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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.)

Background: Autologous haematopoietic stem-cell transplantation (HSCT) in first remission is the current standard treatment in fit patients with mantle cell lymphoma. In this long-term follow-up study, we aimed to evaluate the efficacy of autologous HSCT versus interferon alfa maintenance after chemotherapy without or with rituximab in patients with primary advanced-stage mantle cell lymphoma., Methods: We did a post-hoc, long-term analysis of an open-label, multicentre, randomised, phase 3 trial done in 121 participating hospitals or practices across six European countries. Patients who were aged 18-65 years with previously untreated stage III-IV mantle cell lymphoma and an ECOG performance score of 0-2 were eligible for participation. Patients were randomly assigned (1:1) to receive either myeloablative radiochemotherapy (fractionated total body irradiation with 12 Gy/day 6-4 days before autologous HSCT and cyclophosphamide 60 mg/kg per day intravenously 3-2 days before autologous HSCT) followed by autologous HSCT (the autologous HSCT group) or interferon alfa maintenance (the interferon alfa maintenance group; 6 × 10 6 IU three times a week subcutaneously until progression) after completion of CHOP-like induction therapy (cyclophosphamide 750 mg/m 2 intravenously on day 1, doxorubicin 50 mg/m 2 intravenously on day 1, vincristine 1·4 mg/m 2 [maximum 2 mg] intravenously on day 1, and prednisone 100 mg/m 2 orally on days 1-5; repeated every 21 days for up to 6 cycles) without or with rituximab (375 mg/m 2 intravenously on day 0 or 1 of each cycle; R-CHOP). The primary outcome was progression-free survival from end of induction until progression or death among patients who had a remission and the secondary outcome was overall survival from the end of induction until death from any cause. We did comparisons of progression-free survival and overall survival according to the intention-to-treat principle between both groups among responding patients and explored efficacy in subgroups according to induction treatment without or with rituximab. Hazard ratios (HRs) were adjusted for the mantle cell lymphoma international prognostic index (MIPI) numerical score, and in the total group also for rituximab use (adjusted HR [aHR]). This trial was started before preregistration was implemented and is therefore not registered, recruitment is closed, and this is the final evaluation., Findings: Between Sept 30, 1996, and July 1, 2004, 269 patients were randomly assigned to receive either autologous HSCT or interferon alfa maintenance therapy. The median follow-up was 14 years (IQR 10-16), with the intention-to-treat population consisting of 174 patients (93 [53%] in the autologous HSCT group and 81 [47%] in the interferon alfa maintenance group) who responded to induction therapy. The median age was 55 years (IQR 47-60), and R-CHOP was used in 68 (39%) of 174 patients. The median progression-free survival was 3·3 years (95% CI 2·5-4·3) in the autologous HSCT group versus 1·5 years (1·2-2·0) in the interferon alfa maintenance group (log-rank p<0·0001; aHR 0·50 [95% CI 0·36-0·69]). The median overall survival was 7·5 years (95% CI 5·7-12·0) in the autologous HSCT group versus 4·8 years (4·0-6·6) in the interferon alfa maintenance group (log-rank p=0·019; aHR 0·66 [95% CI 0·46-0·95]). For patients treated without rituximab, the progression-free survival adjusted HR for autologous HSCT versus interferon alfa was 0·40 (0·26-0·61), in comparison to 0·72 (0·42-1·24) for patients treated with rituximab. For overall survival, the adjusted hazard ratio for HSCT versus interferon alfa was 0·52 (0·33-0·82) without rituximab and 1·05 (0·55-1·99) for patients who received rituximab., Interpretation: Our results confirm the long-term efficacy of autologous HSCT to treat mantle cell lymphoma established in the pre-rituximab era. The suggested reduced efficacy after immunochemotherapy supports the need for its re-evaluation now that antibody maintenance, high-dose cytarabine, and targeted