, presented in the intention-to-treat population. This Article is the final analysis of this trial, registered at ClinicalTrials.gov (Europe NCT03593018 and Japan NCT03703375)., Findings: 86 patients (median age 69 years [IQR 62-76], 50 patients were male, 36 were female) were enrolled between Nov 9, 2018, to Feb 22, 2021; 42 in the azacitidine group and 44 in the ICT group. With a median follow-up of 27·4 months (IQR 20·2-32·9), the median progression-free survival was 5·6 months (95% CI 2·7 -8·1) in the azacitidine group versus 2·8 months (1·9-4·8) in the ICT group (hazard ratio of 0·63 (95% CI 0·38-1·07); 1-sided p=0·042). Grade 3-4 adverse events were reported in 32 (76%) of 42 patients in the azacitidine group versus 42 (98%) of 43 patients in the ICT group. The most adverse grade 3 or worse adverse events were haematological (28 [67%] of 42 patients vs 40 [93%] of 43 patients), infection (8 [19%] and 14 [33%]), and gastrointestinal (5 [12%] vs 1 [2%] for azacitidine and ICT, respectively). There were two treatment-related deaths in the azacitidine group (one endocarditis and one candidiasis) and three in the ICT group (one heart failure, one COVID-19, and one cause unknown)., Interpretation: Although the pre-specified primary outcome of the trial was not met, the favourable safety profile suggests that azacitidine could add to the treatment options in these difficult to treat diseases especially in combination with other drugs. Trials with combination are in preparation in a platform trial., Funding: Bristol-Myers Squibb., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests EB reports receiving research funding from Amgen and Bristol-Myers Squibb (BMS); honoraria from Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, and Sanofi; and participation on an advisory committee for Roche, Gilead, ADC Therapeutics, Takeda, Novartis, and Incyte. FM reports receiving consultancy fees from Roche, Gilead, and AbbVie and participation on advisory committees for Roche, Gilead, Novartis, BMS, AbbVie, Genmab, Miltenyi, Allogene Therapeutics, AstraZeneca, and Janssen. GC reports receiving honoraria from Gilead, Novartis, Mylteni, Sanofi, AbbVie, Takeda, Roche, Janssen, Roche, Celgene, Novartis and participation on advisory committees for MabQi, Ownards Therapeutics, AbbVie, Roche, and BMS. NF reports receiving consultancy fees from AstraZeneca, AbbVie, Eli Lilly, HUYA, and Novartis; research funding from Bayer, BMS, Chugai Pharma, Celgene, Genmab, and Incyte; honoraria from AstraZeneca, BMS, Chugai Pharma, Dainippon Sumitomo, Eisai, Janssen, Kyowa Kirin, Nippon Shinyaku, Novartis, Ono, Sanofi, Symbio, Takeda, and Celgene. R-OC reports receiving honoraria from Roche, Takeda, Merck, BMS, Gilead and Kite, AbbVie, ADC Therapeutics, and Incyte; research funding from Takeda and Gilead and Kite; honoraria from Roche, Takeda, Merck, BMS, Gilead and Kite, AbbVie, ADC Therapeutics, Incyte and AstraZeneca; and participation on advisory committees for Roche, Takeda, Merck, BMS, Gilead and Kite, ADC Therapeutics, Janssen, and Incyte. CPF reports receiving consultancy fees from AbbVie, AstraZeneca, Atarabio, Celgene and BMS, GenMab, Gilead and Kite, Incyte, Janssen, Morphosys, Ono Pharmaceutical, Roche, and Takeda; research funding from BeiGene; and speaker bureau fees from Celgene and BMS, Gilead and Kite, Incyte, Janssen, Roche, and Takeda; and travel support from Roche. FAd’A reports receiving research funding from Servier and Nordic Nanovector. PBS reports receiving consultancy fees from Amgen, Roche, Janssen, Gilead, Incyte, Morphosys, CTI Biopharma, BMS, Celegene, AbbVie, Takeda, BMS, Beigene, and Lilly; research funding from Roche; and honoraria from Amgen, Roche, Janssen, Gilead, Incyte, Morphosys, CTI Biopharma, BMS, Celegene, AbbVie, Takeda, BMS, Beigene, and Lilly. AG and MN are current employees and stock option holders at BMS. L-MF reports receiving honoraria from Roche, AbbVie, Janssen, and AstraZeneca. M-HD-L reports receiving research funding from Roche and Celgene; honoraria from Gilead and Amgen and travel support from Mundipharma. LdL reports receiving consultancy fees from Lunaphore Technologies and Bayer and honoraria from Novartis. PG reports receiving consultancy fees from Takeda; research funding from Takeda, Innate Pharma, Alderan, and Sanofi; and honoraria from Takeda Gilead. KT reports receiving consultancy fees from Ono Pharma, Meiji Seika Pharma, Yakuruto, Solasia Pharma, Meiji Seika Pharma, and HUYABIO; research funding from Kyowa-hakko and Kirin, Meiji Seika Pharma, BMS, Byer, Daiich-Sankyo, HUYABIO, and Regeneron Pharmaceuticals; and honoraria from Chugai Pharma, Eizai, and Meiji Seika Pharma. FL reports receiving honoraria from Kiowa, Miltenyi, and BMS; research funding from Roche and BMS; and travel support from Roche and Gilead. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

During the middle Permian through the Triassic, Tasmania moved from paleo-latitudes of 78° to 69°S, wedged between Antarctica and Australia, within the paleo-South polar circle. During this time, significant global carbon cycle disturbances triggered major environmental and climatic changes and mass extinction events globally. The Bicheno-5 core from Eastern Tasmania, Australia, provides the opportunity to examine middle Permian and Upper Triassic sediments from the paleo-Antarctic, using high-resolution organic carbon isotope (δ 13 C TOC ) chemostratigraphy, pXRF, and sedimentology, combined with new palynological data integrated with the existing radiometric age model. While there is a significant unconformity in the Upper Permian to the middle Triassic associated with eustatic sea-level fall as a result of regional uplift in eastern Australia, three distinct carbon isotope excursions (CIEs), characterized by negative shifts of up to - 6 ‰ were identified; the middle Permian Guadalupian Carbon Isotope Excursions (G-CIE), the Carnian Pluvial Episode (CPE), and the mid-Norian Event (MNE). These three events highlight a significant climate shift through glacial and interglacial cycles to warmer non-glacial intervals in the Late Triassic, with evidence of the polar record of the Carnian Pluvial Episode and the mid-Norian Event, which are poorly studied in the Southern Hemisphere, specifically within the Paleo-Antarctic circle., (© 2024. The Author(s).)