treatments have changed the standard of care for patients with mantle cell lymphoma., Funding: Deutsche Krebshilfe, the European Community, and the Bundesministerium für Bildung und Forschung, Kompetenznetz Maligne Lymphome., Competing Interests: Declaration of interests A-KZ declares that this work was done before her employment at Janssen-Cilag. Opinions expressed are solely her own and do not express the views or opinions of her employer. A-KZ has received stock or stock options from Johnson & Johnson. KH has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Celgene, Servier, Sanofi, EUSA Pharma, and Hexal; has received support for attending meetings or travel, or both, from Roche, Celgene, and Sanofi; and has participated on a data safety monitoring board or advisory board from Roche, Celgene, Servier, EUSA Pharma, and Gilead. MT has received consultancy fees and research funding from Amgen, Roche, Regeneron, Kite, and Macrogenics. CS has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Janssen, and Norvatis; and support for attending meetings or travel, or both, from Bristol Myers Squibb, Roche, Novartis, and Kite Gilead. GL has received grants or contracts from AQUINOX, AGIOS, AstraZeneca, Bayer, Gilead, Janssen, Morphosys, Roche, and Verastem (grant to institution); consulting fees from Roche, Gilead, Janssen, Bayer, Bristol Myers Squibb/Celgene, Novartis, AstraZeneca, Takeda, NanoString, AbbVie, Incyte, Morphosys, Genmab, and Karyopharm; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Gilead, Janssen, Bayer, Bristol Myers Squibb/Celgene, Novartis, AstraZeneca, AbbVie and Incyte; payment for expert testimony from Morphosys; support for attending meetings or travel, or both, from Roche, Janssen, and Bristol Myers Squibb/Celgene; and participated on a data safety monitoring board or advisory board from Roche, Gilead, Janssen, Bayer, Bristol Myers Squibb/Celgene, Novartis, AstraZeneca, Takeda, Nanostring, Oncopeptides, AbbVie, Incyte, Morphosys, Genmab, and Karyopharm. JD has received personal fees from Janssen, Roche, AbbVie, Celgene, Takeda, and AstraZeneca. VV has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen; support for attending meetings or travel, or both, from Amgen and AbbVie; and participated on a data safety monitoring board or advisory board from Beigene, Gilead, and Bristol Myers Squibb. WK has received report grants from Roche, Amgen, Takeda, and Regeneron. WH has received support for the present manuscript in research funding from Roche. MD has received institutional research grants by AbbVie, Bayer, Celgene, Janssen, and Roche; honoraria for scientific advisory boards from AstraZeneca, Bayer, Beigene, Celgene, Genmab, Gilead, Incyte, Janssen, Novartis, and Roche; and speaker's honoraria from Amgen, AstraZeneca, Bayer, Celgene, Gilead, Janssen, and Roche. EH has received travel support for attending meetings or travel, or both, from Roche. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles., Methods: LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to <66 years) who were eligible for autologous stem-cell transplantation received four cycles of obinutuzumab plus DHAP (obinutuzumab 1000 mg/m 2 intravenously on days 1, 8, and 15 at cycle 1 and day 1 at cycles 2, 3, and 4; dexamethasone 40 mg intravenously on days 1-4, cytarabine 2 g/m 2 intravenously every 12 h on day 1, and according to local investigator, cisplatin 100 mg/m 2 by continuous infusion over 24 h on day 1 or carboplatin area under the curve 5 or oxaliplatin 130 mg/m 2 ) every 21 days before transplantation, and 3 years of obinutuzumab (1000 mg/m 2 every 2 months) maintenance followed by minimal residual disease-based obinutuzumab on-demand maintenance. The primary outcome was minimal residual disease negativity in the bone marrow after four cycles of obinutuzumab plus DHAP at the end of induction, measured in the efficacy set (all minimal residual disease-informative [bone marrow or peripheral blood] patients who received at least one dose of obinutuzumab). Obinutuzumab plus DHAP was considered effective if bone marrow minimal residual disease negativity was 70% or more by intention to treat. The trial is closed to recruitment and registered with ClinicalTrials.gov, NCT02896582., Findings: 86 patients were enrolled between Nov 29, 2016, and May 2, 2018. 