Background: There is no evidence base to support the use of 6-monthly monitoring blood tests for the early detection of liver, blood and renal toxicity during established anti-tumour necrosis factor alpha (TNFα) treatment., Objectives: To evaluate the incidence and risk factors of anti-TNFα treatment cessation owing to liver, blood and renal side-effects, and to estimate the cost-effectiveness of alternate intervals between monitoring blood tests., Methods: A secondary care-based retrospective cohort study was performed. Data from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) were used. Patients with at least moderate psoriasis prescribed their first anti-TNFα treatment were included. Treatment discontinuation due to a monitoring blood test abnormality was the primary outcome. Patients were followed-up from start of treatment to the outcome of interest, drug discontinuation, death, 31 July 2021 or up to 5 years, whichever came first. The incidence rate (IR) and 95% confidence intervals (CIs) of anti-TNFα discontinuation with monitoring blood test abnormality was calculated. Multivariate Cox regression was used to examine the association between risk factors and outcome. A mathematical model evaluated costs and quality-adjusted life years (QALYs) associated with increasing the length of time between monitoring blood tests during anti-TNFα treatment., Results: The cohort included 8819 participants [3710 (42.1%) female, mean (SD) age 44.76 (13.20) years] that contributed 25 058 person-years (PY) of follow-up and experienced 125 treatment discontinuations owing to a monitoring blood test abnormality at an IR of 5.85 (95% CI 4.91-6.97)/1000 PY. Of these, 64 and 61 discontinuations occurred within the first year and after the first year of treatment start, at IRs of 8.62 (95% CI 6.74-11.01) and 3.44 (95% CI 2.67-4.42)/1000 PY, respectively. Increasing age (in years), diabetes and liver disease were associated with anti-TNFα discontinuation after a monitoring blood test abnormality [adjusted hazard ratios of 1.02 (95% CI 1.01-1.04), 1.68 (95% CI 1.00-2.81) and 2.27 (95% CI 1.26-4.07), respectively]. Assuming a threshold of £20 000 per QALY gained, no monitoring was most cost-effective, but all extended periods were cost-effective vs. 3- or 6-monthly monitoring., Conclusions: Anti-TNFα drugs were uncommonly discontinued owing to abnormal monitoring blood tests after the first year of treatment. Extending the duration between monitoring blood tests was cost-effective. Our results produce evidence for specialist society guidance to reduce patient monitoring burden and healthcare costs., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Objective: To explore the acceptability of an individualised risk-stratified approach to monitoring for target-organ toxicity in adult patients with immune-mediated inflammatory diseases established on immune-suppressing treatment(s)., Methods: Adults (≥18 years) taking immune-suppressing treatment(s) for at-least six months, and healthcare professionals (HCPs) with experience of either prescribing and/or monitoring immune-suppressing drugs were invited to participate in a single, remote, one-to-one, semi-structured interview. Interviews were conducted by a trained qualitative researcher and explored their views and experiences of current monitoring and acceptability of a proposed risk-stratified monitoring plan. Interviews were transcribed verbatim and inductively analysed using thematic analysis in NVivo., Results: Eighteen patients and 13 HCPs were interviewed. While participants found monitoring of immune-suppressing drugs with frequent blood-tests reassuring, the current frequency of these was considered burdensome by patients and HCPs alike, and to be a superfluous use of healthcare resources. Given abnormalities rarely arose during long-term treatment, most felt that monitoring blood-tests were not needed as often. Patients and HCPs found it acceptable to increase the interval between monitoring blood-tests from three-monthly to six-monthly or annually depending on the patients' risk profiles. Conditions of accepting such a change included: allowing for clinician and patient autonomy in determining an individuals' frequency of monitoring blood-tests, the flexibility to change monitoring frequency if someone's risk profile changed, and endorsement from specialist societies and healthcare providers such as the National Health Service., Conclusion: A risk-stratified approach to monitoring was acceptable to patients and HCPs. Guideline groups should consider these findings when recommending blood-test monitoring intervals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Sulfasalazine-induced cytopenia, nephrotoxicity and hepatotoxicity is uncommon during long-term treatment. Some guidelines recommend 3 monthly monitoring blood tests indefinitely during long-term treatment while others recommend stopping monitoring after 1 year. To rationalise monitoring, we developed and validated a prognostic model for clinically significant blood, liver or kidney toxicity during established sulfasalazine treatment., Design: Retrospective cohort study., Setting: UK primary care. Data from Clinical Practice Research Datalink Gold and Aurum formed independent development and validation cohorts., Participants: Age ≥18 years, new diagnosis of an inflammatory condition and sulfasalazine prescription., Study Period: 1 January 2007 to 31 December 2019., Outcome: Sulfasalazine discontinuation with abnormal monitoring blood-test result., Analysis: Patients were followed up from 6 months after first primary care prescription to the earliest of outcome, drug discontinuation, death, 5 years or 31 December 2019. Penalised Cox regression was performed to develop the risk equation. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination., Results: 8936 participants were included in the development cohort (473 events, 23 299 person-years) and 5203 participants were included in the validation cohort (280 events, 12 867 person-years). Nine candidate predictors were included. The optimism adjusted R 2 D and Royston D statistic in the development data were 0.13 and 0.79, respectively. The calibration slope (95% CI) and Royston D statistic (95% CI) in validation cohort was 1.19 (0.96 to 1.43) and 0.87 (0.67 to 1.07), respectively., Conclusion: This prognostic model for sulfasalazine toxicity uses readily available data and should be used to risk-stratify blood-test monitoring during established sulfasalazine treatment., Competing Interests: Competing interests: AA has received personal fees from UpToDate (royalty), Springer (royalty), Cadilla Pharmaceuticals (lecture fees), NGM Bio (consulting), Limbic (consulting) and personal fees from Inflazome (consulting) unrelated to the work. GPA has received consulting fees from Abbott, Albereo, Amryth, AstraZeneca, Benevolent AI, DNDI, GlaxoSmithKline, NuCANA, Pfizer, Roche Diagnostics, Servier Pharmaceuticals, W.L. Gore & Associates paid to the University of Nottingham unrelated to the work. CPF has received Consultancy/Advisory board fees from AbbVie, GenMab, Incyte, Morphosys, Roche, Takeda, Ono, Kite/Gilead, BMS/Celgene, BTG/Veriton and departmental research funding from BeiGene unrelated to the work. The other authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Richter transformation (RT) represents an aggressive histological transformation from chronic lymphocytic leukaemia, most often to a large B cell lymphoma. It is characterised by chemo-resistance and subsequent short survival. Drug development has struggled over recent years in light of the aggressive kinetics of the disease, lack of pivotal registrational trials and relative rarity of the phenomenon. In this review we will highlight the diagnostic and therapeutic challenges of managing patients with RT as well as taking a look to the future therapeutic landscape. Highly active therapies developed across B cell malignancies are starting to impact this field, with T-cell activation therapies (CAR-T, bispecific antibodies), antibody-drug conjugates, and novel small molecule inhibitor combinations (e.g. BTKi-BCL2i) being actively studied. We will highlight the data supporting these developments and look to the studies to come to provide hope for patients suffering from this devastating disease., Competing Interests: Declaration of Competing Interest AB has received travel expenses from Ionis Pharmaceuticals. NA has received speakers fees from Janssen and worked on trials funded by Janssen and AstraZeneca. CPF: Kite/Gilead/ Roche: Consultancy/ Advisory Boards, Educational Activities, Travel. AbbVie/ Incyte/ Janssen/ Takeda: Consultancy/ Advisory Boards, Educational Activities. AstraZeneca/ Atarabio/ BNS/ GenMab/ Lilly/ Morphosys/ Ono/ SERB/ SOBI: Consultancy/ Advisory Boards. BeiGene: Research Funding. TAE: Roche: Education Honorarium, Advisory Board Honorarium, Travel to scientific conferences. Gilead: Honorarium; Research support; Travel to scientific conferences. KITE: Education Honorarium, Advisory Board Honorarium, Janssen: Honorarium. Abbvie: Honorarium; Travel to scientific conferences. AstraZeneca: Honorarium, Research funding, Travel to scientific conferences. Loxo Oncology: Advisory Board Honorarium, Trial steering committee. Beigene: Advisory Board Honorarium, Research funding. Incyte: Advisory Board Honorarium. Secura Bio: Advisory Board Honorarium. HD and TM have no relevant conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Abstract: Bendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicenter observational study evaluating bendamustine toxicity in real-world practice. Patients receiving at least 1 dose of bendamustine with/without rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details, and grade 3 to 5 adverse events (AEs) were analyzed and correlated. In total, 323 patients were enrolled from 9 National Health Service hospitals. Most patients (96%) received bendamustine-R, and 46%, R maintenance. Overall, 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%) and the relative risk highest during maintenance (54%), induction (34%), and follow-up (28%). Toxicity led to permanent treatment discontinuation for 13% of patients, and 2.8% died of bendamustine-related infections (n = 5), myelodysplastic syndrome (n = 3), and cardiac disease (n = 1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor preinduction performance status (PS), poor premaintenance PS, and abnormal preinduction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3 of 10 opportunistic infections occurred despite prophylaxis. In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to those of trial populations of younger, fitter patients. Poor PS, mantle cell histology, and maintenance R were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death, warranting extended antimicrobial prophylaxis and infectious surveillance, especially for maintenance-treated patients., (© 2024 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.)

Background: The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear., Methods: In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety., Results: A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%)., Conclusions: MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.)., (Copyright © 2023 Massachusetts Medical Society.)

Abstract: Plasmablastic lymphoma (PBL) is a rare and aggressive non-Hodgkin lymphoma associated with immunodeficiency, characterized by uncertain treatment approaches and an unfavorable prognosis. We conducted a multicenter, international, retrospective cohort study, aiming to characterize the clinical features, risk factors, and outcomes of patients with PBL. Data were collected from 22 institutions across 4 countries regarding patients diagnosed with PBL between 1 January 1999 and 31 December 2020. Survival risk factors were analyzed using both univariate and multivariate regression models. Overall survival (OS) was calculated using Kaplan-Meier statistics. First-line treatment regimens were stratified into standard- and higher-intensity regimens, and based on whether they incorporated a proteasome inhibitor (PI). A total of 281 patients (median age, 55 years) were included. Immunodeficiency of any kind was identified in 144 patients (51%), and 99 patients (35%) had HIV-positive results. The 5-year OS for the entire cohort was 36% (95% confidence interval, 30%-42%). In multivariate analysis, inferior OS was associated with Epstein-Barr virus-negative lymphoma, poor performance status, advanced stage, and bone marrow involvement. In an independent univariate analysis, the international prognostic index was associated with OS outcomes. Neither immunosuppression nor HIV infection, specifically, influenced OS. Among patients treated with curative intent (n = 234), the overall response rate was 72%. Neither the intensity of the treatment regimen nor the inclusion of PIs in first-line therapy was associated with OS. In this large retrospective study of patients with PBL, we identified novel risk factors for survival. PBL remains a challenging disease with poor long-term outcomes., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: High-dose methotrexate (HDMTX) is administered for the treatment of some malignancies. Serious complications after the administration of HDMTX are rare, but occasionally MTX may precipitate in the renal tubes causing a delayed elimination leading to renal, multiorgan toxicities and to life-threatening complications. This study aims to estimate the incidence and clinical management of delayed MTX elimination in France, Germany, Italy, and the UK., Methods: Twelve haemato-oncology and pediatric oncology clinical experts from leading European hospitals participated in the study. A two-round Delphi methodology was used to gather data on different variables relevant to evaluate the HDMTX induced-toxicity impact. For quantitative data, median and interquartile ranges were calculated. Data on prevalence was calculated considering the number of patients in each hospital and the population they cover, and then, extrapolated to the country population., Results: The total number of patients treated annually with HDMTX in France, Germany, Italy, and the UK is estimated in 7155. Of these, 16% are estimated to develop delayed MTX elimination and around 9% may develop HDMTX-induced acute kidney injury (AKI). Leucovorin, hyperhydration and urine alkalinization are applied to prevent MTX toxicity and precipitation whilst glucarpidase, hemofiltration and hemodialysis are being used for persisting toxic MTX serum levels. Grade 3 systemic toxicities are common in these patients, hematologic and gastrointestinal being the most common ones., Conclusions: This report provides expert clinical practice experience and opinion of the incidence and management of HDMTX-delayed elimination in France, Germany, Italy and the UK, thereby contributing to the evidence available on this relevant medical condition which can be life-threatening., Competing Interests: SB, CPF and KH‐X received consulting fees from BTG. AG‐P is employee of Omakase Consulting S.L. Omakase Consulting S.L. received funding from SERB. CR has received fees from SERB Pharmaceuticals for consultation activities and participation in Advisory Boards., (© 2024 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Purpose: CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication., Patients and Methods: Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti-CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts)., Results: Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, -1.5 to 4.4; all-pts) and 1.4% (95% CI, -1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup., Conclusion: In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Background: Patients established on thiopurines (e.g., azathioprine) are recommended to undergo three-monthly blood tests for the early detection of blood, liver, or kidney toxicity. These side-effects are uncommon during long-term treatment. We developed a prognostic model that could be used to inform risk-stratified decisions on frequency of monitoring blood-tests during long-term thiopurine treatment, and, performed health-economic evaluation of alternate monitoring intervals., Methods: This was a retrospective cohort study set in the UK primary-care. Data from the Clinical Practice Research Datalink Aurum and Gold formed development and validation cohorts, respectively. People age ≥18 years, diagnosed with an immune mediated inflammatory disease, prescribed thiopurine by their general practitioner for at-least six-months between January 1, 2007 and December 31, 2019 were eligible. The outcome was thiopurine discontinuation with abnormal blood-test results. Patients were followed up from six-months after first primary-care thiopurine prescription to up to five-years. Penalised Cox regression developed the risk equation. Multiple imputation handled missing predictor data. Calibration and discrimination assessed model performance. A mathematical model evaluated costs and quality-adjusted life years associated with lengthening the interval between blood-tests., Findings: Data from 5982 (405 events over 16,117 person-years) and 3573 (269 events over 9075 person-years) participants were included in the development and validation cohorts, respectively. Fourteen candidate predictors (21 parameters) were included. The optimism adjusted R 2 and Royston D statistic in development data were 0.11 and 0.76, respectively. The calibration slope and Royston D statistic (95% Confidence Interval) in the validation data were 1.10 (0.84-1.36) and 0.72 (0.52-0.92), respectively. A 2-year period between monitoring blood-test was most cost-effective in all deciles of predicted risk but the gain between monitoring annually or biennially reduced in higher risk deciles., Interpretation: This prognostic model requires information that is readily available during routine clinical care and may be used to risk-stratify blood-test monitoring for thiopurine toxicity. These findings should be considered by specialist societies when recommending blood monitoring during thiopurine prescription to bring about sustainable and equitable change in clinical practice., Funding: National Institute for Health and Care Research., Competing Interests: A.A. has received Institutional research grants from AstraZeneca and Oxford Immunotech; and personal fees from UpToDate (royalty), Springer (royalty), Cadilla Pharmaceuticals (lecture fees), NGM Bio (consulting), Limbic (consulting) and personal fees from Inflazome (consulting) unrelated to the work. GPA has received consulting fees from Abbott Products, Albireo Pharma, Amryth, AstraZeneca, BenevolentAI Bio, Clinipace, DNDI, GlaxoSmithKline, Merck, NuCANA, Puretech, Pfizer, Roche Diagnostics, Servier Pharmaceuticals, W.L. Gore & Associates paid to the University of Nottingham unrelated to the work. CPF has received Consultancy/Advisory board fees from Abbvie, GenMab, Incyte, Morphosys, Roche, Takeda, Ono, Kite/Gilead, BMS/Celgene, BTG/Veriton and departmental research funding from BeiGene unrelated to the work. The other authors have no conflict of interest to declare. Keele University has received research funding for CDM from NIHR, MRC, Versus Arthritis and BMS. CDM is Director of the NIHR School for Primary Care Research. HCW worked for the National Institute of Health Research 2015–2021. He had no part to play in the funding of this study., (© 2023 The Author(s).)