81 patients completed induction, 73 underwent autologous stem-cell transplantation, and 69 started maintenance therapy. 55 (75%) of 73 patients in the efficacy set reached minimal residual disease negativity in bone marrow at end of induction. According to the protocol definition, 18 (25%) of 73 patients in the efficacy set were minimal residual disease-positive: 12 patients who were minimal residual disease-positive in the bone marrow, plus two patients who progressed during induction, and four patients who did not have minimal residual disease assessment. The most common grade 3-4 treatment-emergent adverse events were anaemia (grade 3, 26 [31%] of 85 patients; grade 4, three [4%] of 85 patients) and neutropenia (grade 3, 13 [15%] of 85 patients; grade 4, 32 [38%] of 85 patients). 58 serious adverse events occurred during the induction phase. There were no treatment-related deaths., Interpretation: Obinutuzumab plus DHAP is a well tolerated regimen and has good activity for inducing minimal residual disease negativity in the bone marrow of transplant-eligible patients with mantle cell lymphoma. Obinutuzumab plus DHAP has potential activity as induction chemotherapy, with bone marrow minimal residual disease negativity potentially predicting long-term disease control., Funding: Roche SAS., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Radioimmunotherapy represents a potential option as consolidation after chemoimmunotherapy in patients with diffuse large B-cell lymphoma who are not candidates for transplantation. We aimed to assess activity and toxicity of fractionated radioimmunotherapy using anti-CD22 90 Y-epratuzumab tetraxetan as consolidation after front-line induction chemoimmunotherapy in untreated elderly patients with diffuse large B-cell lymphoma., Methods: We did a prospective, single-group, phase 2 trial at 28 hospitals in France, with patients recruited from 17 hospitals. Eligible patients were aged 60-80 years with bulky stage 2-3 or stage 3-4 CD20-positive diffuse large B-cell lymphoma, previously untreated, and not eligible for transplantation. Patients received six cycles of R-CHOP (rituximab [375 mg/m 2 ], cyclophosphamide [750 mg/m 2 ], doxorubicin [50 mg/m 2 ], and vincristine [1·4 mg/m 2 , up to 2 mg] all on day 1, and prednisone [40 mg/m 2 ] daily for 5 days), administered every 14 days. 6-8 weeks after R-CHOP, responders received two doses of 15 mCi/m 2 (555 MBq/m 2 ) 90 Y-epratuzumab tetraxetan administered 1 week apart. The primary endpoint was 2 year event-free survival in all registered eligible patients who received at least 1 day of study treatment; the safety analysis was done in the same population. This trial is registered with ClinicalTrials.gov, number NCT00906841., Findings: Between Oct 22, 2008, and Dec 16, 2010, we recruited 75 patients, of whom four (5%) were excluded after central pathology review; hence, 71 (95%) patients were included in the analysis. All patients started induction treatment; 57 (80%) received radioimmunotherapy. With a median follow-up of 37 months (IQR 30-44), the estimated 2 year event-free survival was 75% (95% CI 63-84). Radioimmunotherapy toxicity consisted of grade 3-4 thrombocytopenia in 48 (84%) of 57 patients and neutropenia in 45 (79%) of 57 patients. One patient developed myelodysplastic syndrome 28 months after receiving radioimmunotherapy and one patient developed acute myeloid leukaemia 5 months after receiving radioimmunotherapy., Interpretation: Fractionated radioimmunotherapy with 90 Y-epratuzumab tetraxetan might be appropriate for response consolidation after induction chemotherapy in older patients with advanced diffuse large B-cell lymphoma, but further comparative studies are needed., Funding: Immunomedics, Amgen, Canceropôle Grand Ouest, the GOELAMS/LYSA group and the French National Agency for Research (Investissements d'Avenir)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)