Primary Central Nervous System Lymphoma (PCNSL) is a highly malignant brain tumour. We investigated dynamic changes in tumour volume and apparent diffusion coefficient (ADC) measurements for predicting outcome following treatment with MATRix chemotherapy in PCNSL. Patients treated with MATRix ( n = 38) underwent T1 contrast-enhanced (T1CE) and diffusion-weighted imaging (DWI) before treatment, after two cycles and after four cycles of chemotherapy. Response was assessed using the International PCNSL Collaborative Group (IPCG) imaging criteria. ADC histogram parameters and T1CE tumour volumes were compared among response groups, using one-way ANOVA testing. Logistic regression was performed to examine those imaging parameters predictive of response. Response after two cycles of chemotherapy differed from response after four cycles; of the six patients with progressive disease (PD) after four cycles of treatment, two (33%) had demonstrated a partial response (PR) or complete response (CR) after two cycles. ADC mean at baseline, T1CE at baseline and T1CE percentage volume change differed between response groups (0.005 < p < 0.038) and were predictive of MATRix treatment response (area under the curve: 0.672-0.854). Baseline ADC and T1CE metrics are potential biomarkers for risk stratification of PCNSL patients early during remission induction therapy with MATRix. Standard interim response assessment (after two cycles) according to IPCG imaging criteria does not reliably predict early disease progression in the context of a conventional treatment approach.

This retrospective, observational study evaluated patterns of inpatient versus outpatient tumour lysis syndrome (TLS) monitoring during venetoclax ramp-up in 170 patients with chronic lymphocytic leukaemia. The primary outcome was clinical/biochemical TLS. Two clinical and four biochemical TLS occurred (4.1%). Five of the six events occurred in high-risk patients, four occurred at 20 mg dose and three at the 6-h time-point. Inpatient versus outpatient TLS rates within the high-risk subgroup were 15% and 8%. Risk category was the only predictor of TLS events in multivariate analysis. Outpatient escalation did not associate with clinically meaningful TLS events, suggesting outpatient escalation has manageable associated TLS risks, including in high-risk cohorts. These observations require confirmation in larger studies., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) have limited treatment options. Ceralasertib, a selective ataxia telangiectasia and Rad-3-related protein (ATR) inhibitor, demonstrated synergistic preclinical activity with a Bruton tyrosine kinase (BTK) inhibitor in TP53 - and ATM -defective CLL cells. Acalabrutinib is a selective BTK inhibitor approved for treatment of CLL., Objectives: To evaluate ceralasertib ± acalabrutinib in R/R CLL., Design: Nonrandomized, open-label phase I/II study., Methods: In arm A, patients received ceralasertib monotherapy 160 mg twice daily (BID) continuously (cohort 1) or 2 weeks on/2 weeks off (cohort 2). In arm B, patients received acalabrutinib 100 mg BID continuously (cycle 1), followed by combination treatment with ceralasertib 160 mg BID 1 week on/3 weeks off from cycle 2. Co-primary objectives were safety and pharmacokinetics. Efficacy was a secondary objective., Results: Eleven patients were treated [arm A, n  = 8 (cohort 1, n  = 5; cohort 2, n  = 3); arm B, n  = 3 (acalabrutinib plus ceralasertib, n  = 2; acalabrutinib only, n  = 1)]. Median duration of exposure was 3.5 and 7.2 months for ceralasertib in arms A and B, respectively, and 15.9 months for acalabrutinib in arm B. Most common grade ⩾3 treatment-emergent adverse events (TEAEs) in arm A were anemia (75%) and thrombocytopenia (63%), with four dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia. No grade ⩾3 TEAEs or DLTs occurred in arm B. Ceralasertib plasma concentrations were similar when administered as monotherapy or in combination. At median follow-up of 15.1 months in arm A, no responses were observed, median progression-free survival (PFS) was 3.8 months, and median overall survival (OS) was 16.9 months. At median follow-up of 17.2 months in arm B, overall response rate was 100%, and median PFS and OS were not reached., Conclusion: Ceralasertib alone showed limited clinical benefit. Acalabrutinib plus ceralasertib was tolerable with preliminary activity in patients with R/R CLL, though findings are inconclusive due to small sample size., Registration: NCT03328273., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: WJ: Contract/grant – AstraZeneca, Janssen, and Lilly. NE: Conference registration grants – AbbVie; speakers fees – Roche and AstraZeneca. CPF: Consultancy and honoraria – AbbVie, Acerta Pharma/AstraZeneca, Atara Biotherapeutics, Celgene/BMS, GenMab, Gilead/Kite, Incyte, Lilly, Janssen, MorphoSys, Ono, Roche, and Takeda; research funding – BeiGene. WT: Consultancy and honoraria – BMS, Gilead, Incyte, and Roche; travel expenses – Gilead and Takeda. AGP: Consultancy – CellCarta; founder – Precision Assays. JRW: Consultancy – CellCarta. FK: Employment and stock ownership – AstraZeneca. CW: Employment – AstraZeneca. GP: Employment and stock ownership – AstraZeneca. SS: Employment and stock ownership – AstraZeneca. VM: Employment and stock ownership – AstraZeneca (a family member is an employee and stock owner of Gilead). RM: Employment and stock ownership – AstraZeneca. ED: Employment and stock ownership – AstraZeneca. TM: Honoraria – AstraZeneca, Alexion, Gilead, Novartis, Roche, Janssen, AbbVie; advisory board – AstraZeneca, AbbVie, Janssen, MorphoSys, Alexion., (© The Author(s), 2023.)

Objective: To develop and validate a prognostic model to inform risk stratified decisions on frequency of monitoring blood tests during long term methotrexate treatment., Design: Retrospective cohort study., Setting: Electronic health records within the UK's Clinical Practice Research Datalink (CPRD) Gold and CPRD Aurum., Participants: Adults (≥18 years) with a diagnosis of an immune mediated inflammatory disease who were prescribed methotrexate by their general practitioner for six months or more during 2007-19., Main Outcome Measure: Discontinuation of methotrexate owing to abnormal monitoring blood test result. Patients were followed-up from six months after their first prescription for methotrexate in primary care to the earliest of outcome, drug discontinuation for any other reason, leaving the practice, last data collection from the practice, death, five years, or 31 December 2019. Cox regression was performed to develop the risk equation, with bootstrapping used to shrink predictor effects for optimism. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination., Results: Data from 13 110 (854 events) and 23 999 (1486 events) participants were included in the development and validation cohorts, respectively. 11 candidate predictors (17 parameters) were included. In the development dataset, the optimism adjusted R 2 was 0.13 and the optimism adjusted Royston D statistic was 0.79. The calibration slope and Royston D statistic in the validation dataset for the entire follow-up period was 0.94 (95% confidence interval 0.85 to 1.02) and 0.75 (95% confidence interval 0.67 to 0.83), respectively. The prognostic model performed well in predicting outcomes in clinically relevant subgroups defined by age group, type of immune mediated inflammatory disease, and methotrexate dose., Conclusion: A prognostic model was developed and validated that uses information collected during routine clinical care and may be used to risk stratify the frequency of monitoring blood test during long term methotrexate treatment., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Institute for Health and Care Research. AA has received institutional research grants from AstraZeneca and Oxford Immunotech and personal fees from UpToDate (royalty), Springer (royalty), Cadilla Pharmaceuticals (lecture fees), NGM Bio (consulting), and Limbic (consulting), and personal fees from Inflazome (consulting) unrelated to the work. GP Aithal has received consulting fees from Clinipace, Amryth, GSK, DNDi, Pfizer, BenevolentAI Bio, Albireo Pharma, Abbott Products Operations, AstraZeneca, Merck, and PureTech paid to the University of Nottingham unrelated to the work. CPF has received consultancy or advisory board fees from Abbvie, GenMab, Incyte, Lily, Morphosys, Roche, Takeda, Ono, Kite/Gilead, BMS/Celgene, and BTG/Veriton and departmental research funding from BeiGene unrelated to the work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival., Methods: This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m 2 on day 1 of cycle 1 and at 500 mg/m 2 on day 1 of cycles 2-6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m 2 per day orally on day 1-5, cyclophosphamide 150 mg/m 2 per day orally on days 1-5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete., Findings: Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56-67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41-61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63-NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0·44 [95% CI 0·32-0·60]; p<0·0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group., Interpretation: Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder., Funding: Cancer Research UK and Janssen., Competing Interests: Declaration of interests PH reports funding for the study and provision of investigational medicinal products from Janssen and AbbVie; personal consulting fees from Janssen, AbbVie, and AstraZeneca; personal speaker fees from Janssen, AbbVie, AstraZeneca, and BeiGene; institutional support of clinical trials from Janssen, AbbVie, Gilead Sciences, and F Hoffman-La Roche. AP reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie. ABl reports speaker fees from Janssen and AbbVie and support for conference attendance from AbbVie. ABr reports personal payment for presentations from Janssen-Cilag and AstraZeneca and personal payment for attending meetings from AbbVie. BK reports personal payment or honoraria for lectures from AbbVie and AstraZeneca and a voluntary unpaid role as CLL Support Associate Trustee. RW reports payment for lectures from AbbVie, AstraZeneca, Janssen, and BeiGene; support for attending meetings from AbbVie and Janssen; and participation on a data safety monitoring board or advisory board for AstraZeneca, Janssen, SecuraBio, and AbbVie. MF reports travel support for conference attendance from AbbVie and remunerated participation on an advisory board for AstraZeneca. GP reports honoraria for delivering educational sessions from Janssen-Cilag and Roche. NM reports payment or honoraria for presentations from Amgen and Kite Gilead; support for attending meetings or travel from Takeda; and participation on a data safety monitoring board or advisory board for Kite Gilead, Amgen, and AbbVie. KC reports personal speakers fees from Roche, Takeda, Kite, Gilead, and Incyte; support for travel and registration for meetings from Roche, Takeda, Kite, and BMS; and participation on a data safety monitoring board or advisory board for Roche, Takeda, Celgene, Atara, Gilead, Kite, Janssen, and Incyte. AS reports receipt of part of her salary from the Oxford Biomedical Research Centre; grants from Janssen and AstraZeneca; honoraria for presentations from Roche, AbbVie, Janssen, BeiGene, and AstraZeneca; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Illumina, Oxford Nanopore Technology, and Adaptive Biotechnology. FF reports grants from Cancer Research UK and AbbVie; consulting fees from BC Platform; payment or honoraria for presentations from AbbVie, Janssen-Cilag, Acerta, and BeiGene; support for attending meetings or travel from AbbVie; and participation on a data safety monitoring board or advisory board for BeiGene. NE reports personal speaker payments from AstraZeneca and Roche and support for attending meetings and travel from AbbVie. SP reports personal honoraria for presentations from Gilead, AstraZeneca, AbbVie, BeiGene, and Takeda. CPF reports personal consultancy fees from AbbVie, AstraZeneca, Atarabio, BMS, GenMab, Gilead–Kite, Incyte, Lilly, Morphosys, Ono, Roche, and Takeda; payment for educational events from Janssen, Incyte, and Roche; institution research funding from BeiGene; support for attending meetings or travel from Roche; and participation on trial steering committees for GenMab, Morphosys, and Roche. DRH is employed by Roche and holds stock or stock options from Roche. AH reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie and receipt of a speaker fee from AbbVie. JMB reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie. DAC reports unrestricted educational grants to his institution from Janssen, Pharmacyclics, and AbbVie; payment to institution for educational lectures from Janssen; participation on a data safety monitoring board for an academically led investigator-initiated CLL study and personal payment for meeting attendance and report preparation from University Hospital Cologne. SJ reports receipt of unrestricted educational grants to her institution from Janssen, Pharmacyclics and AbbVie. NG reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie and participation on an advisory board for AbbVie. PEMP reports grants from Roche and Gilead; payment or honoraria for presentations from AbbVie, AstraZeneca, BeiGene, Gilead, and Janssen; support for attending meetings or travel from AbbVie; and participation on a data safety monitoring board or advisory board for AbbVie, BeiGene, and Novartis. DA reports receipt of part of his salary from the National Institute for Health and Care Research and Medical Research Council and support to attend meetings from CSL Behring. AR reports grants to his institution from AbbVie, Janssen, Pharmacyclics, and Roche; consulting fees from BeiGene and Pharmacyclics paid to a company of which AR is a director; payment or honoraria for presentations from AbbVie, Beckman Coulter, BD Biosciences, BeiGene, and Janssen paid to a company of which AR is a director; support for attending meetings or travel from Janssen; participation on a data safety monitoring board or advisory board from AbbVie and Janssen; and receipt of equipment from Beckman Coulter. TM reports payment for lectures and presentations from Janssen, AbbVie, and AstraZeneca; support for attending conferences from Janssen, AbbVie, and AstraZeneca; and participation on advisory boards for Janssen, AbbVie, AstraZeneca, Lilly, BeiGene, and Morphosys. All other authors declare no competing interests., (Copyright © 2023 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.)

This study used a real-world population as a synthetic comparator for the single-arm TRANSCEND NHL 001 study (TRANSCEND; NCT02631044) to evaluate the efficacy of lisocabtagene maraleucel (liso-cel) compared with conventional (noncellular) therapies in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Inclusion and exclusion criteria for the real-world study closely matched the enrollment criteria in TRANSCEND. The analytic comparator cohort was created by matching and balancing observed baseline characteristics of real-world patients with those in TRANSCEND using propensity score methodology. Efficacy outcomes comparing liso-cel- ( n  = 257) and conventional therapy-treated ( n  = 257) patients, respectively, significantly favored liso-cel: overall response rate (74% vs 39%; p  < 0.0001), complete response rate (50% vs 24%; p  < 0.0001), median overall survival (23.5 vs 6.8 months; p  < 0.0001), and median progression-free survival (3.5 vs 2.2 months; p  < 0.0001). These results demonstrated a statistically significant and clinically meaningful benefit of liso-cel in patients with third- or later-line R/R LBCL relative to conventional therapies. Clinical trial registration: ClinicalTrials.gov identifier: NCT02631044.

To optimise management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection identifying high-risk patients and maintaining treatment dose intensity is an important issue in patients with aggressive lymphomas. In the present study, we report on the presentation, management, and outcome of an international series of 91 patients with primary central nervous system lymphoma and SARS-CoV-2 infection. SARS-CoV-2 was diagnosed before/during first-line treatment in 64 patients, during follow-up in 21, and during salvage therapy in six. Among the 64 patients infected before/during first-line chemotherapy, 38 (59%) developed pneumonia and 26 (41%) did not clear the virus. Prolonged exposure to steroids before viral infection and/or treatment with high-dose cytarabine favoured pneumonia development and virus persistence and were associated with poorer survival; 81% of patients who did not clear virus died early from coronavirus disease 2019 (COVID-19). Vaccination was associated with lower pneumonia incidence and in-hospital mortality. Chemotherapy was initiated/resumed in 43 (67%) patients, more commonly among patients who did not develop pneumonia, cleared the virus, or did not receive steroids during infection. Chemotherapy resumption in patients with viral persistence should be indicated cautiously as it was associated with a poorer survival (6-month, 70% and 87%, p = 0.07). None of the 21 patients infected during follow-up died from COVID-19, requiring similar measures as infected subjects in the general population., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Natural killer (NK)/T-cell lymphomas arise mainly from NK-cells and occasionally T-cells, and are universally infected with Epstein Barr virus (EBV). They are uncommon lymphomas more prevalent in Asian and Central/South American populations. NK/T-cell lymphomas are clinically aggressive and predominantly extranodal. The most commonly involved sites are the nasal cavity, followed by non-nasal sites including the skin, gastrointestinal tract and testis. The diagnosis of extranodal NK/T-cell lymphoma is established with histological and immunohistochemical examination, together with the demonstration of EBV in the tumour cells. Staging by positron emission tomography computed tomography is essential to inform the optimal management. Plasma EBV DNA quantification should be performed as it serves as a marker for prognostication and treatment response. Survival outcomes of patients with early-stage disease are good following treatment with nonanthracycline based chemotherapy, together with sequential/concurrent radiotherapy. For advanced-stage disease, asparaginase-containing regimens are mostly used and allogeneic haematopoietic stem cell transplantation should be considered for those at high risk of relapse. Salvage chemotherapy is largely ineffective for relapsed/refractory disease, which has a grave prognosis. Novel therapeutic approaches including immune check-point blockade, EBV-specific cytotoxic T-cells, and monoclonal antibodies are being investigated to improve outcomes for those with high risk and relapsed/refractory disease., Competing Interests: Conflicts of interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNSL) is a rare disorder with an increasing incidence over the past decades. High-level evidence has been reported for the MATRix regimen (high-dose methotrexate (HD-MTX), high-dose AraC (HD-AraC), thiotepa and rituximab) followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) supporting this approach to be considered a standard therapy in newly diagnosed PCNSL patients ≤ 70 years. However, early treatment-related toxicities (predominantly infectious complications), occurring in up to 28% per MATRix cycle, diminish its therapeutic success. Furthermore, sensitivity to first-line treatment is an independent prognostic factor for improved overall survival (OS) in PCNSL. Thus, patients achieving early partial remission (PR) after 2 cycles of MATRix might be over-treated with 4 cycles, in the context of consolidation HCT-ASCT., Methods: This is an open-label, multicentre, randomized phase III trial with two parallel arms. 326 immunocompetent patients with newly diagnosed PCNSL will be recruited from 37 German, 1 Austrian and 12 UK sites. Additional IELSG (International Extranodal Lymphoma Study Group) sites are planned. The objective is to demonstrate superiority of a de-escalated and optimised remission induction treatment strategy, followed by HCT-ASCT. Randomization (1:1) will be performed after completion of all screening procedures. Patients in Arm A (control treatment) will receive 4 cycles of MATRix. Patients in Arm B (experimental treatment) will receive a pre-phase (R/HD-MTX), followed by 2 cycles of MATRix. Patients in both arms achieving PR or better will proceed to HCT-ASCT (BCNU, thiotepa). The primary endpoint of the study is event-free-survival (EFS), defined as time from randomization to premature end of treatment due to any reason, lymphoma progression or death whichever occurs first. Secondary endpoints include OS, progression free survival (PFS), toxicity, neurocognitive impairment and quality of life. Minimal follow-up is 24 months., Discussion: Current treatment options for PCNSL in patients ≤ 70 years have improved remarkably over recent years. However, the potential efficacy benefits are offset by an increased incidence of short-term toxicities which can impact on treatment delivery and hence on survival outcomes. In patients ≤ 70 years with newly diagnosed PCNSL addressing the need to reduce treatment-related toxicity by de-escalating and optimising the induction phase of treatment, is a potentially attractive treatment strategy., Trial Registration: German clinical trials registry DRKS00022768 registered June 10 th , 2021., (© 2022. The Author(s).)

Objective: To develop and validate a prognostic model for LEF discontinuation with abnormal blood test results., Methods: Data from the Clinical Practice Research Datalink Gold and Aurum were used for model development and external validation, respectively. Participants prescribed LEF between 1 January 2007 and 31 December 2019 were followed up from 6 months after the first general practitioner prescription to the earliest of date of outcome, death, 5 year follow-up or 31 December 2019. Candidate prognostic factors were ascertained using theory and data-driven approaches. Penalized Cox regression was performed to develop the risk equation, followed by internal validation using 500 bootstraps to correct for optimism. Multiple imputation was applied to handle missing data. Model performance was assessed in terms of calibration and discrimination., Results: Data for 1487 and 2329 participants contributing 3140 and 5246 person-years follow-up were included in the development and validation cohorts, respectively. Thirteen candidate predictors were included in the model. Epilepsy and either cytopenia or elevated liver enzymes during the first 6 months of shared-care LEF prescription were strong predictors of drug discontinuation with a hazard ratio of 4.39 (95% CI 1.74, 11.06) and 3.06 (2.15, 4.35), respectively. The unadjusted and optimism-adjusted calibration slope in development data was 1.00 (95% CI 0.75, 1.25) and 0.72 (95% CI 0.47, 0.97), respectively. The calibration slope in validation data was 0.91 (95% CI 0.74, 1.07). The model showed prognostic separation with an optimism-adjusted Royston D statistic of 0.73 (95% CI 0.44, 1.02)., Conclusion: We have developed and externally validated an easy-to-use prognostic model that may be used to risk stratify monitoring for LEF toxicity and to make informed choices about risks when choosing treatments., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: The aim was to examine the incidence and pattern of MMF discontinuation associated with abnormal monitoring blood-test results., Methods: Data from people prescribed MMF for common inflammatory conditions in the Clinical Practice Research Datalink were used. Participants were followed from the first MMF prescription. The primary outcome was drug discontinuation with an associated abnormal blood-test result within 60 days. Secondary outcomes were drug discontinuation for any reason and discontinuation associated with severely abnormal blood-test results within 60 days. Multivariable Cox regression was used to examine factors associated with the primary outcome., Results: The cohort included 992 participants (68.9% female, mean age 51.95 years, 47.1% with SLE) contributing 1885 person-years of follow-up. The incidence of MMF discontinuation associated with any (severely) abnormal blood-test results was 153.46 (21.07) per 1000 person-years in the first year of prescription and 32.39 (7.91) per 1000 person-years in later years. Of those patients prescribed MMF, 11.5% (1.7%) discontinued treatment with any (severely) abnormal blood-test results in the first year of prescription. After this period, a mean of 2.6% (0.7%) of patients discontinued treatment with any (severely) abnormal blood-test results per year. Increased serum creatinine and cytopenia were more commonly associated with MMF discontinuation than elevated liver enzymes. Chronic kidney disease stage   3 or higher was significantly associated with MMF discontinuation with any blood-test abnormalities [adjusted hazard ratio (95% CI) 2.22 (1.47, 3.37)]., Conclusion: MMF is uncommonly discontinued for blood-test abnormalities and even less often discontinued for severe blood-test abnormalities after the first year of prescription. Consideration can be given to less frequent monitoring after 1 year of treatment, especially in those without chronic kidney disease stage   3 or higher., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Central nervous system (CNS) lymphomas are rare malignancies characterised by lymphoid infiltration into the brain, spinal cord, cranial nerves, meninges and/or eyes in the presence or absence of previous or concurrent systemic disease. Most CNS lymphomas are of the diffuse large B-cell lymphoma (DLBCL) subtype for which treatment strategies, particularly the use of high-dose methotrexate-based protocols and consolidation with autologous stem cell transplantation, are well established. Other histopathological subtypes of CNS lymphoma are comparatively less common with published data on these rare lymphomas dominated by smaller case series and retrospective reports. Consequently, there exists little clinical consensus on the optimal methods to diagnose and manage these clinically and biologically heterogeneous CNS lymphomas. In this review article, we focus on rarer CNS lymphomas, summarising the available clinical data on incidence, context, diagnostic features, reported management strategies, and clinical outcomes., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Patients with hematological malignancies are at increased risk of severe COVID-19 outcomes due to compromised immune responses, but the insights of these studies have been compromised due to intrinsic limitations in study design. Here we present the PROSECO prospective observational study ( NCT04858568 ) on 457 patients with lymphoma that received two or three COVID-19 vaccine doses. We show undetectable humoral responses following two vaccine doses in 52% of patients undergoing active anticancer treatment. Moreover, 60% of patients on anti-CD20 therapy had undetectable antibodies following full vaccination within 12 months of receiving their anticancer therapy. However, 70% of individuals with indolent B-cell lymphoma displayed improved antibody responses following booster vaccination. Notably, 63% of all patients displayed antigen-specific T-cell responses, which increased after a third dose irrespective of their cancer treatment status. Our results emphasize the urgency of careful monitoring of COVID-19-specific immune responses to guide vaccination schemes in these vulnerable populations., (© 2022. The Author(s).)

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion., (© 2022 by The American Society of Hematology.)

Background: There are no head-to-head clinical studies comparing chimeric antigen receptor (CAR) T-cell therapies for the treatment of relapsed or refractory aggressive large B-cell lymphomas. Naive, indirect comparisons may be inappropriate, as the study designs and patient populations could differ substantially. Matching-adjusted indirect comparisons (MAIC) can reduce many biases associated with indirect comparisons between studies. To determine the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) to tisagenlecleucel, we describe an unanchored MAIC of the pivotal studies TRANSCEND NHL 001 (TRANSCEND; NCT02631044; liso-cel) and JULIET (NCT02445248; tisagenlecleucel)., Methods: Individual patient data (IPD) from TRANSCEND were available to the authors; for the JULIET pivotal study, summary-level data from the published study were used. To balance the populations between two studies, IPD from TRANSCEND were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors among patients from JULIET., Results: Results from the primary MAIC showed liso-cel had statistically significant greater efficacy than tisagenlecleucel (objective response rate: odds ratio [OR] = 2.78, 95% confidence interval [CI]: 1.63‒4.74; complete response rate: OR = 2.01, 95% CI: 1.22‒3.30; progression-free survival: hazard ratio [HR] = 0.65, 95% CI: 0.47‒0.91; overall survival: HR = 0.67, 95% CI: 0.47‒0.95). MAIC of safety outcomes showed lower ORs for all-grade and grade ≥ 3 cytokine release syndrome, and grade ≥ 3 prolonged cytopenia for liso-cel when compared with tisagenlecleucel; there were no statistically significant differences detected for other safety outcomes., Conclusions: Overall, this MAIC of two CAR T-cell therapies indicates liso-cel had favorable efficacy and a comparable or better safety profile relative to tisagenlecleucel., Clinical Trial Registration: ClinicalTrials.gov identifiers: NCT02631044 and NCT02445248., (© 2022. The Author(s).)

Systemic anaplastic large-cell lymphoma (sALCL) is a rare T-cell lymphoma associated with poor prognosis after relapse. The immunoconjugate brentuximab vedotin (BV) first became available for relapsed sALCL in England in 2013, following the results of a pivotal phase II study. We present a population-based study describing outcomes of relapsed sALCL in England after BV, using Public Health England data. We obtained information on all relapsed/refractory (r/r) sALCL patients ≥18 years treated with BV monotherapy in England between 1 January 2014 and 31 December 2019. The final cohort comprised 127 patients with a median age of 60 years (range 19-89). Eighteen (14·2%) had received stem cell transplant in first remission. Median two-year overall survival (OS) was 46·6%. The vast majority of deaths (59) occurred within 18 months, with very few events after this. Receipt of BV as second line compared to third or fourth line was associated with significantly improved survival (two-year OS 50·3% vs 29·7%, P = 0·03). There was no difference in OS for different subgroups, including anaplastic lymphoma kinase status, age, gender, or receipt of stem cell transplantation in first response. We report excellent survival following treatment with BV in a real-world setting, comparable with previous clinical trial data., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Background: We wished to examine treatment and outcome patterns in older diffuse large B-cell lymphoma (DLBCL) patients, with a focus on the effect of route-to-diagnosis to outcome., Methods: Data were extracted from Public Health England's National Cancer Registration and Analysis Service between 2013 and 2015 included route-to-diagnosis, disease characteristics and survival for 9186 patients ≥65 years. Systemic Anti-Cancer Therapy data identified front-line regimens, cycles and doses., Results: Route-to-diagnosis were emergency (34%), NHS urgent cancer pathway (rapid haemato-oncologist review <2 weeks), (29%) and standard GP referral (25%). The most common regimen was R-CHOP (n = 4392). 313 patients received R-miniCHOP (7% of R-CHOP). For all patients, 3-year overall survival (OS) for 65-79 years was 57% and for ≥80 years was 32%. Three-year OS for R-CHOP-treated patients diagnosed via emergency presentation was 54% (adjusted hazard ratio (HR) 1.63, p < 0.01) and 75% (adjusted HR 0.81, p < 0.01) on the NHS urgent cancer pathway (reference HR:1.00: GP referrals). 3-year OS was 54% for both R-miniCHOP and R-CHOP in ≥80 years., Conclusions: Our comprehensive population analysis is the first to show that the NHS urgent cancer pathway is associated with a superior survival after adjusting for multiple confounders. Equivalent survival for R-CHOP and R-mini-CHOP was demonstrated in those ≥80 years., (© 2021. The Author(s).)

In a phase 1b study of acalabrutinib (a covalent Bruton tyrosine kinase (BTK) inhibitor) in combination with vistusertib (a dual mTORC1/2 inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), multiple ascending doses of the combination as intermittent or continuous schedules of vistusertib were evaluated. The overall response rate was 12% (3/25). The pharmacodynamic (PD) profile for acalabrutinib showed that BTK occupancy in all patients was >95%. In contrast, PD analysis for vistusertib showed variable inhibition of phosphorylated 4EBP1 (p4EBP1) without modulation of AKT phosphorylation (pAKT). The pharmacokinetic (PK)/PD relationship of vistusertib was direct for TORC1 inhibition (p4EBP1) but did not correlate with TORC2 inhibition (pAKT). Cell-of-origin subtyping or next-generation sequencing did not identify a subset of DLBCL patients with clinical benefit; however, circulating tumor DNA dynamics correlated with radiographic response. These data suggest that vistusertib does not modulate targets sufficiently to add to the clinical activity of acalabrutinib monotherapy. Clinicaltrials.gov identifier: NCT03205046.

Observational studies with long-term follow-up of patients with primary central nervous system lymphoma (PCNSL) are scarce. Patient data over a period of four decades were retrospectively analysed from databases at Nottingham University Hospitals Trust, UK. The cohort was delineated by two distinct therapeutic eras; the first from 01/01/1982 to 31/12/2010 (n = 147) and the second 01/01/2011 to 31/07/2020 (n = 125). The median age at diagnosis was significantly older in the second era compared to the first (69 and 65 years respectively, P = 0·003). The 3-, 6- and 12-month overall survival (OS) rates in the second era were significantly higher compared to the first, at 85%, 77%, 62% versus 56%, 49%, 38% respectively (log-rank test P < 0·0001). On multivariate analysis, high-dose methotrexate (HD-MTX)-based induction protocols employed in the second era were associated with improved OS compared to those used in the first [hazard ratio (HR) 0·40, 95% confidence interval (CI) 0·28-0·57]. Within the second era, superior OS rates were seen with the use of intensive HD-MTX protocols (including consolidation with high-dose chemotherapy and autologous stem cell transplantation) compared to non-intensive HD-MTX schedules (HR 0·47, 95% CI 0·22-0·99). Initiating chemotherapy within 14 days of biopsy and use of rituximab were independently associated with improved OS and progression-free survival during the second era. These data suggest that prompt treatment initiation and use of intensive HD-MTX- and rituximab-based protocols have resulted in improved survival outcomes for patients., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 + 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473., (© 2021 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.)